1 
 
                 DEPARTMENT OF HEALTH AND HUMAN SERVICES 
 
                       FOOD AND DRUG ADMINISTRATION 
 
                 CENTER FOR DRUG EVALUATION AND RESEARCH

                           PHARMACY COMPOUNDING 
 
                            ADVISORY COMMITTEE

 
 
                         Thursday, July 13, 2000 
 
                                8:30 a.m.

 
                 Advisory Committee Conference Room 1066 
                       Food and Drug Administration 
                            5630 Fishers Lane 
                           Rockville, MD 20852 

                                                                  2

                               PARTICIPANTS 
 
       Randy P. Juhl, Ph.D., Chairperson 
       Igor Cerny, Pharm.D., Executive Secretary 
 
       MEMBERS 
 
                 Loyd V. Allen, Jr., Ph.D. 
                 Elizabeth I. McBurney, M.D. 
                 Garnet E. Peck, Ph.D. 
                 Judith Martin Riffee, R.Ph. 
                 William J. Rusho, R.Ph. 
                 Sarah L. Sellers, Pharm.D. 
                 Lawrence Trissel, F.A.S.H.P. 
                 Tony Welder, R.Ph. 
 
       INDUSTRY REPRESENTATIVE 
 
                 Joan M. LaFollette, R.Ph. 
 
       CONSUMER REPRESENTATIVE 
 
                 Rose‑Ellen M. Hope, R.Ph 
 
       FDA 
 
                 Kathleen Anderson, Pharm.D. 
                 Jane Axelrad 
                 Peter H. Cooney, Ph.D. 
                 Amit Mitra, Ph.D. 
                 Lana Ogram 
                 Brian Rogers, Ph.D. 
                 Capt. George Scott 
                 Vinod P. Shah, Ph.D. 

                                                                  3 
 
                             C O N T E N T S 
 
       Call to Order 
         Dr. Randy Juhl                                         4 
 
       Conflict of Interest Statement 
         Dr. Igor Cerny                                         4 
 
       Introductory Remarks 
         Lana Ogram                                             7 
 
                 3,4‑diaminopyridine and 4‑aminopyridine 
                         Update to the Committee 
 
       Introduction: Ms. Jane Axelrad                          19 
 
       Acorda Therapeutics: Dr. Andrew Blight                  20 
 
       Committee Discussion                                    23 
 
                Withdrawn or Removed List of Drug Products 
 
       Remarks:  Capt. George Scott                            40 
 
                    Demonstrably Difficult to Compound 
 
       Introduction, Factors and Approach 
         Dr. Kathleen Anderson                                 58 
 
       Committee Discussion                                    64 
 
       Metered‑Dose Inhalers and Dry Powder Inhalers 
         Dr. Brian Rogers                                      90 
 
       Committee Discussion                                   105 
 
       Open Public Hearing 
 
         Mr. Jana Nestlerode                                  122 
         Dr. Larry Sasich                                     139 
         Ms. Shelley Capps                                    145 

       Transdermal Delivery Systems 
         Dr. Vinod Shah                                       149 
         Dr. Amit Mitra                                       155 
 
       Committee Discussion                                   162 
 
       Sterile Drug Products 
         Dr. Peter H. Cooney                                  167 
 
       Committee Discussion                                   179 

                                                                  4 
 
   1                      P R O C E E D I N G S

   2                          Call to Order 
 
   3             DR. JUHL:  Good morning.  We will begin.  Welcome 
 
   4   to I believe the third meeting of the Pharmacy Compounding 
 
   5   Advisory Committee. 
 
   6             Let us begin with the reading of the Conflict of

   7   Interest Statement, Dr. Igor Cerny. 
 
   8                  Conflict of Interest Statement 
 
   9             DR. CERNY:  The following announcement addresses 
 
  10   the issue of conflict of interest with regard to this 
 
  11   meeting and is made a part of the record to preclude even

  12   the appearance of such at this meeting. 
 
  13             In accordance with 18 U.S.C. 208, general matters 
 
  14   waivers have been granted to all committee participants who 
 
  15   have interests in companies or organizations which could be 
 
  16   affected by the committee's discussions of the five drug

  17   products for inclusion on a list of drug products that 
 
  18   cannot be compounded because they have been withdrawn or 
 
  19   removed from the market because such drug products or 
 
  20   components of such drug products have been found to be 
 
  21   unsafe or not effective.

  22             With respect to the second topic on the agenda to 
 
  23   be discussed today and Friday, July 14th, the agency has 
 
  24   determined that all reported interests in firms regulated by 
 
  25   the Center for Drug Evaluation and Research present no 

                                                                  5 
 
   1   potential for a conflict of interest at this meeting with

   2   the following exception:  In accordance with 18 U.S.C. 
 
   3   208(b), a full waiver has been granted to Mr. Welder. 
 
   4             A copy of this waiver statement may be obtained by 
 
   5   submitting a written request to the agency's Freedom of 
 
   6   Information Office, Room 12A‑30 of the Parklawn Building.

   7             In the event that the discussions involve any 
 
   8   other products or firms not already on the agenda for which 
 
   9   an FDA participant has a financial interest, the 
 
  10   participants are aware of the need to exclude themselves 
 
  11   from such involvement, and their exclusion will be noted for

  12   the record. 
 
  13             With respect to all other participants, we ask in 
 
  14   the interest of fairness that they address any current or 
 
  15   previous financial involvement with any firm whose product 
 
  16   they may wish to comment upon.

  17             DR. JUHL:  Let's begin by going around the table 
 
  18   and having microphone practice and introductions, so that 
 
  19   the members of the audience know who we are. 
 
  20             We will start with you, Joan. 
 
  21             MS. LaFOLLETTE:  Joan LaFollette, Bristol‑Myers

  22   Squibb, Director of Regulatory Science, CMC. 
 
  23             DR. ALLEN:  Loyd Allen, International Journal of 
 
  24   Pharmaceutical Compounding. 
 
  25             MR. WELDER:  Tony Welder, Community Pharmacist 

                                                                  6 
 
   1   from Bismarck, North Dakota.

   2             DR. PECK:  Garnet Peck, Professor of Industrial 
 
   3   Pharmacy and Director of the Industrial Pharmacy Laboratory, 
 
   4   Purdue University. 
 
   5             DR. SELLERS:  Sarah Sellers, Pharmacist, 
 
   6   Greenville, North Carolina.

   7             MR. RUSHO:  William Rusho, University of Utah. 
 
   8             DR. McBURNEY:  Elizabeth McBurney, Dermatologist, 
 
   9   Slidell, Louisiana. 
 
  10             MS. RIFFEE:  Judy Riffee, the College of Pharmacy, 
 
  11   University of Florida, Gainesville, Florida.

  12             MR. TRISSEL:  Larry Trissel, M.D. Anderson Cancer 
 
  13   Center. 
 
  14             MS. HOPE:  Rose‑Ellen Hope, Pharmacist, associated 
 
  15   with Public Citizen. 
 
  16             MS. AXELRAD:  Jane Axelrad, the Associate Director

  17   for Policy, Center for Drugs, and Co‑Chair of the Pharmacy 
 
  18   Compounding Steering Committee, FDA. 
 
  19             MS. OGRAM:  Lana Ogram.  I am the Director of the 
 
  20   Division of Prescription Drug Compliance and Surveillance, 
 
  21   and I am the other Co‑Chair of the Pharmacy Compounding

  22   Steering Committee, FDA. 
 
  23             CPT SCOTT:  George Scott, Regulatory Operations 
 
  24   Officer, Office of Compliance, FDA. 
 
  25             DR. ANDERSON:  Kathy Anderson, Consumer Safety 

                                                                  7 
 
   1   Officer, Office of Compliance, FDA.

   2             DR. ROGERS:  Brian Rogers, CMC Reviewer, Division 
 
   3   of Pulmonary Analogy Drug Products. 
 
   4             DR. JUHL:  We will proceed with our agenda.  For 
 
   5   those of you in the audience who have come in, if you 
 
   6   happened to walk past the table without picking up a copy of

   7   the agenda, they are on the outer table. 
 
   8             Let me turn it over to Lana Ogram for introductory 
 
   9   remarks.  Lana. 
 
  10                       Introductory Remarks 
 
  11             MS. OGRAM:  Good morning.  I would like to also

  12   welcome you back for the third meeting of the Pharmacy 
 
  13   Compounding Advisory Committee meeting and to thank you 
 
  14   again for your willingness to participate on this committee. 
 
  15             [Slide. 
 
  16             Pharmacy compounding is a very complicated and

  17   far‑reaching area and we truly appreciate your continuing 
 
  18   support, your dedication, and your in‑depth preparations for 
 
  19   each meeting. 
 
  20             I would like now to pause just for a moment and 
 
  21   have members of our Steering Committee introduce themselves. 

  22   They are sitting on the far side. 
 
  23             Rita, would you start. 
 
  24             MS. HOFFMAN:  Rita Hoffman, Consumer Safety 
 
  25   Officer, Center for Drug Evaluation and Research. 

                                                                  8 
 
   1             MR. RICHMAN:  Fred Richman, Office of Compliance,

   2   Center for Drugs. 
 
   3             MS. REID:  Kim Keller Reid, Special Government 
 
   4   Employee working on a company project in the Office of 
 
   5   Compliance. 
 
   6             MR. HOROWITZ:  David Horowitz, Office of the Chief

   7   Counsel. 
 
   8             MS. MISCAELLI:  Andrea Miscaelli, Regulatory 
 
   9   Policy Staff in CDER. 
 
  10             MR. MITCHELL:  William Mitchell, Regulatory Policy 
 
  11   Staff.

  12             MS. PALLAS:  Lou Ann Pallas, Consumer Safety 
 
  13   Officer and Pharmacist, Division of Manufacturing and 
 
  14   Product Quality, Office of Compliance, CDER. 
 
  15             MR. BROWN:  Ron Brown, Regulatory Operations 
 
  16   Officer, Office of Compliance.

  17             MS. ORTUZAR:  Liz Ortuzar, Executive Operations 
 
  18   Staff. 
 
  19             MR. JONES:  Mike Jones, Office of the Center 
 
  20   Director. 
 
  21             MS. MILLE:  Yana Mille, Operations Staff.

  22             MR. LENISH:  John Lenish, Office of Policy, 
 
  23   Planning, and Legislation. 
 
  24             MS. OGRAM:  Thank you.  I would like to thank each 
 
  25   of these individuals who has really been working diligently 

                                                                  9 
 
   1   to implement the provisions of Section 503A of the Act.

   2             It has been almost a year since we met last, and 
 
   3   before we proceed with our formal agenda, I would like to 
 
   4   bring you up to date on some of the issues that have 
 
   5   transpired. 
 
   6             I will briefly talk about the status of the

   7   lawsuit, the bulk drug substances list, the Memorandum of 
 
   8   Understanding between FDA and the States, and our general 
 
   9   compounding regulations. 
 
  10             As we mentioned during our last meeting, the day 
 
  11   before Section 503 went into effect in November of 1998,

  12   seven compounding pharmacies sued FDA in the Federal 
 
  13   District Court of Nevada.  They challenged the 
 
  14   constitutionality of two provisions of the law based on 
 
  15   First Amendment grounds as an abridgement of the right to 
 
  16   freedom of speech.

  17             As you may recall, the law exempts compounded 
 
  18   drugs that are produced under specified conditions from 
 
  19   three key requirements of the Food, Drug, and Cosmetic Act, 
 
  20   and those requirements are:  that the drugs are produced 
 
  21   under current Good Manufacturing Practices, that they are

  22   labeled with adequate directions for use, and that drugs 
 
  23   undergo agency approval of New Drug Applications and 
 
  24   Abbreviated New Drug Applications. 
 
  25             The two provisions that were challenged in the 

                                                                 10 
 
   1   lawsuit state that in order to qualify for the exemptions

   2   provided for by the law, the compounded drug may not be 
 
   3   based on a prescription that has been solicited by the 
 
   4   compounding pharmacist, pharmacy, or compounding physician, 
 
   5   and that the pharmacy, pharmacist, or compounding physician 
 
   6   may not advertise or promote the compounding of a particular

   7   drug, class of drug, or type of drug. 
 
   8             It is important to remember, though, that the law 
 
   9   always permitted the advertisement of compounding services. 
 
  10             On December 18th of '98, the court issued a 
 
  11   temporary restraining order which enjoined FDA from

  12   enforcing these two provisions of the law. 
 
  13             On September 16th of '99, the U.S. District Court 
 
  14   of Nevada decided that the two speech‑related restrictions 
 
  15   of Section 503A violated the First Amendment of the 
 
  16   Constitution.

  17             In addition, the Court concluded that the 
 
  18   advertisement and solicitation provisions can be severed 
 
  19   from the remainder of the law, and this means that for the 
 
  20   moment, Section 503A is fully operative as a law, but 
 
  21   without the restrictions on advertisement and solicitation

  22   of prescriptions. 
 
  23             In June of this year, FDA filed an appeal in the 
 
  24   Ninth Circuit Court of Appeals, and that appeal is pending. 
 
  25             As you may remember, Section 503A restricts the 

                                                                 11 
 
   1   universe of bulk drug substances that may be used in

   2   compounding and qualify for the exemptions.  In addition to 
 
   3   certain other requirements, only bulk drug substances that 
 
   4   fall into one of three major categories may be used in 
 
   5   compounding. 
 
   6             Each bulk drug substance must comply with an

   7   applicable current USP or NF monograph and the USP chapter 
 
   8   on pharmacy compounding.  If a monograph does not exist, 
 
   9   then, it must be a component of an FDA‑approved drug, and if 
 
  10   neither, it must appear on a list of bulk drug substances 
 
  11   published by FDA in the Federal Register.

  12             FDA originally solicited nominations for this drug 
 
  13   from the public in April of 1998, and after reviewing 
 
  14   candidates for the list, in January of 1999, we published a 
 
  15   proposed bulk drug substances rule, and we received a number 
 
  16   of additional nominations for the list.

  17             We have discussed each nomination with this 
 
  18   committee at the first two Pharmacy Compounding Advisory 
 
  19   meetings in October of '98 and May of '99. 
 
  20             USP, with whom we have been consulting in the 
 
  21   development of this list, has agreed to develop standard

  22   monographs that will establish the identity, strength, 
 
  23   quality, and purity of bulk drug substances that will appear 
 
  24   on the agency's published list. 
 
  25             They are working quickly to develop these 

                                                                 12 
 
   1   standards and have already developed seven monographs for

   2   drug which were nominated for inclusion on the list.  Final 
 
   3   monographs now exist for bismuth citrate, iodoform, sodium 
 
   4   butyrate, diloxanide furoate, myrrh topical solution, 
 
   5   tinidazole, and ferric sulfate hydrate. 
 
   6             Ferric sulfate will most likely stay on the list

   7   because USP's monograph is for ferric sulfate hydrate 
 
   8   solution, and since the substance is available as both a 
 
   9   solution and a powder, listing the ferric sulfate will 
 
  10   clarify that either the solution or the power form may be 
 
  11   used in compounding.

  12             Once a USP standard monograph is published, a bulk 
 
  13   drug substance no longer requires listing within FDA's 
 
  14   regulation, so these drugs will not be included in the final 
 
  15   rule. 
 
  16             Several months ago, FDA approved a drug containing

  17   caffeine citrate as an active ingredient, therefore, this 
 
  18   substance may be used in pharmacy compounding and it also 
 
  19   will not appear in the final rule. 
 
  20             USP is also tackling monographs for eight other 
 
  21   drug substances listed in the proposed rule, and these

  22   include betahistine chloride, choline bitartrate, 
 
  23   cyclandelate, levoglutamide, metronidazole benzoate, 
 
  24   phenindamine tartrate, and phenyltoloxamine dihydrogen 
 
  25   citrate. 

                                                                 13 
 
   1             These proposed monographs are in the very early

   2   stages of development and have appeared in the U.S. 
 
   3   pharmacopeial form as preview proposals.  Monographs 
 
   4   proposed as previews must then be reproposed as in‑process 
 
   5   revisions before they can be made official. 
 
   6             A monograph for taurine has also been published as

   7   an in‑process revision. 
 
   8             The bulks final rule is currently undergoing 
 
   9   agency review, and after clearance, it will go to OMB and 
 
  10   then publication. 
 
  11             This regulation will continue to evolve as

  12   substances are recommended for addition to, or removal from, 
 
  13   the list through the petition process. 
 
  14             It is also important to remember that the list is 
 
  15   not intended to interfere in any way with the agency's 
 
  16   investigational New Drug Program, and that drug substances

  17   that are excluded from this list may still be available 
 
  18   under an IND protocol. 
 
  19             Since our last meeting, we received a petition to 
 
  20   amend the bulk drug substances list to include one more drug 
 
  21   ‑ D‑ribose.  The nominator intends to supply the substance

  22   as a powder and as a sterile concentrated solution for IV 
 
  23   injection. 
 
  24             Unfortunately, we didn't receive this nomination 
 
  25   in enough time to review and present it at this meeting, 

                                                                 14 
 
   1   however, as part of our deliberations on this substance, we

   2   will in the future consult with the USP and this committee 
 
   3   as required by statute.  We will go through the formal 
 
   4   rulemaking process before we take a final action on 
 
   5   D‑ribose. 
 
   6             [Slide.

   7             At our last meeting, we discussed the Memorandum 
 
   8   of Understanding that FDA is developing in consultation with 
 
   9   the National Association of Boards of Pharmacy.  The MOU is 
 
  10   designed to address the interstate distribution of 
 
  11   compounded drugs, and a compounded drug may qualify for the

  12   exemptions of 503A that I mentioned before if, among other 
 
  13   conditions, either of these two conditions apply, and that 
 
  14   is, that it is in a state in which the drug is compounded, 
 
  15   and that state has entered into an MOU with FDA. 
 
  16             If this is the case, then, the MOU must address

  17   the distribution that inordinate amounts of compounded drug 
 
  18   outside of the state and the MOU must provide for the 
 
  19   appropriate investigation by the state of complaints related 
 
  20   to compounded drugs which are distributed outside of the 
 
  21   state.

  22             On the other hand, if the state in which the drug 
 
  23   is compounded has not entered into an MOU, then, the amount 
 
  24   of compounded drug products shipped out of the state by the 
 
  25   licensed pharmacy would not be permitted to exceed 5 percent 

                                                                 15 
 
   1   of the total prescription orders dispensed or distributed by

   2   the pharmacy and still qualify for the exemptions from the 
 
   3   law. 
 
   4             One of the elements that must be defined in the 
 
   5   MOU is guidance on the meaning of "inordinate amounts," and 
 
   6   also a safe harbor in excess of 5 percent which would not be

   7   considered to be inordinate. 
 
   8             [Slide. 
 
   9             We have been working with NABP to develop the 
 
  10   draft standard MOU as required by the law, and although the 
 
  11   law did not require it, because of the complicated nature of

  12   this provision, FDA did publish the draft standard MOU in 
 
  13   the Federal Register in January of 1999, and we made it 
 
  14   available for public comment. 
 
  15             The MOU generated a tremendous amount of interest  
 
  16   and we wound up reopening and extending the comment period t

  17   twice, in March and again in June of 1999.  By the end of 
 
  18   August, we had received over 6,000 comments from a variety 
 
  19   of sources, from trade associations, from compounding 
 
  20   pharmacies, prescribers, as well as 13 state boards of 
 
  21   pharmacy.

  22             A large proportion of the comments that we 
 
  23   received were as form letters from customers from several 
 
  24   large compounding pharmacies. 
 
  25             To kind of put the volume of comments received 

                                                                 16 
 
   1   into perspective, we received a little over 200 comments on

   2   the bulk drug substances proposed rule and approximately 30 
 
   3   comments on the withdrawn and removed proposed rule. 
 
   4             Most of the comments that we received on the MOU 
 
   5   centered around the definition of the term "inordinate" 
 
   6   although we also received some comments on the portion of

   7   the MOU that deals with the investigation of complaints. 
 
   8             We have reviewed the comments and we understand 
 
   9   and we are sympathetic to many of the concerns voiced, so we 
 
  10   have continued to consult with the National Association of 
 
  11   Boards of Pharmacy, and we are revising the draft standard

  12   MOU in the areas which were the primary focus of comments. 
 
  13             We intend to republish the revised draft MOU and 
 
  14   again solicit comments from the public.  After we consider 
 
  15   those comments and we revise the draft, we intend to 
 
  16   finalize the MOU and make it available for signature by

  17   individual state agencies. 
 
  18             We plan to continue to exercise our enforcement 
 
  19   discretion and will not normally take regulatory action 
 
  20   regarding this requirement until at least after 90 days 
 
  21   after the standard MOU is finalized and made available for

  22   signature. 
 
  23             [Slide. 
 
  24             I would like to talk just a little bit about our 
 
  25   general implementing regulations.  In addition to the three 

                                                                 17 
 
   1   specific regulations which list drugs which may or may not

   2   be compounded, and the MOU which I just described, we are 
 
   3   continuing to work on a proposed rule which will address 
 
   4   general regulations necessary to implement certain 
 
   5   provisions of the pharmacy compounding law although most of 
 
   6   the provisions of 503A are self‑implementing.

   7             In our proposed regulations, we will define what 
 
   8   it means to compound regularly or in inordinate quantities, 
 
   9   copies of commercially available drug products that will not 
 
  10   qualify for the exemption from the Act, and the regulation 
 
  11   will also address such things as supplying of compounded

  12   drugs to physicians for office stock, the labeling of 
 
  13   compounded drugs, and elements of the certificate of 
 
  14   analysis which is required to accompany bulk drug 
 
  15   substances. 
 
  16             The regulations will, of course, go through notice

  17   and comment rulemaking, and we hope to publish something in 
 
  18   the near future. 
 
  19             Before we begin our in‑depth discussions of the 
 
  20   two topics which are the subject of this meeting, the 
 
  21   additions to the list of the drugs that have been withdrawn

  22   or removed from the market and may not be compounded under 
 
  23   the exemptions of 503A, and our preliminary thoughts on the 
 
  24   list of drugs that are demonstrably difficult to compound, I 
 
  25   would like to turn to Jane Axelrad, who will discuss some 

                                                                 18 
 
   1   additional recent development in the bulks drug arena.

   2             DR. JUHL:  Before we move on, are there questions 
 
   3   for Lana about any of the topics that she covered? 
 
   4             [No response.] 
 
   5             DR. JUHL:  Any rough idea of how long it will be   
 
   6   before the MOU will be available?

   7             MS. OGRAM:  It will be reproposed, republished, 
 
   8   and I would say that is months away. 
 
   9             DR. JUHL:  Sometime before the end of the year 
 
  10   perhaps? 
 
  11             MS. OGRAM:  Yes.

  12             DR. JUHL:  Okay.  Has there been any activity at 
 
  13   the state board level with regard to enforcement of any of 
 
  14   the provisions that you are aware of? 
 
  15             MS. OGRAM:  There has been some state activity.  
 
  16   As you know, we do have a final rule in the area Withdrawn

  17   and Removed Drugs, so pharmacies that are compounding those 
 
  18   types of drugs are going through a warning process.  Since 
 
  19   the law is fairly new, we are making sure that compounders 
 
  20   that are working in that area are being advised, and then we 
 
  21   will take action if there is a continuation of compounding

  22   of drugs that are on that list. 
 
  23             DR. JUHL:  Are the state boards taking the lead on 
 
  24   this and consulting with you?  How is that working? 
 
  25             MS. OGRAM:  We are working with the state boards, 

                                                                 19 
 
   1   it's a partnership.  Information has come to us, and we are

   2   sharing information with the state boards and working 
 
   3   together. 
 
   4             DR. JUHL:  Okay.  Good.  Thank you. 
 
   5             Jane. 
 
   6            3,4‑diaminopyridine and 4‑aminopyridine ‑

   7                     Updates to the Committee 
 
   8                           Introduction 
 
   9             [Slide. 
 
  10             MS. AXELRAD:  We, at the meeting a year ago, when 
 
  11   we were discussing the bulks list, we discussed two compound

  12   that had been nominated for consideration on the list ‑ 
 
  13   4‑aminopyridine, which is being used to treat a spinal cord 
 
  14   injury and multiple sclerosis, and 3,4‑diaminopyridine, 
 
  15   which is principally used to treat Lambert‑Eaton's disease. 
 
  16             Those were two of the compounds that we had

  17   originally indicated that we had concerns about and that we 
 
  18   were consulting with the committee, and we were not 
 
  19   proposing to put them on the list because we had concerns 
 
  20   about the toxicity profile with those drugs, and we had 
 
  21   presentations by two firms at the meeting who indicated that

  22   they were studying those drugs under INDs. 
 
  23             At the time, the Advisory Committee asked us to 
 
  24   give them an update, and this is the first time we have met 
 
  25   since then, so we wanted to provide you with an update on 

                                                                 20 
 
   1   where we stand in terms of working with the companies on

   2   making those drugs available under open label trials. 
 
   3             As you will recall, the committee voted against 
 
   4   putting those drugs on the bulk drugs list, but we wanted to 
 
   5   provide you the update about where we were.  I spoke with 
 
   6   Dr. Jacobus from Jacobus Pharmaceuticals who produces

   7   3,4‑diaminopyridine and who is involved in studies in that, 
 
   8   and Dr. Jacobus has authorized me to tell you that they have 
 
   9   submitted a protocol to us for an open label trial and that 
 
  10   they believe, and we also believe, that we can work out the 
 
  11   details of that, and that they will be able to supply any of

  12   the patients with Lambert‑Eaton's disease with 
 
  13   3,4‑diaminopyridine. 
 
  14             We have representatives here from Acorda 
 
  15   Pharmaceuticals who will address the situation with regard 
 
  16   to 4‑aminopyridine.

  17             DR. JUHL:  We have Dr. Andrew Blight, Vice 
 
  18   President of Research and Development from Acorda, and Dr. 
 
  19   Veronica Mallon, Vice President of Intellectual Property and 
 
  20   Government Affairs. 
 
  21             I presume you are Dr. Blight.

  22             DR. BLIGHT:  Yes. 
 
  23             DR. JUHL:  Welcome. 
 
  24                       Acorda Therapeutics 
 
  25             DR. BLIGHT:  I am, in fact, Andrew Blight.  I am 

                                                                 21 
 
   1   here today to answer any questions that you may have

   2   regarding Acorda Therapeutics and the proposed expanded 
 
   3   access program. 
 
   4             I know we were not originally on the agenda, 
 
   5   therefore, I will keep my statement brief and leave details 
 
   6   to questions should you have them.

   7             As you know, at the meeting in May of '99, Acorda 
 
   8   agreed to initiate an expanded access program that would 
 
   9   make its sustained released formulation of fampridine 
 
  10   available to patients who are currently taking compounded 
 
  11   formulations, and it's with sincere regret that I have to

  12   report that Acorda does not feel it is possible to initiate 
 
  13   an expanded access study of fampridine at the present time. 
 
  14             This is a difficult position for us, as you will 
 
  15   realize, because we took our commitment very serious and 
 
  16   expended a great deal of effort towards that goal.  The

  17   reasons for the change in our outlook are quite 
 
  18   straightforward. 
 
  19             As intended following the 1999 meeting, we planned 
 
  20   extensively for the study.  We retained a specialize 
 
  21   clinical research organization and put together two

  22   protocols that were submitted to the FDA in December of last 
 
  23   year. 
 
  24             In the process of doing this, it became clear to 
 
  25   us and to our board of directors that such a program would 

                                                                 22 
 
   1   constitute a much larger drain on our resources and capital

   2   than we initially envisioned when we met with you last year. 
 
   3             In trying to assess the actual costs of 
 
   4   undertaking this kind of study, we found that it wasn't 
 
   5   possible to obtain sufficiently detailed information about 
 
   6   the numbers of patients already taking compounded

   7   fampridine, the doses that they receive, or the proportion 
 
   8   of cost recovery that we might reasonably expect. 
 
   9             Without such information on which to base a 
 
  10   detailed plan and budget, we believe it would be 
 
  11   irresponsible for a small company like ours with no current

  12   revenue stream to initiate such an open‑ended study. 
 
  13             This is particularly because, of course, it would 
 
  14   threaten our ability to proceed in a timely manner with a 
 
  15   clinical development program designed to bring fampridine to 
 
  16   regulatory approval.

  17             So, in summary, I repeat that we regret our 
 
  18   inability to provide an immediate solution for people 
 
  19   currently taking this drug, however, I will add that our 
 
  20   development program is on track with active Phase II studies 
 
  21   in both MS and spinal cord injury, and plans for entering

  22   Phase III in the next calendar year. 
 
  23             Our primary concern as a company must be to 
 
  24   complete our development program for fampridine in these two 
 
  25   indications, so that everyone who may benefit can have 

                                                                 23 
 
   1   access to a well‑characterized drug with demonstrated

   2   efficacy and safety. 
 
   3             I would be happy to answer any questions that you 
 
   4   may have. 
 
   5             Thank you. 
 
   6                       Committee Discussion

   7             DR. JUHL:  Questions from the committee? 
 
   8             MR. TRISSEL:  Maybe this is more directed to the 
 
   9   agency.  Where does the situation stand with the 
 
  10   implementation of 4‑AP on to any list? 
 
  11             MS. AXELRAD:  We haven't published the final list

  12   yet, but I don't think it is any secret that we really 
 
  13   changed our position since we proposed it to the committee.  
 
  14   You know, we are considering the comments, but we had some 
 
  15   fairly serious concerns about the drug. 
 
  16             We indicated that although we would try to work

  17   with the company to make it available under an open label 
 
  18   trial, our decision on whether to put it on the list did not 
 
  19   depend on whether it would be made available in that 
 
  20   situation. 
 
  21             We felt that since this was a drug to treat a

  22   serious life‑threatening disease, and it had a significant 
 
  23   toxicity profile, it was only in very early trials, and we 
 
  24   really did not have any sound evidence that it would work, 
 
  25   that we did not feel that it should go on the list. 

                                                                 24 
 
   1             I don't think that the fact that it won't be made

   2   available is likely to change that decision. 
 
   3             Also, we, too, have been trying to get a better 
 
   4   handle on how many patients are out there.  The only thing 
 
   5   that we have are the representations from IACP of the 
 
   6   numbers of patients that are actually on the drug.  We have

   7   talked to people with the Multiple Sclerosis Society and 
 
   8   some of the other organizations, and it may not be that 
 
   9   there are that many patients on it. 
 
  10             We are having the same difficulty that the company 
 
  11   has in trying to estimate how many patients are actually

  12   taking this and how many would be affected, but I think that 
 
  13   we agree that the best thing to do is to get this drug 
 
  14   studied under an IND and if it shows that it is safe and 
 
  15   effective, then, it can be made available to everybody who 
 
  16   needs it under an approved application.

  17             DR. JUHL:  Could I ask, then, the reason that this 
 
  18   would be not be financially feasible for the company is that 
 
  19   the access would have to be expanded to too many patients 
 
  20   for you to afford? 
 
  21             DR. BLIGHT:  No.  Really, the issue is one of

  22   needing to be able to plan for it, so that the cost recovery 
 
  23   could make this self‑sustaining.  As a small company, we 
 
  24   don't have the resources obviously to undertake this based 
 
  25   on existing capital because that would derail our 

                                                                 25 
 
   1   development program.

   2             DR. JUHL:  So, what are your estimates of the 
 
   3   number of patients that would be involved in such a 
 
   4   possibility? 
 
   5             DR. BLIGHT:  As Jane said, we really don't have an 
 
   6   estimate that we can put any reliance on.  Originally, I

   7   think we had estimates that were in the range of 10‑ to 
 
   8   20,000 patients, and what calculations we could make based 
 
   9   on existing information suggested that the numbers might be 
 
  10   much lower than that. 
 
  11             Clearly, in a cost‑sharing program of this kind,

  12   the fewer patients you have, the most expensive that it will 
 
  13   become for each individual.  The point that it becomes a 
 
  14   positive feedback, where less and less people enroll.  So, 
 
  15   that was the major ‑‑ the major issue was that it was very 
 
  16   difficult to know what the costs would be and how they could

  17   be planned for. 
 
  18             DR. JUHL:  If I could go back to the minutes of 
 
  19   the last meeting, you weren't the person who appeared the 
 
  20   last time, but the committee felt intimidated by the 
 
  21   presentation from your company.

  22             Let me read from the minutes.  "With this in mind" 
 
  23   ‑‑ this was Dr. Cohen reading ‑‑ "Acorda has informed CDER 
 
  24   that if fampridine is not placed on the list on allowable 
 
  25   substances for compounding, Acorda would be willing to 

                                                                 26 
 
   1   sponsor long‑term expanded access, clinical study of our

   2   formulation." 
 
   3             Later on he continues, "If the compound fampridine 
 
   4   is allowed, we will be unable to offer such a program."  At 
 
   5   least in my recommendation, that weighed heavily on what I 
 
   6   decided to recommend to the agency.  Now, the agency

   7   obviously has the last word in this, but it appears to me to 
 
   8   be rather irresponsible for your company to come in with 
 
   9   such a strong position, be so cocksure of what it is that 
 
  10   you are going to do, tell the committee you had better not 
 
  11   put this drug on the list for pharmacists to use, because

  12   otherwise we won't do the program, and now a year later you 
 
  13   are not doing the program. 
 
  14             Why is that? 
 
  15             DR. BLIGHT:  I think that statement was factually 
 
  16   correct, that if, in fact, compounding were to continue,

  17   there would be very little pressure on us to put forward an 
 
  18   expanded access program at this time in the development 
 
  19   process. 
 
  20             I am sure we are very sorry if that came across as 
 
  21   being at attempted intimidation.  That was simply a

  22   statement, I think at its base of the situation as it stood 
 
  23   from our point of view, and it was very clear that that was 
 
  24   only our point of view and that clearly, there are other 
 
  25   issues to be considered.  So, I would apologize for such an 

                                                                 27 
 
   1   impression, and I am sure Dr. Cohen would also if he were

   2   here. 
 
