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7.2 Finished Product Inspection, Sampling, Testing, and Release for Distribution
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 skip-lot testing, for batch release purposes, acceptable under CGMPs?
What types of failures must a batch of new drug product exhibit to trigger a field alert report?
Are ASTM or NIST test methods considered "official" like those published by the USP and AOAC?
What kinds of USP dissolution test failures are significant enough to be noted on Forms FD-483 ?
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
review
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:
 | Deficient capping/sealing station design resulted in excessive stress to the vial neck. |
| Rough transfer mechanism exerted excessive force on containers while being conveyed down the processing line. |
| Lyophilizer operation included rough loading or stoppering step. |
| Container-closure system could not withstand autoclave process. |
| Vial washer was not compatible with the dimensions/durability of a new container. The new vial size did not adequately fit with the guides in the washer and caused chips in the vial neck. |
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, reconciliation 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
Reprinted from: FDA's HUMAN DRUG CGMP NOTES (Volume 8, Number 2) June, 2000.
This same text is also reprinted in Framework sections 4.1 and 4.5.
For a non-sterile compendial drug product, which includes an antimicrobial preservative in the original formulation, is it acceptable to release and market lots of this drug product that have initial release test results exhibiting out-of-specification total aerobic plate counts, when these lots test within specification two weeks later?
References:
21 CFR 211.113(a)
21 CFR 211.165(f)
USP 24 General Chapter <51>
No! 21 CFR 211.113(a) provides for appropriate written procedures to be followed during manufacturing to assure that objectionable microorganisms are not introduced into drug products not required to be sterile. This regulation mandates the establishment and adherence to written procedures to prevent the inclusion of objectionable organisms in drug products during manufacture.
Additionally, the second paragraph of USP 24 General Chapter <51> reads in part:
"…Antimicrobial preservatives should not be used as a substitute for good manufacturing practices or solely to reduce the viable microbial population of a nonsterile product or control the presterilization bioburden of multidose formulations during manufacturing... "
This compendial section advises against the use of antimicrobial preservatives as a sole means of reducing viable microbial populations in nonsterile products. We interpret this to mean that drug manufacturers should not rely upon antimicrobial preservatives to reduce initial out-of-specification plate counts to within specification levels and then market the product. This is particularly true when the initial out-of-specification results may have been due to organisms that were contributed to the product during the manufacturing process.
For example, in a recent case, a drug manufacturer had initial release test results for several lots of a non-sterile drug product that were each out-of-specification for total aerobic count. Testing a short time later on samples from the same lots gave results that were in specification. We did not regard it acceptable for the manufacturer to release and market these products, even though a reduction of microbial counts to levels near zero had been demonstrated to be attributable to the effectiveness of the preservative.
21 CFR 211.165(f) mandates that drug products failing to meet established standards or specifications shall be rejected. A company’s reliance on an antimicrobial preservative to reduce out-of-specification levels of microbes to within specification levels does not disqualify the initial release test. We would still expect the manufacturer to reject the drug product based on the initial out-of-specification results found upon release testing.
It is also not acceptable for a company to allow an inappropriate amount of time to pass before testing the product to permit the preservative to reduce levels of microbes possibly added during manufacture. This is particularly true when testing data demonstrates that initial release testing conducted a short time after manufacture shows the drug product to be frequently out-of-specification for total aerobic plate count.
Finally, manufacturing procedures should be reviewed to determine procedures or equipment that might be contributing organisms to the process and product. In the case discussed above, standing water that had been allowed to remain in equipment after cleaning, was identified as a CGMP deficiency likely to have contributed to microbial growth in the product. Removal of the standing water has resulted in no detectable total aerobic counts to date. Adherence to CGMPs should prevent manufacturing conditions that contribute microbes to the finished product.
Contact for further information: Randall Woods, HFD-324; phone (301)-827-0062; e-mail: woodsr@cder.fda.gov
Reprinted from HUMAN DRUG CGMP NOTES (Volume 8, Number 1), March, 2000.
Formulating a drug product using active ingredient overages; what can happen when there's too much of a good thing.
Reference:
21 CFR Sections 211.101,
Charge-in of components,
211.165, Testing and release
for distribution, and,
211.186 Master production and
control records.
