Handling OOS Deviations and CAPA for Regulatory Auditors

Handling OOS Deviations and CAPA for Regulatory Auditors

 Handling OOS Deviations and CAPA for Regulatory Auditors

As standards and regulations go on upgrading, but very basic GMP GLP Requirements with respect to OOS Deviations, failure investigation and CAPA are not properly handled in the industry due to various reasons, but regulators are expecting the Following CAPA measures are mandatory.


Through hands-on exercises and lectures, you will discuss and explore international cGMP principles and approaches for active pharmaceutical ingredients (APIs), excipients, and finished pharmaceuticals. Learn easy-to-grasp basics of regulatory requirements, current issues, and trends in the Indian pharmaceutical industry with an emphasis on applying GMP in day-to-day operations. After understanding the importance behind the GMP regulations, participants discuss the history of the GMP regulations, the regulatory process, and the concept of operating OOS/ Deviations and CAPA in a "state of control," with an emphasis on the regulation of pharmaceutical products.

Understanding Current Status:

 OOS /Deviations and CAPA remain hot topics in inspections. The auditors' observations show that things do not always work as desired results. Recently, the U.K. drug inspections authority MHRA (Medicines and Healthcare Products Regulatory Agency) published some very interesting and comprehensive information in their MHRA GMP Inspection Deficiency Data Trend 2016, covering 324 GMP inspections performed in 2016. According to the report, deficiencies relating to 'Quality Systems' are by far the most prevalent observed during inspections.

As in the previous years, appropriate handling of OOS, deviations, investigations, and CAPA again causes a lot of concerns. Taking a closer look at the examples of the findings it becomes obvious that root cause analysis, impact assessment, and associated actions are still challenging for many companies:
  • OOS/Deviations were not fully recorded and investigated
  • Deviation investigations did not include an appropriate level of investigation and did not capture all relevant information
  • Significant lack of detail in investigations of OOS and batches are released based on invalidated OOS.
  • Root cause was not always adequately considered during Release of batches
  • Appropriate CAPAs were not implemented
  • The quality impact of the deviation and CAPAs implemented were not appropriately assessed
  • Appropriate measures may not have been taken to prevent reoccurrence
  • No recorded measures to consider prevention
  • No process for assessing the effectiveness of CAPA in line with Quality Risk Management principles

And what about the FDA? In a recent Warning Letter to Porton Biopharma in the U.K. from January 19, 2017, the US Food and Drug Administration (FDA) cited the company for failing to "thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications" and they directly refer to corrective action and preventive actions:
 Even recent USFDA warning letter to one of the Chinese major Pharmaceutical company cited the following

 For example, you failed to provide: 
  • The quality control test methods and specifications used to analyze each drug product batch prior to a batch release decision, including both chemical and microbial quality attributes and in complete OOS investigations.
  • A clear commitment to testing all drug products for identity and strength of active ingredients and all other appropriate quality attributes, including total count and objectionable microorganisms.
  • Specific timelines for process performance qualification for each of your drug products, and a detailed summary of your approach for routinely monitoring intra-batch and inter-batch variations. ( Capa has to monitor these variables through monthly batch  CPP and CQA trends)
Based upon the result of the violations, we strongly recommend engaging an auditor qualified as set forth in 21 CFR 211.34 to assist your pharmaceutical company in meeting cGMP requirements. 

Other Observations:
  • "The only correction implemented at that time was to update your standard operating procedure"
  • "Your firm's corrective action and preventive action (CAPA) plan was inadequate"
  • "We encourage you to consider additional CAPA to mitigate risk"
  • "Your firm has failed to implement prompt and sufficient corrective and preventive actions"
  • On January 18th, the FDA sent a Warning Letter to the Indian API manufacturer, with the conclusion that the company failed to "ensure all production deviations are reported and evaluated, and those critical deviations are investigated and conclusions are recorded" and that batch disposition was made before "adequate investigations into these significant deviations" were conducted.
Based on the above observations the right CAPA to be addressed by following guidelines:
For Handling of OOS (Out-of Specification ):
The following guidelines detailed and helps to revise and right approach on OOS
  • Evaluation & Reporting of Results – Core Document
  • Evaluation & Reporting of Results – Annex 1A: Model Template for Failure Investigation of OOS Results
  • Evaluation & Reporting of Results – Annex 1B: Responsibilities of the Laboratory Supervisor
  • Evaluation & Reporting of Results – Annex 2A: Examples of Re-Test Programmes for Quantitative Tests
  • Evaluation & Reporting of Results – Annex 2C: Re-Test Programmes for Qualitative Tests
  • Evaluation & Reporting of Results – Annex 2D: Special Considerations for Animal Testing (Verification of OOS Results)
For Handling Deviation with QRM

For handling Of CAPA:

The CAPA system is described as an integral part of the Quality Management System (QMS) and consists of 4 phases:
Phase I: Planning 
- Planning for Measurement, Analysis and Improvement Processes
- Establish Data Sources and Criteria
Phase II: Measurement and Analysis within and across Data Sources
- Measurement
- Analysis
Phase III: Improvement
- Investigate
- Identify Root Cause
- Identify Action
- Verification of identified action
- Implement Actions 
- Determine Effectiveness of Implemented Actions (Effectiveness of CAPA)
Phase IV: Input to Management 
- Reporting to Management 
- Management Review
The above-mentioned guidelines taught us how important it is to integrate regulatory, market and customer requirements for GMP compliance complete product range into a streamlined Quality Management System (QMS).
 Author Biography :
G.Sundar has completed his MSc Chemistry from Annamalai University and qualified as GxP compliance person with 24 years of rich experience. He is the director of PharmQa compliance services, a premier GxP consultancy service organization. He has published more than 22 papers in reputed journals and has been serving as an editorial board member of repute. 
For any of our assistance contact us on techsupport@marcepinc.com

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