While only 18 cell and gene therapy products have been approved by the FDA in the United States, there are 37,000 clinical trials underway for cell therapies.  Of these trials, 1,000 of them are for chimeric antigen receptor T cells, commonly known as CAR-T cells.  40 of these trials are already in phase III.

On Sept. 29, Adam Lambert, Vice President, Product and Process Development, Pharmatech Associates, discussed the CMC requirements for these innovative products in the Redica (then Govzilla) webinar, “CMC Considerations for Cell and Gene Therapy Products.”

Lambert began his presentation by reviewing production processes. He described three processes:

  • Upstream processes
  • Downstream processes
  • Post-production processes required as part of product development

“This is not a complete list,” he said.  “A lot of these processes are similar to what you find in biologics, but they’re very different as well.  For example, viral vector production is both an upstream process for gene packaging in CAR T-cell therapy, as well as for the viral vectors that are also used as therapeutics themselves.”

[Related: Download the full webinar, “CMC Considerations for Cell and Gene Therapy Products,” featuring Pharmatech Associates’ Adam Lambert.]

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CGTs Frozen Out in Supply Chain

Further, Lambert explained that post-production processes are extremely critical.  “Cold chain storage and distribution is also a critical process because most cell therapies or gene therapies, a lot of these are stored at -80 degrees.  They’re cold, they’re frozen, and maintaining that cold state chain storage and distribution is critical.”

The supply chain for cell and gene therapy products is also complex. Raw materials could even include a patient’s own cells. Other supply chain challenges include:

  • Limited raw material suppliers
  • Multiple vendors producing critical components
  • Maintaining the cold chain
  • Shipping validation

Data management tools can be a vital tool in managing supply chain challenges and CMC processes.

“There’s a lot of data management software that’s specifically tooled towards pharma that can be used,” Lambert said.  “And that’s really important to put in place in the beginning if you’re going to do that because of the processes and because of the complexity of the processes.” 

But the journey for cell and gene therapy products doesn’t end when they reach their destination in the supply chain.

A Testy Process for CGTs

“You need to then test these materials. In cell gene therapy, there’s a significant amount of testing,” he said.  You have all your critical process parameters and critical quality attributes and your ancillary materials.  Then you need to verify and qualify these materials for, and all the tests need to be in place to ensure the safety and quality of these materials is appropriate.”

Ensuring proper potency is crucial due to the level of variability with these products. 

“If you’ve got a method that’s, say you’ve got a range from 70% to 130% potency, you may need to have a second method in place to ensure that you’re getting consistency. Because if you’re at the edge of your specification on the test, are you really sure that the quality of the material is there? So, given the range of these tests and the variability, that’s something that really needs to be considered. Is a second potency method needed to ensure the quality of the product?”

Analytical methods also prove challenging.

“Many of these methods are novel, and not only do you have the analytical method, but you also have reference standard considerations for these methods,” Lambert explained.  “For reference standards, you need to identify the reference standards that are required for the different methods, which ones are needed for the critical process parameter, CQAs, and the ancillary material methods. You have to source them.”

Ancillary materials is one area specific to cell and gene therapy manufacturing. He pointed to USP <1043> Ancillary Materials for Cell, Gene, and Tissue-Engineered Products. This chapter “details the risk assessments and qualification requirements for ancillary materials. Ancillary materials are defined as any raw material or material used in the production of your product.”

Case Study 1: CAR-T Process

After reviewing the myriad CMC considerations for cell and gene therapy products, Lambert provided two case studies showing how manufacturing issues can impact products. His first case study concerned a CAR-T product.

“CAR T-cell therapy is a very complex process,” Lambert said. “It starts out most of the time with a patient’s own blood being taken.  There’s a lot of factors that impact the efficacy of this therapeutic.”

While he admits that many consider CAR-T cell production a six-step process, he considers it more of a nine or ten-step process that begins with apheresis. This step involves separating a patient’s blood sample into different components in order to remove one. 

His first case study concerned a CAR-T cell product’s cell viability. In this case, 6-7% of batches could not be sold due to viability issues. The set specification of 80% is not achievable on a routine basis, and this number seemed to be selected from limited data. 

In this case, the failed lots could be administered to patients under “compassionate use.”

Interestingly, “they’re still observing efficacy though. So, even though they’re failing that criteria, the product is still observed to be effective in the patients. It’s still having a lot of clinical success.”

As far as the cause of the viability, Lambert said it could be due to a number of factors:

  • The patient
  • Collection process
  • Expansion process media
  • Cryopreservation
  • Transport

To prevent cell viability, “this is where beta software and where a beta management plan comes into play because you’re collecting a lot of information, a lot of data, and then you can go back, versus just using a spreadsheet.  You can go back. You use different software packages and identify key areas that may have an influence on the cell viability…better data analysis capability will at least provide you a little bit of a leg up on understanding the overall problem.”

Case Study 2: AAV Process

Lambert’s next case study covered an adeno-associated virus (AAV) vector gene therapy for the treatment for a retinal disorder.  This is another complex manufacturing process (Figure 1) that starts with harvesting of cells from a master cell bank that are then transfected as part of the process of producing vectors. The vectors contain a specific gene that is inserted into the viral vector. Then, the virus is recovered from the cells and purified prior to formulation and filling of product. This entire process has to be validated.

Figure 1 AAV Production Process
FIGURE 1 | AAV Production Process

For this product, Lambert reviewed the FDA filings, starting with the May 2017 submission which was accepted in July of that year. FDA completed CMC review and found it acceptable in December 2017.

He found that FDA issued 16 CMC information requests and that 58 amendments were made to the submission. His review of the information requests allowed him to locate items that failed to meet FDA expectations or were not presented clearly.

The following are some of the areas where FDA required additional information:

  • Complete data and purpose for all produced lots
  • Complete annotated sequences for all vectors used in production
  • SOPs for qualification of started materials
  • A full listing of all materials used in production
  • Cleaning verifications for plasmid purification processes
  • Data supporting drug substance and drug product
  • Assay for subvisible particulates
  • Comparison of results from different manufacturing sites
  • Shipping validation reports
  • Full 18-month shelf-life stability data (only three to nine months provided)
  • Diluent development studies
  • Storage and distribution information for post-secondary packaging of drug product
  • Data for methods supporting suitability of use

In the end, FDA only asked the manufacturer for two post-marketing commitments: a statistical sampling plan based on acceptable quality limit along with appropriate acceptance criteria for critical product defects and perform cleaning verification. 

In Lambert’s view, these two case studies illustrate the complexity of CMC requirements for cell and gene products.

“These processes are complex and they’re not getting any easier,” he said. “With treatment advances and technology advances, the development’s going to improve, but process complexity isn’t going to get any easier. So, a data management plan really should be established very early, as early as you can to be able to manage the data, but also to be able to have a plan or a means of extracting relevant information out quickly and easily that’s tied to your different quality attributes of the product.”

[Related: Are you overseeing quality and compliance for a pharma firm manufacturing cell and gene therapy products? Let us know what CMC challenges you are facing on our LinkedIn page.]

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