The CGMP regulations, at Section 211.101(a) require that a batch be formulated with the intent to provide not less than 100 percent of the labeled or established amount of active ingredient. However, this section is silent on formulating to provide more than 100 percent (i.e., overages.) Nonetheless, as discussed below, other sections of the regulations do address overages. The following case study illustrates potential problems that can result from using formulation overages when firms do not follow other CGMP provisions intended to ensure that products meet established specifications.
A pharmaceutical manufacturer was routinely adding 10-16% overage (above the labeled amount) of active ingredients into a tablet formulation. The firm did this to ensure that the assay of this tablet met the label claim near the end of its expiry period. This overage did serve to extend the tablet's shelf life. However, it also caused the product to be superpotent upon release for distribution. Samples were collected and analyzed at an FDA laboratory. The laboratory results demonstrated that not only was the product superpotent, it also failed content uniformity. Moreover, CDER medical officers advised that the degree of superpotency posed a health hazard to consumers. Upon FDA's complaint, the court subsequently seized the lot that was in distribution. (The firm did not claim the goods and the court ordered the product destroyed.)
This problem was not limited to the lot seized. The firm formulated all lots of this product with these overages, resulting in similar potency problems with every batch. The firm's master formula record did not justify its use of overages. The batch records demonstrated that the use of overages was inconsistent from lot to lot. (The firm has since discontinued manufacturing this product for a variety of reasons.)
During your inspections, if you encounter a firm that is formulating a product at less than 100% of labeled active ingredient, the practice would be a clear CGMP violation that you should consider listing as an objectionable condition in an FDA 483. You should not automatically so list the use of overages. When you find use of overages you need to investigate the practice further to determine if, among other things, the resulting product is superpotent, or otherwise outside of its established specifications, upon its release for distribution.
Section 211.165(f) of the CGMP regulations requires that drug products failing to meet established standards or specifications be rejected. It would therefore be objectionable for a firm to release for distribution a lot it had determined to be superpotent. Therefore, as part of your investigation, determine the firm's end product testing results.
Note that a firm may be able to justify its decision to use overages, and the practice may not always result in product that is superpotent. It is therefore important that you review the firm's documentation, especially the master production and control record. The CGMP regulations, at section 211.186, require that the master record contain the weight or measure of each component, along with justifications for reasonable variations in the amount of components necessary for the dosage form's preparation. This section also requires that the master record contain A[A] statement concerning any calculated excess of component.@ Thus, the regulations allow for the justified use of overages in some instances. In general, firms will have determined justifiable amounts of excess components during the product's development and process validation.
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 7, Number 3) September, 1999.
This same text is also reprinted in Framework section 1.2.
When should a firm perform a sterility re-test? How should a microbiology laboratory handle deviations during sterility testing?
Reference:
1987 Guideline on
Sterile Drug Product Produced by Aseptic Processing;
USP 23, Section <71>, Sterility Tests;
21 CFR 211.22, Responsibilities
of quality control unit;
211.192, Production record
review;
211.160 General Requirements
[Subpart I, Laboratory Controls]
The USP Sterility Test is limited in its ability to detect whether a batch contains contaminated units. Finding any unit that exhibits growth is a serious matter, and the subsequent investigation is generally quite involved and covers both the laboratory and production areas. The drug product lot fails the USP test requirement if any microbial growth is found and the test is not invalidated. The USP (Supplement 8) states that a firm should not perform a sterility re-test without evidence that the sterility test positive can be attributed to contamination introduced by the laboratory. Further, the 1987 Aseptic Guideline explains that a batch should not be released without clear documented evidence that the contamination occurred during testing.
It is difficult to justify invalidation of an initial sterility positive result. For example, the presence of any specific microorganism in both the test sample and the sterility testing environment would not alone rule out the aseptic manufacturing operation as the origin of the contamination. A comprehensive evaluation of manufacturing and testing operations, as well as multiple trending reports (e.g., long term trends at specific environmental monitoring locations) which can be revealing, would be consistent with section 211.192 of the CGMP regulations. Because of the low sensitivity of sterility testing, a finding of no growth during retesting should be afforded minimal weight relative to other parts of the investigation.
In summary, a high threshold of justification is needed for a decision to invalidate a sterility test positive result and perform re-testing. When investigations into the origin of the product's contamination are inconclusive, the decision to release or reject the batch should err on the side of patient safety.