   3             DR. JUHL:  Dr. Allen. 
 
   4             DR. ALLEN:  I guess a couple of comments.  One, I 
 
   5   believe the vote of the committee was very dependent upon 
 
   6   the input from the manufacturer and the understanding that

   7   they would follow through, so I think I would like to 
 
   8   request that that be revisited at some point in time. 
 
   9             As far as having patients available for your 
 
  10   clinical studies, in many clinical studies, you know, the 
 
  11   drug products are provided free of charge to the

  12   participants in the studies, whereas, in the current 
 
  13   distribution system for compounding, the patients have to 
 
  14   pay for the product, so there is an incentive for them to be 
 
  15   a part of a clinical study. 
 
  16             So, I am not sure that it would adversely affect

  17   the number of participants in the studies, you know, 
 
  18   provided you had your principals involved.  So, I guess I 
 
  19   would like to request that we at some point revisit this 
 
  20   bulk drug substance. 
 
  21             DR. JUHL:  Larry.

  22             MR. TRISSEL:  I would like to second that.  We 
 
  23   certainly discussed the extent of the potential patient load 
 
  24   for your company, and 10‑ and 20,000 patients was discussed, 
 
  25   and the company assured us that they could meet that with no 

                                                                 28 
 
   1   problem.

   2             There were some of us who thought that was 
 
   3   probably not going to happen, and apparently that was true.  
 
   4   I think it is incumbent on us now to revisit this issue 
 
   5   based on the reality of the situation the way it is now, 
 
   6   because the committee's consideration was based on fault

   7   information provided by Acorda. 
 
   8             DR. BLIGHT:  I think that, in fact, if the numbers 
 
   9   could be assured to be between 10‑ and 20,000, it would be 
 
  10   possible to calculate sufficiently well to produce such a 
 
  11   study, but if, in fact, the numbers fall significantly below

  12   10,000, then, it becomes much more difficult to distribute 
 
  13   the costs of such a study, and that is the major concern, 
 
  14   not that it would be too big, but that it would be not big 
 
  15   enough. 
 
  16             DR. JUHL:  Are you more interested in patients

  17   with MS or spinal cord injuries? 
 
  18             DR. BLIGHT:  Well, as a company, we were founded 
 
  19   primarily to develop therapies for spinal cord injury, but 
 
  20   because of our interest in demyelination in spinal cord 
 
  21   injury, we have broadened that to include MS.

  22             So, we are now equally interested in both 
 
  23   conditions, although our roots are in the spinal cord injury 
 
  24   side of this. 
 
  25             DR. SELLERS:  I would just like to comment that 

                                                                 29 
 
   1   supply was not one of the criteria that we were supposed to

   2   base our decision on, and we would have to reestablish new 
 
   3   criteria for listing drugs on the list. 
 
   4             DR. JUHL:  Other comments? 
 
   5             [No response.] 
 
   6             DR. BLIGHT:  Thank you.

   7             DR. JUHL:  Thank you. 
 
   8             I believe given the situation that has occurred, 
 
   9   at anytime anyone can repropose that a drug be reconsidered 
 
  10   for the bulks list, and as disappointed as I am at the 
 
  11   company not being able to fulfill the promises that were

  12   made to us with some degree of emphasis, neither have we 
 
  13   seen the development of information about people who were on 
 
  14   this drug, who have been severely and adversely affected by 
 
  15   it either, so I think we also need to call upon the 
 
  16   community who would propose that the drug be reconsidered to

  17   provide information to the agency that could be examined by 
 
  18   the committee in order to reexamine the issue, if that meets 
 
  19   with the committee's approval and if I make a bit of sense 
 
  20   to you. 
 
  21             DR. ALLEN:  Just one comment along those lines, it

  22   is my understanding that as soon as the bulks list becomes 
 
  23   official, the compounding can no longer be done on anything 
 
  24   that does not meet the FDAMA requirements, USP,NF, et 
 
  25   cetera, et cetera. 

                                                                 30 
 
   1             So, if this continues on the list to not be

   2   included and the bulks list is published sometime in the 
 
   3   next few months, and it may be longer than that, and it may 
 
   4   be longer than that before we meeting again, that means 
 
   5   there may be an interim period of time where this product 
 
   6   could not be compounded.

   7             Could we ask that this product be put on hold 
 
   8   until we review it?  Do you see what I mean? 
 
   9             DR. JUHL:  I understand.  Does the agency have a 
 
  10   response to that? 
 
  11             MS. AXELRAD:  Well, I think that there is two ways

  12   to go here.  We don't have any additional technical 
 
  13   information to present on this.  I am not sure what 
 
  14   information you would be seeking to have someone who wants 
 
  15   it reconsidered that they would propose. 
 
  16             I am not sure you are looking for technical

  17   information about the safety of the product.  I gather you 
 
  18   are looking for how many people are actually taking it and 
 
  19   what effect would it have if it was not made available to 
 
  20   them. 
 
  21             DR. JUHL:  I guess what I am suggesting is that on

  22   the MOU, for example, compounding pharmacists generated 
 
  23   6,000 responses to the agency on your request for comment.  
 
  24   Compounding pharmacists at this point haven't generated that 
 
  25   kind of information and comments on this drug. 

                                                                 31 
 
   1             If those patients are out there, I would really

   2   like to know about it.  That was really the concern of the 
 
   3   committee, are there patients believe, and their physicians 
 
   4   believe, that they are being helped by this, that will no 
 
   5   longer have it available to them. 
 
   6             A year ago we had some concern.  We were told some

   7   numbers.  The agency was quite clear in its decision about 
 
   8   the drug.  That has not seemed to raise alarm amongst 
 
   9   patients, pharmacists, or physicians regarding the drug.  I 
 
  10   guess that is the kind of information that I thought should 
 
  11   we make one more last plea for.

  12             MR. TRISSEL:  But also we were expecting to have a 
 
  13   program in place, so no one should have been particularly 
 
  14   concerned.  The drug would be available through Acorda, but 
 
  15   that didn't happen, and now we are going to have a potential 
 
  16   where the drug is in some sort of limbo state that makes it

  17   unavailable for patients, and that is different than what we 
 
  18   had been led to believe last time. 
 
  19             MS. AXELRAD:  I would like to say we did that in 
 
  20   the proposed rule where we were not going to put 4‑AP on the 
 
  21   list.  We received a number of comments, somewhere in the

  22   neighborhood of 200.  Somebody can correct me, but my 
 
  23   recollection is it is somewhere in the neighborhood of 200 
 
  24   comments on 4‑AP from MS patients, families and friends of 
 
  25   MS patients, physicians, and other individuals in favor of 

                                                                 32 
 
   1   including the substance on the book drugs list, but the

   2   majority of these were letter and E‑mail testimonials about 
 
   3   the benefits of 4‑AP, and they really did not provide any 
 
   4   scientific data that contradicted the information that we 
 
   5   have.  I mean they are just anecdotal statements of how it 
 
   6   may have worked in individual cases, which is a far cry from

   7   scientific data that shows that the drug is, in fact, 
 
   8   effective, which is why we believe that it ought to be 
 
   9   studies in adequate and well‑controlled trials, because 
 
  10   there is a large placebo effect and unless you do those 
 
  11   kinds of trials, you really don't know.

  12             Also, it needs to be studied in numbers of 
 
  13   patients before you can get a true safety profile.  We 
 
  14   already know that there are some concerns about this.  We 
 
  15   have somebody here from the division who is probably better 
 
  16   able to address this if you wanted more detail.

  17             But I guess what I am saying is we did get a lot 
 
  18   of comments on this.  We didn't get any scientific evidence 
 
  19   that would suggest a change. 
 
  20             DR. JUHL:  Well, I think it is kind of ridiculous 
 
  21   to expect that you are going to get scientific evidence when

  22   we know there isn't any.  The committee is concerned there 
 
  23   is patients who are receiving the drug, they and their 
 
  24   physicians believe that they are receiving benefit.  They 
 
  25   are going to be put in a situation of not having it, or they 

                                                                 33 
 
   1   and their pharmacists are going to be breakers of the law.

   2             We were looking for a way around that.  The 
 
   3   company promised us a way around that, and now we don't have 
 
   4   that anymore.  So, it is the concern for those 200 patients 
 
   5   who sent in their testimonials, and that is all we have at 
 
   6   this point.

   7             MS. AXELRAD:  What I am suggesting is that rather 
 
   8   than having us put it on hold, if the committee would like 
 
   9   to revote now.  I don't perceive that by putting it on hold 
 
  10   we would be getting any additional scientific evidence for 
 
  11   the committee to consider that would justify us waiting

  12   until the fall. 
 
  13             What I would suggest is the committee could 
 
  14   revote. 
 
  15             DR. JUHL:  We are talking right past each other.  
 
  16   We are not looking for scientific evidence.  Again, what we

  17   are looking for is some estimation of the number of patients 
 
  18   who are going to be inconvenienced and possibly adversely 
 
  19   affected by having the drug removed from their access. 
 
  20             MS. AXELRAD:  I have no way of getting that 
 
  21   number.

  22             DR. JUHL:  I understand that, but that's the issue 
 
  23   that I have for me anyway.  If other members of the 
 
  24   committee would like to jump in ‑‑ Garnet? 
 
  25             DR. PECK:  Since last year ‑‑ and I am not 

                                                                 34 
 
   1   prepared to present scientific data ‑‑ I have a concern over

   2   stability.  We have been approached about this compound, and 
 
   3   there is a feeling of interest about the stability of the 
 
   4   material.  Consequently ‑‑ well, first of all, there may 
 
   5   have been information presented a year ago and I do not 
 
   6   remember it from the chemical standpoint, so I would

   7   question the compound from that standpoint. 
 
   8             DR. JUHL:  Yes, there was information that was 
 
   9   presented on the difficulty in providing a suitable 
 
  10   formulation. 
 
  11             DR. PECK:  Well, that is the reason for the

  12   controlled release system, it supposedly stabilizes it, but 
 
  13   basically, it is my understanding that there is a stability 
 
  14   problem, and it should be addressed.  So, I have a concern 
 
  15   even though there have been patients taking the drug. 
 
  16             DR. SELLERS:  At our last meeting, we were

  17   instructed not to use supply as a basis for deciding whether 
 
  18   or not we should list these drugs.  In addition, we also 
 
  19   discussed the availability of these drugs under emergency 
 
  20   INDs.  I think we need to remember that in this discussion. 
 
  21             DR. JUHL:  Other comments?

  22             MS. AXELRAD:  Dr. Juhl, what I was going to 
 
  23   suggest is that we can just assume, you know, that there is 
 
  24   at least a large number of patients that are taking this 
 
  25   drug.  It may be in neighborhood of, you know, anywhere over 

                                                                 35 
 
   1   1,000 patients are on it, and the committee, without sort of

   2   stipulation, might want to take another vote based on the 
 
   3   evidence that they heard, and determine whether given that 
 
   4   it may not be available to those patients if it is not put 
 
   5   on the list, you know, whether they want to change their 
 
   6   position having heard the statements about the toxicity of

   7   the drug and our position about the need to study it under 
 
   8   an IND. 
 
   9             DR. JUHL:  Maybe if I could ask Dr. Blight, what 
 
  10   is your status of your controlled clinical trials and the 
 
  11   need for enrollment in, and the availability, of the trials

  12   to patients in distant geographies from where we are 
 
  13   studying. 
 
  14             DR. BLIGHT:  As I mentioned, we are in Phase II 
 
  15   with both indications.  We have just begun a 90‑patient 
 
  16   study in spinal cord injury, just completed a 24‑patient

  17   study in MS that was addressing issues of dosage, and our 
 
  18   plan is to complete Phase II's in both indications by the 
 
  19   beginning of next year.  It is obviously not clear what the 
 
  20   outcome will be, but in the best case, we would move into 
 
  21   Phase III's in the first half of next year and proceed from

  22   there. 
 
  23             Obviously, this is not a predictable course for 
 
  24   any drug development, but it is in our interest, of course, 
 
  25   to do this as rapidly as we can, and our current time line 

                                                                 36 
 
   1   calls for completion of Phase III's again within the course

   2   of a year, but we obviously cannot guarantee any stage of 
 
   3   the development program, but we are pushing ahead with it. 
 
   4             DR. JUHL:  Thank you. 
 
   5             Loyd. 
 
   6             DR. ALLEN:  Related to the stability that Garnet

   7   brought up, I don't see any difficulty in determining the 
 
   8   stability of solid or oral dosage form as capsules and a 
 
   9   beyond use date, for example, could be published in the 
 
  10   literature, whether it is 15 days, 30 days, 45 days, 60 
 
  11   days.

  12             We are certainly not looking for a two‑year 
 
  13   expiration date, but something that would be appropriate 
 
  14   guarantee the purity and the stability of the product for a 
 
  15   reasonable amount of time.  That should not be too difficult 
 
  16   to come up with.

  17             DR. JUHL:  But we don't have that data. 
 
  18             DR. ALLEN:  Not yet.  I think it could be 
 
  19   generated in a matter of a few months, though, pretty 
 
  20   quickly. 
 
  21             DR. McBURNEY:  I am a little reluctant today to

  22   reconsider the issue and vote on it because the data was 
 
  23   presented over a year ago, and I did not come prepared to 
 
  24   this meeting and have reviewed the data, so I would have 
 
  25   some reluctance at that today. 

                                                                 37 
 
   1             I would be glad to review it this evening if that

   2   material was given to me, but that would be my concern as an 
 
   3   informed committee member. 
 
   4             MR. TRISSEL:  Far be it from me to declare 
 
   5   stability not to be an important issue, and make a career 
 
   6   out of this, but these are two very significant health

   7   problems that have no effective treatments, and to me, 
 
   8   stability, while the love of my life, may not be the most 
 
   9   important issue on a short‑term, few weeks basis from 
 
  10   compounding. 
 
  11             To me, the treatment of someone with a spinal cord

  12   injury or MS, where there is nothing else effective, may be 
 
  13   something to consider. 
 
  14             MS. LaFOLLETTE:  I just wanted to reemphasize that 
 
  15   all these drugs can be available by an emergency IND.  It is 
 
  16   not like we are eliminating patients from getting the drug.

  17             DR. ALLEN:  The emergency IND or the compassionate 
 
  18   IND is a topic that I would like to discuss at some point at 
 
  19   this meeting, to try to get more information.  As I 
 
  20   understand it, it is a little bit more complex than just 
 
  21   filling out a single sheet of paper and submitting it.

  22             So I think it would help us as committee members 
 
  23   to understand the situation a little better if we could have 
 
  24   a discussion of it and, you know, possibly look at some 
 
  25   alternatives. 

                                                                 38 
 
   1             DR. FEENEY:  If I could address that.  I am Dr.

   2   Feeney from the Division of Neuropharm Drug Products. 
 
   3             The emergency IND regulations would allow us, on 
 
   4   an individual patient basis, to supply the drug, but I would 
 
   5   anticipate that whatever number of patients are on the drug 
 
   6   already, be it 1,000, be it 200, be it 10,000, would

   7   eventually have to be supplied with drug, and to my 
 
   8   knowledge, right now Acorda is the only company in a 
 
   9   position to do that. 
 
  10             So, I don't know that financially, this puts them 
 
  11   in any different position than they would be if they opened

  12   up a large open label treatment protocol. 
 
  13             MS. AXELRAD:  Dr. Feeney, could we grant emergency 
 
  14   or compassionate use INDs if the pharmacist who was 
 
  15   compounding the drug indicated the formulation and how they 
 
  16   were preparing it?  In other words, if the supply was coming

  17   from a compounding pharmacist as opposed to from Acorda, 
 
  18   could we do that? 
 
  19             DR. FEENEY:  I guess we would be able to do that.  
 
  20   That would be kind of a monumental task for our chemists to 
 
  21   review the individual data.  It might be worth talking to

  22   our chemists about that. 
 
  23             To give you an example of how the emergency IND 
 
  24   works, for diaminopyridine, Jacobus has been ‑‑ if the 
 
  25   patient needs diaminopyridine for Eaton‑Lambert, they 

                                                                 39 
 
   1   currently get an emergency IND through their treating

   2   physician with an LOA to Jacobus' chemistry. 
 
   3             MS. AXELRAD:  That is a letter of authorization. 
 
   4             DR. FEENEY:  And then Jacobus supplies the drug 
 
   5   free of charge.  I don't know if Acorda would be willing to 
 
   6   do that.

   7             DR. JUHL:  I am assuming that they wouldn't.  That 
 
   8   was kind of the situation that we had hoped would be 
 
   9   established, and the real question is can a patient who is 
 
  10   receiving a non‑Acorda compounded product from a pharmacy 
 
  11   avail themselves to the IND process on a one‑time emergency

  12   basis, and if your contention is that they would need a 
 
  13   chemist review, similar to the chemist reviews that the 
 
  14   agency is accustomed to seeing, all that obviously isn't 
 
  15   something that a compounding pharmacist would be able to 
 
  16   provide.

  17             DR. FEENEY:  Sure, and beyond that, it does create 
 
  18   a certain roadblock in terms of paperwork for the patient 
 
  19   and their physician.  So, you know it is not going to be 
 
  20   easy for them. 
 
  21             DR. JUHL:  So, we have an answer about the IND.

  22             MS. AXELRAD:  I wouldn't rule it out.  I mean I 
 
  23   think there are a lot of obstacles, I think, you know, we 
 
  24   would have to explore among ourselves exactly what the 
 
  25   paperwork would be.  We do emergency ‑‑ there are different 

                                                                 40 
 
   1   kinds of INDs we are talking about here, but we would have

   2   to see what would be involved in terms of chemistry. 
 
   3             It certainly isn't the kind of chemistry seen in 
 
   4   New Drug Application.  The chemistry submission for an IND 
 
   5   is pretty basic.  We would have to discuss how basic it 
 
   6   would be and what kind of paperwork would be involved for

   7   all the parties, whether the pharmacist, the physician, and 
 
   8   the patient, and then whether we would have the resources to 
 
   9   deal with something of that size, you know, where we are 
 
  10   going to get 1,000 or these. 
 
  11             We could look into that.

  12             DR. JUHL:  Let's defer further discussion on this, 
 
  13   and if it is possible to get some clarification sometime 
 
  14   during the day on that topic. 
 
  15             MS. AXELRAD:  We might be able to do that, but we 
 
  16   are going to be here, so it might be hard for us to get in

  17   contact with all the people that we need to, to get back to 
 
  18   you. 
 
  19             DR. JUHL:  Let's give it a try and then reconsider 
 
  20   this later on, if that is okay.  You don't mind 
 
  21   procrastinating?  Okay.  Thank you.

  22             Let us now move to the drugs withdrawn or removed 
 
  23   for reasons of safety or efficacy. 
 
  24             Captain Scott. 
 
  25            Withdrawn or Removed List of Drug Products 

                                                                 41 
 
   1             CPT SCOTT:  Good morning.  I will be talking with

   2   you about several proposed additions to the list of drug 
 
   3   products that have been withdrawn or removed from the market 
 
   4   for reasons of safety or effectiveness. 
 
   5             First, I would like to briefly review what has 
 
   6   been done up to this point with the withdrawn or removed

   7   drug product list and then I will present the five drug 
 
   8   products that we are proposing to add to the list. 
 
   9             [Slide. 
 
  10             As you know, one of the conditions of Section 503A 
 
  11   of the Act is that the licensed pharmacist or licensed

  12   physician may not "compound a drug product that appears on a 
 
  13   list published by the Secretary in the Federal Register of 
 
  14   drug products that have been withdrawn or removed from the 
 
  15   market because such drug products or components of such drug 
 
  16   products have been found to be unsafe or not effective."

  17             In October 1998, we presented to this committee 60 
 
  18   drug products, represented by 60 ingredient names, as 
 
  19   potential candidates for the Withdrawn or Removed Drug 
 
  20   Products list. 
 
  21             [Slide.

  22             We published a proposed rule on October 8, 1998, 
 
  23   which was 63 FR 54082, for this first list containing the 60 
 
  24   drug products.  The primary focus of the list was drug 
 
  25   products that have been withdrawn or removed from the market 

                                                                 42 
 
   1   for reasons of safety.

   2             Because of a comment received to the proposed 
 
   3   rule, the agency decided to postpone final action on 
 
   4   parenteral drug products containing neomycin sulfate because 
 
   5   of the pendency of various administrative actions concerning 
 
   6   that drug.  That brought us to 59 drug products.

   7             [Slide. 
 
   8             The final rule, published on March 8, 1999, and it 
 
   9   was in 64 FR 10944, and it contained 59 drug products that 
 
  10   may not be used for pharmacy compounding under the 
 
  11   exemptions in Section 503A of the Act.

  12             [Slide. 
 
  13             I would now like to briefly discuss five 
 
  14   additional drug products that we are proposing to include on 
 
  15   the Withdrawn or Removed Drug Products list. 
 
  16             The first two drug products are aminopyrine and

  17   astemizole.  On January 4, 2000, in 65 FR 256, we published 
 
  18   a proposed rule to include these two drug products on the 
 
  19   Withdrawn or Removed list. 
 
  20             The other three drug products, cisapride, 
 
  21   grepafloxacin, and troglitazone, were identified after we

  22   had prepared the proposed rule.  They will appear in a 
 
  23   future proposed rule proposing to add them to this list. 
 
  24             [Slide. 
 
  25             Aminopyrine, which is chemically related to 

                                                                 43 
 
   1   dipyrone, a drug product already on the list, was

   2   inadvertently overlooked during our first review and is now 
 
   3   being proposed for addition to the list, and we are 
 
   4   proposing to add it to the list, so that no drug products 
 
   5   may be compounded using aminopyrine. 
 
   6             [Slide.

   7             Drug products containing aminopyrine were used as 
 
   8   an analgesic and an antipyretic.  Aminopyrine caused 
 
   9   agranulocytosis, some cases of which were fatal.  In 1964, 
 
  10   we declared drug products containing aminopyrine to be new 
 
  11   drugs.

  12             We invited New Drug Applications, NDAs, for these 
 
  13   drug products, but only for use as an antipyretic in serious 
 
  14   situations where other safer drugs could not be used.  We 
 
  15   received no NDAs for the drug products containing 
 
  16   aminopyrine, and so those unapproved drug products were

  17   removed from the market by their manufacturers, and that was 
 
  18   42 FR 53954, October 4th of 1977. 
 
  19             [Slide. 
 
  20             The second drug product appearing in the January 
 
  21   proposed rule is astemizole, and we are also proposing that

  22   no drug products may be compounded using astemizole. 
 
  23             Astemizole tablets were marketed under the 
 
  24   proprietary name Hismanal and were indicated for the relief 
 
  25   of symptoms associated with seasonal allergic rhinitis and 

                                                                 44 
 
   1   chronic idiopathic urticaria.  We approved the NDA for

   2   astemizole tablets in December of 1988. 
 
   3             Within a few years of the approval, it was learned 
 
   4   that low‑level overdosages of astemizole were resulting in 
 
   5   life‑threatening heart arrhythmias.  Patients with liver 
 
   6   dysfunction or who were taking other drugs that interfered

   7   with the metabolism of astemizole were also found to be at 
 
   8   risk of serious cardiac adverse events while taking this 
 
   9   drug. 
 
  10             The manufacturer of astemizole tablets, the only 
 
  11   astemizole drug product on the market, removed the product

  12   from the market on June 18, 1999.  A notice was published in 
 
  13   the Federal Register on August 23, 1999, 64 FR 45973, 
 
  14   announcing FDA's determination that astemizole tablets were 
 
  15   withdrawn from the market for safety reasons. 
 
  16             [Slide.

  17             As I mentioned before, the following three drug 
 
  18   products that I will present are not in the current proposed 
 
  19   role.  This is because the proposed rule was prepared prior 
 
  20   to the removal from the market for safety reasons. 
 
  21             The first one is cisapride, and we are proposing

  22   that all products may not be compounded using cisapride. 
 
  23             Cisapride tablets and suspension are marketed 
 
  24   under the proprietary name Propulsid and are indicated for 
 
  25   severe nighttime heartburn experienced by adults with 

                                                                 45 
 
   1   gastroesophageal reflux disease not adequately responding to

   2   other therapies. 
 
   3             We approved the tablets on July 29, 1993, and the 
 
   4   suspension on September 15, 1995.  As of December 31, 1999, 
 
   5   use of cisapride had been associated with 341 reports of 
 
   6   heart rhythm abnormalities, including 80 reports of deaths.

   7             Most of these adverse events occurred in patients 
 
   8   who were taking other medications or suffering from 
 
   9   underlying conditions known to increase the risk of cardiac 
 
  10   arrhythmia associated with cisapride. 
 
  11             Because of the risk of serious cardiac

  12   arrhythmias, including ventricular tachycardia, ventricular 
 
  13   fibrillation, torsades de pointes, QT prolongation, and 
 
  14   death associated with use of cisapride in certain patients, 
 
  15   the manufacturer of cisapride, in consultation with the FDA, 
 
  16   has decided to discontinue marketing both cisapride tablets

  17   and suspension as of July 14, 2000, and make them available 
 
  18   only through an investigational limited access program. 
 
  19             Because cisapride will only be available through 
 
  20   treatment protocols under this limited access program, 
 
  21   institutional review board approval, completion of a Form

  22   1572, and signed informed consent will be required. 
 
  23             [Slide. 
 
  24             The next drug is grepafloxacin, and again all 
 
  25   products containing grepafloxacin we are proposing should 

                                                                 46 
 
   1   not be compounded.

   2             Grepafloxacin tablets were marketed under the 
 
   3   proprietary name Raxar.  Grepafloxacin is a fluoroquinolone 
 
   4   antibiotic indicated for the treatment of infections caused 
 
   5   by strains of bacteria susceptible to the drug, such as 
 
   6   community acquired pneumonia, chronic bronchitis, and

   7   various sexually transmitted diseases. 
 
   8             We approved grepafloxacin tablets on November 11, 
 
   9   1997, and Glaxo Wellcome, who marketed grepafloxacin under a 
 
  10   licensing agreement with Otsuka, voluntarily removed all 
 
  11   licensed formulations of grepafloxacin from the market on

  12   October 27, 1999, as a result of emerging safety concerns. 
 
  13             Glaxo Wellcome conducted an extensive review of 
 
  14   the safety of grepafloxacin and determined that due to an 
 
  15   effect of the drug on cardiac repolarization, manifested as 
 
  16   QT interval prolongation on the electrocardiogram, some

  17   patients may be at risk of a very rare but serious 
 
  18   ventricular arrhythmia known as torsades disease pointes. 
 
  19             Although torsades disease pointes had been 
 
  20   reported very rarely in patients taking grepafloxacin, it 
 
  21   was considered by the company that the therapeutic benefit

  22   of treatment with grepafloxacin may be outweighed by the 
 
  23   potential risk to patient safety, especially given the 
 
  24   availability of alternative treatments. 
 
  25             [Slide. 

                                                                 47 
 
   1             The last drug we will be discussing is

   2   troglitazone.  Again, all products containing troglitazone 
 
   3   are proposed not to be compounded. 
 
   4             Troglitazone tablets were marketed under the 
 
   5   proprietary name Rezulin.  Troglitazone was indicated for 
 
   6   the treatment of type 2 diabetes mellitus.  We approved the

   7   tablets on January 29, 1997. 
 
   8             Severe liver toxicity has been known to occur with 
 
   9   troglitazone since 1997, and the drug has been linked to 
 
  10   reports of confirmed liver failures and deaths. 
 
  11             On March 21, 2000, the manufacturer removed

  12   troglitazone tablets from the market due to a recent review 
 
  13   of safety data that had showed that troglitazone tablets 
 
  14   were more toxic to the liver than two similar drugs in its 
 
  15   class. 
 
  16             FDA felt that compared to similar alternative

  17   diabetes drugs, the continued use of troglitazone tablets 
 
  18   posed an unacceptable risk to patients. 
 
  19             [Slide. 
 
  20             In summary, we are proposing to update the 
 
  21   Withdrawn or Removed Drug Product list to add the five drug

  22   products discussed above.  We invite the Pharmacy 
 
  23   Compounding Advisory Committee to discuss these five 
 
  24   proposed drug products. 
 
  25             Specifically, we are seeking advice on whether 

                                                                 48 
 
   1   additional drug products should be added to the list and

   2   whether the drug products now being proposed should go on 
 
   3   the list. 
 
   4             Thank you. 
 
   5             DR. JUHL:  Thank you, Captain Scott. 
 
   6             Are there comments or questions from the

   7   committee? 
 
   8             DR. ALLEN:  So, the current discussion will be 
 
   9   primarily on all five or just the top two that action would 
 
  10   be taken on at this meeting?  I am not clear. 
 
  11             DR. JUHL:  I think the agency would be interested

  12   in hearing comments on any of the five.  I think in all 
 
  13   instances, these are drugs that have a clear record, they 
 
  14   have been withdrawn from the market, and in all instances, 
 
  15   there are alternatives with the possible exception of 
 
  16   cisapride, for which there is a limited use program that is

  17   in force. 
 
  18             Do I assume by the lack of comments that there is 
 
  19   general agreement with the proposal? 
 
  20             MR. WELDER:  I would just like to comment on the 
 
  21   cisapride.  How tough will it be to get cisapride on special

  22   needs? 
 
  23             CPT SCOTT:  I have invited Dr. Talarico, the 
 
  24   division director from Gastrointestinal and Anticoagulation 
 
  25   Drug Products to speak on any questions you may have about 

                                                                 49 
 
   1   that.

   2             DR. TALARICO:  There are three limited‑access 
 
   3   protocols available for cisapride.  One is in the pediatric 
 
   4   population for newborns with very severe reflux which 
 
   5   manifests with apnea, bradycardia and other serious 
 
   6   complications.

   7             The second is in adults with gastroparesis with 
 
   8   motility disorder.  This is use of cisapride in off‑label 
 
   9   use because the drug was approved initially only for 
 
  10   nocturnal heartburn.  But the therapeutic value of the drug 
 
  11   was perceived to me more in this additional indication than

  12   in the approved one. 
 
  13             And then the third protocol is for children with 
 
  14   failure to thrive because of reflux that would be beyond the 
 
  15   age of a few months of first group I mentioned. 
 
  16             There is a registration needed by the physician to

  17   enroll and they will have to provide evidence that they can 
 
  18   comply with all the requirements, which are quite stringent, 
 
  19   for these protocols. 
 
  20             The physicians will be screened, will be found to 
 
  21   be suitable to handle these patients.  There is a very

  22   extensive, very detailed informed consent for both the 
 
  23   physician and the patients, any legal representative for the 
 
  24   patient, and so forth. 
 
  25             The hospital IRB will have to be informed of these 

                                                                 50 
 
   1   programs going on.  So I would say they are limited‑access

   2   protocols to make sure that, first of all, the patients 
 
   3   enrolled is the patient who really needs the drug and that 
 
   4   the drug is used in the safest possible way. 
 
   5             These are the two aims of this program. 
 
   6             DR. JUHL:  So, it would be safe at least in the

   7   pediatric population to assume that the distribution would 
 
   8   in all likelihood be limited to specialists in children's 
 
   9   hospitals and other specialty tertiary care? 
 
  10             DR. TALARICO:  Yes, neonatal intensive care unit 
 
  11   mostly.  Some of them might continue the drug outside the

  12   step‑down units, but primarily in intensive care unit. 
 
  13             DR. JUHL:  And for the adult populations? 
 
  14             DR. TALARICO:  Adult population will be mostly 
 
  15   gastroenterologist specialty, board‑certified 
 
  16   gastroenterologists with knowledge of the disease, so that

  17   truly the patient selection is very, very stringent, very 
 
  18   appropriate, and that the drug is given appropriately. 
 
  19             The drug is influenced a lot in terms of safety by 
 
  20   concomitant factors like additional drugs that are 
 
  21   metabolized by the same pathways and by concomitant

  22   underlying condition.  It just so happened that many drugs 
 
  23   that interfere with the safety of cisapride are common 
 
  24   drugs, like antibiotics, for example, and many underlying 
 
  25   conditions are not grave diseases, are diseases that are 

                                                                 51 
 
   1   frequently found in patient population and older people.

   2             That is the reason why this drug is unsafe, 
 
   3   because many factors continue to be a problem. 
 
   4             MR. WELDER:  My concern, we have used cisapride, 
 
   5   and in pediatrics, my concern would be to get some of those 
 
   6   for those kids that need it, and from the comments made, it

   7   was most of the patients that have problems had many other 
 
   8   problems and also were taking other meds, and the kids that 
 
   9   we have used it for, that would not be a criteria, because 
 
  10   they weren't on other meds that I know of. 
 
  11             DR. TALARICO:  Yes, that limits quite a bit.  Of

  12   all the physicians or centers that have applied, the 
 
  13   requirements are so stringent that some have not pursued it, 
 
  14   and some have not found it to be suitable, so there is a big 
 
  15   selection in the process of all will be allowed to use 
 
  16   cisapride.

  17             DR. JUHL:  And this is in a patient‑by‑patient 
 
  18   selection. 
 
  19             DR. TALARICO:  Yes, patient‑by‑patient selection. 
 
  20             DR. JUHL:  And also I think it would be fair to 
 
  21   say that the scrutiny of the physician prescribing is quite

  22   heavy, too. 
 
  23             DR. TALARICO:  Oh, yes, indeed, yes. 
 
  24             DR. ALLEN:  As I read the materials that were 
 
  25   provided, Janssen is only going to make the product 

                                                                 52 
 
   1   available through mid‑August 2000.  What will occur after

   2   that point, will the patients' physicians not have it to 
 
   3   use? 
 
   4             DR. TALARICO:  I am sorry? 
 
   5             DR. ALLEN:  On the materials that were provided to 
 
   6   us, it states that Janssen will market the product until

   7   July 14, 2000, and the product will remain available through 
 
   8   pharmacies until approximately mid‑August 2000. 
 
   9             Does that mean that after ‑‑ 
 
  10             DR. TALARICO:  No, Janssen will cease distribution 
 
  11   on July 14, but today, they will continue to make it, the

  12   formulation, or they might have enough that they anticipate 
 
  13   a substantive period of time suitable for deciding how 
 
  14   valuable this drug, or if a new drug, say, might come on the 
 
  15   market. 
 
