Meeting requirements for Chemistry, Manufacturing and Control (CMC) is complex for any drug developer, but is even more so in the rare disease space. These challenges are further compounded for non-EU sponsors seeking to initiate clinical trials in Europe where the differences in requirements and expectations from their home market are often not well-understood.
Manoeuvring through these complexities will require sponsors to understand what the European Medicines Agency (EMA) expects. There are several steps sponsors must take to prepare Module 3 of their CTD dossier or their Investigational Medicinal Product Dossier (IMPD) in the EU.
Step 1: Know what is expected
Start by identifying the relevant EMA regulatory requirements and making sure you comply with them. While this might seem obvious, it’s not necessarily a sponsor’s top consideration when developing their product. If you’re applying for Orphan Designation, do you understand the criteria you need to fulfil? If your product is an advanced therapy medicinal product (ATMP), how well do you understand the specific requirements for manufacturing these products for your clinical trials?
Step 2: Have a resolution in mind
Sponsors from the United States are accustomed to how the Food and Drug Administration (FDA) reviews trial applications, which is to review the data and tell the sponsor if they are right or wrong. The EMA, however, is looking to the sponsor to work with them to resolve questions and that requires having a robust risk-based quality control approach to CMC.
Step 3: Speak the right language
The language in your dossier is key. It needs to explain what you are doing and why. It’s important to be able to pre-empt questions from the health authority by preparing your CMC dossier – be it your CTD Module 3 or IMPD – in such a way that it helps the agency to understand what you’re doing and your thinking behind that.
Step 4: Be transparent about any problems
There are several common CMC difficulties that can arise, such as problems with part of the quality control or product identification, or critical quality attributes (CQAs), or struggling to define why the formulation works the way it does. These types of challenges are more likely to arise with rare disease treatments where small patient populations mean limited data sets. When this happens it is important to be transparent and seek appropriate advice with regulators, who can then help you address those questions.
Step 5: Adopt a GMP-led mentality
It is important to document the steps you are taking to ensure contamination control measures are in place (particularly key with ATMPs) and make sure you have a risk management plan. It’s crucial that you don’t have DNA or viral contaminants in your process. Sponsors need to document all their processes to show they have a specific process to remove any viral DNA that may contaminate the sample. A clean and consistent product is the goal, and this is what it means to have a GMP mentality.
Step 6: Police all your facilities
Make sure you have proper oversight of facilities through your own rigorous monitoring and quality assurance systems. Determine which facilities have GMP certification and which don’t and apply a risk-based process to monitoring their activities and outputs. You need to be able to show the regulators that you are in control of what’s happening to your product at every step of the way at every facility, and on its journeys between them.
Step 7: Consider the EU Pharmacopeia
Consider EU specifics such as the EU Pharmacopeia (Ph. Eur.) certifications versus a US monograph for an orphan product. The EMA is committed to maintaining global standards for medicines and publishes scientific guidelines that are harmonised by ICH. These subtle differences are issues that are often overlooked and cause Requests for Information from regulators during Clinical Trial Application and Marketing Authorisation Application procedures, often resulting in application withdrawals, rejections and delays to approval.
Step 8: Engage with the health authorities
The EMA offers many different avenues for scientific engagement, which sponsors from outside the EU often don’t fully understand. Taking advantage of EMA schemes like the Orphan Drug Designation and PRIME and the opportunities for scientific advice can improve your product quality and transform the approval process.
A big picture perspective with ATMPs
These issues need to be top of mind with ATMPs – which currently mostly target rare diseases. Additionally, the scale-up process with orphan drug products is much faster, which means your dossier will need to be ready with validations and quality control methodologies in place much sooner than a non-orphan product to be ready for launch. It is therefore vital to carefully plan your CMC approach and work with experienced regulatory consultants to help you through each of these steps to ensure consistency and robustness with your clinical studies.
“Manoeuvring through (CMC) complexities will require sponsors to understand what the EMA expects.”