Per section 211.160 of the CGMP regulations, when deviations occur during sterility testing, they should be documented concurrent with the test, investigated, and remedied. As explained in the 1987 guideline, such deviations should be trended, with corrective measures taken in a timely manner. If any of these deviations may have compromised the integrity of the sterility test, it would be consistent with CGMP not to proceed with the test. For example, if asepsis is compromised during sample manipulation, then samples should not be incubated. Finally, it is important to note that an unreliable laboratory is an objectionable condition that underscores the need to err on the side of safety when investigating a sterility positive rather than risk overlooking a genuine production problem.
Contact for further information: Richard L. Friedman, HFD-322, 301-594-0095; e-mail: friedmanr@cder.fda.gov; 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.
This same text is also reprinted in Framework section 6.5.
How often must manufacturers examine finished product reserve samples? Can FDA investigators visually examine a manufacturer's reserve samples?
Reference:
21 CFR 211.170(b), Reserve Samples;
211.192, Production record review;
211.160, General requirements [Subpart I, Laboratory Controls]
The CGMP regulations, at section 211.170, require that at least annually manufacturers visually examine reserve samples from representative lots of each drug product manufactured, unless such examination would affect the integrity of the samples. This section also requires firms to use acceptable statistical procedures in selecting the samples. (Note that the regulation exempts medical gases, radioactive drug products, and radioactive drug kits from the reserve sample retention requirement; therefore, the examination provision would, of course, not apply to those products.)
Per section 211.160, firms must have written procedures for those reserve sample examinations.
Although section 211.170 specifies at least annual visual examination, firms may themselves determine that for certain products, and under some circumstances, a more frequent interval may be warranted. The regulation gives manufacturers considerable leeway in this regard. For example, as part of complaint or failure investigations performed in accordance with section 211.192 (that requires a thorough investigation of any unexplained discrepancy or failure of a batch to meet specifications), a firm may, in addition to conducting an immediate examination of the reserves, conclude that reserve samples for one or more products, or particular lots of one or more products, merit more frequent visual examination for a given period of time.
During inspections, investigators should not on a surveillance basis routinely examine a manufacturer's reserve samples. However, on a for cause basis, such as when investigating product contamination or mix-ups, it may be appropriate for investigators to open and examine a manufacturer's reserve samples. In those situations, if the manufacturer produces evidence that such examination would affect the integrity of its remaining reserve samples, an attempt should be made to examine samples of the suspect products taken from other sources, such as commercial inventories.
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 2) June, 1999.
This same text is also reprinted in Framework section 7.1.
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:
21 CFR 211.22(a & b),
Responsibilities of quality control unit,
21 CFR 211.160(b), General
requirements [Subpart I—Laboratory Controls];
21 CFR 165, Testing and
release for distribution (sic);
Draft Guidance for
Industry: Investigating Out of Specification (OOS) Test Results for
Pharmaceutical Production, 9/30/98;
21 CFR 211.194, Laboratory
records
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.
This same text is also reprinted in Framework sections 1.1,
4.3,
4.4, 5.2, 5.5,
6.3
and 6.4.
Is skip-lot testing, for batch release purposes, acceptable under CGMPs?
Reference:
21 CFR, Subpart I, Laboratory Controls, 211.165(a), Testing and release for distribution
No. CGMPs must be followed all of the time, and not just sometimes, as would be the case with skip-lot testing.
At section 211.165(a), the CGMP regulations specify that: FOR EACH BATCH OF DRUG PRODUCT, there shall be appropriate laboratory determination of satisfactory conformance to final specifications for the drug product, including the identity and strength of each active ingredient, prior to release. (Emphasis added)
If only every other lot is tested, or if only one out of every ten lots manufactured is tested, then this would be in violation of 211.165.
The argument for skip-lot testing is that for a validated manufacturing process, testing of each lot shouldn't be necessary. If that were true then there should never be any batch failures or drug product recalls, and we all know that batch failures and recalls are not uncommon. More importantly, though, there is always the possibility of human error or equipment failure, and that is the reason why all manufactured batches must undergo laboratory testing prior to release; things can and do go wrong, such that the process applied to a given batch may differ from the validated process.
