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Manufacturing Support for “Breakthrough Therapy” Designation for Solid Oral Dosage Forms

In November, this author participated in an open forum at the AAPS Annual Meeting focused on streamlining manufacturing and scale up to support ‘breakthrough therapy’ designation for solid oral dosage forms. The goal was to provide clarity for breakthrough therapies and chemistry, manufacturing and controls (CMC) challenges to develop a quality submission in a shortened timeframe where often — as in the case of oncology drugs, where phases II and III are combined — a 505(b)(2) filing will also have an accelerated CMC timeline.

In the case of standard 505(b)(2) filings, the qualifications and components for submission do not change. However, with a breakthrough designation, the FDA will work intensely to help fulfill tasks in parallel. Therefore, interaction with the agency can never happen too soon. When a 505(b)(2) filing gets a breakthrough designation, it’s all hands on deck, and any misstep could cause unnecessary delays.

In the session, Takeda reviewed a few key areas of concern with oncology drugs including contract manufacturing organization (CMO) selection, batch size and dose escalation. Dr. Sarah Pope-Miksinski, Acting Division Director for the Division of New Drug Quality Assessment 2 in the FDA’s Office of New Drug Quality Assessment (ONDQA), relayed agency expectations of a quality submission through joint cooperation and touched on risk-based review with the sponsor. She expressed that the FDA is open to additional meetings, a site visit when a new technology is involved and rolling submission when done with transparency. When bringing a drug to market that is meeting an unmet patient need, the standard 12 months of stability is not mandatory, and the FDA expects to work with the sponsor that has a body of data for a manageable expiry at launch.

Pfizer shared information on the recent completion of its continuous manufacturing approach to shorten the CMC timeline by eliminating the need for further scale up, continuing to amass process knowledge without losing time in site and group transfers. A pod of equipment was also reviewed — it’s a prototype for tableting with in-line mixing for dry or wet granulation. The goal is to establish a more flexible and portable way to address immediate manufacturing needs of breakthrough therapies and emerging markets.

Vertex’s continuous process system for a product in the late stage of development was also highlighted. This tableting process has feedforward and feedback controls, with five locations of near-infrared monitoring, inline mixing and loss on weight feeders. The throughput is sufficient for product launch and will move tablets to packaging with real-time testing.

In an active question and answer period, topics ranged from developing an understanding of an API’s physicochemical characteristics, to the restrictions of high and low dose drugs and drug loading, to the impact of choosing dosage format relative to best supportive care (BSC) classification and target product profiles. Specific insight was also shared into how CMC readiness and the shortened timing to commercial readiness align with the 505(b)(2) development strategy. Completing scale up and validation before approval is a requirement for a breakthrough designation. It is generally part of an aggressive 505(b)(2) program for a new drug, and often, new company. All to say, our team enjoyed the event and insightful discussions.