Minutes from the Laboratory FDA/Industry Discussion Group

Laboratory FDA/Industry Discussion Group held on November 20, 1996 in Rockville, Maryland in conference room M.

On November 20, 1996 a public meeting was held in Rockville, MD with representatives from the Food and Drug Administration (FDA) Office of Regulatory Affairs, the Center for Drug Evaluation and Research and the pharmaceutical industry. This meeting was a follow-up to one held on March 28, 1996. The Office of Regulatory Affairs, Division of Field Science, Richard A. Baldwin was asked to facilitate this meetings. The purpose of this meeting was designed to get feedback from the participants on laboratory practices and procedures on topics that they felt needed further guidance from FDA. Prior to this meeting, attendees were asked to submit topics with its relevance and significance to the pharmaceutical laboratory.

Deborah Ralston, Deputy Director, Office of Regional Operations, opened with introductory remarks. She welcomed the participants and indicated that this is the first in a series of public meetings that we will be held, and the main purpose of these meetings is to address issues that are of mutual concern to industry and to the Food and Drug Administration (FDA) in regard to pharmaceutical laboratory practices and procedures, and "to share our views in an honest and open exchange".

Dr. Beverly Corey, Team leader, Industry and Business Liaison staff, for the Office of the Commissioner spoke on facilitating partnerships and reemphasized how strongly the office of the commissioner supports public meeting partnerships. "Our main purpose is to listen to your needs and concerns and as you outline topics to be discussed also identify specific resolutions that you (industry) think you need to achieve." This will be your (industries) specific opportunity to ask questions and our (FDA's) opportunity to listen to needs and concerns of the pharmaceutical industry." She indicated that this format allows the agency the opportunity to get feedback and encourages a positive dialogue.

The Division of Field Science requested that the Center for Drug Evaluation and Research (CDER) provide industry with an update on center initiatives. We asked Drs. Williams, and Vishwanathan to speak. Dr. Roger Williams, Deputy Center Director, for Pharmaceutical Science, Center for Drug Evaluation and Research gave a presentation on Local and Global CMC Initiatives. "It is an incredible time for Chemistry Manufacturing and Controls (CMC)." "If I could imagine a Global CMC dossier that we all could use for all permutations, I don't think we are far from that dream." (See attachment 1 for excerpts)

Dr. C.T. Viswanathan, Associate Director of Division of Scientific Investigations for CDER Compliance spoke on Good Laboratory Practices and Bioequivalence. (See attachment 2 for excerpts)

Addressing Industry Concerns

Richard A. Baldwin, Director, Division of Field Science, Office of Regional Operations, facilitated the afternoon sessions. The focus of the afternoon session was to discuss and evaluate the thirty-six topics that were submitted prior to the session. This was accomplished by facilitating a discussion with the attendees where they could provide their input.

For each topic ( for topics see attachment 3), the group rated and ranked the importance of the issues associated with a particular topic and determined if a full all day session would be feasible.

To select the most important topic out of the thirty-six, the participants were asked to rate and rank each topic through an iterative dialogue process facilitated by Mr. Baldwin using the following criteria:

Questions and topics that were similar were categorized and grouped together and a ballot given to all industry participants. (FDA attendees were not allowed to vote). The industry participants were given the charge that they had ten votes and they could use up to five votes on one topic until they total ten votes on the most critical issues.

The process discussion included:

I. How these issues impact the participants (industry)

II. How these issues effect the outcomes you wish to achieve (in the pharmaceutical arena)

III. Voting on the issues

IV. Ranking - Identifying which seminars will be developed from the top two or three issues which received the most votes

After the votes were tallied, the two main categories were Out-of-Specification testing, and System Suitability for Chromatographic Techniques. A commitment was made by Mr. Baldwin that there would be at least one workshop on each topic, and that it would noticed via the Federal Register.

The meeting was adjourned by Richard A. Baldwin who thanked all participants for coming.