  16             DR. ALLEN:  Well, it states here ‑‑

  17             DR. JUHL:  Limited access will continue.  It's the 
 
  18   in‑pharmacy distribution ‑‑ 
 
  19             DR. ALLEN:  Well, this talks about the 
 
  20   investigational limited access program. 
 
  21             DR. TALARICO:  Right.

  22             DR. JUHL:  Oh, really. 
 
  23             DR. TALARICO:  The limited access program is just 
 
  24   initiated, and will continue we don't know until when, but 
 
  25   the distribution, the marketing of the drug will stop as of 

                                                                 53 
 
   1   tomorrow.

   2             DR. ALLEN:  Maybe they have two different things 
 
   3   in this one paragraph, and it was a little bit confusing, I 
 
   4   guess. 
 
   5             So, in essence, this means that physicians that 
 
   6   will prescribe this will either need to be board certified

   7   or eligible for board certification in specific areas, et 
 
   8   cetera. 
 
   9             DR. TALARICO:  Yes.  There will be many patients 
 
  10   who may indeed need the drug, and they may have some 
 
  11   contraindication, some very severe contraindication, and

  12   that is typical of patients that is still at this point 
 
  13   difficult to determine. 
 
  14             I am not sure whether there will be a 
 
  15   compassionate use additional distribution.  We haven't 
 
  16   looked into that yet, whether the responsibility will be

  17   strictly between patient and the physician. 
 
  18             DR. ALLEN:  I guess my concern would be a lot of 
 
  19   the individual patient's physicians that don't live close to 
 
  20   major medical centers, you know, to try to be involved in a 
 
  21   study like this, it's the death knell, you know, for that

  22   patient, they will not go through the necessary processes, 
 
  23   and with the hundreds of thousands of patients that have 
 
  24   been on cisapride successfully, you know, I would hope that 
 
  25   those patients could continue, the specific pediatric 

                                                                 54 
 
   1   patients would have access to the drug until something new

   2   came along. 
 
   3             DR. TALARICO:  The newborn population, it is 
 
   4   straightforward, because they will have to be in neonatal 
 
   5   intensive care unit.  The adult patient with gastroparesis 
 
   6   represents probably the biggest population where there might

   7   be limited access to research center, sophisticated 
 
   8   hospitals, et cetera, but then it will be on the physician 
 
   9   responsibility to document that the diagnosis has been done 
 
  10   appropriately. 
 
  11             In other words, even a known specialist can

  12   communicate with some specialists, they can have 
 
  13   consultations and make sure that the diagnosis has been made 
 
  14   accurately. 
 
  15             DR. JUHL:  Other questions or comments? 
 
  16             [No response.]

  17             DR. JUHL:  Then, if I could reassert, I am 
 
  18   assuming that lack of comments means agreement by the 
 
  19   committee that these drugs that have been withdrawn for 
 
  20   reasons of safety, we would recommend that they be added to 
 
  21   the list, that they not be available for pharmacy

  22   compounding. 
 
  23             DR. ALLEN:  Would that be the top two that have 
 
  24   been requested, that have already been withdrawn, thinking 
 
  25   the other three have not been withdrawn yet? 

                                                                 55 
 
   1             MS. AXELRAD:  They may never be withdrawn.  I mean

   2   most drugs, and many of the drugs that we considered before, 
 
   3   are never formally withdrawn.  They don't have to 
 
   4   necessarily withdraw the application.  As long as they are 
 
   5   withdrawn from the market for reasons of safety, we believe 
 
   6   that they ought to go on the list.

   7             DR. JUHL:  And I again was taking the group as a 
 
   8   group of five.  If anyone wants to consider them 
 
   9   individually, I would be happy to do that, too. 
 
  10             DR. ALLEN:  Could we consider them individually? 
 
  11             DR. JUHL:  We can indeed.

  12             First taking aminopyrine.  May I assume 
 
  13   concurrence with aminopyrine? 
 
  14             The shaking of heads, are we willing to do that?  
 
  15   The shaking of heads doesn't show up in the transcript is my 
 
  16   reason for ‑‑ we haven't been asked for a vote, but ‑‑

  17             MS. AXELRAD:  You should take a vote.  We should 
 
  18   have asked you to take a vote. 
 
  19             DR. JUHL:  You want to?  Okay. 
 
  20             MS. AXELRAD:  Why don't you just vote on each one, 
 
  21   and then we will have a clear record.

  22             DR. JUHL:  Let's do it formally then. 
 
  23             Those who are eligible to vote that concur with 
 
  24   aminopyrine being put on the Withdrawn for Reasons of Safety 
 
  25   and therefore not available for pharmacy compounding list, 

                                                                 56 
 
   1   please signify by raising your hand.

   2             [Show of hands.] 
 
   3             DR. JUHL:  Opposed? 
 
   4             [No response.] 
 
   5             DR. JUHL:  None were opposed.  It was unanimous. 
 
   6             Astemizole.  Comments?

   7             [No response. 
 
   8             DR. JUHL:  Same question.  Those who would 
 
   9   recommend that it be placed on the withdrawn list, and not 
 
  10   available for pharmacy compounding, please raise your hands. 
 
  11             [Show of hands.]

  12             DR. JUHL:  Opposed? 
 
  13             [No response.] 
 
  14             DR. JUHL:  Again, it's unanimous. 
 
  15             Cisapride.  Additional comments? 
 
  16             MR. RUSHO:  In our hospital, the withdrawal of

  17   cisapride has not made any impact at all.  Physicians have 
 
  18   been able to go to proton pump inhibitors and other things, 
 
  19   and the loss of cisapride has not been significant. 
 
  20             DR. JUHL:  Other comments? 
 
  21             [No response.]

  22             DR. JUHL:  If not, the same question.  Those who 
 
  23   would recommend that cisapride be placed on the withdrawn 
 
  24   and therefore not available for pharmacy compounding list, 
 
  25   please signify by raising your hand. 

                                                                 57 
 
   1             [Show of hands.]

   2             DR. JUHL:  Opposed? 
 
   3             [One hand raised.] 
 
   4             DR. JUHL:  One opposed.  And how many voting?  
 
   5   Nine in favor of the recommendation, 1 opposed ‑‑ excuse me 
 
   6   ‑‑ 8 in favor, 1 opposed.

   7             Grepafloxacin.  Comments? 
 
   8             [No response.] 
 
   9             DR. JUHL:  All those who would recommend to the 
 
  10   agency that grepafloxacin be placed on the withdrawn list 
 
  11   and therefore not available for pharmacy compounding, please

  12   signify by raising your hand. 
 
  13             [Show of hands.] 
 
  14             DR. JUHL:  Opposed? 
 
  15             [No response.] 
 
  16             DR. JUHL:  It's unanimous.

  17             Troglitazone.  Comments?  Discussion? 
 
  18             [No response.] 
 
  19             DR. JUHL:  All those who would recommend that 
 
  20   troglitazone be placed on the withdrawn and therefore not 
 
  21   available for pharmacy compounding list, please signify by

  22   raising your hand. 
 
  23             [Show of hands.] 
 
  24             DR. JUHL:  Any opposed? 
 
  25             [No response.] 

                                                                 58 
 
   1             DR. JUHL:  None opposed.  It also is unanimous.

   2             Additional comments on the Withdrawn for Safety 
 
   3   list? 
 
   4             [No response.] 
 
   5             DR. JUHL:  If not, we are five minutes early.  We 
 
   6   will take a 15‑minute break and reconvene at 10:10.

   7             [Recess.] 
 
   8             DR. JUHL:  We will reconvene.  Our next topic is 
 
   9   the Demonstrably Difficult to Compound.  Section 127 of 
 
  10   FDAMA instructed the agency to prepare a list of drug 
 
  11   products that had demonstrable difficulties in compounding.

  12             This is the first introduction that we, as a 
 
  13   committee, have had to the white paper on this topic, and to 
 
  14   get us started is Dr. Kathleen Anderson. 
 
  15                Demonstrably Difficult to Compound 
 
  16               Introduction:  Factors and Approach

  17             DR. ANDERSON:  Good morning. 
 
  18             [Slide. 
 
  19             I will be providing an overview of the approach 
 
  20   FDA is proposing to use in developing the Difficult to 
 
  21   Compound list.  This afternoon, our CDER experts will

  22   present the scientific rationales based on our preliminary 
 
  23   findings for including certain products on this list.  They 
 
  24   will also be available to answer any technical questions. 
 
  25             [Slide. 

                                                                 59 
 
   1             Section 503A(b)(3)(a) of the Federal Food, Drug,

   2   and Cosmetic Act states that "a drug product may be 
 
   3   compounded under Subsection (a) only if such drug product is 
 
   4   not identified by the Secretary by regulation as a drug 
 
   5   product that presents demonstrable difficulties for 
 
   6   compounding that reasonably demonstrate an adverse effect on

   7   the safety or effectiveness of that drug product." 
 
   8             To do this we convened an internal agency work 
 
   9   group and worked with experts from CDER.  It was decided 
 
  10   that the best approach to develop this list would be to 
 
  11   identify criteria or factors that we could use to evaluate

  12   products for inclusion on the list. 
 
  13             [Slide. 
 
  14             In developing these factors, we considered 
 
  15   attributes that could affect a product's safety and 
 
  16   efficacy, namely a product's potency, purity, and quality. 

  17   We then identified factors that we could use to help us 
 
  18   evaluate the effect of compounding on a product's potency, 
 
  19   purity, and quality. 
 
  20             [Slide. 
 
  21             The first factor is the drug delivery system.  Is

  22   a sophisticated drug delivery system required to ensure 
 
  23   dosing accuracy and/or reproducibility? 
 
  24             [Slide. 
 
  25             Another factor was drug formulation and 

                                                                 60 
 
   1   consistency.  Is the sophisticated formulation of the drug

   2   product required to ensure dosing accuracy and/or 
 
   3   reproducibility? 
 
   4             Because of the sophisticated formulation, is 
 
   5   product‑to‑product uniformity of the drug product often 
 
   6   difficult to achieve?

   7             Is the safety or efficacy of the product a concern 
 
   8   if there is product‑to‑product variability? 
 
   9             [Slide. 
 
  10             The third factor is bioavailability.  Is it 
 
  11   difficult to achieve and maintain a uniformly bioavailable

  12   dosage form? 
 
  13             Is the safety or efficacy of the product a concern 
 
  14   if the bioavailability varies? 
 
  15             [Slide. 
 
  16             Complexity of Compounding.  Is the compounding of

  17   the drug product complex? 
 
  18             Are there multiple, complicated or interrelated 
 
  19   steps? 
 
  20             Is there a significant potential for error in one 
 
  21   or more of the steps that could affect drug safety or

  22   effectiveness? 
 
  23             [Slide. 
 
  24             Facilities and Equipment.  Are sophisticated 
 
  25   facilities and/or equipment required to ensure proper 

                                                                 61 
 
   1   compounding of the drug product?

   2             Is there a significant potential for error in the 
 
   3   use of the facilities or equipment that could affect the 
 
   4   drug safety or effectiveness? 
 
   5             [Slide. 
 
   6             Training.  Is specialized, highly technical

   7   training essential to ensure proper compounding of the drug 
 
   8   product? 
 
   9             [Slide. 
 
  10             Testing and Quality Assurance.  Is sophisticated, 
 
  11   difficult to perform testing of the compounded drug product

  12   required to ensure potency, purity, performance 
 
  13   characteristics, or other important characteristics prior to 
 
  14   dispensing? 
 
  15             Is there a significant potential for harm if the 
 
  16   product is compounded without proper quality assurance

  17   procedures and end‑product testing? 
 
  18             [Slide. 
 
  19             We propose to evaluate products in light of each 
 
  20   of these factors in developing the list of Difficult to 
 
  21   Compound Drugs.  Each factor would be balanced on a

  22   case‑by‑case basis in deciding whether a product would be an 
 
  23   appropriate candidate for inclusion in the list. 
 
  24             We seek input from this committee on any 
 
  25   additional factors that should be used in evaluating 

                                                                 62 
 
   1   products for the list.  We specifically request comment on

   2   whether to consider as a factor the difficulty or importance 
 
   3   of achieving stability for a drug product on this list. 
 
   4             We would like the advice of the committee on the 
 
   5   use of these factors.  Are they appropriate? 
 
   6             [Slide.

   7             After we developed the factors, we then began a 
 
   8   preliminary evaluation for inclusion on the list, focusing 
 
   9   on products with evidence in the literature and potential to 
 
  10   affect the public health. 
 
  11             [Slide.

  12             In this preliminary evaluation, we found that some 
 
  13   products with similar characteristics raise similar concerns 
 
  14   for pharmacy compounding.  For example, all drug products 
 
  15   contain uncertain dosage forms, such as metered dose 
 
  16   inhalers, if compounded, could present the same difficulties

  17   in assuring the safety or effectiveness of that product. 
 
  18             We have also tentatively determined that the 
 
  19   compounding of all dry powder inhalers and transdermal drug 
 
  20   delivery systems are difficult to compound.  Therefore, we 
 
  21   are tentatively proposing to include both specific drug

  22   products and categories of drug products grouped by relevant 
 
  23   factors, such as metered dose inhalers, on the list of 
 
  24   Difficult to Compound Drugs. 
 
  25             [Slide. 

                                                                 63 
 
   1             We also found in this preliminary evaluation that

   2   some products could raise concern for pharmacy compounding 
 
   3   if minimum standards are not met.  For example, we recognize 
 
   4   that the compounding of sterile products is a complicated 
 
   5   issue. 
 
   6             As described in our concept paper, the preparation

   7   of sterile products is unavoidably complex.  We believe that 
 
   8   the concerns associated with the compounding of sterile 
 
   9   products may be alleviated by the use of minimum standards. 
 
  10             We evaluated a variety of existing guidelines for 
 
  11   pharmacy‑prepared sterile products and have tentatively

  12   concluded that USP Chapter 1206 describes comprehensive 
 
  13   controls that, if followed, would ensure the quality of 
 
  14   sterile drug products. 
 
  15             Therefore, we are tentatively proposing to include 
 
  16   drug products that are demonstrably difficult to compound

  17   unless certain minimum standards are met, and we are 
 
  18   tentatively proposing that sterile drug products, compounded 
 
  19   under procedures other than those described in USP Chapter 
 
  20   1206, would be considered demonstrably difficult to 
 
  21   compound.

  22             [Slide. 
 
  23             Our concept paper describes in detail our 
 
  24   preliminary findings.  We seek input from this committee on 
 
  25   our proposed approach and whether it is appropriate to 

                                                                 64 
 
   1   include the following products on the Difficult to Compound

   2   list:  metered dose inhalers, dry powder inhalers, 
 
   3   transdermal delivery systems, and sterile products 
 
   4   compounded under procedures other than those described in 
 
   5   Chapter 1206 of the USP. 
 
   6             [Slide.

   7             This afternoon our CDER experts will be presenting 
 
   8   the scientific rationales for tentatively including each of 
 
   9   these products on the Difficult to Compound list.  Dr. Brian 
 
  10   Rogers from the Office of New Drug Chemistry will discuss 
 
  11   metered dose inhalers and dry powder inhalers.

  12             Dr. Vinod Shah and Dr. Amit Mitra, from the Office 
 
  13   of Pharmaceutical Sciences, will discuss transdermal drug 
 
  14   delivery systems.  Dr. Peter Cooney, also from the Office of 
 
  15   New Drug Chemistry, will discuss sterile drug products. 
 
  16             [Slide.

  17             We view this process as an ongoing project and 
 
  18   intend to continually identify and evaluate additional 
 
  19   products, as well as categories of drug products for 
 
  20   inclusion on this list. 
 
  21             We seek input from this committee for products for

  22   evaluation as candidates for the list. 
 
  23             Thank you. 
 
  24                       Committee Discussion 
 
  25             DR. JUHL:  I would like now to have the committee 

                                                                 65 
 
   1   engage in a discussion of the criteria that have been

   2   presented by Dr. Anderson, and your view of the suitability 
 
   3   of those criteria in making determinations of both the 
 
   4   products and product categories that are before us at this 
 
   5   meeting and may come before us at other meetings. 
 
   6             Who would like to start?  Larry.

   7             MR. TRISSEL:  First, I would like to say that I do 
 
   8   think that a good effort has been made to put together some 
 
   9   valid points for consideration here, so anything I have to 
 
  10   say that is not positive should be taken in that light. 
 
  11             I have a couple of concerns with regard to the

  12   criteria, not many.  The complexity of compounding issue may 
 
  13   be one of interpretation.  It is hard to envision something 
 
  14   more complex than a multi‑component parenteral nutrition 
 
  15   admixture, but it must be compounded, there is no way to 
 
  16   deliver this in any other way.  So, that issue should be

  17   viewed in the light of having to delivery complex mixtures 
 
  18   when there is no alternative. 
 
  19             The other thing that you had specifically asked 
 
  20   for was about stability, something that is, as I pointed 
 
  21   out, near and dear to my heart.  The stability issue clearly

  22   is one related, not to categories, but to specific 
 
  23   molecules. 
 
  24             I would note that the agency has approved over the 
 
  25   years any number of commercial drugs for sale that have 

                                                                 66 
 
   1   really remarkably short stabilities.  The one that comes to

   2   mind right now is a melphalan injection with a 60‑minute 
 
   3   stability from time of compounding.  We don't like that by 
 
   4   any stretch of the imagination, but we do work within that 
 
   5   to deliver this drug to patients. 
 
   6             It is hard to envision trying to give something

   7   with a lower stability than 60 minutes, but we did have one, 
 
   8   an investigational drug that had 30 minutes, and even at 30 
 
   9   minutes it was 15 percent decomposition.  That was imidazole 
 
  10   carboxamide some years ago. 
 
  11             Fortunately, for those stability purists, this is

  12   not a drug that had much therapeutic value, but melphalan 
 
  13   does, and is approved for sale in this country with a 
 
  14   60‑minute stability.  I am not sure how you would use 
 
  15   stability in light of that other than to make professional 
 
  16   recommendations of use within some time frame.

  17             I think I will stop there because you are just 
 
  18   asking at this point about the criteria. 
 
  19             DR. JUHL:  Loyd. 
 
  20             DR. ALLEN:  I have a couple of things.  
 
  21   Incidently, this is a very good presentation as far as the

  22   components of it. 
 
  23             On drug delivery system, is a sophisticated 
 
  24   delivery system required, I think probably the intent was to 
 
  25   include a delivery system, active drug product component 

                                                                 67 
 
   1   together, however, the way it currently reads is any

   2   sophisticated drug deliver system, for example, I.V. 
 
   3   ambulatory pumps are very complex, programmable systems that 
 
   4   pharmacists have to work with, intrathecal pumps are very 
 
   5   sophisticated.  We could even look at iontophoresis and 
 
   6   phonophoresis as being sophisticated delivery systems even

   7   though they are not necessarily a part of a system that I 
 
   8   think may have been envisioned by the metered dose inhalers 
 
   9   and the DPIs, the dry power inhalers. 
 
  10             So, I think the terminology of sophisticated drug 
 
  11   delivery systems needs to be considered and narrowed down.

  12             Like Larry, sophisticated formulation, you have 
 
  13   got TPNs, you know, that are very sophisticated, so again 
 
  14   the use of that term might be one that needs to be modified. 
 
  15             A little concern related to bioavailability, and I 
 
  16   think the intent here was reasonable bioavailability, but

  17   Larry brought up an example of a very short stability item, 
 
  18   and I will bring up an example of a very low 
 
  19   bioavailability, FDA‑approved product fosamax with a 
 
  20   bioavailability of less than 1 percent. 
 
  21             If you look at some of the variances in

  22   bioavailability, you know, you are looking at 30, 40 percent 
 
  23   variation among the products, you know, at least it is 
 
  24   listed in the PDR. 
 
  25             So, I am not sure exactly how that will be 

                                                                 68 
 
   1   applied, if it is measurable, because with compounded

   2   products, we don't generally measure bioavailability.  I 
 
   3   understand what the concept and the intent was, but it does 
 
   4   need to be looked at. 
 
   5             As far as testing and quality assurance, I guess 
 
   6   we will get into this more in detail tomorrow on sterile

   7   products.  There are some tests which, for example, 
 
   8   sterility, which may take seven days, and so if you got a 
 
   9   product that the patient and the physician is waiting on, in 
 
  10   fact, may only be stable for 24 hours, then, we can't wait 
 
  11   for a stability, but I guess we will take that up tomorrow.

  12             So, that would be all at this point. 
 
  13             DR. JUHL:  Other general comments? 
 
  14             MR. RUSHO:  Just a couple comments.  First of all, 
 
  15   those of us in the hospital are already under JCAHO 
 
  16   regulations.  We have ASHP regulations, and ABP is already

  17   in here, and now we have FDA regulations. 
 
  18             All of these have a slightly different twist, you 
 
  19   know, and it would be nice if they were consistent.  For 
 
  20   example, certification of laminar flow hoods.  One agency 
 
  21   will say once a year, other agencies will say twice a year.

  22             The other general comment or a question on this 
 
  23   one is who is going to enforce this. 
 
  24             DR. JUHL:  I think that does bring a good 
 
  25   question, although I think JCAHO, the ASHP isn't 

                                                                 69 
 
   1   regulations, it is suggestions and guidelines.  What we are

   2   talking about here, though, is going to be having the effect 
 
   3   of law on pharmacists. 
 
   4             MR. RUSHO:  Well, ASHP does if you have a 
 
   5   residency, which we do. 
 
   6             DR. JUHL:  And the question of enforcement, I

   7   guess it falls back to the State Board of Pharmacy to 
 
   8   enforce, and they would be responsive, not only to their 
 
   9   regular inspections, but to complaints that are filed, as we 
 
  10   have now. 
 
  11             Larry.

  12             MR. TRISSEL:  We are just now beginning the 
 
  13   process of preparing for our next JCAHO inspection, and one 
 
  14   of the criteria that we are looking at, that they have set 
 
  15   out for us, is compliance with the FDA rules on compounded 
 
  16   formulations, so JCAHO may be doing some enforcement on

  17   this, as well. 
 
  18             DR. JUHL:  You are going to have to be quite a 
 
  19   sage to comply with those before they are written. 
 
  20             MR. TRISSEL:  Well, I did point that out, but do 
 
  21   the best you can.

  22             DR. JUHL:  Other general comments? 
 
  23             MR. TRISSEL:  I am sorry, one more.  Loyd brought 
 
  24   up about bioavailability, and I had forgotten to mention the 
 
  25   real problematic ones are the ones that are erratic, not 

                                                                 70 
 
   1   that are low.  We can deal with it when they are consistent,

   2   it is when they are erratic that is a problem, but even 
 
   3   then, we have an example of an commercial product with 
 
   4   extremely high variability that was approved by the agency 
 
   5   in THC capsules. 
 
   6             Clearly, an inhaled dosage form might be a more

   7   consistent delivery system, but for other reasons, this 
 
   8   drug, this more erratically bioavailable product has been 
 
   9   approved, and we have lived with that. 
 
  10             DR. JUHL:  Fortunately, no one suggested that be 
 
  11   added to the bulks list as yet, so ‑‑ although I wouldn't

  12   rule it out. 
 
  13             I have a couple of general comments.  One, I would 
 
  14   like to echo Larry's statement that I can tell there has 
 
  15   been a lot of work that has gone into this document, and 
 
  16   some of the things that you probably fought back and forth

  17   on with yourselves. 
 
  18             These things are difficult to understand when you 
 
  19   don't have examples, and it is much easier in that context, 
 
  20   and it is also, as has been pointed out, difficult to deal 
 
  21   with when we are not talking about drugs ‑‑ I don't mean

  22   drug products ‑‑ I mean a drug compound. 
 
  23             There is much variability in a lot of things that 
 
  24   don't really have a significant effect on safety and 
 
  25   efficacy, and with some drugs it has a tremendous impact, so 

                                                                 71 
 
   1   that has a difference, too.

   2             We will see when we talk about the general 
 
   3   categories a difference in the way that they are dealt with.  
 
   4   In the case of sterile products, what the white paper 
 
   5   suggests is that sterile products should not be done unless 
 
   6   certain guidelines are followed.  With the other categories

   7   of products, the recommendation is that they shouldn't be 
 
   8   done, period. 
 
   9             Now, it is much easier to deal with the former 
 
  10   than the latter, but the profession has developed guidelines 
 
  11   that allows the agency to feel comfortable in making that

  12   kind of a recommendation with sterile products, whereas, 
 
  13   guidelines and standards haven't been developed for the 
 
  14   compounding of inhaled dosage forms for transdermals, and so 
 
  15   on.  So, I think that difference will become apparent as we 
 
  16   go through the discussions.

  17             I found that Nos. 2 through 4 are kind of hard to 
 
  18   differentiate, again examples of specific drugs will make it 
 
  19   easier, and as also has been pointed out, the definition of 
 
  20   sophisticated and specialized and complex is kind of in the 
 
  21   eye of the beholder, but it is inherent to each of the

  22   definitions. 
 
  23             For example, are sophisticated facilities of 
 
  24   equipment required?  Well, someone who is a compounding 
 
  25   pharmacist would say yes, but I have those sophisticated 

                                                                 72 
 
   1   facilities and equipment.  They would be sophisticated

   2   probably by virtue of their cost. 
 
   3             Is technical training essential?  Well, being in 
 
   4   that business, a pharmacy degree is a technical and highly 
 
   5   specialized training.  So, I think we will have a set of 
 
   6   guidelines that could be applied in most any direction. 

   7   There is great flexibility in that, but there also is not 
 
   8   much predictability in that without having gone through, I 
 
   9   guess, and developed what amounts to case law in the 
 
  10   treatment of various examples. 
 
  11             One final comment.  The testing and quality

  12   assurance, most every compounded product would have a 
 
  13   shortcoming in this area almost by definition.  There is 
 
  14   very little in the way of testing and quality assurance on 
 
  15   the product, as the FDA understands, it for other products 
 
  16   that occurs with compounded products.

  17             Are there other general comments that this group 
 
  18   would like to make?  We are going to have to live with these 
 
  19   guidelines for some difficult discussions, so now is the 
 
  20   time to speak up if there are specific changes or 
 
  21   suggestions you could make to the agency.

  22             MR. RUSHO:  Tomorrow, aren't we going to discuss 
 
  23   the sterile product guidelines specifically? 
 
  24             DR. JUHL:  We will. 
 
  25             MR. RUSHO:  Okay.  I will reserve comments until 

                                                                 73 
 
   1   then.

   2             DR. JUHL:  Okay. 
 
   3             DR. ALLEN:  I have one question.  According to the 
 
   4   FDAMA '97, there are two professions that can be involved in 
 
   5   compounding.  One would be pharmacists, the other would be 
 
   6   the physicians.  So, am I correct in understanding that

   7   physicians would also fall under everything that we discuss 
 
   8   in the next two days? 
 
   9             DR. JUHL:  My hope and my assumption is that is 
 
  10   true. 
 
  11             MS. AXELRAD:  Yes.

  12             DR. JUHL:  I see a nodding concurrence from the 
 
  13   agency. 
 
  14             MR. TRISSEL:  That is a point I was going to raise 
 
  15   tomorrow, but since it comes up now, I am aware of at least 
 
  16   one large chain of oncology centers that uses nurses to do

  17   all of their compounding, so are you telling me that they 
 
  18   don't have to comply with these rules because they are 
 
  19   nurses? 
 
  20             I think that would be a poor precedent to set.  If 
 
  21   I was the president of a company using pharmacists and could

  22   get out of doing anything for quality assurance by hiring 
 
  23   nurses, I might be inclined to do so.  I am not sure that is 
 
  24   the right thing to do. 
 
  25             MS. AXELRAD:  We are going to be addressing the 

                                                                 74 
 
   1   issue of who can compound in our general regulations, but we

   2   also know that pharmacy technicians also do a lot of the 
 
   3   compounding under the direction and supervision of a 
 
   4   pharmacist, and so we will be addressing how it would work 
 
   5   in terms of nurses or others that would be compounding under 
 
   6   the supervision of a physician.  That is something we will

   7   handle in our general compounding regulations. 
 
   8             DR. JUHL:  And will there be a relatively specific 
 
   9   definition of, "under the supervision"? 
 
  10             MS. AXELRAD:  Well, we hope there will be enough 
 
  11   of a definition to allow for what is actually happening out

  12   there, as long as there is somebody who is qualified, who is 
 
  13   responsible for actually happens. 
 
  14             Also, it will probably be, in part, it will be a 
 
  15   matter of state law.  You know, different states allow 
 
  16   different people to do different types of activities.  So,

  17   we will have to have a definition that is broad enough to 
 
  18   encompass differences between the states in terms of what 
 
  19   they allow. 
 
  20             It will be put out for comment, and there will be 
 
  21   an opportunity for comment on it, so if we draw it too

  22   narrowly in the first instance, and we get comments on it, 
 
  23   we can adjust it. 
 
  24             DR. JUHL:  Do you have an idea of when that might 
 
  25   be available? 

                                                                 75 
 
   1             MS. AXELRAD:  We are hoping by the end of this

   2   year. 
 
   3             DR. JUHL:  Okay.  Garnet. 
 
   4             DR. PECK:  So, that would handle, then, No. 6, 
 
   5   which involves training of individuals to do this particular 
 
   6   compounding, and it is recognized that highly technical, it

   7   could also ‑‑ the words "well trained," and I am assuming 
 
   8   that that will take care of that. 
 
   9             DR. JUHL:  I think we are talking about two 
 
  10   different things here.  In one instance, she is talking 
 
  11   about the general regulations for who may compound, and here

  12   we are talking about drugs that fall under the Difficult to 
 
  13   Compound rubric, and training is one of the components we 
 
  14   are considering. 
 
  15             DR. PECK:  What I heard had to do with who will 
 
  16   direct the compounding and the like, and that does have an

  17   element of training to it. 
 
  18             DR. JUHL:  It certainly does, but it is not No. 6. 
 
  19             DR. PECK:  I realize it's not No. 6, but it also 
 
  20   is covering training. 
 
  21             MS. AXELRAD:  Well, I think we are going to cover

  22   in the definitions, the general discussion of who is allowed 
 
  23   to compound and the relationship between their people and 
 
  24   people that they supervise.  I don't think we have any 
 
  25   particular plans at the moment to put out any detailed 

                                                                 76 
 
   1   criteria, and certainly not in the regulations, on what kind

   2   of training would be appropriate. 
 
   3             I think that the use of this factor here is 
 
   4   designed to say for certain kinds of things, there are some 
 
   5   very specialized training that the pharmacists or physicians 
 
   6   or nurses, or whoever might be doing it, might not be likely

   7   to have, and if there is a dosage form or a type of drug or 
 
   8   a particular drug for which that kind of training that is 
 
   9   not the norm in pharmacy compounding as required, then, that 
 
  10   would be one thing that we would consider in determining 
 
  11   whether that particular drug or category of drug should go

  12   on the list of products that are difficult to compound. 
 
  13             DR. JUHL:  Other comments?  I think in our 
 
  14   questions to be answered ‑ Do you agree that the following 
 
  15   are the appropriate factors to use in evaluating drug 
 
  16   products or categories of drug products to determine if they

  17   should be included on the difficult to compound list?  If 
 
  18   not, what additional factors would you suggest we use in the 
 
  19   evaluation?  Do you think that the difficulty or importance 
 
  20   of achieving stability should be considered as a factor? 
 
  21             There are several questions there.  Let me take

  22   the first one and have a formal discussion and conclusion on 
 
  23   it. 
 
  24             Do we agree that the following are appropriate 
 
  25   factors to be used in evaluating the products as to whether 

                                                                 77 
 
   1   or not they should be on the difficult to compound list?

   2             Is there further discussion on that before calling 
 
   3   the question? 
 
   4             I think it is one of your handouts, Pharmacy 
 
   5   Compounding Advisory Committee questions, and the factors to 
 
   6   which I refer are those which were made in Dr. Anderson's

   7   presentation and in the white paper in your preliminary 
 
   8   information. 
 
   9             Is everyone ready? 
 
  10             Do we agree?  All those that agree, would you 
 
  11   please signify by raising your hand?

  12             Do you agree that the following are the 
 
  13   appropriate factors to use in evaluating drug products or 
 
  14   categories of drug products to determine if they should be 
 
  15   included on the difficult to compound list? 
 
  16             MR. TRISSEL:  All of them in this category?

  17             DR. JUHL:  Or we can take them individually 
 
  18   depending upon the wishes of the committee.  I am calling 
 
  19   all right now. 
 
  20             All those that agree, would you please signify by 
 
  21   raising your hand?

  22             [Show of hands.] 
 
  23             DR. JUHL:  Opposed? 
 
  24             [No response.] 
 
  25             DR. JUHL:  It's unanimous. 

                                                                 78 
 
   1             Are there additional or different factors that we

   2   would suggest that would be used in the evaluation?  This is 
 
   3   multiple choice. 
 
   4             MR. TRISSEL:  I think, not additional, but 
 
   5   different in the sense of providing some explanation for 
 
   6   some of the more nebulous terminology would be very helpful. 

   7   What is sophisticated?  Give some examples.  What is 
 
   8   complex?  Is it more complex than the TPN, and in what way, 
 
   9   that sort of thing, would be very helpful for guidance for 
 
  10   everyone on what you are thinking. 
 
  11             DR. JUHL:  Yes, my assumption is that our

  12   recommendation to the agency would be taken in the context 
 
  13   of our previous discussion and suggestions. 
 
  14             Sarah. 
 
  15             DR. SELLERS:  At our first meeting, we described 
 
  16   compounded drugs as representing maybe 1 or 2 percent of the

  17   total amount of drugs that are dispensed, but for certain 
 
  18   drug products, the amount that are compounded from bulk 
 
  19   active substances may be a lot higher, and the sheer volume 
 
  20   of the amounts of certain drug products that may be 
 
  21   compounded from bulk active materials may suggest that we

  22   need to consider that because if we are compounding much 
 
  23   more amounts, we are going to increase risk. 
 
  24             I am thinking specifically of nebulized 
 
  25   medications and potentially intrathecal type of medications. 

