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Oos Guidance | Outlier | Food And Drug Administration
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October 2006 Pharmaceutical CGMPs
Office of Training and Communication Division of Drug Information HFD-240 Center for Drug Evaluation and Research Food and Drug Administration 5600 Fishers Lane Rockville, MD 20857 (Tel) 301-827-4573 http://www.fda.gov/cder/guidance/index.htm
III. IDENTIFYING AND ASSESSING OOS TEST RESULTS — PHASE I: LABORATORY INVESTIGATION
This guidance for industry provides the Agency’s current thinking on how to evaluate out-of- specification (OOS) test results. For purposes of this document, the term OOS results includes all test results that fall outside the specifications or acceptance criteria established in drug applications, drug master files (DMFs), official compendia, or by the manufacturer. The term also applies to all in-process laboratory tests that are outside of established specifications. 2
This guidance applies to chemistry-based laboratory testing of drugs regulated by CDER. It is directed toward traditional drug testing and release methods. These laboratory tests are performed on active pharmaceutical ingredients, excipients and other components, in-process materials, and finished drug products 3 to the extent that current good manufacturing practice (CGMP) regulations (21 CFR parts 210 and 211) and the Federal Food, Drug, and Cosmetic Act (the Act) (section 501(a)(2)(B)) apply. The principles in this guidance also apply to in-house testing of drug product components that are purchased by a firm. This guidance can also be used by contract firms performing production and/or laboratory testing responsibilities. Specifically, the guidance discusses how to investigate OOS test results, including the responsibilities of
1 This guidance has been prepared by the Office of Compliance/Division of Manufacturing and Product Quality in the Center for Drug Evaluation and Research (CDER).
2 In certain instances, in-process testing is done solely for purposes of triggering real time equipment or system adjustments to prevent process drift. This guidance does not address these situations.
3 Chemistry-based laboratory testing of biotechnology products that are under the jurisdiction of CDER are within the scope of this guidance. However, this guidance is not intended to address biological assays (e.g., in vivo, immunoassays).
Testing also supports analytical and process validation efforts. 4 General CGMP regulations covering laboratory operations can be found in part 211, subparts I (Laboratory Controls) and J (Records and Reports). These regulations provide for the establishment of scientifically sound and appropriate specifications, standards, and test procedures that are designed to ensure that components, containers and closures, in-process materials, and finished drug products conform to the established standards. Section 211.165(f) of the CGMP regulations specifies that finished drug products that fail to meet established standards, specifications, or other relevant quality control criteria will be rejected.
4 Specifications must be scientifically sound and appropriate (§ 211.160(b)), test procedures must be validated as to their accuracy, sensitivity, specificity, and reproducibility (§ 211.165(e)), and the suitability of the test procedures under actual conditions of use must be documented (§ 211.194(a)(2)). For products that are the subjects of new drug applications (NDAs), abbreviated new drug applications (ANDAs), or investigational new drug applications (INDs), specifications are contained in the application or DMF. Specifications for nonapplication products may be found in official compendia or established by the manufacturer.
501(a)(2)(B) of the Act. Current good manufacturing practice for APIs includes the performance of scientifically sound raw material testing, in-process monitoring, release and stability testing, process validation, and adequate investigations of any OOS result obtained from such testing. All citations to part 211 in this document pertain to finished pharmaceuticals, but these referenced regulatory requirements are also consistent with Agency guidance on CGMPs for APIs with respect to laboratory controls, which include out-of-specification investigations. See FDA’s guidance for industry Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients (ICH Q7A) for specific recommendations. 5
FDA regulations require that an investigation be conducted whenever an OOS test result is obtained (§ 211.192). 6 The purpose of the investigation is to determine the cause of the OOS result. The source of the OOS result should be identified either as an aberration of the measurement process or an aberration of the manufacturing process. Even if a batch is rejected based on an OOS result, the investigation is necessary to determine if the result is associated with other batches of the same drug product or other products. Batch rejection does not negate the need to perform the investigation. The regulations require that a written record of the investigation be made, including the conclusions and follow-up (§ 211.192).
5 We update guidances periodically. To make sure you have the most recent version of a guidance, check the CDER guidance page at http://www.fda.gov/cder/guidance/index.htm.
6 Although the subject of this document is OOS results, much of the guidance may be useful for examining results that are out of trend.
• Solutions can be re-injected as part of an investigation where a transient equipment malfunction is suspected. Such hypotheses are difficult to prove. However, reinjections can provide strong evidence that the problem should be attributed to the instrument, rather than the sample or its preparation.
