CMC Pitfalls: From Benchtop to IND
ART PODCAST | SEASON 3 | EPISODE 4
In this episode of Advancing Revolutionary Therapies, Kevin Hennegan, Director of Regulatory Affairs at Veristat, talks to Lisa Erickson, Sarah Roemer, and Erin Flynn of Veristat’s Chemistry, Manufacturing and Controls (CMC) Regulatory team. These CMC experts outline key fundamentals – and pitfalls – new sponsors must consider when determining readiness to file an Investigational New Drug (IND) from a manufacturing perspective.
Check out the full episode to learn more about how to successfully transition from academic or bench-top production to manufacture clinical-grade material to support an IND with the U.S. FDA – or read the summary below.
Key Manufacturing Considerations when Preparing for an IND
Kevin: From a manufacturing perspective, how can new sponsors prepare to file an IND?
Lisa Erickson: There are a few top line basic criteria you must fulfil from a manufacturing perspective.
- Know your product - Have a deep understanding of your final Drug Substance and your final Drug Product or final dosage form.
- Establish a manufacturing strategy and plan - You need to have a concrete manufacturing process and plan for process updates throughout the drug’s development. Simply put, know your product and your process.
- Focus on safety - For a Phase 1 IND the focus is on safety since this is the first time your drug will be administered to humans. Is it crucial to understand your product and process for an initial IND. Be prepared to back up your claims with data and provide assurance to the FDA that there are no significant safety risks from a CMC perspective.
The FDA guidance regarding Content and Format for INDs for Phase 1 points out, ‘The identification of a safety concern or insufficient data to make an evaluation of safety is the only basis for a clinical hold based on the CMC section.'
Choosing the Right CMO to Partner With
Kevin: What key factors should sponsors consider when selecting a CMO to produce material for early clinical trials?
Erin Flynn: Choose a CMO with experience in your type of synthetic or biological process, experience with analytical development, a dedicated regulatory staff, a robust quality system, and the full complement of manufacturing documentation. Facility location, language barriers, availability, production capacity, and supply chain reliability are also important factors to consider.
It’s ideal for your CMO to have experience with regulatory submissions, or that your team has a dedicated regulatory CMC expert that can oversee the CMO from this perspective. Everything used to
write the CMC sections of the IND will come from source documents prepared by the CMO. Most CMOs
have experience with this but you’ll want to ensure that what you get from your CMO is what you need
to write the CMC sections of your IND.
Kevin: What should a Quality Agreement with a CMO cover?
Sarah Roemer: A quality agreement is particularly important for analytical and manufacturing contracting as the Sponsor will be relying on the CMO’s or vendor’s quality system to properly implement and adhere to Good Manufacturing Practice or GMP. However, reliance on the contractors' quality system does not absolve the Sponsor of the responsibility to ensure adherence to GMP. Therefore, a written quality agreement that clearly defines the CMO’s and Sponsor’s quality roles and responsibilities is necessary to guarantee the oversight and appropriate implementation of GMP at the contract facility.
Kevin: Are there any topics that are outside the scope of a quality agreement?
Sarah Roemer: A quality agreement should not address the business and financial aspects of the project, which would be included in a separate service agreement.
Kevin: Does a sponsor need their own Quality System, independent of the CMO?
Erin Flynn: It’s not necessary for a Phase 1 IND but sponsors should review their CMO’s quality system to ensure that everything is in compliance with ICH Q7, Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients.
Sarah Roemer: If a sponsor establishes a Quality System, it should be flexible and limited in scope with a focus on selection and ongoing auditing of vendors to ensure that the contractors' system is robust and implemented properly.
Fostering a Strategic and Successful Partnership with a CMO
- A description of your product and its physical, chemical, and biological characteristics along with the evidence generated which support its structure, identity, and activity. Usually, a characterization report would provide this information.
- Details on how the drug substance and drug product are made and how the process is controlled. FDA expects to see flow diagrams, process controls, and controls for raw materials as part of the submission. A manufacturing process summary report would provide this information.
- Test results supporting the quality of the product. You should have qualified analytical methods and procedures or SOPs, and provide a summary of these in the IND. You need to provide acceptable limits to ensure identity, strength, quality and purity of the drug and FDA expects to see the release testing results for the intended clinical batch as part of the IND submission.
- Provide information to support stability of both the drug substance and the drug product in their intended container closure to support the duration of the clinical studies. Stability protocols and reports are needed and support this.
CMC Fundamentals for Preparing for a Pre-IND FDA Meeting
Kevin: What should Sponsors discuss with the FDA during pre-IND meetings from a CMC perspective?
Erin Flynn: One of the most important things the FDA looks for when reviewing an IND is the impurity profile of the product. For a Phase 1 IND, the nonclinical studies are usually conducted with an early development batch, prior to manufacturing your GMP clinical material. The FDA will look to see that the impurity profile between the nonclinical batch and clinical batch is similar, so if there is any doubt there, it would be beneficial to talk with FDA early about that. We also recommend that sponsors run their specification list by FDA to ensure that the release of their product is adequate.
Kevin: Are there any topics that should be avoided in a pre-IND meeting with the FDA?
Erin Flynn: If you have concerns with problematic data, the FDA will most certainly have similar concerns. It’s best to initiate a discussion early on to address any CMC-related issues. The sooner you identify and discuss an issue, the sooner it can be resolved.
Sarah Roemer: You should also avoid asking general program questions (e.g., is the CMC program adequate for Phase 1?). The FDA may not be able to answer general questions and it could potentially warrant unwanted responses. CMC questions should be targeted and have sufficient data or information to allow FDA to develop an informed response.