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Ashley Krull, Ph.D.
Associate Director, Cell Therapy Manufacturing and Engineering
James Cancer Hospital Cellular Therapy Laboratory 
Assistant Professor, Hematology
The Ohio State University
Columbus, Ohio, United States

Disclaimer: This article reflects the author's notes from attending the webinar and is not a direct transcription or official statement from the FDA.

On September 5th, 2024, the Office of Therapeutics Products within the Center for Biologics Evaluation and Research (CBER) of the US Food and Drug Administration (FDA) held a Town Hall event focused on “Cell Therapy CMC Readiness for Late-Stage INDs.” 

The event was moderated by Dr. Heather Lombardi, PhD, Director of the Office of Cellular Therapy and Human Tissues (OCTHT). The panelists from the OCTHT included: Dr. Alyssa Kitchel, PhD, Chief of the Tissue Engineering Branch 2, Division of Cellular Therapy 2; Dr. Karin Knudson, PhD, Biological Reviewer, Cell Therapy Branch 2, Division of Cellular Therapy 1; and Dr. Kyung Sung, PhD, Chief, Cellular and Tissue Therapy Branch, Division of Cellular Therapy 1.   

In the 90-minute town hall, the panel answered previously submitted questions with prepared statements and took real-time audience questions regarding preparation of late-stage investigational new drug (IND) applications. Late-stage INDs seek to gather primary evidence of effectiveness to support a marketing application for a novel cell therapy. The panelists discussed topics ranging from common pitfalls to release testing validation. The questions asked and brief notes from the panelists’ answers are included below. The full recording is available at FDA CBER OTP Town Hall: Cell Therapy CMC Readiness for Late-Stage INDs - Zoom (zoomgov.com). The session transcript will also be posted to the FDA website. 
 
Question 1: What are the most common CMC challenges that sponsors encounter when starting late-stage studies?
Key Takeaways:

• Implementing manufacturing changes and needing comparability studies
• Highly advise sponsors not to make changes but it is sometimes necessary to manufacture larger lots for Ph 3 trials, which leads to three big issues:
  o   Scale up
  o   Scale out
  o   Reagent modifications
• Upgrading quality or changing supplier due to larger volumes needed
• For all cases, comparability studies are needed.
• Ensuring an adequate potency strategy. FDA highly recommends evaluating potency assays in the early stages of development using acceptance criteria that can start wide and then narrow later as more data is collected.
• Often find issues with timing of potency assays – if the time the sample is taken is changed, then need comparability
• Develop an assay based on product understanding and experience
• Sponsors should come in to discuss questions 
   

Question 2: What is the expected progression of assay qualification/validation from early stage to BLA submission?
Key Takeaways:

• Increasing rigor
• Qualification and validation require assay to be suitable for the purpose
• Validation shows the assay performs in a predictable way across a range of conditions that could be expected in manufacturing
• Safety studies and dose determining studies should be qualified for early stage studies
• Evaluate assay performance at all stages
• By the time you start pivotal assays, all of your assays, even potency, should be qualified
• Qualification includes: precision, specificity, LOD, LOQ, linearity, robustness
• Robustness is often missed
• Think about validation before you start even though it is required later in the process
• Analytical Procedures for Biologics – resource from FDA
• Q2R2 Validation of Analytical Procedures
   

Question 3: Does the FDA have recommendations on how to identify and establish product critical quality attributes (CQAs) during product development and for commercial manufacturing?
Key Takeaways:

• CQAs are derived from target product profile (TPP)
• As part of PD, recommend measuring a wide range of product attributes that could define mechanism of action (MoA) and clinical effectiveness
• As you continue, you can narrow down options
• Guidance – Q8R2 Pharmaceutical Development
   

Question 4: The “Potency Assurance for Cellular and Gene Therapy Products” draft guidance highlights the importance of using formal risk assessment tools to comprehensively assess risks to potency. Could the FDA elaborate further on how to effectively conduct risk assessments?
Key Takeaways:

• Risk assessment (RA) begins with identifying what might go wrong and factors that could impact potency at various stages: manufacturing, pre-release, post-release, shipping, etc.
• Have a good understanding of MoA and potency-related CQAs
• Look beyond release – consider shipment container
• Can evolve as manufacturing process changes
• RA needs to be done before implementing any manufacturing changes or reagent substitutions
   

Question 5: What types of readouts are suitable for potency assays, and does the FDA recommend using multiple potency assays or specifications for release testing?
Key Takeaways:

