Thursday, July 14, 2011

QUALITY CONTROL - Part 3 of 3 | OOS: The Last Resort

A 70-person PerkinElmer OneSource on-site team takes complete responsibility for maintaining and qualifying more than 50,000 Merck Research Laboratories assets in six facilities.
A 70-person PerkinElmer OneSource on-site team takes complete responsibility for maintaining and qualifying more than 50,000 Merck Research Laboratories assets in six facilities.

Practical advice for handling the second phase of out-of-specification investigations

In the previous two articles, we discussed the background of laboratory out-of-specification (OOS) investigations and Phase I of the OOS investigation as outlined in the U.S. Food and Drug Administration (FDA) OOS guidance. If Phase I (see Figure 1) of the laboratory investigation does not identify an attributable laboratory error as the cause of the original OOS observation, the OOS guidance allows the organization to move into an expanded laboratory investigation (Phase IIB) in parallel with a review of the production activities (Phase IIA).
How the two parts of the investigation are coordinated depends on the corporate culture. Review of production records should be a priority, because there is a reasonable possibility that it will reveal that the OOS is attributable to an error in the operations area.
The Phase IIB (Step 11) laboratory investigation focuses on retesting to demonstrate that the original value does not represent the material. There are a number of conflicting opinions and expectations that must be considered as the organization develops its OOS retest policy, procedure, and protocols:
  • The operations unit is generally not willing to consider that the OOS observation may be an accurate measure of the quality of the material.
  • There is often pressure to release the product, as well as a belief that the path to quick release involves demonstrating that the original failing result does not reflect the quality of the batch.
  • There is some debate in the pharmaceutical industry as to whether there should be any retesting—any effort to identify the original value as an outlier—if an attributable laboratory error has not been identified in Phase I.
  • It is unlikely that the retesting will identify the cause of the original OOS. At best, it will only confirm that the original value is an outlier without identifying the cause of the original value. The investigation will not be complete in the eyes of the FDA until the cause is identified and corrected.
  • The organization should consider the FDA position that for any deviation, the investigation should identify the cause and recommend a corrective and/or preventive action.
Figure 1. An out-of-specification process chart.
Figure 1. An out-of-specification process chart.
Before moving to Phase IIB, (Step 11) retesting, of the investigation, the supervisor and analyst should ask themselves: Does the test under consideration already include the retest? Some tests defined in the United States Pharmacopeia (USP) have the retest steps built into them, specifically, tests for uniformity of dosage and drug release (dissolution). If the analyst has completed the 24 dosage units described in the USP dissolution procedure or the 30 units described in the USP uniformity of dosage procedure, retesting has been completed. If the criteria are not met, batch failure has already been confirmed.
Unfortunately, many do not comprehend the impact of completing these tests with failing results. The laboratory might consider a policy or procedure that requires that the analyst inform laboratory management when moving to the second stage of testing so that management is aware of the potential problem. Because the rest of the organization does not understand that these procedures already include the retest, it will expect the laboratory to move to the OOS observation investigation mode. In reality, the organization should move into the investigation of a confirmed material failure, which will be driven by quality assurance and will involve the whole organization.
Any laboratory OOS standard operating procedure should clearly identify the company’s policy on the use of outlier testing and the expectation that the cause of the original OOS observation (a deviation) will be identified. The following observations in an FDA warning letter demonstrate that the investigators are looking for the identification of the cause of the deviation:
“Your OOS procedure contains no provision for conducting retest of new samples, yet your firm released these batches for distribution based on passing repeat test results without conducting a thorough investigation as required under 21 C.F.R. §211.192 to support your conclusion and rationale to release the affected lots … . Your firm’s OOS investigation relating to impurity levels for _____ concluded that the root cause was laboratory error, but the investigation did not identify what specific laboratory error occurred.”
The regulatory expectation requires that retesting be conducted according to an approved protocol. Since the landmark 1993 Barr ruling, industry representatives have asked the FDA and others for a recommendation on what should be in the protocol. This is not addressed in the OOS guidance. The following should be identified in the OOS procedure as required content for the retest protocol, and the points should be covered in each retest protocol:
