With reduced resources accessible (both in personnel and funding), smaller emerging sponsors will seldom have a sizable Chemistry, Manufacturing and Controls (CMC) group, and in many cases may only have one support individual within their organization. It is common for all CMC activities from pre-IND through Phase 2 and even beyond to be coordinated by this one individual, often simultaneously with other responsibilities. Most if not all these sponsors, who in many cases are also virtual, use contract manufacturing organizations (CMOs) for the CMC aspects of their development and manufacturing.
Within early-phase development, resources are limited and in many cases are spent on CMC activities that may not contribute significantly to the overall program. Given the typical background of personnel in small innovator organizations, the responsible individual often has limited direct experience with GMPs or CMC development activities. Furthermore, covering the whole range of outsourced CMC activities for even a single product in development is a demanding task for a single individual.
While the primary function of a CMC strategy is to meet obligations for regulatory filings, the process of developing an effective CMC program can offer immediate and long-term benefits including lower development costs and avoiding unnecessary delays. The CMC essentials, as outlined in the regulations and guidance(s), are to ensure the drug is manufactured safely and consistently from testing through commercialization and the post-approval lifecycle of the drug.
Much has been written—in FDA and ICH guidance documents, presentations, articles, and books
Because each drug candidate has unique characteristics, dosage forms, patient groups, and other factors, a one-size-fits all approach to CMC development may not be an effective approach. Tailoring a program starts with understanding the drug and its characteristics. By establishing and documenting a quality target product profile, critical quality attributes, and critical process parameters in early development phases, companies can develop a strong understanding of process requirements and change control for the lifecycle of the product.
Guiding an innovator drug through development, clinical trials, regulatory approval and, in due course to market launch is a delicate balancing act. For small innovator companies with limited time, resources, and expertise available to address the crucial elements of drug development, the focus frequently is on the clinical trial pathway.
A new drug’s progress and external funding is often measured by the completion of clinical trial milestones. While these trials are evaluating the safety and efficacy of the drug, formulation and manufacturing processes must be developed, as well as analytical methods to characterize the drug and test its potency, stability, impurity profile and other properties.
Simultaneously, information about the drug, its properties, test methods, and manufacturability must be documented for regulatory filings as described in the CMC section of an investigational new drug application (IND). Sponsors need to plan for manufacturing processes with the same consideration they give to clinical studies, how the product will be supplied, how much product is required in the clinical phase, what is needed at launch, and how to validate these production processes.
Strategizing a phase-appropriate approach is crucial to filing of too little or too much information, too early or too late in the process. FDA defines the requirements for CMC filings in 21 CFR 312. The regulation specifies that the CMC section of an IND should describe the composition, manufacture, and control of the drug substance and the drug product.
Uncertainty about how much information needs to be filed with FDA, and when it needs to be submitted, can lead to confusion, delays in the development and the clinical trial approval process, and cost overruns.
CMC activities include the establishment of manufacturing processes and product characteristics, as well as defining product testing methods to ensure that the product is safe, effective, and consistent between batches. To minimize the risk of later-stage failure, several key CMC areas must be considered in early development.
Decision to accelerate the overall development plan should not compromise the CMC work required to maintain an acceptable level of control, as required by the regulator and industry.
Key CMC considerations in early development include the use phase-appropriate analytical methods versus fully validated methods and understanding the development history of the product. In addition, issues related to safety assessment, the solid state of drug substance (polymorph and salt form), the transition from the early-phase to the late-phase clinical and commercial dosage forms, the transition from a small scale manufacturing process train to a multi-product process train.
FDA’s website lists 70 guidance documents in the Pharmaceutical Quality/CMC category. These guidance documents state FDA’s thinking on requirements for different clinical phases, different drug types, analytical testing, and post-approval changes.
Important to note: FDA also recommends agency-sponsor meetings to discuss CMC-related questions in advance of IND filings.
Drugs receiving a breakthrough therapy (BT) designation may face a number of CMC related challenges including unavailable commercial manufacturing supply chain, necessitating the launch of drug with initial commercial supplies from a clinical trial manufacturing facility, limited data for setting specification acceptance criteria and reduced real-time stability for commercial material.
While FDA is trying to be more flexible for accelerated review with less complete data on manufacturing process and validation, product specifications, and stability to expedite the approval process, the standard requirements still apply. FDA’s accelerated review process has complicated CMC efforts; the shorter timelines for clinical review give sponsors less time to develop and validate manufacturing processes compared with traditional review timelines. Potential accelerated development timelines could lead to insufficient time to complete all “traditional” CMC studies for approval for example;
With insufficient time to complete the traditional CMC studies, breakthrough programs should prioritize resources to gather the information needed to support the filing.
Sponsors should expect changes in formulation, manufacturing, and raw material suppliers may be required commitment to additional post-approval activity will be needed including additional stability data and process robustness studies.
Just as a juggler must struggle and lunge and refocus his attention to keep a lot of balls in the air, these innovator organizations often seek external assistance from a range of service providers, from individual consultants and consulting firms that provide CMC strategic advice and development oversight of the CMC program, to the CMOs that execute the formulation and process development, the manufacturing steps, testing and validation work.
Due to the complexity of drug development, smaller emerging sponsors often rely on multiple CMO providers to perform various product development and analytical testing steps. While contracting with an external CMO for vital development tasks can be a viable option, the sponsor needs to monitor and manage and ensure protection for the intellectual property associated with the drug and its development.
While large integrated pharma companies on average have a regulatory affairs team alongside a technical operations group to address CMC requirements and submissions, small emerging sponsors routinely delegate these tasks to one or a few individuals who also juggle other responsibilities for the company. Securing the technical, and regulatory expertise to complete CMC steps while deciding the most cost-effective use of limited resources, can test the capabilities of these sponsors.
For sponsors looking for development partners or seeking to sell an asset, an effective CMC program can make the drug more attractive to potential suitors. Defining manufacturing needs early in the development process presents risk and challenges.
Typical CMC failures typically include not identifying critical process parameters or a quality target profile; not developing and validating proper assays for stability, potency, and other factors; such as not using quality risk management, not auditing suppliers or setting up quality agreements, not characterizing raw materials or finding alternate suppliers. In addition, vendor-related noncompliance problems can upset a drug sponsor’s carefully defined CMC plans.
Shortfalls in the manufacturing area of CMC information can be a stumbling block for some applications. A complete response letter (CL) due to CMC deficiencies can not only delay drug approvals but also dismiss a partnership or terminate a license deal.
When emerging innovator organizations are looking to in-license a product, beginning to develop a compound while looking for initial funding, or even worse facing a disruption, it’s natural to reexamine strategy and evaluate options for inventive approaches and exceptional quality work products intended to enhance product development, approval, and marketing presence.
Whether advocating Chemistry, Manufacturing and Controls (CMC) strategy, directing CMC operations or developing CMC submission content that represent the best interests of an emerging biotech, you will need to focus on the critical CMC issues and build programs that meet development obligations.
You can prepare for any eventuality by making sure you’re able to ensure that all the proper documentation is in place, so when called to act, you can move forward with confidence.