What's involved in creating an in-house aseptic drug preparation facility?
Gavin Statham, Regional Director at BES, a specialist in the design and construction of cleanrooms, aseptic facilities and other sophisticated environments, discusses the demanding requirements for hospital aseptic facilities and how the healthcare sector can benefit from the experience of the pharmaceutical industry.
High-specification, specialist facilities for the preparation of aseptically-prepared drugs need to provide a sterile environment that safeguards the purity and accuracy of the formulation. Such facilities are frequently built into pharmaceutical manufacturing environments where GMP (Good Manufacturing Practice) guidelines ensure compliance to recognised standards.
As treatments become more advanced, aseptic facilities are an increasingly common addition to hospital estates too, driven by a need for preparation of patient-specific drug formulations on site. This includes patient-centred prescriptive aseptic manufacture for chemotherapy preparation, along with Parental Nutrition (PN), Advanced Therapy Medical Products (ATMP), Central Intravenous Additives (CIVAs) and Monoclonal Antibodies (MAbs).
Several NHS Trusts have already invested in adding an aseptic facility to their oncology or pharmacy departments. Indeed, BES is currently delivering a design and build project for a new pharmacy and aseptic suite at Weston Park Hospital in Sheffield. Over the next few years, there are likely to be many more aseptic suites built within hospitals. The need to plan aseptic facilities into acute care hospital development programmes has been clearly identified as a growing trend. In his 2016 report “Operational productivity and performance in English NHS acute hospitals”, Lord Patrick Carter of Coles, Chairman of the review panel examining the future of NHS pathology, identified the need for NHS Aseptic facilities to enable a ‘future-ready, resilient, high quality, safe and efficient’ service. The report pointed to year-on-year growth in demand for aseptically-prepared treatments, indicating urgent and significant demand for the specialist expertise required to design, specify, construct and validate aseptic facilities.
Meeting the Aseptic Challenge
The challenge for healthcare estates managers is to ensure that the increased need for aseptic production within hospitals is met by utilising the appropriate level of project design and delivery expertise. Only then can NHS Trusts and private hospital operators be assured of accurate and safe preparation of these specialist treatments.
Aseptic production is carried out within a cleanroom facility, which can be defined as a specially-constructed, environmentally-controlled enclosed space. Different drug preparations and processes require varying cleanroom classifications and compliance criteria.
The production area should be designed and constructed with an expert eye for detail that ensures airborne particulates, temperature, humidity, air pressure, airflow patterns, vibration, noise and lighting can be controlled in compliance with the appropriate standards. It’s also important to take into account end user workflows, material flows, staffing levels, specialised manufacturing equipment and production capability; all of which adds up to a highly complex project.
As the design and specification of aseptic suites is relatively new to the NHS, there is a risk that the existing healthcare supply chain and procurement network does not include proven, competent, specialist contractors who are familiar with cleanroom and aseptic production. Identifying a supply chain partner that can provide specific expertise in the design, construction and validation of aseptic environments is essential to avoid any delays in completing these new hospital facilities.
There is also a risk that an inexperienced and disconnected supply chain may not be able to deliver aseptic facility projects to the exacting requirements of the Medicines and Healthcare products Regulatory Agency (MHRA). Where these high standards are not met, the facility will not achieve validation, leading to a costly re-design and modification process and delays in beginning drug production at the hospital. As a result, the hospital’s spend could be much larger than planned and operational targets, including improvements to positive patient outcomes, may not be met.
As experts in delivering aseptic facilities for the pharmaceutical sector, BES is at the forefront of bringing that specialist experience to the healthcare sector. With a fully-integrated, multi-disciplinary team, we work with NHS Trusts to guide them from initial concept and feasibility, through to full turnkey project delivery, commissioning and validation, in accordance with GMP and MHRA regulatory guidelines.
Workflows and Spatial Layout
The design of an aseptic facility must begin with a consideration of the processes required and the flow of both people and materials within the available space. Expert design of workflows enables optimised spatial efficiency of the available footprint of the facility. This both maximises the production efficiency of the aseptic facility and embeds a comfortable, practical workspace into the design parameters for the project.
The design team’s detailed understanding of processes and workflows is also central to achieving the quality of drug preparation required from the aseptic suite. Facilities must be designed to cascade airflows between ‘dirty’, ‘clean’ (according to the required cleanroom classification) and ‘unclassified’, which ensures that pressure regimes are maintained throughout. Preventing contamination of clean areas by the movement of materials or people from dirty or unclassified areas is mission critical for the aseptic facility and should be the cornerstone of spatial layout planning.
Layout planning is an element of the architectural design that demands specialist expertise in cleanroom and aseptic facilities. For example, at a recent project, BES inherited a proposed layout that needed to be revised for a number of reasons.
Detailed solar calculations and analysis proved the benefit of a fundamental shift to relocate the cleanrooms and laboratories from the south elevation to the shaded north elevation. Easy to implement, this change of layout reduced the cooling load considerably, thereby reducing operational cost and energy demand, together with an optimised plant layout.
