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FDA recently published a final guidance for making post-approval manufacturing changes to drugs and biologics, the culmination of a long-running effort to facilitate improvements in medical product quality through the product life cycle. The Q12 standard, crafted by members of the International Council for Harmonization (ICH), aims to help manufacturers manage changes in chemistry, manufacturing and controls (CMC) of marketed drugs and biologics, including generics and biosimilars and certain combination products, to encourage continual improvement in biopharmaceutical production.
The main premise of the Q12 standard is that increased product and process knowledge can enhance understanding of which post-approval changes have potential to affect product quality and carry risks for patients. Such changes would require regulatory approval prior to implementation. But manufacturers can reduce such oversight by managing CMC changes through a Pharmaceutical Quality System (PQS) that can identify and manage those Established Conditions (ECs) of a product that are essential to assuring quality and safe use.
Through such efforts, FDA officials and other regulatory authorities hope to provide “a more predictable and efficient approach to management of postapproval changes,” commented Michael Kopcha, director of the Office of Pharmaceutical Quality in the Center for Drug Evaluation and Research (CDER) in announcing the final standard.1 Without regulatory harmonization on an international basis, manufacturers often find it too difficult and costly to make changes to approved products, even if the new method offers important product improvements and production efficiencies.
This international effort to gain agreement on policies for overseeing post-approval manufacturing changes builds on a long series of ICH quality manufacturing standards. Ashley Boam, director of CDER’s Office of Policy for Pharmaceutical Quality, summarized the history and main goals of Q12 at the FDA and Health Canada Regional ICH Consultation held on May 14, 2021 to update and discuss with stakeholders this and other leading ICH initiatives.2
The Q12 guideline maps out a process for manufacturers to identify those higher risk postapproval changes, as opposed to those that offer little risk of reducing product quality or safety.3 The guidance emphasizes the importance of manufacturers identifying key ECs to determine how they should be monitored and assessed. Changes that affect those ECs that are essential for safe product use, for delivery of the labeled dose, or that impact the drug’s critical quality attributes (CQAs) should be reported to regulatory authorities in preapproval or changes-being-effected filings. Conversely, those changes that do not alter product safety do not have to be approved prior to implementation and often require only notification of an authority in a later filing.
Manufacturers may be able to shift more changes to the notification category by devising a control strategy upfront for accomplishing later innovations. Q12 discusses the value of preparing post-approval change management protocols (PACMPs) and a product life cycle management document early on to facilitate future improvements.
To further assist manufacturers in utilizing and benefiting from the Q12 process, FDA issued a companion guidance with Annexes that present illustrative examples of how drug and biotech manufacturers can identify ECs for manufacturing processes and for analytical procedures.4
The value and impact of ICH Q12 will depend on its adoption and use by regulatory authorities around the world. Wide acceptance of a modernized change management process is key for manufacturers to be able to implement improvements to authorized products more quickly and efficiently, in order to encourage investment in modern manufacturing systems in multiple markets.
To this end, FDA and other regulatory authorities are devising and offering training for pharmaceutical reviewers and inspectors that helps them understand and utilize the Q12 process. An ICH Implementation Working Group is developing global training materials for regulatory authorities and working with PIC/S on training for inspectorates, Boam noted. Topics of the training modules include established conditions for various products, drug-device combination products, and change management protocols.
And manufacturers have gained additional advice on utilizing Q12 through another FDA guidance that maps out the new process. The draft advisory spells out the process for determining whether a planned change requires regulatory approval, with the aim of assisting manufacturers in anticipating data requirements and filing procedures in regions where the product has been approved for market.5
The larger goal of this harmonized post-approval changes policy is to encourage manufacturers to adopt innovations in product quality and production. More effective management of changes ideally will help avoid supply disruptions and shortages arising from drug quality issues, increase efficient use of resources, and facilitate innovation in pharmaceutical manufacturing.