• For release rate testing of certain specialized dosage form drugs that are not destroyed during testing, where possible, examination of the original dosage unit tested might determine whether it was damaged during laboratory handling in a way that affected its performance. Such damage would provide evidence to invalidate the OOS test result, and a retest would be indicated.
• Further extraction of a dosage unit, where possible, can be performed to determine whether it was fully extracted during the original analysis. Incomplete extraction could invalidate the test results and should lead to questions regarding validation of the test method.
IV. INVESTIGATING OOS TEST RESULTS — PHASE II: FULL-SCALE OOS INVESTIGATION
When the initial assessment does not determine that laboratory error caused the OOS result and testing results appear to be accurate, a full-scale OOS investigation using a predefined procedure should be conducted. This investigation may consist of a production process review and/or additional laboratory work. The objective of such an investigation should be to identify the root cause of the OOS result and take appropriate corrective and preventative action. 7 A full-scale investigation should include a review of production and sampling procedures, and will often include additional laboratory testing. Such investigations should be given the highest priority. Among the elements of this phase is evaluation of the impact of OOS result(s) on already distributed batches.
7 Please note that § 211.192 requires a thorough investigation of any discrepancy, including documentation of conclusions and follow-up. Implicit in this requirement for investigation is the need to implement corrective and preventative actions. Corrective and preventive action is consistent with the FDA’s requirements under 21 CFR part 820, subpart J, pertaining to medical devices, as well as the 2004 draft guidance entitled Quality Systems Approach to Pharmaceutical Current Good Manufacturing Practice Regulations, which, when finalized, will represent the Agency’s current thinking on this topic.
A full-scale OOS investigation should consist of a timely, thorough, and well-documented
review. A written record of the review should include the following information.
If this part of the OOS investigation confirms the OOS result and is successful in identifying its
root cause, the OOS investigation may be terminated and the product rejected. However, a failure investigation that extends to other batches or products that may have been associated with the specific failure must be completed (§ 211.192). If any material was reprocessed after additional testing, the investigation should include comments and the signatures of appropriate production and quality control personnel.
OOS results may indicate a flaw in product or process design. For example, a lack of robustness
in product formulation, inadequate raw material characterization or control, substantial variation
introduced by one or more unit operations of the manufacturing process, or a combination of these factors can be the cause of inconsistent product quality. In such cases, it is essential that redesign of the product or process be undertaken to ensure reproducible product quality. 8
A full-scale OOS investigation may include additional laboratory testing. A number of practices
are used during the laboratory phase of an investigation. These include (1) retesting a portion of the original sample and (2) resampling.
8 OOS results might also be the result of the objectionable practice of making unauthorized or unvalidated changes to the manufacturing process.
9 In other words, all data are reported in, for example, quality control reports, batch records, Certificates of Analysis, in accordance with §§ 211.188 and 211.192.
It should be noted that a test might consist of a specific number of replicates to arrive at a result. For instance, an HPLC assay result may be determined by averaging the peak responses from a number of consecutive, replicate injections from the same preparation (usually 2 or 3). The assay result would be calculated using the peak response average. This determination is considered one test and one result. This is a distinct difference from the analysis of different portions from a lot, intended to determine variability within the lot, and from multiple full analyses of the same homogenous sample. The use of replicates to arrive at a single reportable 10 result, and the specific number of replicates used, should be specified in the written, approved test method. Acceptance limits for variability among the replicates should also be specified in the method. Unexpected variation in replicate determinations should trigger remedial action as required by § 211.160(b)(4). If acceptance limits for replicate variability are not met, the test results should not be used.
In some cases, a series of complete tests (full run-throughs of the test procedure), such as
assays, are part of the test method. It may be appropriate to specify in the test method that the average of these multiple assays is considered one test and represents one reportable
result. In this case, limits on acceptable variability among the individual assay results
should be based on the known variability of the method and should also be specified in the test methodology. A set of assay results not meeting these limits should not be used.
Reliance on averaging has the disadvantage of hiding variability among individual test
For this reason, all individual test results should normally be reported as separate
Where averaging of separate tests is appropriately specified by the test method, a
single averaged result can be reported as the final test result. In some cases, a statistical treatment of the variability of results is reported. For example, in a test for dosage form content uniformity, the standard deviation (or relative standard deviation) is reported with the individual unit dose test results.
