Accelerated Pharma Product Development, Registration, Commercialization, & Life Cycle CMC Lessons Part 1

ISPE’s Accelerated Medicinal Product Working Group has examined case studies of accelerated development programs, many of which have had product approvals, to develop key considerations and themes to assist ISPE members and their companies progressing such programs. From this extensive work, the group has produced a two-part article series, which will be published in the July-August and September-October issues of Pharmaceutical Engineering: “Accelerated Pharmaceutical Product Development, Registration, Commercialization, and Life Cycle CMC Lessons,” Parts 1 and 2.

Part 1 introduces key considerations and themes in general terms and highlights future opportunities in accelerated pharmaceutical product development programs. Part 2 provides more detailed discussion of the considerations and themes and presents several case studies upon which the article series is built.

The group is also preparing for two important upcoming public discussions where participants will be able to listen to experienced industry speakers and hear regulators, as well as interact with speakers and other experts both during and outside the sessions. At the 2019 ISPE Annual Meeting & Expo in Las Vegas, NV on 28 October, two industry case studies for advanced therapies such as cell therapies and nucleotides will be presented and FDA is invited to present the regulatory position relating to advanced therapies. The group hopes to have a session at the 2019 ISPE Regulatory Conference on 6–7 December in North Bethesda, MD where regulators from several agencies in addition to the FDA will be invited to provide regulatory agency perspective on the CMC challenges associated with accelerated product development.

Since the introduction of Breakthrough Therapy designation in the US1 and PRIME2 in the EU sponsors have taken advantage of these regulatory pathways and are applying for more drug development programs to be included so that more drug products can become available to met unmet clinical need in patients more quickly than has been the case historically. Regulators are taking a positive approach and supporting accelerated development regulatory pathways. For example, the FDA’s Center for Drug Evaluation and Research (CDER) granted 250 Breakthrough Therapy designation requests as of 31 December 2018 for original new drug applications (NDAs)3 and EMA accepted 54 medicines into the PRIME scheme as of 29 May 20194 . Other regions have also introduced regulatory pathways to expedite drug development programs for drug products meeting criteria for unmet clinical need.

Cross-regulatory authority interaction is occurring. For example, in November 2018, FDA representatives participated in a one-day workshop hosted by EMA, at which industry experts presented case studies of CMC challenges and approaches to accelerated development.

Nonetheless there is not consistency of clinical criteria for acceptance into these new regulatory pathways and case studies show that, because of the fluidity and evolving nature of the regulations, sponsors must negotiate with each regulatory authority separately on a case-by-case basis.

However, the regulatory expectations and regulations associated with the CMC portion of a submission for small chemical molecules and biotechnological and biological molecules as defined by the scope of ICH guidelines Q6A and Q6B5 ^, 6 have not changed.

From the case studies the group has observed:

• Companies continue to pursue accelerated programs on a case-by-case basis, resulting in inefficiencies and perpetuating divergence in regulatory views. This situation is understandable in part given that there is no “one size fits all” development program, and certainly not for accelerated programs.
• There are now more instances where the CMC program is on the critical path to approval and supply to patients. In one case study, the accelerated development program was 6 years shorter than “typical” historical timelines.
• CMC challenges of insufficient time, resources and materials can lead to stress points such as:
  • The potential for suboptimal drug substance route/process and drug product formulation.
  • Site readiness for commercial supply for a suboptimal process—for example, use of a clinical process and site to support initial submission, approval, and launch, followed by post-approval changes using an improved process, which is potentially developed in parallel with initial submission.
  • The amount of stability data to support a practical shelf life at the time of approval.
  • The process validation strategy, particularly for large molecules where there may not be time to complete at least three batches manufactured at commercial scale with data submitted in the BLA application.
  • Setting specification acceptance criteria, particularly for a large molecule, where there may have been relatively few batches of product administered to patients.
  • Studies and/or planned changes proposed to be conducted and submitted post-approval. This approach leads to great supply chain and regulatory complexity. For example, companies may need to use the clinical process to produce supplies for clinical studies, and potentially for the product launch, while simultaneously introducing a more efficient manufacturing process to supply patients more reliably. Supply chain issues, regulatory submissions, and, most importantly, approvals all must be juggled, which creates a significant resource and logistics burden, especially because the timing of approvals varies by region or country.

Part 1 of the article series identifies the key considerations and themes from which the headline considerations are:

• Team working and project planning
• Control strategy
• Process Validation
• Pharmaceutical quality system readiness
• Regulatory

Many themes are common to large and small molecules; however, some are specific to a type of molecule.

Furthermore, Part 1 of the article series also suggests some future opportunities for:

• Improving Cooperative Engagement Between Sponsors and Regulators Globally
• Changes to approaches of Process Validation based on science and risk rather than drug modality
• Global review of CMC expectations based on accelerated program approvals
• Development of harmonized guidelines for advanced therapies

In Part 2 more detailed discussion of the considerations and themes is given as well as several case studies, the learnings from which are the basis of Part 1 and 2 article series.

In summary, parts 1 and 2 of the article series should be read together. High-level key considerations and themes and future opportunities are given in Part 1. Part 2 provides the case studies and provides detail of the key considerations and themes.

• 1US Food and Drug Administration. “Guidance for Industry: Expedited Programs for Serious Conditions—Drugs and Biologics.” Published May 2014. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/expedited-programs-serious-conditions-drugs-and-biologics
• 2European Medicines Agency Committee for Medicinal Products for Human Use. “Enhanced Early Dialogue to Facilitate Accelerated Assessment of PRIority MEdicines (PRIME).” EMA/CHMP/57760/2015, Rev. 1. Published May 2018. https://www.ema.europa.eu/documents/regulatory-procedural-guideline/enhanced-early-dialogue-facilitate-accelerated-assessment-priority-medicines-prime_en.pdf
• 3US Food and Drug Administration. “CDER Breakthrough Therapy Designation Requests by Fiscal Year. https://www.fda.gov/media/95292/download
• 4European Medicines Agency. “Data for Entry into PRIME Scheme.” https://www.ema.europa.eu/en/human-regulatory/research-development/prime-priority-medicines
• 5International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). “Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances, Q6A.” Published 6 October 1999. https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q6A/Step4/Q6Astep4.pdf
• 6International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). “Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products, Q6B.” Published 10 March 1999. https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q6B/Step4/Q6B_Guideline.pdf