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Volume 31, Issue 11
Advanced therapy medicinal products pose unique manufacturing challenges that will require appropriate and thoughtful facility design and equipment.
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).
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:
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.
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).
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.
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.
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.
Manufacturing techniques and equipment are evolving rapidly in the ATMP commercial space, and adoption of improvements requires verification that outcomes are comparable to the previous clinical results. This is achieved through process validation and product comparability studies, both of which rely heavily on strong quality by design implementation and well-developed manufacturing control strategies.
The ability of the process to meet quality and reproducibility requirements requires early stage clinical development of product and therapy-specific critical quality attributes (CQAs) that will address both in vitro behavior during cell transduction and expansion, as well as in vivo function and performance (potency, efficacy, etc.) (10). For example, current process analytical technology and automation sensor capabilities may require advancement of in-line/on-line technology to adequately control defined critical process parameters (CPPs) through the ATMP manufacturing process.
Patient-specific starting materials (autologous) and the collection of that material at a clinical site introduce a significant variability at the beginning of the manufacturing process. Often, this activity occurs in a hospital or clinic that is controlled not by GMP but by current good tissue practices. In many cases, this is seen not as a manufacturing operation but more of an extension of patient therapy.
It is crucial to standardize these operations across multiple sites/operators to minimize patient-to-patient variability and ensure GMP compliance under a defined quality management system. Rapid and robust collection, handling, processing, and testing are critical to patient safety and effective therapy.
This aspect of material supply/control also necessitates well-defined supply chain control, from track-and-trace sourcing and temperature control through manufacturing and cryopreservation of finished product. This time-critical, circular supply chain model is at the heart of the manufacturing and quality infrastructure for ATMP therapies and is markedly different than the deliberate, methodical linear supply chain of typical mAb production.
For some ATMPs, the timely, successful completion of the manufacturing process is a CPP. Commercially paced quality/integrity, batch record reviews, and release testing will again require highly automated platforms. The need for real-time visibility and control of manufacturing and supply chains will drive many Industry 4.0 solutions into implementation. Manufacturing and supply of autologous products must address chain-ofidentity through well-documented steps. It is recognized that the implementation of higher levels of automation will facilitate scale-out of manufacturing and logistics of these types of products. In addition, compliant change-control management and sound comparability practices are critical to perform development and manufacturing lifecycle activities.
ATMP development will require an integrated approach with end-to-end data management and analysis. Understanding CQAs and CPPs will be key to a successful development and product commercialization. This should start from the initial material drawn ex vivo from patients through to the clinical response to ensure the quality of commercial ATMP products over their entire lifecycle.
Capacity planning for ATMPs and traditional biologic therapies share the same challenging landscape of unknown regulatory timing, uncertain demand, and highly variable reimbursement decisions A flexible facility design will contribute to reduced financial risk as products progress from Phase I to Phase III clinical and ultimately commercial launch (or patient use). Just as with traditional biologics, changes in product demand, process improvements, or increases in automation implementation, and continued process improvements during the clinical phases will challenge the facility attributes around flexibility.
ATMPs can be manufactured in a multi-product-based facility that is designed to address the potential risk factors normally associated with this type of manufacturing flexibility. Risk factors include product contamination, product mix-ups, human, and documentation errors.
Current regulatory focus around flexibility remains on product protection. As an example, the European Union (EU) clearly defines expectations around concurrent manufacturing and batch/product protection in its guidance (2).
Other examples of flexible attributes that are acceptable in the case of investigational ATMPs by European Medicines Agency (EMA) regulators (Figure 5) that do mirror FDA requirements include:
Many of the fundamental GMP requirements for equipment and facility qualification and validation are similar to those implemented for traditional biologic therapeutics manufactured in fed-batch process platforms. Again, the EU is clear regarding the principles of qualification for ATMPs (2). Some of the key qualification attributes outlined in the EU guidance include:
Much of the leading regulatory focus on specific ATMP guidance was first initiated in Europe. In 2015, the EC issued the ATMP GMP Open Access Research Alliance–AGORA Report that laid the groundwork for the tech transfer, training, and information transfer of ATMPs in the EU (11).
As the global interest in these types of products grew, a more detailed approach to ensuring product safety and regulatory compliance was needed.
As previously defined and according to the EMA (12, 13), ATMPs are medicines for human use that are based on genes, cells, or tissues.ATMPs are classified into three main types:
In addition, some ATMPs may be combined with one or more medical devices as an integral part of the medicine, such as cells embedded in a biodegradable matrix or scaffold.
