Sustainable Compliance for Out of Specifications (OOS) Results, Deviations, and Corrective and Preventive Actions (CAPA)

Quality Control (QC) Unit plays a critical role in assuring the identity, strength, quality, purity, and stability of drugs and biologics. QC Unit is responsible to approve or reject all procedures and specifications impacting quality, and all components, raw materials and the drug at all stages of manufacture, including intermediates, drug substance and drug product (21 CFR 211.22). Robust Laboratory Quality Management Systems (QMS) are essential to achieve and maintain sustainable regulatory compliance in a QC Unit. The course will start with an introduction to roles and responsibilities of QC Unit with an overview of Laboratory QMS, then focusing on key quality systems or issues, such as data of exceptions, including out of specifications (OOS), and Corrective and Preventive Actions (CAPA).

Out of Specification (OOS) test results have been a major concern during manufacture of drugs for many decades. To avoid OOS in order to release the product, it has been found during audits and inspections that data or testing was manipulated (including compromising data integrity), product was re-tested repeatedly until a passing result was obtained or tests results were averaged using unapproved procedure to mask failing results. As most product specifications are based on statistical principles or methods, these methods were applied in an unethical manner to test a lot repeatedly until a passing result was obtained. The product was released on one passing result. Such practice has been known as "testing into compliance" and became a major issue following the 1993 lawsuit between the US Government and Barr Laboratories. Following historic judgement by Judge Alfred M. Wolin in 1993 on US versus Barr and FDA’s OOS Guidance issued in 2006 (Draft Guidance in 1998), handling OOS results and performing investigation into OOS by pharmaceutical companies receive close scrutiny during regulatory inspections. In this Seminar, historical aspects of OOS and understanding of the stigma associated with OOS will be presented in order to mitigate the risk for OOS. A thorough investigation procedure into OOS results following the FDA Guidance will be discussed with an aim to finding a root cause for the OOS. Challenges in Investigating OOS results for Microbiology testing will also be presented. Ways to avoid OOS risk will be discussed.

The CAPA system is an important QMS in the Pharmaceutical Industry, and is a critical tool to achieve sustainable compliance through continuous improvement. A robust CAPA system, supported by a thorough investigation to find a root cause helps in improving manufacturing operations, the company and the business. As per ICH Q10 Guidelines, the pharmaceutical company should have a system for implementing CAPA resulting from the investigation of complaints, product rejections, non-conformances, recalls, deviations, audits, regulatory inspections and findings, and trends from process performance and product quality monitoring. This seminar will discuss the data of exceptions during manufacturing operations and performing investigations into these observations using a structured approach with the objective of determining the root cause. The level of effort, formality, and documentation of the investigation should be commensurate with the level of risk, in line with ICH Q9 guidelines. Ways to implement corrections, corrective actions and preventive actions and a follow-up to monitor effectiveness and sustainability of these procedures will be described.

Throughout the course, specific examples with regard to achieving regulatory compliance during inspections and audits will be discussed. More importantly, the seminar will focus on understanding data of exceptions, including OOS, their impact on quality, finding a root cause in order to develop robust and effective CAPA procedures to achieve sustainable compliance.