CMC Pitfalls: From Benchtop to IND 



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.

  1. Know your product - Have a deep understanding of your final Drug Substance and your final Drug Product or final dosage form.
  2. 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.
  3. 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.


Fact Sheet: Regulatory Consulting & Planning for Clinical Development Success



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

Kevin: As regulatory CMC experts, what do you need from sponsors to prepare the manufacturing sections of an IND? 
Lisa Erickson: There is a lot of documentation or source documents that are needed to prepare the CMC sections of an IND and going through a laundry list of the documents needed can be overwhelming. It’s better and more approachable if we break it down into these high-level areas for consideration:
  • 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.
Erin Flynn: One thing that is often overlooked is a Style Guide – a document that outlines how things will be consistent across all the different CMC sections of the IND and the entirety of the submission. It’s key to presenting a unified and consistent picture of your manufacturing to the FDA, as you most likely have multiple authors working to assemble CMC sections. 
Kevin: Can sponsors rely on CMOs to provide all the information for an initial IND, or are there parts of that data set that are often missing?
Erin Flynn: The document I most often go without is a manufacturing process summary. Getting the CMC sections of the IND written can still be done, but it requires tediously combing through the batch records, and requires much more time and effort than if a manufacturing process summary is available. 
Sarah Roemer: Process and formulation development is also often overlooked in contract manufacturing documentation. It is very typical for a manufacturer to provide unofficial updates in lieu of development reports, which typically do not appropriately identify pivotal studies and lack definitive conclusions used to drive development. Characterization of the drug substance and its impurities, and reference standard qualification is also often overlooked aspects of an initial IND CMC program. Analytical release alone is not sufficient, and characterization and reference standard qualification programs should be implemented even in early clinical development. 
Kevin: Are there any best practices that help make communication between the CMO, Sponsor, and the regulatory team more efficient?
Lisa Erickson: Begin with the end in mind. Having Regulatory CMC involved up front and early in the review of CMO source documents helps enormously with the end product, the final IND application.  Regulatory CMC teams know what’s needed and what to look for, so when we can be involved in that process from the beginning, it benefits us all. For example, we sometimes see discrepancies in how data is recorded in the manufacturer’s documents versus how the Sponsor plans to report the data as part of the product specification. This could be something as simple as the number of significant figures and how final data is rounded. These decisions should be addressed up front and prior to finalizing the IND to avoid questions from the FDA reviewer or findings of inconsistency.


Case Study: Preparing an Investigational New Drug Application (IND)



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.



Infographic: Why and When to Hold a Pre-IND Meeting with the FDA



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.

Develop a sound strategic plan when preparing for your IND – speak with our regulatory experts today.  


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