FDA Guidance - Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production

Testing is a critical process in the pharmaceutical industry to verify the authenticity, presence or absence of certain components, pass or fail and determine quality of a given sample. The tests samples consists of different types, such as final finished product , packaging and raw materials. It helps determine whether the process or product fulfils its intended function or not. The main part of testing is acceptance criteria, which sets a clear boundary between passed and failed results.

Acceptance Criteria in the pharmaceutical industry is a critical parameter that represents the success or failure of any process, product, or system. Any test result that does not fulfil the acceptance criteria is called Out of Specification. Unlike other industries, the failed results are further investigated to rectify the fault and determine the root cause. The main idea behind this is to improve product quality, prevent occurrence of problems and save the market reputation of the pharmaceutical product manufacturer. 

Out-of-specification test results are also regulated by the United States Food and Drug Administration (FDA), and describe methods to identify and investigate them. The main advantage of FDA guidelines is to provide guidance to industries in solving issues, and focus on implementing improvements to their processes rather than inventing new procedures. 

What are Out-of-Specification (OOS) Test Results

Out of Specification (OOS) test results refer to those that fall outside the acceptance criteria as defined in the drug application, drug master file, or as specified by the manufacturer. The scope of OOS results includes finished products, in-process materials, laboratory testing, and raw materials. 

The OOS test results indicate problems with the process, individual components, raw materials, and other related elements, and these must be investigated.  These are the first indications of the problems, and by carefully and strategically addressing these issues, pharmaceutical product manufacturers can decrease the chances of recalls and increase the likelihood of a quality reputation for their drugs in the market. In addition to product effectiveness, it also represents the established practices, facilities, and preparedness of the product manufacturer for implementing quality and solving safety related issues. 

United States FDA guidance for Out of Specification Test

The United States FDA has published its guideline for OOS, titled "Investigating Out-of-ofSpecification (OOS) Test Results for Pharmaceutical Production Guidance for Industry". In it, the US FDA provides its thinking on how to evaluate OOS test results, covering chemistry-based laboratory testing of CDER-regulated drugs.  This guidance applies to tests performed on Active Pharmaceutical Ingredients (API), excipients, in-process materials, and finished drug products.

This guidance can also be used for in-house testing of different components of the drug. Additionally, any firms involved in testing laboratories or production are also responsible for following these guidelines. 

Investigating OOS Test in light of FDA Guidance

Whenever there are OOS tests, it is necessary to investigate the source. Because it could be a deviation in the approved manufacturing process or the problem with the measurement device. If a batch is rejected based on OOS results, the relationship determines whether other batches or products are involved. The investigations must be in written form with detailed procedures, conclusions and follow-up.

For an effective outcome, the investigation should be based on scientific procedures, unbiased, timely, and well-documented. In the first phase, personnel should assess the accuracy of laboratory data related to the OOS tests, which must be performed before test preparations. 

Suppose the test is related to the CDMO. In that case, the investigation is performed by the laboratory section of the CDMO, which then conveys the results to the manufacturing firm's quality unit. 

There are two parts to the OOS test investigation: the first phase and the full-scale test. Initially, first phase assessment is performed, and if it does not provide any valid reasons, the full scale is initiated. For a CDMO, a full-scale investigation begins after the quality unit of the manufacturing form receives the initial assessment results from the CDMO.

Initial Laboratory Investigation

Let's discuss what's inside the initial laboratory investigation

Assessment of analyst's performance

An analyst is a key personnel when testing pharma products and is directly responsible for achieving the outcome of a laboratory test. The ability of an analyst to conduct accurate tests is the first requirement for the authenticity of the test, and they must be trained, qualified, and capable of conducting such tests.

They must be aware of all potential problems with the test and pay special attention to those that could lead to inaccurate results. It is also the responsibility of analysts to use instruments that are calibrated & meet the required specifications. 

Some other responsibilities of an analyst include, 

Checking data for compliance with test specifications before discarding the test sample

In the event of out-of-specification results with no valid explanation, the analyst must retain the test samples.