                                                                 79 
 
   1             DR. JUHL:  There is in the criteria neither a

   2   mention of risk of the product nor of benefit.  As has been 
 
   3   suggested, TPN, the only we can do that is to compound, so 
 
   4   it would seem that some consideration of risk and benefit 
 
   5   would need to be considered, as well. 
 
   6             Other additional factors that you would like to

   7   see the agency consider and for us to use in considering? 
 
   8             MS. LaFOLLETTE:  I believe stability, even though 
 
   9   we have mentioned it, that the compatibility and interaction 
 
  10   with the packaging component and with the formulation 
 
  11   definitely needs to be discussed.

  12             DR. JUHL:  That is the next question. 
 
  13             MS. LaFOLLETTE:  Okay. 
 
  14             DR. JUHL:  Good.  Moving on to that ‑ Do you think 
 
  15   that the difficulty or importance of achieving stability 
 
  16   should be considered as a factor?

  17             Other comments on that? 
 
  18             MR. TRISSEL:  I am not sure how you can do that 
 
  19   other than on a case‑by‑case basis, and as I have said, 
 
  20   other than pointing out what the demonstrated stability 
 
  21   criteria are, particularly ‑‑ we do have guidance from the

  22   USP on this for compounded products by category, and I 
 
  23   suppose the idea is if you want to exceed those maxima that 
 
  24   are in the USP, you need some documentation of that, but we 
 
  25   do have criteria already established for this, that we are 

                                                                 80 
 
   1   supposed to be following for all compounded formulations.

   2             So, I am not sure what the agency is proposing 
 
   3   with regard to stability, something different than the USP 
 
   4   has already said? 
 
   5             MS. AXELRAD:  Well, we are not proposing it.  We 
 
   6   were asking the committee, it was something that came up in

   7   our discussions.  In fact, it could be taken into account in 
 
   8   the second factor on drug formulation and consistency.  You 
 
   9   know, we decided it didn't deserve a special mention at 
 
  10   least at this time, but we really did have a lot of debate 
 
  11   about it, so we wanted to hear what the committee had to say

  12   with regard to that. 
 
  13             DR. JUHL:  Loyd. 
 
  14             DR. ALLEN:  Yes, it is addressed in Chapter 795, 
 
  15   pharmacy compounding practices in detail, and there will 
 
  16   probably be more additional work done on that in the future,

  17   but basically, there is a general guideline, but those can 
 
  18   be modified by any published valid data, you know, that has 
 
  19   been published in the literature or whatever documentation 
 
  20   the pharmacist might have. 
 
  21             DR. ANDERSON:  I think the intention, I think it

  22   was more if there are specific products, that maybe there 
 
  23   would be a problem with stability, that maybe we should be 
 
  24   considering for certain things.  There may be things out 
 
  25   there that maybe it would be a factor that we should 

                                                                 81 
 
   1   consider.

   2             DR. JUHL:  Do you have some examples that would be 
 
   3   helpful? 
 
   4             DR. ANDERSON:  I think Dr. Trissel had mentioned 
 
   5   one earlier, but we haven't looked at any of those, we 
 
   6   haven't considered this yet, it is just something that the

   7   work we have had, have debated about, and I think we needed 
 
   8   more guidance on it, and that is why we brought it to the 
 
   9   committee. 
 
  10             DR. JUHL:  Well, it is certainly a factor that any 
 
  11   pharmacist would take into consideration when making

  12   anything, but the question is I guess would we use it in our 
 
  13   considerations of difficult to compound, and I think the 
 
  14   answer is yes. 
 
  15             DR. ANDERSON:  Some drugs maybe, there is the 
 
  16   polymorphic, which could relate back to the formulation.  It

  17   may fit better under the formulation. 
 
  18             MS. LaFOLLETTE:  My concern was more with the type 
 
  19   of delivery systems that we are talking about today, the 
 
  20   metered dose inhalers and transdermals.  You could be having 
 
  21   interaction with material components, and that isn't going

  22   to be obvious to everyone, and it may not be in the 
 
  23   literature if a unique formulation is being used, it hasn't 
 
  24   been demonstrated before, and these things do occur, I can 
 
  25   attest to that by experience. 

                                                                 82 
 
   1             DR. JUHL:  Garnet.

   2             DR. PECK:  This is a general statement about 
 
   3   stability, but we are going to be talking about specific 
 
   4   types of delivery system, and there you can cite specific 
 
   5   examples, metered dose inhalers, for example, and the 
 
   6   stability of the particulates that are inside a system that

   7   has particulates or insolubles, so you can cite those as 
 
   8   specifics, and that is nice, and also you can cite it 
 
   9   specifically in sterile products. 
 
  10             So, as a general category, maybe you cannot come 
 
  11   up with examples.  It is just something that we all live

  12   with, and that is stability.  I guess that was the reason 
 
  13   for asking the question. 
 
  14             MS. AXELRAD:  In some cases, I think, establishing 
 
  15   stability and making sure that it is there in a particular 
 
  16   product is more difficult than in other places, and those

  17   are the cases where we would focus in terms of whether 
 
  18   somebody ought to be compounding them when they don't have a 
 
  19   regular stability program or some way of making sure that 
 
  20   the product is stable when it is made and stays stable for 
 
  21   its use.

  22             Again, I think that fits fine under Factor 2, 
 
  23   under Drug Formulation and Consistency, and could be 
 
  24   incorporated in those cases where, for example, in metered 
 
  25   dose inhalers, there is that type of an issue. 

                                                                 83 
 
   1             DR. JUHL:  Other comments on stability?  Any last

   2   comments on the criteria before we move forward? 
 
   3             [No response.] 
 
   4             DR. JUHL:  Hearing none, then, let's proceed to a 
 
   5   discussion of metered dose inhalers and dry powder inhalers.  
 
   6   Dr. Brian Rogers.

   7             MS. AXELRAD:  Dr. Juhl, it might be helpful to 
 
   8   actually have a vote, so that we have in the record a vote 
 
   9   on the stability issue, like does the committee want to or 
 
  10   does not want to include as a factor, stability 
 
  11   specifically.

  12             DR. JUHL:  Let me propose that we not have a 
 
  13   specific factor on stability, but include that in the 
 
  14   various places of the existing criteria where it would 
 
  15   normally be considered, such as drug formulation and 
 
  16   consistency, Category No. 2.

  17             MR. TRISSEL:  Possibly 1, too. 
 
  18             DR. JUHL:  Possibly 1, drug delivery system.  
 
  19   Other possibilities? 
 
  20             Let me make that as a proposal and then is there 
 
  21   further discussion before we vote on that?

  22             [No response.] 
 
  23             DR. JUHL:  Seeing none, let's call the question 
 
  24   then.  The recommendation to the agency that they not have a 
 
  25   specific stability criteria, but include that in the other 

                                                                 84 
 
   1   criteria where it is appropriate.

   2             Those that would favor that recommendation, please 
 
   3   raise your hands. 
 
   4             [Show of hands.] 
 
   5             DR. JUHL:  Opposed? 
 
   6             [No response.]

   7             DR. JUHL:  I see that as unanimous. 
 
   8             MR. WELDER:  On the basic question that we took a 
 
   9   vote on a while ago, I have a little bit of concern.  Are we 
 
  10   going to discuss each one of these categories individually 
 
  11   at some time, because we took a general vote on approving

  12   from the drug delivery systems all the way to the testing 
 
  13   and quality assurance, because there are a lot of questions 
 
  14   in between there on a lot of these things like who defines 
 
  15   whether a compound is complex or not, how do we determine 
 
  16   that, are we going to discuss that in this meeting?

  17             DR. JUHL:  We can discuss that further if you 
 
  18   would like. 
 
  19             MR. WELDER:  Does no one else have a question on 
 
  20   who defines these things?  When I have a pharmacy that does 
 
  21   compounding, who determines whether the drug product is

  22   complex? 
 
  23             DR. JUHL:  I think the use of these guidelines is 
 
  24   to determine whether or not products or categories of 
 
  25   products get placed on the Difficult to Compound list.  So, 

                                                                 85 
 
   1   that judgment would need to be made by the agency and by

   2   this committee.  Individual pharmacies wouldn't need to make 
 
   3   the judgments because we are making the judgment on the 
 
   4   categories. 
 
   5             MR. WELDER:  So, these individual items won't be 
 
   6   up for discussion at this meeting then.

   7             DR. JUHL:  They can be. 
 
   8             MR. WELDER:  The vote that we took approves all 
 
   9   these things, and I kind of had a half a hand up because 
 
  10   there are so many questions. 
 
  11             DR. JUHL:  Let's go ahead.  I want you to have the

  12   opportunity to make suggestions for clarification changes or 
 
  13   anything that would you feel more comfortable. 
 
  14             MR. WELDER:  One of my questions would be what is 
 
  15   a sophisticated facility and/or equipment required to ensure 
 
  16   proper compounding of the drug product.  I can speak for my

  17   pharmacy in that we have everything that we need for a 
 
  18   particular product.  We don't do compounding ‑‑ we don't do 
 
  19   all compounds, but what we do compound, we have the proper 
 
  20   equipment and facility. 
 
  21             My question is, are the rules going to be

  22   developed for everyone, and does every compounding pharmacy 
 
  23   have ‑‑ will they be required to have every piece of 
 
  24   equipment if it fits in a category by the FDA?  The category 
 
  25   itself bothers me a little bit, in categories of drugs. 

                                                                 86 
 
   1             MS. AXELRAD:  I think that others have pointed out

   2   the issue of sophistication of the facility being not as 
 
   3   clear and asked for examples of that.  I think that when we 
 
   4   got through the particular categories that we are going to 
 
   5   talk about today, you will see some examples of where we 
 
   6   think sophisticated equipment or facilities are necessary.

   7             Certainly not all pharmacies would be required to 
 
   8   have it, but I think for certain categories of products 
 
   9   where you have to have very specialized equipment that is 
 
  10   not likely to be something that your average pharmacy would 
 
  11   have, but more likely something that a manufacturer would

  12   have, then, those are the types of things that we think 
 
  13   should go on the list as difficult to compound. 
 
  14             DR. JUHL:  This is where we get into the problem 
 
  15   of the two approaches that are being taken, one for sterile 
 
  16   products, there is sophisticated equipment, there is

  17   sophisticated training, there is sophisticated this, that, 
 
  18   and the other thing, but if you have them, you can do them. 
 
  19             With the metered dose inhalers, even if you have 
 
  20   the equipment, we are saying you can't do it.  I think that 
 
  21   is the issue that raises its head on this.

  22             DR. ANDERSON:  We are trying to use these to help 
 
  23   us evaluate the products.  We are not trying to say that 
 
  24   every pharmacy has to have these, but again, you said it 
 
  25   depends on the approach, but it is something for us to use 

                                                                 87 
 
   1   to look at these different drugs to say are they difficult

   2   or not. 
 
   3             DR. JUHL:  Larry. 
 
   4             MR. TRISSEL:  I hadn't actually thought of what 
 
   5   Tony was saying.  Are you thinking like State Boards require 
 
   6   every pharmacy to have a sink and a balance, and those are

   7   mandatory, and you are concerned that somebody will make 
 
   8   every single piece of compounding equipment mandatory in 
 
   9   every single pharmacy, something like that, because I didn't 
 
  10   read it that way. 
 
  11             I thought if you were going to compound a

  12   particular product, you needed suitable facilities and 
 
  13   equipment for that product.  That is the way I understood 
 
  14   it.  If that is not the intention, we should know that now. 
 
  15             DR. ANDERSON:  Yes, right. 
 
  16             MR. WELDER:  Well, that was my intent of the

  17   question, because every serious compounding pharmacist would 
 
  18   have those things available, and the definition of what is 
 
  19   complex still bothers me, a little better categories of 
 
  20   drugs that would be put in difficult to compound. 
 
  21             For instance, in Item 4, Complexity of

  22   Compounding, is the compounding of the drug product complex, 
 
  23   are there multiple, complicated or interrelates steps?  
 
  24   Well, sure there is a lot of things that we compound that 
 
  25   have many steps, they are multiple, and they could be 

                                                                 88 
 
   1   complicated, but who defines ‑‑ I mean they are easy steps,

   2   you take them one at a time, it is like reading a recipe in 
 
   3   a lot of case ‑‑ so who defines, are these drugs going to be 
 
   4   on a list because there are multiple steps?  I am concerned 
 
   5   about that. 
 
   6             DR. ANDERSON:  I don't think that it is one,

   7   everything is going to be a case‑by‑case basis, and I don't 
 
   8   think that one single factor would make a product on the 
 
   9   list.  There are things that we are trying to use to 
 
  10   evaluate the products, to consider, to look at these 
 
  11   products, and look at each product.

  12             MR. TRISSEL:  Tony, I don't read these as 
 
  13   pass/fail kinds of things.  They are just topics for 
 
  14   consideration.  Is that what the agency intends? 
 
  15             DR. ANDERSON:  Right. 
 
  16             MR. TRISSEL:  These are just things that normal

  17   people would consider. 
 
  18             DR. ANDERSON:  Right, and we just need input 
 
  19   whether we are going in the right direction, whether these 
 
  20   are the things that we should be looking at, when we are 
 
  21   looking at different drug products.

  22             MR. WELDER:  Okay. 
 
  23             DR. ANDERSON:  I don't think any single factor 
 
  24   would be overriding or any one would be dispositive.  It's 
 
  25   an overall thing to help us how would we approach this list, 

                                                                 89 
 
   1   how are we going to make this list.

   2             MR. WELDER:  Okay.  I was just a little bit 
 
   3   uncomfortable with the vote and including all of these 
 
   4   things without any questions being asked, and so they are 
 
   5   not just blanket okay on it.  Okay. 
 
   6             DR. JUHL:  If anyone wants, after we go through

   7   these categories of drug products, to go back and look at 
 
   8   the criteria and say, well, you know, after our discussion, 
 
   9   this one didn't seem to work or we need to add one more, so 
 
  10   I will reserve our opportunity to do that at the end of our 
 
  11   discussions if we want to.  I want everybody to feel

  12   comfortable with this when we get done with it, because it 
 
  13   is going to be used along down the line. 
 
  14             Sarah. 
 
  15             DR. SELLERS:  Do we cover under these points, the 
 
  16   route of delivery?

  17             MS. AXELRAD:  You mean the route of 
 
  18   administration? 
 
  19             DR. SELLERS:  I am thinking risk of applying a 
 
  20   drug directly to the lungs that may be contaminated 
 
  21   certainly is a concern, likely injecting pyrogens into the

  22   intrathecal space is a big concern.  It appears to me that 
 
  23   the route of delivery may be a consideration when you are 
 
  24   compounding. 
 
  25             DR. ANDERSON:  It could fall under several, but I 

                                                                 90 
 
   1   don't think there is a specific one, but it is something

   2   that we could look at. 
 
   3             DR. JUHL:  I think that would actually be 
 
   4   important in the overall risk to benefit considerations. 
 
   5             Any other comments. 
 
   6             [No response.]

   7             DR. JUHL:  Let me move on then to the metered dose 
 
   8   inhalers and dry powder inhalers, Dr. Brian Rogers. 
 
   9          Metered Dose Inhalers and Dry Powder Inhalers 
 
  10             DR. ROGERS:  Good morning. 
 
  11             [Slide.

  12             I am going to be talking about the difficulties 
 
  13   associated with compounding metered dose inhalers and dry 
 
  14   powder inhalers.  I will summarize the characteristics of 
 
  15   these drug products, which not only have potentially complex 
 
  16   and environmentally sensitive formulations, but are required

  17   to be contained in complex drug delivery devices. 
 
  18             These devices require tight controls with 
 
  19   difficult‑to‑perform tests to assure reproducible and 
 
  20   accurate drug delivery to the patient.  In these two drug 
 
  21   products, reproducibility of the drug delivery to the

  22   patient means both accurate delivery of both the mass of the 
 
  23   active expelled from the device, but accurate and 
 
  24   reproducible deposition at the correct site in the lungs, 
 
  25   and this is controlled by control of the particle size 

                                                                 91 
 
   1   distribution.

   2             [Slide. 
 
   3             Metered dose inhalers are a pressurized system 
 
   4   containing a liquified gas, the propellant.  The propellant 
 
   5   suspends the micronized drug substance and provides energy 
 
   6   to both propel and disperse the drug substance in metered

   7   doses. 
 
   8             Generally, surfactants are used to stabilize the 
 
   9   suspension formulation.  Co‑solvents may be present to aid 
 
  10   in formulating.  MDIs may dispense from a few micrograms to 
 
  11   milligrams of a drug substance per actuation, and the volume

  12   of formulation delivered by the valve in an MDI is typically 
 
  13   25 to 100 microliters. 
 
  14             [Slide. 
 
  15             Once the specified quantity of formulation is 
 
  16   expelled from the valve, the liquified gas vaporizes, both

  17   propelling and dispersing the suspended or dissolved drug 
 
  18   substance along with any non‑volatile excipients. 
 
  19             The dispersed drug substance in a discrete 
 
  20   actuation contains a range of particle sizes characterized 
 
  21   by the size distribution.  Also, the distribution of the

  22   drug substance mass per minimum dose is characterized by 
 
  23   dose content uniformity. 
 
  24             [Slide. 
 
  25             Dry powder inhalers contain a micronized drug 

                                                                 92 
 
   1   substance with or without a carrier, with lactose being the

   2   most commonly used carrier. 
 
   3             Energy for dispersion of particles is supplied by 
 
   4   either patient inspiration, compressed gas, or some form of 
 
   5   motor‑driven device.  Current designs in include pre‑metered 
 
   6   and device‑metered DPIs.

   7             [Slide. 
 
   8             This slide shows the various designs of DPIs 
 
   9   currently available.  The devices may have its formulation 
 
  10   dispersed by the patient's energy of inhalation or by some 
 
  11   form of internal power source, as I just described.

  12             These two types may be further subdivided by 
 
  13   whether a device has an internal metering process or has the 
 
  14   dose pre‑metered as in a blister or a capsule.  The 
 
  15   pre‑metered type of DPI can either have the dose removed 
 
  16   directly from its container or the dose can be transferred

  17   to a holding cavity for later inhalation. 
 
  18             The device‑metered DPI generally has the dose 
 
  19   transferred to a holding chamber. 
 
  20             The pre‑metered type of device may contain either 
 
  21   single or multiple doses, and the device‑metered DPI is

  22   exclusively multiple dose in character. 
 
  23             [Slide. 
 
  24             In addition to dose measurement and particle size 
 
  25   issues, further complex and subtle interactions may occur 

                                                                 93 
 
   1   between the drug substance carriers and components of the

   2   container closure system. 
 
   3             These may include gravitational, fluid dynamic, 
 
   4   and other interactive forces, such as electrostatic, Van der 
 
   5   Waals, and capillary forces.  Together, these forces are 
 
   6   responsible for the differences in fluidization behaviors

   7   exhibits by different powders within an inhaler. 
 
   8             It is critical to have a precisely reproducible 
 
   9   formulation to obtain device‑to‑device and batch‑to‑batch 
 
  10   reproducibility. 
 
  11             [Slide.

  12             General Concepts.  The aerodynamic particle size 
 
  13   of the inhaled particles containing the drug substance 
 
  14   affects the point of deposition in the airways.  Normally, 
 
  15   the smaller the particles, the greater the penetration into 
 
  16   the lungs.

  17             Patients need to inhale drug substance particles 
 
  18   generally particles generally less than 5 micrometers in 
 
  19   diameter to be effective in treating diseases of the 
 
  20   airways.  The range of effective particle sizes is narrow 
 
  21   with larger particles only contributing to systemic exposure

  22   and contribute no clinical benefit. 
 
  23             Unlike other conventional drug products, these are 
 
  24   highly dependent on the particle size distribution for their 
 
  25   safety and effectiveness.  Concepts of classical 

                                                                 94 
 
   1   bioequivalence and bioavailability are usually not

   2   applicable. 
 
   3             Bioavailability is difficult to determine since 
 
   4   the dose is too small for blood analysis.  Its concentration 
 
   5   ends up being in the parts per billion range in general.  
 
   6   Bioequivalence studies are hindered by having 85 to 90

   7   percent of the dose absorbed through the GI tract instead of 
 
   8   the biological target. 
 
   9             [Slide. 
 
  10             Dosing and performance and thus safety and 
 
  11   efficacy are directly dependent on design reproducibility

  12   and performance characteristics of the container and closure 
 
  13   system.  The most important dosing and performance 
 
  14   characteristics are particle size distribution and dose 
 
  15   content uniformity. 
 
  16             Both the metering valve and any canister lining

  17   must be compatible with the formulation.  A canister lining 
 
  18   should be proven to not have pinholes.  Pinholes or porosity 
 
  19   in the lining will allow corrosion of the canister metal by 
 
  20   reaction of the underlying metal with components of the 
 
  21   formulation.

  22             There is also a definite potential for absorption 
 
  23   of the drug into plastic components.  Absorption may also 
 
  24   cause swelling of elastomers.  Extraction of plastic and 
 
  25   elastomeric component by the formulation may result in 

                                                                 95 
 
   1   leaching of carcinogens or compounds that patients are

   2   sensitive to. 
 
   3             [Slide. 
 
   4             Here are a couple of versions of actuators.  This 
 
   5   first example is an actuator designed to be used with an 
 
   6   integral spacer.  The second drawing here shows the same

   7   actuator with the first part of the spacer shown, and the 
 
   8   spacer extends in this direction for a little distance. 
 
   9             The other example of an actuator on the right is a 
 
  10   standard actuator, such as used in standard MDIs.  Above the 
 
  11   actuator is a canister with a valve stem shown here and the 

  12   ferrule here, and this is the canister proper. 
 
  13             The canister fits within the actuator down in here 
 
  14   with the valve stem seeding in this insert here, and that 
 
  15   forms a seal, and when the canister is actuated by pushing 
 
  16   down with finger pressure on the top, the valve stem is

  17   compressed and the plume is expelled from the valve stem 
 
  18   down into this area here and out through the orifice in this 
 
  19   direction, so that the plume is expelled approximately 90 
 
  20   degrees from the angle of the valve stem. 
 
  21             In this device, the canister sits at a slight

  22   angle and again the plume exits more or less perpendicularly 
 
  23   to the valve stem. 
 
  24             [Slide. 
 
  25             Here is a diagram of a typical MDI valve in a 

                                                                 96 
 
   1   relaxed or a pre‑actuation configuration.  As you can see,

   2   the valve is very complex with many of the components 
 
   3   interacting with and depending on one another.  Any changes 
 
   4   to a valve will likely cause changes in the performance 
 
   5   characteristics.  The parts of the valve are labeled there, 
 
   6   and I won't go into them.

   7             In the rest position, as shown here, the metering 
 
   8   chamber is full, that is this area here, and in contact with 
 
   9   the bulk formulation, which fills this outside area here, 
 
  10   the canister inserting in this area and basically forming 
 
  11   this kind of shape here, and a good portion of the canister

  12   not occupied by the valve is formulation. 
 
  13             Once the canister is depressed to actuate the 
 
  14   device, the stem is pushed upward by the finger pressure and 
 
  15   as soon as this happens, the metering chamber is closed off 
 
  16   from the bulk formulation in the canister, and then a little

  17   further pressure and distance moved of the valve stem allows 
 
  18   this little hole here to actually come into the metering 
 
  19   chamber, and then the metering chamber becomes exposed to 
 
  20   the atmosphere and the pressurized contents of the metering 
 
  21   chamber is expelled through the valve stem under great

  22   pressure. 
 
  23             [Slide. 
 
  24             The function of the actuator is to generate 
 
  25   aerosol particles, direct the dose, influence the velocity 

                                                                 97 
 
   1   of the aerosol, control the amount of medication delivered,

   2   and the particle size distribution available to the patient. 
 
   3             The valve precisely measures the formulation 
 
   4   volume and provides a leak‑proof seal to prevent changes in 
 
   5   the formulation concentration. 
 
   6             [Slide.

   7             Here is a diagram of a typical dry powder inhaler.  
 
   8   The one shown here is only average in complexity relative to 
 
   9   others, and this DPI is considered a pre‑metered multi‑dose 
 
  10   unit.  It has the formulation inserted into individual 
 
  11   blisters on a strip coiled around a wheel here in the bottom

  12   of the device, as it is shown here. 
 
  13             When the dose is desired, the patient causes a 
 
  14   ratcheting of the device, so that a new blister is moved 
 
  15   into position here, and just prior to the moving into the 
 
  16   position, the backing strip off of these blisters is removed

  17   by this wheel, and the formulation is exposed to the air 
 
  18   intake that the patient will pull air through. 
 
  19             Once the dose is removed by inspiration, the used 
 
  20   portion of the blister, the used half of the blister will be 
 
  21   coiled on this wheel.

  22             [Slide. 
 
  23             In conclusion, the MDI and DPI drug delivery 
 
  24   systems are sophisticated and complex.  Precise formulating 
 
  25   is crucial to drug dosing accuracy and reproducibility from 

                                                                 98 
 
   1   the standpoint of both dose uniformity and particle size

   2   distribution.  Container enclosure components directly 
 
   3   affect potency, purity, and quality of the drug product, 
 
   4   hence, safety and efficacy of the product. 
 
   5             [Slide. 
 
   6             In the interest of time, I have chosen to focus on

   7   the complexity of compounding MDIs, however, the issues are 
 
   8   equally applicable to DPIs with some obvious exceptions 
 
   9   which pertain to liquid formulations, and I think those will 
 
  10   be obvious to you. 
 
  11             The formulation in an MDI is a mixture of

  12   micronized or solubilized drug substance in a matrix of oily 
 
  13   excipient material, propellant, and possibly a co‑solvent. 
 
  14             The composition and physical chemical properties 
 
  15   of each component is crucial to performance.  Also, the 
 
  16   composition has a direct effect on the extent of

  17   agglomeration and suspension stability. 
 
  18             [Slide. 
 
  19             Important drug substance properties which must be 
 
  20   controlled during compounding include the particle size 
 
  21   distribution, particle morphology, solvates and hydrates,

  22   clathrates, morphic forms, the amorphic character, the 
 
  23   solubility profile, the moisture content and/or residual 
 
  24   solvent content, microbial quality, pH profile, and specific 
 
  25   rotation. 

                                                                 99 
 
   1             [Slide.

   2             Important aspects of the formulation liquid phase 
 
   3   include propellant identity, the presence of a co‑solvent, 
 
   4   surfactant identity, concentration, and quality.  Relative 
 
   5   proportion of the volatile components influence the internal 
 
   6   canister pressure.

   7             Important physical/chemical properties of the 
 
   8   formulation include polarity, surface tension, and density.  
 
   9   These all affect the suspension characteristics of the 
 
  10   two‑phase formulation. 
 
  11             [Slide.

  12             Factors adversely affecting the formulation's 
 
  13   physical stability include preferential interaction of the 
 
  14   suspended drug substance with container components, settling 
 
  15   and creaming resulting from differential densities between 
 
  16   the liquid phase of the formulation and the drug substance.

  17             The above factors result in a less homogeneous 
 
  18   suspension and thus greater inconsistency in the dose 
 
  19   delivery and particle size distribution. 
 
  20             These inconsistencies are seen in the beginning to 
 
  21   end of canister variability, canister‑to‑canister

  22   variability, and batch‑to‑batch variability. 
 
  23             Properties of the liquid phase need to be 
 
  24   carefully optimized and controlled to minimize the above 
 
  25   problems. 

                                                                100 
 
   1             [Slide.

   2             The individual formulation components require very 
 
   3   careful control of impurities and degradation products.  
 
   4   Minor changes in concentration or dose of an excipient can 
 
   5   be result in large changes in toxicological properties. 
 
   6             Very careful control of impurities and degradation

   7   products in all formulation components is required to 
 
   8   prevent possible bronchospasm in lungs of sensitive 
 
   9   individuals. 
 
  10             As a result of the Montreal protocol, CFC 
 
  11   propellants are becoming very difficult to obtain an

  12   acceptable purity.  Tight controls on purity are needed to 
 
  13   be implemented to assure drug product quality. 
 
  14             As a result, the composition of the formulation 
 
  15   and complexity of this dosage form make it very difficult to 
 
  16   formulate outside of a dedicated manufacturing environment. 

  17   Minimizing product‑to‑product variability, that is, 
 
  18   obtaining the best possible dosing accuracy is necessary for 
 
  19   obtaining safety and efficacy. 
 
  20             [Slide. 
 
  21             Compounding of MDIs and DPIs require multiple,

  22   complicated and interrelated steps.  In each of these, there 
 
  23   is a significant potential for error.  The formulation must 
 
  24   be carefully handled, mixed, dispensed, and so on. 
 
  25             The container and closure system design and 

                                                                101 
 
   1   performance characteristics are critical and require careful

   2   assembly.  Temperature control at well‑controlled 
 
   3   sub‑freezing temperatures may be necessary at certain stages 
 
   4   of compounding. 
 
   5             At all times during compounding, environmental 
 
   6   conditions, such as temperature, humidity, and so on, must

   7   be carefully monitored and controlled.  Manufacturing 
 
   8   parameters, such as the assay of the concentrate, pressure 
 
   9   filling, in‑line heating, and aging, et cetera, add 
 
  10   considerable complexity to the compounding process. 
 
  11             It is important to remember that even the simplest

  12   type of DPI requires complex formulation development to 
 
  13   ensure accurate and reproducible dose delivery. 
 
  14             [Slide. 
 
  15             Errors in compounding have a high potential to 
 
  16   adversely affect safety and effectiveness.

  17             All of the factors I have mentioned in the 
 
  18   previous slide need to be carefully controlled to ensure 
 
  19   dosing reproducibility, performance, stability, and 
 
  20   bioavailability where the concept of dosing reproducibility 
 
  21   applies equally to the dose content uniformity and the

  22   particle size distribution. 
 
  23             [Slide. 
 
  24             The complex formulation and container closure 
 
  25   system require extensive manufacturing controls.  Stringent 

                                                                102 
 
   1   environmental controls are required for air cleanliness,

   2   humidity, and temperature. 
 
   3             Temporary exposure to high temperatures or 
 
   4   humidity can disrupt the particle size distribution.  In 
 
   5   some cases, exposure to high temperature has resulted in 
 
   6   recalls of commercial products.

   7             Some sophisticated equipment required for assembly 
 
   8   include crimpers, pressure fillers, a propellant pump, and 
 
   9   precision product filler. 
 
  10             [Slide. 
 
  11             Special formulation requirements and attributes of

  12   the container closure system necessitates specialized 
 
  13   technical training for both production and quality 
 
  14   assurance.  Lack of proper training in manufacturing 
 
  15   requirements may affect all aspects of product performance.  
 
  16   Inadequate training in quality assurance will prevent

  17   detection of compounding errors. 
 
  18             [Slide. 
 
  19             Examples of complex tests which are necessary to 
 
  20   ensure product quality include:  particle size distribution, 
 
  21   moisture content, leak rate, leachables, and microbial

  22   limits. 
 
  23             [Slide. 
 
  24             The control of particle size distribution is more 
 
  25   critical for MDI and DPIs than most other conventional 

                                                                103 
 
   1   dosage forms, and not solely determined by the size of the

   2   drug substance particles initially suspended in the 
 
   3   formulation. 
 
   4             Changes in the particle size may lead to a 
 
   5   decrease in efficacy and an increase in systemic exposure.  
 
   6   It is critically dependent on formulation, valve, and the

   7   mouthpiece, and the inability to meet particle size 
 
   8   distribution specifications has resulted in product recalls. 
 
   9             [Slide. 
 
  10             The control of moisture content is most critical 
 
  11   for MDI suspension formulations and for DPIs.  Strict limits

  12   are needed to prevent changes in, for example, particle size 
 
  13   distribution, morphic form, crystal growth, and aggregation. 
 
  14             The leak rate is required control because canister 
 
  15   pressure directly influences the performance of the actuator 
 
  16   and valve, and thus, the delivery of the proper dose to the

  17   patient.  Leakage of the propellant may be great enough to 
 
  18   influence the composition of the formulation and change the 
 
  19   particle size distribution and/or the dose content 
 
  20   uniformity. 
 
  21             Failure to meet leak rate specifications have

  22   resulted in recalls of commercial drug products. 
 
  23             [Slide. 
 
  24             Leachables result when the liquid formulation 
 
  25   extracts compounds from either elastomeric or plastic 

                                                                104 
 
   1   components.  Identification and quantitation of potential

   2   leachables are necessary. 
 
   3             A concentration profile of leachables in the 
 
   4   formulation must be established for each drug product to 
 
   5   prevent undisclosed changes in the container closure 
 
   6   components.

   7             [Slide. 
 
   8             The testing of microbial content includes testing 
 
   9   for total aerobic count, total yeast and mold count, and 
 
  10   assured freedom from pathogens. 
 
  11             Additional testing is necessary to ensure the

  12   formulation does not support the growth of microorganisms, 
 
  13   and the microbial quality is maintained throughout the 
 
  14   expiration dating period. 
 
  15             [Slide. 
 
  16             Because of the above complex and necessary

  17   criteria for compounding, MDI and DPI drug products clearly 
 
  18   present demonstrable difficulties in this endeavor. 
 
  19             These difficulties would likely have an adverse 
 
  20   effect on the safety and effectiveness of such drug 
 
  21   products.

  22             [Slide. 
 
  23             Difficulties in compounding result from the 
 
  24   following characteristics and requirements:  MDIs and DPIs 
 
  25   are sophisticated drug delivery systems that require 

                                                                105 
 
   1   extensive development to ensure dosing accuracy and

   2   reproducibility. 
 
   3             Precise dosing must be achieved by accurate and 
 
   4   reproducible delivery of both the mass and the particle size 
 
   5   distribution of the active.  A sophisticated formulation of 
 
   6   the drug product is required to ensure dosing accuracy and

   7   reproducibility.  Product‑to‑product uniformity is critical 
 
   8   for dosing accuracy and is usually difficult to achieve. 
 
   9             Reproducible bioavailability of the compounded 
 
  10   drug product is difficult to achieve.  Compounding of MDI 
 
  11   and DPI products is very complex.  Sophisticated facilities

  12   and equipment are required to ensure the proper compounding 
 
  13   of the drug product. 
 
