Sterile manufacturing

With increasingly stringent regulations in today’s pharmaceutical market, there is now, more than ever, a heavy emphasis placed on validated sterility facilities and processes to manufacture medicines that will be safe patients to use. BioCity Nottingham, the UK's largest biotech innovation centre, has initiated a new project to build a sterile facility for the manufacture of aseptic and terminally sterilised injectable products for phase I and II clinical studies. To ensure the success of such a project, it is essential to plan every stage meticulously and assess all possible eventualities. A process of rigid planning and careful implementation will serve to minimise the difference between the expected outcomes and the final, delivered result.

Design considerations

The conceptual design of a new facility must be thoroughly analysed taking into consideration a number of important factors. The scope of the work - whether new chemical entities, biologicals or cytotoxics, for example - will greatly affect the design, as will, the scale of manufacture and type of build. Financial implications need also be given serious thought.

The exact use of the facility will determine the design requirements. There are significant differences between conventional sterilisation methods to those used for disposable technology for example. Conventional methods will inherently require much larger space due the necessary storage of autoclaves, vessels and the need for a washing area. Steam sterilisation will mean that water for injection must be available for final rinses after washing and for sterilisation.

Alternatively, if disposables are used for product contact parts, sterilisation is usually carried out through a process of irradiation, making the ‘water for injection’ (WFI) plant less important. It is essential to factor in the sourcing and validation of the sterile product contact parts into the project timings.

Once all considerations have been carefully assessed and analysed, the tendering process can begin. The project is presented to a number of potential contractors who can then bid to provide the solutions that will enable the facility to operate as desired. This could include the use of walk-in UniDirectional Air Flow (UDAF) areas or isolators. Once the contractor has been selected, it is vital to maintain a continual dialogue to ensure that all participants of the project have a clear understanding of the current status as well as any changes to be made.

Documentation

With so many issues to be considered and such a detailed plan to be implemented, it is absolutely essential that a comprehensive set of documents are produced to support each stage of the project and to ensure compliance with regulations. It is important to establish early on, who is responsible for which documents. The User Requirement Specification (URS) should be independent of the contractor so as to ensure that there are no misinterpretations further down the line.

The extent of the validation documents is determined by a number of factors. It may be necessary to decide on either a separate or combined qualification, both installation and operational (IQ or OQ). Additionally, a Performance Qualification (PQ) may be required. All of these issues need addressing to minimise risk of future complications, changes and delays in the project. The overall master plan should establish whether each piece of equipment requires its own plan or whether the entire project will be covered. This will also determine the specifications, design qualification and the necessity for combined or separate qualifications. It is essential to include all tests and verification checks within this document as it becomes more complicated to do so further into the progress of the project.

Disposable technology

The creation of several aseptic connections of tubing and filters to a pre-assembled, irradiated receiving vessel can greatly assist in reducing the risk of product contamination. Once these parts have been combined with the peristaltic tubing, they provide the attachment of a filling needle. Not only does this reduce the conventional storage requirements, which can be significant if using vast autoclaves, but it also greatly increases sterility assurance and lowers cleaning validation requirements. It is essential that sufficient time is factored into the project to allow for careful analysis of all components. This may be necessary when considering small-scale equipment and batches, as it may be more efficient to break up large bulk batches of pre-cleaned components into usable quantities prior to irradiation. This can be exemplified by stoppers. If the expected average batch size was 500 vials and the stoppers are packaged in bags of 5,000, commercially it would be unacceptable to incur this level of wastage. Breaking down bulk batches and sterilising the components into less wasteful quantities offers a much more cost-effective and practical option.

Project management

In any project, there must be sufficient time invested to ensure that the day-to-day running aligns to what was originally planned at the design stage. It is of course inevitable that changes will occur. However, involvement from inception of the project will serve to create a comprehensive understanding of what is required including any changes that may be implemented along the way. This will avoid potential misunderstandings due the altered scope of the project. As mentioned previously, a continual dialogue with the contractors is vital to the entire process.

Close checks should be performed to ensure that all areas meet you own standards. While everyone would like to show a quality facility, the profit motive can drive substantial cuts in areas that you may not approve of. After all, at the final stage of the project, it will be you as the client that will face the regulatory body. Therefore, the documentation needs to reflect the real situation with any problems explained as deviations or change controls. Additionally, the progress of all solutions should be carefully documented.

Every effort should be made to protect the structure of the facility throughout each phase of construction. Physical damage can be limited through rigid operational supervision and floor protection during the build. This process of careful monitoring will also minimise the difficulties involved in cleaning the facility to the required area classification.

Completion and verification

The importance of a continual dialogue and fluid understanding of the status of the project cannot be emphasised enough. As a result, the sign-off process becomes a great deal easier with all parties absolutely clear on their participation and where their responsibilities lie. All successful projects should also account for checks that include a certain degree of contractor independent tests. This could be, for example, the microbiological testing of the area after the first clean. Such testing along with extensive knowledge of the entire project, from inception through to completion, will provide you with the confidence to take over all responsibility for the facility once the sign-off is finally complete.