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1.5 Internal Quality/GMP Audit Program
This page will address various regulatory issues related to this section of the GMP Institute framework. Click below to view the issues that are relevant to you.
Is there a requirement to conduct an annual product review?
Do the CGMP regulations specify how frequently firms must review their SOPs?
Does FDA have any guidance regarding the color of ink used to prepare CGMP production records?
Is there a requirement to conduct an annual product review?
References:
Subpart J - Records and Reports
21 CFR 211.180 (e), General Requirements
21 CFR 211.192 Production Record Review
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:
 | Does the firm adequately maintain the records required in Part 211? |
| Does the firm have an adequate procedure written for directing the review of, at least annually, the maintained CGMP data for indications that product specifications or manufacturing or control procedures need to be changed? |
| Does the firm perform an adequate review following the procedure? Some features of an adequate product review procedure and an adequate review are: |
| Does the procedure require a review by product; is the review done for each product? |
| Does the procedure require the product review annually or more frequently; are the product reviews done annually or more frequently? |
| Does the procedure specify the batches and records of batches to be reviewed, with adequate provision for selection of a representative number of approved and rejected batches/records? |
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:
| Complaints? |
| Recalls? |
| Incidents of returned (non-recall) and salvaged drug products? |
| Investigations of unexplained discrepancies or failures of batches or components to meet any specification noted during the production or quality control unit review for release of such batches or components? |
| 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
Reprinted from: FDA's HUMAN DRUG CGMP NOTES (Volume 8, Number 2) June, 2000
What records do the CGMPs require a firm to examine under the 211.180(e) periodic review? Must such records be stamped with a review or expiration date?
Reference:
21 CFR 211.180(e), General requirements, Subpart J - Records and Reports;
Federal Register 1/20/95 (60 FR 4087) Final Rule, Current Good Manufacturing
Practice in Manufacturing, Processing, Packing, or Holding of Drugs; Amendment
of Certain Requirements for Finished Pharmaceuticals
Section 211.180(e) states that, "Written records required by this part shall be maintained so that data therein can be used for evaluating, at least annually, the quality standards of each drug product to determine the need for changes in drug product specifications or manufacturing or control procedures." (Emphasis added)
This section is intended to require firms to perform a systematic review of data relating to product specifications and manufacturing and control procedures to determine if changes are warranted. Data that indicate a need for such changes can be contained within a broad range of records. That's why the regulation is explicit in referring to records required "by this part"; part means 21 CFR part 211. The data must be in a retrievable form so firms can use the information as needed when conducting the evaluation. This does not mean that every record a firm creates to meet a part 211 requirement must be reviewed. Rather, records specified by 211.180(e)(1) and (2) must always be part of that review whereas other records would be reviewed as indications for needed change arise.
The regulations give firms a great deal of latitude in exactly how they conduct periodic evaluations. However, the CGMPs establish key principles. First, the purpose of the review itself is to determine if changes in specifications or manufacturing or control procedures are needed. Second, the review both corrects and prevents product quality problems; that's why the regulations specify that reviewed batches represent those that have been both approved and rejected. [Note that although 211.180 states that "batches" and applicable associated records are to be reviewed, the preamble to the 1995 final rule that last modified this section clearly indicates that "batches" means "batch records."] In other words, indications of the need for change can be contained in records relating to conforming and non-conforming products. For example, production records for conforming lots may nonetheless indicate that a process is drifting out of control. Third, the review must be conducted at least annually.
A broad CGMP principle that runs throughout the regulations is the concept of redundant checks and balances to ultimately ensure product quality. The 211.180 periodic review provides that balance with respect to change control because, in addition to having an effective change control system, reviews of records that establish product specifications or manufacturing or control procedures can help firms maintain the currency and accuracy of such things as: (1) Cross references to other documents and standards; (2) materials' specifications (e.g., ensuring they match what's in a firm's most recent NDA submission or USP monograph); (3) equipment references (e.g., too generalized a manufacturing instruction to use a "suitable mixer" where different types and sizes are at hand would need to be made specific); (4) process step sequencing; (5) process step parameters; and, (6) acceptance criteria. Especially where a firm makes significant or frequent changes, this complex matrix of interrelated instructions and specifications can make change control difficult and may result in operators using outdated or otherwise incorrect procedures or standards to make medicine. We have encountered situations where an effective periodic review could have prevented such problems.
The regulations mandate that certain core records most likely to indicate a need for changes be reviewed. Included are records: (1) For each drug product covering complaints, recalls, returned or salvaged products and discrepancy/failure investigations conducted under section 211.192; and, (2) applicable to, and associated with, a representative number of batches produced over the review period. Master production records would be part of the second (batch related) grouping. Also included in that grouping would be other records that establish product specifications or manufacturing or control procedures. These records are intrinsically relevant to the review because: (1) Per CGMP, batches must be made according to those procedures and specifications; and, (2) those very procedures and specifications are what may need to be modified. Because those records may in and of themselves hold indications that changes are needed (e.g., outdated/superseded instructions), a meaningful assessment of the need for change would thus be impossible without at least a minimal review of those records. Be aware that some firms may call some records in this latter category standard operating procedures (SOPs) (e.g., how to collect an in-process sample).