• Start with broader risk-based potency assurance strategy
• Ensures that CQAs that impact potency are well-controlled
• Prioritize high-risk potency-related CQAs and ensure they are accurately assessed
• Should use quantitative readouts
• Clear acceptance criteria should have a well-defined lower limit and upper limit and should be based on data collected during clinical trials and refined as more is learned about the product
• Recommend using multiple potency assays to measure several CQAs that contribute to the therapeutic effect
• New CQAs may be identified and included over time

 
Question 6: How does the FDA recommend assessing the potency of complex tissue-engineered products in late-stage development, especially when the product’s therapeutic effect is influenced by multiple cell types or scaffold materials?
Key Takeaways:

• Potency often depends on combination of attributes and how they interact
• Conduct broad assessment that considers characteristics from all stages of product manufacturing (cells, cells on scaffold, cells off scaffold, etc.)
• Detailed characterization data with combo of destructive and non-destructive tests
• Assess the integrity of final construct and uniform cellular distribution across scaffold
• Potency-related CQAs should be included in late stage IND

Question 7: Does the FDA have recommendations on how to establish release specifications for inherently variable cell therapy products?
Key Takeaways:

• Yes! For all stages the IND should provide product specifications and criteria for how you chose them and data to support choice
• Phase I is less stringent than later stages
• BLA needs commercial specifications from lots shown to be safe and effective during clinical studies
• Release acceptance criteria may be based on clinical manufacturing experience if CQAs don’t necessarily correlate with clinical outcomes
• Submit proposed product specs under an amendment to IND before final BLA
   

Question 8: What are the FDA’s expectations for batch release testing when batch sizes are small or available material is limited?
Key Takeaways:

• Optimize release assays throughout product development to ensure you can perform all tests with amount of product you have
• If not possible (limited material), may be able to use surrogate sample for some release testing, but this would need detailed scientific justification that the surrogate is representative of the final product
• Could use of less than conventional sample size – has been used for sterility testing – but must be shown through qualification and validation studies
   

Question 9: For tissue-engineered medical products that are not amenable to destructive sampling, what alternative approaches does the FDA recommend for conducting product release testing?
Key Takeaways:
Strategies:
o   Manufacturing an additional unit in same batch specifically for testing
o   Use by-product from product or smaller size of the product

• Need to represent CQAs of the final product
• Consult FDA before implementing alternative strategies
  

Question 10: Do late-stage INDs have different requirements for raw material/reagents than early-stage INDs? Does raw material identity testing need to be implemented prior to initiation of a pivotal study?
Key Takeaways:

• No differences
• Want to ensure consistency of manufacturing and safety
• Amount of information needed to support safety of the material will depend on the nature of the reagent
• Raw material identity testing is not needed during pivotal studies, but FDA would recommend looking into it during pivotal studies because it is needed for BLA
   

Question 11: Can master files be referenced for late-stage INDs and in BLA submissions?
Key Takeaways:

• Yes – However, depending on information in the master file, that may not work for BLA
• Drug substance (DS), DS intermediate, or drug product (DP) info cannot be referenced in master file for BLA submission
  2019 FDA Guidance – Drug Master File Guidance for Industry
   

Question 12: What are the FDA’s expectations regarding the use of surrogate materials (e.g., healthy donor material) for the process performance qualification (PPQ) runs?
Key Takeaways:

• Obtaining patient material for PPQ runs can be tough
• Healthy donor material can be acceptable, but needs validation of healthy donor material system since healthy donor material may not reflect behavior of patient cells during manufacturing and release
• Discuss with FDA prior to initiation of PPQ studies
   

Question 13: Does the FDA have recommendations for how to perform stability studies for products with limited material or shelf life?
Key Takeaways:

• Design of stability study protocols is dependent on unique nature of product and product stability
•  Provide justification on study design plan if you have limitations in final product size
• Could use justified surrogate for certain shipping studies to assess stability of product
   
  

Question 14: What are the FDA’s expectations for stability testing of tissue-engineered products during late-stage IND development, given their unique storage and handling requirements?
Key Takeaways:

• Address factors that impact stability, potency, structure over time
  o   Temperature, vibrations, transit time, environment
• Look at under real-time and accelerated timelines 
• Assess scaffold for ability to maintain cell distribution and stability of scaffold over time
• Flow dynamics, nutrient supply
• Ensure CQAs remain consistent and final product maintains potency and efficacy
• Simulate real-world handling and shipping conditions and assess how factors impact product potency and efficacy
   
  

Question 15: How should sponsors determine when a late-stage manufacturing change requires a comparability study?
Key Takeaways:

• Recommend reviewing ICH Q5
• Manufacturing Changes and Comparability FDA Guidance (2023)
• Perform risk assessment to determine is manufacturing changes have the potential to impact product quality
• Ask: How likely is it that the risk could occur? How significant is the risk to product quality?
   

