Excellence by design

A desire to build on the bio-manufacturing expertise already present in North West England and the requirement to support UK biotechnology growth as a whole has led the North West Development Agency to sponsor the establishment of a National Biomanufacturing Centre (NBC) in Liverpool. The NBC is due to open in Q1 of 2006 and, in a unique public-private partnership, will be operated by Eden Biodesign, whose role will be to provide the necessary expertise and resources required by many biotechnology companies; from bench top ideas to early phase clinical trial manufacture.
The NBC must be able to support a wide range of current and future technologies and processes under a Manufacturing Licence for the production of clinical material, to current Good Manufacturing Practice (cGMP). In order to achieve an appropriate facility design, Eden Biodesign has been an integral part of the design team (architects, engineers and validation consultants) and led workshops where robustness, compliance with Medicines and Healthcare products Regulatory Agency (MHRA) guidelines and the flexibility to deliver the product-specific client requirements were assessed, prior to the formal approval of each design phase.

Identifying the technologies

The remit of the NBC is to provide for a wide range of product technologies. Therefore the first task was to recognise the types of biotechnology products that this facility would need to support. A market research exercise was performed that helped identify a pipeline of new and future product types that would require specialist development and clinical material manufacturing supply (from monoclonal antibodies and vaccines to therapeutic proteins and gene therapy products). Based on this information a series of ten different established or approvable model processes were drawn up, along with the most appropriate production scales required for early phase clinical studies. The production steps associated with these candidate processes were then used as a basis for establishing a facility design and the equipment list for the cGMP production area. The requirements for the ten candidate processes have resulted in the modelling of a cGMP facility comprising separate viral, microbial and mammalian production suites. Cell revival and cell expansions (for inoculum and cell bank preparation) will be performed in clean rooms designed to incorporate the equipment (including Class II microbiological safety cabinets) necessary for aseptic cellular manipulations. Further scale up will be possible using a combination of disposable and re-usable bioreactor technology that will permit the manufacture (via batch, fed-batch or perfusion culture of adherent or suspension cell lines) of 20L to 200L maximum batch volumes respectively. Within the viral suite isolator technology will also be used to ensure an additional level of containment for open viral-based manipulations. For the downstream steps the types of equipment selected reflect the diverse range of product specific process steps identified by the candidate processes.

For primary processing the methods used will depend on the product type – be it an intracellular or extracellular protein, live or inactivated whole cell or viral product. The equipment identified will allow separation, clarification and concentration steps for the virus, cell or cellular protein either by depth-filtration, centrifugation, tangential flow filtration and/or expanded bed adsorption chromatography. Where cell lysis is required, chemical methodology may be used but high-pressure homogenisers will also be available as an alternative. When there is a requirement for viral clearance the downstream area has been further segregated into pre and post viral clearance rooms with additional ultrafiltration and depth-filtration process steps supporting secondary purification. Secondary purification will be based on a combination of affinity, adsorption and ion-exchange chromatography. Each area will be supported by common supply, preparation and decontamination facilities that include equipment such as a double ended glasswasher, sterilisation and decontamination autoclaves, automated liquid nitrogen storage and a modular dispensary. To ensure that the equipment purchased for the utility would be suitable for its intended use, a User Requirement Specification (URS) was drafted for each of the ‘critical’ systems documented as part of a systems level impact assessment exercise, performed by the project Validation Team.

Equipment specifications and the URS document

In its most basic form a URS document defines the functional requirements of a specific system, (be it a room, piece of equipment or a utility) against which a supplier will tender. The URS helps the user establish a level of confidence that the system will be suitable for use and is the basis for evaluating the tender package and the system design as part of the equipment qualification life cycle. With the additional input from both in-house and external specialist knowledge a URS can be further developed to provide a very detailed list of specific deliverables, which can also form part of the technical, commercial, quality and validation assessment of the supplier tender package. With the URS drafted and approved by the user and quality representatives, the document can be issued for tender and the submitted supplier proposals assessed as part of a technical review. This review identifies whether the suppliers have met the URS and where their proposal may not be acceptable. Where there is more than one available compliant package to choose from, the preferred supplier is identified ultimately on commercial grounds. As stated earlier, owing to the importance of the URS as the basis for system acquisitions there is more to consider and document than simply the functional aspects, or indeed the capital costs, for a specified system. Other specifications that were issued within the NBC URS documents for the cGMP production equipment have been summarised under the headings of: robustness, flexibility and supplier support.

Robustness

Specific design options, historical evidence and the ability to meet cleaning and sterilisation requirements were some of the key criteria specified to ensure that the most robust process equipment was purchased for the NBC.

Design options

Whilst an appropriate level of build quality is an obvious requirement for all cGMP process equipment, some manufacturer designs meet this requirement to a greater extent than others. It is also worth noting that functional aspects for certain equipment can be achieved through a number of different design options that can deliver the same operation. These different designs often have their pros and cons and in some cases the user may have a favoured approach. To ensure that the most appropriate design options were tendered, specific selection criteria were identified, along with design features that would be looked for within the technical review of the supplier’s tender offer. A simple example was specifying the requirement for magnetically coupled stirrers for the fermenters. Compared to the cheaper mechanical designs, magnetic drives have the obvious benefits of providing a robust seal and being easier to maintain, clean and sterilise.

