 |
 |
 |
|
 | |||||
| |||||||||
 | |||||||||
|
|
|
HUMAN DRUG CGMP NOTES (Volume 8, Number 2)June, 2000(A Memo for FDA Personnel on Current Good Manufacturing Practice For Human Use Pharmaceuticals) Issued By: The Division of Manufacturing and Product Quality, HFD-320 This level 2 guidance document represents the agency's current thinking on Current Good Manufacturing Practice for human use pharmaceuticals. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statute, regulations, or both. IN THIS EDITION: IntroductionRuss's RamblingsPolicy Questions On:
Subject Contact List Fax-Feedback (Your input requested) RUSS’S RAMBLINGS Welcome to another edition of Human Drug CGMP Notes, our periodic guidance memo for FDA personnel on CGMP for human use pharmaceuticals.Last edition (March 2000) was my first as the Project Manager. I appreciate the many warm e-mails you have written welcoming me in this position.Your FAX FEEDBACK responses have proven valuable, and we appreciate your suggestions. This is one way which we identify and attempt to address items of current interest. Additionally, you may use other means to communicate with us. Feel free to call, write, or e-mail your comments. Specific questions on an article would best be answered by the contributing authors. We also welcome brief articles which other FDAers may wish to contribute. Subjects should be CGMP related and would be especially valuable if they address emerging new technologies.DMPQ decided to publish Human Drug CGMP Notes exclusively in electronic format posted on the CDER website. This decision was made while the last edition was being posted. As a result, my editorial and the Fax-Feedback form contained outdated information on obtaining an e-mail subscription. Consequently, I received scores of requests for inclusion on the "mailing list". I answered each of these requests with an explanatory letter. I apologize for any inconvenience this may have caused you. The updated Fax-Feedback form is included in this edition.We have also included an updated list of Division of Manufacturing and Product Quality subject contacts in this issue. As in many organizations, we have had our share of turnover this year. Updating this list is another service we intend to continue.We receive many inquiries regarding which guidance documents are available on various subjects, and where to obtain the latest revision. The first article in this issue addresses this. The last web site address given (for CDER) contains paths leading to most guidance documents currently available from CDER. It would be worth your while to become familiar with this site.Appended to each edition of the memo is a FAX FEEDBACK sheet to make it easier for us to communicate. In addition to FAX (at 301-594-2202), you can reach us by interoffice paper mail, using the above address, by phone at (301) 594-0098, or by electronic mail. Once again, we’re now available exclusively on the Internet at: Thanks! Russ POLICY QUESTIONS: What FDA guidance documents pertain to drug repackaging operations and how can they be obtained?
http://www.fda.gov/ora/compliance_ref/cpg/cpgdrg/Default.htm
http://www.fda.gov/cder/dmpq/cgmpregs.htm http://www.fda.gov/cder/guidance/index.htm Contact for further information: Barry Rothman, HFD-325; phone (301)-594-0098; e-mail: rothmanb@cder.fda.gov What is meant by the term "beyond-use date" and does it differ from a drug’s expiration date? References:USP 24, Supplement No. 1, "General Notices" Expiration Date and Beyond-Use Date, pp. 2589-259021 CFR 211.137 and 211.166FDA Compliance Policy Guide, sections 430.100 and 480.200 (CPG 7132b.10 and 480.200)The term "beyond-use date" is used by the USP to specify the date placed by a pharmacy dispenser on the label of a prescription drug, and is meant to convey to the patient a date beyond-which a drug dispensed pursuant to a prescription should not be used. Clearly, the use of a "beyond-use date" applies to pharmacy dispensing practice only, and does not apply to manufacturers and non-pharmacy type commercial repackagers, (i.e., repackaging that is not done pursuant to a prescription for an identified patient). For manufacturers and commercial repackagers of finished drug products the CGMP regulations require the use of an expiration date that is based on appropriate stability testing.Additionally, repackagers may refer to FDA’s Compliance Policy Guides cited above for guidance on deriving an expiration date from the manufacturer’s container for drugs that are repackaged into unit-dose containers. Contact for further information: Barry Rothman, HFD-325; (301) 594-0098; e-mail: rothman@cder.fda.gov Gas What? Can the Fresh Air document or the February 1989 Guideline be cited on an FDA-483, in Warning Letters, etc.? References:See 21 CFR Parts 210 and 211U.S.C. Federal Food, Drug, and Cosmetic Act, as amended; 21 U.S.C. 331(k).This question, which was addressed in the December 6, 1996, edition of the HUMAN DRUG CGMP NOTES, Volume 4, Issue 4, bears revisiting from time to time. The answer of course is no.The Federal Food, Drug, and Cosmetic Act establishes the requirement that all drugs, including medical gases