Question 16: How do sponsors successfully demonstrate comparability when the number of batches manufactured or samples available for testing are limited?
Key Takeaways:

• Always start with risk assessment to identify impact of proposed change and inform the level of studies needed to inform change
• Recommend using split starting materials for comparability assessments to remove variability in starting materials
• If not feasible, study may be designed as comparison of pre-change data to testing of post-change lot data. The study needs to be statistically valid, so consider number of lots that might be needed.
• The single change made between lots should be the only change being evaluated in the comparability study.
• Also ensure analytical method does not change.
   
  

Question 17: What are the most common issues the FDA sees when assessing a comparability package for a manufacturing process change?
Key Takeaways:

• Insufficient identification of CQAs and evaluation
• Start product characterization early and continue throughout PD to identify good CQAs
• Release testing alone is generally insufficient to demonstrate comparability
• Analytical assays may not be properly qualified.
• Assays used for extra assessments outside release criteria do not have to be qualified but should have scientific justification.
• Request FDA input through IND amendment or meeting

 
Question 18: What specific design controls and testing strategies should be implemented for combination products in late-stage INDs, particularly when introducing a new device or a new version of a device with a biologic?
Key Takeaways:

• Implement specific design controls and testing strategies to ensure safety, effectiveness, and useability / stability
• Risk assessment should identify potential failure modes and new risks introduced by the integration
• Does the device affect the product’s stability, safety, effectiveness, quality?
• Should set clear performance thresholds for the device and biologic
• Conduct a risk assessment (RA) and verification of CPPs
   

Question 19: What are the FDA’s CMC expectations and key considerations when submitting late-stage INDs based on products manufactured and studied in foreign countries, particularly regarding alignment with U.S. regulatory requirements?
Key Takeaways:

• Aligns with 21 CFR and guidances
• Have to be produced under standards of the United States
• CMC documentation should address the manufacturing site, controls, and product specifications to ensure alignment with FDA expectations
• Discuss differences in foreign vs US regulations with FDA
• Differences in donor eligibility criteria may require exemption request – especially if the foreign lab is not CLIA approved or do not use testing verified under 1271

Question 20: Are there any FDA resources/programs to further help sponsors with CMC development?
Key Takeaways:

• New program called “CMC Development and Readiness Project” (CDRP)
• Expedite CMC development of CGT products through more communication with FDA
• Help CMC keep pace with clinical development timelines
• RMAT eligible to apply – other eligibility criteria apply
• Get two new Type B CMC meetings
• For more information, search on the web for FDA CDRP 

Town Hall Portion:
Common issues with container closure, extractables, and leachable studies?
Key Takeaways:

• Most critical when product moves from late-stage studies to BLA
• Perform extractables studies with exaggerated conditions
• Leachable studies are performed with actual DP under real-time product storage conditions over product shelf life
• Toxicology RA is used to determine if chemicals detected are within limits per route of administration
• Leachables start to accumulate as early as the DS stage from tubing, containers, container closures
• Issues seen at scale up and scale out can change container systems
• Issue seen – sponsor relies solely on studies conducted by container supplier that do not replicate actual DP
   

FDA expectations for demonstrating comparability of manufactured tissue engineered medical products (TEMPS)?
Key Takeaways:

• Recommend thorough RA that determines effect of change on cells/scaffold/final construct
• May need comparability studies to assess all relevant parts of the product
• Should include effect of drug product quality post-administration as well 
• Evaluate the performance of TEMP in a physiologically relevant environment
• Could sample incubation media for certain CQA evaluations

Recommendations for potency assay development for cell therapies when there is limited time between harvest and administration?
Key Takeaways:

• Use other rapid assays for lot release
• Potency assay can be performed after releaseAre the requirement
   

Are the requirements for process validation similar for all cell therapies?
Key Takeaways:

• Yes, validation should be performed to evaluate all steps, including product release
• 2011 guidance - Process Validation Practices
   

For a Ph 3 study, do the potency assays require established acceptance criteria or can this be determine during Ph 3?
Key Takeaways:

• We would want acceptance criteria before Ph3, but it can be refined over Ph3.
   