Track record

Historical evidence for system robustness was also a requirement. Suppliers had to submit their proprietary, standard system for the tender. Tried and tested systems that were in use within other licensed facilities were selected in preference to new or bespoke systems, which could potentially come under more regulatory scrutiny. Suppliers had to demonstrate a track record within the biopharmaceutical industry and that their proposed system was being used successfully for similar (cGMP production) applications. As part of the tender package the technical review team were provided with customer references and, where appropriate, site visits were arranged as part of the technical review. In other cases the equipment and/or the supplier was already well known to the technical team: a list of case studies, historical data or published information provided sufficient evidence to support the supplier’s claim that their system met the requirements stipulated in the URS.

Cleaning and sterilisation

The prevention of cross contamination is a key consideration for any multi-product facility, as is the need for the final product to meet safety testing acceptance specifications for endotoxin and bioburden levels. Eden Biodesign identified where there was a requirement to either clean in place (CIP) and steam in place (SIP) the equipment or where other alternative methodologies including sanitisation were acceptable. To help the supplier identify the most appropriate design, examples of typical cleaning and sterilisation methodologies were identified in the URS, along with the specifications for the associated utilities and equipment used to perform these procedures. Because external surfaces must also be cleaned and non-routinely sterilised as a component of the clean room, the types and concentrations of disinfectants and fumigant used within the facility were also identified to ensure compatibility of the materials of construction.

Flexibility

One of the main philosophies behind the design of the cGMP suites is the ability to meet all ten candidate process requirements. Whilst this was achieved by the overall design of the room layouts and the utility distribution loops, it was only possible if the equipment itself met certain functional, physical and control systems criteria.

Functional flexibility

The functionality and ability to process a range of different products and volumes was a key requirement for cGMP production. Within the downstream rooms a broad scope of batch sizes, flow rates, column diameters and heights were specified for the chromatography systems. Ensuring that the system was flexible enough to use consumables from a number of different suppliers was another important specification. An example of this is where the specifications for the ultrafiltration systems included the ability to operate with a range of compatible filter types from a number of key manufacturers. In some instances the level of functional flexibility could not be justified for the candidate processes and was therefore not requested. However, where the system needed to be future-proofed there was a requirement to be able to easily upgrade the equipment at a later date.

Physical flexibility

Movable skid-mounted equipment, with an ergonomic design and small footprint was specified as a requirement to allow for the design of a truly configurable cGMP production suite. Used in conjunction with ‘plug and play’ utility wall plates and the high reliance on disposable technology, the suites can be tailored to meet the specific process trains, as opposed to the alternative where a process must be designed around the limitations of the room and the systems within. These specifications also facilitate the removal of equipment (for maintenance, re-engineering or replacement) and minimise the impact of changes on the functionality and cGMP status of the suite.

Control systems flexibility

For a single product facility with an established process there are clear benefits for fully automated and integrated process control systems. The requirements for the ten candidate processes dictated a level of flexibility that could only be achieved through more manual (semi-automated) control systems. Limited automation was specified, primarily for the standard functions and where feedback loop control (e.g. pH and temperature control on fermenters) was necessary to ensure a process consistency that could not be achieved through manual operation. To help facilitate the technology transfer of the client products between the NBC process development and cGMP functions, it was stipulated that (in addition to similar functional designs) the equipment must share common control systems and user graphical interface.

Supplier support

Though not always specified within the URS, the successful installation, qualification and ongoing maintenance of equipment necessitates a level of supplier support that should be identified prior to system purchase.

Installation support

Failure to install systems that lie on the critical path of the construction schedule may delay the completion date for the NBC. To this end suppliers were provided with projected delivery dates for equipment and asked to verify that these would be met. Where necessary the suppliers were also requested to provide client references for similar projects to demonstrate their ability to deliver. Ultimately, however, the mitigation of risk (as with all construction projects of this size) can only be assured with the inclusion of penalty clauses within the supplier/client contract.

Validation support

To ensure that the equipment purchased can be validated, references to the appropriate regulatory and industry guidelines and standards, which the suppliers are expected to comply with, were identified in the URS. Example documentation (including certification, quality plans and qualification protocols and reports) was also requested so that a top level assessment could be performed by the project validation consultants. In addition to the provision of validation-related documentation (and where a bespoke design necessitated a level of design assessment), the suppliers were requested to participate in the Design Qualification (DQ) reviews. In most cases the suppliers were also required to provide all the necessary resource, test materials and equipment needed to perform the qualification tests, as identified in the DQ.

Maintenance support

The operability reviews concluded that the NBC would outsource most of the maintenance support required, on completion of equipment qualification. To ensure that the systems would be maintained to an appropriate standard, the recommended routine engineering schedules and indicative costs were requested in the equipment URS for assessment as part of the formal technical reviews. For the more critical systems where system failure presented the greatest business risk, the ability to provide 24 hour or next day support was also specified.

Conclusion

The National Biomanufacturing Centre will supply state-of-the-art product development services to biotech companies in the UK and world wide. The Centre has been designed to develop novel biopharmaceutical medicines and deliver a first class service by taking account of the long term business objectives in the facility design, right from day one. This means paying attention to defining the requirements: a process that calls for the establishment of detailed URS documentation.