Advanced Medicinal Therapy Products (ATMPs) have quickly solidified their place in the industry through recent regulatory approvals and high efficacy in saving patients. As a result, we have seen a sharp incline in demand for these products, and to meet demand and ensure safety and quality, ATMP products are pushing the scientific and regulatory boundaries, asking how we can, as regulators and manufacturers, work together to ensure these critical products are delivered to patients quickly and safely.
The PDA ATMP Advisory Board and Its Mission
The PDA ATMP Advisory Board (AB) was created three years ago to lead the industry in finding answers to the many remaining questions in pursuing cutting-edge science and technology. The mission of the PDA ATMP AB is to help navigate the complexities during ATMP product development and commercialization and facilitate consistency through collaboration between volunteers and engagement with worldwide regulatory agencies. Currently, the 18 AB members consist of experts in cell, gene, tissue, and other novel therapeutic modalities, including experience in raw and ancillary materials quality, drug product manufacturing science, quality systems, product and process comparability, analytical methods, and supply chain. Together, the AB aims to tackle the ATMP industry’s biggest challenges and strives towards collaboration to achieve best industry practices in these to-be-built processes and conditions.
The mission to develop and standardize best-practice processes and to stimulate a regulatory and industry dialogue aligns with PDA’s four key strategic pillars for 2020-2026: people, science, regulation, and leadership. The ATMP AB is focused specifically on science and regulation. The new science of ATMP development has pushed manufacturing and quality to respond to emerging trends and encouraged increased collaboration with regulators. As ATMPs continue to challenge long-lasting standards and outdated norms, the ATMP AB is at the forefront of change in the industry.
In 2022, the ATMP AB focused on publications for several key initiatives, such as points-to-consider (PtCs) for consideration for microbial control(s), facility and engineering, and viral vector compounds. Additionally, the ATMP AB supported regulatory commenting coordination and identified key roadblocks for ATMPs, highlighting the key differences between the ATMP process and traditional pharma. Throughout 2023, the ATMP AB has been working on several key initiatives, reflected through the development of PtC documents for ATMP facilities, ATMP raw materials, and viral vectors. These PtC documents will provide important guidance on how to address these common challenges within ATMP development and manufacturing. Now looking forward into 2024 and beyond, the ATMP AB’s strategic goals include the following:
Additional ATMP AB publications in 2024 are expected for the following topics:
- Concepts and practical establishment of manufacturing and testing reference sites for autologous ATMPs to assure a state of “continuous comparability”.
- ATMP analytics, specifically sequencing-based quality control (QC) and providing clear examples of different sequencing-based QC methods to enable more streamlined tech transfers and guidance from regulatory agencies.
- PtC for raw materials in ATMP Manufacturing.
With the 2024 and beyond goals in mind, the ATMP AB organized and hosted the 2023 PDA ATMP Conference in Baltimore, Maryland, to continue the dialogue among industry and regulators in the ATMP space and how to work together to find solutions. The conference included key ATMP industry and regulatory leaders who shared their knowledge of critical challenges. During the conference, we addressed our initial question of how industry and regulators can best work together to ensure the approval and supply of life-saving products. To understand why chemistry, manufacturing, and controls (CMC) development often lags behind clinical development, we must address four main challenges:
- Lack of standardization
- Challenges with scaling to manufacturing and outsourcing
- Lack of risk-based and advanced planning
- Supply chain issues, specifically regarding raw materials procurement
Addressing these issues will support and simplify the advanced risk-based planning necessary to support timely and efficient movement from clinical development to CMC.
