Manufacturing & Control Challenges for Accelerated Development
Enhanced and accelerated regulatory pathways for “Breakthrough Therapies (United States) and “PRIME” medicines (European Union) have been introduced to provide faster access to exciting new therapies developed to treat unmet medical needs.1,2 Jokura et al. give an interesting comparison of American, European, and Japanese expedited regulatory pathways.3
Given the importance of accelerated access for patients, regulators, and industry, ISPE has assembled the Expedited Programs for Patients team, a subteam of the PQLI® Committee. The new group has worked for more than a year to compare experiences and challenges faced by chemistry, manufacturing, and control (CMC) development teams as they work toward initial approval while continuing to supply product for clinical studies and patients.
A 2015 article by Dye et al.4 suggests that shortening the regulatory filing period for an expedited development program by 18 to 24 months could challenge delivery of CMC information. This paper was based on hypothetical examples of accelerated development for small and large molecules, since at that time there was little experience of approvals for programs that had been assigned as breakthrough therapy status at an early development stage—i.e., after receipt of preclinical or early clinical positive information. Dye et al. summarize emerging industry CMC challenges as time, resources (amount and expertise), and materials.
Since the paper’s publication, more CMC programs are part of the critical path to approval, and accelerated development pro- grams have helped companies and regulators make new medicines available to patients.
The ISPE team, which represents both small and large molecule development, presented its preliminary findings at the ISPE Quality Manufacturing Conference on 5 June 2018. Case studies for real drug approvals presented during the conference provide some emerging considerations:
- Early, effective, and detailed communication between sponsors and agencies throughout development facilitates more and better-informed CMC development decisions, and leads to greater regulatory flexibility built upon joint understanding of the risk-to-benefit profile.
- Accelerated development can significantly shorten the time to market, benefitting both patients and sponsors, but does not eliminate CMC activities, lessen quality expectations, or reduce any obligation to provide adequate supply. In one assessment, for example,5 premarket development time was considerably shorter among approved breakthrough-designated drugs (median 5.2 years) than nondesignated drugs (7.4 years), a difference of 2.2 years.
- A compressed timeline challenges the sponsor to develop process and product understanding commensurate with the risk profile agreed with regulatory authorities.
- There is no “one-size-fits-all” approach. Agreements are highly individualized and based on the sponsor plan to demonstrate an adequate level of process understanding to the regulator, leading to a drug product that consistently meets predetermined acceptance criteria.
- Early development of a full lifecycle strategy (including post-approval change), and documentation of the control strategy (e.g., quality target product profile, critical quality attributes, critical process parameters, and approach to control) allows for earlier understanding of functional requirements and systematic process change control, which is almost certain to be required.
- Where possible, there is significant benefit in leveraging prior knowledge and platform processes to support product- and process-specific understanding, process validation, and reduce redundant experimentation.
- Strategic utilization of supply chain options provides launch flexibility:
- Manufacturing site selection can be critical—e.g., using a clinical manufacturing facility in a pilot plant within a commercial facility and pivotal clinical study manufacture in a commercial facility.
- Using expansion strategies where it is most appropriate to minimize scale-up variability and maximize process portability.
- Minimizing process changes whenever possible allows more bridging of early clinical data.
The team intends to issue an article expanding on the points above in the next few months. Although each development is different, actual case studies appear to provide key considerations and guiding principles common to most programs, which should help sponsors.
- 1. US Food and Drug Administration. Guidance for Industry. “Expedited Programs for Serious Conditions— Drugs and Biologics.” May 2014. https://www.fda.gov/downloads/Drugs/Guidances/UCM358301.pdf
- 2. European Medicines Agency. Research and Development. “PRIME: Priority Medicines.” http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000660.jsp&mid=WC0b01ac05809f8439
- 3. Jokura Y., K. Yano, and M. Yamato. “Comparison of the New Japanese Legislation for Expedited Approval of Regenerative Medicine Products with the Existing Systems in the USA and European Union.” Journal of Tissue Engineering an Regenerative Medicine 12, no. 2 (February 2018).
- 4. Dye, Earl S., et al. “CMC Considerations When a Drug Development Project Is Assigned Breakthrough Therapy Status.” Pharmaceutical Engineering 35, no. 1 (January-February 2015): 22–36.
- 5. Shea, M., et al. “Regulatory Watch: Impact of Breakthrough Therapy Designation on Cancer Drug Development.” Nature Reviews Drug Discovery 15, no. 3 (March 2016).