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Pharma Guidelines Validations Clean Room Classification Sterile Aseptic Process Regulatory Guide: How to Investigate Out-of-Specification OOS Test Results out of trend results
How to Investigate Out-of-Specification OOS Test Results out of trend results
Out of specification test results investigation , is a task where one should apply logical approach , US FDA has provided a guidance document on Oct 2006 stands a current one till today ,
we are providing this guidance article over this website to provide a good knowledge for the constant increasing number of readers of this website .
Response for subscriptions for this website very encouraging .
The guidance document for how to Investigate Out-of-Specification (OOS) Test Results for Pharmaceutical starts from here
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.
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 products3 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
laboratory personnel, the laboratory phase of the investigation, additional testing that may be necessary, when to expand the investigation outside the laboratory, and the final evaluation of all test results.
The Agency, in accordance with its August 2002 “Pharmaceutical CGMPs for the 21st Century” initiative, encourages modern approaches to manufacturing, monitoring, and control to enhance process predictability and efficiency. Process Analytical Technology (PAT) takes a different approach to quality assurance by using process controls and in-process data as the release specification instead of relying on single laboratory determinations to make batch acceptability decisions. This guidance is not intended to address PAT approaches, as routine in-process use of these methods might include other considerations. For information on timely in-process testing, see the CGMP guidance entitled PAT — A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance.
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.
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 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
The responsibility of a contract testing laboratory in meeting these requirements is equivalent to that of a manufacturing firm.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.
Both finished pharmaceuticals and active pharmaceutical ingredients (APIs) are to be manufactured in accordance with current good manufacturing practice under section
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).
To be meaningful, the investigation should be thorough, timely, unbiased, well-documented, and scientifically sound. The first phase of such an investigation should include an initial assessment of the accuracy of the laboratory's data. Whenever possible, this should be done before test preparations (including the composite or the homogenous source of the aliquot tested) are discarded. This way, hypotheses regarding laboratory error or instrument malfunctions can be tested using the same test preparations. If this initial assessment indicates that no meaningful errors were made in the analytical method used to arrive at the data, a full-scale OOS investigation should be conducted. 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.
Once an OOS result has been identified, the supervisor's assessment should be objective and timely. There should be no preconceived assumptions as to the cause of the OOS result. Data should be assessed promptly to ascertain if the results might be attributed to laboratory error, or whether the results could indicate problems in the manufacturing process. An immediate assessment could include re-examination of the actual solutions, test units, and glassware used in the original measurements and preparations, which might provide more credibility for laboratory error hypotheses.
5. Determine that appropriate reference standards, solvents, reagents, and other solutions were used and that they met quality control specifications.
6. 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.
It is important that each step in the investigation be fully documented. Laboratory management should ascertain not only the reliability of the individual value obtained, but also the significance these OOS results represent to the laboratory quality assurance program. Laboratory management should be especially alert to developing trends. As part of an effective quality
system, a firm’s upper management should appropriately monitor these trends and ensure that any problematic areas are addressed.
determine the possible cause of the OOS result(s).
1. A clear statement of the reason for the investigation.
2. A summary of the aspects of the manufacturing process that may have caused the problem.
3. The results of a documentation review, with the assignment of actual or probable cause.
4. The results of a review made to determine if the problem has occurred previously.
5. A description of corrective actions taken.
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.
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.
FDA inspections have revealed that some firms use a strategy of repeated testing until a passing result is obtained, then disregarding the OOS results without scientific justification. This practice of “testing into compliance” is unscientific and objectionable under CGMPs. 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. The number of retests should not be adjusted depending on the results obtained. The firm's predetermined retesting procedures should contain a point at which the additional testing ends and the batch is evaluated. If the results are unsatisfactory at this point, 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. In such cases, before starting additional retesting, a protocol should be prepared (subject to approval by the QCU) that describes the additional testing to be performed and specifies the scientific and/or technical handling of the data.
If no laboratory or calculation errors are identified in the first test, there is no scientific basis for invalidating initial OOS results in favor of passing retest results. All test results, both passing and suspect, should be reported 9 and considered in batch release decisions.
The original sample from a batch should be sufficiently large to accommodate additional testing in the event an OOS result is obtained. In some situations, however, it may be appropriate to collect a new sample from the batch. Control mechanisms for examination of additional specimens should be in accordance with predetermined procedures and sampling strategies (§ 211.165(c)).
When all 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)). Improper sample preparation might be indicated, for example, by widely varied results obtained from several aliquots of an original composite (after determining there was no error in the performance of the analysis). Resampling should be performed by the same qualified, validated methods that were used for the initial sample. However, if the investigation determines that the initial sampling method was inherently inadequate, a new accurate sampling method must be developed, documented, and reviewed and approved by the QCU (§§ 211.160 and 211.165(c)).
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.
In the context of additional testing performed during an OOS investigation, averaging the result(s) of the original test that prompted the investigation and additional retest or
resample results obtained during the OOS investigation is not appropriate because it hides variability among the individual results. Relying on averages of such data can be 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)
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
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 laboratory13 does not determine an assignable cause, all test results should be reported to the customer on the certificate of analysis.
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).
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. After a thorough investigation, a firm’s QCU might conclude that the initial OOS result did not reflect the true quality of the batch.
For 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.
Investigating Out of specification test results