Chemistry, Manufacturing and Controls (CMC) is a vital part of the drug development process. A CMC strategy gives companies a template for bringing a drug through the early clinical stages all the way to commercial manufacturing. 

The CMC process has a number of benefits for a company: it can reduce development costs and reduce delays, as well as ensuring that the end product is safe and consistent. 

In larger pharmaceutical companies, CMC is not often an issue: enough resources exist to fund sufficient personnel to deal with strategy creation and ensure that no mistakes are made. In contrast smaller companies have a much greater challenge in CMC: their lack of staff or subject experts means that even if they had the resources to conduct CMC duties well, they lack the knowledge to put it into action and create robust strategies to characterise and control a product. 

There are a number of challenges, both process and regulatory, that hamper smaller companies from performing CMC as well as they could. But the solution is simply greater understanding of these issues and being aware of the right procedures and rules to navigate them. Proventa takes a look at how smaller companies can better conduct CMC. 

Current Challenges in Small Pharma CMC

As mentioned above, a major CMC challenge for smaller companies is a lack of technical and subject expertise. Without resources or knowledgeable experts mistakes can easily be made across the CMC template, from failing to spot significant impurities in a product to setting up inadequate formulation recipes. 

Often CMC activities up to phase 2 of a product’s trial will be co-ordinated only by one individual, often alongside other duties. Even should they have the background and experience to understand the complexities of the CMC process, managing it can be extremely difficult. 

This is often exacerbated by timelines that are too short for the necessary development, potentially jeopardising qualification and validation of assays and suppliers, not to mention storage conditions, tech transfer and process validation. 

These challenges are compounded by recent regulatory decisions. This is not helped by the fact that other values like safety and efficacy often overshadow CMC concerns, particularly in small molecule new chemical entities. The FDA’s accelerated review process, which comes as part of the 501(b)(2) approval pathway, allows smaller companies to use CMC shortcuts when approving drugs. This shortcut, however, has in some cases resulted in millions of dollars and huge amounts of times being added on to development timelines due to CMC deficiencies. Over the last few years, the FDA has increasingly sent out complete response letters (CRLs) to manufacturers putting a stop to drug approval until CMC issues are addressed, with 25% of the 33 CRLs sent out between January 2017 and May 2018 focusing specifically on CMC. 

Greater Development Strategies

Developing a clear CMC strategy can be made easier by focusing on a target product profile and understanding what needs to be achieved. This should take into account the therapy method, patient sub-populations, and the drug’s chemical characteristics. It’s also important to look at the product’s cost and any intellectual property issues at play, to understand how a CMC strategy would fit into the larger clinical and regulatory strategy for the product. 

While every development program is different and will require a tailored approach – that can be learned from experience – it is important still to focus on the data generated and understand the potential problems that each program could have. This, naturally, is difficult for companies with limited experience or a lack of understanding around the data, but it is important nonetheless to avoid errors of omission or unforeseen problems. 

This can mean looking out for red flags during analytical development, like changes in a compound under certain conditions, or other changes that result in a polymorph form through solubility differences – differences that can be caused even through minor additions like a new colouring. 

Regulatory Strategies

Certainly with newer companies, it can be difficult to understand what CMC requirements regulators need. While the FDA specifies in 21 CFR 312 that an Investigational New Drug (IND) form requires a clear description of a drug’s manufacture and control, it is hard to know how much information to give and when it should be submitted. 

Working with regulators early on is a vital step in CMC that smaller companies can leave out or think they lack the time for. But hiring an individual for later trial stages, preferably with an advanced degree and experience both of management and integration, and being able to consult regulators on any issues which arrive is vital for a smooth transition through different stages without any major setbacks. It will also clarify any vagaries companies find when filling in INDs or other forms. 

Similarly, it is important for a company to write their new drug applications (NDAs) in a clear, coherent structure. Particularly, critical information must be clearly presented and easy to find. Without this, progress can stall as regulators fail to find the information they need within the time limit.  

Other areas in CMC to be explored early in development and relayed carefully to regulators include safety assessments; transition from early- to late-phase commercial and clinical dosage forms; and analytical testing methods. 

Conclusion

To a smaller company, CMC can seem like an area that is both less vital than others but also a worrying complexity that would take an inordinate amount of energy to understand and complete.

But taking the first step of understanding where to look and what to do can do wonders for the CMC abilities of a company. With that small knowledge, pharma organisations can begin to seek out the necessary talent they need to get started, collate the rules and regulations that overarch this area, and work more closely with expert regulators and CMOs to fill in the details they lack and become more proficient with the complex area of CMC. 

To ensure you remain up-to-date on the latest in clinical development, sign up for Proventa International’s online Biomanufacturing Strategy Meeting 2020.

Joshua Neil, Editor
Proventa International