Basic to the CGMP approach is the concept of checks and balances to build quality into a product. Omitting end product testing reduces such checks and can increase the likelihood of distributing a defective product. For instance, if (under a vendor validation program) only an identification test is conducted for what is, in fact, a substandard raw material, and a batch of finished drug product incorporating that material was selected as a skip-lot, then there would be a higher probability that the problem would go undetected.
Contact for further info: Brian Nadel, HFD-325, (301)594-0098: e-mail: nadelb@cder.fda.gov
Reprinted from: FDA's HUMAN DRUG CGMP NOTES (Volume 6, Number 2) June 1998.
Is it acceptable under section 211.176 to release products to market as long as the products are tested and no penicillin is found?
Reference:
21 CFR 211.176, Penicillin contamination
It is not acceptable to release the product when other CGMP requirements have not been met. Although this section prohibits marketing of products found to be contaminated with penicillin, it does not sanction marketing of non-penicillin products based only on test results that show no detectable levels of such contamination. Other CGMP requirements must still be met. For example, there must still be adequate separation of facilities used for operations relating to penicillin production from facilities used for non- penicillins for human use.
Section 211.176 is an additive requirement to 21 CFR 211.42.(d) and 211.46(d), and does not mean that testing a product and finding it free from contamination renders the product marketable when produced under a reasonable possibility of contamination. Firms have inappropriately applied 211.176 as a means to market products that have been produced under adverse CGMP conditions.
FDA would not necessarily condone the shipment of potentially contaminated drugs that happen to test negative for penicillin. Drug products that are prepared, packed and held in a facility whereby they may have become contaminated or were in violation of CGMP, may be subject to regulatory action as adulterated (in the CGMP context). The question is not whether they were physically contaminated or even if they were "pharmacologically perfect". Rather, FDA has the enforcement discretion to decide whether to bring an action against such drugs. This prerogative would be based on factors such as violation significance, proposed corrections, and other case related circumstances. FDA's Office of Chief Counsel has indicated "To prevail on a charge of adulteration based upon a failure to conform to CGMP regulations, the government need not establish that any particular drug is actually deficient as a result." See U.S. vs. Western Serum Co., Inc., 498 F. Supp. 863 (D. Arizona 1980.)
Contact for further info: Edwin Melendez, HFD-322, 301-594-0095; e- mail; melendeze@cder.fda.gov
Reprinted from: FDA's HUMAN DRUG CGMP NOTES (Volume 6, Number 2) June 1998.
Should a manufacturer be cited on an FDA-483 for CGMP violations on the part of a contract testing lab it uses for stability testing?
Reference:
CFR 211.22, Responsibilities of quality control unit;
211.180(c), General requirements [Subpart J-
Records and Reports];
FD&C Act 501(a)(2)(B)
No. CGMP deviations that relate to the practices of a contractor should be documented at the contractor facility. And if the deviations appear to be significant, the contractor should be cited on an FDA-483 for the deviations. It would not be appropriate to cite the manufacturer for CGMP deviations relating to any aspect of manufacturing, packaging or testing of drugs performed at the contractor's facility. If the deviations are serious, regulatory action could be taken against the adulterated drugs, even though the adulteration occurred at the contractor facility.
Moreover, if it can be shown that the manufacturing firm's QC unit releases product for distribution, even though it is aware of CGMP deviations, (e.g., it is aware that the test methods used by the contractor have not been validated), it then would be appropriate to cite the manufacturer for the CGMP deviation of releasing the inadequately tested drug.
In both cases, the contracting firm also could be held responsible for shipping adulterated drugs in interstate commerce.
The Contact for further info: Barry Rothman, HFD-325, 301-594-0098, e- mail: rothmanb@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 5.5.
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
211.22 Responsibilities of quality control unit
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.
This text is also reprinted in framework sections 1.1,
5.2, and 6.4.
If a USP drug product meets USP specifications, but fails a firm's internal, more stringent, lot release specifications, and the lot is released for distribution, should investigators note this on the FDA-483?
Reference:
21 CFR 211.165(f) General requirements [Subpart I, Laboratory Controls] and
211.192, Production record review.
Before deciding on whether or not the situation should be reported on an FDA-483, be sure to determine how the firm intends to apply the internal specification. If the more stringent specification functions as an alert limit, and not a hard and fast lot release criterion, then the failure should not be recorded on the FDA-483. On the other hand, if the firm has committed itself (e.g., in a new drug application, or otherwise) to the specification as a lot release condition, then the item should be included on the FDA-483, because as a matter of CGMP, the firm did not adhere to its established release specifications.