Update: Seminars are scheduled (as of 5/27/97) as follows:

System Suitability for Chromatographic Analysis; Public Workshop
June 9, 1997 Nutley, NJ - Hoffmann LaRoche (see May 13, 1997 Federal Register for further details)

Out-of-Specification Testing
June 20, 1997, San Juan, Puerto Rico - Westin Rio Mar Beach Resort (see May 30, 1997 Federal Register for further details)

Attachment 1

Chemistry Manufacturing and Controls - Excerpts from Dr. Roger Williams

Outlining the reviewing disciplines that constitute the Information Technology that contributes to the review of an NDA/ANDA application one notes the following: The disciplines for NDA are: clinical, clinical pharmacology, (pharmacokinetics), pharmaceutical toxicology, biopharmaceutics, chemistry manufacturing and controls, microbiology and environmental assessments. To yield an NDA review these disciplines are regarded as the team that would assess it for safety and efficacy.

For an ANDA review, the above scheme would omit the clinical (IND, phase studies). For review of the CMC portion of an application, in particular the critical Pre-Approval Inspection, CDER works through their office of compliance in conjunction with ORA's field analysts and field inspectors for approval of an New Drug Application (NDA) and Abbreviated New Drug Application (ANDA). They rely on ORA for method validations, and Division of Testing and Applied Analytical Development (formerly DDA) St. Louis; and have critical links to United States Pharmacopeia (USP) in terms of how testing for specifications of a drug substance and drug monograph get into the compendial standard.

From a regulatory perspective the three layers that support this effort are:

1) Good Review Practices -a critical component that all the disciplines have put into practice

2) Policy, (Guidance for Industry) - Recommendations to Industry as how to generate and submit information for an application, (International Committee for Harmonisation (ICH) operates in this arena). The policy generated is a strong connection in the Center for Drug Evaluation and Research (CDER) coordinating committees and ICH.

3) Research (applied regulatory research that supports public policy). One must have a good understanding of the science to form good regulatory policy, and conduct good assessments which is highly beneficial to the industry. Forming collaborative enterprises with industry and academia to produce quality product that safe and efficacious.

ICH: Common Technical Document

Concept of a common structure and format that provides information support and information technology initiatives.

Coordinating Committees

The coordinating committees are an outgrowth initiative in the Center for Drug Evaluation and Research from the various review disciplines such as: Pharmacology/Toxicology Coordination Chemistry Committee, Chemistry Manufacturing and Controls Coordinating Committee which was a precursor to the Biopharmaceutics, and Medical Policy Coordinating Committee, in addition there are 5-6 additional coordinating committees in the Center. The committees are designed to promote coordination, communication and harmonisation across the Center.

Organogram: CMC

The purpose of the working groups is to put out guidances for industry, and clarify what information is needed in an application. The new co-chairman of Chemistry Manufacturing and Controls Coordinating Committee (CMCCC) are: Eric Sheinin (ONDC) and Douglas Sporn (OGD) the subsidiary members are the five division directors of the chemistry branches, two in OGD and three in ONDC.

As a result of these committees, one ends up with twenty or thirty guidances that replace the previous guidances that were developed in 1987 for Chemistry Manufacturing and Controls and Microbiology.

Guidances:

Post Approval
The guidance documents for Scale Up Post - Approval Changes (SUPAC) are being developed by dose form (i.e. immediate release, modified release, transdermal, semi-solids, and sterile parenterals).

Pre-Approval
For Drug Substance, Drug Product, Packaging, Drug Master File (administrative approach) and setting of Tests and Specifications for Drug Substance, and Drug Product (Q6A & Q6B), Stability comprises each category in addition to analytical methods and sterility assurance. The Post-Approval Change (Pac) concept may be extending to Bulk Actives (BACPAC) and sterile parenteral products.

All the Q documents are also ICH documents. ICH guidance for industry will not cover everything; however, their will still be additional recommendations within the U.S. that will cover in the CMC part of the application. All the ICH documents with the exception of Q6A are at step 2 or 4.

The SUPAC's are well along the path. There will be a workshop on Bulk Active Post Approval Changes (BAPAC) guidance. The guidance looks at the concept what the applicant should provide in application to continue to assure sterility in an application after it found satisfactory.

