Cell and Gene therapies hold the promise of a cure for a wide range of life-limiting diseases. Until recently, these therapies could only be found in academic laboratories, being produced on laboratory equipment.
They are now being commercialised at pace, often with equipment with a laboratory
heritage. In parallel, regulatory frameworks and guidance documents for this nascent sector are being developed. In response, automation in closed systems is gaining momentum.
Cell and Gene therapies hold the promise of a cure for a wide range of life-limiting diseases
Advanced Therapy Medicinal Products (ATMPs) as they are known in Europe, or cellular and gene therapies (C>) products in the US, offer innovative treatments for a variety of complex diseases and conditions.
Many of these products can be administered as one-off treatments, offering lifelong benefits or curing a potentially life-limiting disease.
Why are they so challenging to manufacture?
When compared to conventional solid oral dose or injectable therapies, ATMPs are significantly more complex to produce.
The variability and fragility in starting material and the overall number of processing steps present a significant opportunity for error.
Overlaid upon this are further complications around manual processes that were recently developed in academic laboratories and that now need to be carried out aseptically.
When compared to conventional solid oral dose or injectable therapies, ATMPs are significantly more complex to produce
These products are typically delivered as infusions or injections and being cellular in nature, they cannot be terminally sterilised.
This adds an additional layer of complexity, namely the need to ensure that the product is not contaminated by any viable or non-viable particulate.
Unlike with orally delivered therapeutics, the body struggles to defend against contaminants delivered into the bloodstream via injected therapeutics: poisoning a patient with a viable particulate in the bloodstream is not an option!
However, to meet regulatory requirements and reduce contamination risks, the industry is shifting towards “closed” or “functionally closed” systems and automation using robotics
These products should therefore be produced according to Annex 1, which states that “The manufacture of sterile products is subject to special requirements in order to minimise risks of microbial, particulate and endotoxin/pyrogen contamination”.
Currently, manual production involves skilled technicians using aseptic techniques in biosafety cabinets; difficult, manual work where humans pose the greatest contamination risk due to shedding skin cells and respiratory droplets.
However, to meet regulatory requirements and reduce contamination risks, the industry is shifting towards “closed” or “functionally closed” systems and automation using robotics.
Functionally closed systems
Many of the therapies have elected to use what are known as “functionally closed” systems. So-called “bag-sets” are complex arrangements of welded bags and tubes that are pre-sterilised.
A number of vendors have developed their own ecosystems of disposable processing containers and bags containing costly reagents to be used within their equipment.
The advantage of these systems is that they can operate in a relatively low-grade clean room (grade C) whilst maintaining sterility inside the tube set.
There is, however, a downside. These machines spend most of their time on one unit operation - cell expansion.
Many of the therapies have elected to use what are known as “functionally closed” systems
The machine acts as an incubator for much of its life, and spends a small amount of time on the other value-added and specialist unit operations, such as cell separation, activation, and transduction.
As a result, more lab space and equipment are required than necessary from the perspective of a “cycle-time” analysis. Within the automation of complex products, there is the concept of matching “Takt” time.
Takt time is the time needed to ensure all production unit operations match the needs of production.
From a classical automation perspective, functionally closed systems make no sense. The use of these systems drives
up the cost of goods for these therapies.
These therapies are typically cryopreserved for transport from centralised “hubs” to clinical “spokes”
In Functionally Closed Systems, the primary drug container is usually a small bag, and the equipment retains a laboratory feel - colourful epoxy-coated steel rather than stainless-clad machinery.
These therapies are typically cryopreserved for transport from centralised “hubs” to clinical “spokes”.
At cryogenic temperatures, bags become brittle, particularly along natural crease lines formed during
manufacture. Bags are therefore placed in protective cradles, ‘bag and shell’; excess cells are stored in spare bags as backups in case of failure.
The product equipment is increasingly becoming less lab-like, with design principles lifted directly from conventional aseptic fill finish equipment
It is likely that in the near future, regulators will insist that ATMP manufacturers move from the use of operators in BSCs to closed systems.
The product equipment is increasingly becoming less lab-like, with design principles lifted directly from conventional aseptic fill finish equipment.
This has also led to the use of more conventional primary drug containers in the form of vials. These vials are typically
formed from cyclic olefin plastics such as COC or COP rather than glass in order to survive cryogenic temperatures. Vials are naturally “open” systems during filling, and this has led to an increasing trend away from BSCs and towards closed systems.
Closed systems
An alternative to a functionally closed system is a closed system. This is where the production is carried out within a closed box or isolator, engineered to protect operators from toxic drugs and, conversely, sterile products from human contamination.