must be made under "current good manufacturing practices [CGMPs]." Therefore, CGMP deficiencies on an FDA-483 must be based on 21 CFR Parts 210 and 211 [Title 21, Code of Federal Regulations], which were promulgated under the authority of the Food, Drug, and Cosmetic Act.The "Fresh Air" presentation is presented for the sole purpose as FDA outreach and training. It contains an overview of CGMP information, as it would apply to the medical gas industry and is not a regulatory requirement.We plan on issuing an updated CGMP guidance for medical gases in the near future.Contact for further information: Duane S. Sylvia, HFD-325; phone: (301) 594-0095; e-mail: sylviad@cder.fda.gov Is there a requirement to conduct an annual product review? References:Subpart J - Records and Reports21 CFR 211.180 (e), General Requirements21 CFR 211.192 Production Record ReviewYes, Subpart J - Records and Reports, requires periodic product reviews under 211.180 (e), General Requirements. These reviews provide valuable information to the manufacturer for improvement of manufacturing quality. Also, inspection of the reports of product reviews will save the investigator time by not having to ask a lot of questions regarding the number of batches manufactured, released, rejected, etc.Inspection of a firm’s compliance with this requirement should determine:
Representative rejected batches are to be reviewed by the nature of the reason for rejection. For example, if 20 batches had been rejected in a one-year period and each rejection was due to a different reason, all 20 batches should be included in the product review because each batch represents a different category of rejection. If 12 of the 20 batches were rejected for the same reason, a smaller number than 12 could be included in the product review as representative of the 12 in that rejection category.
Consider whether the data maintained and reviewed in the product review indicates deficiencies in the firm’s compliance with other requirements of CGMPs (e.g., adequate complaint files, adequate investigations, adequate handling of OOS test results, etc).Deficiencies noted in FDA-483 items should be expressed as inadequate maintenance of required records, inadequacy of the written procedure for product reviews, or inadequate product reviews with details as to the actual inadequacies and how the inadequacies are demonstrated. Contact for further information: Brian G. Nadel, HFD-325; phone: (301) 594-0098; e-mail: nadelb@cder.fda.gov What is the significance of defects in container-closure integrity of an injectable? Can product sterility be affected? References:211.63 Equipment design, size, and location;211.110 Written procedures; deviations;211.186 Master production and control records;211.192 Production record reviewA number of injectable pharmaceuticals have been voluntarily recalled over the last two years due to critical defects in container-closure systems. These product integrity problems included glass fractures or leaks. Product non-sterility was one of the consequences of these defects.In the case of most recalls, investigations were not conducted in accord with 21 CFR 211.192. In some instances, while the cause of the defects was known, corrective actions were not implemented and impact on past and future batches was not determined. As a result, new lots were produced with the same serious quality problem, the defective product was shipped, and health practitioners began registering complaints with FDA and the manufacturers.The critical defects stemmed from various causes. Rough or irregular handling during specific process steps was a common denominator in each of the recalls. Some specific examples of causes include:
We have seen several other scenarios in which process deficiencies lead to loss of vial, ampul, or cartridge integrity. But mechanical problems have not been the only cause identified. Investigations have also attributed problems to improper manual handling. Trays dropped by personnel after final packaging, and rough charging of vials to the processing line, have resulted in recalls. In the former case, vial integrity was lost and the product was subsequently found to be non-sterile. Contaminated water from a washing step performed by the firm after autoclaving was named as the source of the predominant water-borne bacterium contaminating the vials.Just as the container-closure system chosen by a firm needs to be a robust one to ensure sterility and stability, there must also be compatibility with the production line on which the product will be manufactured. As cited above, incompatibility of a new container-closure with an existing line has resulted in loss of integrity. FDA requires firms to develop consistent processes employing suitable manufacturing equipment (see 211.65 and 211.100). This equipment should be qualified to process product in a manner that assures integrity of the specific container-closure.As a final measure, a batch manufacturing operation includes an inspection stage intended to reject defective units. It is important to be mindful that final visual/electronic inspection has its limitations. In particular, the