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While new industry guidance documents issued by FDA speak to the agency’s efforts to promote the development of new gene therapies, certain hurdles remain to challenge stakeholders.
The focus on developing emerging therapies, especially cell and gene therapies, has intensified, making the need for good manufacturing practices (GMP) guidance more imperative. In its specific efforts to promote the development of novel gene therapies, FDA published six final guidance documents on gene therapy manufacturing and clinical development and released a draft guidance on gene therapy products under orphan drug regulations in January 2020. To date, the agency has approved four gene therapy products (1).
How do these new FDA guidance documents help gene therapy developers and contract service providers navigate the challenges of gene therapy development and manufacturing? TheChemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs) (2) guidance, for one, provides a comprehensive framework to guide the development of a broad range of products, says Karen Magers, head of Regulatory Affairs Cell and Gene Therapy Technologies, Lonza. The guidance document provides many recommendations that help to clarify the expectations for product development, characterization, manufacturing, and testing of these products, she points out.
“Stakeholders, including Lonza, submitted comments [to FDA] requesting clarification on the information to be submitted prior to a first-in-human clinical study and information to be submitted in a phased approach, as more manufacturing experience is obtained during product clinical development. FDA acknowledged in the final document that ‘information may be limited in the early phases of development and recommends that sponsors provide additional information and updates as product development proceeds’,” she states. However, because limited specific recommendations and examples were provided in the guidance, there are remaining challenges in determining the requirements for first-in-human studies and subsequent clinical studies, she continues.
Others note that, with the guidance documents, the challenges to gene therapy development and manufacturing are what they have always been. “I don’t think there is anything unexpected in the final CMC guidance,” says James Blackwell, PhD, principal consultant and president of The Windshire Group, a Boston, MA-based biopharmaceutical consulting group. “The challenges are what they have always been. However, there are numerous challenges posed in the guidance for developers.”
Blackwell narrows down challenges his group has experienced, which will likely be the same experiences that other stakeholders in gene therapy development will also experience. First, for any combination product or potential combination gene therapy product, developers should carefully assess the available guidance and make early assessments in the program because the regulatory and documentation requirements can vary significantly for various components. “For areas of doubt, one should engage the Health Authorities early. This can be a challenging area for emerging technologies,” Blackwell says.
Blackwell also points out that there is a higher burden, compared to traditional products, for gene therapies to understand critical attributes and parameters earlier in the development cycle while trying to establish as robust of a process as early as possible. This burden stems from the complexity of a gene therapy product.
“The benefits of doing so are dual. First, you minimize the need for change later and, if change is needed, you have a more solid basis for rationalizing and approaching it to minimize impact to development timelines. The latter point is always important but will be a key consideration for many of these programs,” Blackwell states.
“Containers used for drug substance and drug product need to be closely scrutinized for products that can’t be filtered,” he continues. “The level of particulates may not be controlled as closely as needed during the manufacture of these components, and the particulates will end up in your product if not controlled or removed in advance. For some of these suppliers, a gene therapy developer represents such a small part of their overall business that the supplier will not accommodate changes deemed necessary by the developer. Particulates and their potential to cause adverse events have been the subject of increasing regulatory scrutiny.”
The bottom line to having these gene therapy guidance documents, however, is to facilitate not only the development and current good manufacturing practice (CGMP) compliance of gene therapies, but also the regulatory pathway to drug approval. “I’ve found the guidances, including these, to be invaluable to understanding expectations. One thing that stands out to me in these guidelines was the number of places the agency understood there may be differences in approach or technical, practical, and scientific limitations to meeting the ideal requirements of the guidances,” Blackwell emphasizes.
“Still, in those situations, knowing what the expectation is helps one develop a rationale, data set, and construct that address the issue and why the alternate approach does not represent a risk to the safety, identity, strength, purity, and quality (SISPQ) of the product,” he adds.
The two guidance documents (2,3) that include CMC-specific recommendations also provide clarity on many aspects related to the manufacturing and testing requirements for gene therapy products, Magers asserts. “[These] documents provide both general guidelines and specific recommendations. As an example of a general guideline, FDA provided information supporting the classification of viral vectors. Comments on the draft Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs) document sought this clarification. In the final version, FDA cited regulation to confirm their position that a vector ‘used to transduce cells ex vivo and which furnishes a pharmacological activity for the treatment of disease is a critical component. Without the vector, the resulting cell product would not have the same pharmacological activity. Similarly, a vector in its final formulation for administration of the genetic material is generally considered a DP [drug product]’,” Magers cites.