Before production can begin, isolators require thorough decontamination of all internal surfaces, typically using hydrogen peroxide vapour. Isolators can be either “hard-wall”, constructed from stainless steel with glass windows and glove ports, or “soft-wall”, formed from welded clear plastic fitted over a space frame.
A slight positive pressure is maintained within the isolator to prevent ingress of airborne contamination from the surrounding cleanroom in the event of minor leaks.
If one lesson stands out from over 150 years of pharmaceutical machinery development, it’s that sectors inevitably move away from manual
The internal processing zone is supplied from above with HEPA-filtered, unidirectional airflow to continuously “wash” the area and maintain cleanliness.
These systems often include transfer mechanisms to safely move materials in and out of the process area while maintaining sterility.
Continuous viable and non-viable particle monitoring ensures the aseptic integrity of each batch. Isolators also offer an energy efficiency advantage: Annex 1 permits their use within a Grade D background, reducing the overall cleanroom classification requirements compared to functionally closed systems.
The need for GMP-compliant systems
If one lesson stands out from over 150 years of pharmaceutical machinery development, it’s that sectors inevitably move away from manual, laboratory-based processes toward automated operations on GMP-compliant production equipment.
The cell and gene therapy space will be no exception. But what does this mean for equipment c producers and users?
Fundamentally, the equipment needs to be designed from the ground up to comply with the various standards that cover pharmaceutical machinery.
Guidelines are often interpreted in subtly different ways within User Requirements Specifications (URSs) of producers who are mainly big pharma.
In hygienic design, even fasteners require careful consideration
This means that equipment producers need to ensure their equipment is to the highest “gold” standards. In particular, the relatively new version of Annex 1 for sterile manufacture will increasingly be applied to cell and gene therapies.
As one would expect from a producer of equipment with a heritage in commercial pharmaceutical equipment 3P innovation has a comprehensive set of internal engineering standards that ensure equipment complies with these external standards and guidelines.
It may seem trivial, but even the bolts used within such equipment are important and need attention to detail.
What’s in a bolt?
In hygienic design, even fasteners require careful consideration. Conventional bolts can allow air leakage and have rough, sharp heads that are difficult to clean, posing a glove-tear risk in isolators, which would breach aseptic containment.
Hygienic bolts, by contrast, are polished, shaped for easy wipe-down, and incorporate elastomeric seals to prevent leaks. As with fasteners, the entire machine must be designed for cleanability. Sharp corners are avoided, surfaces are smooth, and all materials must be certifiable.
Engineers from traditional automation backgrounds are often surprised by the cost and complexity of pharmaceutical components, much of it driven by the need for ease of cleaning, separation of process and technical zones, and full traceability of materials.
Beyond mechanical design, careful selection of electrical components is essential. Conventional parts often contain hidden leakage paths or materials incompatible with sterilants.
Hygienic bolts, by contrast, are polished, shaped for easy wipe-down, and incorporate elastomeric seals to prevent leaks
Cable routing must be designed to prevent leaks between process and technical areas. Given the limited space in
cleanrooms, compact control components are preferred—an approach that has shaped 3P’s standard electrical library.
Software, too, must meet strict standards. Systems must log user activity and record any changes in line with 21CFR11, the regulation governing electronic records.
Software must also be developed and tested following GAMP5, which outlines a validation framework based on the “V model”.
This ties into validation, a cornerstone of pharmaceutical equipment. The FDA defines it as “establishing documented evidence that provides a high degree of assurance” that a process consistently meets specifications.
Software must also be developed and tested following GAMP5
3P’s development process embeds validation considerations from the outset, through design, build, and testing, to ensure our equipment is not only compliant but also easy to validate, much to the satisfaction of clients worldwide.
One final consideration when it comes to Annex 1 is the principle of “first air”, requiring that HEPA-filtered air reaches critical product zones without contacting other surfaces.
This has led to a decline in cross-flow isolators and a shift toward designs with unidirectional airflow, verified by CFD simulations and smoke studies to ensure compliance
This article has explored what good manufacturing practice (GMP) means for equipment intended to produce sterile injectable products.
In particular, it focuses on the production of cell and gene therapies and how they comply with the latest international regulations and industry body guidance.
GMP compliance is essential for the successful development and commercialization of cell therapy products. By understanding and adhering to GMP principles, manufacturers can mitigate risks, optimize processes, and ultimately deliver innovative therapies that meet the highest standards of safety and efficacy.
