The FDA recently developed a new Manual of Policies and Procedures (MAPP) to address the challenges of Chemistry, Manufacturing and Control (CMC) readiness for products with accelerated clinical development programs. This MAPP became effective on December 7, 2022 and will affect regulatory strategy and regulatory operations teams.

Products with accelerated clinical development programs often face challenges in aligning CMC readiness with compressed clinical timelines and ultimately become rate-limiting in approval of the products intended to address serious conditions.

The new MAPP includes policies and procedures used in the Office of Pharmaceutical Quality (OPQ) that facilitates and expedites the development, time to submission, assessment, and marketing approval of New Drug Applications (NDAs) and Biologics License Applications (BLAs) for products that address unmet medical needs in the treatment of serious or life-threatening conditions.

This MAPP harmonizes CMC readiness commitments described in the Prescription Drug User Fee Act (PDUFA) VII commitment letter, including supporting the CMC Development and Readiness Pilot (CDRP) program.

MAPP 5015.13 is specific to products for NDAs under Section 505 of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C 355) or BLAs under Section 351(a) of the Public Health Service Act (PHS Act) and does not include other mechanisms, such as Emergency Use Authorizations (EUAs).

What’s New in MAPP 5015.13?

MAPP 5015.13 allows the OPQ to use regulatory flexibilities to help overcome CMC readiness challenges. For example, at the time of submission and approval for certain components in an application, Sponsors may receive some flexibility on the type and extent of manufacturing information, such as stability updates, validation strategies, inspection planning, and manufacturing scale-up.

Additional interactions with the FDA, including the use of science-based and risk-based regulatory approaches, are necessary to allow for the use of regulatory flexibilities.

In addition, the OPQ will deem regulatory flexibility options to marketing applications for products based on adequate clinical, nonclinical, and manufacturing information provided to comply with the safety, effectiveness, and quality, including Current Good Manufacturing Practice (CGMP) standards.

The OPQ will also conduct risk assessments with the principles outlined in the guidance for industry on Expedited Programs for Serious Conditions.

The regulatory flexibility options will be determined on a case-by-case basis based on the modern pharmaceutical principles, such as International Council for Harmonization (ICH) guidances for industry, the extent of product and process understanding, the strength of the quality risk management approach, the effectiveness of the pharmaceutical quality system, and the adequacy of the Sponsor’s proposal for an integrated post-marketing plan.

This approach applies to Breakthrough Therapy (BT), Fast Track (FT) designation products, and products included in the CDRP program.

The policies described in this MAPP may also apply to products that are “mission critical,” as defined in this guidance for industry dated May 2021.

Updated Procedures in MAPP 5015.13: What You Need to Know

The MAPP 5015.13 outlines procedures in the following four main areas:

• Expedited program designation
• Meetings and communications
• Expedited manufacturing facility readiness
• Regulatory flexibility options

The MAPP specifies that the Office of New Drugs (OND) is responsible for identifying the products for a BT or FT expedited program designation based on evidence provided the product meets the qualifying criteria.

As for meetings and communications, the OPQ assessment team cooperates with Sponsors for a CMC-focused meeting (Type B or Type C) as quickly as possible for products with expedited designations of BT, FT, or those enrolled in the PDUFA VII CDRP.

At the initial CMC‑focused meeting, OPQ will focus on the following:

• Determining the Sponsor’s progress in product development
• Understanding the Sponsor’s strategy to make sure proposed facilities are ready under CGMP
• Working to identify potential regulatory opportunities to expedite CMC development
• Establishing a communication plan for future interactions with the Sponsor on regulatory approaches

Further, OPQ emphasizes the importance of having key information as early as possible (e.g., at the earliest CMC‑focused meeting) to successfully expedite manufacturing facility readiness.

OPQ will notify the Sponsor if:

• The commercial facility information can be submitted as an amendment to the Investigational New Drug (IND)
• Early submission of FDA Form 356h with any complete module is an option for rolling NDA/BLA submissions
• They need to submit a complete manufacturing schedule covering the BLA review period for each intermediate, drug substance, and drug product with their BLA

Further, the OPA’s Office of Pharmaceutical Manufacturing Assessment (OPMA) will evaluate the facilities based on the facility information and other available information (i.e., past inspections by FDA, adverse event reports, facility compliance history, etc.) and get input from the Office of Regulatory Affairs (ORA).

Lastly, OPQ will make a determination regarding the facility, such as:

• Recommending accepting the facility
• Mitigating identified facility risks for the information requested under section 704(a)(4) of the FD&C Act or remote regulatory assessments
• Conducting preapproval inspections (PAI) or pre-license inspections (PLI)

Most importantly, MAPP 5015.13 provides additional details around regulatory flexibility options, including the following areas:

• Control strategies
• Process validation
• Concurrent validation (CV)/concurrent release (CR)
• Decoupling drug substance and drug product process validation
• Other process validation streamlining approaches
• Analytical procedures validation
• Marketing of batches manufactured with the clinical manufacturing process
• Stability studies
• Use of predictive stability models

The Future of CMC Readiness

The new MAPP 5015.13 provides Sponsors with additional tools to achieve CMC readiness for drugs under expedited programs.

Most importantly, it provides regulatory flexibility to bring products that address unmet medical needs to patients faster.

If you have any questions or would like to learn more about MAPP 5015.13, email info@mmsholdings.com to speak to our CMC regulatory experts.

Learn more about MMS regulatory experts here.

By: Nancy Hsu, Regulatory Affairs Associate, and Margaret Studzinska, Associate Director of CMC and Nonclinical Writing