Cmc: Crucial Aspect of Drug Development Ensuring Quality and Safety

By Lilyanne Rice - On Sep 20, 2023

The United States Food and Drug Administration (FDA) and other health authorities (EMA, etc.) require a clearly defined and consistently used medicine and biologics development process and life cycle management. Methods are validated, raw materials are selected and tested, and purity requirements are met by following the defined protocols for ‘Chemistry, Manufacturing, and Controls,” or CMC.

As changes in manufacturing affect drug quality in accordance with current Good Manufacturing Practices, the CMC helps preserve the quality relationship between the medicine used in clinical studies and the marketed drug during product development. After a product has been approved, the CMC must ensure that any changes adhere to all applicable quality and regulatory standards.

This article will provide a comprehensive summary of CMC factors to help emerging biotech companies. Developing an asset involves various steps and considerations, with product creation as the backbone. This article also delves into how the correct development partner can keep your asset’s development on track from start to finish.

Drug Life Cycle Management and Drug Development using CMC

It is only the first step on a long road to getting a product approved after finding a potential target, whether the products are monoclonal antibodies (mAbs) or biologics. An early focus on “Chemistry, Manufacturing, and Controls” (CMC) is necessary to ensure a successful product and the shortest path to approval, even though the development focus is often on pre-clinical and clinical elements.

CMC is particularly essential for businesses that invest in monoclonal antibodies (mAbs) and other biologics rather than small chemicals. Antigen binding specificity relies on the variable and hypervariable sections of MAbs, which are too large to undergo thorough characterization like small molecules. Finding this and other problems, which your development/CMC partner can help you spot early on, is crucial because fixing them later can be expensive.

The following are some of the most important things to keep in mind when working with CMC:

Upstream Process
Functional Characterization
Downstream Process
Structural Characterization
Process/Analytical

-Formulation

-Glycosylation

-Stability

-Impurity profile –

Why is CMC So Important in the Pharmaceutical Industry?

It is essential to guarantee that all of the CMC components are collected and managed properly, as the complexity of the manufacturing process and controls grows during product development. Although there are many technical difficulties to overcome during the development of a new biologic, not having sufficient expertise in the areas mentioned below might cause significant setbacks:

CMC data requirements at each stage as set by the agency
Having the ability to adapt to developmental changes
Scaling up a product requires the ability to compare results
Factors to address with the change in manufacturing site
Finding the suitable approaches to analysis
Specifying the acceptable volume of degradants and impurities
Serving as a resource from the design of clinical trials to product launch

Why is early problem identification so crucial?

The need to restart development due to a problem with the selected process or molecule is very expensive and time-consuming. When dealing with complex issues, having a CMC pharma consultant who is well-versed in them can be valuable in facilitating early agency contact for seeking advice and guidance on matters like:

Identifying existing CMC gaps
The proactive regulatory approach to CMC issues
Identifying problems that may arise during further scale-up
Making preparations for potential outcomes and assessing risks
Expert resources with expertise working with many companies and regulatory bodies
Providing the Agency with the necessary technical knowledge to answer its inquiries
“Preparation of the Meeting and Briefing Book”

Why are CMOs (Contract Manufacturing Organizations) so important?

The success or failure of a product often hinges on the supply chain. Therefore, having a positive working relationship with the CMO is essential. Investigations into stock-outs, broken equipment, inefficient processes, and out-of-specifications (OOS) are essential to running a smooth CMO.

The success of CMOs can be attributed to several factors, including quick responses to clients, cooperation with health authorities, and excellent change management. You need to understand and assess the nuances/risks of where you want to produce – some CMOs have facilities working on the “edge of GMP.” A lower price per unit is not necessarily better.

For the product to last, the GMP facility is essential. Product supply is hampered if the contract manufacturing organization (CMO) or the internal sites (sites within the organization) are not operating optimally.

What are some more crucial factors to think about?

Maintaining samples from the earliest stages of development is crucial for linking tox/pharmacokinetic (PK)/pharmacodynamic (PD) studies with later manufacturing procedures and better assays.

Refrain from relying on what other people are utilizing; instead, qualify your assays thoroughly to show that they’re suitable for your product. Manufacturing campaigns with on-site technology transfer will see fewer problems and more results. Also, consider not just the product’s current state but its potential in the future as they expand and grow (for example, do you need in-vitro in-vivo correlation (IVIVC) or bioequivalent (BE) studies or different zone stability studies to support future growth?)

Because of their reliability in achieving positive outcomes in patients, small molecules continue to dominate the pharmaceutical industry’s research and development pipelines and the market. It’s about a classic class of man-made organic compounds with low molecular weights and short chemical formulas. Many small-molecule medications have been around for quite some time and have even been repurposed for other uses in recent years. Innovative pharmaceuticals, frequently modified for specific patient genetic subgroups, are on the rise.

Examining chemical characteristics and the criticality of excipients in the formulation and when making adjustments is one area that the FDA has been paying more attention to. The following are elements that should be accounted for in such a shift, as evidenced by recent events:

All specifications are specified in monographs and by manufacturers.
Examining the excipient’s pre- and post-modification test results to see if there is a statistically significant difference.
There needs to be a comparison of physical attributes between the RM manufacturer and the user, considering the excipient’s physical shape and usefulness and the specifications between the two parties.
The impact on bioburden, especially for microbially-growing excipients
Bovine spongiform encephalopathy (BSE), genetically modified organisms (GMO), and transmissible spongiform encephalopathies (TSE) are all examples of changes in origin that might affect the safety of a product.

Conclusion

Creating a development strategy for an asset includes CMC as a crucial “first step” component. Without a well-thought-out plan for developing the investigational materials utilized in clinical studies, HAs will be unable to provide reliable assessments of the product’s efficacy or safety. When creating a CMC program for your investigational product, your development partner will work closely with you to ensure its success. The timeliness of clinical trials can be accelerated if your development partner can also handle IP manufacture, packaging, and labeling.