The sample that will be used for the retesting. Retest replicates should come from the same sample that was used for the original test. Under circumstances in which the original sample is unstable, the sampling procedure will identify this and proceduralize resampling in the event of retest. If the original sample is inadequate, the sampling plan does not meet current regulatory expectations that the laboratory sample be adequate for the original test and any necessary retesting in the event of an OOS observation. If the laboratory continues, a resample will have to be justified and a resampling plan prepared and approved by the quality unit before resampling occurs and retesting is begun. The original, inadequate sampling plan should be investigated and corrected through the site deviation system.
Figure 2. Retesting Scenarios
Figure 2. Retesting Scenarios
The method that will be used for the testing. The method used to obtain the original result will be used. For each retest sample preparation, the analyst will perform the complete procedure, including the preparation of mobile phase, standards, system suitability solutions, and other required preparations. If any compromises to this are allowed, they are identified in the protocol. For example, the analysts might batch the analytical and standard preparations on a chromatograph and use a common system suitability preparation to evaluate the operation of the chromatographic system.
The analysts who will perform the retesting. The draft OOS guidance stated that the original analyst should not be included in the retesting. This requirement could cause a hardship for some laboratories. The final guidance suggests that at least two analysts, not including the original analyst, be involved in the retesting. Some feel that there is value in having the original analyst participate. Any analyst, including the original, could have a procedural bias that impacts his/her results. That potential must be considered in the preparation of the retest protocol and the evaluation of the data.
Suggestion: Retesting should be performed by three analysts, including the original. The protocol should have acceptance criteria for intra- and inter-analyst result agreement, as well as the requirement that any lack of conformance to these criteria be resolved before the data analysis for an outlier begins.
The number of replicates that will be tested. The purpose of retesting is to demonstrate that the original value, the OOS observation, does not accurately reflect the material under test. This is done by demonstrating that the original value is a statistical outlier when compared to multiple, independent retest results of the same material. Two retests will not provide any statistical confidence. Five or six retests will provide borderline confidence. Several possible retest scenarios are shown in Figure 2. Scenario 1 has been published and accepted by many. It is based on a chromatographic procedure in which each injection is calculated as a separate result. However, the individual results lack the independence appropriate for the evaluation. In the other scenarios, the complete test procedure is followed for each retest sample preparation. This includes replicate injections and calculations defined by the procedure.
Suggestion: Use nine retests, three by each of three analysts. The protocol should require intra- and inter-analyst agreement as part of the overall outlier study.
How the results will be evaluated and what constitutes an outlier. The protocol should identify acceptance criteria for the test results before they are evaluated for the outlier. Where possible, the laboratory should use a statistician to lead it through this evaluation. If a statistician is not available, the laboratory can use one of the standard statistical packages. Test method system suitability criteria must be met. There should be acceptance criteria for intra- and inter-analyst agreement. For the determination that the original value is an outlier, a number of statistical routines have been used. The student T is one routine that is used often; however, the use of any routine to identify a value as an outlier must be justified. Any criteria for determining whether or not the original value is an outlier must be established in the protocol before retesting is initiated.
Suggestion: One possible criterion to consider is the following: The original is an outlier if it is outside of calculated average ±3σ for the retest results. When retesting is complete, the laboratory will report its complete investigation, results, and conclusions to quality assurance, which will be responsible for determining the disposition of the material.
Often the firm looks for ways to measure the performance of the laboratory OOS investigation process. Performance measures that should be considered include:
  • Outstanding OOS investigations;
  • OOS investigations going beyond X days;
  • OOS observations per 100 laboratory tests;
  • OOS observations per month; and
  • Average time for completion of an OOS investigation.
John G. (Jerry) Lanese is an independent consultant with a focus on quality systems and the components of an effective quality system. In 1994, he formed The Lanese Group and consults on quality systems and cGMP compliance for small and large medical device and pharmaceutical companies, including companies under FDA Consent Decree, API and excipient manufacturers, electronic firms, device component manufacturers, and other manufacturing organizations.

Editor’s Choice

  1. U.S. Food and Drug Administration. Guidance for Industry: Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production. FDA. Available at: Accessed June 12, 2011.
  2. Kuwahara SS. A history of the OOS problem. Biopharm International website. November 1, 2007. Available at: Accessed June 12, 2011.
  3. Kuselman I, Pennecchi F, Burns C, et al. Investigating out-of-specification test results of chemical composition based on metrological concepts. Accred Qual Assur. 2010; 15(5):283-288.

No comments: