Investigating Out-of-Specification (OOS)

Test Results for Pharmaceutical Production Guidance for Industry (May 2022)

Remarks:

The Final Guidance for Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production Guidance for Industry was published in May 2022. This Final Guidance superseded the Draft Guidance issued in October 2006. The revision highlights the following:

• Provide additional clarification in the Introduction

• Delineate a Phase I and Phase II, Laboratory Investigation

• Responsibilities of Laboratory Supervisor

• The Phase II section set an expectation for Corrective Action Preventive Action (CAPA), specifically on prevention.

• As part of the Phase II investigation, request the signature of appropriate personnel for any material reprocess after additional testing.

• Outlier Test, reference USP<111> and their value.

• Caution section, Averaging results from the same final sample preparation is a new section.

• Field Alert Report Section refers to an approved new drug application (NDA) and abbreviated new drug applications (ANDA).

• All the references were updated to align with the most recent publications.

• Below is a synopsis of the Final Guidance.

I. INTRODUCTION

The guidance is on how to evaluate out-of-specification (OOS) test results.

• The OOS results include:

• All test results that fall outside the specifications or acceptance criteria established in DMFs, official compendia, or by the manufacturer. Also, it included all in-process laboratory tests that are outside of established specifications.

• Chemistry-based laboratory tests drugs performed on active pharmaceutical ingredients, excipients and other components, in-process materials, and finished drug products.

• Chemistry-based laboratory testing of biotechnology products under the CDER jurisdiction is within the scope.

• This guidance is not intended to address Process Analytical Technology (PAT) approaches, as routine in-process use of these methods might include other considerations. Refer to "A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance (September 2004)"

• The guideline can be employed to examine results that are out of trend.

II. BACKGROUND

• Laboratory testing, which is required by the CGMP regulations (211.160 and 211.165), is necessary to confirm that components, containers and closures, in-process materials, and finished products conform to specifications, including stability specifications. Also, 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 must be rejected. In addition, 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.

• For specific recommendations Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients (September 2016) (ICH Q7)

III. IDENTIFYING AND ASSESSING OOS TEST RESULTS — PHASE I: LABORATORY INVESTIGATION

• The purpose of the investigation is to determine the cause of the OOS result (211.192).

• 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 must 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 first investigation phase should include an initial assessment of the accuracy of the laboratory's data. Next, laboratory error or instrument malfunctions hypotheses should be tested using the same test preparations. If this initial assessment indicates that no causative errors were made in the analytical method used to arrive at the data, a full-scale OOS investigation should be conducted.

• The laboratory should convey its data, findings, and supporting documentation to the manufacturing firm's quality unit (QU) for contract laboratories. The manufacturing firm's QU should initiate the Phase 2 (full-scale) OOS investigation whenever no clearly causative laboratory error was identified.

A. Responsibility of the Analyst

• The Analyst should be aware of potential problems during the testing process and watch for issues that could create inaccurate results.

• Equipment, not meeting System Suitability should not be used.

• Analysts should check the data for compliance with test specifications before discarding test preparations or standard preparations. In addition, the laboratory Supervisor must be informed when unexpected results are obtained and no obvious explanation exists.

• The Analyst should not continue the analysis knowingly if they expect to invalidate the results at a later time for an assignable cause.

• Hypotheses should be tested (e.g., dilution error, instrument malfunction). However, OOS test results should not be attributed to analytical error without completing an investigation that clearly establishes a laboratory root cause.

B. Responsibilities of the Laboratory Supervisor

• The supervisor's assessment should be objective and timely independently if the OOS results be attributed to laboratory error or whether the results could indicate problems in the manufacturing process.

• The following steps should be taken as part of the supervisor's assessment:

• Discuss the test method with the Analyst; confirm analyst knowledge of and performance of the correct procedure.

• Examine the raw data obtained in the analysis, including chromatograms and spectra, and identify anomalous or suspect information.

• Verify that the calculations used to convert raw data values into a final test result are scientifically sound, appropriate, and correct; also determine if unauthorized or unvalidated changes have been made to automated calculation methods.

• Confirm the performance of the instruments.

• Determine that appropriate reference standards, solvents, reagents, and other solutions were used and met quality control specifications.

• Evaluate the performance of the test method to ensure that it is performing according to the standard expected based on method validation data and historical data.

• Fully document and preserve records of this laboratory assessment.

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 should be conducted.

• A predefined procedure should be established.

• A full-scale investigation should include a review of production and sampling procedures and will often include additional laboratory testing. In addition, an evaluation that includes the impact of OOS result(s) on already distributed batches must be included.

• Appropriate corrective action and preventive action should be taken.

• Such investigations should be given the highest priority.

A. Review of Production

• The QU should conduct the investigation, and all other departments that could be implicated, including manufacturing, process development, maintenance, and engineering, should be included.

• All sites involved should be included in the investigation. In addition, other potential problems should be identified and investigated.

• The manufacturing process records and documentation should be fully reviewed to determine the possible cause of the OOS result(s).

• A written record of the review should include the following information.

• A clear statement of the reason for the investigation.

• A summary of the aspects of the manufacturing process that may have caused the problem.

• The results of a documentation review, with the assignment of actual or probable cause.

• The results of a review made to determine if the problem has occurred previously.

• A description of corrective actions taken. Refer to ICH guidance for industry Q10 Pharmaceutical Quality System (April 2009).

• Any discrepancy, including documentation of conclusions and follow-up, should be documented. (211.192)

• The investigation should be extended to other batches or products that may have been associated with the specific failure (211.192).

• If any material was reprocessed after additional testing, the investigation should include comments and the signatures of appropriate personnel, including production and QU personnel.

B. Additional Laboratory Testing

• Additional laboratory testing may be included as part of the investigation, which is beyond the testing performed in Phase I. These include (1) retesting a portion of the original sample and (2) resampling.

1. Retesting

• The sample used for the retesting should be taken from the same homogeneous material that was initially collected from the lot, tested, and yielded the OOS results. For a liquid, it may be from the original unit liquid product or composite of the liquid product; for a solid, it may be an additional weighing from the same sample composite prepared for the original test.

• Decisions to retest should be based on the objectives of the testing and sound scientific judgment. QU must approve the retesting plan.

• A predefined retesting plan should be defined to include retests performed by an analyst other than the one who performed the original test. A second analyst performing a retest should be at least as experienced and qualified in the method as the original Analyst.

• The maximum number of retests to be performed on a sample should be specified in advance in a written standard operating procedure (SOP).

• The number may vary depending upon the variability of the particular test method employed but should be based on scientifically sound principles.

• If the results are unsatisfactory, the batch is suspect and must be rejected or held pending further investigation (211.165(f)). Any deviation from this SOP should be rare and done in accordance with 211.160(a), which states that any deviations from written specifications, sampling plans, test procedures, or other laboratory control mechanisms shall be recorded and justified.

• All original data must be retained (211.180), and an explanation should be recorded. This record should be initialed and dated by the involved persons and include a discussion of the error and supervisory comments.

2. Resampling

• Control mechanisms for examination of additional specimens should be in accordance with predetermined procedures and sampling strategies (211.165(c)).

• After all, the data have been evaluated, an investigation might conclude that the original sample was prepared improperly and was therefore not representative of the batch quality (211.160(b)(3)).

• Resampling should be performed by the same qualified, validated methods that were used for the initial sample.

• If the investigation determines that the initial sampling method was inherently inadequate, a new accurate sampling method must be developed, documented, reviewed, and approved by the QU (211.160 and 211.165(c)).

C. Reporting Testing Results

1. Averaging - There are both appropriate and inappropriate uses of averaging test data during original testing and during an OOS investigation:

• Appropriate uses - Averaging data can be a valid approach, but its use depends upon the sample and its purpose. For example, the optical rotation test.

• If the sample can be assumed to be homogeneous (i.e., an individual sample preparation designed to be homogenous), using averages can provide a more accurate result.

• Microbiological assays, the U.S. Pharmacopeia (USP) prefers the use of averages because of the innate variability of the biological test system.

• 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.

• The use of replicates to arrive at a single reportable 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).

• A series of complete tests (full run-throughs of the test procedure), such as assays, are part of the test method. In the test method, it may be appropriate to specify that the average of these multiple assays is considered one test and represents one reportable result.

• Results should be based on the known variability of the method and should also be specified in the test methodology.

• These appropriate uses of averaging test data should be used during an OOS investigation only if they were used during the original testing.

1. Inappropriate uses

• All individual test results should normally be reported as separate values. 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.

• The laboratory should provide all individual results for evaluation and consideration by the QU (211.22).

1. Outlier Tests

• A statistically valid quality control criteria include appropriate acceptance and/or rejection levels (211.165(d)).

• An outlier may result from a deviation from prescribed test methods, or it may be the result of variability in the sample.

• It should never be assumed that the reason for an outlier is an error in the testing procedure rather than inherent variability in the sample being tested.

• The possible use of outlier tests should be determined in advance and should be written into SOPs for data interpretation and be well documented. The SOPs should include the specific outlier test to be applied with relevant parameters specified in advance. In addition, the SOPs should specify the minimum number of results required to obtain a statistically significant assessment from the specified outlier test.

• 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. (USP<111>).

• In these cases, the outlier observation is omitted from calculations.

V. CONCLUDING THE INVESTIGATION

• To conclude the investigation, the results should be evaluated, the batch quality should be determined, and a release decision should be made by the QU.

A. Interpretation of Investigation Results

• An initial OOS result does not necessarily mean the subject batch fails and must be rejected. However, the OOS result should be investigated, and the findings of the investigation, including retest results, should be interpreted to evaluate the batch and reach a decision regarding release or rejection (211.165).

• For inconclusive investigations — in cases where an investigation does not reveal a cause for the OOS test result and does not confirm the OOS result — the OOS result should be given full consideration in the batch or lot disposition decision.

• If the investigation concludes that the source of the OOS result was a cause unrelated to the manufacturing process, the investigation should include appropriate follow-up and scrutiny to prevent the recurrence of the laboratory error(s).

B. Cautions

1. Averaging results from multiple sample preparations from the original sample

• The firm should err on the side of caution and treat the average of these values as an OOS result, even if that average is within specification.

1. Averaging results from the 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 predefined 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 is 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 the variability are met, the result of any individual replicate in and of itself should not cause the reportable result to be OOS.

1. Borderline results that are within specification

• An assay result that is low but within specifications should also raise a concern. Caution should be used in the release or reject decision.

• Records must be kept of complete data derived from all tests performed to ensure compliance with established specifications and standards (211.194).

C. Field Alert Reports

• For 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)).

• 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.