10 The term reportable result as used in this document means a final analytical result. This result is appropriately defined in the written approved test method and derived from one full execution of that method, starting from the original sample.
resample results obtained during the OOS investigation is not appropriate because it
hides variability among the individual results.
particularly misleading when some of the results are OOS and others are within specifications. It is critical that the laboratory provide all individual results for evaluation and consideration by the QCU, which is responsible for approving or rejecting, e.g., drug products, in-process materials (§ 211.22)
Relying on averages of such data can be
For example, in an assay of a finished drug with a specification of 90 to 110 percent, an initial OOS result of 89 percent followed by additional retest results of 90 percent and 91 percent would produce an average of 90 percent. While this average would meet specifications, 11 the additional test results also tend to confirm the original OOS result. However, in another situation with the same specifications, an initial OOS result of 80 percent followed by additional test results of 85 percent and 105 percent would also produce an average of 90 percent, but present a much different picture. These results do not confirm the original OOS result but show high variability and may not be reliable. In both examples, the individual results, not the average, should be used to evaluate the quality of the product.
For biological assays having a high variability, an outlier test may be an appropriate statistical analysis to identify those results that are statistically extreme observations. The USP describes outlier tests in the general chapter on Design and Analysis of Biological Assays < 111 > . 12 In these cases, the outlier observation is omitted from
11 When arriving at a batch disposition decision, it is important for a firm to assess whether the low assay value may project to a subpotency failure before the product’s labeled expiration date.
12 The United States Pharmacopeia, 29th Revision, Rockville, MD: The United States Pharmacopeial Convention,
calculations. The USP also states that “arbitrary rejection or retention of an apparently aberrant response can be a serious source of bias… the rejection of observations solely on the basis of their relative magnitudes is a procedure to be used sparingly” (USP <111 >).
When using these practices during the additional testing performed in an OOS investigation, the laboratory will obtain multiple results. It is again critical for the laboratory to provide all test results for evaluation and consideration by the QCU in its final disposition decision. In addition, when investigation by a contract laboratory 13 does not determine an assignable cause, all test results should be reported to the customer on the certificate of analysis.
In those instances where an investigation has revealed a cause, and the suspect result is invalidated, the result should not be used to evaluate the quality of the batch or lot. Invalidation
13 The Agency also recommends that OOS investigation reports be provided to the customer.
of a discrete test result may be done only upon the observation and documentation of a test event
that can reasonably be determined to have caused the OOS result.
In those cases where the investigation indicates an OOS result is caused by a factor affecting the
batch quality (i.e., an OOS result is confirmed), the result should be used in evaluating the quality of the batch or lot. A confirmed OOS result indicates that the batch does not meet established standards or specifications and should result in the batch's rejection, in accordance with § 211.165(f), and proper disposition. For inconclusive investigations — in cases where an investigation (1) does not reveal a cause for the OOS test result and (2) does not confirm the OOS result — the OOS result should be given full consideration in the batch or lot disposition decision.
In the first case (OOS confirmed), the investigation changes from an OOS investigation into a
batch failure investigation, which must be extended to other batches or products that may have
been associated with the specific failure (§ 211.192).
In the second case (inconclusive), the QCU might still ultimately decide to release the batch. For
example, a firm might consider release of the product under the following scenario:
A product has an acceptable composite assay range of 90.0 to 110.0 percent. The initial (OOS)
assay result is 89.5 percent. Subsequent sample preparations from the original sample yield the following retest results: 99.0, 98.9, 99.0, 99.1, 98.8, 99.1, and 99.0 percent. A comprehensive laboratory investigation (Phase 1) fails to reveal any laboratory error. Review of events during production of the batch reveals no aberrations or indication of unusual process variation. 14
Review of the manufacturing process and product history demonstrates that the process is robust. The seven passing retest results are all well within the known limits of variability of the method used. Batch results from in-process monitoring, content uniformity, dissolution, and other tests
are consistent with the passing retest results.
might conclude that the initial OOS result did not reflect the true quality of the batch.
After a thorough investigation, a firm’s QCU
It is noteworthy in this scenario that the original, thorough laboratory investigation failed to find
any assignable cause. However, if subsequent investigation nonetheless concludes that the source of the OOS result was a cause unrelated to the manufacturing process, in response to this atypical failure to detect the laboratory deviation, it is essential that the investigation include appropriate follow-up and scrutiny to prevent recurrence of the laboratory error(s) that could have led to the OOS result.
14 As an example, evaluation of process variation would determine if established equipment, facility, and process control limits were met.
In cases where a series of assay results (to produce a single reportable result) are required by the test procedure and some of the individual results are OOS, some are within specification, and all are within the known variability of the method, the passing results are no more likely to represent the true value for the sample than the OOS results. For this reason, a firm should err on the side of caution and treat the reportable average of these values as an OOS result, even if that average is within specification. This approach is consistent with the principle outlined in the USP General Notices that an official article shall comply with the compendial standard any time a compendial test is applied. 15 Thus, every individual application of the official test should be expected to produce a result that meets specifications.
15 See USP 29, General Notices, “Test Results, Statistics, and Standards.”
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