Since 2017, FDA has approved three separate gene therapy products, reflecting continued advancements and a focus in the ATMP field. Furthermore, on July 11, 2018, the agency issued new guidance documents on disease-specific gene therapy products, which included a draft guidance on gene therapy products for hemophilia treatment and guidances for retina disorder and rare disease gene therapies (14).In addition, with global input from stakeholders, FDA has updated three existing guidance documents that address manufacturing issues related to gene therapy: Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs) (15), Testing of Retroviral Vector-Based Gene Therapy Products for Replication Competent Retrovirus (RCR) During Product Manufacture and Patient Follow-up (16), and Long Term Follow-Up (LTFU) After Administration of Human Gene Therapy Products (17). The review of gene therapy products was based on the RCR and LTFU guidance documents previously issued by FDA in November 2006 and the CMC guidance document issued in April 2008.
One of the early key challenges facing the development-to-commercialization of ATMPs is how to ensure these products are meeting current GMP guidelines, regardless of whether they are being developed in an academic or commercial environment. ATMP manufacturing design spaces are subject to GMP protocols and regulatory guidance; regulatory mandates enforced by national agencies but internationally harmonized to ensure production of high quality non-adulterated drug products that pose no risk to patients and or the public. ATMP manufacturing requires a stringent and carefully controlled bioprocess to control the intrinsically complex and variable nature of cell and gene therapy drug substances and products.
The value chain for ATMPs places notable emphasis on novel manufacturing solutions. Manufacturers are now limited by the usefulness and scale of available manufacturing solutions. Innovation of scalable bioprocessing solutions is crucial for the commercial success of advanced therapies over the next 5–10 years.
Current bioprocessing solutions are largely adopted from biopharmaceutical manufacturing supply chains and are usable but sub-optimal for long-term commercial sustainability because of the potential for high failure risks, high manufacturing costs, and inflexibility for optimization. Advanced therapies are currently manufactured through manual, labor intensive processes that limit the supply, demand high production costs, and ultimately hinder return on investment (ROI). The long-term unsustainability of this model is becoming increasingly apparent as technology developers realize the importance of innovative manufacturing solutions.
Designing and implementing advanced manufacturing solutions early in ATMP product development is crucial to controlling risk. Upfront process development and manufacturing optimization before the major value inflections offered by clinical trial results is an understandably high-risk investment, compounded by a relatively long time to ROI. Historical and ongoing case studies demonstrate that manufacturing remains central to controlling therapy cost and, therefore, facility design and that flexibility concepts remain central to the commercial success of ATMPs.
The authors would like to thank Andre Walker of Andre Walker Consulting, David Estape, technology manager Biotechnology at CRB, and Diane Dream, associate partner at Infosys Consulting, for their contributions.
1. US National Library of Medicine, “How Does Gene Therapy Work?” July 2018.
2. European Commission, EudraLex-Volume 4, Good Manufacturing Practice: Guidelines on Good Manufacturing Practice Specific to Advanced Therapy Medicinal Products, pp. 22–59, Nov. 22, 2017.
3. ISPE, Baseline Guide Vol 6: Biopharmaceutical Manufacturing Facilities, 2nd ed., December 2013.
4. J. Odum, et al., “Aseptic Manufacturing Considerations for Biomanufacturing Facility Design,” in Process Architecture in Biomanufacturing Facility Design, p. 129 (Wiley & Sons, Hoboken, NJ, December 2018).
5. FDA, Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing-Current Good Manufacturing Practice (Rockville, MD, Sept. 2004).
6. D. James, “Therapies of Tomorrow Require More Than Factories from the Past,” bioprocessintl.com, Mar. 1, 2011.
7. D. Estape, et al., Pharmaceutical Engineering 37 (5) 51-59 (2017).
8. R. Denk, “Aseptic Processing Requirements for Sterility, Cleaning, and Cross Contamination,” presentation at ISPE Europe Annual Meeting (Rome, Italy, May 2018).
9. D. Clarke, et al., Cytotherapy, 18 (9) 1063–1076 (2016).
10. R. Haddock, et al., National Academy of Medicine online, DOI: 10.31478/201706c, June 23, 2017.
11. European Commission, AGORA Report Summary, December 2015.
12. EMA, Regulation No. 1394/2007, Nov. 13, 2007.
13. EMA, Directive 2001/83/EC, Nov. 6, 2001.
14. FDA, “Statement from FDA Commissioner Scott Gottlieb, MD on Agency’s Efforts to Advance Development of Gene Therapies,” Press Release, July 18, 2018.
15. FDA, Draft Guidance for Industry: Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs) (Rockville, MD, July 2018).
16. FDA, Draft Guidance for Industry: Testing of Retroviral Vector-Based Human Gene Therapy Products for Replication Competent Retrovirus During Product Manufacture and Patient Follow-Up (Rockville, MD, July 2018).
17. FDA, Draft Guidance for Industry: Long Term Follow-Up After Administration of Human Gene Therapy Products (Rockville, MD, July 2018).
Robert Dream is managing director at HDR Company LLC, and Jeffery Odum is a consultant with NCBiosource.
Vol. 31, Number 11
When referring to this article, please cite as R. Dream and J. Odum, “Impact of ATMP Manufacturing on Process Equipment and Facility Design,”BioPharm International 31 (11) 2018.