Common Compliance Issues in a Quality Control Laboratory - Data Integrity, Out of Specifications (OOS), Corrective and Preventive Actions (CAPA)
This seminar will be taught by Former Deputy Director and the Lab Chief in the Division of Biological Standards and Quality Control, FDA/CBER.
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 these systems, their impact on quality and finding a root cause in order to develop robust systems and procedures to achieve sustainable compliance.
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 integrity, out of specifications (OOS), Corrective and Preventive Actions (CAPA). These have been frequently cited as deficient in recent regulatory inspections by the FDA and MHRA in pharmaceutical companies from a number of countries around the world.
In this seminar:
Issues related to data integrity will be discussed with emphasis on finding a root cause for data integrity in a company. Various ways to implement sustainable quality systems to avoid issues with the data integrity will be presented. Often data integrity issues are due to human behavior and social/cultural aspects in an organization. A major objective of this seminar is to understand data integrity issues and the root cause for such issues. Discussion on these will be a great opportunity for senior management and a team from the corporate office to participate 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. Ways to avoid OOS risk will be discussed.
Will discuss the data of exceptions during manufacturing operations, 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.
Upon completing this course the participants will understand:
Role and Responsibilities of Quality Control Unit with regard to assuring manufacture of quality products consistently and to achieve sustainable compliance during laboratory operations
Laboratory Quality Management Systems and their role in QC operations
Data Integrity issues and their Importance for public health
Raw Data - Paper, Hybrid, Electronic
Causes for Data Integrity Issues
Correcting and Preventing Data Integrity Issues
Data of Exceptions - Deviations, Non-Conformances, Out of Specifications (OOS), Out of Trend (OOT), Out of Frequency (OOF)
Managing Data of Exceptions
Regulations, History, Background and Importance of Out of Specifications (OOS)
Uncertainty of Methods & Re-testing,
Re-test and Investigative Testing
Issues with Testing into Compliance
Reportable Results and Averaging of Data
OOS Investigation - Phase I Investigation, Phase II Investigation, Re-testing, Re-Sampling, Outlier Tests
Root Cause Analysis for Investigations from Deviations, Non-Conformances, Out of Specifications (OOS), Out of Trend (OOT), Out of Frequency (OOF)
Correction, Corrective Actions and Preventive Actions
Effectiveness and Sustainability of 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.
Issues with data integrity have been a common citation in FDA’s “Form 483 observations” and “Warning Letters” during recent regulatory inspections. This is not only a serious non-compliance issue affecting the quality of the product, but affects the integrity of the management and staff of the company. Data Integrity issues may include simple errors or mistakes, carelessness in recording observations and raw data during manufacture, not following good documentation practices, poor training and oversight, lack of security and audit trail on electronic records and manipulation of data or operations to release products not meeting specifications.
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.
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.
Day One (8:30 AM – 4:30 PM)
Registration Process: 8:30 AM – 9:00 AM
Session Start Time: 9:00 AM
Introduction – Roles & Responsibilities of Quality Control Unit and Overview of Laboratory Quality Management System
Quality Control Unit (21 CFR 211.22)
Laboratory Quality Management Systems
Relevance of Data Integrity to Public Health and Company Reputation
Recent Citations by Regulatory Agencies
Regulatory Guidance and Requirements
Good Documentation Practices
Assessment of Data Integrity Issues
Quality of Documentation System
Paper Based (Control and Accountability)
Hybrid (Paper and Electronic)
Electronic (21 CFR Part 11) – Security, Audit Trail, Electronic Signatures
Root Cause Analysis of Data Integrity Issues
Human Behavior (Social and Cultural Issues)
Management of Data and Ensuring its Security and Integrity
Record Keeping and Archiving
Training on Documentation Practices, Risks of Data Integrity and its Impact on Public Health
Routine Monitoring and Oversight (Audits)
Day Two (8:30 AM – 4:30 PM)
Data of Exception
Understanding Data of Exceptions
Deviations, Non-Conformances, Out of Specifications (OOS), Out of Trend (OOT), Out of Frequency (OOF)
How to Manage Data of Exceptions Deviations & Non Conformances
Biological Product Deviations (BPD)
Out of Trend Out of Tolerances Out of Frequency
Out of Specifications (OOS)
Regulations, History and Background
FDA’s Citations on OOS in QC Labs
Uncertainty of Methods & Re-testing
FDA Guidance Document on OOS
Phase I Investigation
Phase II Investigation
Concluding the Investigation & Final Thoughts
Root Cause Analysis
Mitigating OOS Risk
Corrective and Preventive Actions (CAPA)
Regulatory Requirements and Guidance CAPA Process
Non Conformance/Deviation/OOS (Problem)
Root Cause Analysis
Identify Root cause (Critical for Effectiveness of CAPA)
Correction of Problem
Monitoring Effectiveness and Sustainability of CAPA
Verify (Problem does not recur)
Making Change to Approved Applications (Change Control)