Start Early
Seeking early guidance from regulators can be invaluable when navigating preliminary product development strategies. Still, the task of seeking approval from the FDA can be extremely challenging. It’s become vital to get your relationship with the FDA off to a solid start from day one.
The FDA recognizes that CMC-specific discussions, during Pre-IND meetings, are typically unnecessary when projects are “straightforward.” However, unlike more traditional 505(b)(2) products, certain new chemical entities (NCE’s) and biologics are anything but straightforward. These novelties can create unique manufacturing roadblocks that impede the path to clinical development.
To make matters even more challenging, sponsors must grapple with the unending race between advancing technologies and the cost of development, as it’s nearly impossible for any sponsor to outspend the clinical program. Consequently, agency meetings are an opportune time for sponsors to align with FDA and/or the EMA on CMC strategies that will allow for product development while maintaining regulatory compliance.
To ensure scientific and commercial success, it is critical to understand the drug development process and the myriad tasks and milestones that are vital to a comprehensive development plan. Consider some
The following examples highlight CMC-specific topics that sponsors should address during discussions around your product.
The Selection and Justification of Starting Materials
A key challenge for any developmental product is The selection of appropriate Regulatory Starting Materials (RSMs). Certain products are extremely sensitive to slight changes in starting material quality which means that Settling on non-GMP materials early in the process may pose significant challenges during later phase development.
In addition, some manufacturing processes are sometimes reliant on animal- or human-derived raw materials, or master and working cell banks. Ideally, process(es) should be optimized to exclude these materials or avoid major changes in later phases, but barring that, sponsors should ensure that starting materials are high-grade, suitably compliant and provided with the necessary supportive regulatory documentation.
Consider discussing your approach to Regulatory Starting Material selection with the FDA or EMA. Early engagement on this topic may reduce the need for significant process changes late in the game. This question-and-answer (Q&A) document is intended to provide additional clarification and to promote convergence and improve harmonization of the considerations for the selection and justification of starting materials and of the information that should be provided in marketing authorization applications and/or Master Files.
Phase Appropriate Approaches to Manufacturing
As development expands so does the diversity of choices and timing. Correspondingly, sponsors are facing unique and previously unseen manufacturing challenges. For example, terminal sterile filtration is an essential component of the purification process for therapeutic proteins. Sourcing of API is an essential component of most drug substance supply chains considering costs and availability. Scale-up and process changes etc. Issues are commonly encountered during development of sterilization processes for aseptically filled and many parenteral products.
When facing of these types of challenges, consider alternative approaches using science- and risk-based justifications for the proposed control strategy in the absence of traditional practices. Early alignment between sponsors and the Agency can pave the way for manufacturing plans that are both technically viable and suitable to ensure phase-appropriate compliance.
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.
Establishing Acceptance Criteria
A fundamental understanding of the product’s manufacturing process is critical to appropriately identify and establish the critical quality attributes and critical process parameters. While that’s easier said than done for some products, it’s important to gain FDA’s input on analytical methodology early in development. Ask yourself: are the proposed methodologies enough for the stage of development that you are in?
Can alternate assays or orthogonal methods be utilized to provide additional insight if you aren’t entirely sure of the process? Could the FDA recommend any additional attributes that should be evaluated and controlled early on? The FDA is gaining significant product-specific experience with the continued rise of new drug applications. They may be able to help steer you in the right direction to support specification development, based on their internal learnings from historical reviews.
The Guidance describes or provides recommendations concerning the selection of test procedures and the setting and justification of acceptance criteria for new chemical drug substances and new drug products produced from them.
Where the Current Guidance Doesn't Fit
In several areas of product development, the Current CMC guidance might not fit due to the nature of the product. There may not be enough final product to allow for retain sampling or full stability testing, too short of a shelf life to allow for traditional sterility testing, or analytical methodology that simply doesn’t work with the product as development progresses.
For first-time sponsors, the prospect of a formal meeting with FDA can be more daunting than a blind date, but with ample preparation and the proper tools, it's more than possible to nail the first impression. Despite the natural apprehension, all sponsors should exercise the opportunities to engage in early discussions with the Agency, as an important first step in establishing a strong working relationship and familiarizing the review division with the program. Recent FDA announcements highlight the Agency’s perspective on the critical nature of these early.
It can be a real challenge to follow some of the most basic requirements laid out by developmental guidance documents. Discuss these areas with FDA/EMA and provide some alternative solutions or controls to these issues. Ask the agencies early on if these approaches will be suitable throughout the development of your program. It’s important to show the agency that you are acknowledging gaps that might exist and that you are trying to address them early. They understand the challenges that products experience and may provide some important guidance on your approach(es) and recommendations on the corresponding control strategy.
Although, the Pre-IND and later in development, the End of Phase 2 (EoP2) meeting (Type B Meetings) have long been the gold standard for seeking preliminary feedback at each milestone, sometimes a single interaction simply isn’t enough for complicated programs. Therefore, to provide additional touch points during early development, Type C Meetings can afford sponsors increased opportunity to connect with FDA staff, further upstream in the development process prior to an EoP2 interface. In addition to streamlining development plans and vetting development considerations, the doubling of face time with FDA also allows for expanded discussion pertaining to CMC-specific strategies.
The unique CMC challenges faced by sponsors are not insurmountable, but they can significantly complicate the path to clinical study. Both traditional small molecule pharmaceuticals as well-characterized proteins, the manufacturing processes must consider commercial scalability and viability at a very early stage. These challenges underscore the importance of CMC-focused communications with the FDA early and often. By maximizing milestone engagements, 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.
