Although cell and gene therapy (CGT) products that treat previously untreatable diseases are being approved, manufacturing these products can be challenging. Cell therapy manufacturing uses living cells, so stability can be an issue for both source materials and final products.

Frequently the shelf life of these products is just a few hours. This presents logistical issues, including scheduling, manufacturing, shipping the cells, and ensuring the product gets to the treatment site before it expires.

At the ISPE Biopharmaceutical Manufacturing conference held virtually in early June, CBER Division of Manufacturing and Product Quality Facilities Reviewer and Investigator Ekaterina Allen reviewed manufacturing and quality challenges for CGT products, the regulatory requirements, and the most common agency observations made during inspections of cell and gene therapy manufacturing facilities by quality system [Editor’s Note: Part II will cover the latter.]

[Related: Learn more about the CMC aspects of CGTs in our on-demand webinar featuring Pharmatech Associates’ Adam Lambert. Download the webinar here.]

What are CGT Products?

“Before we delve into the problems, I would like to talk about the challenges that manufacturers of these products face and regulatory requirements they must meet, as well as how meeting these requirements is evaluated during inspections,” Allen said.

What are CGT products? Cell therapies encompass a wide spectrum of patient-specific products. They can be both autologous and allogeneic. Each one of these subtypes comes with its own regulatory concerns.

Autologous products are those where cells are taken from an individual patient, treated, or expanded in some way, and then returned back to the patient they came from in order to treat their disease.

For allogeneic products, the source material is donor cells. They can range from a single product that is targeted to a relatively small population of patients to highly customized products designated for just a single patient.

That is true for gene therapy as well, which entails modifying a person’s genes to treat or cure a disease. There are several ways gene therapy works:

  • A faulty gene can be replaced with a healthy copy
  • A disease-causing gene can be inactivated by a gene therapy product
  • A completely new or modified gene can be introduced into the body to help treat a disease

Another aspect of gene therapy is how it is administered. It can be administered directly into the body of a patient, or a patient’s cells can be removed from the body, treated with gene therapy, and then returned back to the patient.

Manufacturing and Quality Challenges

The nature of these products drives the challenges that manufacturers face and must resolve. When it comes to cell therapy manufacturing, the main challenge comes from the use of living cells, so stability can become an issue. This is true for both source materials and final products.

Frequently the shelf life of these products is just a few hours. As mentioned above, these present logistical challenges. Normally the final product must arrive at the treatment site before it expires. It must be administered, and sometimes it is quite challenging to make sure that everything is orchestrated and is on time.

With a short shelf life also comes a challenge of QC testing. Some release tests, like sterility testing, normally require 14 days to get the results. If the product’s shelf life is only 24 hours, “clearly that test is not going to work for you,” Allen pointed out. “So that must be resolved in some alternative way.”

There are additional concerns regarding sterility. Cells cannot be sterile-filtered or sterilized in any other way. “These products must be manufactured aseptically from beginning to end, which is why we, as a regulatory agency, are particularly concerned about the sterility of these products,” Allen emphasized.

For autologous patient-specific therapies, even though each lot is not a new product, technically, it is still unique because it is made of the cells of a specific patient. As a result, segregation, change over, and line clearance becomes critical.

These are not only critical for autologous products but for all others as well because typically cell therapy products are manufactured in multi-product facilities. The product may be highly variable and often insufficiently characterized due to inherent variability in the starting material. And it can be difficult to develop a potency test that would be a good reflection of the product’s function.

These products must be manufactured aseptically from beginning to end

As far as gene therapy manufacturing is concerned, challenges also stem from the nature of the product. “In most cases, gene therapy products are viral vectors, so containment, segregation, changeover, and line clearance play a particularly important role in the manufacture of these products,” Allen said. “Some of the commonly used viral vectors, such as adeno-associated virus, are notoriously sticky and difficult to clean. So disinfectant effectiveness and cleaning become also important.”

Although many gene therapy products can be sterile-filtered, some of them cannot be, so there are sterility concerns. Those that cannot be sterile-filtered, just like cell therapy products, must be manufactured aseptically from beginning to end. In addition to that, if the gene therapy product is one where the patient’s cells are treated rather than the patient, then all the cell therapy challenges also apply.

3 Types of Inspections

These products must meet the statutory GMPs per section 501(a)(2)(b) of the FD&C Act. CGT products are biologics, but biologics are also drugs. As a result, the current GMP (CGMP) regulations, 21 CFR 210 and 211 would also apply, as would the additional biological product regulations in 21 CFR 600-680 and 1271 on human cells, tissues, and tissue-based products.

Meeting these requirements is verified during inspection. There are three different types of inspection FDA performs depending on the developmental stage of the product. If it is a new product, then a prelicensing inspection is typically performed during the last part of the review of the Biologics License Application (BLA).

If the product is already approved and a significant change occurs and the manufacturer submits a preapproval supplement, then a pre-approval inspection can be performed—for example, if it is a change such as a new facility, a new manufacturing suite, or a new formulation.

CGT products are biologics, but biologics are also drugs

In addition to those inspections, there is also a biannual surveillance inspection that is performed to ensure that the manufacturer continues to meet CGMP requirements. That one is performed by Team Biologics within the Office of Regulatory Affairs. The other two inspections are performed by CBER’s Office of Compliance Division of Manufacturing and Product Quality.

At the end of the inspection, if the team found any objectionable observations, they will issue a Form 483 where all these observations would be listed in the order of importance by criticality.

The CGT Inspection Landscape

Allen pulled all the 483s issued for cell and gene therapy facilities since the very first inspection in 2007 and analyzed what types of observations were the most common.

When she did the review, she explained, she excluded pre-approval inspections “because those typically have an extremely limited focus. I also excluded cord blood products. Those products are cell therapy products, but they are regulated somewhat differently from the bulk of cell and gene therapy products. It made sense to exclude them” (Figure 1).

Figure 1 Cell and Gene Therapy Inspections 2007-2020
FIGURE 1 | Cell and Gene Therapy Inspections 2007-2020

483s were issued to 17 facilities between 2007 and 2020. Most of those facilities are cell therapy facilities, and they are mostly located in the US. A total of 35 inspections were performed in the past 13 years, so 35 483s were issued at the 17 facilities.

Keep in mind that some of these products have been around for a while and have been inspected more than once. Some facilities have been inspected multiple times by Team Bio. There were also issues with a couple of pre-license inspections.

About half of the 483s were issued at the end of pre-licensing inspections, and the other half resulted from surveillance inspection by Team Bio.

[Editor’s Note: Part II of this series provides extensive detail on the FDA’s quality systems approach to CGT inspections.]

[Related: Learn more about the CMC aspects of CGTs in our on-demand webinar featuring Pharmatech Associates’ Adam Lambert. Download the webinar here.]

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