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6.4 In-Process Inspection, Sampling, and Laboratory ControlThis 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. Does the OGD Draft Guidance document on Blend Uniformity Analysis (BUA) represent CGMP requirements? Are ASTM or NIST test methods considered "official" like those published by the USP and AOAC? Does the OGD Draft Guidance document on Blend Uniformity Analysis (BUA) represent CGMP requirements?References: No, this Office of Generic Drugs (OGD) guidance document presents recommendations for application filing based on 21 CFR 314, not on CGMP regulations. Also, this is a draft document subject to review and comment, and has not yet been implemented. OGD current policies are based on earlier policy documents rather than on this draft guidance. Additionally, the guidance document presents recommendations only, not requirements. Alternative approaches may also be used to submit data with an application. The CGMP regulations, 21 CFR 211.110, do not require Blend Uniformity Analysis (BUA). It requires some type of test or examination on each batch, but that test or examination does not have to be BUA as described in the guidance document. Failure to perform BUA type testing on routine production batches should not be cited as a CGMP deficiency. BUA type testing is recommended for low dose powder blend products (e.g., less than 50% or 50 mg) but other approaches may also be used to satisfy this CGMP requirement. The draft guidance also permits the submission of a supplement to delete BUA testing. This is also an application filing issue and does not exempt a manufacturer from the CGMP requirement for some type of test or examination on each batch. If BUA type testing is discontinued, an alternate approach to comply with 21 CFR 211.110 should be implemented. Contact for further information: John Dietrick, HFD-322; (301) 594-0095; e-mail: dietrickj@cder.fda.gov Reprinted from HUMAN DRUG CGMP NOTES (Volume 8, Number 1), March, 2000. Is there a requirement specifying the level of light intensity when performing visual inspection of parenteral drug products for the presence of particulates?Reference: No. However, 21 CFR 211.160 (b) requires that laboratory controls include the establishment of scientifically sound and appropriate test procedures designed to assure that drug products conform to appropriate standards of identity, strength, quality and purity. Accordingly, a test method for the visual detection of particulates would be expected to account for the intensity of the light as well as backgrounds that may be needed for the adequate visual detection of particulates in the finished drug product. We would assess, on a case by case basis, the adequacy of a firm's determination of what levels of light would be sufficient. Contact for further information: Tracy Roberts, HFD-325, 301-594-0098, e-mail: robertst@cder.fda.gov Reprinted from: FDA's HUMAN DRUG CGMP NOTES (Volume 7, Number 2) June, 1999. Do the CGMP regulations require a contract laboratory to have a quality control unit for the operations it performs?Reference: Yes. By definition, testing and quality control of drug products are part of manufacturing. At section 210.2, the regulations explain that where persons engage in only some operations subject to provisions of parts 210 and 211 (of Title 21), persons need only comply with those regulations applicable to the operations they perform. Therefore, a contract laboratory is subject to those portions of the CGMP regulations that cover activities it performs. We would expect that many of the laboratory's activities would fall under Subpart I, Laboratory Controls, of the CGMP regulations. (Other provisions, such as those pertaining to personnel qualification, recordkeeping, facilities, and laboratory animals would also apply.) The responsibilities of a quality control unit are pervasive in the CGMP regulations, and many lab functions require review and approval of a quality control unit. For example, per section 211.160, the quality control unit must review and approve test procedures and laboratory control mechanisms. It should be clear, therefore, that section 211.22 applies to a contract laboratory and that the lab would have to have a quality control unit. However, that unit's responsibilities would only extend to the CGMP operations that the lab performs. What's more, be aware that in smaller establishments, as might be the case in a contract laboratory, the responsibilities of a quality control unit may be assigned to as few as one or two individuals. In a larger organization, of course, an effective quality control unit may warrant a larger staff. This is consistent with the definition of quality control unit, at section 210.3(b). Reprinted from: FDA's
HUMAN
