Chemistry, manufacturing, and controls (CMC) plays a critical role in the development of a biological product from the research lab to preclinical to clinical stages and through to drug approval/licensure and commercial manufacturing. The right CMC strategy and perfect execution are important to the success of drug development in the biotech industry.
In an intensely competitive environment, small biotech companies are continuously seeking creative ways of CMC management to accelerate their biologics development process. Timelines to initiate clinical trials are becoming shorter as companies press for definitive results that would prove or disprove their product’s potential. With venture capitalists and other financiers looking to invest in a biotech industry that is continuously pursuing innovative new products and where small biotech companies compete for their share of the financial pie, the race to demonstrate positive clinical results is intense.
Biologic drug development is complex, time consuming, and expensive. Clinical trials make up a substantial portion of the overall drug development costs. Oftentimes, the other significant part of the project — the development of the actual product, the focus of chemistry, manufacturing, and controls (CMC) — is not given the same level of attention. When embarking on the transition from preclinical studies to clinical trials – the true onset of drug development, biotech companies must think through and understand their risks and risk tolerance and accept the consequences of their decisions on CMC strategy as they traverse through the product development process.
Small biotech companies tend to make more mistakes in CMC. Unlike the large biotech and pharma companies that have abundant resources, much more experienced personnel, and access to external experts and consultants, smaller biotech companies, especially in the forefront of technology innovation, typically do not have the resources or the required number of experienced people in different CMC functions. This puts a greater risk on product development by not knowing and focusing on important aspects -not knowing critical quality attributes, not knowing and developing stability-indicating assays, not developing a rugged and reliable bioassay, not identifying important impurities, not developing stable formulations, etc.
Small biotech companies with limited budgets and experience are usually on aggressive development timelines, and that’s a recipe for compromising quality and regulatory compliance in many areas (such as assay qualification and validation, supplier and raw material qualification, facility and equipment qualification, storage and stability qualification, process validation and performance qualification, and deviation investigation leading to corrective and preventive actions (CAPAs)).
Sound science and technology are the fundamental ingredients of CMC for the optimal design and successful development of high-quality and regulatory compliant biologic or biopharmaceutical products. In most cases, it’s not possible for early to mid-size and stage biotech companies to have all the necessary CMC resources to steer through the maze and tangle of drug development challenges. Therefore, it’s often a good idea to seek the services of consultants or outside experts to effectively manage all or part of CMC development activities, including strategic planning and the tactical oversight needed to ensure efficient and timely development.
The first of the ten essential components to avoiding costly drug development mistakes is to have a clear CMC strategy.
Have a Clear CMC Strategy
Smaller innovative biotech companies must appreciate and stress the importance of having a clear CMC strategy. The shortcuts, taken sometimes due to lack of knowledge and increasing time pressures, usually end up being time consuming and very expensive in the long run.
The biologic drug development timelines are very short, especially now with accelerated approvals. It’s vital that the CMC managers think through the development process meticulously by adopting step-by-step and unit operation by unit operation analysis to determine risk and predict where challenges and issues are likely to show up during technology transfer, process demonstration, scale-up, analytical development and validation, and clinical manufacturing. Biotech companies must be proactive and drive their CDMO/CMO partners to work in concert and perform this exercise and analysis with them [Contract development and manufacturing organization (CDMO)/Contract manufacturing organization (CMO) are key CMC service providers. In most cases, development is outsourced along with manufacturing. Hence, CDMO is solely used in rest of the discussion.]
Some of the important components of CMC strategy include defining:
- Critical process parameters (CPPs)
- Critical quality attributes (CQAs)
- Control strategies for genotoxic impurities
- Drug substance and drug product specifications
- Selection of drug substance starting materials
- Analytical method development and validation
- Regulatory compliant stability studies
- Process analytical technology (PAT) and quality by design (QbD) approaches to product and process design
- Selection and management of CDMO, project management
It’s critical that the strategy incorporates all aspects of U.S. FDA and ICH CMC regulatory guidance needed to obtain license for the biological product.
Every biological drug and every development program are different. It’s a matter of understanding what information is needed and when and generating it in real time. Based on what is learnt with time along the development path, one can adjust the strategy at every stage so that right decisions are made to forge the right course of action at every step.
Errors of omission and oversight are typically the biggest problem; many small companies fail to anticipate potential problems based on the generated data. In some cases, right data hasn’t been generated and potential scenarios have not been thought through and analyzed. Lack of experience and expertise in the CMC area is often the reason for not having a comprehensive strategy or plan.
It’s important for small biotech companies to perform scenario planning and ‘what if’ analyses at critical junctures. They must think one step ahead of where they are, such that if they’re in Phase I development, they should already be thinking ahead and incorporating elements that will be needed in Phase II. This way, even if they decide to sell the asset, the buyer will look at it more favorably and be interested in it.
A strategy that looks from the end through to the beginning and determines the best path to achieve the desired goal has considerable merits. It’s imperative that quality and regulatory groups are actively involved in all CMC strategies and decision points leading to actions.
In our next blog, we will discuss the second of the ten most important CMC “musts” in order to avoid costly mistakes – Have a Clear Quality Target Product Profile (QTPP)!