Antibody-drug conjugates (ADCs) are a class of therapy primarily focused on targeting cancer. They are made up of three components: a cytotoxic agent, commonly referred to as a “warhead” or “payload”, which is attached to a monoclonal antibody through a chemical linker.
When administered to a patient, the monoclonal antibody is directed towards a specific cell surface target in the tumour cells, releasing the cytotoxic agent that kills the cancer cells reducing harm to healthy tissues.
However, it is because of the very cytotoxic nature of the warhead that the handling and manufacturing of ADCs must be carried out in contained environments.
Sterling Pharma Solutions, a global contract development and manufacturing organisation (CDMO) acquired ADC Bio in April 2021, a UK-based company that had a purpose-built high potency biologics contract manufacturing facility in Deeside, Wales.
The 6,500 sqm bespoke site had recently been constructed, and included laboratories designed specifically to develop and perform the bioconjugation steps that assemble the three components of the ADC together.
Its activities had previously focussed on pre-clinical technical services, but since the acquisition, Sterling has invested further, so that the site is now qualified to manufacture clinical material under current Good Manufacturing Practice (cGMP).
The GMP suite has Grade C manufacturing capabilities which can support the manufacturing of ADCs on gram to kilogram scale with an operational exposure limit (OEL) of less than 0.01 mg/m3, and an 8-hour time weighted average (TWA) of 0.052 ng/m3.
This is supported by three ancillary rooms, where reagents and buffers can be prepared, and there is an additional option for the use of closed-fill manifold systems, customisable to fill size and container type.
Operators have changing areas to gown and de-gown in a uni-directional flow, on their entry to and exit from the suite, and personnel routes are separate from material moving routes, which have dedicated airlocks to and from the warehouse and stores area.
Material used in the suite are transferred in layers of packaging, which are only removed once within the contained area and undergo a regimented cleaning in and out procedure. Waste and product have two separate routes from the GMP areas to their specified destinations.
Safe handling and containment
As the first step, it is imperative to make a solution of the powder warhead, in order to reduce the risk of exposure to the cytotoxic compounds.
As a liquid, the material is easier to handle and poses less hazards compared to a lightweight powder, and any spillages can be cleaned up and contained. Once in solution, the ADC conjugation steps remain within water throughout the processing, through to the final product.
The facility is constructed in such a manner that it easily allows further expansion for a second suite to provide additional manufacturing capacity to undertake two projects in parallel, or the flexibility to manufacture larger and / or more complex processes.
The GMP suite has a dedicated air handling unit, fully equipped with double HEPA filters. There is a pressure regime between the rooms within the manufacturing suite to ensure that in the unlikely event of spillage or release material cannot escape and circulate around the suite.
Chromatography can also be carried out dependent on process requirements
Handling materials and processing within the suite is carried out in campaign / batch-dedicated single-use flexible containment, which allows equipment to be installed for a variety of processes, including toxin handling, tangential flow filtration (TFF) and conjugation/reaction steps.
Reactions are currently carried out using removable 25-70 litre glass reactors set up within the appropriate flexible containment. There is the option for these to be replaced with either single-use reactor bags, or fixed assets.
Design decisions are based on customer requirements, with the current set up has been chosen for maximum flexibility at this stage.
Chromatography can also be carried out dependent on process requirements, with the system installed potential of running with gradient, high and low flow capabilities in conjunction with pre-packed columns.
WFI is supplied directly to the suite via circulation loop and take off points
Other services supply the suite – including water for injection (WFI), which is generated on-site. WFI is supplied directly to the suite via circulation loop and take off points, and reagents can be transferred from outside of the manufacturing room through flexible lines from ancillary areas to avoid manual transfers of large volumes.
There are also waste ports throughout the suite for washing and wastes to be removed into a sealed external waste tank, ready for disposal.
As with all containment facility designs, the Deeside site operates using a multi-layered approach, ensuring that operations are as safe and controlled as possible, and risks to personnel are minimised.
Any handling of cytotoxic material is done within a glovebox
Any handling of cytotoxic material is done within a glovebox located in one of the cleanrooms, with operators wearing suitable personal protective equipment. This allows operators good dexterity and movement within the suite, being unhindered by having to wear full air suits for everyday tasks.
