Manufacturers and regulatory authorities seek coordinated lifecycle management policies.
By Jill Wechsler
Frequent revisions and updates in manufacturing processes and operations are routine after a drug comes to market to improve products and systems and ensure reliable supply of high-quality drugs and biologics that meet regulatory standards. With more breakthrough and critical therapies gaining fast approval based on limited data and manufacturing experience, more postapproval changes are needed to increase batch size, shift to a new manufacturing facility, or improve process robustness and analytical methods.
Expanded global sourcing and sales complicates lifecycle product management, though, by requiring sponsors to deal with dozens of regulatory authorities that follow widely varying rules and legal requirements. FDA and other regulators have sought to address these issues by encouraging industry adoption of continual improvement and quality-by-design approaches, along with change management protocols and lifecycle management plans in initial market applications to reduce oversight of later changes. Drug company concerns that vetting such proposals will delay initial approval, however, has limited their adoption.
This disappointing response now is renewing interest in devising common standards for managing postapproval change. An International Council for Harmonization (ICH) expert working group (EWG) seeks to define those established conditions (ECs) that affect product quality and thus should be reported to regulatory authorities when changed or modified. The ICH Q12 program also seeks agreement on basic postapproval reporting categories set by regulatory authorities and where and how to list ECs in dossiers (1). And by encouraging greater reliance on pharmaceutical quality systems (PQSs) and change management protocols, policy makers hope to prevent drug shortages, while also reducing the time and cost involved in submitting and evaluating unnecessary regulatory filings.
Manufacturers typically make dozens of routine changes in facilities, equipment, processes, and testing every year for every product; the vast majority are minor and managed within a firm’s quality system. But those few significant changes that have to be reported to authorities according to different local regulations can take years to process, particularly for biotechnology-derived products that are more complex to produce.
Varying regulatory and data requirements in each nation means that approximately 140 regulatory bodies review the same core data and information over and over again, following 140 separate timelines, explained Suzanne Murray, Biogen senior director of regulatory affairs. She and others described efforts to streamline this cumbersome and costly postapproval change process at the July 2016 CMC Strategy Forum on “Change Happens” organized by CASSS.
Gaining regulatory approval of a move to a new site or change in process or materials often takes more than four years, she noted, and global sourcing of drug components makes the process even more complex.
The lack of a harmonized approach for product lifecycle management has stymied implementation of other ICH quality standards and limited manufacturer operational flexibility, commented Anthony Ridgway, senior regulatory scientist at Health Canada. He sees Q12 as an opportunity to promote drug manufacturing innovation and continual improvement and to help regulators gain more confidence in a firm’s PQS for managing post-approval CMC changes.
But reaching agreement among multiple regulatory authorities and industry sectors on the ICH Q12 standard for postapproval change management is proving to be a difficult and lengthy process. The EWG is circulating draft proposals with the aim of reaching consensus on a Step 1 standard at the ICH November 2016 meeting in Japan. If successful, the group anticipates approval of a final standard by the end of 2017.
Established conditions are key
The main approach of the collaborators is to clarify which established conditions require prior approval and where notification or annual report listings suffice. This approach would provide a framework for limiting oversight of less critical CMC changes, while also overcoming industry reluctance to institute improvements in manufacturing systems and processes. Ridgway described a continuum of ECs, including specifications, raw materials, in-process testing and controls, critical hold times, and manufacturing process elements. While changes in an EC normally would require a regulatory submission, a firm able to demonstrate greater product and process knowledge may justify reduced reporting. If the industry gets ECs right, Ridgway commented, the ICH Q12 document could be “quite useful;” if not, ICH Q12 “will not lead to a transformation in lifecycle management” that he and others desire.
FDA is looking for ICH Q12 to outline how a sponsor should manage ECs and plan for major changes during the product lifecycle to support continuous improvement, said Mahesh Ramanadham, acting director of the Division of Inspection Assessment in the Office of Process and Facilities (OPF), in the Center for Drug Evaluation and Research’s Office of Pharmaceutical Quality. This effort will build on ICH standards Q8, Q9, Q10, and Q11, which define how firms should establish product quality systems and demonstrate robust product and process understanding. Together, these approaches provide confidence that the firm can manage most manufacturing changes and justify modified postapproval reporting requirements.
To spur the Q12 process, FDA in 2015 issued a draft guidance on defining and reporting ECs (2). The guidance describes which elements of a control strategy could be considered ECs necessary to assure process performance and product quality, and which changes can be managed under a product quality strategy, explained OPF acting director Bob Iser at the CASSS forum. Manufacturers objected that the proposal could undermine harmonization efforts. But it did rev up Q12 discussion, and now FDA says it will wait until Q12 is adopted before proceeding with this advisory.
Another FDA guidance, published in April 2016, encourages manufacturers to utilize comparability protocols, also known as PACMPs in the European Union, to outline planned future changes and how they will verify the acceptability of such actions (3). The aim is to encourage greater use of these protocols to reduce change reporting as part of the Q12 guideline.
A particularly tricky issue is how to apply the Q12 framework to already marketed products that lack clearly defined ECs. The EWG is considering several approaches that it hopes to resolve by its autumn meeting, said Iser. And combination products raise even more complex issues for product lifecycle management, as changes to a drug or device component can involve multiple quality regulatory systems and rules.
The panel also is examining where information on ECs and change management should be submitted in market applications. Sponsors now report ECs in various sections of the Common Technical Document, Iser noted. One option under discussion is for manufacturers to provide a table of ECs and non-ECs in module 3 that gives a clear picture of how changes in ECs affect product quality. This approach could set a framework for regulatory authorities. FDA would gain from ready access to this information across the agency, Iser added, which would enhance its integrated review and inspection model.
Similar efforts by the World Health Organization (WHO) further support the adoption of common postapproval change approaches by diverse regulatory authorities. WHO recently issued guidelines on procedures and data requirements for changes to approved vaccines (4). The agency also is developing guidelines for dealing with variations in prequalified products, in multisource pharmaceuticals, and in biotherapeutics, all with an eye to encouraging changes in manufacturing processes after licensure to improve product quality.
1. ICH, Final Concept Paper Q12: Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management (ICH, July 28, 2014),
2. FDA, Established Conditions: Reportable CMC Changes for Approved Drug and Biologic Products Guidance for Industry, Draft Guidance (Silver Spring, MD, May 2015),
3. FDA, Comparability Protocols for Human Drugs and Biologics: Chemistry, Manufacturing, and Controls Information Guidance for Industry, Draft Guidance (Silver Spring, MD, April 2016),
4. WHO Expert Committee on Biological Standardization, Annex 4 Guidelines on procedures and data requirements for changes to approved vaccines (Geneva, Switzerland, 2015).