SUPAC concept:

First SUPAC document SUPAC Immediate Release released in Nov. 1995 in the processing of updating SUPAC guidance packaging site change and analytical methods working on solutions. The purpose of SUPAC was to reduce regulatory burden, and to clarify requirements that were mirky in 21 CFR 314.70. (i.e. SUPAC IR is the first SUPAC however, with continue experience and understanding we can move more things to SUPAC IR to an annual report).

The Other SUPAC's: SUPAC Semi-solids is out and the guidance mostly deals with topicals. SUPAC Transdermal in the drafting stage SUPAC Modified Release is drafted waiting for industry comment, and hope that finalize the draft by the end of 1996 (solid oral), and begin training and federal register.

SUPAC - UPDATE
To provide SUPAC guidance one had to update and connect with prior regulatory policy. It focuses on the same thing as SUPAC-IR it is based on a prior AAPS workshop cumulative academic, and industry and the agency and it being supported by research that is completed at the University of Maryland (Baltimore).

SUPAC MR (Modified Release) - Highlights
One of the reasons SUPAC recommendations are done by dose forms is the concern with the more complicated (sophisticated dose) forms and the quality of performance (i.e. Controlled Release).

The F2 equation: equation that looks at dissolution profiles and compares them and says that you are within a region, and we don't think their is a difference in dissolution.

Number of batches - Need for Biostudy The number of batches that one uses for an ANDA is one batch; however, SUPAC MR states for a biostudy you need 3 batches. A requirement of 3 batches for a controlled release product are some of the changes that are being proposed and is an example of how SUPAC had ANDA's will conform to each other.

SUPAC TDS (Transdermal Delivery Systems)
Following the same path as the other SUPAC guidances, there was a workshop on April 29, 1996 the format is similar to SUPAC-MR hopefully a draft guidance by the end of this year (December, 1996).

IND Reform Initiative
Preliminary Concept: Information you submit in the IND phase relative to CMC and biopharmaceutics, is the process that is connected, with the assessment practices. For instance the Drug substance and drug product an IND phase may be evaluated in the early stages of submission so that one may come to the NDA filing with a real high quality submission.

NDA Information
Guidance - One may need to file and IND (Phase 1) guidance - CMC, and pharmtoxicology information before the NDA is subnitted.

ICH Q1A - states that 3 stability batches with data for standard application will be needed 12 months for filing.

Bioavailability - phase three- pivotal batches, stability batches, after filing pre-approval inspection. After approval one goes to full scale production and validating.

CDER Initiatives

Biopharmaceutics drug classification system - relates to characterizing drug substances on the basis their solubility, permeability of the characteristics and the drug product on the basis of dissolution characteristics so that if you have a (i.e. highly soluble drug, highly permeable drug and drug product that dissolved rapidly in suitable media you may not have to repeat biopharm. information.

Attachment 2 - Excerpts from Dr. C.T. Vishwanathan's speech

Bioequivalence is a recent focus in Division of Scientific Investigations (CDER compliance) it was always there in some form however more emphasis on the new drug side. Good Laboratory Practices have always been and is outlined in 21 CFR Part 58, and he addressed this issues in the second part of his presentation.

Bioequivalence Inspection has always been with us however the program had primarily been applied to ANDA's (generics). The last three to four years been applied to New Drug Application component.

For NDA's a pilot study to assess data integrity that is designed to validate the pivotal bioequivalence study has been addressed.

The objective is to verify the data integrity, and promote the quality and consistency across the studies conducted by the pharmaceutical industry is one of the main goals. To promote equity to insure consistency across the studies between ANDA's and NDA's. The ultimate goal is to foster volunteer compliance.

Who Do we (FDA) inspect for this program
We go to the sponsors themselves (contract organizations) their facilities and we (FDA) look at their data, individual laboratories and occasionally their are program interview of the study subjects and IRB members.

