I Stock 949947128

Key Highlights

In Part One of our Decoding FDA Gene Therapy Guidances series, we discuss the significance of several new FDA guidances regarding human gene therapy and the impact they will have for drug sponsors and the future of gene therapy products. This installment discusses the FDA guidance on chemistry, manufacturing, and control (CMC) processes that was released January 2020.

Rare Disease Gene Therapy Working Group
Rare Disease Gene Therapy Working Group

The field of human gene therapy is exploding with innovation. The US Food and Drug Administration (FDA) approved multiple gene therapy products in recent years, and many more are currently in development. As of January 2020, the Center for Biologics Evaluation and Research has received more than 900 investigational new drug (IND) applications, with many more applications and approvals expected in the next few years.

With this explosion of scientific advancements come new FDA guidances regarding human gene therapy products, which are defined as all products that utilize transcription or translation of transferred genetic material, or that specifically alter human genetic sequences. These products include nucleic acids—things like plasmids, in vitro RNA, and genetically modified microorganisms—engineered site-specific nucleases used for human genome editing, and ex vivo genetically modified human cells. These products also meet the definition of a biological product, based on the Public Health Service Act.

“As a molecular biologist, it’s been amazing to watch these new technologies develop and move into clinical testing, with ever-more tools being introduced at a rapid pace,” says Amy Raymond, PhD, Director of Therapeutic Expertise at PRA’s Center for Rare Diseases.

We’ve developed this Decoding FDA Gene Therapy Guidances series to discuss the significance of several new FDA guidances regarding human gene therapy, as well as the impact they will have for drug sponsors and the future of gene therapy products. This installment discusses the FDA guidance on chemistry, manufacturing, and control (CMC) processes that was released January 2020.

Ensure quality in human gene therapy products

FDA regulations aim to ensure quality in products by requiring sponsors of IND products, including investigational products for human gene therapy, to describe the CMC processes for each drug substance. Applications for these investigational new drugs can be placed on the FDA’s clinical hold if sufficient CMC information for a risk-benefit assessment isn’t included. A recent FDA guidance specific to CMC for human gene therapy products takes this one step further.

Far too often, sponsors run into program delays due to unmet FDA expectations. Many of these unanticipated and unwanted delays can be avoided by early and transparent communication with the regulators. Sponsors that rely on vendors to manufacture their materials rather than manufacturing in-house face additional challenges, especially regarding products that may make a potentially permanent change in humans, such as gene therapy products. The latest CMC guidance lays out a clear path for drug developers to ensure they have everything they need to move forward with the development process.

Following the FDA’s framework will help sponsors provide sufficient CMC information that’s required to assure product safety, identity, quality, purity, and strength of their investigational gene therapy products. Ideally, sponsors should satisfy these requirements before submitting their IND for approval and partnering with a CRO. Unfortunately, that’s often not the case. FDA expectations surrounding CMC for human gene therapy products were not always so cut and dry, which led to many sponsors failing to realize the extent of data and information required to move their clinical programs onto the next step.

“Finalization of the CMC guidance for human gene therapy INDs will prevent some of the misalignment of expectations between sponsors and regulators, which has been an unfortunate source of delay in the development of these treatments,” Dr. Raymond explains. “Not only does the shared understanding support efficiency, but it also helps give all stakeholders confidence that, despite this being a relatively new modality, quality is assured from the earliest stages.”

Below, we outline the key components of the new FDA CMC guidance for gene therapy to help ensure your IND is ready for submission.

IND Content Review

IND applications must contain the correct administrative documents, labeling information, environmental analysis, and a general informational overview of the gene product in question. The overview should include:

  • A description of active ingredients
  • The mechanism of action
  • The proposed clinical use
  • A summary of the manufacturing process, quality controls, and information on components and starting materials’ qualifications

Critical quality attributes, including the physical, chemical, biological, or microbiological properties and characteristics associated with the desired product quality must also be submitted.