  14             Specialized technical training is essential to 
 
  15   ensure proper compounding, and sophisticated and 
 
  16   difficult‑to‑perform testing is required to ensure potency

  17   and purity. 
 
  18             Thank you. 
 
  19             DR. JUHL:  Thank you, Dr. Rogers. 
 
  20             Are there questions for Dr. Rogers?  Elizabeth. 
 
  21                       Committee Discussion

  22             DR. McBURNEY:  Dr. Rogers, thank you for that 
 
  23   presentation.  I would like you to help me understand a 
 
  24   little bit better about the delivery system. 
 
  25             To my way of thinking, there are actually two 

                                                                106 
 
   1   components here.  One is the compounding of the medication

   2   that is going to be delivered, and the second is the 
 
   3   mechanical device that is going to be used to deliver that 
 
   4   compounded medication. 
 
   5             When the pharmacy is carrying it out, the device 
 
   6   that is used, those are not assembled by the pharmacist,

   7   those are the ones that all pre‑packaged and used, are they 
 
   8   not? 
 
   9             DR. ROGERS:  Basically, pharmacists do not 
 
  10   assemble or produce these devices.  They don't obtain a 
 
  11   formulation and don't create the drug product from pieces. 

  12   In every case, these drug products are assembled and 
 
  13   manufactured, and the formulation created in very secure 
 
  14   manufacturing environments that are unavailable to all but 
 
  15   very few drug companies. 
 
  16             It is very difficult even for a good drug company

  17   to make these devices with good and reproducible particle 
 
  18   size distribution and dose content uniformity.  So, that the 
 
  19   concept of a pharmacist doing this is hard to understand. 
 
  20             DR. McBURNEY:  Is there not now ‑‑ and I would 
 
  21   turn to the pharmacists on our committee ‑‑ is there not now

  22   compounding pharmacists that are doing this presently? 
 
  23             MR. WELDER:  Not that I know of. 
 
  24             DR. McBURNEY:  Not at all, even with the dry 
 
  25   powder? 

                                                                107 
 
   1             MR. WELDER:  Not that I know of.

   2             DR. ROGERS:  Even the simplest dry powder inhalers 
 
   3   would require measurement and controls of the device and 
 
   4   what was put in the device beyond that available. 
 
   5             MR. RUSHO:  As far as the dry powder inhalers, 
 
   6   there is another delivery system ‑‑ and I am blanking on the

   7   name of it ‑‑ for delivering of albuterol where the capsule 
 
   8   is partially filled with albuterol and lactose, and you put 
 
   9   it in the device and break the capsule, and it falls down on 
 
  10   a screen.  The patient tips her head back, and they can 
 
  11   inhale that.

  12             I have had one request prior to budesonide and 
 
  13   fluticasone propionate being available to make one using 
 
  14   triamcinolone.  The problems that you just mentioned, 
 
  15   particle size distribution and everything else, were things 
 
  16   that I looked at, and I finally threw up my hands and said

  17   this is not possible. 
 
  18             But I think if the agency is considering this, we 
 
  19   need to put that type of dosage form in there, because I can 
 
  20   see that as being able to be compounded much more easily 
 
  21   than the devices you have shown us today.

  22             DR. ROGERS:  Well, the device that you are talking 
 
  23   about would strictly fall under the category of dry powder 
 
  24   inhalers, single dose devices, so it would be covered. 
 
  25             MS. AXELRAD:  I would just like to clarify 

                                                                108 
 
   1   something that I think addresses Dr. McBurney's question.

   2             The product that we are talking about here are 
 
   3   combinations of drugs and devices, and they are regulated as 
 
   4   drugs in the Center for Drug Evaluation and Research.  New 
 
   5   Drug Applications are submitted for these, and I think that 
 
   6   there is ‑‑ as you saw from Dr. Rogers' presentation, there

   7   is an incredibly close interaction between the drug itself 
 
   8   and the device in order to make sure that the dose that is 
 
   9   delivered is the appropriate dose, and we do regulate them 
 
  10   as drugs, so if there is any question about that, you know, 
 
  11   that is why we are concerned about this, because we want to

  12   make sure that somebody doesn't think, oh, this is a simple 
 
  13   thing, we can just take a drug and stick in a pre‑packaged 
 
  14   device and give it to a patient, and it will deliver the 
 
  15   appropriate dose, you know, it is not a problem. 
 
  16             We think that these are so difficult and so

  17   complex, and there is such a direct connection to safety and 
 
  18   efficacy of the product, that we think that they should be 
 
  19   put on the list of Difficult to Compound products even 
 
  20   though right now maybe nobody is compounding them, but we 
 
  21   want to make sure that even in the future, that they know

  22   that we think that this is something that they shouldn't be 
 
  23   getting into. 
 
  24             DR. ROGERS:  As I mentioned in my talk, poor 
 
  25   compounding of these types of drugs not only results in a 

                                                                109 
 
   1   lack of efficacy, but increases systemic exposure, and that

   2   increases systemic side effects. 
 
   3             DR. JUHL:  There were a couple of opinions offered 
 
   4   through the nodding of heads, and I want to make that is 
 
   5   available for the transcripts.  The question was asked are 
 
   6   compounding pharmacists doing this now, and both Tony and

   7   Loyd had nodding of heads, so I would like you to ‑‑ 
 
   8             DR. ALLEN:  I am not aware of anybody that is 
 
   9   doing it at this point in time, but one I guess 
 
  10   philosophical thing would be, let's say, five to 10 years 
 
  11   from now, if technology develops to the point that it does

  12   become feasible, where you do have a manufacturer, let's 
 
  13   just say, for example, that has an MDI without an active 
 
  14   drug in it, but that manufacturer has gone through and 
 
  15   tested half a dozen drugs for stability, uniformity, you 
 
  16   know et cetera, and they elect to distribute the MDI without

  17   the active ingredient, and the pharmacist then could simply 
 
  18   prepare a solution, not a suspension which most of your 
 
  19   things were oriented towards, but rather a solution of a 
 
  20   drug, sterile filtrate into the pressurized system with 
 
  21   newer technology, that the compounding pharmacist could then

  22   come back to the committee to open that up if the technology 
 
  23   develops that way in the future. 
 
  24             In other words, if we say no today, is that no 
 
  25   forever, or is it still open for new technology that may be 

                                                                110 
 
   1   coming down the road?

   2             MS. AXELRAD:  They can come back and show that 
 
   3   there is new technology that is significantly simpler than 
 
   4   it is at this particular point in time for somebody to take 
 
   5   a drug and put it into a device and make a safe and 
 
   6   effective product.

   7             MR. WELDER:  I have I guess a need for 
 
   8   clarification on your question, Bill.  Would you ask again, 
 
   9   because you said it included ‑‑ I was under the assumption 
 
  10   we were talking about MDIs and dry powder inhalers as a 
 
  11   multiple dose kind of thing.

  12             MR. RUSHO:  Well, what I was requested to compound 
 
  13   was a triamcinolone capsule, a partial filled capsule filled 
 
  14   with lactose as a vehicle in order to put in the device, so 
 
  15   you could put it down there and break it, and the patient 
 
  16   could inhale it.

  17             That can be compounded right now.  I don't know 
 
  18   how much of it is being compounded.  But when I looked at 
 
  19   that, one of the things that I looked at was particle size 
 
  20   distribution, and, number one, I didn't have the sieves in 
 
  21   order to tell what particle size I had.

  22             I went ahead and made one up just to look at it, 
 
  23   and I looked at it under the microscope, and you could see a 
 
  24   wide variation in particle side.  Obviously, this was one of 
 
  25   those areas where it was too complex for me to do it.  I had 

                                                                111 
 
   1   to go back to the physician, and I said, you know, we can't

   2   do it, I am sorry. 
 
   3             MR. WELDER:  And your comment was that procedure 
 
   4   would be included in this as Difficult to Compound? 
 
   5             DR. ROGERS:  That is an example of a single dose 
 
   6   dry powder inhaler, and that would be covered under

   7   exemption of dry powder inhalers. 
 
   8             MR. WELDER:  So, we would ‑‑ 
 
   9             MS. AXELRAD:  You would not be able to do it under 
 
  10   this.  We are suggesting that that type of a thing would not 
 
  11   be permitted, that it would be placed on the Difficult to

  12   Compound list.  That is the proposal. 
 
  13             MR. WELDER:  I would ask that that would be 
 
  14   reconsidered for a single inhalation kind of thing.  As Loyd 
 
  15   said, you know, the technology is changing, but the particle 
 
  16   size would be critical, of course, I realize that, but if

  17   you had a prescription for something that was an inhaled 
 
  18   powder, and it didn't involve a complicated device and 
 
  19   sealing that device, I don't think that should fall in the 
 
  20   same category as what we were talking about the metered dose 
 
  21   inhalers.

  22             DR. JUHL:  I guess the question I am asking is how 
 
  23   could we ensure that an accurate dose would be delivered in 
 
  24   such a single dose preparation. 
 
  25             MR. WELDER:  I am not sure, because I have not 

                                                                112 
 
   1   done this, but if you had an exact amount, say, 2 milligrams

   2   of a substance, and the whole inhalation was done at one 
 
   3   time, you could be assured that it was delivered into the 
 
   4   body.  Now, particle size is something else, but I think 
 
   5   this falls into a different category than what I am taking 
 
   6   as the metered dose inhalers and dry powder inhalers.  That

   7   is all I am saying. 
 
   8             DR. JUHL:  And yet the purpose of the dose being 
 
   9   inhaled is to get it into the lung.  Whether you had 2 
 
  10   milligrams or not doesn't really tell you whether it gets 
 
  11   into the lungs.  As Bill had pointed out, if you had a

  12   micronized particle, then, you would assume that some 
 
  13   portion of that 2 milligrams gets to the lung, and if you 
 
  14   have just regular powder, most of it would be deposited in 
 
  15   the throat. 
 
  16             MR. WELDER:  That happens in the manufactured

  17   products also. 
 
  18             DR. JUHL:  It does indeed, but they do have an 
 
  19   estimate in the clinical trials how much gets in and how 
 
  20   much is effective. 
 
  21             MR. RUSHO:  Just the triamcinolone dry powder,

  22   there was a wide variation in particle size, and that was 
 
  23   supposed to be a micronized particle.  Mixing becomes a 
 
  24   problem at that point, too, because you can't mix that in a 
 
  25   mortar and pestle.  You know, your lactose has to be of a 

                                                                113 
 
   1   set particle size, too, and then you have the problem of

   2   weighing this out, and you are doing a partial filled 
 
   3   capsule, not a full capsule. 
 
   4             You have to weigh each and every one of those 
 
   5   capsules out.  It becomes ‑‑ you know, I have no problem 
 
   6   saying it is too complex for a pharmacist to compound.

   7             DR. ROGERS:  Under the best of circumstances, with 
 
   8   a light microscope, you might be able to estimate a particle 
 
   9   size distribution of the powder under the conditions of 
 
  10   examination under the microscope, but the conditions of 
 
  11   inhalation are different than that, and you are not going to

  12   get the same particle size distribution in the aerosol or in 
 
  13   the inhaled powder that you will see in a microscope. 
 
  14             You have to ensure that the device correctly 
 
  15   creates a particle size distribution in the 1 to 5 micron 
 
  16   range, and it is technically impossible.  You can't show the

  17   reproducible particle size distribution except under the 
 
  18   most extreme testing conditions in a laboratory. 
 
  19             DR. JUHL:  And a particle size distribution 
 
  20   doesn't ensure delivery.  It depends upon the air flow and 
 
  21   all the other factors that go into that, too.

  22             DR. ROGERS:  That is true. 
 
  23             DR. JUHL:  You use particle size distribution as a 
 
  24   quality assurance. 
 
  25             DR. ROGERS:  That is true.  We test it under 

                                                                114 
 
   1   specific conditions and assumed reproducibility.

   2             DR. JUHL:  Garnet. 
 
   3             DR. PECK:  What you have just heard is a 
 
   4   significant comment about lactose as one component.  That is 
 
   5   difficult to get in a reduced particle size necessary for 
 
   6   inhalation therapy, and manufacturers are working very hard

   7   at making appropriate lactose for these particular capsules. 
 
   8             The particle size distribution is paramount to its 
 
   9   success because you have to dilute out the drug, and the 
 
  10   drug is going to have a distribution.  Micronization does 
 
  11   not guarantee a narrow particle size distribution, and you

  12   may have to go through cutting to give you the appropriate 
 
  13   particle size for an inhalation product of this nature as a 
 
  14   capsule. 
 
  15             This is a Fison [?] technique for putting the 
 
  16   capsule in an appropriate unit that pinches the unit and you

  17   inhale it.  You have to consider also that the patient is 
 
  18   the one that is bringing in the material.  It is not a 
 
  19   pressurized device.  So, if you do not have appropriate 
 
  20   particle size distribution of both the diluent and the 
 
  21   active, you may have problems with dosing for that

  22   particular patient because you are relying on a patient who 
 
  23   is ill or affected by something, and they are the ones that 
 
  24   are the driving force. 
 
  25             So, you have to have a very ideal dosage form.  

                                                                115 
 
   1   When you get into pressurized systems, and about aerosols,

   2   aerosol products, the container is an integral part of the 
 
   3   drug delivery system, and too many people forget this.  It 
 
   4   is not like a capsule or a tablet goes into a bottle.  We 
 
   5   are delivering the whole thing, the package and the product 
 
   6   for therapy.

   7             So there are many integral parts and what was 
 
   8   reviewed here was excellent in terms of the components of 
 
   9   the valve assembly.  Various different materials of 
 
  10   construction are used in there, and so one has to be careful 
 
  11   about all these parts.

  12             There was noted particular polymers and also 
 
  13   rubber is within that system, and other things.  So, it is 
 
  14   extremely complex, the containment of what we are trying to 
 
  15   deliver.  But these little units ‑‑ and I can see a possible 
 
  16   need for delivering a few capsules ‑‑ but the components and

  17   their size are crucial. 
 
  18             DR. ROGERS:  Another crucial factor is the 
 
  19   interaction of all the components with each other, the 
 
  20   liquid phase, solid phase, container closure components, 
 
  21   they all interact and there is a large potential for

  22   problems in those interactions that can affect the dosing 
 
  23   and particle size. 
 
  24             DR. JUHL:  How does one achieve, would achieve 
 
  25   sterility or how do they do it commercially in the 

                                                                116 
 
   1   spinhealer [?] kind of thing, the contents of the capsule? 

   2   Obviously, Bill, in your example, you would have need to 
 
   3   have some assurance of ‑‑ 
 
   4             MR. RUSHO:  In my example, there would not have 
 
   5   been sterility. 
 
   6             DR. JUHL:  I know, but I wondered how it is done

   7   commercially and is it possible. 
 
   8             DR. PECK:  You can sterilize dry powders with a 
 
   9   number of different techniques to fill appropriately, but it 
 
  10   would have to be sterile. 
 
  11             DR. JUHL:  Are capsules considered sterile?

  12             DR. PECK:  Well, no, that is a fallacy, but I 
 
  13   think there is a little fuzziness here in terms of that 
 
  14   capsule. 
 
  15             DR. JUHL:  Other questions or comments on this 
 
  16   topic?

  17             MS. LaFOLLETTE:  I would just like to make the 
 
  18   comment, with all the information that we have heard, which 
 
  19   was wonderful to hear, this is a single dose or multi‑dose 
 
  20   inhalers.  These are products that really require in‑process 
 
  21   testing, qualitative or quality assurance protocols, I just

  22   don't see cuts it here.  I mean there are too many things 
 
  23   that can go wrong with, you know, I mean the valve delivery, 
 
  24   the calibration of that.  I mean these are things beyond the 
 
  25   scope of compounding pharmacy. 

                                                                117 
 
   1             DR. ROGERS:  Even batch‑to‑batch variation in

   2   valves is a serious problem. 
 
   3             DR. JUHL:  I see a hand being raised in the 
 
   4   audience, and although we don't usually allow comment from 
 
   5   the audience, if it is on this particular topic, I would be 
 
   6   happy to entertain a brief comment.

   7             If you would identify yourself. 
 
   8             DR. ADAMS:  My name is Wallace Adams, and I am 
 
   9   with the Food and Drug Administration, CDER. 
 
  10             I would like to comment on the issue of the MDIs 
 
  11   and the DPIs just briefly.  The Center has spent a lot of

  12   effort in concerning itself with determination of 
 
  13   bioequivalence of metered dose inhalers and dry powder 
 
  14   inhalers, and the recommendations which we have involve both 
 
  15   in vitro and in vivo testing. 
 
  16             We have seen a lot of aspects, as Brian Rogers has

  17   talked about this morning, about the critical nature of the 
 
  18   formulation, the materials that go into the product, and in 
 
  19   addition to that, there are in vitro tests. 
 
  20             From a bioequivalence standpoint, we do not 
 
  21   believe that in vitro testing only is adequate to assure

  22   these equivalence of two products, and that is to say the 
 
  23   particle size distribution can be the same, the lactose 
 
  24   particle size distribution can be the same, but as was 
 
  25   mentioned, these products are combinations of formulation 

                                                                118 
 
   1   and device, and it is critical that not only the formulation

   2   be well controlled, but there is the formulation‑device 
 
   3   interaction. 
 
   4             So, in the case of a solution formulation MDI, not 
 
   5   only must the concentration of the drug in the solution, and 
 
   6   the concentration of the various inactive ingredients be

   7   controlled, but the characteristics of the metering device 
 
   8   are critical, and many firms make these metering valves, and 
 
   9   they would greatly impact the performance of the product. 
 
  10             They would the particle size distribution, and 
 
  11   this has direct relevance to the bioavailability. I thought

  12   it was interesting to hear questions or comment about taking 
 
  13   a Ventalin rotocap product or rotohaler product and filling 
 
  14   a different capsule other than Ventalin capsule intended for 
 
  15   the purpose, and using that same device. 
 
  16             My suspicion would be that the bioavailability

  17   could be drastically altered by using a formulation 
 
  18   compounded in the pharmacy, and used in that product.  Even 
 
  19   if you knew what the particle size distribution is, I am not 
 
  20   sure that you would know what the particle size distribution 
 
  21   of the drug in the innovator product is, and even knowing

  22   that, it is not the particle size distribution determined by 
 
  23   microscopy that is critical so much as aerodynamic particle 
 
  24   size distribution determine by the cascade impactor.  This 
 
  25   is not equipment which is available in the pharmacy. 

                                                                119 
 
   1             This does require, as Brian had indicated,

   2   sophisticated equipment in a well‑controlled laboratory. 
 
   3             So, there are many aspects to these products, 
 
   4   these combinations of device and formulation which are 
 
   5   critical to the performance of the product, and I think that 
 
   6   we have to be aware, as the discussion has been going this

   7   morning, that these are very complex devices and that in 
 
   8   vitro data alone is not adequate to assure bioequivalence  
 
   9   of the products, but rather we only know that through in 
 
  10   vivo testing, comparative testing. 
 
  11             Thank you.

  12             DR. JUHL:  Thank you. 
 
  13             Are there other comments or questions on the 
 
  14   topic? 
 
  15             MR. TRISSEL:  I will be brief.  As I understand 
 
  16   this, it does not include pump sprays nor nebulizers or any

  17   of those kind of other inhalation devices, am I correct? 
 
  18             DR. ROGERS:  That is true, as being considered at 
 
  19   this point. 
 
  20             DR. JUHL:  I see the International Academy of 
 
  21   Compounding Pharmacists is represented.  Are there comments

  22   that you have on this topic? 
 
  23             Would you come to the microphone, please, and 
 
  24   identify yourself. 
 
  25             MS. CAPPS:  Thank you, Mr. Chairman.  My name is 

                                                                120 
 
   1   Shelley Capps.  I am with the International Academy of

   2   Compounding Pharmacists.  We have requested, and will 
 
   3   present tomorrow.  We do have comments concerning all of 
 
   4   these.  We are concerned about the definition, that it is so 
 
   5   broad that it would include some significant compounded 
 
   6   medications, however, there is no compounding being done

   7   currently of the product that has been described here this 
 
   8   morning. 
 
   9             DR. JUHL:  Thank you. 
 
  10             MS. CAPPS:  Thank you. 
 
  11             DR. JUHL:  I assume then that we are ready for the

  12   question, referring to your handout again. 
 
  13             Question No. 2.  Do you agree that the class of 
 
  14   metered dose inhalers, as described, should be included on 
 
  15   the list of drug products that may not be compounded because 
 
  16   they are difficult to compound properly?

  17             Those that agree, would you please signify by 
 
  18   raising your hand? 
 
  19             [Show of hands.] 
 
  20             DR. JUHL:  No opposed. 
 
  21             That is unanimous.  The committee agrees with that

  22   recommendation. 
 
  23             No. 3.  Do you agree that the class of dry 
 
  24   powdered inhalers, as described, should be included on the 
 
  25   list of drug products that may not be compounded because 

                                                                121 
 
   1   they are difficult to compound properly?

   2             All those that agree with that recommendation, 
 
   3   please raise your hands. 
 
   4             [Show of hands.] 
 
   5             DR. JUHL:  That, too, is unanimous. 
 
   6             We will reconvene at ten minutes after 1:00.

   7             [Whereupon, at 11:50 a.m., the proceedings were 
 
   8   recessed, to be resumed at 1:10 p.m.] 

                                                                122 
 
   1                 A F T E R N O O N  S E S S I O N

   2                                                    [1:30 p.m.] 
 
   3             DR. JUHL:  Let us resume. 
 
   4             Next on our agenda is the open public hearing.  I 
 
   5   apologize to our speakers, we are half an hour behind 
 
   6   schedule.  We won't penalize any of the speakers for out

   7   tardiness, but we will assume the full amount of time as 
 
   8   necessary for the open public hearing. 
 
   9             We have four speakers who have asked for time and 
 
  10   we will see if all are here. 
 
  11             First is Jana Nestlerode who is representing

  12   herself to discuss DMPS, if you would like to step to the 
 
  13   podium.  She has asked for 13 minutes worth of time. 
 
  14                       Open Public Hearing 
 
  15             MS. NESTLERODE:  I have handed out a packet of my 
 
  16   information including my remarks today.  I don't normally

  17   read my remarks, but with 13 minutes I think I had better. 
 
  18             Thank you for the opportunity to address this 
 
  19   committee today.  I have waited a long time to do this. 
 
  20             My name is Jane Nestlerode.  I am a Professor of 
 
  21   Criminal Justice at West Chester University in West Chester,

  22   Pennsylvania.  Before I retired to teaching, I worked in 
 
  23   federal and county governments.  I know that in that 
 
  24   capacity, you are generally overworked and underpaid. 
 
  25             As a government employee, I know the role of 

                                                                123 
 
   1   entertaining viewpoints and inputs from other people and

   2   that you do so with patience and indulgence, but today I 
 
   3   hope you don't feel that you have to indulge me.  I hope 
 
   4   that you will hear me. 
 
   5             I was also an Assistant District Attorney in the 
 
   6   Delaware County District Attorney's Office for many years,

   7   and I prosecuted a lot of violent individuals.  I knew that 
 
   8   every time I spoke to the jury, what I said mattered.  By my 
 
   9   performance, a murdered could go free, to kill again, or he 
 
  10   could be locked up where he couldn't hurt anyone.  I was 
 
  11   acutely aware of my responsibilities in that role.

  12             But those responsibilities pale in comparison to 
 
  13   the purpose for which I am here today.  This may very well 
 
  14   be the most important thing that I do in my entire life.  
 
  15   Dimercapto propane sulfonate (DMPS) is devastating the lives 
 
  16   of too many patients, and this committee has the power to

  17   stop it.  I consider this matter urgent.  Today, I traveled 
 
  18   here to ask you to withdraw your recommendation of this drug 
 
  19   for inclusion on the List of Bulk Drug Substances That May 
 
  20   Be Compounded by Pharmacists.  I made the trip here because 
 
  21   it matters.

  22             I am a DMPS survivor.  A single injection of DMPS 
 
  23   almost took my life.  I went to a doctor recommended by my 
 
  24   dentist for treatment of mild and asymptomatic 
 
  25   hypothyroidism.  This doctor ordered a complete blood workup 

                                                                124 
 
   1   and determined that I had healthy liver, kidney, and immune

   2   functions. 
 
   3             Because I had dental amalgams, he wanted to test 
 
   4   my urine for mercury.  He told me that he would first have 
 
   5   to inject me with a harmless substance which would make the 
 
   6   mercury show up.  I allowed him to inject me, and within

   7   minutes of the injection, I became acutely ill.  I spent the 
 
   8   next 13 months trying to recover. 
 
   9             I suffered from debilitating physical, cognitive, 
 
  10   and psychological symptoms, consistent with metal poisoning.  
 
  11   My symptoms included nausea to the point where I had to

  12   carry a basin and a towel in my car.  I had gnawing stomach 
 
  13   pains, throbbing headaches, joint pain, blurred vision, 
 
  14   sometimes uncontrollable and embarrassing diarrhea, numbness 
 
  15   of the extremities, chest pains, labored breathing, extreme 
 
  16   fatigue, the kind of fatigue that made walking to the

  17   mailbox an enormous effort. 
 
  18             In addition, I suffered an inability to 
 
  19   concentrate, short term memory loss to the point where I 
 
  20   couldn't remember where I worked.  One morning I struggled 
 
  21   to find some clue as to where I worked, so that I knew where

  22   to go. 
 
  23             I experienced severe depression where I would sob 
 
  24   for hours and sometimes days, and I had suicidal ideations.  
 
  25   There were two occasions when I sat with a loaded gun to my 

                                                                125 
 
   1   head debating whether to pull the trigger.

   2             I also suffered frightening psychotic episodes.  
 
   3   At one point my real doctor considered institutionalization. 
 
   4             Prior to this injection I had robust health.  I 
 
   5   worked out rigorously several times each week and held down 
 
   6   a full time job.  I was one of those annoying people who

   7   woke up happy and energetic every day.  I had no history of 
 
   8   depression or mental illness. 
 
   9             But after the injection of DMPS, I longed for 
 
  10   death.  Sleep was my only respite, but the pain would keep 
 
  11   me awake.  I listened to audio tapes to take my mind off the

  12   pain that I could drift off to sleep, but as soon as I woke 
 
  13   up, the tears would start because I was back in the hell 
 
  14   that my life had become. 
 
  15             I was horrified when I later learned that the 
 
  16   substance that had been injected into me was an unapproved

  17   metal chelator (DMPS), with very serious adverse effects.  
 
  18   It never occurred to me that any doctor would use an 
 
  19   unapproved drug on me. 
 
  20             I was not told it was unapproved, nor was I 
 
  21   informed of possible adverse effects.  The Commonwealth of

  22   Pennsylvania has since instituted disciplinary action 
 
  23   against this doctor for improper use of injectable drugs, 
 
  24   including DMPS.  A copy of a recent Philadelphia newspaper 
 
  25   article about this is attached.  I am also instituting my 

                                                                126 
 
   1   own legal action.

   2             Neither the doctor who injected me, or the several 
 
   3   legitimate doctors from whom I subsequently sought help, 
 
   4   knew how to help me.  If fact, none of the other doctors had 
 
   5   ever heard of this drug.  The occupational health physician 
 
   6   with the University of Pennsylvania had to do research to

   7   learn about it, and still had no idea how to treat me.  For 
 
   8   months I lived in despair, not knowing if I would ever 
 
   9   recover.  In the end, it was a chemist who saved my life. 
 
  10             Heyltex, a subsidiary of Heyl in Germany, is the 
 
  11   primary manufacturer of DMPS in this country.  In its

  12   scientific monograph, Heyltex cautions:  "DMPS should be 
 
  13   administered parenterally only if oral administration is not 
 
  14   possible." 
 
  15             Yet, with the inclusion of DMPS on the list, most 
 
  16   complementary/alternative medicine practitioners are using

  17   this drug by infusion and injection. 
 
  18             I actually support certain aspects of alternative 
 
  19   medicine.  But as with any group of professionals, there are 
 
  20   good and bad influences.  I believe that those advocating 
 
  21   DMPS are setting back the alternative health care movement

  22   by decades, and giving a bad name to competent and 
 
  23   compassionate practitioners in the field.  The issue of 
 
  24   whether amalgams cause chronic mercury poisoning is quite 
 
  25   irrelevant to this matter.  This is about detoxification if 

                                                                127 
 
   1   and when such poisoning does occur.

   2             At a prior meeting of this committee, someone said 
 
   3   that it was doubtful that doctors would be pulling patients 
 
   4   in off the street to test them for mercury.  Well, they are 
 
   5   not yanking them in by the collar yet, but it is close. 
 
   6             You see, mercury is considered a "root" in the

   7   alternative practitioners' lexicon, it causes anything and 
 
   8   everything.  Patients are being injected with DMPS for such 
 
   9   diverse medical conditions as headaches, sinus infections, 
 
  10   eczema, depression, hypothyroidism, Lyme's disease, and even 
 
  11   carpal tunnel syndrome.

  12             In what has become a very lucrative and callous 
 
  13   cottage industry, these practitioners are convincing even 
 
  14   well patients that they are poisoned by their dental 
 
  15   amalgams, and must undergo amalgam replacement and DMPS 
 
  16   detoxification programs.

  17             When patients are injured by these programs, they 
 
  18   are often abandoned because these physicians simply don't 
 
  19   know what to do.  It is not just quackery; it is the 
 
  20   practice of experimental medicine on unsuspecting and 
 
  21   uninformed patients on a growing scale, and patients are

  22   paying not only large sums of money for essentially 
 
  23   worthless medical care, but they are sometimes suffering 
 
  24   debilitating adverse effects. 
 
  25             I believe that this practice violates the spirit, 

                                                                128 
 
   1   if not the letter, of the Act which requires a prescription

   2   for an identified patient.  My sense is that the Act was 
 
   3   designed to give physicians certain latitude in treating 
 
   4   unique patients, not adopting a protocol for every patient 
 
   5   in the practice. 
 
   6             As I learned more, I was alarmed at the number of

   7   patients who health had been adversely affected by DMPS.  
 
   8   Like me, none of them had been told that DMPS was an 
 
   9   experimental drug, none had been asked to sign informed 
 
  10   consent forms, and none were warned of possible side 
 
  11   effects.  They had been blindsided, just like I had.

  12             Because I felt I had to do something to warn 
 
  13   patients of the dangers no one was talking about, I recently 
 
  14   started a web site.  It is www.dmpsbackfire.com.  I first 
 
  15   learned all I could about this drug  by speaking with 
 
  16   researchers, toxicologists, and biochemists.  Those

  17   individuals have no financial interest in this drug and were 
 
  18   appalled at its use for the treatment of chronic metal 
 
  19   poisoning. 
 
  20             At the site, I not only inform patients of what I 
 
  21   learn about the dangers of DMPS, but I also offer to post

  22   patient reports of adverse effects.  A summary is attached 
 
  23   which includes in from about two dozen patients who received 
 
  24   this drug in oral or parenteral form. 
 
  25             When I first started learning about this drug, I 

                                                                129 
 
   1   was so naive.  I thought all doctors, researchers, and

   2   pharmacists told the truth.  I thought we were all on the 
 
   3   same page and shared the same goal of patient health.  I am 
 
   4   no longer as naive. 
 
   5             You are probably all aware that alternative 
 
   6   medical practitioners view the FDA with, if not disdain,

   7   then fear.  I have read that fewer than 1 percent of all 
 
   8   adverse reactions to medications are reported to this 
 
   9   agency.  Alternative medical practitioners are probably the 
 
  10   least likely to do so.  The last thing they want is FDA 
 
  11   scrutiny.

  12             And so I have found what I call a conspiracy of 
 
  13   silence regarding the adverse effects of this particular 
 
  14   drug.  Indeed, the president of a large compounding pharmacy 
 
  15   wrote to me at the web site and said, "Shame on you for 
 
  16   suggesting your readers use Medwatch."

  17             He went on to tell me to, "get my facts straight," 
 
  18   that DMPS is now approved by the FDA and that the DMPS 
 
  19   challenge test is "backed by our federal government." 
 
  20             A researcher told me that she had never never 
 
  21   heard of an adverse reaction to DMPS.  I believed her until

  22   I communicated with one of her patients.  He suffered severe 
 
  23   adverse effects from her infusions of DMPS and had been very 
 
  24   vocal to her in his complaints.  He left her clinic and 
 
  25   never returned, and no one from the clinic ever asked why. 

                                                                130 
 
   1             I attended a conference at which a doctor claimed

   2   to never have heard of an adverse reaction to DMPS.  It was 
 
   3   becoming a tiresome refrain.  Later, I was given a copy of a 
 
   4   letter this same physician had written on behalf of a 
 
   5   patient who had become disabled from a single injection of 
 
   6   DMPS.

   7             In that letter, he actually coined the term 
 
   8   "backfire" with regard to this drug.  A vice president of a 
 
   9   prominent midwestern laboratory told me off the record that 
 
  10   I would never find an expert to testify about the dangers of 
 
  11   DMPS in my potential malpractice lawsuit because those in

  12   the alternative health field would never testify against a 
 
  13   colleague.  It is indeed a conspiracy of silence. 
 
  14             It is clear to me that the motive behind the 
 
  15   advocacy of DMPS is not patient health.  It is profits.  It 
 
  16   is estimated that 180 million Americans have amalgam

  17   fillings.  With mercury as a possible cause of just about 
 
  18   any minor or major medical condition, the potential market 
 
  19   is huge.  One doctor confided to me that he had increased 
 
  20   his profits by 300 percent in one year by DMPS therapy to 
 
  21   his repertoire.  Another physician stated that he has

  22   increased his yearly income into seven digits thanks to the 
 
  23   new DMPS protocols. 
 
  24             The protocols do tell the tale.  The typical one 
 
  25   involves intravenous administration of DMPS to just about 

                                                                131 
 
   1   any patient who walks in the door.  Indeed, the doctor who

   2   injected me refused to treat a patient because he declined a 
 
   3   DMPS challenge test. 
 
   4             Because DMPS oxidizes quickly, it is a free 
 
   5   radical generator, so doctors require patients to return in 
 
   6   a few days for intravenous vitamin C.  Because DMPS will

   7   also deplete essential minerals, the patient must return a 
 
   8   third time for intravenous mineral replacement. 
 