Reason for the Audit

1. Pivotal Studies

2. Request from the Review Divisions, (NDA/ANDA)

3. Random Assignment - Scientific Investigations (CDER)

4. History of the Drug

5. Complaints that are produced employees

6. For Cause Situations from the review divisions from particular divisions

Pivotal Studies

Studies have been selected based on the clinically tested versus to be marketed formulation becomes the key issue of one major category. If you are developing a formulation in Phase I and Phase II and find the kinetics and biopharmaceutics delivers what is intended then you have achieved the goal.

Bioequivalence Study

What happens if one changes the formulation for whatever reason after prior to selecting efficacy or safety data or after established the data for efficacy and safety then you have come with different formulation which is the marketed formulation which may or may not directly relate to the earlier data up time to previous formulation. In which case the only way you can correlate all the data in the application is doing a bioequivalence study and comparing the two formulations. This (bioequivalence) becomes a critical study and the data integrity between the original study is a great potential for an audit.

Different Dosage Forms

Different Dosage forms other than the marketed dosage forms - when a second application for the same drug product (one has been approved for tablets and they go to capsule form).

What are we looking for in an Pivotal Study Audit: (Are examples)

1. Blood level data in your NDA/ANDA performance of the dosage form

2. Re-formulation of Marketed Product (SUPAC issues)

3. Change in process the site of manufacture (SUPAC)

4. Change in route of administration w/o new studies to support efficacy

5. Biostudy to determine the clincal appropiateness of the sites applications (i.e. transdermal patches - different sites and plasma data)

Auditing of main components to a biostudy:

1. Clinical Data

2. Analytical Data - (validation issues often times acceptance for criteria is based on biased q.c. acceptance which is unacceptable)

3. DATA - Computerized data of the sponsors - data impact, transcription errors (in-vitro data)

Good Laboratory Practices (GLP's) - 21 CFR 58

Ten major categories of the regulations for Good Laboratory Practices - delineated by 21 CFR Part 58:

1. Personnel, Management and Study Director

2. Quality Assurance Unit & its operations

3. Facilities

4. Equipment Calibration and Maintenance

5. Animal Care

6. Standard Operating Procedures (SOP's)

7. Test and Control Articles

8. Final Study Report

9. Protocol and Study Conduct

10. Records/Reporting

For GLP's routine surveillance is conducted every two years a particular may get audited.

There are three major categories in which the violations occur:

1. Standard Operating Procedures (SOP's) - Lack of following ones own procedures

2. Protocol and Study Conduct violations

3. Study Director related duties and personnel management

Attachment 3 - Topics and Questions submitted for November 20, 1996 - From Richard A. Baldwin's speech

1. Out-of-Specification/Laboratory Failures (re-analyze/retest/resample)
This topic has been the subject of FDA 483s, enforcement action, and legal action in the recent past. The recent Proposed Revisions to the cGMPs published in the May 3, 1996 Federal Register propose to incorporate this subject in the GMPs. This is a complex subject that has great impact on laboratory operations. Possible subtopics of this issue for discussion include the following:

What is the definition of a specification; i.e., does it include only registered specifications, in-process testing, or results that are out of control chart limits but within registered specifications?
When are resamples appropriate?
How many retests/resamples are appropriate?
What is an assignable cause in the laboratory?
When can outlier test be used? Can chemical outlier tests be used?
What, if any, are the differences in interpretation between microbiological and chemical tests?

2. Out-of-specification (OOS)/Outliers for Investigational New Drug (IND) and New Drug Application (NDA)
An IND or NDA states that the average of four results will be reported. Is an Out-of-Specification investigation required if one of the four results is an OOS even though the overall average is within specification? One of our clients told us that an investigation was not necessary; however, we feel it is.

3. Dissolution Testing
Dissolution testing is a critical test for solid dosage forms, both for release testing and for stability testing. Dissolution testing requires strict adherence to equipment and procedural requirements to assure reproducibility of results. A discussion of the technical issues associated with dissolution testing would help to assure consistency of interpretation and application of the test parameters. Possible subtopics of this issue for discussion include:

Impact of the proposed USP revision to dissolution testing which would allow for pooled samples;
Interchangeability of dissolution apparatus components (either basket or paddle, apparatus I and II).

