Regulators and industry seek to streamline and harmonize oversight of manufacturing changes for firms that adopt modern production methods.
The submission and review of manufacturing supplements is costly and time consuming for biopharmaceutical companies and for regulatory authorities in all regions, and a concerted effort is underway to devise more efficient approaches. There’s renewed support for developing an international quality standard for regulating postapproval changes. And new policies and procedures at FDA aim to streamline oversight of manufacturing changes for firms that adopt modern production methods able to ensure the continued safety and efficacy of products after alterations in systems, formulations, or test methods. These developments reflect the struggle for regulators trying to review thousands of supplements, and for manufacturers implementing changes in products and manufacturing facilities around the world. Pfizer is involved with some 24,000 postapproval changes a year for its 30,000 products, noted vice-president Roger Nosal at the April 2015 CMC Workshop sponsored by the Drug Information Association (DIA). FDA officials have long proposed that manufacturers implementing quality-by-design (QbD) approaches and quality controls should be able to manage postapproval changes with less regulatory oversight. This goal has not been realized, though, as seen in a continued rise in manufacturing supplements that require agency approval, and in multiple drug shortages linked to low quality manufacturing operations. The review of manufacturing supplements by the Center for Drug Evaluation and Research (CDER) has increased over the past decade, partly due to the practice of “locking in” an applicant’s manufacturing process before it is fully optimized. Field inspection is not connected to knowledge gained from product review, and there can be a significant disconnect between clinical batch data and commercial production. CDER’s new Office of Pharmaceutical Quality (OPQ) seeks to tackle these problems through more seamless integration of review, inspection, and surveillance throughout the product lifecycle, commented OPQ deputy director Lawrence Yu at the DIA workshop. The goal for OPQ is to ensure that all new and generic drugs meet the quality standards and clinically relevant specifications through pre- and post-approval. Robert Iser, senior scientific advisor in OPQ’s Office of Process and Facilities (OPF), acknowledged that confusion over the level of detail needed to support postapproval changes leads to unnecessary submission of supplements and discourages continual improvement in drug manufacturing processes. OPF acting director Christine Moore noted that differing change filing requirements among multiple health authorities are costly and discourage adoption of “continual improvement” models. She emphasized the importance of appropriately evaluating the potential risks of changes and of rewarding responsible quality management by allowing manufacturers to make changes under quality systems with little or no prior approval. More guidance
Manufacturers have been looking for FDA to streamline the post-approval change process by “down-regulating” reporting requirements for low-risk changes. Industry seeks a “do-and-tell” approach that permits companies to make changes and then list them in annual reports or in changes-being-effected (CBE) supplements. FDA issued a guidance in March 2014 that sought to expand the range of manufacturing changes that can be documented in annual reports, but the list was fairly limited, and industry has found it inconsistent and confusing (1).
In most situations it’s easier to design a new drug than to update existing analytical methods and technology, noted Ganapathy Mohan, head of global CMC at Merck, Sharp and Dohme. Global approval of a manufacturing change can take more than five years, he said, and changing a polymer supplier or reformulating an oral solution can be complex, particularly for products manufactured at multiple sites that have to meet differing regulatory requirements. FDA officials plan to try again to offer regulatory relief in filing supplements and also in undergoing plant inspections for those biopharma companies that implement QbD and advanced manufacturing technologies. New draft guidance is expected this year that will clarify which elements of an application are considered “established conditions” (or regulatory commitments) and should help manufacturers manage postapproval changes in a general way. FDA also hopes to revise guidance on providing CMC information in comparability protocols for approved drugs to encourage adoption of innovative test methods and new approaches to change management. Harmonizing changes
Regulatory authorities and manufacturers also are collaborating through the International Conference on Harmonization (ICH) to produce a new Q12 quality standard for managing postapproval manufacturing changes over the lifecycle of drugs and biologics. An ICH expert working group discussed a Q12 concept paper in Lisbon, Portugal in November 2014, and a more detailed proposal is scheduled for further discussion at the June ICH steering committee meeting in Japan. The aim is to publish a document by June 2016 that builds on other ICH quality guidelines to strengthen quality assurance through harmonized management of post-approval CMC changes.
Agreement and publication of Q12 is a high priority for both industry and regulators, said Moheb Nasr, vice-president for CMC regulatory strategy at GlaxoSmithKline, a former FDA official and rapporteur for the Q12 working group. Nasr observed at the DIA workshop that lack of agreement on change management regulation has inhibited continual improvement and manufacturing innovation and has increased regulatory workloads for both industry and authorities. While previous ICH quality standards have focused on using science- and risk-based approaches in new drug development, the Q12 document aims to address more directly the commercial manufacturing phase of lifecycle product management. A more flexible change management approach has been encouraged in the European Union as part of an effort to reduce “variations” that require prior approval, pointed out Jean-Louis Robert, head of the pharmaceutical chemistry unit at the National Health Laboratory in Luxembourg. Many minor changes can be implemented under a do-and-tell approach, while manufacturers contemplating more complex changes over the product lifecycle are encouraged to prepare a post-approval change management protocol (PACMP) to accelerate and gain more predictability in regulatory response. PACMPs may be appropriate for certain changes to biological products, such as adding a new cell-culture facility, and should be most useful for drugs developed using QbD principles, Robert commented. Lifecycle review at FDA In the US, the new OPQ structure aims to better combine oversight of drug development with postapproval changes to achieve a more seamless adherence to quality standards throughout the life of a drug or biotech therapy. OPQ’s Office of Lifecycle Drug Products (OLDP) now is responsible for assessing post-approval changes for new drugs and generic drugs, as well as CMC submissions for generic drugs. The plan is for reviewers in OPQ’s Office of New Drug Products (ONDP) to hand off to OLDP oversight of new molecular entities (NMEs) after three years, and for standard new drugs after one year. This plan will allow the original reviewers to evaluate initial scale-up and formulation changes for more innovative products. Post-approval changes for biotech therapies will continue to be managed by OPQ’s Office of Biotechnology Products. A smooth hand-off from new drugs to lifecycle is important, commented ONDP acting director Sarah Pope-Miksinski, as is close collaboration with Moore’s OPF to ensure parity in oversight of changes involving drug process, facility, and sterility. OPF evaluates drug manufacturing process design and controls for commercial production and participates in pre-approval inspections to ensure appropriate implementation of control strategies (2). References
1. FDA, Guidance for Industry, CMC Postapproval Manufacturing Changes To Be Documented in Annual Reports (CDER, March 2014), www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM217043.pdf.
2. More information on OPQ operations provided in CDER “Pharmaceutical Quality Oversight” report, April 2015, www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM442666.pdf.