   9             This trio of IV's is repeated for weeks, months, 
 
  10   sometimes years.  For each of these individual intravenous 
 
  11   treatments, patients are charged from $100 to $300.  I have

  12   patients telling me that they have spent tens of thousands 
 
  13   of dollars for these protocols, and only one has ever told 
 
  14   me that he thought his health had benefitted from it.  The 
 
  15   physician profits are simply enormous. 
 
  16             It is quite interesting that the protocol for use

  17   of DMPS is by infusion or injection.  I have heard that the 
 
  18   preparation of the powder for parenteral use is quite 
 
  19   tricky.  It must be done under nitrogen and the ampule must 
 
  20   be topped with nitrogen. 
 
  21             To avoid contamination, the DMPS cannot come into

  22   contact with metal during processing, and the ampule cannot 
 
  23   have a metal cap.  I am sure a scientist could explain to me 
 
  24   how a metal needle is then used to inject this drug. 
 
  25             Besides the summary of patient reports, I have 

                                                                132 
 
   1   attached a June 27th, 2000 report from a Canadian

   2   toxicologist, Dr. Albert Nantel.  This report documents the 
 
   3   adverse effects of DMPS that he witnessed from its oral 
 
   4   administration  to 33 patients being treated for acute 
 
   5   arsenic poisoning. 
 
   6             Dr. Nantel observed eight patients suffering from

   7   erythema multiforme, four of whom required hospitalization.  
 
   8   Two were released after several days of intravenous 
 
   9   cortisone, but as of the date of the report, two were still 
 
  10   hospitalized with Stevens‑Johnson syndrome. 
 
  11             One patient suffered bullous lesions of the upper

  12   extremities, and the other suffered severe ulcerations of 
 
  13   all mucous membranes.  For the adverse effects from DMPS, 
 
  14   ten patients, or 30 percent, required medical intervention, 
 
  15   and four, 12 percent, required hospitalization. 
 
  16             I have also been told that at least two cases of

  17   Stevens‑Johnson syndrome from the administration of DMPS 
 
  18   were reported in London, England in the late 1980's.  It is 
 
  19   my hope that the FDA will investigate this allegation as 
 
  20   part of its review of this drug. 
 
  21             Because they were not accessible from the FDA web

  22   site, I have included with my information three letters sent 
 
  23   in opposition to the inclusion of DMPS on the list.  Two are 
 
  24   mine, the other is from Dr. Steven Marcus, a toxicologist, 
 
  25   who is the Executive Director of the New Jersey Poison 

                                                                133 
 
   1   Information and Education System.  Dr. Marcus refers to the

   2   inclusion of DMPS on this list as a "terrible injustice" to 
 
   3   the consumers and the patients of this country." 
 
   4             I have come to know that this drug is very 
 
   5   dangerous.  Its availability to qualified toxicologists in 
 
   6   cases of acute poisoning by means of an investigative New

   7   Drug Application is appropriate.  Its inclusion on the list 
 
   8   is not.  I say this not only because I believe DMPS to be an 
 
   9   unusually dangerous drug, but because chemists and 
 
  10   toxicologists have told me that DMSA, dimercaptosuccinic 
 
  11   acid, a drug already approved by the FDA, is comparably

  12   effective and much safer. 
 
  13             DMPS is simply not necessary in an effective 
 
  14   program of detoxification for properly diagnosed chronic 
 
  15   metal poisoning and it carries substantial risks of adverse 
 
  16   effects.  But, of course, there is a problem with DMSA.  It

  17   is used in oral form, and there is not much profit for the 
 
  18   physician. 
 
  19             This Tuesday night, night before last, I was asked 
 
  20   to telephone a young woman I will call Jennifer.  She was 
 
  21   suffering from what I now refer to as a DMPS backfire.  We

  22   spoke for four and a half hours, and her story was 
 
  23   heartwrenching.  It all began two years ago. 
 
  24             She was in excellent health, but had been having 
 
  25   migraine headaches after being in a car accident.  To treat 

                                                                134 
 
   1   the migraines, her physician began injecting her head, neck,

   2   and face with a combination of DMPS and procaine. 
 
   3             Within a few weeks of treatment she was unable to 
 
   4   defecate or urinate and became extremely bloated.  She said 
 
   5   her digestive tract just shut down.  Her liver and kidney 
 
   6   tests revealed substantial impairment.  She began having

   7   heart palpitations and her headaches intensified. 
 
   8             Within a short time her hair and skin turned gray.  
 
   9   The ringing in her ears is so severe that she can no longer 
 
  10   hear the rain and she can't hear her beloved bird sing.  She 
 
  11   is so disabled and fatigued that she is essentially

  12   housebound.  After reading the results of her lab tests, her 
 
  13   new doctor doesn't know how she has survived.  Indeed, she 
 
  14   refers to herself as "the walking dead." 
 
  15             This committee is in a powerful position to affect 
 
  16   patients' lives.  The facility with which DMPS was placed on

  17   this list was frightening to me.  I believe that this 
 
  18   committee has been misled as to the "safety" of DMPS, and in 
 
  19   light of this information, I ask you, no, I don't ask you, I 
 
  20   beg you, to withdraw your recommendation of this very 
 
  21   dangerous drug.

  22             Thank you and I am willing to answer any questions 
 
  23   here or later. 
 
  24             DR. JUHL:  Thank you for coming to talk to us. 
 
  25             Are there questions or comments from the 

                                                                135 
 
   1   committee?

   2             MS. NESTLERODE:  Thank you for hearing me. 
 
   3             DR. JUHL:  I am sorry.  Go ahead, Sarah. 
 
   4             DR. SELLERS:  It was just a general question, not 
 
   5   necessarily for you.  But is this something that the FDA can 
 
   6   look into?

   7             MS. AXELRAD:  Yes.  We have the comment letters on 
 
   8   the rule, and we will certainly take your remarks into 
 
   9   account when we decide whether to put it on the list. 
 
  10             MS. NESTLERODE:  Thank you very much. 
 
  11             DR. JUHL:  Refresh my memory, but I think the

  12   basis for our discussion about this drug was as an antidote 
 
  13   for real mercury poisoning, wasn't it? 
 
  14             MS. AXELRAD:  Right. 
 
  15             DR. JUHL:  That was our consideration.  That was 
 
  16   the only information that we had at that time?

  17             MS. AXELRAD:  Right, and I believe it is used in 
 
  18   Europe for actual metal poisoning there. 
 
  19             MS. NESTLERODE:  Yes.  Heyl is the primary 
 
  20   manufacturer out of Berlin, and they say that parenteral use 
 
  21   should be used only in acute poisoning cases.  It is being

  22   used widespread by psychiatrists, by doctors, by dentists 
 
  23   now for everything because mercury poisoning causes 
 
  24   everything. 
 
  25             MS. AXELRAD:  One thing we can do is review the 

                                                                136 
 
   1   literature to see whether the literature, in fact, limits

   2   its use to oral use or suggests safety issues associated 
 
   3   with parenteral use, because one of the things that we did 
 
   4   for some of the other drugs on the bulks list was limit it 
 
   5   to a particular type of use where we felt there were safety 
 
   6   concerns with other kinds of administration.

   7             DR. JUHL:  I do see a letter in here, although the 
 
   8   top of it is cut off, but I think it is from the New Jersey 
 
   9   Poison and Information system, Dr. Steven Marcus.  In his 
 
  10   letter, he suggests that the drug is available by emergency 
 
  11   IND, and I think you had mentioned that, as well, which

  12   would be apparently an alternative route for availability 
 
  13   for those cases that truly need it, so there may be an 
 
  14   alternative way that we can accommodate both its legitimate 
 
  15   need and be able to diminish its illegitimate need. 
 
  16             MS. NESTLERODE:  I would agree with that.  I agree

  17   with Dr. Marcus that in acute poisoning, the IND method is 
 
  18   appropriate and necessary. 
 
  19             What has happened now with its inclusion on the 
 
  20   bulk drug list is that its proponents are telling everyone 
 
  21   that it is an approved drug.  It has become used more

  22   widespread.  I am getting more reports at my web site.  I am 
 
  23   fearful of the increase in the human carnage that is coming 
 
  24   with this. 
 
  25             Thank you. 

                                                                137 
 
   1             DR. JUHL:  Thank you.

   2             If we then could have an update of your findings 
 
   3   at our next meeting or an interim if you have something 
 
   4   sooner than that, we would appreciate that. 
 
   5             Other questions or comments on this topic by the 
 
   6   members of the committee?

   7             MR. RUSHO:  The director of our Poison Control 
 
   8   Center has forwarded the E‑mails on this topic, and there is 
 
   9   a lot of traffic on this.  The Poison Control Centers, I can 
 
  10   tell you are very upset about the approval of the drug on 
 
  11   the list.

  12             MS. AXELRAD:  Dr. Juhl, can I ask the committee, 
 
  13   do they have any feelings or information with regard to 
 
  14   whether it is safe if used orally as opposed to 
 
  15   parenterally, whether there is some legitimate use for this 
 
  16   with an oral capsule or a tablet as opposed to parenteral?

  17             DR. JUHL:  I don't know that anyone on the 
 
  18   committee is prepared with additional information. 
 
  19             MR. TRISSEL:  Maybe you could refresh my memory.  
 
  20   The committee looked at whatever was presented to it in the 
 
  21   way of toxicity information originally, and I have

  22   absolutely no recollection of that at this time of what was 
 
  23   presented, but it must not have been a striking number of 
 
  24   cases, and it sounds like there are more out there than had 
 
  25   been identified. 

                                                                138 
 
   1             Will the agency be following up, can they get case

   2   reports for some of these people? 
 
   3             MS. AXELRAD:  We can certainly look at our 
 
   4   databases to see if we have any adverse event reports in the 
 
   5   system concerning this product. 
 
   6             DR. JUHL:  It sounds like the poison center

   7   database would be another place to search. 
 
   8             MS. AXELRAD:  We can look at that. 
 
   9             DR. SASICH:  May I make a comment to what Jane 
 
  10   just said? 
 
  11             DR. JUHL:  Dr. Sasich, would you identify

  12   yourself? 
 
  13             DR. SASICH:  Oh, excuse me.  Larry Sasich, 
 
  14   pharmacist with Citizen's Health Research Group. 
 
  15             I checked the FDA's database for DMPS reports, and 
 
  16   there are none in the current database.

  17             MR. TRISSEL:  Then, you will have to go outside 
 
  18   the database to find that. 
 
  19             MS. AXELRAD:  We will look at the Poison Control 
 
  20   database. 
 
  21             DR. SASICH:  Janet just raised an important point. 

  22   If it is not approved drug in the United States and it gets 
 
  23   reported to the FDA associated with an adverse drug event, 
 
  24   where does it go? 
 
  25             MS. AXELRAD:  I think we might have some reports 

                                                                139 
 
   1   in the system of even of unapproved drugs, yes, we would get

   2   something like that possibly. 
 
   3             DR. JUHL:  Other comments or questions? 
 
   4             [No response.] 
 
   5             DR. JUHL:  Our second speaker is Larry Sasich, who 
 
   6   was just at the podium.  I would like to ask you to return. 

   7   Larry Sasich has asked for eight minutes worth of time. 
 
   8             DR. SASICH:  Good afternoon.  As the FDA I am sure 
 
   9   is aware, and perhaps the Advisory Committee members are 
 
  10   also aware, that Public Citizen has long been opposed to the 
 
  11   pharmacy compounding provisions of the Food and Drug

  12   Administration Modernization Act. 
 
  13             These anti‑scientific provisions of the law permit 
 
  14   compounding pharmacists to conduct an "end run" around the 
 
  15   FDA's drug approval process.  They have opened the door for 
 
  16   unethical pharmacists to abuse a professional privilege

  17   granted to them by the public and to perpetrate the quackery 
 
  18   that now goes on, for all practical purposes, unrestrained, 
 
  19   as we have just seen. 
 
  20             Given the few options available to this committee 
 
  21   and the FDA within the pharmacy compounding provisions of

  22   FDAMA, we do support the science‑based approach taken by the 
 
  23   agency in its concept paper on developing a list of drugs 
 
  24   that cannot be compounded by pharmacists. 
 
  25             Clearly, Congress was concerned about the safety 

                                                                140 
 
   1   and effectiveness of drug products compounded by pharmacists

   2   when it said in FDAMA that the FDA has the responsibility to 
 
   3   identify and place on a list of drugs that cannot be 
 
   4   compounded any product that, "presents demonstrable 
 
   5   difficulties for compounding that reasonably demonstrate an 
 
   6   adverse effect on the safety or effectiveness of that

   7   product." 
 
   8             The FDA's approach in developing the list has been 
 
   9   to include certain categories of drugs that are 
 
  10   sophisticated final finished dosage forms and whose 
 
  11   production is technologically complex or requires highly

  12   specialized facilities and trained personnel.  This is 
 
  13   scientifically sound, it's intuitive, and within the common 
 
  14   and legal definition of a drug. 
 
  15             Science‑based regulation has evolved over the past 
 
  16   century with the purpose of preventing avoidable harm to

  17   patients.  History and science have taught us that waiting 
 
  18   for a tragedy to materialize before taking regulatory action 
 
  19   needlessly harms patients.  Primary prevention, in the form 
 
  20   of enforceable regulations, has always been the best 
 
  21   approach to protecting the public from avoidable

  22   drug‑induced injury and death. 
 
  23             Any suggestion that the safety of 
 
  24   pharmacy‑compounded products is proven because there have 
 
  25   been few reports of serious adverse events is clearly 

                                                                141 
 
   1   absurd.  The FDA's postmarketing adverse event reporting

   2   system does not and cannot identify all instances of harm to 
 
   3   patients from prescription drugs, let alone those from 
 
   4   compounded ones, and this system does not have the 
 
   5   sensitivity to detect a negative impact on patient survival 
 
   6   from the drugs that patients receive.

   7             Compounding pharmacists are well aware that they 
 
   8   are under no regulatory requirement to report adverse events 
 
   9   that are associated with the use of their products.  Their 
 
  10   financial self‑interest makes it even more likely that they 
 
  11   will not report these adverse events.

  12             Public Citizen agrees that transdermal delivery 
 
  13   systems, metered dose and dry powder inhaler products must 
 
  14   be placed on the list of drugs that are demonstrably 
 
  15   difficult to compound. 
 
  16             We also agree that it should not only be

  17   appropriate, but mandatory, to include all sterile products 
 
  18   that are not compounded in accordance with Chapter 1206 of 
 
  19   the United States Pharmacopeia, on the list, with one 
 
  20   exception. 
 
  21             We do not agree that the procedures described in

  22   Chapter 1206 for compounding sterile products from 
 
  23   non‑sterile bulk drug substances, even if these procedures 
 
  24   could be enforced, would ensure the safety or effectiveness 
 
  25   of these products.  We believe that it is essential that all 

                                                                142 
 
   1   sterile drug products that are compounded from non‑sterile

   2   bulk drug substances be on the list. 
 
   3             We have particular concerns about the preparation 
 
   4   of sterile products.  Our objection is due in part to a 
 
   5   study cited in the FDA's concept paper that evaluated the 
 
   6   sterility and concentration of 100 samples of 1 percent

   7   pilocarpine eye drops.  Of the 100 samples, 66 were prepared 
 
   8   by local pharmacies and 34 were prepared by FDA‑regulated 
 
   9   manufacturers. 
 
  10             Of the 66 solutions prepared by local pharmacies, 
 
  11   52 or 79 percent were contaminated with bacteria or fungi or

  12   both, whereas only one of 34 or 3 percent of samples 
 
  13   prepared by regulated manufacturers were contaminated.  This 
 
  14   result is chilling and it will be repeated more often as a 
 
  15   result of the irresponsible action of Congress in passing 
 
  16   the pharmacy compounding provisions of FDAMA.

  17             Chapter 1206 of the USP provides two examples of 
 
  18   high‑risk sterile products intended for IV injection that 
 
  19   can be produced from non‑sterile bulk drug substances, 
 
  20   morphine and total parenteral nutrition solutions.  Because 
 
  21   these products are readily available in a variety of

  22   formulations, we can conceive of no medical reason why they 
 
  23   should be compounded from non‑sterile bulk drug substances. 
 
  24             Morphine injection is available from numerous 
 
  25   FDA‑regulated manufacturers in a large number of varying 

                                                                143 
 
   1   concentrations including preservative‑free morphine

   2   injection. 
 
   3             TPN solutions, including dextrose solutions, 
 
   4   vitamins, and trace elements that may be needed to meet the 
 
   5   individual requirements of a patient are available as 
 
   6   sterile products for injection from a number of

   7   FDA‑regulated manufacturers. 
 
   8             Public Citizen is unable to conceive of a 
 
   9   legitimate medical scenario in which the benefits to a 
 
  10   patient from compounding an injectable product from a 
 
  11   non‑sterile bulk drug substance would outweigh the risks. 

  12   This is particularly true if the compounded product is 
 
  13   intended to be used in a setting other than an organized, 
 
  14   professionally staffed health care facility. 
 
  15             In addition to the products just mentioned, we 
 
  16   urge the FDA to include in the list of drug products that

  17   present demonstrable difficulties in compounding the 
 
  18   following categories of drugs:  all sustained or 
 
  19   time‑release dosage forms, re‑flavored antibiotics that 
 
  20   according to their FDA‑approved labeling require 
 
  21   reconstitution by a pharmacist at the time of dispensing,

  22   and enteric‑coated products.  All products intended fro 
 
  23   sublingual use should also be considered for listing. 
 
  24             An article appearing in the September‑October 1998 
 
  25   issue of the International Journal of Pharmaceutical 

                                                                144 
 
   1   Compounding, a trade publication of the International

   2   Academy of Compounding Pharmacists, concerning the 
 
   3   compounding of TPN solutions from non‑sterile bulk 
 
   4   substances plainly reveals that the motive for compounding 
 
   5   these solutions is not the health and welfare of patients. 
 
   6   It is instead, in substantial part, financial.

   7             I would like to read this brief paragraph. 
 
   8             In an effort to eliminate the threat of product 
 
   9   shortfalls and remain competitive with home infusion 
 
  10   companies that were divisions of amino acid solutions 
 
  11   manufacturers, HHCA, which is a home health care company,

  12   refined and developed this compounding method.  The company 
 
  13   determined that compounding TPN solutions using bulk drug 
 
  14   substances would be the first step towards full vertical 
 
  15   integration and decreased costs. 
 
  16             That concludes my comments, and I thank you very

  17   much for your attention. 
 
  18             I just have on observation about your earlier 
 
  19   discussions today.  There is an old word that when I was a 
 
  20   real pharmacist that we used to use when we took 
 
  21   FDA‑approved sterile products and manipulated them in an

  22   aseptic manner and under environmentally "conditions," and 
 
  23   we called this admixing, not compounding. 
 
  24             I think it might be easier in your discussions if 
 
  25   you make the distinction between sterile products that are 

                                                                145 
 
   1   FDA‑approved and manipulated properly and bulk drug

   2   substances that are prepared from non‑sterile, excuse me, 
 
   3   sterile products that are prepared from non‑sterile bulk 
 
   4   drug substances.  Only as a suggestion.  It was very 
 
   5   difficult for me to follow the conversation this morning.  
 
   6   It seems you were jumping back and forth between two

   7   different types of products, FDA‑approved products and 
 
   8   non‑approved FDA products. 
 
   9             I would be happy to answer any questions. 
 
  10             DR. JUHL:  Thank you very much. 
 
  11             Questions or comments?

  12             [No response.] 
 
  13             DR. JUHL:  I think we will take up those topics 
 
  14   tomorrow, but I would appreciate it, when we get to that 
 
  15   tomorrow, if anyone on the committee could response to his 
 
  16   challenge of a legitimate medical scenario where there is a

  17   need for bulk drug substances used in TPN or in preparation 
 
  18   of a preservative‑free or otherwise morphine. 
 
  19             We had reserved some time for Susan Guzzo, but I 
 
  20   don't believe she is here.  I think we may have 
 
  21   miscommunicated with each other on which day she was going

  22   to appear, and we will provide time tomorrow. 
 
  23             Shelley Capps of the International Academy of 
 
  24   Compounding Pharmacists has asked for a couple of minutes. 
 
  25             MS. CAPPS:  I really just have a question and 

                                                                146 
 
   1   appreciate the opportunity to pose it.

   2             Will the committee reconsider some of the 
 
   3   decisions that it has made once it hears all of the public 
 
   4   comments, because we are not scheduled to speak until 
 
   5   tomorrow, and many of the things that we are talking about 
 
   6   have been addressed today, so it would seem essentially, our

   7   comments would not be important to the recommendations that 
 
   8   are being made by the committee unless we are given an 
 
   9   opportunity to speak, and then I guess recommendations could 
 
  10   be reconsidered. 
 
  11             DR. JUHL:  That is why I wanted to make sure that

  12   you had the opportunity to speak on the earlier discussions 
 
  13   that we had.  Is there other information on metered dose 
 
  14   inhalers? 
 
  15             MS. CAPPS:  Our fundamental concern is actually 
 
  16   the law, the language in the law.  It specifically says that

  17   a drug product should be considered demonstrably difficult 
 
  18   and does not talk about complete categories of drug 
 
  19   products. 
 
  20             So, looking at broad‑sweeping categories, this 
 
  21   morning I felt like it was very specific, you got down to

  22   the canisters, and that is probably okay, but as we move 
 
  23   into these other broad categories, there is great concern 
 
  24   and I don't ‑‑ that is not what Congress intended.  It says 
 
  25   four times in that demonstrably difficult clause that a drug 

                                                                147 
 
   1   product should be considered, and FDA's own definition of a

   2   drug product is a finished dosage form, for example, tablet, 
 
   3   capsule, solution, et cetera, that contains an active drug 
 
   4   ingredient generally, but not necessarily, in association 
 
   5   with inactive ingredients.  The term also includes a 
 
   6   finished dosage form that does not contain an active

   7   ingredient, but is intended to be used as a placebo. 
 
   8             So, that clearly defined a drug product, and that 
 
   9   is the term that is used in legislation.  So, that is our 
 
  10   fundamental concern with the approach that this committee is 
 
  11   taking, and if you find that valuable, then, maybe some of

  12   the recommendations that you have made would need to be 
 
  13   reconsidered. 
 
  14             DR. JUHL:  I appreciate that.  I think that is a 
 
  15   valid question to be asked, however, it is a question of law 
 
  16   and interpretation, not one of scientific or professional

  17   practice, which is what I view this committee's prerogative 
 
  18   to be. 
 
  19             Obviously, if the attorneys determine that your 
 
  20   interpretation is better than their interpretation, then, 
 
  21   that would require the committee to reconsider their

  22   decisions on these things, too, but at this point, I think 
 
  23   my choice is not to engage the committee in a discussion of 
 
  24   law.  We are not prepared for that.  Technically speaking, 
 
  25   we are a scientific advisory committee. 

                                                                148 
 
   1             MS. CAPPS:  Okay.

   2             DR. JUHL:  But that is not to say you can't make 
 
   3   your case on the topic tomorrow either. 
 
   4             MS. CAPPS:  Oh, we certainly will, yes. 
 
   5             DR. JUHL:  Okay. 
 
   6             MS. CAPPS:  Also, I would love to claim for the

   7   International Academy of Compounding Pharmacists the 
 
   8   International Journal of Pharmaceutical Compounding, but it 
 
   9   is not our trade journal.  So, I just wanted to make that 
 
  10   clarification. 
 
  11             Thank you.

  12             DR. JUHL:  Thank you for the clarification. 
 
  13             Comments or suggestions on the Academy's comments? 
 
  14             [No response.] 
 
  15             DR. JUHL:  Is there anyone else in the audience 
 
  16   who would like to avail themselves of the opportunity to

  17   make a presentation to the committee? 
 
  18             [No response.] 
 
  19             DR. JUHL:  Seeing none, we will move forward with 
 
  20   the next topic on our agenda. 
 
  21             We will continue with our Demonstrably Difficult

  22   to Compound discussion.  The next topic is Transdermal 
 
  23   Delivery Systems.  Dr. Vinod Shah and Dr. Amit Mitra, both 
 
  24   of CDER. 
 
  25             Welcome. 

                                                                149 
 
   1          Demonstrably Difficult to Compound (Continued)

   2                   Transdermal Delivery Systems 
 
   3             DR. SHAH:  Thank you, Chairman, and I want to 
 
   4   thank the committee for giving us this opportunity to 
 
   5   discuss the difficulties of compounding especially the 
 
   6   transdermal drug delivery system.

   7             [Slide.] 
 
   8             What I will be talking today is primarily the 
 
   9   system which is coming out as a patch, and I will not be 
 
  10   discussing the areas of other types of skin delivery system, 
 
  11   drug delivery system called the iontophoretic drug delivery. 

  12   So, that is not going to be discussed today, it is only 
 
  13   discussing the transdermal drug delivery system, so I just 
 
  14   want to make that differentiation between the two types of 
 
  15   products which are available for skin drug delivery. 
 
  16             [Slide.]

  17             The transdermal drug delivery system is a 
 
  18   self‑contained discrete dosage form.  It delivers the drug 
 
  19   through intact skin at a controlled rate into the system 
 
  20   circulation.  Also, it delivers the drug at the controlled 
 
  21   rate through the skin where the skin or the membrane are the

  22   controlling drug delivery factors. 
 
  23             [Slide.] 
 
  24             The transdermal system is a sophisticated complex 
 
  25   delivery system difficult to formulate.  It requires 

                                                                150 
 
   1   specialized manufacturing process and the equipment.

   2             It is formulated to meet specific 
 
   3   biopharmaceutical and functional characteristics.  The 
 
   4   materials of construction, how to make a transdermal system, 
 
   5   the configuration and the combination of the drug with the 
 
   6   proper cosolvents, excipient, penetration enhancers, and

   7   membranes are carefully selected and matched to optimize 
 
   8   adhesive properties and drug delivery requirements in the 
 
   9   transdermal drug delivery system. 
 
  10             The system is also formulated to deliver the drug 
 
  11   at an optimized rate into the systemic circulation, so that

  12   it should adhere to the skin surface for the expected 
 
  13   duration of time.  For example, in some cases, it may be for 
 
  14   a day or in some cases it may be a week, seven days.  So, 
 
  15   the transdermal system should stick to the skin for the 
 
  16   expected length of time, and should not cause any skin

  17   irritation or sensitization reactions when it is being used. 
 
  18             [Slide.] 
 
  19             There are four different major types of the 
 
  20   transdermal drug delivery systems.  One is called the liquid 
 
  21   reservoir patch where the drug is in solution or suspension,

  22   and it is kept between the backing layer and the rate 
 
  23   controlling membrane. 
 
  24             The other type of the system is called the drug in 
 
  25   adhesive patch where the drug is dispersed in adhesive, and 

                                                                151 
 
   1   it is in direct contact with the skin where it delivers the

   2   drug. 
 
   3             The other system is called the polymer matrix 
 
   4   patch where the drug is kept in solution or suspension, and 
 
   5   it is dispersed within a polymer. 
 
   6             The last type is a polymer laminate matrix patch

   7   where the drug is dispersed in adhesive in multi‑layers 
 
   8   separated by the membranes. 
 
   9             The following slide just shows you an example of 
 
  10   the different type of the membranes and the compositions as 
 
  11   to how these patches are being prepared.

  12             [Slide.] 
 
  13             It is important to keep in mind that we need these 
 
  14   types of sophisticated membranes and the drug dispersions 
 
  15   for the appropriate drug delivery into the skin. 
 
  16             [Slide.]

  17             Now, we have considered seven different factors to 
 
  18   see whether the drug product could be manufactured or not.  
 
  19   So, the factors considered to show that the products are 
 
  20   demonstrably difficult to compound are the drug delivery 
 
  21   system itself, the drug formulation and consistency, the

  22   bioavailability of the dosage form, and also the complexity 
 
  23   of compounding, facilities and the equipment needed to 
 
  24   manufacture such patches, the training needed to make such 
 
  25   patches, and the testing and the quality assurance aspects. 

                                                                152 
 
   1             These are the seven factors that we have

   2   considered in evaluating the transdermal dosage form.  The 
 
   3   first three factors, the drug delivery system, formulation 
 
   4   and consistency, and the bioavailability will be discussed 
 
   5   by me.  After that, Dr. Amit Mitra will come on the podium 
 
   6   and will discuss the other three factors, which is the

   7   complexity of compounding, facilities and equipment, 
 
   8   training, and then I will come back and give you my 
 
   9   concluding slides. 
 
  10             [Slide.] 
 
  11             Now, the drug delivery system, as indicated

  12   before, each transdermal system is optimized to deliver the 
 
  13   drug at the desired rate into the systemic circulation.  The 
 
  14   components are selected based on the physicochemical and 
 
  15   pharmacological properties of the drug to optimize the drug 
 
  16   penetration rate.

  17             The variability in the component mixture or 
 
  18   manufacturing process may not ensure adequate 
 
  19   biopharmaceutics quality of the product. 
 
  20             Appropriate quality control measures and the 
 
  21   stability of the formulations are essential to ensure dosing

  22   accuracy  and reproducibility.  It is important to make sure 
 
  23   that each product, each dosage from one after the other will 
 
  24   have the same type of properties, and it will deliver the 
 
  25   drug at the same rate. 

                                                                153 
 
   1             [Slide.]

   2             The drug formulation and the consistency.  The 
 
   3   proper formulation is essential again to provide the 
 
   4   consistency and the reproducible drug delivery.  Components 
 
   5   of the formulation, which includes the vehicle, the 
 
   6   penetration enhancers or surfactant and adhesives must be

   7   adequately tested and studies for compatibility.  You cannot 
 
   8   just take a few components, try to mix it, it may be 
 
   9   incompatible.  So, those things need to be studied before it 
 
  10   is being used. 
 
  11             These components affect the release rate of the

  12   drug and adherence of the device to the skin, which is the 
 
  13   essential for efficacy of the drug product. 
 
  14             [Slide.] 
 
  15             The other factors are the vehicle selection is 
 
  16   very important.  A vehicle that optimally delivers one drug

  17   substance may not be appropriate for delivery of a different 
 
  18   drug substance. 
 
  19             Vehicles can grossly affect the drug 
 
  20   bioavailability and influence the clinical outcome of the 
 
  21   drug.

  22             [Slide.] 
 
  23             Drug formulations and consistency.  The adhesive 
 
  24   selected should provide good skin contact over the total 
 
  25   area of application for entire duration to ensure adequate 

                                                                154 
 
   1   drug delivery.

   2             Interactions with all the components including 
 
   3   skin irritation and sensitization need to be evaluated to 
 
   4   ensure dosing accuracy and reproducibility. 
 
   5             [Slide.] 
 
   6             From the biopharmaceutics point of view, it is

   7   important to ensure that the product effectiveness, the rate 
 
   8   and extent of drug delivery, the pharmacokinetic 
 
   9   reproducibility, and the optimization of application site 
 
  10   with the formulations are really evaluated before the 
 
  11   transdermal drug delivery system is being introduced.  These

  12   are the factors which are being studied extensively before a 
 
  13   formulation is being approved. 
 
  14             [Slide.] 
 
  15             The bioavailability aspects.  Appropriate 
 
  16   biopharmaceutical properties of the transdermal drug

  17   delivery system is most vital to deliver the drug at 
 
  18   optimized rate for therapeutic effectiveness of the drug 
 
  19   product. 
 
  20             Lower rates of delivery may result in ineffective 
 
  21   drug concentrations, and higher rates of drug delivery may

  22   result in toxic and adverse reactions. 
 
  23             The optimized formulation with adequate adhesive 
 
  24   properties at the site of application are important to 
 
  25   assure reproducible bioavailability and drug effectiveness.  

                                                                155 
 
   1   These transdermal delivery systems are generally replacing

   2   the orderly administered drugs at different time intervals.  
 
   3   Once a transdermal system is applied, it is being kept maybe 
 
   4   in some cases up to five to seven days, or three days, and 
 
   5   the drug concentrations are maintained.  They are maintained 
 
   6   at the constant level profile, and that is really essential

   7   to have the product efficacy. 
 
   8             If the rate infiltrate is varied or changed, those 
 
   9   levels will be varied, and the patient may not have a 
 
  10   constant therapeutic effect, and therefore, the proper rate 
 
  11   input is essential for the product quality and effectiveness

  12   to assure that. 
 
  13             I think at this stage, Dr. Amit Mitra will be 
 
  14   coming, and he will be talking about the three other factors 
 
  15   before I come back to the last conclusions of the quality. 
 
  16             DR. MITRA:  Thank you, Vinod.

  17             [Slide.] 
 
  18             As Dr. Shah mentioned, there are several types of 
 
  19   transdermal products.  There are three major types that we 
 
  20   have seen in both my industrial career, as well as in the 
 
  21   FDA ‑ drug in adhesive, drug in reservoir with a membrane,

  22   and drug in matrix with adhesive overlay. 
 
  23             The third one, it dropped off because of the size 
 
  24   disadvantage, and now these two categories, that is what we 
 
  25   see. 

                                                                156 
 
   1             [Slide.]

   2             Of the component and composition, of course, there 
 
   3   is an active moiety, and the active moiety, it could be a 
 
   4   new molecular entity or a compendial item, and since a lot 
 
   5   of these transdermal products, they are not new molecular 
 
   6   entities, these are relating to the different type of dosage

   7   form.  Therefore, these are compendial. 
 
   8             These are pressure sensitive adhesive, solvent, 
 
   9   penetration enhancer, backing, and release liner.  On top of 
 
  10   that, the drug in reservoir formulation would have a 
 
  11   membrane, and I will go into the functionality of each one

  12   of those and why those are important. 
 
  13             The third show would show you the schematic of 
 
  14   these.  There are five components in the drug in reservoir.  
 
