Human Drug cGMP Notes - (Volume 8, Number 2)

Russ's Ramblings(Back to Top)

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.

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 As a result, my editorial and the Fax-Feedback form contained outdated information on obtaining an e-mail subscription.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: http://www.fda.gov/cder/dmpq.

Thanks!
Russ Rutledge

Policy Questions:(Back to Top)
What FDA guidance documents pertain to drug repackaging operations and how can they be obtained?

The "Draft Guideline On Repackaging Of Solid Oral Dosage Form Drug Products" can be obtained from CDER's Office of Training and Communications (OTCOM), phone no. (301) 827-4573. (This guideline is not presently available on CDER's web site.)

The following Compliance Policy Guides are available on FDA's Office of Regulatory Affairs (ORA) web site: http://www.fda.gov/ora/compliance_ref/cpg/cpgdrg/Default.htm Section 430.100 - Unit Dose Labeling for Solid and Liquid Oral Dosage Forms (CPG 7132b.10)
Section 430.200 - Repacking of Drug Products – Testing/Examinations under CGMPs (CPG 7132.13)

Section 446.100 – Regulatory Action Regarding Approved New Drug and Antibiotic Drug Products Subjected to Additional Processing or other Manipulations (CPG 7132c.03)

Section 460.100 - Hospital Pharmacies – Status as Drug Manufacturer (CPG 7132.06)

Section 480.200 - Expiration Dating of Unit Dose Repackaged Drugs (CPG 7132b.11)

Compliance with applicable parts of the CGMP regulations in 21 CFR Parts 210 and 211, is required for repackagers of finished pharmaceuticals. The CGMP regulations are available on CDER's web site: http://www.fda.gov/cder/dmpq/cgmpregs.htm.

Technical guidance documents that have applicability to drug repackaging operations can be found on CDER's web site. These include guidance documents pertaining to stability testing and container-closure systems. The CDER web site address is: 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:

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:

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:

Yes, 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.

For each product, does the procedure and the product review include evaluation of all:

Does the procedure require conclusions, and documentation of conclusion regarding the need for product changes?

Are the conclusions included in the report of the product review, and are conclusions of the product review supported adequately by the data reviewed and by the findings of the review?

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:

A 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, ampule, 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?

Reference: 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. (Back to Top)

Edited by Angelo DePalma
Managing Editor, Pharmaceutical Online