nature (e.g., location, visibility) of a given defect may make its detection problematic. Some critical defects are difficult or impossible (e.g., hidden cracks under the crimp, etc.) to detect during the final inspection stage. This fact underscores the importance of building quality into a manufacturing operation to prevent serious defects. For each batch of a parenteral drug product, reconcilatilon records should document the actual quantities of defective units detected, categorized by major defect type. These results should be compared to established specifications, and an investigation triggered if results are beyond specifications. In addition, upon detection, a critical defect should be investigated. A lot should not be released for shipment in the event that it contains units lacking container-closure integrity.Contact for further information:Richard L. Friedman, HFD-325; phone: (301) 594-0098; e-mail: friedmanr@cder.fda.gov Are firms required to perform an identity test on an approved component (either an active or inactive) after it has been moved to an off site warehouse and then returned to the manufacturing facility for production? References:211.42(b) and (c)(1-3).No, it is not necessary to repeat the identity test if the component lot was securely packaged for storage at the off site location to reduce the risk of mix-up and protect lot integrity, otherwise held under CGMP compliant conditions (including adequate segregation), and properly labeled. As with other types of contracted manufacturing and testing facilities, the warehouse becomes an extension of the manufacturing site and both the manufacturer of the dosage form and the warehouse are responsible for ensuring compliance with the appropriate CGMP regulations, e.g., 211.42(b) and (c)(1-3). This applies to active as well as inactive components. The off site warehouse, however, is not required to register.Contact for further information: Brian Hasselbalch, HFD-325; phone: (301) 827-7283; e-mail: hasselbalchb@cder.fda.gov DIVISION OF MANUFACTURING AND PRODUCT QUALITY, HFD-320 SUBJECT CONTACTS (All numbers in area code 301)Active Pharmaceutical Edwin Rivera 594-0095Ingredients Pat Alcock 827-0064Mike Gavini 594-0095Application Integrity Policy LuAnn Pallas 594-0098Implementation/Removal Bruce Hartman 827-0062Data Integrity Cases Aseptic Processing Richard Friedman 594-0098Edwin Melendez 594-0098Brenda Uratani 594-0095Biotechnology Products Brian Nadel 594-0098Brenda Uratani 594-0095Botanicals Manufacturing Brian Hasselbalch 594-0098Case Management Fred Blumenschein 594-0098Cleaning Validation C. Russ Rutledge 594-2455Pat Alcock 827-0064Clinical Supplies / IND CGMP Bruce Hartman 827-0062Computer Validation Karen Moksnes 594-0098Content Uniformity Monica Caphart 594-2458C. Russ Rutledge 594-2455Mike Gavini 594-0095Electronic Records / Signatures Karen Moksnes 594-0098Foreign Inspections John Dietrick 594-0095Impurities Richard Friedman 594-0095Inspections / Investigations (For Cause) Randall Woods 827-0065Isolator / Barrier Technology Richard Friedman 594-0098Edwin Melendez 594-2454Labeling Controls (CGMP) Barry Rothman 594-0098Laboratory Issues Monica Caphart 594-2458C. Russ Rutledge 594-2455Litigation Guidance and Fred Blumenschein 594-0098Support Nick Buhay 594-0093Medical Gases Duane S. Sylvia 594-0095Paul Haynie 594-0098NDA / ANDA Pre-Approval Inspections Randall Woods 827-0062Packaging Barry Rothman 594-0098Edwin Melendez 594-2454Penicillin Cross Contamination Edwin Melendez 594-2454Pharmacies, CGMP LuAnn Pallas 594-0098Pre-Approval Program Melissa Egas 594-0095Bruce Hartman 927-0062Process Validation, General John Dietrick 594-0098Pyrogen / LAL Test Brenda Uratani 594-0095Repackaging Barry Rothman 594-0098Salvaging Barry Rothman 594-0098Stability / Expiration Dates Barry Rothman 594-0098Sterility Issues, General Richard Friedman 594-0098Edwin Melendez 594-2454Brenda Uratani 594-0095Topical Drugs Randall Woods 827-0062Transdermals Brian Hasselbalch 594-0098Videoconferencing C. Russ Rutledge 594-2455Water Quality Richard Friedman 594-0098Edwin Melendez 594-2454 Brenda Uratani 594-0095 FAX FEEDBACK TO: C. Russ Rutledge, HUMAN DRUG CGMP NOTES, HFD-325FAX: 301-594-2202 (Phone 301-594-0098)FROM:_______________________________________________________________AT: _____________________________________________ MAIL CODE: ________PHONE: ____________________________ FAX: ___________________________E-MAIL ADDRESS: ___________________________________________________This FAX consists of this page plus ______ page(s).I found this issue of HUMAN DRUG CGMP NOTES to be [check as appropriate]:__not very; __ somewhat; __ very; __ extremely informative and,__not very; __somewhat; __ very; __ extremely useful to my inspectional/compliance activities.
Here’s my question/comment regarding: ____________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________Future editions of HUMAN DRUG CGMP NOTES should address the following CGMP questions/issues:____________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________ ____________________________________________________________________ Date created: |
|
|
||||||
 | ||||||
|
||||||