An introduction to Advanced Therapy Medicinal Products
Gene therapy, tissue engineering and cell therapy are quickly becoming the biggest innovations in medicine. These promising biotechnologies aim to correct, restore or repair diseased tissues and function and represent a major shift from classical drug-based therapies. For this reason, regulators worldwide have developed completely new and tailored directives to legislate for the safe manufacturing and use of these nascent and complex medicines. In Europe, they are classified as Advanced Therapy Medicinal Products (ATMP). In the USA, this is the remit of the Center for Biologics Evaluation and Research (FDA).
Developers of such pioneering biomedicines need to rest assured that, although challenging, there are pathways and support in place to guide them from the initial R&D stages towards clinical trials and commercialisation. It would be helpful to imagine the development of an advanced medicinal product more as an engineering endeavour. It then becomes apparent how each and every component entering the manufacturing would need to be defined, qualified and controlled at origin, in-process and at release.
What exactly are those components? If we look at gene therapy, the medicinal product consists of or contains recombinant nucleic acid sequences or genetically modified organisms, viruses or cells. In all those cases the components are the starting materials and reagents (also called raw materials) used in the entire generation of the vectors, viruses, plasmids or genetically modified organisms/cells. Despite a wide diversity of approaches, they all commonly rely on vector technologies in order to deliver the genetic material to cells and produce viral vectors either as a step in the protocol or as the finished product.
Bridging the gap from R&D to GMP
It is generally at this point, when the extent and complexity of starting materials is fully taken on board in the translational pipeline, that developers stumble in one crucial aspect: current Good Manufacturing Practices, or cGMP. In fact, to monitor and guarantee their safety, advanced medicines need to follow strict and specific cGMP regulations (which in Europe are detailed especially for ATMP), similarly to what applies to standard pharmaceuticals. And this is a major challenge. What for pharmaceuticals is a tried and tested industry reliant often on biochemical synthesis, for advanced medicines it is the engineering of living systems into a final active product.
In essence, cGMP require that each material used to produce or that has come into contact with the final medicinal product needs to have extensive proof of origin, safety documentation testing for infectious agents, lack of animal components and complete traceability down to the smaller reagent and equipment. Reagents that satisfy these requirements are considered of superior, or pharmaceutical, quality. Such quality not only guarantees patient safety but also cuts the burden of risk assessment to the developers. In fact, while research-grade reagents are not forbidden, they incur bespoke and complex due diligence and risk assessment to receive approval by regulators. Regulators expect and highly recommend pharmaceutical quality with clinical intended use, which is achieved by manufacture in certified GMP facilities.
It is the difference between conducting small-scale studies with research-grade reagents normally used in academia, to running a highly regulated and controlled manufacturing process in cell and gene factory environment.
A virtual ‘dive’ into a cGMP unit
Of all aspects that concern cGMP, that of the controlled facility remains the most elusive to people looking to transit their discoveries to clinic. However, a basic understanding on their inner workings is extremely useful, as it informs the new environment in which their therapeutic will be built. Everything that enters the cGMP process, from staff to equipment to raw materials, has to negotiate with the limits and constrains of this regulated space.
To date, there is not a harmonised standard as most facilities are bespoke and subjected to national regulation and inspections. As is expected from a fast-developing field, regulations around GMP facilities are constantly amended. Nevertheless, irrespective of design, size and individuality, there are some general, top-level aspects that apply to a cGMP environment.
If we imagine to ‘dive’ into a cGMP facility, this is what we are to expect:
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- The basic blocks: A cGMP facility is purposely built. It can exist within the confinement of an hospital or another site but will be constructed as a totally independent unit. Negative air pressure would be maintained from the most at-risk rooms down to the least risk. Handling of genetically modifying reagents, such as vectors for gene therapy, will be done in class III biological hoods (where personnel operate via glove boxes) and rooms with the highest level of containment for both personnel and product. Each manufacturing process will have a dedicated time/space and no cross-over with other users would be allowed. Patient safety is in-built. Each and every aspect of the facility, from the temperature to the cleaning procedures to the bioburden particles allowed in the air and on surfaces, follows a management system based on Standard Operating Procedures (SOP), Forms and Policies. Every action, from the entering of consumables to a storage room, the lot number of each pipette used in a day to the sterility of staff’s gloves used during a process is recorded, monitored and filed.
- Material storage and routes of access to the unit: Consumables such as plasticwares and reagents follow different routes into the facility than tissues and cells. Each material to be used in a facility needs to come with an accompanying certificate of analysis before it can be stored within the facility and released for use. Certain types of plasticware are required to be double or triple-bagged to reduce the risk of introducing contaminants into the aseptic clean room: each layer is removed as the material pass through the different rooms and towards the final use. Ideally, all reagents benefit from this level of protection. Procedures of decontamination and routine disinfection are crucial to maintain sterility. Both sporicidal and alcohol-based solutions are used in time-sensitive and validated SOPs to sterilise each raw material (including plasticware) or equipment entering the unit. Prior to each use, the reagents are inspected while lot number and expiry date are recorded in appropriate forms.
- Raw materials: Each reagent or solution that is used in the manufacturing is considered a raw material and needs to be fully traceable and accompanied with a certificate of analysis. Extra quality control is applied to some key reagents. For example, if a cell culture medium is prepared and aliquoted from a mixture of other reagents within the facility, such new reagent might have to incur a sterility test prior release for use.