Although we expect that the primary indicators of the need for change reside in those records explicitly identified in 211.180(e)(1) and (2), other records may also hold indications of the need for change. Although the CGMPs don't specify those records, any included in the review need to be identified in a firm's review procedures. During your inspections, be aware of evidence indicating that a firm's review procedures may be inadequate by virtue of failing to consider relevant records that hold change indicators, especially where product defects can be attributable to a failure to make needed changes.
Examples of records we would not normally expect to hold indicators of the need to change product specifications or manufacturing or control procedures include written procedures for component purchasing methods and product distribution recordkeeping.
CGMPs don't require that records be affixed with review dates, nor expiration dates. Records that establish product specifications or manufacturing or control procedures (including such records that firms call SOPs) can therefore continue in effect until superseded or discontinued.
Reprinted from: FDA's HUMAN
DRUG CGMP NOTES (Volume 6, Number 4) December, 1998.
This same text is also reprinted in Framework sections 1.2
and 6.3.
Do the CGMP regulations specify how frequently firms must review their SOPs?
References:
See 21 CFR 211.180(e), General requirements
[Subpart J - Records and Reports]
Yes. At the referenced section, the CGMP regulations call for at least an annual evaluation of each drug product's quality standards to determine the need for changes in product specifications or manufacturing or control procedures. The rule also requires firms to establish and follow written procedures for conducting those evaluations. Such an evaluation would be incomplete if the standard operating procedures for production and process controls were themselves not reviewed.
During your establishment inspections, when auditing for compliance with section 211.180, determine if the firm has established, and is following, those evaluation procedures. Also check to see if the procedures call for reviewing SOPs.
Keeping SOPs current can be a challenging task when manufacturers make frequent changes or have a matrix of SOPs that cross-reference each other. Ensuring that employees are furnished with current versions of SOPs can be problematic. Therefore, during your audits, you might compare dates and version numbers of SOPs that a firm's operators use, against a master list of current SOPs. Discrepancies should be noted as objectionable conditions.
Reprinted from: FDA's HUMAN
DRUG CGMP NOTES (Volume 6, Number 3) September, 1998.
This same text is also reprinted in Framework sections 1.2
and 6.3.
Does the FDA Modernization Act limit FDA's OTC records inspection authority to only those records created after 2/19/98?
References:
U.S. Food, Drug and Cosmetic Act, Section 704(a)(1), as amended by the Food and
Drug Administration Modernization Act (FDAMA) at Section 751;
Compliance Policy Guide 7151.02, Sec 130.300, FDA Access to Results of Quality
Assurance Program Audits and Inspections.
No. OTC records created before 2/19/98 (the effective date of this part of the revised law) are not grandfathered. The FD&C Act now authorizes investigators to inspect records pertaining to over-the- counter, as well as prescription, drugs. The FDAMA amended 704(a)(1) by striking "prescription drugs" each place it appears and inserting "prescription drugs, nonprescription drugs intended for human use,".
Investigators should not, however, routinely ask to review OTC self audit reports (a firm's own audits and inspections of its operations), although FDA reserves the right to review such records. This is consistent with CPG 7151.02, and the Congressional Joint Explanatory Statement of the Committee of Conference regarding the FDAMA.
Reprinted from: FDA's HUMAN
DRUG CGMP NOTES (Volume 6, Number 2) June 1998.
This same text is also reprinted in Framework section 1.2.
What constitutes a "representative number of batches" that must be reviewed periodically for quality standards under the CGMP regulations?
Reference:
21 CFR 211.180(e), General requirements [Subpart J - Records and
Reports],
21 CFR 314.81(b)(1), Other post marketing reports [Subpart B - Applications]
The annual review established by 211.180(e) is for the purpose of "evaluating the quality drug standards of each drug product to determine the need for changes in drug product specifications or manufacturing or control procedures". The selection of records to be reviewed needs to consider "records required by this part" which have "data therein" and include the records specified in 211.180 (e)(1) and 211.180(e)(2).
The number of batches whose associated records will be reviewed must achieve the purpose of the review. Any reasonable approach to achieve the purpose can be acceptable; the word "representative" was inserted into this regulation in January 1995 to simply confirm that every batch does not necessarily have to be included.
Reviewing batches which exhibit varying manufacturing experiences is a critical element in ensuring that a "representative" selection is made. Batches showing different categories of experiences would include those that: (1) Have been approved, rejected, and recalled; (2) have unexplained discrepancies; (3) were the subject of FARs (field alert reports); and, (4) have any other kind of outcome that may indicate changes are needed.