In parallel with inverting the critical spaces to reduce energy, we also recognised the workflow between ‘dirty’, ‘clean’ and ‘unclassified’ was not efficient, and therefore we made significant improvements to the people and material flow through re-sequencing client’s processes.
The overall footprint was also very tight and relocating certain supporting rooms, such as offices and stores, to another part of the hospital released valuable space to optimise the layout and improve process flow.
Visiting the physical space designated for refurbishment of an aseptic facility was a key step in understanding how the layout could be optimised. The spatial layout was also informed by a detailed briefing with the users to understand the processes and staffing levels involved in the facility, along with potential upscaling plans so that future-proofing could be built into the design.
A specialist contractor can add great value from concept stage onwards and helps ensure that the basic layout is optimised before detailed design begins in earnest.
When planning an aseptic facility within an existing hospital, part of the role of the experienced cleanroom design and delivery team is to ensure a level of flexibility in the design to adapt to any latent issues with the legacy building. Historical information on the building structure and services is often inaccurate or unavailable, which can lead to unexpected design and installation challenges once work has begun. In this regard, working with an aseptic facility delivery partner with integrated design and construction expertise can be of considerable benefit.
For example, at a recent project to refurbish an existing area within a hospital into an aseptic facility, the BES team discovered that the floor above the designated accommodation had been constructed of bricks embedded in concrete to provide loadbearing for a plant deck above. This meant that the available locations for service penetrations were severely limited. The proposed ducting routes had to be changed to enable an installation that fitted both the workflow requirements and the limitations imposed by the building.
Unexpected modifications to the design once the project is on site can have varied causes. There may be latent issues or structural limitations, as in the example above. One of the most common latent issues is live services for other areas of the hospital that transcend the void for the project. Where this is the case, all new service routes and connections must to be achieved without taking the legacy services off-line, which can be a complex design challenge.
Devil in the Detail
Fundamental to the design of any aseptic facility is a specification that is easy to clean and compatible with cleaning regimes. This includes selecting materials that offer a smooth, seamless and wipe-able surface that will not degrade as a result of either the facility’s operational processes, or any chemicals used during cleaning. There are a number of materials that are already tried and tested for use in environments classified as clean but an aseptic facility specialist will also be able to advise on any new materials and anti-microbial technology. It is important to avoid assumptions about standard specification of floor, wall, ceiling and coving materials as this can sometimes result in value engineering opportunities being overlooked.
Ease of cleaning should also be supported by the design of surfaces and the interface between walls, floors and ceilings, along with any doors and windows. The design should avoid awkward details and ledges where dirt or bacteria could collect. Sharp corners, joints, crevices and horizontal surfaces should also be avoided, where possible.
Minimising the build-up of bacteria through careful design is only one of many architectural design considerations; equally important is the need to maintain pressure regimes. Air loss can occur through light fittings or plug sockets if the back boxes have not been specified and detailed to maintain air pressure regimes. Potentially, this could compromise compliance to the relevant cleanliness grade. Consequently, all elements of the specification should provide a high level of airtightness, while still being accessible for maintenance.
Pressure regimes in airlocks are usually supported through the use of interlock door systems, which only allow one door to be opened at a time. In principle, it may be assumed that the use of PIR sensors to control the door interlocking provides the cleanest option because the operators are not required to interact with fittings. In reality, however, this can lead to nuisance locking / unlocking of doors, resulting in a restriction of access to the area for other users. A more practical approach is ‘touch-less’ or close proximity sensors, or the use of a conventional push button. Both of these systems operate only when users physically request access via the interlock system, which checks the open / closed status of all other doors and grants access when available. As operatives are either dressed in correct garments for the grade of cleanroom and its cleaning regime, or are entering a change room and will be donning additional garments, and therefore the use of push buttons does not have a negative impact on the cleanroom environment.
Ventilation and Pressure Regimes
One of the key specialist areas of an aseptic facility is the design of high performance ventilation systems, as these play a vital role in reducing airborne particulates within the facility and eliminating the risk of cross contamination.
The particle count for the air within a cleanroom is dependent on the volume and quality of the supply air, management of contamination sources and expert design of the ventilation system. We use mathematical algorithms and software to model airflows and assess the air cleanliness of the facility as part of our design process. This, in turn, can help to refine both the architectural and building services design elements of the project.
Design of the ventilation system is one of the key areas where specialist expertise must be applied to the facility’s specific physical, workflow and operational conditions. Air change rates are traditionally specified using proven and historical air change frequency, aligned to the required cleanroom classification. However, the use of standard data alone can result in energy-hungry ventilation systems that require large amounts of fresh air. NHS Trusts are mindful of the need to build energy-efficient and operationally cost-effective assets and working with a specialist in engineering aseptic facilities ensures that the operational needs of the hospital are met in the most energy-efficient way possible. Such expertise can contribute to reduced build costs, improved spatial efficiency, lower running costs and a better carbon footprint.