4. System Suitability/HPLC Issues

a. Analytical Equipment Change Control

This topic is covered in several of the other topics; however, it may qualify as a separate topic. The decision as to when a piece of equipment needs to be requalified of a method needs to be revalidated is a potential issue for consideration and discussion.

b. Deviations in the Analytical Laboratory

Not all deviations in the analytical laboratories are out-of-specification results. A discussion of other potential errors and how they can be remedied would be extremely useful.

The system suitability test is required by the USP, yet interpretation of this requirement may vary. Possible subtopics for discussion include:

The USP states, "Adjustments of operating conditions to meet system suitability requirements may be necessary." How much adjustment can be made to a chromatographic system in order to meet system suitability and still consider the method which is being run identical to the procedure which was originally validated?
When changes are made (i.e., replacement of a pump in an HPLC, modification of a mobile phase, use of equivalent columns, ...) is system suitability sufficient to assure consistent operation?
When an HPLC is made up of components rather than as a single unit and a replacement of a pump is necessary, for example, what type of installation qualification/operation qualification (IQ/0Q) should be done? Is system suitability testing in methods sufficient or should we be doing something else?
Does FDA have a position on the use of HPLC in combination with mass spectrometry for analyses of drugs? Does FDA use this technique in any of its laboratories?
What is FDA's labs experience with sensitivity, precision etc. of HPLC method for accurately and quantitatively determining impurities of 0.1% in drug substances and drug products using U.S.P. or pharmaceutical methods?
Are the currently used release methods really capable of determining ICH limit for impurities in New Molecular entities? C Are firms buying one line of HPLCs computers, etc. used to generate analytical data so that calibrations and maintenance are more uniform? Is this or should this be the practice in the field?

Analytical system performance qualification/method validation, addressing

current industry practice and FDA expectations regarding analytical system performance qualifications integrated with analytical method validation, including conditions under which requalification is necessary
the current role of system suitability and its acceptance as a measure of system performance

5. Laboratory Training/Analyst Certification

Common Analyst Certification Standards for Industry and FDA

Both the industry and the FDA spend tremendous resources on laboratory training. Possible subtopics for discussion include:

Should training be done on a technique basis (i.e. HPLC) or on a product-by-product basis? Can an analyst who is trained to run HPLC pick up any product and run it? C How do we assure that training is effective?
Do analysts need to be "certified"? If so, what are the requirements; and how often, if ever, should an analyst be "recertified"?

Current industry and FDA attitudes toward Quality control laboratory certification; whether a certified laboratory would be eligible for a less rigorous pre-approval inspection.

6. Computer Validation in the Laboratory (Qualification/Vendor support)

Many laboratory instruments are now associated with computer systems. The application of computer system validation to the laboratories has tremendous impact on the implementation and maintenance of these systems. Possible subtopics for discussion include:

Validation/Qualification - Installation Qualification, Operation Qualification and Performance Qualification of laboratory instrumentation (IQ, OQ, and PQ)

What validation/qualification should be done on instruments with built in microprocessors? What should be done for IQ and OQ of these units?

Qualification/validation requirements for non-configurable standard software packages
Software packages (Non-configurable standard software packages - types of validation needed (qualification or validation)
To what extent should network be qualified or validated? This includes both the hardware and software?

Vendors are releasing new versions of software that will be used in GMP environments at a slower pace to minimize validation efforts and costs. They are more often sending patches that have been validated in isolation. A second issue is that this means they are enhancing programs written using older technology as opposed to moving to newer technology. Are other customers concerned about these issues?

How can we make our validation efforts more cost-effective? Do others use internal resources, outsource the work, or some combination of both? What is a typical level of staffing required? Any metrics or benchmarks?
Who typically audits the internal systems that have been validated to avoid conflict of interest? Is a methodology used? What kind of training is involved?
Who typically audits the vendor's operation to insure GMP compliance is met at that level?
How do you handle qualification or validation of components, either hardware or software, when support (installation and/or maintenance is outsourced?