Where any of these categories include multiple problems, the number of batches selected for review should fully represent the different kinds of problems in each category.
Every drug product must have at least one batch included in the annual review. Different products may not be grouped by "similar processes" or any other similar approach, because the necessary differences in the process and/or specifications which make each product unique may result in different manufacturing outcomes.
Contact for further info: Nicholas Buhay, HFD-325, 301-594-0098; e-mail: buhay@cder.fda.gov
Reprinted from: FDA's
HUMAN
DRUG CGMP NOTES (Volume 6, Number 1) March, 1998.
This text is also reprinted in Framework section 1.2.
Does FDA have any guidance regarding the color of ink used to prepare CGMP production records?
Reference:
21 CFR 211.180, General requirements, Subpart J, Records and Reports
No. However, whatever ink is used should permit the records to meet the inspection, review and archiving requirements in section 211.180 of the CGMP regulations. For example, for a record to be maintained for one year past the expiration date of the related lot, per 211.180(b), one needs to be able to read the record throughout the retention period. Likewise, per 211.180(c), the records are subject to FDA photocopying or other means of reproduction. In addition, paragraph (e) of this section requires that production records be maintained such that firms may review them at least annually to determine if production and control changes need to be made. Keeping these needs in mind, the ink that fades, can't be copied or otherwise obscures information would be troublesome.
Contact for further information: Richard S. Lev, HFD-325, 301-594-0089, e-mail: levr@cder.fda.gov
Reprinted from: FDA's HUMAN
DRUG CGMP NOTES (Volume 5, Number 3) September, 1997.
This text is also reprinted in framework section 1.2.
Must annual evaluations include failed batches? What if such batches are made for "research" purposes?
Reference:
21 CFR 211.180(e) General Requirements, Subpart J Records and Reports
Yes. 21 CFR 211.180(e) requires an annual evaluation of the quality standards of each drug product to determine the need for changes in specifications and/or manufacturing or control procedures. Failed batches made for commercial distribution must be included in the inventory of batches from which a number of batches are selected for a 211.180(e) annual review of the product.
There is no category of manufacture which includes a batch which is intended for commercial distribution if it passes specifications upon testing and at the same time for "research", or "experimental", or any other similarly designated purpose, if it does not pass all specifications upon testing. The status of a batch is to be designated unequivocally and in advance. Equivocation in the status of a batch or changes in status from commercial distribution to research, etc. is unacceptable as good manufacturing practice, and may have data reliability implications. Obviously, information derived from the failed manufacture of a commercial batch may be used for research or product development purposes, but this does not change the commercial nature of the batch.
Information on a failure of a batch of new drug product to meet a specification is required to be submitted to the A/NDA Annual Report under 21 CFR 314.81(b)(2)(i) and 314.81(b)(2)(iv) because it is "significant new information from the previous year that might effect the safety, efficacy, or labeling" and "new information that may affect FDA's previous conclusions about the safety or effectiveness of the drug product." FDA will accept as adequate to meet this requirement submission of a Section 314.81(b)(1) Field Alert Report on the incident, or inclusion in the A/NDA Annual Report.
Contact for further info: Nicholas Buhay, HFD-325, 301594-0098, e-mail: buhay@cder.fda.gov .
Reprinted from FDA's Human
Drug CGMP Notes, (Volume 4 Number 2), June, 1996.
This text is also reprinted in Framework section 1.2 .
Would pharmaceutical industry "teams" be compatible with drug CGMP regulations (e.g., regarding a q.c. unit's role, team approval of its own work, and product release)?
Reference: 21 CFR 211.122 (Responsibilities of quality control unit)
No, not if team implementation effectively usurps or countermands the function of the quality control unit. Overall responsibility of the quality control unit, especially with regard to approving specifications and releasing product for distribution, is clearly stated in the regulations.
Investigators who encounter "teams" in a pharmaceutical manufacturing facility should pay careful attention to the function of, and authority granted to, such units and the net effect that team autonomy may have on established standards and product quality.
For example, be wary of teams that may decide to implement production methods, analytical methods, or product specifications that differ from those in approved new drug applications.
Keep in mind the "so what" of team implementation. The existence of teams, per se, would not be a legitimate 483 observation because in some cases team implementation may not be at odds with the CGMP regulations and may, in fact, be beneficial. For instance, the quality control unit itself may theoretically be structured as a team. Production units may also include teams that could legitimately recommend process improvements to the q.c. unit (which ultimately evaluates and approves or disapproves of the suggestions). Production unit teams should not, however, independently put those changes into effect in the absence of q.c. unit review and approval.
Reprinted
from FDA's Human Drug CGMP
Notes, (Volume 3 Number 4), December, 1995.
This same text is also reprinted in Framework section 1.1
.