- Personnel management: Staff is integral to the working of the facility. Management (Quality Assurance, Facility Manager, Quality Control Manager) is in charge of the overall running of the facility and of responding to inspections by regulators and correction and preventative actions. Manufacturing staff follows a rigorous training which includes theory and practical tests in all aspects of their duties. Staff need to be trained for each specific manufacturing process as well as facility due to the variability between sites. One crucial aspect is that of aseptic operation. In fact, people are the greatest source of contamination in a facility, via skin particles or other infectious agents. This risk is managed through the process of gowning and strict operational procedures. Staff is required to change into scrubs and then undergo a step-by-step gowning process which ensures no part of the exterior of the gown is contaminated and no skin is ever exposed, aside from small parts of the face. Each facility will have a highly controlled SOP for aseptic operations.
- Closed vs open manufacturing processes: Each manufacturing is a unique process. However, there are some major distinctions. An open process is where the active therapy or agent is manipulated openly, for example by a staff under a class II biosafety cabinet. Some steps of the manufacturing processes would most likely require a class III biosafety cabinet within the room with the highest level of containment. Other steps of the manufacturing processes are closed. In this case specialised equipment or bioreactor are used and most operations are monitored electronically. In closed systems, raw materials can be supplied directly to the equipment with minimal risk of bioburden contamination compared to open processes. In this case, the level of containment of the room within the facility can be lower (also known as “grade D”), with less requirements in terms of gowning for the staff and background environmental control.
- Release activities: The final medicinal product is subjected to extensive criteria that define its safety, efficacy and suitability for release to clinic. The quality assurance manager of the unit generally is responsible for making the call and finally sign for release a therapeutic. Although release criteria clearly are therapy-specific, most include sterility and testing against infectious agents. The full documented history of the process would also be consulted to make the final release decision.
Thinking ahead for a GMP transition
Considering the full scale of transitioning to cGMP environments, researchers would be grateful to adapt early to innovations that can ease the task ahead. As we have seen above, even in the best of scenarios, a gene therapy faces a very complex manufacturing process.
Many aspects are out of the control of developers, but the choice of reagents that are of the highest quality, conforming to cGMP requirements and possibly facilitating scalable production are to be considered. If there is one guarantee, it is that the arena of advanced medicinal products will likely become more regulated in the coming years.
However, a silver lining is that more companies are coming together to support developers of cell and gene therapies with reagents that are of clinical standard. For the first time, we are entering a space where developers of gene therapies as well as viral vector manufacturers can count on reliable alternatives to research-grade reagents to cover their cGMP starting materials needs.
How Polyplus answers this unmet need
At Polyplus-transfection®, we understand the demanding cGMP requirements of developers as they move towards pre-clinical scalable manufacturing and clinical trials. For this reason, we have worked to develop pharmaceutical grade transfection reagents making the transfection reagent suitable for viral vector manufacturing as well as safe for direct administration in humans, taking into account the expected increase in regulatory stringency which medical device GMP grade reagents may fall short of answering as they are often labelled “for research use only and further manufacturing. Not for use in humans or animals”.
We developed gene therapy reagents gold standard PEIpro®-GMP for adherent and suspension systems and for FectoVIR®-AAV GMP superior and industrial AAV vector production in suspension cells.
PEIpro®-GMP and FectoVIR®-AAV GMP are produced in cGMP accredited facilities and come with full traceability documentation suitable for clinical submission to regulatory authorities in the EU, USA and worldwide. Patient safety is also assured by a chemically defined and animal component free composition, certificate of origin, analysis and extensive quality control documentation.
Furthermore, to facilitate large-scale manufacturing in close system ensured by aseptic connections, PEIpro®-GMP and FectoVIR®-AAV GMP come in ready-to-use bags with MPC connectors and weldable tubing.
Find out how our range of highest quality grade PEIpro®-GMP and FectoVIR®-AAV GMP reagents can assist your gene therapy manufacturing needs.
References and resources
- ATMP regulation, EU: Directive2001/83/EC and Regulation (EC) No 1394/2007 https://www.ema.europa.eu/en/human-regulatory/overview/advanced-therapies/legal-framework-advanced-therapies
- FDA, USA: https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products
- Alici E, Blomberg P. GMP facilities for manufacturing of advanced therapy medicinal products for clinical trials: an overview for clinical researchers. Curr Gene Ther. 2010 Dec;10(6):508-15. doi: 10.2174/156652310793797757. PMID: 21054243.
- Detela G, Lodge A. EU Regulatory Pathways for ATMPs: Standard, Accelerated and Adaptive Pathways to Marketing Authorisation. Mol Ther Methods Clin Dev. 2019 Jan 29;13:205-232. doi: 10.1016/j.omtm.2019.01.010. PMID: 30815512; PMCID: PMC6378853.
- Iancu EM, Kandalaft LE. Challenges and advantages of cell therapy manufacturing under Good Manufacturing Practices within the hospital setting. Curr Opin Biotechnol. 2020 Oct;65:233-241. doi: 10.1016/j.copbio.2020.05.005. Epub 2020 Jul 11. PMID: 32663771.
- van der Loo JC, Wright JF. Progress and challenges in viral vector manufacturing. Hum Mol Genet. 2016 Apr 15;25(R1):R42-52. doi: 10.1093/hmg/ddv451. Epub 2015 Oct 30. PMID: 26519140; PMCID: PMC4802372.
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