The lot should be rejected, per section 211.165(f), if it fails the hard and fast release specification.
In addition to the appropriateness of lot release, you should also consider whether or not the firm investigated the failure of the lot to meet either the alert or release specifications. If no investigation was conducted, this should be included on the FDA-483. As specified in 211.192, failure of a batch to meet any of its specifications must be thoroughly investigated, and the investigation must include conclusions and follow up.
Contact for further information: Brian Nadel, HFD-325, (301)594-0098: e-mail: nadelb@cder.fda.gov
Reprinted from: FDA's HUMAN DRUG CGMP NOTES (Volume 5, Number 4) December, 1997
Does the 211.170(b) double sample size exemption for reserve samples of sterile drug products mean firms don't have to keep enough samples to run even one sterility test?
Reference:
21 CFR 211.170(b), Reserve Samples.
No. This section states that firms don't have to keep twice the quantity of reserve samples to perform sterility and pyrogen testing. That means firms must still keep sufficient quantity to perform one such sterility and pyrogen test. The sample size must also, per this section, be twice as large as needed to perform other tests.
Once a container closure system has been validated, the sterility characteristic of a drug product would not be expected to change over time. In addition, in many cases, keeping twice the sample size needed to run sterility tests, in addition to samples for other tests, would not be justified by the benefits of keeping the extra units. Furthermore, the sensitivity limits of sterility testing are such that the tests are not likely to detect low levels of contaminated units within a given lot.
Accordingly, should sterility failures be suspected for distributed lots, reserve sample testing would be of less value in confirming the problem than thorough investigation of the relevant production and control records for the affected lot.
Reprinted from: FDA's HUMAN DRUG CGMP NOTES (Volume 5, Number 4) December, 1997
If two contract labs test the pH on samples from the same lot, but arrive at different conclusions, one within specifications and the other out-of-specifications (OOS), would it be appropriate for the manufacturer to ignore the OOS result and use the in-spec result for batch release purposes?
Reference:
21 CFR 211.160, General requirements [Laboratory
Controls];
211.194, Laboratory records.
No. It should not be assumed that the OOS result is incorrect and the in-spec result is accurate. There is an equal possibility that either is the probable true value. Assuming that 1) the solution tested is identical for both laboratories, 2) the analysts followed the correct analytical method, and 3) analysts made no technical errors in performing the analysis, further information would be needed to ascertain which result should be considered reliable. For example, the information might take into account:
(1) the maintenance status of the pH meter (e.g., was it calibrated in accordance with SOPs?; was the probe in good working order?); and,
(2) the solution(s) used in the calibration (e.g., were they current and appropriate?; did they bracket the specification range?).
In this situation the above information for both labs should be compared. In addition, the analysts should be interviewed to ascertain if there was a possibility the sample was contaminated or mishandled.
Acceptance of one result over the other without an investigation could be considered "selective reporting". It would be advisable to look for a reasonable cause for the discrepancy rather than ignore the undesired result. The OOS result may very well be the true value. However, if contamination of the sample or other lab error is a probability, then the result could be invalidated with the above information as justification. In such a case resampling would be indicated, and the retest results would substitute for the original.
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 5, Number 4) December, 1997.
For finished product stability testing, is it necessary to sample from an unopened container at each test interval?
Reference:
21 CFR 211.166, Stability testing;
February, 1987, Guideline For Submitting Documentation For The Stability Of Human Drugs And Biologics.
Except for large containers, a random sample should be collected from an unopened container at each interval. For solid-oral dosage form products which are packaged in large containers intended for repackaging, samples may be taken from an opened container, although more than one container should be sampled during the stability study. Because in large containers dosage units near the closure may have different stability properties from dosage units
in other parts of the container, it may be necessary to collect separately identified samples from different parts of the container to ensure the samples accurately represent any stability differences. Lastly, firms should have written SOPs specifying their sampling protocols.
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 5 Number 2), June, 1997.
Is it acceptable to run accelerated stability testing for less than three months, when predicting a tentative expiration date?
