Medical Council

Product Development as it relates to CMC

When navigating preliminary product development strategies, searching for early guidance from regulators can be invaluable. Nevertheless, the task of seeking approval from the FDA can be extremely tough. It has become crucial to get your relationship with the FDA off to a solid start from day one.


The FDA admits that through Pre-IND meetings, CMC-specific discussions are usually unnecessary when jobs are”straightforward.” Yet, certain new chemical entities (NCE’s) and biologics are anything but straightforward, unlike more conventional 505(b)(2) products.


These novelties have the ability to make unique manufacturing roadblocks that impede the path to clinical development. To make matters even harder, sponsors must grapple with the unending race between the cost of development and advancing technology, as it is almost impossible for any sponsor to outspend the clinical program.


Therefore, agency meetings are an opportune time for patrons to align with the FDA or the EMA on CMC plans that will enable product development while maintaining regulatory compliance.


It’s critical to comprehend the drug development process and the myriad tasks and milestones that are very important to a comprehensive development plan to be able to ensure commercial and scientific success.


The examples below highlight CMC-specific topics that sponsors should discuss during discussions around your product.


The choice of appropriate Regulatory Starting Materials (RSMs) is a central challenge for any developmental item. Some products are extremely sensitive to slight modifications in starting material quality which means that settling non-GMP materials early in the process may bring about significant challenges during later phase development.


Furthermore, some production processes are sometimes reliant on an animal- or human-derived raw materials, or master and working cell banks. Ideally, process(es) should be optimized to exclude those substances or avoid enormous alterations in later phases, but if not, sponsors should be certain that starting materials are appropriately compliant, high-grade, and provided with the necessary supportive regulatory documentation.


Consider discussing your approach to Regulatory Starting Material choice with the FDA or EMA. Early involvement on this topic may decrease the requirement for significant process changes late in the game. This question-and-answer (Q&A) document is meant to provide additional clarification and to encourage convergence and enhance harmonization of the factors for the justification and selection of starting materials and of the data which needs to be given in marketing authorization applications and/or Master Files.

Since the development develops so does the diversity of options and timing. At precisely the exact same time sponsors are facing previously unseen, unique manufacturing challenges. As an example, terminal sterile filtration is a very important part of the purification process for therapeutic proteins.


A vital part of most drug substance supply chains considering prices and availability is the sourcing of API. Scale-up and procedure change issues are frequently encountered during the development of sterilization procedures for aseptically filled and many parenteral products.


When facing these types of challenges, alternative approaches using science- and risk-based justifications should be considered for the proposed control strategy in the absence of standard practices.


Early alignment between agency and sponsors can light the way for manufacturing plans that are both suitable to guarantee phase-appropriate compliance and technically viable.


This guidance provides recommendations to sponsors of investigational new drug applications (INDs) on the chemistry, manufacturing, and controls (CMC) information that would be submitted for phase 2 and phase 3 studies conducted under INDs.

So as to appropriately identify and determine the critical quality characteristics and critical process parameters, a basic understanding of the product’s production process is vital.


While for some products that are easier said than done, it is essential to collect the FDA’s input on analytical methodology early in development. It is worth considering whether the proposed methodologies are enough for the stage of growth that you’re in.


Can alternate assays or orthogonal techniques be used to supply further insight if you are not totally sure of the procedure? Can the FDA recommend any additional attributes that should be assessed and controlled early on?


With the continuing rise of new drug applications, the FDA is gaining significant product-specific experience. Based on their internal learnings from historical reviews they could help to steer you in the right direction to encourage specification development.


Current CMC guidance might not fit due to the nature of the product in multiple areas of product development. There may not be enough final product to permit whole stability testing or retain sampling, too short of shelf life to empower traditional sterility testing or analytical methodology that simply does not work with the product as development progresses.


The prospect of a formal meeting with the FDA can be more daunting than a blind date for first-time patrons, but it’s more than possible to nail the first impression with ample preparation and the best tools.


All patrons should exercise the opportunities to engage in early discussions with the agency regardless of the natural apprehension since it’s a crucial first step in determining a strong working relationship and familiarizing the inspection division with the program. Recent FDA announcements highlight the Agency’s perspective on the crucial character of these early discussions.


It can be tricky to follow some of the most basic requirements laid out by developmental guidance documents. These areas should be discussed with FDA/EMA and a few alternative controls or solutions to those issues should be supplied. If these strategies will be suitable throughout the development of your program ask the services early on.


It is crucial to show the agency that you are acknowledging gaps that might exist and that you’re trying to address them early. They understand the challenges that products experience and may supply some crucial guidance on your own methods and recommendations on the corresponding control strategy.


Although the Pre-IND and later in development, the conclusion of Stage 2 (EoP2) meeting (Type B Meetings) has long been the gold standard for hunting preliminary feedback at every milestone, sometimes just one interaction is just not enough for complicated programs.


So, Type C Meetings can manage sponsors increased opportunity to connect with FDA staff, farther upstream in the development process before an EoP2 interface to supply additional touchpoints during early development.


Additional to vetting development factors and streamlining development plans, the doubling of face time with the FDA also enables expanded discussion pertaining to CMC-specific strategies.


The unique CMC challenges faced by patrons aren’t insurmountable, but they can reevaluate the path to clinical study significantly. For both well-characterized proteins and traditional small-molecule pharmaceuticals, the manufacturing processes must consider commercial scalability and viability at a really early stage.


These challenges underline how crucial CMC-focused communications with the FDA are, early and often. Sponsors can work collaboratively with the agency to de-risk complex CMC-specific roadblocks on the road toward bringing these innovative medicines from concept to approval by maximizing milestone engagements.