Impact of ATMP Manufacturing on Process Equipment and Facility Design

Advanced therapy medicinal products (ATMPs), based on genes, cells, or tissues, are targeted therapies that deliver a therapeutic benefit to a patient-specific population and often treat rare diseases or improve upon existing therapies. Because these products contrast with current biomanufacturing processes for compounds that are synthetically derived (i.e., small molecule) or proteins or peptides expressed by cellular systems (i.e., large-molecule biopharmaceutical), they are often faced with unique manufacturing challenges that must be supported by appropriate facility designs.

Cell therapy products, either autologous or allogenic, are manipulated whole living cells that act at the cellular level to treat disease or injury. Gene therapy consists of recombinant nucleic acid as the active substance that will regulate, repair, replace, add, or delete a genetic sequence in the patient.

Preparation of an autologous cell-therapy presents a significant departure from typical biopharmaceutical manufacturing in that it is manufactured from cells obtained from the patient. Collected by apharesis, the cells are modified, expanded, and returned to the patient. This process presents a difficult challenge to scalability. One batch will treat one individual patient throughout the treatment cycle, so the ATMP volumes are currently small scale, and the presence of whole cells prevents typical bioburden reduction steps, such as filtration through sterilizing grade filters. All processes must be aseptic to prevent the introduction of any contaminant/adulterant.

Batch identity and tracking must be flawless when concurrently processing treatments for multiple patients. Starting material becomes part of the manufacturing process and requires the collection site to be qualified in the specific apheresis and tissue-collection methods along with the shipping preparation process. Control of storage conditions and time during transport of the raw material and finished product is critical to maintain cell viability.

In contrast, some allogeneic cell therapies can be used to treat multiple patients, enabling larger manufacturing process scales, but the contamination control challenges remain the same. It also eliminates the challenge of patient cell harvest and transport (Figure 1).

Figure 1. Advanced therapy medicinal product (ATMP) supply chain.

In gene therapy where a viral vector is used to genetically modify the patient’s cells, the preparation of the viral vector presents a second manufacturing challenge. A gene that is inserted directly into a cell will, under most circumstances, not function. The vector becomes the carrier of the gene to the infected cell (1). Scale can vary from traditional lab scale up to 2000-L scale because a single lot canbe used to transduce cells from a single patient or many different patients.

These processes are similar to typical biopharmaceutical manufacturing platforms that expand a frozen cell line, but the twist is that a virus is purposely introduced into the culture to manufacture viral particles.

Cell-therapy manufacturing, like all current fed batch-based manufacturing processes, is generally segmented into a series of discrete unit operations that may differ between cell types according to the specific needs of the product. But one important difference between these two different manufacturing platforms is in the source of the cells that are used. Traditional monoclonal antibody (mAb)-based protein products use genetically modified cells that have been characterized and tested. Cell therapies come direct from patient donors and therefore have limited potential for the exponential expansion seen in protein-based products, thus the challenge of scale-up.

A typical good manufacturing practices (GMP) process for cell-based allogenic or autologous products follow the general steps identified in Figures 2and 3. In these processes, closed systems, aseptic operations, and automated solutions will play key roles in defining the manufacturing operations. Gene-therapy manufacturing is also a GMP-focused process that follows a similar unit-operations manufacturing approach, but generally involves fewer and often simpler steps. Some critical aspects of the manufacture of ATMPs for both cell and gene therapies include:

• Ensuring the integrity and chain-of-custody of the initial cellular material
• Standardization of procedures, protocols, and testing of materials
• Logistical control, especially in the areas of temperature control and storage
• Equipment and process validation.

Figure 2. Typical allogenic cell expansion and delivery.Figure 3. Typical autologous cell therapy processing and delivery.

Future challenges

The current baseline model defining the majority of biomanufacturing operations for human therapeutics (proteins) is batch driven (Figure 4). Here, the “batch” is based on a paradigm where the target protein is well characterized, screened, banked, and optimized and is focused on a large, well-defined patient population where the goal is a “one-size-fits-all” drug. This model implements a basic flow of well-defined and robust unit operations, well-characterized product and process attributes, and a focus on product quality and risk that has been determined over four decades of regulatory GMP oversite.