She notes that FDA gave examples of specific vector recommendations, which include replication competent retrovirus (RCR) testing of cell banks, vector-harvested material, and ex-vivo transduced cells. FDA had also given an example of the derivation in its recommendation for an appropriate test volume for RCR detection.
At present, there are still hurdles to overcome in the manufacturing of gene therapies, and a number of biopharmaceutical companies as well as contract manufacturing organizations/contract development and manufacturing organizations are tackling these challenges.
For one, gene therapy (and cell therapy) manufacturing is still a highly manual aseptic manufacturing process, which poses several challenges, says Magers. It is important to consider the correct and functional layout of cleanrooms and the number of trained operators needed for those cleanrooms, he points out. She also emphasizes the high importance of ensuring the qualification of sterile consumables and raw materials because, often, only research-grade material is available and there is no GMP material available to replace them when manufacturing is scaled up.
“We are also observing a high investment in infrastructure and facilities in contrast to low throughput areas (personalized medicine, small batch sizes-down to one batch per patient), as well as unclear expectations for concurrent manufacturing of several batches and product segregation strategies,” Magers notes.
Navigating the regulatory landscape and complying with regulations can be difficult as an international manufacturer, Magers also observes. “There are three main regulatory systems: European Union (EU) GMP regulations, United States (US) GMP regulations, and Pharmaceutical Inspection Co-operation Scheme (PIC/S) regulations,” she states. “The new Good Manufacturing Practice Guidelines on Good Manufacturing Practice Specific to Advanced Therapy Medicinal Products (EU GMP part IV) (4) does not provide the most straightforward guidance and expectations. Moreover, it refers to risk management, which is not easy to navigate, as the perception of risk is subjective to a certain extent.”
Magers also points out that these new EU guidelines exclude the link and reference to GMPs for other pharmaceuticals, including in Annex 1, Manufacture of Sterile Medicinal Products (Corrected Version) (5). “However, the PIC/S and the US will not adapt to this move. Therefore, the ‘classical’ pharmaceutical regulations apply to products that will be licensed in those regions. Furthermore, many countries are part of more than one of these regulatory systems (e.g., EU GMP and PIC/S, US regulations and PIC/S); navigating through expectations from different regulatory bodies will soon arise and need to be complied with,” she adds.
“I think one of the biggest challenges will be the complexity of the supply chain demands, both on the front end (starting with supply of materials or patient samples) and back-end (delivery to the patient),” observes Blackwell.
“Some of these products and technologies use relatively novel materials, and the suppliers are not mature from the standpoint of their manufacturing processes and quality systems. In some cases, the sponsor will need to help the supplier and improve and reduce risk. The bar keeps getting raised as the products enter Phase III and commercial manufacturing. So how these critical components will be sourced in a compliant manner needs to be assessed early in development and planned for with risk-reduction strategies,” Blackwell adds.
Blackwell brings up another source of compliance complexity: data integrity requirements and management of these data from patient, to testing and manufacturing, and back to patient. “Now imagine that this is all happening by paper documentation now. As patient loads increase in clinical trials, managing this and avoiding and dealing with mistakes becomes herculean, if not impossible. The integration of compliant electronic tracking and data-sharing technologies from patient to lab, to manufacturing, and back to patient is paramount and a challenge,” he stresses.
Further, the definition of the “control space” around the product is becoming another hurdle. For traditional products the “control space” has entailed batch manufacturing, batch area clearance, and various room checks to limit the risk of cross contamination and product mixups. For many of the newer technologies, Blackwell asserts, the traditional manufacturing model simply won’t be economical.
“The control space around the product will need to shrink to accommodate simultaneous and parallel manufacturing on the same production floor. Again, the interplay of data technologies (e.g., radio frequency identification, wireless, mobile, barcode, manufacturing execution system) and engineered controls (e.g., electronic batch records) to ensure compliance and the SISPQ of the product will be essential. These systems will need to interact with the quality system in real time and be validated to support release by exception. Unexpected events will need to be investigated immediately and alerted by the electronic process monitoring systems,” Blackwell explains.
Gene therapy stakeholders would do well to have a set of best practices that will help keep the development of a novel gene therapy in compliance with new regulatory guidelines. Early and frequent use of risk assessments is a good practice that can greatly enhance process understanding and focus efforts, for instance. Gene therapy, as well as other emerging therapy products, required a broad and deep understanding of the science behind them in order to do proper risk assessments, Blackwell says. “This will often entail close collaboration between R&D scientists, process scientists, and quality control, especially early in the development program before little process data and manufacturing history has been garnered,” he adds.