References:
21 CFR 211.137, Expiration dating;
211.166, Stability testing;
February, 1987 "Guideline For Submitting Documentation For The Stability of Human Drugs and Biologics"
The referenced 1987 document provides guidance for submitting in ANDAs, 3 months of accelerated stability data, for the purpose of determining a tentative expiration dating period of up to 24 months. On several occasions we have received inquiries from manufacturers of grandfathered (not new) drugs asking if it would be acceptable to conduct accelerated testing for a time shorter than 3 months. Mostly, the firms have proposed that they shorten the tentative expiration dating period proportionately. However, other firms have indicated that they would compensate for the shortened period of accelerated testing by using elevated storage temperatures for samples on stability.
Firms are not required to use the approach specified in FDA's guideline. However, if a different approach is taken, firms should be able to demonstrate that the approach is scientifically valid. It should not be assumed that a firm can take the parameters specified in FDA's guideline and, without scientific justification, proportionately modify the period of accelerated testing and tentative expiration dating, or test at a very high temperature for a short time and use a very long expiration dating period. For example, performing accelerated testing at very high temperatures for a short time to extrapolate a long expiration dating period may not be acceptable because the mechanism of degradation at high temperatures may be different from that at room temperature. We recommend that firms discuss alternative approaches with FDA to avoid expenditure on an effort which may not be acceptable.
Division contact for stability matters: Barry Rothman, HFD-325, 301-594-0098, e-mail: rothmanb@cder.fda.gov
Reprinted from FDA's Human Drug CGMP Notes, (Volume 5 Number 1), March, 1997.
Is it proper to cite a firm on an FDA-483 for not demonstrating that its stability test methods are stability indicating? What if the method is the approved assay method in the firm's new drug application?
Reference: 21 CFR 211.166(a)(3), Stability testing
CGMPs require the use of stability-indicating methodology for stability testing. In general, it would be appropriate to cite firms if they don't comply with this requirement. However, because the technology may not have been available, older applications lacking stability-indicating methodology may have been approved. Absent documentation that the methods are stability indicating, districts should contact HFD- 320 and the appropriate review division to coordinate resolution of the matter before determining if an FDA-483 citation is appropriate.
Reprinted from FDA's Human Drug CGMP Notes, (Volume 4 Number 4), December, 1996.
Is it appropriate to cite a firm on an FDA-483 when a product passes a regulatory release specification but not a firm's more stringent internal release limits?
Reference:
21 CFR 211.160(b), General requirements;
211.165(a) Subpart I--Laboratory Controls
An FDA-483 observation would be appropriate if failure to meet the tighter internal specification means that at some point in its expiry period the drug product may not meet the wider regulatory specification.
For a variety of reasons, firms may set internal product release specifications that are more stringent than such regulatory specifications as those in the USP or approved new drug applications. For example, the tighter specifications may be established in anticipation of product degradation over time. Thus, if a product meets those tighter specifications upon release for distribution, it is likely to still meet the less stringent regulatory specifications throughout its shelf life.
In other instances, a firm may set tighter internal release specifications, not for reasons of stability described above, but as a process control indicator -- an alert limit that signals attention to potential problems but that does not necessarily indicate process or product failure. Absent an indication of such failure, deviation from internal release specifications would not be grounds for an FDA-483 observation because the CGMPs do not require a firm to establish such tighter controls in the first place, and we would not want to discourage firms from adopting measures to improve their process controls. We would expect, however, that firms follow written procedures regarding those tighter specifications that they do set and how the firm responds to deviations from such limits.
Therefore, in assessing whether deviation from an internal specification is objectionable, be sure to determine and consider why the firm established the tighter internal release specification initially.
Division contact for stability matters: Barry Rothman, HFD-325, 301-594-0098, e-mail: rothmanb@cder.fda.gov
Reprinted from FDA's Human Drug CGMP Notes, (Volume 4 Number 4), December, 1996.
What types of failures must a batch of new drug product exhibit to trigger a field alert report?
References:
21 CFR 211.192, Production record review, and
21 CFR 314.81(b)(1), Other postmarketing reports, Reporting
Requirements, NDA-Field alert report.
21 CFR 211.192 requires a thorough investigation of, among other things, a failure of a batch to meet any of its specifications. This is required whether or not the batch has been distributed. The meaning of distribution here is distribution of the batch in whole or in part.