DRUG CGMP NOTES (Volume 7, Number 1) March, 1999. If a contract laboratory obtains an OOS result, what are the CGMP responsibilities of the dosage form manufacturer and the lab with respect to follow up investigations?Reference: There are a number of possible scenarios under this question. Under CGMP, FDA would expect the contract laboratory to have a quality control unit. The lab's QC unit has the CGMP responsibility to ensure the analytical results obtained are accurate for the tested material. This means the contract laboratory needs to investigate any OOS result with the purpose of ascertaining such accuracy. This would be accomplished by ensuring that personnel performed the tests properly using: (1) The current validated analytical procedure; (2) correct reagents and reference standards; and, (3) equipment that has been properly maintained and calibrated. There are basically two possible results of the lab's investigation. 1) If the lab determines the analyst made an error, or that instrument malfunction occurred, the test results may be invalidated. The analysis would be re-run according to the approved analytical method. The re-run test results would be considered the original results, and these results would be reported to the manufacturer. The lab does not have a CGMP obligation to report the initial (invalidated) results to the manufacturer; however, the lab must, per 211.194, retain the records pertaining to those initial results. 2) If the laboratory determines that there was no analyst error, and that no instrument malfunction occurred, then the results must be considered accurate and reported to the pharmaceutical manufacturer. In the event of outcome number two, the pharmaceutical manufacturer would have analytical results indicating the material does not meet its specifications. Under CGMP, an investigation must take place. The manufacturer is responsible for investigating the production process to determine if any mistakes were made--things to consider could include charge-in of components, mixing times, and quality of components. Storage conditions of the analyzed material, and the sampling method used also need to be reviewed to ascertain whether the tested material might not have been representative of the batch. If the manufacturer's investigation fails to find a cause, it might also consider whether the contract laboratory is suspect (i.e., if perhaps the lab made an unrecognized error.) The CGMPs do not, however, explicitly require the manufacturer to extend its investigation to the lab's operations. However, it is considered CGMP for manufacturers to qualify their contract laboratories. At comment paragraph 94 of the September 29, 1978 CGMP revisions, 43 FR 45034, the agency said "[a] manufacturer does have a responsibility, however, to see that the outside laboratory used is qualified to do the work and that the work is performed satisfactorily." As part of its investigation, the manufacturer might take the opportunity to requalify the contract laboratory, or may consider changing contract laboratories. Retesting could also be part of this process. It must be stressed that in this situation the manufacturer has information that the batch does not meet its quality standards, and unless that information can be invalidated, it must be used to reach a batch disposition decision, namely, whether to destroy the batch, or reprocess it to bring it into compliance. Contact for further information: Russ Rutledge, HFD-325, 301-594-0098, e-mail: rutledgec@cder.fda.gov Reprinted from: FDA's
HUMAN
DRUG CGMP NOTES (Volume 7, Number 1) March, 1999. Should investigators cite firms for not conducting accelerated stability testing during ongoing stability studies? If firms use more stressful conditions than their protocols require should they be cited?Reference: No and no! The CGMP regulations allow for the use of accelerated stability studies to project a tentative expiration dating period provided that full shelf-life stability studies are conducted to verify the tentative expiration dating period. After the expiration dating period has been verified there should be no reason to conduct stability testing under accelerated conditions during ongoing stability studies. Ongoing stability studies generally involve adding a new lot from the current year's production on stability annually for testing under shelf-life (long-term) conditions. It would be a CGMP violation, and may be a new drug violation as well, if a firm deviates from its approved stability protocol. However, it's not enough for investigators to just report that there was a protocol deviation. For example, if the protocol deviation was well documented by the firm in both its stability test records and NDA submissions and it is very clear that the alternative condition was more stressful than what is required in the approved protocol, the deviation would not be significant and should not be cited on an FDA 483. If the investigator has any doubt as to whether the alternative