Investigation of OOS Results in Analytical Testing

It is important to maintain product quality in the pharmaceutical industry. Product quality, safety and efficacy are ensured by adherence to the regulatory standards and product specifications. Analytical testing by quality control laboratory is the key to ensure the desired quality of pharmaceutical products. Out-of-specification results are critical to deal with during analysis. OOS results are the situation when the product analytical results are found outside the predetermined specification. As per regulatory guidance, all out-of-specification results must be investigated.

Understanding OOS Results

As I have stated above, the results outside the acceptance criteria are considered as out of specification. These product specifications are set by the company itself during product development or by regulatory agencies like the FDA, EMA, ICH, or any country-specific regulatory agency.

For example, if any tablet specification has to contain 50mg of active pharmaceutical ingredient (API) but during the analysis, it is found to have 48mg then it would be considered an OOS.

Here, it is essential to know that all out of specifications results don’t indicate any problem with the product. Sometimes it may occur due to any other error like analytical error, sampling mistake or any other analysis-related error. Therefore, a thorough investigation is required to find the real cause.

Regulatory Guidance and Importance

Regulatory agencies, specifically the US Food and Drug Administration as a detailed guideline on OOS investigation. In 2006 FDA published a guidance on OOS investigation titled “Investigating Out of Specification Test Results for Pharmaceutical Production”. This guidance provides scientific justification for resampling or retesting, proper documentation of the entire investigation process, procedure for identification of root causes and implementation of correct and preventive actions (CAPA).

If a firm fails to investigate the out of specification results properly, they can face regulatory actions like warning letters, product recall or manufacturing shutdowns in severe cases.

Stages of Investigation

A proper OOS investigation travels through the following stages.

Phase 1: Laboratory Investigation

Laboratory investigation is conducted to find out the errors during analysis. This investigation phase includes
1. Checking instrument for calibration and any malfunction.
2. Verifying the Sample and standard preparation
3. Analyst interview
4. Checking raw data, logbooks, chromatograms and graphs

If any lab error is identified like a calculation mistake, the OOS results are considered invalid and retesting of simple is considered but if no laboratory error is found then results are considered valid and further investigation is required.

Phase 2 Full Scale Investigation

If the laboratory investigation is unable to find the root cause, the investigation must be done in the manufacturing process. The following points must be considered during the second phase investigation.

1. Review batch manufacturer records and production logbooks
2. Check details of APIs and excipients used in batch manufacturing
3. Verify environmental conditions and equipment status during manufacturing
4. Interview personnel involved in manufacturing

This phase of investigation helps to identify the type of OOS event whether it is related to the manufacturing process or an isolated event that is rare to happen again. To find the problem, it is required to conduct a root cause analysis.

Root Cause Analysis

Root cause analysis is the most important part of any OOS investigation. Common investigation tools used for root cause analysis include:

• Fishbone Diagram
• 5 Why Analysis
• Failure Mode and Effects Analysis

The possible root causes in the analysis may include:

• Human error during sample and standard preparation
• Incorrect instrument settings
• Cross-contamination during analysis
• Incorrect calculation

The possible root causes in manufacturing may include:

• Error in dispensing of materials
• Inadequate mixing time
• Incorrect equipment settings
• Forgot to add any material
• Skipped any manufacturing step
• Product mix-up or cross contamination

Retesting and Resampling

Retesting is to analyze the original sample again while resampling is to take a new sample again from the same batch. Regulatory agencies have strict rules on retesting and resampling to prevent the misuse of these practices.

Retesting can be only performed, if there is a strong region and justification such as any analyst error. It is also required to define the number of retests and criteria for retesting of samples. Resampling should be done only if there is a strong region for it like the original sample was mishandled or contaminated.

Documentation and Reporting

Proper documentation of investigation is a regulatory requirement. Every step of investigation and observation must be recorded. Documentation may include:

• Who performed the investigation
• When and where it is done
• Evidence of documents viewed
• Corrective and preventive actions and
• Final conclusion

A well-documented OOS investigation report must demonstrate a scientific and unbiased approach that satisfies the regulatory requirements for investigation.

Corrective and Preventive Actions (CAPA)

After identification of the root cause, a suitable corrective and preventive action plan must be implemented. This plan may include

• Training of analysts or manufacturing operators
• Revision in SOPs
• Modifications in equipment or process
• Implementation of more process controls
• Improvement in raw material testing

Implementation and effectiveness of CAPA should be tracked over time to ensure the prevention of reoccurrence of the same issue. This is important for continuous quality improvement in the manufacturing process.

Case Study Example

A batch of tablets fails in content uniformity of drug test.

Phase 1 Laboratory Investigation

• Sample and standard preparation techniques found to correct
• Equipment was timely calibrated
• Chromatograms were found to correct
• Calculations were correct

Phase 2 Investigation

When the batch manufacturing record was reviewed, it was found that mixing time during blending was reduced by mistake.

Root Cause: Inadequate mixing time caused poor mixing of API throughout the blend.

CAPA implemented:

• Checked by sign added for all critical steps in batch manufacturing record
• Equipment setting updated to have minimum mixing time by default
• Additional training provided to the production staff and operators

Out of specification (OOS) investigation is a critical process that ensures the quality of pharmaceutical products. Regulatory agencies require a thorough investigation of issues found during manufacturing. By proper investigation and implementing effective corrective and preventive actions, the manufacturers remain compliant with regulatory requirements and also build a strong quality culture within the manufacturing facility. If you face any problems during the investigation of OOS, we shall be happy to help, you can contact us by email.

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