ATMPs are personalized, targeting either specific groups of patients or individual patients, so efficient commercial production will not be achieved with the large process volumes and higher titers of traditional biopharmaceuticals. Although many unit operations are similar (cell culture, concentration, freeze/thaw, etc.) industrialization of these operations at small scale through robotics and novel equipment will provide the needed scalability.

Figure 4. A typical fed-batch process.

The sum of intrinsic characteristics associated with ATMPs results in manufacturing-specific requirements that significantly deviate from current “typical” biologic products (e.g., mAb). The patient-centric nature of autologous cell therapies requires small volumes and a limited number of batches (e.g., single patient) for an entire treatment duration. Additionally, the presence of cells prevents the use of sterile filtration technology, so all manufacturing steps should be aseptic by both definition and operation.

This scale of manufacturing and the specific 1:1 treatment-to-patient nature of autologous therapies do often mimic hospital laboratory or compounding pharmacy operations, but the need to produce these therapies for larger patient populations in a safe, pure, and effective manner will require GMP-regulated facilities (2).

Manufacturing focus

A manufacturing process can be either open or closed. If the primary goal is to protect the product during the manufacturing operations and transfer, closed processing presents less of a risk to the product. This is a risk that primarily comes from the ability to control the immediate manufacturing environment. The GMP goal is to ensure the product is never exposed to the environment unless the environment is constantly maintained as bioburden-free.

Aseptic operations, “[p]rocesses that are devoid of measurable (detectable) bioburden” (3), generally require sterilization of the environment, equipment, and process solutions to achieve the desired state prior to use (4). Current FDA guidance (5) is often associated with the manufacture of sterile injectable drug product(s) and applies to the manufacture of all cell-based ATMPs to prevent contamination by foreign cells that would pose an unacceptable risk to the patient.

Risk mitigation

In Europe, GMP requirements for ATMPs were adopted at the end of 2017 by the European Commission (EC). As a result, “other documents developing GMP requirements for medicinal products which are contained in Volume 4 are not applicable to ATMPs, unless specific reference thereto is made in these Guidelines” (2).

Despite this specific GMP ruling for ATMPs, the GMP principles are the same as for traditional biologic products. ATMP production, therefore, must be designed to meet the most stringent GMP requirements to guarantee quality and avoid contamination or cross-contamination. If open processes are implemented, then manufacturing must be conducted under Grade A conditions with the appropriate surrounding background environment (Grade B for open systems and Grade C or D for isolatorbased systems) with dedicated areas or some form of time-based segregation for each patient-specific batch to avoid environmental contamination and/or cross-contamination between each batch.

A closed system is preferred in ATMP manufacturing to mitigate risk and achieve optimized production. This has been long discussed (6) and adopted in global GMP regulations. Closure can be claimed at the primary packaging level (i.e., equipment, system) or at the enclosure level (i.e., an isolator). Both scenarios are also supported by the full implementation of single-use systems to minimize exposure, cleaning, and sterilization of product contact surfaces.

Proof-of-closure is a challenge. It must be demonstrated that the system is designed and operated as closed. A structured closure analysis (7) as well as a strong risk assessment (3) can support such a claim. This is not limited to normal production and should address nonroutine operations such as breaches or maintenance incursions.

Requirements for ATMP production can be even more rigorous, considering the nature of an aseptic drug product manufacturing process. The use of large numbers of manual single-use sterile connections and the place where they occur have been questioned as a risk by global regulators (8). The demand to cover (aseptic) lines under Class 100 (ISO 5) when they require intensive manual intervention could become a prescriptive requirement applicable to the aseptic processing of ATMPs. It will be important that the industry continue applying risk management and validation/verification studies for system closure before adapting easier prescriptive GMPs.

Need for automation

ATMP clinical development generally focuses on a small number of patients where the source material from individuals comes from a single site equipped to carry out the required collection operations. Testing of the cells, while time consuming, is manageable for these small volumes/donors.

Scale-out challenges moving into commercial manufacturing, however, will drive the demand and development of new, specialized tooling and instrumentation to automate what are now manual manipulations. This will further enhance the robustness of the commercial process and should notably reduce the risk of contamination. It is a well-documented fact that human presence, intervention, and touch-points are the most significant risk factors and sources of contamination (9). Aggressive implementation of system closure and automation will likely define the success for future lean ATMP manufacturing.

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