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An understanding of continuous process validation can lead the way to consistent approaches, reduced investigation times and observations, the avoidance of lost batches, and high-quality products.
Typically, in the past, the processes involved in manufacturing a biopharmaceutical product were validated over three batches and then considered complete. In 2011, however, FDA issued a guidance document Process Validation: General Principles and Practices (1), which emphasized the principles of ‘continued process verification’ (CPV) as a crucial element in the lifecycle management of a product. Similar guidance followed later from the European Medicines Agency (2). Since then, the expectation has been that validation should be an ongoing effort. Through regular reporting over multiple batches, CPV encourages the collection of more data, linked to process knowledge, providing a vast amount of information about the process. This information enables necessary changes to the process to be made without significantly impacting production of commercial supply and bestows a high level of confidence in the consistency of the process and, by extension, the product, ensuring that every aspect of the process remains in a constant state of control.
Both industry and regulators seem to agree that CPV is necessary for ongoing quality assurance, and the industry is aware that regulators expect manufacturers to implement CPV in order to be in compliance. Understanding how to implement CPV is another matter. Regulatory guidance documents-out of necessity-lack detail, providing scope for companies to implement their own strategies that work for their operations. If every biopharmaceutical company forges ahead with its own interpretation of the guidance, however, no one benefits. Inspections would be time-consuming, possibly resulting in numerous observations, and manufacturers would feel like they were taking random stabs in the dark trying to guess what inspectors might be thinking.
The CPV Case Study
Representatives from manufacturers shared collective CPV-related experiences through a CPV team assembled by the BioPhorum Operations Group (BPOG) to come to an industry-wide understanding of CPV and to increase harmonization and consistency across the industry. The group authored a detailed interpretation of FDA’s guidance document to satisfy both manufacturers and regulators and lead to effective and accurate implementation of CPV industry-wide.
The whitepaper, Continued Process Verification: An Industry Position Paper With Example Plan, was written to shed light on the finer points of implementing CPV in a compliant manner by using the example of a fictitious monoclonal antibody product, named A-Mab (3). The concepts and principles used in the A-Mab case study and the BPOG CPV white paper should be applicable to any manufacturer wishing to understand how to create a CPV plan and implement it for an actual product in real life.
A pre-requisite to the creation of a CPV plan is the existence of a ‘control strategy’ for the product, which is expected to exist at the end of what FDA refers to as ‘Stage 1-Development’ in the lifecycle of the product. ‘Stage 2-Process Performance Qualification’, then provides information related to the operation of the manufacturing processes. From these two stages, an appropriate set of critical quality attributes (CQAs) and critical process parameters (CPPs) are identified for monitoring as part of CPV. The process of identification should be risk-based and justification recorded for attributes and parameters that are included and excluded (4).
Once written and in use, a key element of a CPV plan is the description of what constitutes a ‘CPV signal’, and how signals will be responded to. Good practice here involves the use of statistical rules that are well established in the literature (5), a default set of responses, and a cross-functional team that meets on a regular basis to assess signals against their defaults (6). Extensive discussions amongst BPOG team members has led to the conclusion that, in the case of biopharmaceutical products, responses to signals should not depend on a set of default responses. And of course, it is necessary to document and make traceable the decisions made relating to CPV signals. At a high level, justifiable responses might be: continue to monitor but do nothing, evaluate the background context to the signal, and escalate the signal to the quality management system (QMS). The CPV system is part of the overall quality system, but CPV signals do not relate to batch release, instead they help keep the product under control, within specification over its lifetime. This means that the number of signals escalated to the QMS is likely to be very small.
More than 650 people have downloaded this CPV whitepaper since it was posted on the Biophorum Operations Group website in late 2014, indicating a need for a comprehensive paper on the topic (3). Surveys of BPOG member companies report widespread adoption of the CPV initiative, with approximately 90% of products having a CPV plan in place, up from perhaps 30% of products two years ago. Member companies have increased representation on the CPV team and the group has plans to participate in industry conferences to increase discussion about the topic.
CPV Topics of the Future
A second document is pending publication; this roadmap for implementing CPV provides a guide for CPV implementation and maintenance for throughout the commercial stage of the product’s lifecycle and includes a process flow diagram.
A best practices paper about responses to signals, currently in draft, is intended to address how companies respond to signals indicative of process variation. Other planned documents will address CPV plans for legacy products, and how to implement CPV between a network of sites, particularly between a license holding company and a contract manufacturing organization.
CPV involves the capture of large quantities of data from multiple source systems and potentially different sites and, therefore, requires information technology (IT) systems to collate and analyze data. IT systems must be properly validated and have sufficient data interfacing. Subject matter experts are drafting a best practice paper on validation of informatics systems for CPV.
As a result of the ongoing work in the CPV, process technology, and informatics areas, real-time batch release may be a prospect on the horizon. If this becomes a reality, products would get to the marketplace more quickly, and with full confidence in their quality. Further, there is an opportunity to increase levels of process automation. It may take time for confidence in the technology of online instrumentation to build across the industry, but it is possible, and is an area of future interest.
Continuing the CPV Conversation
With all of the discussions that have been opened about CPV and informatics through collaborative efforts, it is important to share what has been learned with a wide audience including stakeholders from every aspect of the biopharmaceutical endeavor: from manufacturers to contract organizations to IT professionals to regulators. One way to disseminate knowledge is through the widespread, open distribution of white papers, best-practice documents, and conference presentations.
CPV subject matter experts are aware of the many complex issues involved in creating and implementing a CPV plan; are working together to solve these issues in ways that are fully expected to be compliant; and are sharing solutions with interested parties. With representation from biopharmaceutical companies and with widespread adoption of the collaboration’s positions, the messages are gaining credibility from all sides, encouraging all of the stakeholders involved to come to a collective understanding about CPV. This understanding can eventually lead the way to consistent approaches, reduced investigation times and observations, the avoidance of lost batches, and products of the highest quality.
1. FDA, Guidance for Industry. Process Validation: General Principles and Practices (Rockville, MD, Jan. 2011).
2. European Medicines Agency, Guideline on process validation for finished products-information and data to be provided in regulatory submissions (London, United Kingdom, Feb. 2014).
3. BioPhorum Operations Group, Continued Process Verification: An Industry Position Paper With Example Plan, Whitepaper (Sheffield, United Kingdom, 2014).
4. Marcus Boyer, Joerg Gampfer and Abdel Zamamiri on behalf of BioPhorum Operations Group, A Roadmap for the Implementation of Continued Process Verification (to be published in the May/June 2016 edition of the PDA Journal).
5. John Oakland, Statistical Process Control, 6th Edition (London, United Kingdom, Routledge 2008).
6. Mark DiMartino et al. on behalf of BioPhorum Operations Group, Responses to Signals from a Continued Process Verification System in the Biopharmaceutical Industry (to be submitted to an Autumn 2016 edition of the ISPE Journal of Pharmaceutical Engineering).
Article DetailsBioPharm International
Vol. 29, No. 6
When referring to this article, please site it as C. Zigrand, "Continued Process Verification: State of the Industry," BioPharm International 29 (6) 2016.