Advancements in gene- and cell-based therapies now link the emerging field of advanced therapy medicinal products (ATMPs) to all aspects of the pharma industry. Yet traditional GMP approaches to these products face a multitude of challenges, such as short shelf-lives, specific temperature requirements, facility usage, control strategies, and more. Manufacturers, regulators, and suppliers are all responsible for overcoming these challenges.

In the United States, the US FDA is inundated with data regarding the production of these nascent technologies, although presentation of the data in common terms and conversion of it into knowledge and understanding of the products and processes is lagging. The process for using data to rationalize decisions needs to be integrated with the Quality Risk Management (QRM) process.

The Bioassay Methods Group of the US National Institute of Standards and Technology’s Biosystems and Biomaterials Division is working with industry on one specific aspect of this issue: off-target genome editing. Off-target genome editing occurs when a gene therapy modifies genes other than those causing the disease-state of the patient; in other words, genes that are not the “target” of the therapy. Naturally, this introduces the potential for a negative impact, the results of which can be unpredictable. For example, the mistakenly altered genes could result in another ailment, such as dysfunctional enzymes, overreactive hormones, or even cancerous growth of cells. In other cases, the unintended modification may have no repercussions at all. The Bioassay Methods Group is focused on determining the degree of on-target vs. off-target modifications and the subsequent identification, characterization, and evaluation of off-target genome edits and their potential consequences.

Manufacturing operations for advanced therapies can be approached in various ways. Some manufacturers, particularly new companies, may purpose-build a production facility for convenience or out of necessity, while established companies must determine how to reconfigure existing facilities to adapt to these unique products. For instance, a production site may need upgrades to meet particular requirements of a biological product, or a physical plant, while adequate, may operate below capacity due to a decreased volume of production. To compensate, several companies have employed single-use systems alongside, or in place, of conventional stainless steel equipment, a strategy that requires evaluating the possible interactions of the therapeutic product and the raw materials with the disposable equipment— sometimes across several vendors. For autologous therapies, where the starting material is often extremely limited, careful monitoring of materials and processes is crucial, creating a need for increased scrutiny of raw materials and incorporation of process analytical technology to monitor production via inline testing and sampling. Given that many therapies have a limited useful lifetime once produced, the timing of production and the facility’s distance from the recipient of the final material are also key factors. Some companies locate their production facilities geographically to account for these concerns; this may require a significant outlay for facility construction and maintenance. Others rely on contract manufacturing organizations (CMOs) for their operations, which brings its own concerns: not all CMOs are equal, so each must be evaluated individually. Depending on the biological product and processes involved—if a specialized technology/skill is required or if any of the materials are toxic or infectious—there may be few viable CMO options.

Not only do manufacturers need to innovate in this area, suppliers will need to adapt. Materials and equipment suppliers, for example, play a critical role in the development of revolutionary treatments for injuries like damaged spinal cords or knee cartilage, and for diseases like Parkinson’s and multiple sclerosis. Cell-free manufacturing systems employing GMP-compliant processes are being developed to avoid potential endogenous viral contamination and meet regulatory guidelines. Some innovative suppliers are offering microsized bioreactors capable of producing a single autologous cell therapy dose to avoid cross-contamination and drastically reduce the footprint needed to produce the treatment. Others are envisioning a dehydrated, portable “cell factory” with all components included for ondemand biomolecular manufacturing.

In the rapidly evolving arena of gene and cell therapies, there are many moving pieces and, as part of its mission, PDA intends to aid its members in navigating this ever-changing landscape. Volunteer groups are currently working to revise Technical Report No. 42: Process Validation for Protein Manufacturing to reflect the advent of ATMPs and are drafting a new technical report focused on control strategies for producing autologous cell therapies. Both are scheduled for peer review soon.

PDA is sponsoring several events in 2017 that will focus on gene and cell therapies: a workshop following the 2017 PDA Annual Meeting in April; the annual PDA Europe Advanced Therapy Medicinal Products conference in June; and a US-based meeting on ATMPs in December, PDA’s first US conference on the topic. PDA has designed these conferences and technical reports to help ATMP manufacturers, regulators, and suppliers address the challenges of these innovative products.