Fill-finish in ATMP: 5 critical questions to ask on the way to process scale-up
Advanced therapy medicinal products (ATMPs) make up a rapidly growing category of medicines based on genes, tissues, or cells. As the promise of personalized medicine grows, the volume of each batch shrinks—sometimes to as small as a single dose for a single patient. When it comes to scaling fill-finish operations to commercial size, this is a real challenge.
Historically, filling has occurred at a large scale. With most ATMP batch sizes under 1,000 units, smaller-scale filling solutions are required.
Just a decade ago, vendors started offering small GMP automated small-scale filling solutions. Up until that time, many facilities relied on hand filling. For small batches, there were only a handful of small fillers on the market. Recently, there has been a greater industry focus on creating small systems tailored to the growing ATMP clinical and commercial industry. A traditional filling suite may require 6,000 square feet or more. These new small fillers can fit into a footprint as small as 500 to 1,000 square feet. Although the batch runs might be small, the new era of ATMP therapies bring along big questions about the fill-finish process. Answering these questions is critical to manufacturers’ success as they scale their ATMP manufacturing operation out of the lab and into the GMP environment.
1. Have you confirmed fill-finish compatibility?
A growing number of filling vendors see an opportunity in the market for fill-finish solutions that require minimal design input. Pre-designed modularized isolators with manual, semi-automatic or automatic fillers are emerging. Each can accommodate a different quantity range and size of vials. This trend allows a client and design group to quickly determine design parameters with a reputable vendor for the purpose of procurement. The design process after purchase still requires time, however, some of the filling options have fewer variables and possible design changes allowing for a more condensed timeline.
One of the downsides of these smaller fillers is they are typically less customizable in 3 main areas:
- Lack of advanced technology, such as continuous weighing/monitoring of drug products during filling. This limits one’s efforts to optimize the fill-finish process down the road.
- Future adaptability is usually severely limited.
- The compatibility of primary packaging—vials, stoppers, and seals—can also be limiting.
2. Have you factored in long lead times?
Although filling in the ATMP industry takes place on a smaller scale than for other drug categories, it does not mean that design decisions are any less critical. Equipment and primary packaging decisions must be made early so that the building can become operational soon after completion. Lengthy critical design decisions can create misalignment with the completion of the facility and the filling equipment on-site arrival, installation and qualification.
Persistent supply chain challenges plague the industry. A 45 to 70-week lead time for ready-to-use (RTU) components and primary packaging (including vials, syringes, stoppers, seals) can cripple a planned operation. Materials such as vials, syringes, stoppers, and seals need to be provided to the equipment manufacturer early in the design and at subsequent points in the design all the way to the factory acceptance testing (FAT). Missing design milestones within the equipment production schedule can lead to increased lead time, un-tested change parts, or missing fill line capabilities when the equipment arrives on site.
With such long lead times, why choose RTU componentry?
If a facility is planning to fill less than 10,000 units per batch, then pre-sterilized RTU components can be a great choice. This approach can impact the following:
- Shrinks filling equipment footprint
- Eliminates the need for on-site washing and depyrogenation
- Decreases equipment utilities required
- Increases cost per unit for operations
- Increases supply chain governance
3. How will you ensure data integrity?
As a broad category, “data integrity” encompasses tracking and tracing activities, quality control, confidentiality, and measures designed to prevent data breaches. Data integrity includes positive tracking and tracing of manufacturing data, thus ensuring that the correct patients are receiving the correct doses and that those doses were manufactured under quality conditions.
One of the unique challenges of autologous cell therapy is that a single batch can only be administered to a single patient. Data tracking and tracing must be perfect—if it isn’t, a patient’s life is at stake. From the time a specimen is taken from the patient through the entire manufacturing process and final packaging, it must be tracked meticulously. This also ties into final packaging, which includes inspection for good product and possible rejects, as well as labeling. The labeling step of fill-finish in ATMP must be handled very quickly after primary packaging but before the product is frozen and packaged. An improper labeling process can directly impact patient safety.
4. Have you thought about sterilization requirements?
Not every fill-finish operation requires a washer and/or sterilizer, but some of them do based on regulatory requirements. Also, certain format parts may require sterilization in addition to decontamination in an isolator, biological safety cabinet (BSC) or traditional fill-finish space. Unfortunately, if manufacturers overlook this detail, the facility space and material flow may not accommodate the sterilization requirements. It can be very costly to fix this oversight later in the project as a sterilizer may be very difficult to install within an existing facility.
5. Have you defined all the fill-finish details?
While many ATMP facilities are understandably focused on the science of the drug substance, it is essential to anticipate how the equipment and process scales to commercial volumes. Unlike much more well-established processes, cell and gene therapy manufacturing does not have a tried-and-true roadmap to follow. Manufacturers face great uncertainty as they proceed and many are still working out the dosing details while simultaneously trying to plan for a full-scale facility.
Despite these challenges, it’s important to lock down critical points as early as possible. These decisions may include:
- Regulatory environment
- Facility operation cadence
- Batch sizes
- Type of container/primary package
- Fill volumes & accuracy
- Format parts storage
Planning for success
The fill-finish step is a critical part of the ATMP manufacturing process. The suite where final fill occurs is arguably one of the most important parts of the operation. Our team has guided many ATMP producers through the logistics of establishing fill-finish correctly at a commercial scale. We have helped to bring the new and exciting science of cell and gene therapy manufacturing to life in efficient, cost-effective facilities. Reach out to discuss your project, and how we can help you avoid costly oversights through strategic early planning.