7. Uses of Control Samples

Control samples (the use of a single lot on repeated runs) can be a valuable tool to trend the performance of the equipment and method being used. It would be useful to discuss how various laboratories are using such control samples and interpreting the results.

8. Reference Standards

Reference standards are critical to every analytical laboratory. Possible subtopics for discussion include:

Storage and handling of reference standards;
Interpretation of USP requirements for handling of reference standards, including testing for water/volatile content;
Use of secondary standards;
Requirements when a standard is changed.

9. Stability Issues

Interpretation of stability requirements has varied in the past. The ICH guidelines have clarified requirements for new molecular entities (NMEs) but have created much confusion in the handling of existing products. Possible subtopics for discussion:

Will ICH requirements be applied to existing products? If so, how can the transition be made?
Must all products be tested at both the currently approved conditions and ICH conditions?
What if a marketed product fails at ICH conditions?

Most of the Analytical results generated within a firm are obtained in stability studies i.e. 50-75% of every analytical value generated within many firms are in the stability area. Some firms seen to have trouble generating the data at the properly timed stability stations in the stability protocols. Is the latter due to the large volume of data that is needed to be generated? What is FDA's inspectional experience in this area and what may firms do to improve the situation?

10. Electronic Signatures and Approvals

A. Electronic Submissions

This topic has been widely discussed for other applications. Are there specific issues for the use of electronic signatures in the analytical laboratories?

11. Impurity Profiles

The USP has introduced a new requirement for Impurities, with a proposed effective date of November, 1996. A discussion of expectations for these testing requirements and implementation strategies would be very useful to assure consistency in the interpretation of these new requirements.

12. Microbiological Testing

The eventual revision of the USP General Chapters on Antimicrobial Effectiveness testing and Microbial Limits testing provides issues for discussion among all microbiological laboratories. Possible subtopics for discussion:

Applicability and limits of microbial testing in non-sterile products;
Environmental monitoring in non-sterile operations;
Effect of putting these changes in General Chapters rather than in monographs.

13. Harmonization of Compendial Methods

This is a subject of interest to the many pharmaceutical companies who supply to multiple countries.

14. Method Validation/Site Certification

What does the FDA and industry consider as reliable in the process of methods transfer from one site to another?

15. Use of New Technologies (ex. NIR)

It would be useful for industry and FDA to have an open dialogue regarding the best methods for effectively implementing new technology in control laboratories.

16. Definition of Equivalent and/or Alternate Methods

A discussion between FDA and industry to define these terms would provide a more thorough understanding of various interpretations.

17. Good Laboratory Practices (GLPs)

18. ONDC (Office of New Drug Chemistry) update

19. Drug Control Testing labs - GMP

Are the GMP/GLP regulations going to be harmonized with the ISO 9000 series?

It has been stated that the revised GMPs will require protocols. If so, will the format be the same or similar to the GLP format?

20. Nonclinical Testing labs - GLP

Does the FDA's interpretation of the Barr decision have any effect on GLP studies?

21. Bioanalytical Labs supporting in Vivo bioequivalence trials - (21 (CFR part.320)

22. Clinical Labs supporting regulated clinical trials

23. Chemistry Manufacturing and Controls (CMC)

24. Laboratories FDA Regulates (In depth)

25. Pre-Approval Inspection Program

26. Pre-Approval Team Inspections

27. Creating Standard Operating Procedures - i.e. Barr decision

28. Cleaning Validation R&D labs

Validation of manual equipment cleaning procedures, addressing such issues as:

(a) Whether manual cleaning procedures can actually be validated

(b) the role of routine cleaning verification tests

29. Research & Development input Process Validation

30. Contract Laboratories

Why are universities that work for the pharmaceutical industry not held to the same standards as other contract labs?

Are contract laboratories required to audit their suppliers if full monograph testing is not performed on solvents, standards and reagents?

31. Identifying the Acceptable "Best Practices"

32. Research/Quality Assurance

33. Pharmaceutical Science-Data Integrity 34. Acceptable Uses of Technology

35. Barcoding Technology

36. Laboratory Automation and Robotics


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