Sterling has worked with a local manufacturer to design and supply the custom flexible containment canopies that provide the primary isolation barrier.
These can be fully tailored to suit the needs of each project, with glove ports in the optimal locations, as well as numerous fasteners and transfer ports as required.
The bottom of each canopy is a robust, plastic tray that provides a secure base for the equipment inside, with the sides and top clear for maximum visibility.
Once a project is completed, equipment can be cleaned and removed
The canopies are made of a 500 micron PVC and an integrated EPDM base, which is resistant to chemicals that will be used in the process so that in the event of a spillage, containment is maintained.
Once a project is completed, equipment can be cleaned and removed, and the canopy collapsed and disposed of.
In addition to the GMP suite, the facility has process research and development laboratories, as well as analytical and quality control laboratories.
These allow for development, non-GMP work to be undertaken, as well as the provision of analytical services for raw materials and product testing and release, including cell work, microbiology and stability of products in a range of environmental conditions.
The design of the facility and the use of multiple engineering containment measures, means that in an unexpected situation, such as if a spillage or equipment failure, cytotoxic materials cannot enter the GMP suite contaminating personnel and equipment.
Corrective actions such as cleaning and decontamination can then take place
This gives personnel the time to halt operations and assess the situation in terms of potential product impact. Corrective actions such as cleaning and decontamination can then take place, and all contaminated materials can be double bagged, sealed in drums and incinerated.
The air handling system, as well as airlocks within the GMP suite prevent the egress of harmful materials into the wider facility.
Commissioning, testing and licensing of the facility
To commission the facility and to de-risk any customer concerns Sterling executed an exemplar project within the new GMP suite using commercially available materials to manufacture an ADC.
This had two aims: firstly, to demonstrate technical and GMP confidence to customers; and secondly, to demonstrate competence to the licensing authorities while generating data for a Manufacturing and Import Authorisation (MIA(IMP)) license application.
Over a 12-month period, Sterling developed and manufactured three GMP ADC drug product intermediate batches within a program that would be suitable for Phase 1 clinical studies.
The objective was to establish and develop a conjugation process and analytical methods to support the clinical manufacture of an ADC drug substance.
The facility was audited by the UK Medicines and Healthcare products Regulatory Agency
Development of the reactive stages was undertaken, as well as purification steps at laboratory-scale, after which the process was fixed and preparations for full-scale manufacture under GMP began.
Analytical methods required for process and purification development, in-process controls, and product release testing were developed, with material from the non-GMP manufacturing used to qualify these, and establish a working reference standard prior to manufacture of the GMP batches.
GMP manufacturing was carried out in 2022 and resulted in the successful manufacture of the three, GMP batches, which were subsequently analysed and released by the site Qualified Person (QP).
Following the project, the facility was audited by the UK Medicines and Healthcare products Regulatory Agency (MHRA), and the MIA(IMP) license was granted in April 2023. The site is also US FDA registered.
Wider infrastructure and growth potential
The current ADC market is growing, with 12 drugs currently approved by the FDA, and over 400 clinical trials currently ongoing, and it is estimated that the market for ADC drugs will reach over $13 billion by 2026.
CDMOs continue to dominate the ADC business model, with up to 80% of ADC manufacturing operations being outsourced, in a market expected to reach $3 billion by 2030.
Depending upon the market needs, the Deeside facility offers the potential to expand the services that Sterling can offer to ADC developers.
The site is currently planning the construction and qualification of a second manufacturing area
The site is currently planning the construction and qualification of a second manufacturing area, and there is currently additional space within the Deeside facility building that affords the potential for another two manufacturing suites to be constructed with dedicated air handling capabilities for the future.
Sterling is also considering the installation of clinical-scale fill/finish capabilities, and, if required, a commercial-scale manufacturing suite to support later-phase drug programmes.
Having established GMP facilities in Deeside, and obtained the MHRA license for manufacturing, the flexibility in terms of space to expand and grow with ADC innovators will see Sterling capable of meeting the lifecycle needs of these important, and life-saving therapies.