21 CFR 314.81(b)(1) requires the submission within three working days in a Field Alert Report (FAR) of information concerning any failure of a distributed batch to meet any of the specifications established in an application. This is required when the drug product is both the subject of any type of application and when the batch has been distributed, in whole or in part.
For both of the above requirements, a failure includes any test result which falls outside of an established specification, and which has not been invalidated (e.g., found to be laboratory error). (A failure also includes other developments which are not discussed here).
The required FAR should be submitted within the three day time period after the information becomes known or after distribution, whichever occurs later. An initial report should be filed while any investigation is ongoing and which extends beyond the three day period. The FAR, initial and follow-up as necessary, is required even though a batch may have been released after consideration of the failed test result which falls outside of an established specification along with all data which may be generated by the investigation and the information in the drug product production and controls records reviewed and approved in accordance with 21 CFR 211.192.
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 4 Number 3), September, 1996.
This text is also reprinted in Framework section 7.3 .
Are ASTM or NIST test methods considered "official" like those published by the USP and AOAC?
References:
21 CFR 211.160 (General Requirements),
211.165 (Testing and Release for Distribution) and
211.194(a)(2) (Laboratory Records), all in Subpart I, Laboratory Controls;
USP 23, General Notices, p. 2
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.
This same text is also reprinted in Framework sections 5.2
and 6.4 .
Can a company use an older (not updated) version of an official method, or must it use the most updated version?
Reference:
21 CFR 211.160 (General Requirements),
211.165 (Testing and Release for Distribution) and
211.194(a)(2) (Laboratory Records), all in Subpart I, Laboratory Controls;
USP 23, General Notices, p. 2
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
comment on the proposed revisions. Generally, firms are active (and are encouraged by the agency to be) participants in this
process, which usually precludes any problems. Firms may use any scientifically sound method, but should be aware that in the
event of a dispute the current method (what you can call the "official method") will govern.
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.
This same text is also reprinted in Framework sections 5.2
and 6.4 .
What kinds of USP dissolution test failures are significant enough to be noted on Forms FD-483 ?
References:
See 21 CFR 211.165(a), Testing and release for distribution.
Routine failure of manufactured batches of a product to pass USP Dissolution tests at Stage 1 is not significant enough to be noted on Forms
FD-483; neither is occasional failure of individual dosage units at Stage 2. A batch does not fail the USP Dissolution Test until it fails at Stage
3. However, frequent failures at Stage 2 are significant when other
batches of the same product have Stage 3 failures, and therefore should be noted on Forms
FD-483.
CDER requires submission of test data for twelve dosage units in every new drug application, or supplement thereto, that requires dissolution test
information. CDER and the USP define the dissolution test at Stage 2 (twelve units tested). We anticipate that manufacturers should have to
test at Stage 2 routinely, and that there will be occasional failures of individual dosage units at Stage 2. That is why the USP Acceptance Table
in Chapter <771> provides for a third level of testing (24 units). CDER and the USP consider Stage 1 (six units tested) to be a bonus situation in
which, because all of the dosage units tested dissolved so well, we permit manufacturers to do less than the expected amount of testing on the batch.
CDER has been working with the USP for some time to upgrade many USP Dissolution tests that have low tolerances, long test times, and/or high apparatus speeds. Several upgraded tests that have been published in Pharmacopeial Forum have drawn criticism from a number of pharmaceutical manufacturers because the upgraded test would be likely to require companies to do Stage 2 testing--which would precipitate Form FD-483 observations that would not be warranted.
Reprinted from FDA's Human Drug CGMP Notes, (Volume 3 Number 1), March, 1995.
What is the significance of the air liquefaction statement? Is further testing required if this statement is not available?
Reference:
21 CFR 211.165(f), Testing and release for distribution.
The United States Pharmacopeia XXIII Oxygen monograph states that if the air liquefaction statement is present then a firm is exempt from performing the carbon dioxide and carbon monoxide impurities testing.
Let's look at it another way; there are four (4) required tests listed under the oxygen monograph. They are the identification test, the carbon dioxide impurity test, the carbon monoxide impurity test and the assay. As long as the air liquefaction statement is available either by a letter from the supplier or by a certificate of analysis, then the identification and the assay are the only tests required.
Reprinted from FDA's Human Drug CGMP Notes, (Volume 3 Number 1), March, 1995.
