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A risk-based approach to CMC enables drug sponsors to focus on clinical and manufacturing development paths.
Guiding an innovator drug through development, clinical trials, regulatory approval and, ultimately, to market is a delicate balancing act. For small, innovator bio/pharma companies, the focus frequently is on the clinical trial pathway, with limited time, resources, and expertise available to address the crucial elements of process development.
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, however, formulation and manufacturing processes must be developed, as well as analytical methods to characterize the drug and test its stability, potency, and other properties.
And, complex information about the drug, its properties, safety, test methods, and manufacturability must be documented for regulatory filings as described in the chemistry, manufacturing, and controls (CMC) section of the Code of Federal Regulations (CFR) for an investigational new drug application (IND) (1).
Sponsors of innovative therapies need to plan for manufacturing processes with the same forethought they give to clinical studies, determine how much product is needed at launch, how the product will be supplied, and how to validate production processes, said Steven Kozolowski, director of FDA’s Office of Biotechnology Products at a 2016 WCBP symposium (2).
While mid- to large-pharma companies typically have a regulatory affairs team to address CMC requirements, small companies may delegate these tasks to one or a few individuals who also juggle other responsibilities for the company. Securing the technical, scientific, and regulatory expertise to complete CMC steps while deciding the most cost-effective use of limited resources, can test the capabilities of these innovator companies.
To keep all balls in the air at once, small bio/pharma companies frequently seek external assistance from a range of service providers, from individual consultants and consulting firms that provide CMC advice and strategy development, to contract research and development firms that not only develop CMC programs but also execute the testing, formulation, process development, and manufacturing steps.
Technology innovations for analysis, modeling, and formulation development may be cost-prohibitive for most small companies. Due to the complexity of drug molecules, small bio/pharma companies often rely on multiple contract service providers to perform varied product development and analysis steps. In recent years, large contract service providers have acquired smaller outsourcing firms with specialized technology capabilities to offer a “one-stop-shop” for a range of formulation and manufacturing services.
While contracting with an external service provider for vital development tasks can be a viable option, the drug sponsor needs to monitor and manage the contractor and ensure protection for the intellectual property associated with the molecule and its development. The challenge for small companies is to know what expertise is needed at various stages of the drug development and regulatory filing process, and how to best budget valuable resources for external support.
FDA’s accelerated review process has complicated CMC efforts; the shorter timelines for clinical review give drug companies less time to develop and validate manufacturing processes compared with traditional review timelines.
Drugs receiving a breakthrough therapy designation may face a number of CMC-related challenges including reduced real-time stability for commercial material; unavailable commercial manufacturing facilities, necessitating the launch of drug with initial commercial supplies from a clinical trial manufacturing facility; and limited data sets for specification acceptance criteria (3).
With insufficient time to complete the traditional CMC studies, breakthrough programs should prioritize resources using a risk-based approach to gather the information needed to support a new drug application filing. The sponsor should expect additional post-approval activity will be needed including additional stability data and process robustness studies; in addition, changes in formulation, manufacturing, and raw material suppliers may be required (3).
FDA representatives have said the agency is trying to be more flexible in accepting for accelerated review applications with less complete data on product specifications, process validation, and stability to expedite the approval process (2).
The CMC process, as outlined by FDA regulations, is to ensure the drug is manufactured safely and consistently from testing through commercialization and the post-approval lifecycle of the drug. 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.
Much has been written-in FDA and ICH guidance documents, presentations, articles, and books-about best practices for CMC programs. Because each novel drug 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 for a specific therapy 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. And, for companies looking for development partners or seeking to sell an early-stage molecule, 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. FDA has noted that shortfalls in the manufacturing segment of CMC information can be a stumbling block for some applications; in recent years, FDA has reported an increase in complete response letters due to CMC deficiencies, delaying drug approvals (4).
Typical CMC failures include not auditing suppliers or setting up quality agreements; not characterizing raw materials or finding alternate suppliers; not identifying critical process parameters or a quality target profile; not developing and validating proper assays for stability, potency, and other factors; and not using quality risk management (5). In addition, vendor-related non-compliance problems can upset a drug sponsor’s carefully defined CMC plans (see sidebar).
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.
Strategizing a phase-appropriate approach is crucial to filing of too little or too much information, too early or too late in the process. Regulations and FDA guidance documents promote this staged approach. The regulation reads: “Although in each phase of the investigation sufficient information is required to be submitted to assure the proper identification, quality, purity, and strength of the investigational drug, the amount of information needed to make that assurance will vary with the phase of the investigation, the proposed duration of the investigation, the dosage form, and the amount of information otherwise available” (1).
Recognizing that the drug substance, dosage form, and preparation methods will likely change as a drug moves through development, FDA notes that a Phase I submission should focus on the identification and control of raw materials and the new drug substance. As the drug progresses from pilot-stage to clinical trial manufacturing, the sponsor should amend the initial information on the chemistry, manufacturing, and control processes with additional information that is appropriate to the scope of the investigation. Final specifications for the drug substance and drug product are not expected until the end of the investigational process.
The required information about a drug substance and drug product is listed in 21 CFR 312.23 and includes a description of the physical, chemical, or biological characteristics of the drug substance; the components of the drug product, including alternatives for inactive compounds and components used in the manufacturing process; a general description of the manufacturing procedure, acceptable limits and analytical methods used to assure the identity, strength, quality, and purity of the drug substance and product; drug stability information; and the name and address of the manufacturer.
FDA’s website lists 70 guidance documents in the Pharmaceutical Quality/CMC category, the earliest from 1989. These guidance documents state FDA’s thinking on requirements for different clinical phases, different drug types, analytical testing, and post-approval changes (6). FDA also recommends agency-sponsor meetings to discuss CMC-related questions in advance of IND filings.
In addition to the complexities inherent in new therapies, inconsistencies in the CMC requirements of different global regulatory authorities further complicate the development and approvals of novel therapies, according to a recent review article.
“There is a desperate need for a consistent form of regulation where global approaches to regulatory strategies can be harmonized, and specific CMC challenges can be dealt with using the appropriate science and risk-based tools,” the authors wrote (7).
The proposed International Conference for Harmonization Q12 guideline (8), which provides guidance on the management of post-approval CMC changes, is one global effort; however, inconsistencies still remain for approval stages.
1. Code of Federal Regulations, Title 21, Food and Drugs, Part 312 (Government Printing Office, Washington, DC).
2. J. Wechsler, “Improving CMC Review for Breakthrough Therapies,” www.PharmTech.com, Jan. 29, 2016.
3. E. S. Dye, et. al. Pharmaceutical Engineering, 35 (1) 1-11 (January/February 2015).
4. C. Challener, Pharm Tech, 41 (1) 26–29 (January 2017).
5. A. Shanley, Pharm Tech, 42 (11) 20–23, 56 (November 2018).
6. FDA, Guidances (Drugs), accessed July 29, 2019.
7. N.S. Cauchon, et. al., J Pharm Sci, 108(7), 2207-2237 (July 2019).
8. ICH, Q12 Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management, Step 3 version (November 2017).
Vol. 43, No. 8
When referring to this article, please cite it as R. Peters, “Balancing CMC Priorities," Pharmaceutical Technology 43 (8) 2019.