Cell and Gene Therapy (CGT) is one of the fastest-growing areas of research and development in the healthcare sector internationally. Some of the resulting products have been touted as miracle cures and demonstrated to provide transformative results for some patients. CGT products have been developed to treat a wide range of rare and debilitating diseases that previously had no treatment options.

Because cell therapy manufacturing processes use living cells, donor screening and CGT product stability can be issues, potentially impacting both source materials and final products. In addition, the shelf life of these products can be short – in some cases, just a few hours. These characteristics present logistical issues, including scheduling, manufacturing, and ensuring the product gets to the treatment facility and patient before it expires.

With the complexity of CGT products and their rapid growth internationally, a question arises: Would it make sense for the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) to provide regulatory guidance for the development and manufacturing of cell and gene therapy products?

ICH is an internationally recognized body that has participation from major regulatory agencies and pharma companies and has produced dozens of guidelines that have been adopted by numerous member agencies.

According to its website, ICH’s mission is “to achieve greater harmonization worldwide to ensure that safe, effective, and high-quality medicines are developed and registered in the most resource-efficient manner. Harmonization is achieved through the development of ICH Guidelines via a process of scientific consensus with regulatory and industry experts working side-by-side.” 

Should its harmonization efforts include guidelines for CGT products?

Experts Weigh In

At the ISPE Annual Meeting held in Orlando, Florida in early November, the question of approaching ICH to work on a CGT guideline was addressed by top regulators during a “Global Regulatory Town Hall.”

The session was moderated by Lonza Biologics Global Head Sterility Assurance, Cell and Gene Technologies, David Churchward.

Churchward was previously a GMP inspector with the UK Medicines and Healthcare Products Regulatory Authority (MHRA) for 17 years, with his most recent role including responsibility for regulatory collaboration and strategic direction of the GXP inspectorate. He also led the implementation of innovative compliance initiatives and provided GMP expertise to MHRA’s Innovation Office for new products and technologies.

Churchward posed the question, “as part of the recent discussion on the key elements of ICH guidance…what are the pros and cons for starting work on an ICH guide for cell and gene therapies?”

I am a little concerned that if we don’t pick the right topics to put in an ICH guidance document, we could end up having something that is obsolete before it is finalized.

FDA Center for Biologics Evaluation and Research (CBER) Director Peter Marks responded, “I think there is a dialogue that should take place about what is currently ripe for consideration for global harmonization in an ICH process versus what might be handled by some other methodology.”

He pointed out that the ICH guidance process generally takes several years to complete.

“At the rate that we are currently evolving in technology in cell and gene therapy, I am a little concerned that if we don’t pick the right topics to put in an ICH guidance document, we could end up having something that is obsolete before it is finalized.”

Marks continued, “I think we do need to have this discussion. We are going to obviously have ICH guidance on cell and gene therapies. But the question is, I think especially for gene therapy, picking the key things that we want to focus on initially, that we think will be more durable, and will make it through the process.”

Brendan Cuddy, Lead Scientific Officer, EMA, commented. “On one hand, people want ICH guidelines to be very flexible and open and give people a lot of room for maneuvering, whether for industry or regulators.

“On the other hand, I often see, at the same time, a desire for them to be prescriptive, to have a lot of, ‘this is how you do it, and you cannot deviate from this.’”

“I think that is a tension that is always going to be there. They are usually drafted in aspirational language. They are nonbinding. They do not impose additional regulatory obligations. So, you’re always going to have this level of dissension perhaps existing.”

Insights into Observations and Deficiencies for CGT

So, how can one determine the “right” topics to put in an ICH guidance document for CGT? A good starting point might be to look back at what is currently being cited by the FDA for CGT manufacturers. 

Using Redica Systems data, we looked at all 483s given to CGT Manufacturers in the last five years (2018-2022). 

To pull this information, we went to the sites tab in Redica Systems and filtered for site tags that only included “Cell and Gene Manufacturer,” and created a new group. We then went to the reports tab and ran a 483 observation report. 

For context, in the steps above, gathering this information for the analysis took less than 5 minutes. Now to take a look at the results.

For the last five years (2018-2022), we found six inspections involving CGT that resulted in a 483. 

A deeper dive into the 483s shows 33 Inferred Primary Issues, with over 50% being Quality Systems and Production. An inferred issue is one that is not specifically enumerated in the document but is identified by our system by an evaluation of the language used. We have mapped phrases and terms that show a high probability of specific issues to the corresponding quality systems as “inferred issues.”

Based on this data set, we can see that there aren’t yet many 483s directly related to CGT. However, among the primary issues for those 483s that are directly related to CGT, the majority come from Quality Systems and Production. 

Jerry ICH for CGT blog Production Issues
Figure 2 | Breakdown of Production Issue(s)

Within Production issues, Sterile Products is the biggest sub-category. Within Quality Systems, the Quality Unit and Deviations are the biggest sub-categories.

Jerry ICH for CGT blog Quality System Issues
Figure 1 | Breakdown of Quality System Issue(s)

What can we take away from this?

  • The takeaway from the experts at the ISPE meeting is that while ICH is a respected body for promulgating international regulatory guidance, the consensus processes it uses tend to be time-consuming.
  • Since the science behind the development of cell and gene therapy products is in a rapidly evolving phase, faster, more agile processes are needed to develop regulation and guidance. It would seem to make more sense for those processes to take place in individual agencies with potential international harmonization sometime in the future.
  • FDA may want to consider adding CGT guidance relevant to Quality Systems and Production before anything else.

Please contact our team to see more of the analysis or how Redica Systems can save your team time.

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