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5.2 Material/Component Receipt, Inspection, Sampling, and Laboratory TestingThis 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. Are ASTM or NIST test methods considered "official" like those published by the USP and AOAC? 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: 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; This same text is also reprinted in Framework section 5.3. Reprinted from: FDA's HUMAN DRUG CGMP NOTES (Volume 8, Number 2) June, 2000 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. Is a dosage form manufacturer required to conduct full monograph testing on a USP ingredient used in a drug product?Reference: This question has several facets, namely, what tests need be done and who performs them. The tests that need to be performed are those to ensure that established specifications for the component have been met. The CGMP regulations, at section 211.160(b) require the dosage form manufacturer to establish appropriate component specifications. If the manufacturer adopts all of the component monograph specifications then all of those specifications would have to be met as demonstrated by laboratory testing. A firm may commit itself to those specifications, for example, in an approved new drug application. A firm would also adopt full monograph specifications for a USP component if the material is an active ingredient in a USP drug product where the dosage form monograph requires use of an active ingredient that meets the active ingredient monograph. The firm could exempt itself from this USP requirement if it labels the USP end product with a specific disclaimer as to how the dosage form does not meet USP specifications. The next facet relates to who performs the component tests. Before the dosage form manufacturer incorporates the ingredients, the testing must have been completed. Section 211.84(a) specifies that each lot of components, drug product containers, and closures shall be withheld from use until sampled, tested, or examined, as appropriate, and released for use by the quality control unit. Component means ingredient and therefore both actives and excipients require testing. The CGMPs give firms considerable latitude when it comes to who does the testing. The dosage form manufacturer may elect to: (1) Perform the tests itself; (2) have the tests done by a contract laboratory; (3) have tests done by the component supplier; or, (4) perform a combination of these options. Where a firm elects to have the component supplier perform testing, section 211.84(d)(2) states that "a report of analysis may be accepted from the supplier of a component, provided that at least one specific identity test is conducted on such component by the manufacturer, and provided that the manufacturer establishes the reliability of the supplier's analysis through appropriate validation of the supplier's test results at appropriate intervals." We have found that establishing reliability of the supplier's analysis generally involves comparing results of independent tests against the supplier's corresponding certificates of analysis (COAs), usually accomplished by initially conducting full testing on a number of lots. In addition, audits of the supplier's laboratory operations, while not explicitly required by CGMPs, can be enlightening. That's because some chemical suppliers are merely distributors or brokers who might be photocopying the makers' results on their own letterhead, thereby representing that they conducted the analysis themselves. This might only be revealed through a supplier audit. Moreover, this audit may be the only way to establish that the laboratory controls, specifications, standards, sampling plans, and test procedures are scientifically sound. The CGMPs require that the reliability of the supplier's results be conducted at appropriate intervals. Some FDA investigators have included on an FDA-483 that the manufacturer has not conducted this "Vendor Validation" at least once per year. This is an inappropriate citation because the regulations don't specify the frequency, as per 211.84. There is no requirement to conduct this validation annually. Manufacturers have the discretion to determine the interval, and, on a case by case basis, we assess whether or not that interval is appropriate. For instance, if a firm discovers problems with ingredients that contradict COAs, then that may indicate that the frequency of the test comparisons is insufficient. Contact for further info: Brian G. Nadel, HFD-325 (301) 594-0098, e-mail nadelb@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. May firms omit second person component weight checks if scale weights are automatically recorded to a computer system?References: No. Automatically recording weight alone would not meet the specific requirements of 211.101, if the automated system did not include checks on component quality control release status and proper identification of containers. Adequate supervision of weighing operations involves a number of quality control measures that are second nature to humans but not necessarily to machines. For example, while identifying containers, operators are likely to alert the quality control unit if the component being weighed is obviously not the color or granularity it's supposed to be, thus preventing a potential mix-up. In addition, people who observe weighing operations ensure that no objects (such as tools, cart wheels, or feet) rest on platform scales so as to cause inaccurate weights. Per the referenced CPG, an automated system could act as a second "person" if it examines the same conditions a human being would look for, and with at least the same degree of accuracy. Apply this CPG to an automated weighting operation. Reprinted from: FDA's HUMAN DRUG CGMP NOTES (Volume 5, Number 3) September, 1997. Must USP grade APIs be analyzed in accordance with USP monographs? Must manufacturers test each batch for all monograph specifications?Reference: The referenced CPG addresses the issue of whether a firm is required to use the compendial methodology as a batch release test for drug products to determine compliance with monograph specifications. The CPG states that a pharmaceutical manufacturer is not required to apply compendial analytical methods as a batch release test unless the firm has made specific commitments to do so (as in an NDA or a drug master file), or where the official method is the only appropriate test. Neither the USP nor the CGMP regulations specifically requires a firm