The analyst should document any errors, such as slipping related to the test sample and inform the supervisor immediately. 

When obvious errors are known, the analyst should not continue the test.

Instrument Calibration and Maintenance

Calibration and maintenance of instruments involved in the test can significantly impact the entire testing activity and its results. The instruments used during testing must be regularly calibrated and adequately maintained to ensure accurate test results. 

If instruments are not calibrated and maintained, the result will continually show errors in test results. 

Test Method

The test Method is an approved procedure used during the testing process. It must demonstrate the effectiveness of the test during the method development stage. 

The supervisor is responsible for evaluating the performance of the test method based on method validation data and historical data.

Supervisor's responsibilities 

The supervisor is responsible for evaluating the OOS results once they are identified. Rather than making assumptions, the supervisor's opinion must be objective. They must use scientific data to assess whether OOS results are related to laboratory error or manufacturing processes.

The supervisor should also consider re-examining the samples, test units, and glassware, which will enable the supervisor to reach a definitive conclusion. Some additional steps on the part of the supervisor include the following

Discussion with the analyst and assessing their knowledge and capabilities

Examine raw data and identify any deviation.

Verify the calculations used in the test and ensure they are scientifically correct and sound.

Verify the correct working of instruments.

Verify that appropriate reference standards, solvents, and reagents were used and were able to meet approved specifications.

Evaluate the performance of test methods and perform according to the standard specifications.

Recording and documenting the laboratory assessment

Full-Scale Investigation

If, in the laboratory investigation, it is established that there is no laboratory error and the results of the tests are accurate, a full-scale investigation is carried out.

Its main objective is to identify the root cause and initiate Corrective and Preventive Action, and consists of a production review and additional laboratory testing. 

Production Review

The Quality Unit conducts production reviews and may also involve other relevant departments, such as maintenance, manufacturing, and process development.  Additionally, all records must be analyzed & reviewed to determine the root cause. 

The entire activity must be documented and include the following information

Reason for the investigation 

A summary of  the manufacturing process resulting in the problem 

Documentation review indicating the potential cause 

Review indicating the occurrence of the problem previously 

Corrective action plans

At this stage, if the OOS tests are verified with proper identification of the root cause, the investigation of OOS is eliminated, and the product is rejected. On the other hand, if a specific failure type extends to other products or batches, the investigation must be continued and completed. 

Product or Process re-design

The OOS results may indicate a flaw in the process or product, such as raw material problems and variation due to any unit operations, and many more.  In such cases, the process of the product must be re-design

Additional Laboratory Testing

At this stage, additional testing is performed beyond Phase 1, including retesting and resampling.

Retesting -  a part of the sample is retested, and a sample is collected from the original homogeneous material from the lot that yielded the OOS test. Some situations that require retesting include sample handling problems or instrument malfunctions. During retesting, cGMP regulations, such as the establishment of specifications, standards, sampling plans, and test procedures, must be implemented and followed accordingly.

Resampling involves sampling from other units, either as part of the original sample or from a new sample drawn from a batch.  If the previous sample is used, it must be large enough to accommodate the texting process. 

Reporting - there are two types of reporting  -  averaging and outlier tests

Averaging depends on the test sample and its purpose. If the sample is homogeneous, averaging can yield accurate results. Additionally, in cases of microbiological assays, USP also prefers averaging methods.

Outlier - it includes defining valid acceptance criteria and/or rejection levels. 

Concluding the Tests

The quality unit is responsible for evaluating results, determining batch quality, and making release decisions. If the batch has been rejected, all further tests, including those for corrective action, must be halted.

The quality unit is responsible for interpreting the results. 

About the Author

Muhammad Asim Niazi has a vast experience of about 11 years in a Pharmaceutical company. During his tenure he worked in their different departments and had been part of many initiatives within the company. He now uses his experience and skill to write interested content for audiences at PharmaSources.com.