Comparison of FDA OOS guidelines October 2006 and May 2022

Comparison of FDA OOS guideline 2006 vs 2022

U.S. FDA has published the revised guideline after 16 years-old final guidance on Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production applicable for chemical analysis in the laboratory.

The revision consists of responsibilities of procedure, references, and the responsibility of analyst and supervisor in reporting these results.

The revision of May 2022 includes minor content and editorial changes. The guideline also provides clarity on concepts on outlier results, and provides further explanation on averaging results from the same final sample preparation.

In the entire guideline, the terminology “quality control unit” is replaced with “quality unit.”

The guideline of October 2006 was published after 13 years of the 1993 U.S. v. Barr Laboratories decision.

Following table provides page wise and step wise exact changes that has been made in the OOS guideline of October 2006 vs May 2022.

Comparison between FDA OOS guidelines: October 2006 vs May 2022

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October 2006	May 2022
Revision 0	Revision 1
https://www.fda.gov/media/71001/download	https://www.fda.gov/media/158416/download
In index – IV. B, C, and V. B, subheading not provided	In index – IV. B, C, and V. B, subheading provided
Page 1 Comment 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).	Page 1 Comment 1:Additional information:You may submit comments on this guidance at any time. Submit comments to Docket No. FDA-1998-D-0019 (available at https://www.regulations.gov/docket/FDA-1998-D-0019).
Page 1 Comment 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).	Page 1 Comment 3: Chemistry-based laboratory testing of biotechnology products that are under the jurisdiction of CDER is within the scope of this guidance. While this guidance is not intended to address biological assays (e.g., in vivo, immunoassays) it does briefly discuss Design and Analysis of Biological Assays (USP<111>).
Page 2 (September 2004) not referred.	Page 2 (September 2004).
Page 2 FDA’s guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required.	Page 2 The contents of this document do not have the force and effect of law and are not meant to bind the public in any way, unless specifically incorporated into a contract. This document is intended only to provide clarity to the public regarding existing requirements under the law. FDA guidance documents, including this guidance, should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidance means that something is suggested or recommended, but not required.
Page 3 See FDA’s guidance for industry Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients (ICH Q7A) for specific recommendations.	Page 3 See FDA’s guidance for industry Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients (September 2016) (ICH Q7) for specific recommendations.
Page 3 For contract laboratories, the laboratory should convey its data, findings, and supporting documentation to the manufacturing firm’s quality control unit (QCU), who should then initiate the full-scale OOS investigation.	Page 3 For contract laboratories, the laboratory should convey its data, findings, and supporting documentation to the manufacturing firm’s quality unit (QU). The manufacturing firm’s QU should then initiate the Phase 2 (full-scale) OOS investigation, whenever no clearly causative laboratory error was identified.
Page 3 Comment 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.	Page 3 Comment 5 We update guidances periodically. To make sure you have the most recent version of a guidance, check the CDER guidance page at https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs.
Page 6 It should not be assumed that OOS test results are attributable to analytical error without performing and documenting an investigation. Both the initial laboratory assessment and the following OOS investigation should be documented fully.	Page 6 OOS test results should not be attributed to analytical error without completing an investigation that clearly establishes a laboratory root cause. Both the initial laboratory assessment and the following OOS investigation should be documented fully.
Page 6 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.	Page 6 The objective of such an investigation should be to identify the root cause of the OOS result and take appropriate corrective action and preventive action.
Page 6 A. Review of ProductionThe investigation should be conducted by the QCU and should involve all other departments that could be implicated, including manufacturing, process development, maintenance, and engineering.	Page 6 A. Review of ProductionThe investigation should be conducted by the QU and should involve all other departments that could be implicated, including manufacturing, process development, maintenance, and engineering.
Page 6 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.	Page 6 Corrective action and preventive action are consistent with the principles in ICH guidance for industry Q10 Pharmaceutical Quality System (April 2009).
Page 7 If any material was reprocessed after additional testing, the investigation should include comments and the signatures of appropriate production and quality control personnel.	Page 7 If any material was reprocessed after additional testing, the investigation should include comments and the signatures of appropriate personnel, including production and QU personnel.
Page 8 B. Additional Laboratory TestingA 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.	Page 8 B. Additional Laboratory TestingA full-scale OOS investigation may include additional laboratory testing beyond the testing performed in Phase I. These include (1) retesting a portion of the original sample and (2) resampling.
Page 8 In the case of a clearly identified laboratory error, the retest results would substitute for the original test result. All original data should be retained, however, and an explanation recorded. This record should be initialed and dated by the involved persons and include a discussion of the error and supervisory comments. (See section III of this guidance for more details on a laboratory investigation.)	Page 8 In the case of a clearly identified laboratory error, the retest results would substitute for the original test result. However, all original data must be retained (§ 211.180) and an explanation should be recorded. (Comment 9) This record should be initialed and dated by the involved persons and include a discussion of the error and supervisory comments. (See section III of this guidance for more details on a laboratory investigation.) Comment 9 – 9 See §§ 211.68 and 211.188. See also FDA guidance for industry Data Integrity and Compliance With Drug CGMP (December 2018).
Page 10 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 reportable10 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.	Page 9 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. (Comment 11) 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 reportable12 result, and the specific number of replicates used, should be specified in the written, test method approved by the QU. 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. Comment 11: 11 See section V.B Cautions for further clarification.
Page 10 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.	Page 10 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. (Comment 13) A set of assay results not meeting these limits should not be used. Comment 13 – See footnote 11.
Page 11 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>. (Comment 12) In these cases, the outlier observation is omitted from 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>). Comment 12: The United States Pharmacopeia, 29th Revision, Rockville, MD: The United States Pharmacopeial Convention, 2006.	Page 11 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 (USP<111>). In these cases, the outlier observation is omitted from 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, without investigation as to cause, is a procedure to be used sparingly” (USP <111>).
Page 11 For validated chemical tests with relatively small variance, and if the sample being tested can be considered homogeneous (for example, an assay of a composite of a dosage form drug to determine strength), an outlier test is only a statistical analysis of the data obtained from testing and retesting. It will not identify the cause of an extreme observation and, therefore, should not be used to invalidate the suspect result. Occasionally, an outlier test may be of some value in estimating the probability that the OOS result is discordant from a data set, and this information can be used in an auxiliary fashion, along with all other data from the investigation, to evaluate the significance of the result.	Page 12 For validated chemical tests with relatively small variance, and if the sample being tested can be considered homogeneous (for example, an assay of a composite of a dosage form drug to determine strength), an outlier test is only a statistical analysis of the data obtained from testing and retesting. It will not identify the cause of an extreme observation and, therefore, should not be used to invalidate the suspect result. Occasionally, an outlier test may be of some value in understanding how discordant from a data set a result is, but can be used solely in an informational capacity in the course of an investigation to determine the distance of a result from the mean.(Comment 15) Comment 15 Outlier testing should not be used to invalidate chemical assays. See United States District Court for the District of New Jersey, U.S.A. v. Barr Laboratories, Inc., et al. Civil Action Number 92-1744, OPINION, February 4, 1993.
Page 12 V. CONCLUDING THE INVESTIGATIONTo conclude the investigation, the results should be evaluated, the batch quality should be determined, and a release decision should be made by the QCU. The SOPs should be followed in arriving at this point. Once a batch has been rejected, there is no limit to further testing to determine the cause of the failure so that a corrective action can be taken.	Page 12 V. CONCLUDING THE INVESTIGATIONTo conclude the investigation, the results should be evaluated, the batch quality should be determined, and a release decision should be made by the QU. The relevant SOPs should be followed in arriving at this point. Once a batch has been rejected, there is no limit to further testing to determine the cause of the failure so that a corrective action can be taken.
Page 14 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.(Comment 15) Comment 15: See USP 29, General Notices, “Test Results, Statistics, and Standards.”	Page 13 B. Cautions1. Averaging results from multiple sample preparations from the original sample 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.Comment 18 Comment 18: USP, General Notices, Section 7.10, “Test Results, Statistics, and Standards” states “Analytical results observed in the laboratory (or calculated from experimental measurements) are compared with stated acceptance criteria to determine whether the article conforms to compendial requirements.”
Page 14 An assay result that is low, but within specifications, should also raise a concern. One cause of the result could be that the batch was not formulated properly. Batches must be formulated with the intent to provide not less than 100 percent of the labeled or established amount of active ingredient (§ 211.101 (a)). This would also be a situation where the analytical result meets specifications, but caution should be used in the release or reject decision. As with all analytical testing conducted to evaluate the quality of a drug, all records pertaining to the OOS test result should be retained. Records must be kept of complete data derived from all tests performed to ensure compliance with established specifications and standards (§ 211.194).	Page 13 2. Averaging results from same final sample preparation As noted in the Averaging section (IV.C.1.), there may be cases where the test method specifies appropriate acceptance criteria for variability and a pre-defined number of replicates from the final diluted sample solution to arrive at a result. For example, an HPLC test method may specify both acceptance criteria for variability and that a single reportable result be determined by averaging the peak response from a number of consecutive, replicate injections from the same test vial. In these cases, and given the acceptance criteria for variability are met, the result of any individual replicate in and of itself should not cause the reportable result to be OOS. 3. Borderline results that are within specificationAn assay result that is low, but within specifications, should also raise a concern. One cause of the result could be that the batch was not formulated properly. Batches must be formulated with the intent to provide not less than 100 percent of the labeled or established amount of activeingredient (§ 211.101(a)). This would also be a situation where the analytical result meets specifications, but caution should be used in the release or reject decision. (Comment 19)As with all analytical testing conducted to evaluate the quality of a drug, all records pertaining to the OOS test result should be retained. Records must be kept of complete data derived from all tests performed to ensure compliance with established specifications and standards (§ 211.194). Comment 19 As noted in the ICH guidance for industry Q1E Evaluation of Stability Data (2004), “[i]f the assay value of a batch is lower than 100 percent of label claim at the time of batch release, it might fall below the lower acceptance criterion before the end of the proposed shelf life.” Appropriate actions must be taken if testing results indicate that a batch may fall below assay specifications prior to its expiration date (see § 211.137 and 211.165).
Page 14 C. Field Alert ReportsFor those products that are the subject of approved full and abbreviated new drug applications, regulations require submitting within 3 working days a field alert report (FAR) of information concerning any failure of a distributed batch to meet any of the specifications established in an application (21 CFR 314.81(b)(1)(ii)). OOS test results on these products are considered to be one kind of “information concerning any failure” described in this regulation. Unless the OOS result on the distributed batch is found to be invalid within 3 days, an initial FAR should be submitted. A follow-up FAR should be submitted when the OOS investigation is completed.	Page 14 C. Field Alert ReportsFor those products that are the subject of an approved new drug application or abbreviated new drug application, regulations require submitting within 3 working days a field alert report (FAR) of information concerning any failure of a distributed batch to meet any of the specifications established in an application (21 CFR 314.81(b)(1)(ii)).(Comment 20) OOS test results on these products are considered to be one kind of “information concerning any failure” described in this regulation. Unless the OOS result on the distributed batch is found to be invalid within 3 days, an initial FAR should be submitted. A follow-up FAR should be submitted when the OOS investigation is completed. Comment 20: See FDA guidance for industry Field Alert Report Submission Questions and Answers (July 2021).