to utilize the compendial method as a batch release test. This policy also applies to API manufacturers. CGMP, however, requires that batch release test methods be scientifically sound. Non-compendial methods can be used for batch release purposes, as long as the capabilities of these methods are shown to be equivalent to or better than the compendial test methods. However, in the event of a dispute regarding conformance of the API with USP specifications, the compendial method is the referee test. CPG 7132.05 also establishes that in some cases, it may not be necessary for a manufacturer to test each batch for all compendial monograph specifications. The nature and extent of end product testing beyond potency should be determined by the manufacturer based on the adequacy of process validation and adequacy of in-process manufacturing controls. Reprinted from FDA's Human Drug CGMP Notes, (Volume 5 Number 2), June, 1997. In many countries, where it may be difficult to obtain USP reference standards, API manufacturers use secondary standards (usually production lots that are further purified and qualified in the laboratory) for analysis. Is use of such secondary reference standards acceptable for analysis of compendial articles?Reference: USP 23, <11> Reference Standards. Many USP tests and assays of APIs are based on comparing a test sample with a USP Reference Standard. Page 1653 of USP 23 states that "where it is directed that a Standard solution or a Standard preparation be prepared for a quantitative determination by stepwise dilution or otherwise, it is intended that the Reference Standard substance shall be accurately weighed. . ." We generally recommend use of official reference standards for analysis of compendial articles. However, use of secondary reference standards is acceptable if each lot's suitability is determined prior to use by comparison against the current official USP reference standard and each lot is requalified periodically in accordance with a written protocol. The protocol should clearly address the receipt, storage, handling and use of primary reference standards, the purification of secondary standards, and their qualification against USP reference standards. Contact for further Information: Edwin Rivera, HFD-322, 301-594-0095; e-mail: rivera@cder.fda.gov Reprinted from FDA's Human Drug CGMP Notes, (Volume 5 Number 2), June, 1997. Is it acceptable for a firm to use drug components, drug product containers, or drug product closures simultaneously with testing and/or prior to determination of conformity to all specifications?References: No. It is not acceptable to use drug components, containers, or closures prior to completion of all testing to determine conformance to established specifications. The above preamble to 21 CFR 211.84, clearly states that the use of drug components, containers, or closures prior to completion of testing for conformity to specifications violates the precept of good quality control because untested and possibly noncomplying materials would be used in drug product processing. This type of procedure substantially increases the risk to the consumer that an unsatisfactory lot might erroneously be released. Contact for Further Information: Luann Pallas, HFD-325, 301-594-0098, e-mail: pallasl@cder.fda.gov Reprinted from FDA's Human Drug CGMP Notes, (Volume 4 Number 4), December, 1996. Should APIs be tested solely for those impurities, if any, named in their USP monographs, or must batches be sufficiently characterized for purity?Reference: Some specific ordinary, related compound, and organic volatile impurity tests are included in USP drug substance and dosage form monographs. API producers should establish analytical methods and specifications to test for other impurities potentially found in the drug substance, but not named in the USP. We expect that prior to being used in dosage form production, APIs will have met both groups of tests. "Impurity" is a broad term essentially meaning anything present in the drug substance that is not the chemical entity itself (other than water). The profile of drug substance purity at release, developed over the course of process development and process validation studies, is known as an "impurity profile." Regarding monographs published in USP XXIII, the Pharmacopeia's General Notices Section states:
Sufficient analytical methods should be in place to detect and quantify any impurities which may result from the production of an API batch. These impurity testing methods, employed on a batch-by-batch basis, allow for assessing process consistency by impurity profile comparisons. The results of these tests are, in turn, the impetus for an appropriate investigation when atypical levels of individual or total impurities are obtained. It is noteworthy that USP Supplement 5, official November 15, 1996, includes an addition to the General Notices Section referenced above. This revised section further underscores the need for manufacturers to monitor impurities beyond those named in the USP product monograph. It essentially states that, for most APIs, "major impurities" (0.1% level or greater) which are not listed in the product monograph and cannot be reliably analyzed by its methods should be named, quantified, and included on the certificate of analysis of the official substance. In contrast to "major impurities," a lower qualification threshold, with specialized test methods and more stringent specifications, should be performed for those impurities for which toxicity is a concern. We'll address the issue of API impurities, including impurity profiles, in future editions of HUMAN DRUG CGMP NOTES. 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 4 Number 4), December, 1996. 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. Has the odor test been eliminated from the prefill inspections, due to concerns over pathogenic contamination or other dangerous compounds?Reference: No. The Compressed Medical Gases guideline, page 5 and 6, states that At the present time, we are unaware of any problems and have received no reports of medical gases becoming contaminated with pathogens. However, if this is a problem or a major concern, then a medical gas manufacturer would be required in accordance with 21 CFR 211.113, Control of Microbiological Contamination, to establish written procedures designed to prevent objectionable microorganisms in the drug product. Reprinted from FDA's Human Drug CGMP Notes, (Volume 3 Number 1), March, 1995. |
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