  15   Going from the back, there is a backing here, and then there 
 
  16   is drug in the reservoir form with penetration enhancer and

  17   solvent, and then there is a rate controlling membrane on 
 
  18   top of that, and, of course, the adhesive has to be there, 
 
  19   so that the product can be sticking to the skin.  There is a 
 
  20   peel‑up release liner for this type of product. 
 
  21             For the drug in adhesive, it is simpler.  There

  22   are three components.  There is the backing portion, there 
 
  23   is drug into solution, adhesive formulation, and then there 
 
  24   is a peel‑up release liner. 
 
  25             [Slide.] 

                                                                157 
 
   1             As I mentioned earlier, the functional components

   2   are adhesive, penetration enhancer, backing, release liner, 
 
   3   and membrane.  I will go into each of them in detail, what 
 
   4   they are composed of, and why they are difficult to control. 
 
   5             The adhesives are made out of either silicon or 
 
   6   acrylate or rubber‑based polymers.  These adhesives would

   7   have to maintain a skin contact for long period of time, 
 
   8   either one to seven days as Vinod mentioned. 
 
   9             The penetration enhancer and the backing, the 
 
  10   penetration enhancer has to be compatible with the adhesive, 
 
  11   as well as the active component will have to be compatible

  12   with it. 
 
  13             The companies employ technical staff to determine 
 
  14   the suitability of the pressure sensitive adhesives and the 
 
  15   penetration enhancers.  It is a very costly process, and the 
 
  16   penetration enhancer itself is responsible for the

  17   penetration enhancement. 
 
  18             What we have seen, there are penetration enhancers 
 
  19   like ethanol, which is fairly pure, but there are 
 
  20   penetration enhancers which are like surfactants, which is a 
 
  21   combination of various different components.

  22             For characterization of this type of ingredients, 
 
  23   high performance liquid chromatography is necessary to 
 
  24   maintain the consistency in the product performance. 
 
  25             The backing is a functional component.  The 

                                                                158 
 
   1   surface of the backing has to be characterized and carefully

   2   evaluated.  The corona treatment is a process where an 
 
   3   electrostatic charge is placed on the backing to make it 
 
   4   adhere to the adhesive. 
 
   5             With proper characterization and quality control, 
 
   6   the performance of the product would not be achieved.  The

   7   release liner has, even though it looks simple, but it has a 
 
   8   functional property to release easily, so that the patient 
 
   9   can take it off and apply the patch quickly. 
 
  10             For the drug in reservoir type systems, the 
 
  11   membrane permeability is very important, whereas, the

  12   porosity and the gurley properties of the membrane, in a 
 
  13   sense determine the permeability of the membrane is 
 
  14   important.  Without that, the drug would not be delivered at 
 
  15   the proper rate. 
 
  16             Ultimately, the pouch is a configuration which is

  17   used for storing these transdermal products, and especially 
 
  18   important for the products components like ethanol.  These 
 
  19   components, as I mentioned before, like penetration 
 
  20   enhancers, those enhancers, the penetration rate through the 
 
  21   skin, and if it is not stored properly in a safe manner, the

  22   ethanol is going to evaporate off and we wouldn't get the 
 
  23   efficacy we need. 
 
  24             [Slide.] 
 
  25             The facilities and the equipment.  The facilities 

                                                                159 
 
   1   involve the installation of the following equipments, like

   2   mixer, dryer, coater‑laminator, Slitter, die cutting, and 
 
   3   the pouching equipment. 
 
   4             For mixer, usually, the high shear mixer is used 
 
   5   for proper uniformity of the active and the penetration 
 
   6   enhancer in the system.  The coater and laminator can be

   7   purchased from outside vendor, however, there is a drying 
 
   8   step involved, which needs installation of an 
 
   9   explosion‑proof oven, because of the fact that there are 
 
  10   volatile components involved, and which could be explosive 
 
  11   in nature.

  12             Because of the problem associated with 
 
  13   installation of both vacuum processor as well as the dryers, 
 
  14   it is difficult to install in a non‑industrial setting. 
 
  15             For proper ventilation of the solvent, we need the 
 
  16   ventilation of solvents like hexane, toluene, heptane, ethyl

  17   acetate, which are fairly toxic, and also the pressure 
 
  18   sensitive areas has a small concentration of monomers and 
 
  19   which are fairly toxic, and those have to be ventilated. 
 
  20             It is essential that the facilities used have 
 
  21   adequate space to install the equipment and that individuals

  22   with sufficient engineering knowledge and the training be 
 
  23   utilized. 
 
  24             [Slide.] 
 
  25             The hazard involved, for storage of adhesives and 

                                                                160 
 
   1   solvents, special solvent cabinets for explosion‑proof

   2   solvents are necessary, and as I said earlier, these are 
 
   3   part of the formulation which are operated up.  Since 
 
   4   flammable solvents are driven off during the preparation of 
 
   5   the laminate, installation of the explosion‑proof oven is 
 
   6   necessary.  Moreover, ventilation of the solvents and

   7   monomers are of utmost importance for safety reasons.  In 
 
   8   certain areas, the workers need to be put on respirators to 
 
   9   avoid exposure to solvents. 
 
  10             [Slide.] 
 
  11             As far as the quality control of the finished

  12   product, these are the attributes that are tested ‑ content 
 
  13   of the drug, active drug, which is 90 to 110 percent as a 
 
  14   limit, and assay of the penetration enhancer, and high 
 
  15   performance liquid chromatography is used for determining 
 
  16   the content of the drug of penetration enhancer.

  17             The content uniformity, the criteria should meet 
 
  18   USP 905.  For release rate, several USP apparatus, 
 
  19   recommended apparatus, App 5, 6, and 7, so installation of 
 
  20   this equipment and proper training of the staff to run this 
 
  21   equipment is necessary, along with an HPLC apparatus, and

  22   the staff to run this equipment is necessary. 
 
  23             For residual solvents and residual monomers, since 
 
  24   they are toxic, irritating, or sensitizing, GC is 
 
  25   recommended for monitoring those. 

                                                                161 
 
   1             The microbiology, it's a non‑sterile product.  We

   2   ask for total aerobic and mold count, and also absence from 
 
   3   objectionable microorganisms. 
 
   4             Finally, there is a pouch integrity test, as I 
 
   5   mentioned earlier.  The pouch is where the transdermal drug 
 
   6   is stored, and if a volatile component is there, you have

   7   got to make sure that the pouch is sealed in a way that the 
 
   8   solvent doesn't evaporate off. 
 
   9             With that, I will have Dr. Shah make the 
 
  10   preliminary conclusion for FDA. 
 
  11             DR. SHAH:  Well, we just heard the importance of

  12   testing and the quality assurance from product to product, 
 
  13   from one patch to the next patch, and that is very essential 
 
  14   to assure that the product effectiveness would be maintained 
 
  15   when it is being applied. 
 
  16             [Slide.]

  17             With these seven factors now then already 
 
  18   considered, our preliminary findings suggest the following:  
 
  19   difficulties in compounding results from the following 
 
  20   characteristics and requirements. 
 
  21             The transdermal drug delivery systems are

  22   sophisticated and complex.  It requires extensive experience 
 
  23   to develop a product that can ensure dosing accuracy and 
 
  24   reproducibility. 
 
  25             Sophisticated equipment and facilities are needed 

                                                                162 
 
   1   to ensure proper compounding of the transdermal drug

   2   delivery systems. 
 
   3             Sophisticated technical training is essential to 
 
   4   ensure the proper compounding of the TDS products, and also 
 
   5   again sophisticated, difficult to perform testing of the 
 
   6   compounded product is required to ensure product‑to‑product

   7   uniformity from one batch to the other batch, potency, 
 
   8   purity, and quality of the drug product prior to the 
 
   9   dispensing of the product. 
 
  10             [Slide.] 
 
  11             The preliminary conclusions are we have

  12   tentatively determined that the transdermal drug delivery 
 
  13   system drug products present demonstrable difficulties in 
 
  14   compounding, and these difficulties would likely have an 
 
  15   adverse effect on the safety and effectiveness of such drug 
 
  16   products.

  17             Those are our preliminary conclusions, and we will 
 
  18   be happy to answer any questions that the committee may 
 
  19   have. 
 
  20             DR. JUHL:  Thank you, Dr. Shah and Dr. Mitra. 
 
  21             We will open it up to discussion amongst committee

  22   members. 
 
  23                       Committee Discussion 
 
  24             DR. ALLEN:  Very nice presentations.  I don't have 
 
  25   any problems with that.  I don't think anybody is actually 

                                                                163 
 
   1   compounding transdermal patches anyway, but I would have one

   2   request, and that is, in the definition, at some point, 
 
   3   where we read that it is self‑contained discrete dosage 
 
   4   forms, et cetera, could we also include the terminology 
 
   5   commonly called patches, so that we would differentiate 
 
   6   patches from other transdermal types of dosage forms.

   7             DR. JUHL:  Such as a transdermal cream? 
 
   8             DR. ALLEN:  Ointments, creams.  At least this way 
 
   9   we know exactly what we are referring to. 
 
  10             DR. JUHL:  It is my understanding that was the 
 
  11   area that you carved out to include.

  12             DR. ANDERSON:  Yes.  I think we worded it, saying 
 
  13   we are only talking about these four types, that is listed 
 
  14   in the paper. 
 
  15             DR. JUHL:  And it doesn't include creams, it 
 
  16   doesn't include topicals that are on an adhesive, used for

  17   direct application or direct action. 
 
  18             DR. ANDERSON:  Right, it is the only the four 
 
  19   types that we had put in the paper.  Dr. Shah had mentioned 
 
  20   it in the beginning. 
 
  21             DR. JUHL:  If you would add that clarification,

  22   then, we would be clear. 
 
  23             DR. ANDERSON:  Sure. 
 
  24             DR. SHAH:  May I make a comment on that?  
 
  25   Generally, the transdermal drug delivery system is defined 

                                                                164 
 
   1   as one in which it is applied to the skin, the drug is

   2   delivered through the skin, and it goes into the systemic 
 
   3   circulation for any activity. 
 
   4             Now, only the nitroglycerine cream and ointment 
 
   5   are the only ones where it does not fall into that category 
 
   6   that it is a patch, because in that case also, it goes to

   7   the skin, and it is being used for the systemic activity, so 
 
   8   that is an exclusion, and that is why we had the cream on 
 
   9   that solvent, I showed you the different types of the 
 
  10   systems. 
 
  11             DR. JUHL:  So that I am real clear in what is

  12   included in the area of the types of the products that you 
 
  13   are recommending not be available for compounding, they are 
 
  14   patches only? 
 
  15             DR. SHAH:  Yes. 
 
  16             DR. JUHL:  And they don't include creams and

  17   ointments. 
 
  18             MR. TRISSEL:  With that in mind, the second 
 
  19   category there includes cotton pads, and I am not sure that 
 
  20   is what you are talking about.  That would be band‑aids and 
 
  21   cotton plagets, and whatever.

  22             DR. SHAH:  Band‑aids are different.  I am not 
 
  23   talking about the band‑aids.  I am talking about the 
 
  24   therapeutic drugs where it is prepared, manufactured in the 
 
  25   form of a patch, transdermal delivery, and then it is being 

                                                                165 
 
   1   administered.

   2             MR. TRISSEL:  Then, perhaps the terminology cotton 
 
   3   pad needs to be deleted from that. 
 
   4             MS. AXELRAD:  Could you say for the record where 
 
   5   that is in the concept paper? 
 
   6             MR. TRISSEL:  It is on page 20, about the second

   7   paragraph, second item. 
 
   8             DR. ALLEN:  It is actually in the third paragraph 
 
   9   under B, Transdermal Systems.  The paragraph starts, "The 
 
  10   four major types," and then you have got number 1, number 2, 
 
  11   and it's the matrix type.

  12             DR. ANDERSON:  The four major types? 
 
  13             DR. ALLEN:  Yes.  It says, "matrix, which consists 
 
  14   of a solution or suspension." 
 
  15             DR. ANDERSON:  Why don't we just take the word 
 
  16   "cotton pad" out of the definition.

  17             MS. RIFFEE:  I think there is further 
 
  18   clarification at the last paragraph on that page, where it 
 
  19   specifically says this does not include things like ‑‑ 
 
  20             DR. ANDERSON:  Right. 
 
  21             DR. JUHL:  Other comments?  Does anyone on the

  22   committee have knowledge of pharmacists that are making 
 
  23   patches?  Does the Academy have knowledge of pharmacists 
 
  24   that are extemporaneously preparing patches? 
 
  25             Let the record show that heads were shaking in the 

                                                                166 
 
   1   no direction.

   2             Are you ready for the question or is there other 
 
   3   discussion? 
 
   4             Question No. 4.  Do you agree that the class of 
 
   5   transdermal drug systems, as defined in the concept paper, 
 
   6   should be included on the list of drug products that may not

   7   be compounded because they are difficult to compound 
 
   8   properly? 
 
   9             MR. TRISSEL:  Can we amend that to say "commonly 
 
  10   called patches" or something, so that we are clear on what 
 
  11   we are enacting here?

  12             DR. JUHL:  We can do that. 
 
  13             Do you agree that the class of transdermal drug 
 
  14   systems, as defined in the concept paper, and commonly 
 
  15   called patches, should be included on the list? 
 
  16             Are you ready for the question?

  17             All those who agree with that recommendation, 
 
  18   please signify by raising your hands. 
 
  19             [Show of hands.] 
 
  20             DR. JUHL:  It is unanimous.  Thank you very much. 
 
  21             We are now an hour ahead of time.  Is the

  22   individual who is scheduled to present the overview for the 
 
  23   committee for tomorrow here, and could we get that out of 
 
  24   the way now? 
 
  25             MS. AXELRAD:  He isn't here, but we could probably 

                                                                167 
 
   1   see if we could get him here, if you could give mr perhaps

   2   five minutes, and let me see if I can contact him. 
 
   3             DR. JUHL:  We can take a 15‑minute break and 
 
   4   decide our strategy at that point. 
 
   5             [Recess.] 
 
   6             DR. JUHL:  We will begin.  We appreciate the

   7   flexibility of both the FDA staff and the committee members 
 
   8   for allowing us to alter our agenda slightly. 
 
   9             We were scheduled tomorrow to have a presentation 
 
  10   to the committee on sterile drug products by Dr. Peter 
 
  11   Cooney, and we have located him, and he has graciously

  12   agreed to give the presentation now, so that will help us 
 
  13   get a headstart tomorrow morning. 
 
  14             Please rest assured that the open public session 
 
  15   for 8:30 tomorrow will go off as scheduled.  We will not 
 
  16   change that part of our agenda, so that does mean we will be

  17   here overnight for committee members. 
 
  18             So, let us proceed.  Dr. Cooney. 
 
  19                      Sterile Drug Products 
 
  20             DR. COONEY:  Thank you.  Apparently, my voice mail 
 
  21   didn't work, and I did get contacted, and I am here.

  22             [Slide.] 
 
  23             The topic, of course, for discussion in this time 
 
  24   slot, as just stated, is the inclusion of sterile drug 
 
  25   products as a class on the list of products that are 

                                                                168 
 
   1   demonstrably difficult to compound if they are prepared on

   2   procedures other than those described in Chapter 1206 of the 
 
   3   United States Pharmacopeia. 
 
   4             Now, the comments that I want to make are from the 
 
   5   perspective of the preparation of drugs as that process 
 
   6   applies to sterilization, sterility assurance, and

   7   microbiological safety of drug products. 
 
   8             The FDA and sterile drug product manufacturers are 
 
   9   well aware of the difficulty in production of these drugs, 
 
  10   the pitfalls that can be encountered, and the consequences 
 
  11   to the public health if the processes used to make such

  12   drugs are not well controlled. 
 
  13             Sterility of parenteral, ophthalmic, and aqueous 
 
  14   inhalation solution drug products is a fundamental and 
 
  15   essential quality attribute of these products, and as such, 
 
  16   is a critical aspect of the safety assessment of these

  17   products. 
 
  18             Sterility assurance cannot be tested into a 
 
  19   product, nor any tests sensitive enough to detect 
 
  20   unacceptable sterility assurance levels in these products.  
 
  21   The preparation of sterile products is an exacting,

  22   difficult, and highly controlled series or processes 
 
  23   especially in the case of aseptically filled products. 
 
  24             Critical scientific assessment of the experimental 
 
  25   methods in process controls, tests, and other aspects of 

                                                                169 
 
   1   this processing is essential to ensure adequate safety of

   2   these products and to protect the public health. 
 
   3             Determination of the efficacy of a given 
 
   4   sterilization process for a specific drug product entails a 
 
   5   series of protocols and scientific experiments designed to 
 
   6   demonstrate that the sterilization process and associated

   7   control procedures can reproducibly deliver a sterile 
 
   8   product. 
 
   9             The data derived from the experiments and control 
 
  10   procedures allow certain conclusions to be drawn about the 
 
  11   probability of non‑sterile product units, sterility

  12   assurance level. 
 
  13             The scientific validity of the protocols and 
 
  14   methods, the scientific validity of the results, and the 
 
  15   conclusions drawn from those results constitutes a 
 
  16   validation of the efficacy of the sterilization process.

  17             Product testing in concert with total control of 
 
  18   the manipulations, processes, equipment, environment, and 
 
  19   highly trained personnel are required to ensure that the 
 
  20   produced product is sterile. 
 
  21             When preparing sterile products, there is

  22   essentially only two ways to do it.  Products can be 
 
  23   terminally sterilized, that is, sterilized in their final 
 
  24   containers with no further manipulations which could result 
 
  25   in contamination. 

                                                                170 
 
   1             Examples of terminal sterilization processes are

   2   autoclaving, radiation, or ethylene oxide.  For drug 
 
   3   products, use of autoclaves is by far the most common 
 
   4   method. 
 
   5             The other method of preparation, that is, the 
 
   6   other method than terminal sterilization, is by aseptic

   7   processing.  Aseptic processing involves the use of 
 
   8   components which are independently sterilized and then 
 
   9   assembled together aseptically. 
 
  10             The difference is significant in that there is no 
 
  11   manipulation of product components after sterilization for

  12   terminally sterilized products, whereas, there is such 
 
  13   manipulation for aseptically produced products. 
 
  14             [Slide.] 
 
  15             Now, so far, all I have talked about concerns 
 
  16   sterility aspects of sterile products.  This is, from our

  17   point of view, particularly important because of the 
 
  18   potential for even a single microorganism in a product to 
 
  19   proliferate. 
 
  20             Hence, the risk associated with these types of 
 
  21   operations is linked to the potential for introduction of

  22   microorganisms into the product through manipulation during 
 
  23   compounding, and whether the organisms introduced can 
 
  24   proliferate in the product, and under what conditions of 
 
  25   storage, that is, time and temperature, that the product is 

                                                                171 
 
   1   stored after compounding.

   2             [Slide.] 
 
   3             Now, USP Chapter 1206 utilizes the concept of 
 
   4   relatively low risk and relatively high risk compounding 
 
   5   operations for production of sterile finished drug products.  
 
   6   Essentially, relatively low or high risk is defined by the

   7   potential for introduction of microbial contamination. 
 
   8             Relatively low risk operations are those in which 
 
   9   commercially available, presterilized drug products and 
 
  10   components are used.  In addition, the production or 
 
  11   compounding process involves only a few simple and basic

  12   aseptic manipulations in which "closed system" transfers are 
 
  13   used. 
 
  14             What is meant here I think is a transfer where 
 
  15   there is a minimum exposure of the contents of a container 
 
  16   to the outside environment.  As an example, the penetration

  17   of elastomeric closures with a needle or cannula. 
 
  18             Note that the whole idea here with relatively low 
 
  19   risk products is that the chances of inadvertent 
 
  20   contamination are relatively low. 
 
  21             [Slide.]

  22             Relatively high risk operations are simply those 
 
  23   that offer higher risk of contamination.  A relatively 
 
  24   higher risk of contamination could occur because 
 
  25   intermediate closed systems or open systems are used in the 

                                                                172 
 
   1   compounding operation.

   2             Why is that?  Because the system containing 
 
   3   sterile product had a greater exposure to the environment. 
 
   4             A high risk operation could be one where complex 
 
   5   or numerous aseptic operations are carried out over longer 
 
   6   periods of time.  Here again, because the greater the number

   7   of the more complex or the longer the operation is, the 
 
   8   greater the chances for inadvertent contamination. 
 
   9             Finally, a relatively high risk operation could be 
 
  10   one where non‑sterile drugs substances or components are 
 
  11   used to compound sterile products.  Here, additional risk is

  12   added because the non‑sterile components have to be 
 
  13   sterilized in‑house using a validated sterilization process, 
 
  14   a step not involved in the compounding when presterilized 
 
  15   commercially available materials are used. 
 
  16             Now, further concern, of course, is the presence

  17   of contaminants other than viable microorganisms.  Such 
 
  18   contaminants, which may be introduced to or contained in or 
 
  19   on the materials used to make the product, may include 
 
  20   products of microbial origin, such as exotoxins or 
 
  21   endotoxins, or non‑viable particulates, or chemical

  22   contaminants. 
 
  23             It is important to realize here that filtration of 
 
  24   the liquid portion of such products through bacterial 
 
  25   retentive filters will not remove molecular contaminants. 

                                                                173 
 
   1             So, for example, use of filtration to prepare a

   2   sterile parenteral solution from a non‑sterile endotoxin 
 
   3   contaminated powder will not remove the endotoxin component. 
 
   4             It is also important to be aware that bacterial 
 
   5   retentive filters, also referred to as sterilizing grade 
 
   6   filters, are not as they are purported to be, absolute. 

   7   That is, they do not always render a liquid product sterile 
 
   8   since they will not retain viruses, and they may not retain 
 
   9   all bacteria, especially those of diminutive size. 
 
  10             [Slide.] 
 
  11             I mention all of this just to emphasize three

  12   points.  First, sterility must be built into a product 
 
  13   through the preparation process and its associated controls. 
 
  14             Secondly, the preparation processes and associated 
 
  15   controls are unavoidably complex even for the most 
 
  16   sophisticated commercial manufacturers of sterile products.

  17             Lastly, any lapse in controls and processes used 
 
  18   to manufacture or compound sterile products can result in 
 
  19   significant public health hazards. 
 
  20             [Slide.] 
 
  21             Now, I would like to turn for a minute and discuss

  22   the evaluation factors that were discussed earlier this 
 
  23   morning in determining the potential effect of compounding 
 
  24   on the quality, purity, potency of a product as those 
 
  25   factors may relate to the safety and effectiveness of the 

                                                                174 
 
   1   product.

   2             Four of the factors we have determined in a 
 
   3   preliminary sense show a potential to demonstrate adverse 
 
   4   effects of the safety and effectiveness.  Those factors are 
 
   5   complexity of compounding, facilities and equipment, 
 
   6   training, and testing and quality assurance programs.

   7             [Slide.] 
 
   8             Complexity of compounding.  The manipulations, 
 
   9   processes, and controls necessary to successfully compound a 
 
  10   sterile product make the procedure unavoidably complex.  As 
 
  11   previously stated, the relative risk of a compounding or

  12   manufacturing operation for a sterile product is linked to 
 
  13   the risk for inadvertent contamination. 
 
  14             Each step of the process provides an opportunity 
 
  15   for inadvertent contamination.  Since contamination by even 
 
  16   a single microorganism may lead to proliferation with time,

  17   significant public health consequences may be the result.  
 
  18   Importantly, the contamination event would be totally 
 
  19   undetected at the time it occurs, and hence, extreme care 
 
  20   must be taken during processing of sterile products. 
 
  21             In addition to the possibilities of a single

  22   microorganism contaminating the product, other contaminants, 
 
  23   such as endotoxins, particulates, and foreign chemical 
 
  24   components must be excluded from certain types of sterile 
 
  25   products. 

                                                                175 
 
   1             Contaminants, whether viable microorganisms or

   2   others, can originate from any or all of the sources during 
 
   3   the preparation of a sterile product.  They may come from 
 
   4   the drug substance itself, the water, the containers, the 
 
   5   closures, the equipment, the environment, or maybe, most 
 
   6   importantly of all, the personnel.

   7             Exclusion of contaminants then is a complex and 
 
   8   difficult process, so that the manipulations and processes 
 
   9   must be tightly controlled.  This factor, namely, complexity 
 
  10   of compounding, would support we think the inclusion of 
 
  11   these products as a demonstrably difficult to compound.

  12             [Slide.] 
 
  13             Facilities and equipment.  The highly controlled 
 
  14   environment and procedures used require exacting standards 
 
  15   and often require sophisticated facilities and equipment.  
 
  16   Since contamination may come from any and all sources during

  17   preparation of sterile products, the facilities and 
 
  18   equipment used in such preparation must also be tightly 
 
  19   controlled. 
 
  20             Even if all the components used in the preparation 
 
  21   are of the highest quality possible, contamination can

  22   result from the environment, facilities and equipment, in 
 
  23   which the sterile drug is prepared. 
 
  24             Environmentally controlled work spaces suitable 
 
  25   for aseptic processing are necessary, such as laminar air 

                                                                176 
 
   1   flow work benches or rooms with concomitant design

   2   considerations for surrounding areas. 
 
   3             The facilities and equipment are specialized in 
 
   4   design for the purpose of preparation of sterile products.  
 
   5   In other words, they are designed to protect the product 
 
   6   from contamination.

   7             A tentative conclusion regarding this factor would 
 
   8   be that it also supports a difficult to compound 
 
   9   classification for sterile products. 
 
  10             [Slide.] 
 
  11             Training.  Pharmacy compounding of sterile

  12   products is likely highly personnel intense, and therefore, 
 
  13   pharmacy personnel involving compounding sterile products 
 
  14   must, of course, have sufficient knowledge, training, and 
 
  15   experience to perform the tasks correctly and safely. 
 
  16             Personnel must adhere to uniform and strict

  17   performance standards and have a fairly sophisticated level 
 
  18   of knowledge and training in aseptic technique.  Training in 
 
  19   aseptic technique alone, however, would likely be 
 
  20   insufficient.  Cleaning, sanitizing, and organization of the 
 
  21   laminar air flow workstation and rooms requires properly

  22   trained operators who should follow written procedures. 
 
  23             Special training may also be necessary for gowning 
 
  24   and operation of critical equipment or specialized aseptic 
 
  25   procedures, and any other operation necessary for the 

                                                                177 
 
   1   preparation of the sterile product.

   2             [Slide.] 
 
   3             Testing and quality assurance factor.  There is a 
 
   4   significant potential for harm to patients if sterile 
 
   5   products are compounded without proper quality assurance 
 
   6   programs in place.  Quality assurance can be accomplished

   7   when training, testing, facilities, and equipment are 
 
   8   properly used and monitored. 
 
   9             Quality assurance programs help to assure that the 
 
  10   program for preparation of sterile products, as a whole, is 
 
  11   under a state of control.  Testing, for example, a testing

  12   program to monitor the microbiological and particulate 
 
  13   quality of the environment is part of the quality assurance 
 
  14   program. 
 
  15             For purposes of monitoring microbiological quality 
 
  16   of the environment, non‑volumetric methods, such as settling

  17   plates are used, and volumetric methods, such as rooter 
 
  18   centrifugal air samplers can be used. 
 
  19             Monitoring and control of personnel, procedures, 
 
  20   facilities, bioburden, equipment, and training programs all 
 
  21   serve to help maintain a state of control in the preparation

  22   of sterile products. 
 
  23             Therefore, this aspect would also support a 
 
  24   demonstrably difficult to compound decision. 
 
  25             [Slide.] 

                                                                178 
 
   1             Preliminary conclusions indicate that these

   2   factors, drug delivery system, drug formulation and 
 
   3   consistency, and bioavailability, probably are not as 
 
   4   important as the four factors that I just discussed. 
 
   5             Sterile products do not usually require 
 
   6   sophisticated drug delivery systems.  They are also not

   7   particularly difficult to formulate in a consistent manner 
 
   8   since many of them are aqueous solutions, and 
 
   9   bioavailability of these drugs is not a major factor in most 
 
  10   cases since most are either injected or delivered directly 
 
  11   to the site of action.

  12             [Slide.] 
 
  13             So, a tentative conclusion is that these drug 
 
  14   products should be classified as difficult to compound.  We 
 
  15   recognize that compounding sterile products is unavoidably 
 
  16   complex and that if such products are compounded incorrectly

  17   there could be significant hazard to patients receiving such 
 
  18   medications. 
 
  19             We also recognize that there is a substantial need 
 
  20   for compounded sterile drug products especially in the area 
 
  21   of extemporaneous compounding.

  22             If compounding of such products occurs without 
 
  23   adherence to certain standards, the potential for adverse 
 
  24   effects on the safety and effectiveness of these drugs is 
 
  25   increased.  FDA has tentatively now concluded that USP 

                                                                179 
 
   1   Chapter 1206 describes such standards and that products

   2   compounded using these standards would not pose demonstrable 
 
   3   difficulties regarding safety of the drugs compound. 
 
   4             [Slide.] 
 
   5             We are therefore today asking for advice on at 
 
   6   least three specific questions related to this area.

   7             The first is:  Should sterile products not 
 
   8   compounded in accordance with USP 1206 be on the list of 
 
   9   drugs that are difficult to compound? 
 
  10             Secondly, is USP Chapter 1206 an appropriate 
 
  11   standard?

  12             Thirdly, should compliance with USP Chapter 1206 
 
  13   be required for compounding the relatively low‑risk sterile 
 
  14   products from sterile components? 
 
  15             Thank you. 
 
  16             DR. JUHL:  Thank you, Dr. Cooney.

  17             Do we have questions for Dr. Cooney about his 
 
  18   presentation? 
 
  19                       Committee Discussion 
 
  20             DR. JUHL:  If I might, let me start out.  This has 
 
  21   to do with the suitability of the USP Chapter as opposed to,

  22   say, something else, and in general, I would like to 
 
  23   compliment the agency for the good sense approach that you 
 
  24   have taken in referring to an already acknowledged standard 
 
  25   to refer to.  I like doing that rather than having to hammer 

                                                                180 
 
   1   that out here, and you probably like it even better than I

   2   do.  I appreciate that. 
 
   3             There are two categories in the USP Chapter and 
 
   4   three in ASHP.  Is there a utility in the three versus the 
 
   5   two disregarding where they came from in your review of the 
 
   6   various standards?

   7             DR. COONEY:  My personal view? 
 
   8             DR. JUHL:  Yes. 
 
   9             DR. COONEY:  I believe the individuals who are 
 
  10   involved in the compounding operation itself really are the 
 
  11   best people suited to determine what kind of a low risk or

  12   high risk type category the operation is in. 
 
  13             So, the bottom line is you need more care with 
 
  14   high risk operations than with low risk operations just 
 
  15   because there is a higher chance of contamination.  So, that 
 
  16   is kind of a subjective judgment that occurs at the time the

  17   operation is going on. 
 
  18             I really don't have an opinion on whether the 
 
  19   three categories are better than two or vice versa. 
 
  20             DR. JUHL:  The purpose, at least as I see it, in 
 
  21   promulgating these guidelines to have the effect of

  22   regulation is to prevent what happened in Pittsburgh with 
 
  23   the pharmacist, who with all good intents, formulated an 
 
  24   ophthalmic preparation that resulted in the loss of sight of 
 
  25   some individuals, but at the same time, not to close down 

                                                                181 
 
   1   every hospital pharmacy in the country.

   2             Do you have an idea where Chapter 1206 fits on 
 
   3   that spectrum, how many hospital pharmacy operations are 
 
   4   able to comply with it in its entirety, and I guess a more 
 
   5   general question, is that chapter written as a minimal 
 
   6   standard guideline or is it written as an ultimate gold

   7   standard, things we should all reach for kind of guideline? 
 
   8             DR. COONEY:  The chapter itself, of course, claims 
 
   9   not to be prescriptive.  The reason the FDA tentatively 
 
  10   concluded that Chapter 1206 is a reasonable standard is that 
 
  11   we believe that if you followed the standard, the products 

  12   you would make would not be demonstrably difficult to 
 
  13   compound, and the risk of their being contaminated would be 
 
  14   minimized. 
 
  15             We would really like input here today, and one of 
 
  16   the points of this, is to determine the practicality of

  17   complying with that standard, and that is why we asked is it 
 
  18   an appropriate standard. 
 
  19             There may be parts of that, that are difficult to 
 
  20   comply with, there may be parts that are not.  It is 
 
  21   certain, though, to respond to part of your question, it is

  22   certainly a goal to which to aspire.  Whether one could 
 
  23   actually meet every single statement in it, I don't know.  
 
  24   Perhaps the USP could comment better on that. 
 
  25             DR. JUHL:  I will ask them that question tomorrow.  

                                                                182 
 
   1   Joe Valentino was here, and he is not here now.  Oh, Frank

   2   is here. 
 
   3             Could I ask you to come to the microphone, please, 
 
   4   and identify yourself for the record. 
 
   5             MR. BARLETTA:  My name is Frank Barletta.  I am on 
 
   6   the scientific staff of the USP.  I am the liaison to the

   7   Water and Parenteral Subcommittee.  I have worked for the 
 
   8   last 10 years on this chapter. 
 
   9             I can give you the whole history, the whole 
 
  10   shooting match, but I think basically we will wait until 
 
  11   tomorrow and see what develops.  But I can give you USP's

  12   official statement, which I will read. 
 
  13             "In the May‑June 2000 issue of the Pharmacopeial 
 
  14   Forum, USP published a proposal to revise General Chapter 
 
  15   1206 regarding sterile preparations to expand its scope, to 
 
  16   include products for institutional as well as home use.

  17             "The revised chapter has not yet been made final.  
 
  18   This USP chapter was developed as an informational chapter 
 
  19   designed to provide guidelines as to what the USP believes 
 
  20   pharmacists should be doing to ensure the proper 
 
  21   preparation, dispensing, and control of sterile

  22   preparations. 
 
  23             "It was not developed with the intent that it 
 
  24   constituted minimal standards that must be complied with at 
 
  25   this time.  If this is to be the case, USP would have to 

                                                                183 
 
   1   review the chapter with this in mind prior to its becoming

   2   official to ensure that it was suitable for this purpose. 
 