Addressing the Key Challenges…
As ATMP development can highly vary, depending on cell types, sources, and manufacturing techniques, it can be difficult to standardize the development and manufacturing processes across products. As Mikhail Ovanesov from the Center for Biologics Evaluation and Research CBER (a center within the U.S Food and Drug Administration) suggested, relying on poorly uncontrolled analytical methods in early clinical development could limit the sponsors’ ability to rely on early-phase clinical data in the biologics license application (BLA) unless sponsors can retest early-phase lots using the BLA-described commercial methods. Questions about method suitability upon approval of a BLA can lead to challenging post-approval commitments. This can lead to a complete response letter (CRL), though, as Ovanesov added, it may require analytical deficiencies to be addressed regardless of the reason for the CRL. Therefore, the ability to invest in analytical development early on is important. However, this can also be a challenge for smaller companies that may not readily have this option. Scaling-up the manufacturing process can be difficult as early-phase clinical trial material is often made in small-scale production facilities.
In addition to the lack of resources, smaller start-up companies may face additional challenges when developing test method platforms for ATMPs. Paraphrasing, Carmen Warren from Kite advised that healthy donor material used to establish test system suitability and product specifications may not be appropriate, as it may not represent test results from actual patients. This can lead to an increased likelihood of an out-of-specification (OOS) result when a product manufactured from patient material has relatively low potency compared to a healthy donor. The challenge with defining a potency method early in development could be that a final method selection may not occur until late in development once experience is gained through manufacturing with patient material. However, as Tiffany Lucas from CBER FDA framed it, the FDA still expects manufacturers to exhaust every analytical method to get to know their products very well and as soon as possible.
When looking to outsource, the scale-up challenges become exponential, introducing additional complexity around choosing outsourcing partners and not having access to all their historical development and validation data for their platform analytical procedures (PAP).
Lastly, the ATMP industry sees unique challenges with raw material procurement, as many ATMPs require critical starting materials, like growth factors (cytokines, serum), plasmids, and viruses. The need to take a proactive approach to understanding the risk(s) associated with raw and starting material selection(s) and the desire to dual source those materials is crucial for successful ATMP development and commercialization. As Andy Case from Roche-Genentech emphasized, CMC teams often focus on cost-savings through closed and automated manufacturing processes and the resulting reduced labor costs. However, raw material optimization can be just as, if not more, impactful in reducing costs. In many cases, only about a dozen critical materials can be the greatest cost generators on our bill of materials. Therefore, targeting smaller raw material batch production and other solutions to reduce raw materials costs is essential to control costs.
To better address these challenges, it was agreed by the industry and agency leaders that conducting risk assessments as early as possible can help identify potential challenges and prioritize required mitigation strategies. Standardization and platform approaches are also key in addressing those challenges. Leveraging existing manufacturing knowledge, processes, and analytical methods can streamline product development, scale‐up, and technology transfer.
For tech transfer and contract development and manufacturing organizations (CDMO) relationship management, the key is to start the process considering scalability early in CMC development. Stephan Krause from BMS suggested thoroughly evaluating the potential use of PAPs before locking into a CDMO and relying on their potentially non-ideal PAP conditions. The sponsor should establish and use technical and quality agreements to get quick access to critical information and transparency from the CDMO. Specifically, full access to all critical processes for development, change management, “emergency reviews”, and their resolution processes should be negotiated. Expectations by the sponsor should be clear, established upfront, and laid out in sufficiently detailed quality/technical agreements to support the development and commercial operations as well as future technology transfer. Otherwise, changing to or adding another CDMO may become very problematic for the sponsor.
Reflecting on the key dialogue from the 2023 PDA ATMP Conference and the ATMP ABs areas of focus for 2024 and beyond, we as regulators and manufacturers should work together to deliver these critical products to patients safely and efficiently by addressing our key challenges around our ability to standardize ATMP processes and by strengthening the collaboration between manufacturers and regulators. ATMPs are uniquely positioned to become the primary live-saving drug product globally. By thinking innovatively and openly sharing best practices, the ATMP AB will help lead the industry in a cultural shift away from repeating “because that’s how we’ve always done it, and toward asking, “How can we do it better”? Through these endeavors, we can ensure regulators and manufacturers work together harmoniously to ensure critical ATMPs are delivered safely and efficiently, keeping patients as the driving force behind what we do.
Special thanks to Sarah Barkow (BMS Cell Therapies) for her conference notes and review of this article.