Sponsors should describe the composition of both the drug substance and the drug product. Descriptions of drug substances need to contain information on the physical, chemical, or biological characteristics, the manufacturing controls, and the testing limitations. This allows the FDA to ensure that both drug substances and drug products meet “acceptable limits” for identity, potency, quality, and purity.

For products in early development, the FDA acknowledges that CMC information may be limited and recommends that sponsors provide additional information and updates as product development proceeds, including revised limits as applicable.

INDs should include an overview of shipping, receiving, and handling of drug product processes to ensure the product’s safety, quality, and stability. Information on shipping and storage conditions, applicable expiration dates and times, and chain of custody from manufacturer to clinical site are also relevant. Be sure to describe how the product will be handled at the clinical site before administration. This includes thawing information, the addition of diluent or adjuvant, loading into a delivery device, and transport to patients, as relevant.

Addressing Quality and Manufacturing Control

Sponsors must also provide information on the drug substance’s genetic sequence. This can be represented through a schematic diagram, including a map of relevant regulatory elements, restriction enzyme sites, and functional components such as transgenes and selection markers.

The FDA guidance provides specific examples of the structural elements for different gene therapy products. Viral-based gene therapies need to include a description of the composition of both the viral capsid and envelope structures. The FDA recommends that sponsors also include specific biophysical and biochemical characteristics in addition to describing the nature of the genome.

Microbial-based gene therapies must also include:

  • The defining physical and biochemical properties
  • Growth characteristics
  • Genetic markers
  • Location
  • Description of inserted foreign genes

For gene therapies with ex vivo genetically modified cell-based products, sponsors should describe the expected major and minor cell populations in addition to the vector that contains the transgene cassette that transfers into the cell.

As sponsors describe the manufacturing process and process controls, they should include information on cell cultures, transductions, cell expansions, harvests, purification, filing, and storage and shipping conditions, as applicable.

Addressing Impurities

The manufacturing process should be designed to remove both process- and product-related impurities. Sponsors should set tests to measure residual impurity levels in products, and these tests should be described within the IND.

Process-related impurities to be tested for include:

  • Residual cell-substrate proteins
  • Extraneous nucleic acid sequences
  • Helper virus contaminants
  • Reagents used during manufacturing

One common process-related impurity for viral genetic therapy preparations is residual nucleic acid, such as substrate DNA. The presence of impurities may result in adverse effects on product quality and safety.

Product-related impurities might include defective interfering, non-infectious, or empty capsid particles or replicating recombinant virus contaminants. Ex vivo genetically modified cells may contain additional impurities, including non-target cells and unmodified target cells. The FDA encourages sponsors to measure the percentage of genetically modified cells to better understand the cellular phenotypes present in products to target specific impurity tests toward these cell populations.

Drug Process INDs

INDs should describe the drug product and its composition, including:

  • A dosage description and a list of all active and inactive components
  • The amount per unit
  • The function
  • Reference to each component’s quality standards

Components include all drug substances and excipients and inactive components. INDs should briefly describe the development of the drug product formulation, potential overages to compensate for degradation during manufacturing or shelf life, and physiochemical and biologic properties.

Learn how COVID-19 is impacting CMC processes

Navigate the complexities of human gene therapy product development

As the gene therapy space continues to develop, so do the regulations and recommendations for ensuring the safe and effective development of these therapeutics. PRA’s regulatory strategy and therapeutic experts are here to help you navigate the complexities of human gene therapy product development from initial planning to market approval and beyond. Next up in our Decoding FDA Gene Therapy Guidances series, we discuss several FDA guidances for running gene therapy studies within the rare disease space.

Learn more about our Center for Immuno-oncology, Cellular, and Gene Therapy


Sandra Bihary-Waltz, DBA, MSN—Senior Director, Global Regulatory Affairs, Regulatory Strategy and Agency Liaison

Maxime Thomas, Manager of Global Regulatory Affairs, Global Regulatory Clinical Services, Country Consultant for France

Amy Raymond, PhD, PMP—Director of Therapeutic Expertise, Center for Rare Diseases

Explore related content and topics