condition exceeds protocol requirements (i.e., higher temperatures or humidity are not always more stressful; it depends on such factors as the dosage form and labeled storage condition), CDER Office of Compliance should be contacted for guidance and coordination with CDER reviewers. One note of caution, however, it would not be acceptable if, after using the alternative condition, a firm ignores the data generated. Also, it would not be acceptable if stability chambers are not properly controlled, and there are haphazard excursions from required storage conditions. If the latter is found, it should be cited on an FDA 483. In any event, investigators should fully describe in their inspection reports any changes from approved protocols, even if it appears that the alternative conditions used were acceptable. Contact for further information: Barry Rothman, HFD-325, 301-594-0098, e-mail: rothmanb@cder.fda.gov Reprinted from: FDA's HUMAN DRUG CGMP NOTES (Volume 7, Number 1) March, 1999. What is the significance of the Total Organic Carbon (TOC) test for compendial processing waters (Purified Water, Water for Injection)?Reference: Implicit in the term "Purified Water" is that it has some reasonable, objective level of purity. TOC testing allows for evaluating impurities in water besides those which are inorganic anions and cations. Carbon-based (organic) compounds are often more complex than inorganic impurities. TOC allows for a quick, broad test for organic impurities. Numerous compounds can be detected under the umbrella of TOC, but it is important to be aware that this method is not capable of differentiating between specific organic compounds. There is a long history of testing water for the presence of organic compounds. TOC's predecessor, oxidizable substances, is widely considered a less accurate, outdated test. As of May, 1998, TOC is the official organic impurities test for USP pharmaceutical processing waters. Contact for further information: Richard L. Friedman, HFD- 322, 301-594-0095; e-mail: friedmanr@cder.fda.gov . Reprinted from: FDA's HUMAN DRUG CGMP NOTES (Volume 6, Number 4) December, 1998. Do the CGMP regulations prohibit a firm from outsourcing (contracting out) the functions of the quality control unit?Reference: 21 CFR 210(3)(a),(b)(15), Definitions and No. The CGMP regulations do not prohibit a firm from contracting out the functions of the quality control unit, or any other function the regulations identify. It would therefore be inappropriate to list such QC unit outsourcing, per se, as an FDA 483 item. The CGMP regulations define a quality control unit as "any person or organizational element designated by the firm to be responsible for the duties relating to quality control". The regulations incorporate by reference the definitions in the Federal Food Drug, and Cosmetic Act. The Act's definition of "person" includes an individual, partnership, corporation and association. Therefore, a quality control unit could be a corporation external to the drug product manufacturer. More important than who takes on the QC role is the matter of how well the quality control unit performs its responsibilities as required in section 211.22 and elsewhere in the CGMP regulations. That should be the primary focus of inspectional attention when it comes to auditing the work of the QC unit. For example, the unit must have available to it adequate laboratory facilities for testing and approval (or rejection) of components, drug product containers, closures, packaging materials, in-process materials, and drug products. Those facilities may be at the manufacturing location or elsewhere, but the regulations mandate their availability to the QC unit. Nonetheless, investigators who encounter firms that contract out the Q.C. unit should be aware of any aspect of the outsourcing that might impair the unit's ability to perform its many CGMP responsibilities. For example, if the contracted QC unit is remote from the manufacturing operations it is charged with monitoring, it might not be able to perform that oversight effectively and in a timely manner. Again, any FDA 483 item should speak directly to QC unit performance and not to outsourcing arrangements themselves. Despite any division of CGMP activities, both the manufacturer and the outsourced Q.C. unit can be held responsible for introducing, or causing the introduction of, violative products into interstate commerce, each firm with respect to its actions. In addition, the violative products themselves would be subject to seizure. Reprinted from: FDA's HUMAN