At BES, we use a number of tools to help calculate required air change rates, designing the mechanical services to meet the bespoke requirements of each aseptic facility. These include mathematical calculation of ‘clean up rates’, such as the WEI Sun calculation method, for example, which uses particle balance equations to mathematically model a particular cleanroom. We use input data that includes the level of room cleanliness required, the number of people who will occupy the facility, the particle emissions from cleanroom gowns and the outdoor environment particle concentration at the specific location. This ensures the design is based on both operational factors and the physical location of the facility.
Computational fluid dynamic (CFD) calculations are also now commonly used, enabling us to model the room in full 3D, including all finishes and equipment, heat gains and heat losses. We can then apply ventilation rates to the model, creating an accurate graphical representation of the dynamic room state, helping to inform the final design solution.
Validation is a critical stage in delivering an aseptic facility. Described by the US Food & Drugs Administration (FDA) as a process to ‘establish documented evidence which provides a high degree of assurance that a specific process will constantly produce a product meeting its predetermined specifications and quality attributes’, it ensures the facility is operating in line with its agreed design intent.
As a specialist in cleanroom and aseptic facility design and construction, BES ensures that validation criteria are embedded throughout the design and installation process. This is essential when considering the critical path involved in taking an aseptic facility from concept to operational asset, because any validation failures could result in costly modifications and delays.
Validation is an extensive qualiative and quantitiave process that should involve both the design and construction team and the hospital, in accordance with GMP requirements. It should prove and document the quality, functionality and performance of the process as a whole, as well as scrutinising individual pieces of equipment.
For BES, this means that the multi-disciplinary team involved in designing and building the facility works closely with the client to complete each stage of validation.
This collaborative approach ensures the aseptic facility both meets the hospital’s brief and delivers the compliance standards demanded for its classification.
Validation is divided into four stages, beginning at the design stage with the Design Qualification (DQ), which involves completing and documenting design reviews to illustrate that all quality aspects for the aseptic facility have been fully considered. Establishing all requirements at the start of the project allows the finished facility to be measured against this detailed criteria when the construction work is complete.
The next stage is Installation Qualification (IQ), which involves checking that all components meet the approved specification, deliver the detail of the original design and have been correctly installed. Detailed documentation is required to evidence the quality and accuracy of the installation and this can then be used to support planning and management of future maintenance regimes or modification programmes.
Operational Qualification (OQ) is the third stage of the validation process. This process is designed to test that individual and combined systems function in line with agreed performance criteria, and have been installed to manufacturer requirements. It is vital that all tests be carried out using certified and traceable test equipment so that all test results can be verified as accurate.
The final stage of the validation process is the Performance Qualification (PQ) which verifies that the aseptic facility will consistently deliver the desired outcome, aligned to the required classification. This is carried out to clearly defined parameters during the facility’s operational phase and is summarised in a report which is a pre-requisite for GMP certification.
Compliance and Licensing
Once construction and validation have been completed, the aseptic facility can become fully-operational to serve the hospital’s pharmaceutical preparation requirements. In order to produce aseptically-prepared drugs within an NHS hospital, however, the Trust must either choose to operate under a Section 10 exemption or apply for a full MHRA Drugs Licence.
Before embarking on a project to create an aseptic facility within a hospital campus, it is important to understand these two options. The purpose and capabilities of an on-site aseptic facility will influence which route is taken. If the funding model for the aseptic facility is based on using it for commercial drug preparation as a revenue stream, it is particularly important to understand the legislative obligations involved in producing aseptically-prepared drugs for use beyond the hospital’s own patient community.
A Section 10 exemption is likely to apply for most hospital aseptic facilities. This provides an exemption from The Medicines Act 1968, which was introduced as a licensing system to regulate the manufacture, distribution and importation of medicinal products. A hospital’s aseptic facility can gain an exemption if the medicinal product is prepared, assembled or dispensed in the hospital by a pharmacist (or under their supervision) in accordance with a doctor’s prescription. The exemption can also be applied if a stock of medicinal products is being prepared in the hospital by or under the supervision of a pharmacist, with a view to dispensing them.
Any NHS Trusts that intend to use their facility to produce aseptically-prepared drugs for commercial sale or to supply other hospitals outside of their own NHS Trust will require an MHRA License. To gain this, the hospital will need to undergo a thorough inspection process and may also be asked to provide additional documentation and samples of the aseptically-prepared drugs for testing during the inspection.
Right First Time
The complexity of designing, installing and validating an aseptic cleanroom for the manufacture of advanced medical treatments within a hospital requires a right-first-time approach to ensure the demands of financial due diligence, operational planning and regulatory compliance are met.
Current advances and future growth in demand for personalised gene-based medicines are driving a need for bespoke aseptic facilities within hospital campuses, tailored to hospital-specific clinical services and patient requirements. Such facilities must, therefore, be designed with the input of all stakeholders and the expert guidance of specialists with proven experience of delivering highly specified pharmaceutical environments like these. Only then can the hospital be confident of a smooth project delivery, from initial concept through to detailed design, construction and validation, which will support individual treatment plans and help deliver improved patient outcomes.
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