Blackwell considers that stakeholders for a number of these products will seek expedited approval pathways, which will compound the challenges with CMC because of the shortened timelines. He notes that it is always challenging to keep CMC off the critical pathway under any circumstance, and when these pathways get expedited, the pressures on CMC activities are enormous. Unfortunately, there will be no relief from FDA in terms of meeting the expectations and spirit of the guidance documents. “Again, strategic and project planning that links to the data and technical reports requirement and regulatory expectations is clearly a best practice,” Blackwell says.
Blackwell believes it is helpful to always keep the end-goal (i.e., commercialization) in mind. “Is a change really needed now, or can it wait until after approval and commercial launch? But, having the end-in-mind is not enough. Starting early with a strategic and project plan focused on regulatory requirements and guidance pays tremendous dividends. It helps to make sure things are not overlooked, and helps the team make appropriate adjustments quickly when things don’t go as planned. They almost never do,” he says.
Another best practice Blackwell recommends, though on a different tact, relates to process, equipment, and facility validation. “Many of these processes will need to scale up on parallel and not in scale like traditional products. Thus, the master validation plan should accommodate this by simplifying the level of qualification needed for new product lines and suites,” Blackwell says.
He also advocates using quality-by-design and product lifecycle approaches, which are the best ways to meet all these challenges. “For example, the target product profile is one of the few tools in an organization that brings most of the key stakeholders together, including commercial, medical, CMC, regulatory, and quality; keeps everyone on the same page; and focuses efforts. Start early with it since it becomes a living document that has the end-in-mind,” Blackwell states.
Meanwhile, although the new gene therapy guidelines issued by FDA are a significant step forward in moving new gene therapies through the regulatory process toward approval, some note that further GMP guidelines are still needed. Magers points out that although GMP requirements have been issued that are specific to gene therapy products, FDA has not yet issued a guidance document that contains detailed GMP recommendations.
The EC’s GMP guidelines for advanced therapy medicinal products (4) that went into effect in May 2018 contain detailed recommendations, Magers observes. “Some of these recommendations were included in the PIC/S GMP Guide Annex 2A Manufacture of Advanced Therapy Medicinal Products for Human Use (6), which was issued for public comment from September to December 2019. FDA is providing recommendations to address specific topics (e.g., recommendations for multiproduct cell and gene therapy manufacturing facilities) in public forums, however, no guidelines have been issued,” Magers states.
“In addition, it would be beneficial if FDA would update some CMC guidance documents to reflect their current thinking. Guidelines that should be updated include the Content and Review of Chemistry, Manufacturing, and Control (CMC) Information for Human Somatic Cell Therapy Investigational New Drug Applications (INDs), issued April 2008, and the Potency Tests for Cellular and Gene Therapy Products Final Guidance for Industry, issued January 2011. Further, a guideline addressing comparability approaches for cell and gene therapy products is needed, as changes are often made during the development of these products that require an assessment of comparability,” Magers adds.
Blackwell points to an area where future guidance will likely be needed, and that is in “bedside manufacturing” and “distributed manufacturing” in non-GMP environments. “The CGMPs, guidances, and technology will be pushed to its limits to ensure the SISPQ of the product is ensured. Guidances that will be particularly useful will be on process analytic technology (PAT), CFR [Code of Federal Regulations] Part 11, and risk assessment, but I expect new guidance that tie these together in conjunction with these types of technologies will be needed. For example, how will the quality unit oversee and interact with these technologies? What will be deemed acceptable? Appropriate engineering controls; analytics, testing, and release; validation; data integrity; handling unexpected events; handling and control over the manufacturing equipment will be especially challenging,” he concludes.
1. FDA, “FDA Continues Strong Support of Innovation in Development of Gene Therapy Products,” Press Release, Jan. 28, 2020.
2. FDA, Guidance for Industry, Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs) (CBER, January 2020).
3. FDA, Guidance for Industry, Testing of Retroviral Vector-Based Human Gene Therapy Products for Replication Competent Retrovirus During Product Manufacture and Patient Follow-up (CBER, January 2020).
4. EC, Guidelines on Good Manufacturing Practice Specific to Advanced Therapy Medicinal Products (Nov. 22, 2017).
5. EC, Annex 1, Manufacture of Sterile Medicinal Products (Corrected Version) (Nov. 25, 2008).
6. PIC/S, GMP Guide, Annex 2A, Manufacture of Advanced Therapy Medicinal Products for Human Use (Sept.–Dec. 2019).
Vol. 33, No. 3
When referring to this article, please cite it as F. Mirasol, “Navigating GMPs for Gene Therapies,” BioPharm International 33 (3) 2020.