CURRENT REGULATIONS AND COMPARABILITY PROTOCOLS

An overview of current FDA regulations and guidance is helpful to discover hidden opportunities and how they can be leveraged for the QbD paradigm for therapeutic protein products moving forward. The requirements regarding changes to an approved biologics license application are described in 21 CFR 601.12. With respect to product and process changes, the regulation states that each change in product, production process, quality controls, equipment, or facilities must be reported to the agency (16). This section also describes the need for conducting appropriate validation, including clinical and nonclinical studies to demonstrate that the change has no adverse effect on the identity, strength, quality, purity, or potency of the product. Reporting of the change must be in accordance with regulation or guidance that provides for less burdensome notification of the change. The changes requiring submission of supplements and approval prior to distribution of product made using the change (major changes), changes requiring supplement submission at least 30 days before distribution of product made using the change, and changes to be described in an annual report (minor changes) are provided in 21 CFR 601.12(b). The 1997 Guidance for Industry: Changes to an Approved Application for Specified Biotechnology and Specified Synthetic Biological Products provides additional guidance on the reporting categories (17). The comparability protocol described in 21 CFR 601.12(e) is used to demonstrate the lack of adverse effect on the safety and effectiveness of a product for specific types of manufacturing changes. A comparability protocol approach can be used to effect changes under a QbD paradigm with more regulatory flexibility. This approach has been used successfully for drug substance manufacturing site transfers when certain requirements were met.

Comparability protocols can be leveraged to effect many different manufacturing changes that include many products and manufacturing sites. They are not recommended for one-time changes as the protocol must be submitted as a preapproval supplement (PAS) and be followed by additional filings. Regulatory flexibility is achieved by submitting the same change approved in a comparability protocol for other products or facilities as changes being effected supplements (CBEs) or even as annual reports. Therefore, such protocols are a good regulatory strategy tool when a particular change affects multiple products. For example, if the container–closure system is modified for many products that use the same system, or if a stopper changes, then the comparability protocol offers a way to submit one PAS containing the studies to be performed, the acceptance criteria, and the quality risk-management concepts to be followed, especially regarding container-closure integrity aspects. Once the protocol is approved, the first product with the change can be introduced to the market through a PAS or CBE. Subsequent products can be introduced immediately and reported in annual reports. It is important to note that the submission strategy should be agreed upon between the firm and the FDA. Therefore, meetings are recommended when such strategies are followed. The comparability protocol offers advantages as the submission strategy for new in-process testing methods as well. For example, if a traditional method is replaced with a new more advanced and rapid microbiological method (i.e., polymerase chain reaction mycoplasma testing for cell culture instead of traditional microbiology methods) at many facilities and for many different products, a comparability protocol can serve as the platform to effect these changes without submitting a PAS for each product and facility.

Traditionally, a comparability protocol is submitted to the agency to support the proposed changes. In July 2008, a notice was issued in the Federal Register seeking participation of pharmaceutical companies in a pilot program for the submission of quality (CMC) information in an eCP consistent with the principles of QbD and risk management in pharmaceutical manufacturing. This protocol can cover changes to manufacturing scale, changes across unit operations, changes to equipment, and/or manufacturing site transfers previously submitted as comparability protocols. The ICH Q5E guidance, Comparability of Biotechnological/Biological Products Subject to Changes in Their Manufacturing Process, applies to eCPs as well as traditional comparability protocols to demonstrate product comparability (18). Expanded change protocols describe the holistic QbD and risk-based approaches to demonstrate the lack of adverse effect on safety and efficacy of a product and focus on critical quality attributes. Such submissions allow for decreased filing requirements for postapproval changes.