   3             "In this regard, we would welcome the comments of 
 
   4   FDA, pharmacists, their associations, and others to ensure 
 
   5   that it was appropriate for this purpose." 
 
   6             The chapter has been published in the PF as a

   7   proposal.  It was published in May and June.  
 
   8   Pre‑publication copies were sent to several pharmacy 
 
   9   organizations.  We are sitting waiting for comments at this 
 
  10   point.  So, that is basically where we stand right now. 
 
  11             DR. JUHL:  Good.  I appreciate that.  Let me see

  12   if I understand the implications then.  As I understand law, 
 
  13   you have complied with the law 100 percent of the time.  
 
  14   With guidelines, it is kind of like my test, if you get an 
 
  15   85 percent, you are doing okay, and we would like you to get 
 
  16   90.  So, what I am hearing is that your chapter is not

  17   written for minimal standards, and it would need to be 
 
  18   reexamined were it to be adopted as such. 
 
  19             So, my question to the agency, are you willing to 
 
  20   go through this iterative process, reviewing the chapter for 
 
  21   that purpose, or are you saying that the standards that are

  22   proposed in the chapter are what they ought to be, period? 
 
  23             MS. AXELRAD:  I think we are certainly prepared to 
 
  24   go through the iterative process if it were agreed that that 
 
  25   would be a good starting point, and if the committee were to 

                                                                184 
 
   1   say that as opposed to some of the other standards that are

   2   out there, that we considered, such as the NABP and the ASHP 
 
   3   standards, you know, once we decided which of these was the 
 
   4   best starting point for this, we would certainly be prepared 
 
   5   to go over it and comment on it, and work with the USP 
 
   6   process to make sure that it was appropriate for what we

   7   were trying to do with it, that may not have been intended 
 
   8   originally when it was written. 
 
   9             DR. JUHL:  I think given that Congress directed 
 
  10   the agency to work with USP on other things, and the USP has 
 
  11   a long‑established open public process, that makes good

  12   sense to begin on that route. 
 
  13             MS. AXELRAD:  I am sure we would be working on it 
 
  14   anyway.  I am sure that we will be commenting on it even 
 
  15   were it just to be an informational chapter that had nothing 
 
  16   to do with compounding.  The people in the agency who deal

  17   with these things would be commenting on it in any event.  
 
  18   But if we were trying to use it for this particular purpose, 
 
  19   then, we would certainly be involved. 
 
  20             MR. BARLETTA:  That is what the briefing said in 
 
  21   the PF, and I will read it.

  22             "The chapter will remain an information chapter 
 
  23   since it contains no standards, tests, or assays, nor other 
 
  24   mandatory specifications with respect to any pharmaceutical 
 
  25   article as stated" ‑‑ and we give the chapter and verse. 

                                                                185 
 
   1             It does, however, represent guidelines developed

   2   through a public process by a legally‑recognized standard 
 
   3   body, which gives it special national standing. 
 
   4             It is numbered 1206 because that is a general 
 
   5   information chapter.  Any below 1000 is a mandatory chapter.  
 
   6   That was the intent of the chapter.

   7             MR. TRISSEL:  The compounding chapter is below 
 
   8   1000, right? 
 
   9             MR. BARLETTA:  The compounding chapter is a 
 
  10   mandatory chapter.  It's 790‑something. 
 
  11             DR. ALLEN:  The compounding chapter originally was

  12   11‑something.  It was a guideline.  But now FDAMA 97 
 
  13   specifically referred to the compounding chapter.  It has 
 
  14   not been renumbered to 795. 
 
  15             MR. BARLETTA:  This could become part of 795, 
 
  16   right?  We could have Part A and Part B.  It could be very

  17   easily made mandatory, and we have plenty of examples where 
 
  18   general information chapters became mandatory, like the PET 
 
  19   chapter. 
 
  20             DR. JUHL:  Other questions from the committee? 
 
  21             MR. TRISSEL:  I would like to comment on your

  22   three versus two categories.  Correct me if I am wrong, 
 
  23   Frank, but really the high risk category has two 
 
  24   subcategories within it, so it winds up being three. 
 
  25             MR. BARLETTA:  Whether you have one and two and 

                                                                186 
 
   1   subcategories, it is basically the same.  I don't know how

   2   much you want to hear about this, but in the very beginning 
 
   3   we did invite ASHP to participate in this whole process, and 
 
   4   they chose to go off on their own and establish their own 
 
   5   guidelines, and they changed it, so that we now have two 
 
   6   guidelines.

   7             The USP, however, is the national compendium, 
 
   8   which is recognized in law since 1906.  It is not an 
 
   9   organization, professional organization that publishes 
 
  10   guidelines for its members, so there is a big difference 
 
  11   between their guidelines and our guidelines.

  12             Ours is a national ‑‑ international because there 
 
  13   are about 20 countries that recognize the USP ‑‑ I like to 
 
  14   call it the gold standard. 
 
  15             MR. TRISSEL:  Randy, I haven't finished yet.  Not 
 
  16   that the pitch is over ‑‑

  17             MR. BARLETTA:  I am sorry. 
 
  18             MR. TRISSEL:  What I was getting to with that was 
 
  19   that both standards recognize that there are some sterile 
 
  20   product preparations that are not unavoidably complex, but 
 
  21   nevertheless, have a higher risk to the patient, and that

  22   would be something like prefilling unit dose syringes, a 
 
  23   very simple operation, but if they are stored for long 
 
  24   periods of time, they wind up being a higher risk than a 
 
  25   syringe that is drawn up and used within a short period of 

                                                                187 
 
   1   time.

   2             So, there was this intermediate category, a very 
 
   3   simple operation, but nevertheless, stored for longer 
 
   4   periods, and both of them have that feature in there, 
 
   5   something intermediate. 
 
   6             Not all things are truly unavoidably complex, but

   7   I will say that that is true for any compounding from a raw 
 
   8   material that is not sterile. 
 
   9             DR. JUHL:  Sarah, go ahead. 
 
  10             DR. SELLERS:  I have a question for Peter. 
 
  11             When drug delivery system was decided that it did

  12   not demonstrate any adverse effects, did you look at how 
 
  13   some of these sterile products that are made from 
 
  14   non‑sterile materials are being used, because some of them 
 
  15   are being used in complex delivery systems like implanted 
 
  16   intrathecal pumps, where if you do have a variation in the

  17   concentration of that drug from lot to lot, you can 
 
  18   adversely affect your patient.  Even a small change in drug 
 
  19   concentration can manifest in either adverse reactions or 
 
  20   withdrawal, for instance, with morphine sulfate, 
 
  21   additionally with nebulized medications that are used in

  22   nebulizers. 
 
  23             DR. COONEY:  There is no question that there is 
 
  24   risk associated with all of those things.  What this was, 
 
  25   was a preliminary conclusion on whether sterile products as 

                                                                188 
 
   1   a class should be included on the difficult to compound

   2   list, if not, compounded under some certain set of 
 
   3   standards, and there is a lot more examples of problems with 
 
   4   sterile products like you just mentioned. 
 
   5             I mean, for example, bioavailability can be a 
 
   6   problem.  I mean if you put the wrong preservative in an

   7   ophthalmic preparation, you alter its absorbability into the 
 
   8   site of action in the eye. 
 
   9             But in total, we thought that the four items that 
 
  10   I talked about were most important, but the other items are 
 
  11   certainly not without risk.

  12             DR. ALLEN:  I might mention also with the USP, the 
 
  13   USP is never a finished document.  One advantage to the USP 
 
  14   is the entire USP is constantly under revision based upon 
 
  15   input from all different segments of society.  That is why 
 
  16   we have basically supplements that come out every six

  17   months. 
 
  18             But I would anticipate that the committee, when 
 
  19   any difficulties start coming up, that they would 
 
  20   immediately address those difficulties, and at least the 
 
  21   mechanism is there for constant upgrading and revision

  22   through the USP. 
 
  23             MR. TRISSEL:  Previously, we were asked about 
 
  24   whether there was any need whatsoever for a high risk 
 
  25   category of compounding from non‑sterile raw materials, and 

                                                                189 
 
   1   I would contend that there is.  It is a relatively small

   2   part of the overall sterile product preparation that goes on 
 
   3   in this country, probably less than 1 or 2 percent, but 
 
   4   there are a number of things, some of which this committee 
 
   5   has already dealt with. 
 
   6             As I recall, there are two amino acids for

   7   supplements to TPNs, that are only available as raw powders, 
 
   8   and they are used in supplementing TPN, so there would be an 
 
   9   example.  We have a problem with implantable pumps that you 
 
  10   had mentioned, only these are for regional therapy for 
 
  11   cancer treatment.

  12             The pump manufacturers recommend between doses 
 
  13   that a 50 percent sterile glycerine solution be put in there 
 
  14   as having the right viscosity to keep that patent while 
 
  15   waiting for the next dose of drug. 
 
  16             There is no commercial product of 50 percent

  17   sterile glycerine, so we must compound this, and yet it is 
 
  18   in the manufacturer of the pump's labeling to use this.  So, 
 
  19   there is an example. 
 
  20             We just had a recent one with a leukemia drug that 
 
  21   is experimental, it is under an IND, but the IND specified

  22   that we would acquire this from a contract manufacturer 
 
  23   making it under GMPs, and due to an unfortunate set of 
 
  24   circumstances, we ran out ‑‑ not my fault ‑‑ but we 
 
  25   solicited input from the agency. 

                                                                190 
 
   1             We submitted basically an amendment to the IND

   2   allowing us to compound that to keep the patients going.  
 
   3   Unfortunately, we did not get a response for six months, and 
 
   4   during that time we did not use the compounded product, and 
 
   5   we wound up having the GMP product arrive before we ever 
 
   6   needed to use it, but nonetheless, it was an attempt to use

   7   compounding in that way, to keep the patients going. 
 
   8             DR. JUHL:  How about morphine solutions? 
 
   9             MR. TRISSEL:  We don't personally use any 
 
  10   compounding of morphine solutions.  I was telling Rose‑Ellen 
 
  11   earlier we use morphine topically.  We compound morphine

  12   topically for local application and wound pain control, but 
 
  13   we don't do any I.V. or intrathecal preparation from raw 
 
  14   powder, but I know it is done elsewhere in society. 
 
  15             DR. JUHL:  Is that a common practice I guess 
 
  16   within hospitals that hospital pharmacies are compounding

  17   what are essentially copies of commercially available 
 
  18   products, either TPN or morphine or other things? 
 
  19             MR. TRISSEL:  My opinion? 
 
  20             DR. JUHL:  Yes. 
 
  21             MR. TRISSEL:  I think morphine is the principal

  22   example, and I don't know how far it extends beyond that, 
 
  23   but will bet you the vast bulk of those that are copies are 
 
  24   really morphine solutions of one kind or another. 
 
  25             DR. JUHL:  And those are almost exclusively for 

                                                                191 
 
   1   financial purposes or are there medical purposes that I am

   2   not aware of? 
 
   3             MR. TRISSEL:  For a long time it was because we 
 
   4   couldn't get a high concentration morphine, but I think that 
 
   5   is available now.  So, it may be for financial reasons where 
 
   6   a patient can't afford it, so it is either, you know, do

   7   this and they control their pain or they don't get it. 
 
   8             MR. RUSHO:  Just continuing on Larry's comments, I 
 
   9   think there needs to be a high risk category, but I would 
 
  10   make two categories there, one, that is the individualized 
 
  11   patient, so that I am making my morphine bupivacaine

  12   epidural for that patient, and the other one is a batch 
 
  13   preparation, such as progesterone and oil, where I am making 
 
  14   larger quantities. 
 
  15             I think there needs to be a differentiation there 
 
  16   when you are dealing with one patient or if you are dealing

  17   with a lot of patients. 
 
  18             Now, as far as your comment as far as is morphine 
 
  19   compounded, morphine is compounded at least in our 
 
  20   institution, but it is generally with another drug.  It is 
 
  21   like morphine or bupivacaine.  I can think of one patient

  22   that's a gunshot wound victim, takes hydromorphone 30 
 
  23   milligrams per mL, and bupivacaine 30 milligrams per mL.  
 
  24   That is done extemporaneously, and I guess tomorrow we will 
 
  25   be talking about quality assurance measures that we use. 

                                                                192 
 
   1             But, yes, we do a lot of it because we are a

   2   referral hospital, and we do have a pain service. 
 
   3             DR. SELLERS:  Commercial products are also copied. 
 
   4             DR. JUHL:  Other comments or questions? 
 
   5             MS. HOPE:  I have a couple of comments.  I wanted 
 
   6   to thank Dr. Cooney for emphasizing the thing about

   7   filtration, because I think it is not as much the type, but 
 
   8   just, you know, I think there is a big over‑reliance on 
 
   9   filters to assure sterility, and there is a big 
 
  10   over‑reliance when we have a hood.  I mean that is a pretty 
 
  11   simple concept that we still haven't got totally across.

  12             I think there is a big problem on quality 
 
  13   assurance testing because, like Loyd was talking this 
 
  14   morning, where you have sterility testing that is not back 
 
  15   for a week, but the patient needs it within 24 hours for 
 
  16   stability, but yet if you are going to do that procedure on

  17   a regular basis, I think there should be some testing of it 
 
  18   on some periodic basis to know that your technique is good, 
 
  19   and I think in most of the guidelines we have already 
 
  20   addressed this.  I think it is a matter more of enforcement. 
 
  21             MR. WELDER:  I would just like to comment that I

  22   have a little bit of difficulty with the description that 
 
  23   all sterile products are difficult to compound, and it is 
 
  24   just the wording thing, but I just want to make that 
 
  25   comment, because not all sterile products are difficult.  

                                                                193 
 
   1   You have to use the correct technique, as you do in any

   2   compounding, but they are not all necessarily difficult to 
 
   3   compound. 
 
   4             DR. JUHL:  As difficult for whom? 
 
   5             MR. WELDER:  If you don't know how to do 
 
   6   something, anything is difficult, but we do have people that

   7   know what they are doing, and it is not difficult to 
 
   8   compound. 
 
   9             DR. COONEY:  Perhaps a better term would be easy 
 
  10   to contaminate. 
 
  11             DR. ALLEN:  Following up on Bill's comment

  12   concerning the high risk, you know, he made a good 
 
  13   observation, and that is something I think that I will 
 
  14   mention to the committee in charge of 1206, and that is the 
 
  15   two different levels of high risk or compounding from bulk 
 
  16   drug substances, those for individual patients versus those

  17   that are batch compounded quite possibly, a little more 
 
  18   detail on batch compounding with some additional testing 
 
  19   might be a good idea. 
 
  20             It is hard to test individual items obviously, but 
 
  21   you can test certain batch‑prepared products.

  22             MR. RUSHO:  First of all, I disagree with testing 
 
  23   individual items because pharmacists do have LAL pyrogen 
 
  24   tests available to them.  This is what we use on our 
 
  25   individual products.  Products do not go out of our I.V. 

                                                                194 
 
   1   center that are compounded from non‑sterile ingredients

   2   without an LOL test run on them. 
 
   3             If it is a batch‑prepared, then it goes through 
 
   4   potency testing and sterility testing also, and if we can do 
 
   5   pyrogen testing on it, we will do pyrogen testing on it. 
 
   6             DR. ALLEN:  Pyrogen testing is no problem.  You

   7   can do that in a matter of a few hours, but what I am after 
 
   8   is sterility testing which does take a longer time to get 
 
   9   the results back. 
 
  10             MR. RUSHO:  Well, I will go back to some of the 
 
  11   comments that were made to me when I took my sterile

  12   products training down at the University of Tennessee.  Dr. 
 
  13   Avis told us at that time that a pyrogen test was a better 
 
  14   indicator of quality control than a sterility test. 
 
  15             In my own products that I have made, I can make a 
 
  16   product that is sterile, but it is loaded with pyrogens.  I

  17   cannot make, I have never been able to make a pyrogen‑free 
 
  18   product that is non‑sterile.  I think the USP chapter needs 
 
  19   to put more emphasis on LAL testing than on that, because 
 
  20   it's geared towards extemporaneous type compounding.  That 
 
  21   is where it was developed was in nuclear pharmacy.

  22             DR. JUHL:  We have wandered into an area that we 
 
  23   know something about.  I love that. 
 
  24             MS. LaFOLLETTE:  I wanted to make a comment about 
 
  25   the bioburden loading to Dr. Cooney, especially on the high 

                                                                195 
 
   1   risk compounds where we are dealing with non‑sterile, and

   2   the bioburden loading could be very high and unknown with 
 
   3   all the different components and packaging that is being 
 
   4   used. 
 
   5             It is welcoming to hear that LAL is being used, I 
 
   6   wasn't aware of that, so I would like to hear Dr. Cooney's

   7   comments because sterile filtration won't address all that, 
 
   8   and what type, you know, is autoclaving being used in 
 
   9   hospital settings, is LAL being done, which would be a 
 
  10   preferred over a pyrogen test with the rabbit, comments, 
 
  11   just open comments here I am looking for.

  12             DR. COONEY:  First, let me comment on the end 
 
  13   product sterility test.  It doesn't really tell you a lot 
 
  14   even if you perform it before you release the product, and 
 
  15   there is a lot of different reasons for that. 
 
  16             One is that it only tells you if there is viable

  17   microorganisms at the time you did the test.  You could have 
 
  18   had 106 per mL, and they all died off. 
 
  19             Also, it only detects organisms that grow in 
 
  20   either of the two test media under either of the two 
 
  21   incubation conditions.

  22             Thirdly, most microbiologists recognize that only 
 
  23   about 10 percent of the microorganisms that are around in 
 
  24   the world have been identified so far, so there could be a 
 
  25   plethora of other things. 

                                                                196 
 
   1             You could have 100 millions AIDS virus particles

   2   in the product, and it would pass perfectly well.  But what 
 
   3   it is, as I like to comment on, it is kind of a quality 
 
   4   control thing.  It is a system check.  If you are badly out 
 
   5   of control, it will tell you that. 
 
   6             The LAL testing is a good idea, as well.  The

   7   unfortunate part about that is for semi‑gram‑negative 
 
   8   microorganisms, the LAL detection level of about 0.1 
 
   9   endotoxin unit per mL, you won't get that until after you 
 
  10   have 105 organisms per mL, and if you have that, and you 
 
  11   inject it into a patient, that's not good either.

  12             But that is what I was trying to say in what I 
 
  13   spoke about, that is why for this type of operation, system 
 
  14   control is the only way that you can do it, and you do need 
 
  15   some in‑process quality control, monitoring and assessments 
 
  16   of your environment, of the pieces that you are using if

  17   it's non‑sterile products, and if you have a non‑sterile 
 
  18   drug substance or component that you are going to compound 
 
  19   into a sterile product, and you do do testing, and you do 
 
  20   find that it's very high, you have got to start questioning 
 
  21   where you got that stuff from, and its background.

  22             So, all of that together is useful and it is why 
 
  23   it makes ‑‑ I appreciate the fact that difficult is probably 
 
  24   a relative term, and not the best way to do it, but it's 
 
  25   easy for these things to become potentially significantly 

                                                                197 
 
   1   hazardous.

   2             MR. TRISSEL:  Another problem with LAL is some 
 
   3   drugs interfere with that test, and you can't run them with 
 
   4   LAL, and we have had to use rabbits, go back to rabbits for 
 
   5   some things. 
 
   6             It is my perception that most hospital and home

   7   care pharmacies, and probably most other compounding 
 
   8   pharmacies that make sterile products have the facilities, 
 
   9   have the fundamentals of the facilities and procedures for 
 
  10   making those in compliance with this chapter. 
 
  11             I think the problem comes when you have the

  12   products made that are truly high risk, made from 
 
  13   non‑sterile products, but treated as if they were low risk 
 
  14   because of the lack of knowledge on the part of the 
 
  15   pharmacist and lack of facilities and training in all the 
 
  16   procedures necessary.

  17             So, that is what we really should be trying to get 
 
  18   at, is recognizing that difference. 
 
  19             MR. RUSHO:  I realize that the LAL test does have 
 
  20   some problems as far as some of the drugs.  The drugs that 
 
  21   we use, for example, it works fine on, and we have learned

  22   that over the years which drugs we can use it on and which 
 
  23   ones we can't use it on. 
 
  24             The progesterone and oil, for example, the oil 
 
  25   sequesters any endotoxins, and so you can't use a pyrogen 

                                                                198 
 
   1   test on that.  You have to depend on a sterility test.

   2             I think, going back to your comments, there needs 
 
   3   to be in‑process controls.  If pharmacists are making these 
 
   4   on a routine basis, they need to have a dry heat oven, they 
 
   5   need to have their beakers dry‑heat sterilized, they need to 
 
   6   have this material ready, so they reduce the bioburden when

   7   it comes to the filter. 
 
   8             If they don't do that, there is a build‑up that 
 
   9   you can see, and if you do the LAL test where you actually 
 
  10   have sequential dilutions, you can see a build‑up on your 
 
  11   equipment, and that is why they need to be dry‑heat

  12   sterilized, so you depyrogenate the glassware before you use 
 
  13   it. 
 
  14             DR. JUHL:  Other comments? 
 
  15             MR. TRISSEL:  One more, I am sorry.  The only 
 
  16   reservation I have about Chapter 1206 in the USP is that it

  17   does not anticipate the development of improving technology.  
 
  18   It is descriptive of a fixed technology without any 
 
  19   potential for changing that, improving it in any way, and we 
 
  20   are seeing the proliferation of the use of isolators in this 
 
  21   country, in hospitals, for the first time.  They have been

  22   used in Europe in 15 years, but here it is relatively new 
 
  23   technology.  It is new to the U.S., but it is probably an 
 
  24   improvement over poorly‑maintained clean rooms. 
 
  25             So, the only reservation I would have is whether 

                                                                199 
 
   1   there should be some provision for improvements in

   2   technology that is not now in the USP chapter.  That is 
 
   3   probably best addressed with the USP. 
 
   4             DR. JUHL:  Are you suggesting that ‑‑ I mean they 
 
   5   do a revision, so that that could address things, but they 
 
   6   are kind of behind ‑‑ you would like to see a paragraph or

   7   two that talks about new technology and the steps to take ‑‑ 
 
   8             MR. TRISSEL:  Right, a new technology that 
 
   9   achieves the same end or in a better way or a better end is 
 
  10   not allowed with that chapter, and I would like to see the 
 
  11   chapter contain that, but as I say, it is probably a comment

  12   best directed to the USP. 
 
  13             DR. JUHL:  Frank, if you would come forward and 
 
  14   address that. 
 
  15             MR. BARLETTA:  The USP has a chapter on isolators.  
 
  16   That is why we didn't incorporate it in this particular

  17   chapter. 
 
  18             MR. TRISSEL:  Really.  Which one? 
 
  19             MR. BARLETTA:  I am not sure if it has been 
 
  20   approved or proposed, but that happens to be a Microbiology 
 
  21   Subcommittee responsibility, so there is something going on

  22   there.  We looked at that years ago, and we were told to bug 
 
  23   off, that Microbiology has it under control. 
 
  24             MR. TRISSEL:  Frank, you also ought to take a look 
 
  25   at the PhaSeal system coming from Sweden, which is a 

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   1   microisolator for single‑unit vials.

   2             MR. BARLETTA:  Dr. Allen brought up the subject.  
 
   3   He said that the USP is under continuous revision.  That is 
 
   4   what is good about the USP is that ‑‑ and it is true with 
 
   5   every monograph and every general chapter ‑‑ as things 
 
   6   change, and you people notify us, we revise the monograph

   7   and revise the chapter, so it is under continuous revision. 
 
   8             You can't hit everything, and from my experience 
 
   9   with technology moving so fast, you would have to change a 
 
  10   chapter every six months. 
 
  11             MR. RUSHO:  Are we getting into specifics on 1206

  12   or are we waiting until tomorrow on that? 
 
  13             DR. JUHL:  I am happy to let us go anywhere we 
 
  14   want to be taken with the exception of making our final 
 
  15   determinations, which I think we need to do tomorrow. 
 
  16             MR. RUSHO:  I have a couple of comments then.  The

  17   section in there on using media fills, I have a real problem 
 
  18   with that.  One of the reasons I have the problem is for 
 
  19   three years at the College of Pharmacy, I made my own soy 
 
  20   broth medium, and you have to remember approximately 50 
 
  21   percent of our students have never touched a syringe in

  22   their life before they come to this class, and for three 
 
  23   years I did not have any growth at all, and I had them 
 
  24   making a simulated piggy‑back admixture. 
 
  25             So, I thought maybe I had a problem with the way I 

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   1   was preparing the product.  So, I went to a commercial one

   2   where I had a series of vials, and they moved the culture 
 
   3   medium back and forth, and once again, no growth at all. 
 
   4             At this point, I got a little suspicious, so in 
 
   5   one vial, I took a needle, and I moved it on my hand, 
 
   6   similar to the way you used to sharpen an old straight‑edge

   7   razor, put it in there, no growth. 
 
   8             I finally got an 18‑gauge needle and stuck the 
 
   9   palm of my hand until I got skin the needle, put it in, I 
 
  10   finally got growth.  Over at the hospital, we use the same 
 
  11   commercial product for our annual employee evaluation and

  12   for new employee hire.  Once again, no growth. 
 
  13             We went to a commercial product that simulated TPN 
 
  14   preparation.  Once again, no growth.  One of the pharmacists 
 
  15   took his gloves off once again, put it on his bare palm, put 
 
  16   it in, no growth.  He finally had to spit in his hand, draw

  17   it up in a syringe, and put it into the bag. 
 
  18             MR. TRISSEL:  At least he didn't stick himself. 
 
  19             MR. RUSHO:  I think that these are giving people a 
 
  20   false sense of security.  I would suggest, like I said 
 
  21   before, that we replace that with LAL testing, because I

  22   think LAL testing is a far superior test, and it will give 
 
  23   you the results within an hour.  You don't have to wait 
 
  24   seven days or 14 days. 
 
  25             The employee can get almost immediate feedback, 

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   1   and they can see if they have got good technique or bad

   2   technique. 
 
   3             DR. JUHL:  I would like to congratulate you and  
 
   4   your staff on your apparently excellent hand‑washing 
 
   5   technique.  I am not suggesting that jab in the hand go in 
 
   6   the USP.  A point well taken, though.

   7             MR. TRISSEL:  Could I ask the agency, obviously, 
 
   8   that procedure from the USP was based on or extracted from 
 
   9   the use of media fills in industrial manufacturing, at least 
 
  10   that was probably the concept of where it came from.  As I 
 
  11   recall, there are media‑filled failures all the time in drug

  12   companies.  Sometimes whole plants are shut down because of 
 
  13   it.  Why the difference? 
 
  14             DR. COONEY:  That is, in fact, true.  I can tell  
 
  15   you that the media that is used in the media fill programs 
 
  16   and commercial manufacturers has to undergo growth promotion

  17   testing, where you have to show the support of growth of 10 
 
  18   to 100 microorganisms, a whole panel of them, so the 
 
  19   growth‑promoting properties of that have to be determined. 
 
  20             Let me give you an idea in case anyone here is not 
 
  21   aware.  In a commercial manufacturing operation, companies

  22   run media fills, and there is a lot of dispute and a lot of 
 
  23   argument internationally about how many units to fill and 
 
  24   what is an acceptable criteria, et cetera, et cetera, but in 
 
  25   general, companies have no problem at all in filling at 

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   1   least 3,000 vials of media and seeing no contamination in

   2   those 3,000 vials. 
 
   3             That is where you get the concept that the 
 
   4   sterility assurance level for aseptically produced products 
 
   5   is about 1 in 1,000 or 10‑3.  That is where that came from, 
 
   6   but it is not really sterility assurance.  It is just the

   7   rate of failure of your media fill. 
 
   8             You talked about the barrier isolators.  There is 
 
   9   a lot of manufacturing companies worldwide now and in the 
 
  10   United States installing these rather elaborate systems, and 
 
  11   when you do that, when you actually sterilize the

  12   environment in which the filling of the vials takes place, 
 
  13   the failure rate is more like 1 in 100,000 than 1 in 1,000, 
 
  14   so it actually makes a big difference. 
 
  15             It tells you what people do to a filling 
 
  16   operation.  I tend to agree with you.  I think there is some

  17   sort of over‑reliance on media fills because there is 
 
  18   misunderstanding that it is actually measuring sterility 
 
  19   assurance, which it does not. 
 
  20             DR. JUHL:  I guess you need to use the 
 
  21   preservative‑free broth.

  22             DR. JUHL:  Other comments? 
 
  23             MR. RUSHO:  Oh, yes, I have got several.  On the 
 
  24   in‑process revision, one of the things that I checked, one 
 
  25   of the examples here is to make a simulated epidural 

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   1   injection using lactose and 5 percent dextrose in water.  I

   2   think that should be stricken.  I talked with our Acute Pain 
 
   3   Service.  They have never heard of making an epidural with 5 
 
   4   percent dextrose.  It is always saline, and it is always 
 
   5   adjusted for isotonicity. 
 
   6             There are a couple of points once again on the

   7   settling plates.  I don't see the validity of that.  
 
   8   Infection Control, I have talked with our epidemiologists at 
 
   9   great length.  They have stopped using settling plates in 
 
  10   the 1970s.  The use of rodac plates on the surface, we know 
 
  11   the surface of the laminar flow hood is contaminated.  I

  12   mean that is good as a training tool to show new employees 
 
  13   that the surface is contaminated, but does that really do 
 
  14   any good to see if there is growth there.  It is treated as 
 
  15   a contaminated surface. 
 
  16             So, I would question whether or not those things

  17   should be in there. 
 
  18             I think there should be more material on 
 
  19   procedures, such as using dry‑heat sterilized beakers.  
 
  20   Dry‑heat sterilization is not even discussed in this 
 
  21   chapter.  It talks about autoclaves, steam under pressure.

  22             I think dry‑heat sterilization is ‑‑ you know, 
 
  23   Larry talks about glycerine ‑‑ we make 100 percent 
 
  24   glycerine, and that has to be dry‑heat sterilized.  
 
  25   Progesterone and oil is dry‑heat sterilized. 

                                                                205 
 
   1             That is a higher risk operation because you have a

   2   final aseptic putting the stopper in, in the vial.  It is a 
 
   3   very high risk operation. 
 
   4             One of the things that I haven't seen in this 
 
   5   chapter ‑‑ and I can't remember where I read it ‑‑ but when 
 
   6   people use filter sterilization, especially if they are

   7   filling several vials with that filter, if you are going to 
 
   8   test one, you test the final vial, not the first vial, not a 
 
   9   random sampling, because the pores are not all 0.2 micron.  
 
  10   There is a variation there, and the probability is the 
 
  11   smaller pores will be filled first, leaving the larger ones

  12   there, and the contamination there. 
 
  13             So, there needs to be a little bit more in there 
 
  14   about how people go about it, because most of the 
 
  15   pharmacists don't have the knowledge base here, and if this 
 
  16   chapter is going to be mandatory, we need to have that

  17   material in there. 
 
  18             DR. JUHL:  Some good practical tips for 
 
  19   consideration in the revision.  Thank you. 
 
  20             Other comments? 
 
  21             Let me conclude with an observation for today.  We

  22   have heard discussion of multiple dose inhalers and patches, 
 
  23   and we have heard the extreme difficulty and the number of 
 
  24   factors that are associated with the production of these 
 
  25   primarily from an industrial perspective, and it has 

                                                                206 
 
   1   convinced us that we would not recommend that a mere mortal

   2   attempt these types of things. 
 
   3             I would like to remind you that I suspect that 
 
   4   were he allowed the time, Dr. Peck could provide us with a 
 
   5   lecture on suspensions and capsules, citing an equal number 
 
   6   of factors and complications in the fine art of making

   7   suspensions and capsules that would lead us to believe that 
 
   8   we wouldn't want to do those either, but we, as of 
 
   9   tradition, have accepted the compounding of capsules and 
 
  10   suspensions, not because they meet those standards, but 
 
  11   because they are better than nothing at all in those

  12   instances where a patient is not suitably served by a 
 
  13   commercially available product, which is I guess my ongoing 
 
  14   bias that when a commercially available product is suitable 
 
  15   for a patient, that ought to be used. 
 
  16             I think we have had a good demonstration today of

  17   why that rule ought to be the rule of thumb that is 
 
  18   followed. 
 
  19             I can see I have attracted some interest in Dr. 
 
  20   Peck to comment.  Go ahead. 
 
  21             DR. PECK:  It would be difficult to discuss

  22   capsules, and not having a compounding pharmacist prepare 
 
  23   capsules.  I think that has been with us for so many years, 
 
  24   and all pharmacists have some feeling and experience for 
 
  25   that. 

                                                                207 
 
   1             We may have some thoughts about suspensions and

   2   what could or could not happen with suspensions, but I am 
 
   3   not aware of any systems that are objectionable as far as 
 
   4   compounding is concerned, but there could be. 
 
   5             DR. JUHL:  I remember having about a semester‑long 
 
   6   course on all the things that can go wrong with the

   7   suspension, and then having to go to the lab and finding out 
 
   8   I could do that and make them go wrong. 
 
   9             DR. PECK:  Well, the microbiologist could help us 
 
  10   in suspensions because that is, as you know, an inherent 
 
  11   problem with those systems.  But capsules, we put our arms

  12   and shoulders onto them to solve certain problems. 
 
  13             DR. JUHL:  But there are interactions with 
 
  14   excipients, there are interactions with the capsule.  There 
 
  15   is the absorption of water.  There is all those kinds of 
 
  16   things that could enter in, as well.

  17             DR. PECK:  We are dealing with the gelatin 
 
  18   interaction for the last several years, and the FDA 
 
  19   committee is still in session on that. 
 
  20             DR. JUHL:  Other final comments? 
 
  21             [No response.]

  22             DR. JUHL:  We will then reconvene at 8:30 promptly 
 
  23   tomorrow morning, and try and conclude our business 
 
  24   hopefully before noon. 
 
  25             We are adjourned. 

                                                                208 
 
   1             [Whereupon, at 4:15 p.m., the proceedings were

   2   recessed to be resumed at 8:30 a.m., Friday, July 13, 2000.] 
 
   3                              ‑ ‑ ‑ ®