DRUG CGMP NOTES (Volume 6, Number 1) March, 1998. When analyzing a sample by HPLC to determine variance within a batch, such as content uniformity or dissolution, and the result for one tablet is out of specifications (OOS), if there is clearly an HPLC malfunction, does the whole test need to be re-run, or only the one solution?References: In general, when the intent of the test is to measure variance within the batch, retesting is not an option. The reason is there are multiple stages of this testing. For example, the Dissolution test starts with stage S1 where 6 tablets are analyzed under wide limits, but if these 6 don't pass S1 limits, then a second stage (S2) allows for 6 additional tablets to be tested with even broader limits. If needed, there is a third stage for 12 more tablets (S3). All stages actually used in the test (i.e., S1 , S2, and S3) are used in the evaluation, and the sample must fail all stages to be considered OOS. Content Uniformity likewise has multiple stages. However, if the analytical instrument was clearly shown to give unreliable results by the laboratory investigation, then the test results must all be invalidated and the entire test run again, using the original sample solutions if possible. The new results are substituted for the invalidated results, and only these are used in the batch evaluation. To merely re-run the one sample solution is inadequate because the rejection of data is based on instrument malfunction. Thus, all results from this test should be considered unreliable. Contact for further information: Russ Rutledge, HFD-325, 301-594-1089, e-mail: rutledgec@cder.fda.gov Reprinted from: FDA's HUMAN DRUG CGMP NOTES (Volume 5, Number 3) September, 1997. Are ASTM or NIST test methods considered "official" like those published by the USP and AOAC?References: No. Under the Food, Drug, and Cosmetic Act, "official" relates to "official compendium", meaning USP/NF or Homeopathic Pharmacopeia. Unfortunately, the word "official" has taken on much broader meaning in common usage -- extending to NDAs, other government agencies, and quasi-governmental organizations. The question needs a context for a clear answer that relates to what we expect firms to do. Let's consider two facets -- the analytical method which governs determination of conformance to a standard, and the need for methods validation. Determination of compliance involves the measurement of a drug's conformance to a given standard or legal yardstick -- an objective way of determining compliance when there's a question. The customary hierarchy of legal yardsticks consists of: (1) methods in an approved NDA; (2) methods in the USP/NF or HP( for compendial drugs) and the AOAC (Association of Official Analytical Chemists) Book of Methods ; and (3) other scientifically sound methods. The third category is one that may be subject to debate in any dispute, even if the scientifically sound method is generated by NIST (the National Institute of Standards and Technology), ASTM (American Society for Testing and Materials), or some other organization. Regarding methods validation, the CGMP regs, at 211.194(a)(2), relieve firms from having detailed data relating to method accuracy for methods in approved NDAs, the USP/NF, or the AOAC Book of Methods. The regulation doesn't recognize other sources and doesn't use the word "official". Relief is conditional upon having a reference to the specific method and not deviating from the method. Reprinted
from FDA's Human Drug CGMP
Notes, (Volume 3 Number 4), December, 1995. Can a company use an older (not updated) version of an official method, or must it use the most updated version?Reference: Here again, we need context for clarity. In resolving issues of conformance to an "official standard" (broadly meaning NDA or compendial), the current version of the analytical method is the method that FDA will use to determine compliance. From a compliance point of view, all compendial products (most ANDA products or NDA products which have become compendial) must meet, at any point in their shelf lives, the standards set forth in the revision of the compendia that was current at the time the drugs were manufactured. Monographs published in the current revision of the compendia supersede all earlier revisions. Thus, a firm which cites a USP monograph as a test method in its application (ANDA products) or firms whose products subsequently become compendial (NDA products) should be mindful of this and update their methods accordingly. In the context of lot to lot release testing, firms should use the approved methods they've committed to use, per their approved
applications. While this statement may seem to be at "odds" with the paragraph above, the following indicates that it is not. The
process used by the USP to revise its contents -- the Pharmacopeial Forum (PF) -- is a gradual one. The PF is the medium
used by the USP to publicize proposed monograph revisions and provide opportunities for firms or other interested parties to Contact for Further Info: Monica Caphart, HFD- 325, 301-594-0098, e-mail: caphartm@cder.fda.gov Reprinted
from FDA's Human Drug CGMP
Notes, (Volume 3 Number 4), December, 1995. |
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