Does FDA have advice on how to set acceptance criteria for comparability studies?
Key Takeaways:

• Criteria should be based on understanding of the effect of the attribute on the safety and effectiveness of the product
• If you don’t have a data set to establish biologically relevant acceptance criteria, you can use historical data to set acceptance criteria
• Should justify how your statistically based acceptance criteria fit the product
   

Can one potency assay by used for multiple products and indications?
Key Takeaways:

• Potency assays are designed to measure specific biologic activity that aligns with distinct MoA, so it is challenging for one assay to be applicable across products
• Related products with similar MoAs and CQAs may share a common core assay, but even then other product-specific qualifiers are needed
• Can you use one potency assay when a product is used across indications? Yes, if the product’s MoA does not vary across indications (maybe targets same biological pathway across indications)
   
  If a major manufacturing change was implemented after the pivotal study, can comparability studies be accomplished using an analytical comparability study alone?
  Key Takeaways:
• Hard to answer – depends on the type of change and level of understanding of product CQAs and impact on safety and efficacy of product
• Discuss with us first
   

What are FDA expectations for use and qualification for reference standards for release assays?
Key Takeaways:

• Limited availability
• Don’t typically see reference standards included in cell therapy INDs
• Testing should be performed for qualified in house reference materials
• Need appropriate documentation and material reserved for study to avoid issues with data analysis
• Need to qualify batch of reference material – identified, tested, released, stored, and qualified upon first use by comparison with previous lot
• Include all data in IND
   

Can in vivo potency tests be used for lot release in late stage INDs?
Key Takeaways:

• Yes, they can be used, but are generally less recommended as you move to commercial approval
• Replace with in vitro alternatives when possible – 3 Rs of animal use
• Often have higher variability due to biological differences between animals and are time consuming, which can delay release
• In vitro tests are often cheaper and more practical
   

Recommendations when setting a low viability for cell therapy products (less than 70%)?
Key Takeaways:

• Yes, this can be encountered, and we ask that you provide scientific justification in support of this criterion, including data that product is safe at that level

FDA expectations for reference material for potency assays?
Key Takeaways:

• Can use potency reference material with an assigned value for potency
• Can develop in house reference material that is thoroughly qualified and monitored for stability
• Have a plan for replacement before exhausting the supply
• In some cases, you may select a well-characterized lot of DS or DP as reference material
• Material needs to be relevant to CQAs and available in an ongoing manner 
   

What data is necessary to assess container closure in Ph 3 study?

• Need data for compatibility of container closure with product
• Will need new shipment studies for stability
   

During late stage INDs, can product lots that do not meet release criteria be administered?
Key Takeaways:

• Out of spec products should be rejected but can be administered if the patient has been preconditioned
• Sponsors needs to reach out to FDA PM and provide RA and request to release before release of out of spec product
   

Expectations for shipping stability studies in late stage?
Key Takeaways:

• Have stability protocol to evaluate shipping conditions
• Conditions need to be fully validated before BLA
• Conditions need to be qualified before IND
   

How can we get FDA feedback on comparability studies?
Key Takeaways:

• Submit comparability protocol as amendment to IND with feedback prior to performing comparability studies
• Can submit meeting request to RPM and provide specific questions
   

Should we use licensed HSA only?
Key Takeaways:

• We recommend that you use the best available HSA that is licensed in the US
• Submit package insert in IND and ensure no lots of HSA have been withdrawn from the market
   

Does FDA expect numerical criteria for all in process controls and release specs?
Key Takeaways:

• Yes, all need numerical criteria
• Is okay to have broad range that can be refined through Ph3 studies
   

Facility controls expected for manufacturing of Ph 3 biologics? Does FDA inspect Ph 3 facilities?
Key Takeaways:

• Cover earlier phases as well
• Phase specific cGMPs are expected for all products under IND
• Need increasing amounts of information and requirements as product progresses 
• By later phase, you should have control of the process to ensure control of product quality
• Segregation, tracking, deviation investigations, QC/A oversight documented
• Many sponsors use contract manufacturing and testing organizations for studies – important that IND sponsor is responsible for making sure cGMPS are followed and info is provided under IND
• FDA does inspect during BLA review period and there are surveillance inspections after licensure
   
  

Can multiple scientifically sound and fit for purpose potency studies be used at the stage of the pivotal study? And then can one final study be validated for final submission?
Key Takeaways:

• Absolutely
• Recommend you ensure you collect sufficient information to justify selection of final potency assay and acceptance criteria
   

Besides potency, what are some common challenges for late stage studies?
Key Takeaways:

• Manufacturing changes necessitating comparability studies
• Introduction of commercial manufacturing facilities – we recommend moving to this facility prior to the pivotal study with all planned release criteria testing
  See additional upcoming sessions

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