By Michelle Anastasi
The road to drug innovation involves many steps and hurdles amid the need to meet tough regulatory efficacy and safety standards. One of the most challenging steps along the way is navigating CMC (Chemistry Manufacturing and Controls) requirements in order to identify and mitigate potential risks and ensure the safety of the final product.
Too often, drug development programs fall into common CMC pitfalls such as insufficient control strategy, lack of risk assessment and inadequate regulatory compliance perhaps due to lack of expertise or not fully understanding the necessary process steps.
An important starting point for any company is the target product profile (TPP). Moving a product from the laboratory to manufacturing requires a clear understanding of the TPP and the product quality criteria that need to be controlled when scaling up. It also requires ensuring key steps are established and understood.
Data and documentation
The TPP must be developed continuously based on data collected during the different stages of process and product development to help define the critical attributes of the product to ensure the safety and therapeutic efficacy that you’re targeting and the patient groups you are aiming to treat. All too often, the nuances that are integral to defining the product’s characteristics reside with a small number of experts.
To avoid this pitfall, it’s imperative that as R&D conducts experiments and gathers data, this knowledge is properly documented so it can be shared with all key stakeholders within the company. As the process moves from the lab to CMC, that data will be key to controlling each step for each batch to ensure uniformity of dosage, and to demonstrate efficacy and safety.
Data gathered during product development and document integrity will also be vital to support decision-making and change management. It will help to define what worked, what didn’t, how to control for parameters and how to progress to the next stage of development. And that data will be integral to providing the evaluation, assessment and justification as to why that change was deemed necessary.
Testing for safety concerns
Through comprehensive testing and evaluation of the manufacturing process and raw materials, CMC provides insights into potential impurities, contaminants, or other safety concerns that could affect the quality and safety of the final drug product. Thus CMC ensures drug quality and reproducibility which plays an important role on the safety of new drugs while provides the ability to identify and mitigate potential risks.
Companies must perform certain tests to ensure the safety of a product, for example, sterility testing for biological products such as vaccines, blood product and cell and gene therapies to ensure there are no impurities.
Since products can have specific impurities, companies need to develop specific test methods that are unique to either a portion of the process, the full manufacturing process or the end product. As you gain product knowledge, you also gain knowledge about potential contaminants or impurities, and with it, the type of testing needed to test for those.
These tests need to consider all potential causes of contaminants, including the process itself as well as raw materials. Testing must ensure that any potentially unsafe raw materials, such as solvents, are fully cleared out of the final product so patients aren’t put at risk. That means there must be quality control and validation for the test method to ensure it is precise and accurate.
De-risking drug development
The ability to identify and mitigate potential risks is key to addressing CMC challenges. This objective is supported by the concept of Quality by Design (QbD), which is included in ICH Q8, Q9 and Q10 guidelines.
QbD is widely encouraged by regulators, and the Food and Drug Administration (FDA) and European Medicines Agency are closely aligned on QbD concepts. These concepts include understanding the quality TPP (QTTP) and that the TPP identifies the critical quality attributes of the drug you are designing.
This process understanding helps you to define your critical processing parameters (CPP), your critical material attributes and your critical quality attributes (CQA). This allows you to come up with a control strategy and how it applies to your drug substance. It helps you to define the specifications you need to control for within your process to ensure drug product quality and, where necessary, to apply corrective and preventative actions.
One of the main components of QbD is the use of statistical techniques such as Design of Experiments (DoE), which helps you control the quality of the design by defining what you are controlling for and what your variables are to reduce the risk of not hitting your TPP.
Bringing it all together for regulatory compliance
The CMC portion of your regulatory filing requires that you include certain data. Avoiding those common pitfalls, however, is about more than just the inclusion of data. It’s about the strategic approach you have in place to gather the data, ensuring you have looked at different perspectives from that data, and the conclusions you draw from that data to rationalize your product’s benefit-risk ratio.
That benefit-risk ratio will vary depending on the therapy and patient population. A product designed for a large patient population for which there are alternative products will need to demonstrate a stronger benefit to risk ratio than, for example, a therapy area for which there are no alternatives, and which would improve quality of life for patients in need. It is the data, and the strategic approach to gathering that data, that informs the benefit-risk ratio.
All the steps involved in navigating the CMC and avoiding pitfalls come back to understanding the process, having a well-defined control strategy, conducting thorough risk assessment and ensuring you have a robust system to support data integrity.
