Validation is the key to approval

Building a cleanroom is straightforward enough, but without the validation audit trail it is only half a job, at least from the relevant regulatory body's perspective.

The starting point for any project is the User Requirement Specification (URS) which the end user should initially develop. Often, however, Daw will advise on the spatial layout, the physical parameters of the facility, pressure regimes and room classifications capacity planning issues. This advice is based on European Community Guidelines on Good Manufacturing Practice as well as in-house experience and expertise. The URS is key, as all following documentation is referenced back to it, so that the client can demonstrate that the vendor has built what was required. After the URS, the DQ, IQ,PQ and OQ phase of the project is entered: • Design Qualification • Installation Qualification • Performance Qualification • Operation Qualification Design Qualification (DQ) is the responsibility of the cleanroom vendor which also has to develop the client's URS into a working solution. It is important that all design decisions are documented, so that at any stage it can be demonstrated to a licensing authority how any given point has been arrived at. DQ does not just look at the HVAC, it must also take into account the functional layout of a facility. This is a key stage in the design process and a detailed risk assessment with regard to product flow and process segregation must be carried out in conjunction with the end user. Often designs contain potential risks. For example, Daw has seen a design which had gene therapy activities accessed by a common change area leading to pharmacy production areas. These areas were both supplied by an air handling unit (AHU), recirculating a proportion of the air which is then supplied to other more conventional production areas. How, in such circumstances, can one demonstrate that there is "no risk" of gene related products entering into the main pharmacy facility? It simply is not possible. The solution was to incorporate separate entry and exit routes and support facilities as well as dedicated or 100% loss AHUs. It is also common to see single change areas that are used for several pharmaceutical activities such as cytotoxic and TPN. Here again, in the DQ stage, the proposition would be to install separate, dedicated change facilities to minimise the risk of any product cross contamination. Functional layout is just one facet of the DQ process. The design must incorporate products that are fit for the purpose, that is, designed specifically for, or proven in the intended application. Before any product can be purchased, a supplier audit is carried out to establish if the company has the capability of supplying appropriate products. The supplier must maintain its own control documentation. For example, even the intended cleaning chemicals to be used in the facility will be included in the URS. Daw selects finishes that should withstand repeated applications of the chemicals and the suppliers must demonstrate that they meet this criterion. Furthermore, for paint finishes, test results for the actual batch of paint used would be required. This demonstrates total traceability. Once the DQ is complete, and only when all this documentation is complete, can the Installation Phase be entered. The audit trail for the Installation Qualification (IQ) stage starts with the delivery of all products to the construction site. Each delivery must be cross-checked with the order. Only when this has been done should the product be issued to the construction team. The level of detail to be checked includes motor sizes and electrical specifications. This is especially crucial when working in hazardous environments.

Implementing strict protocols The complete installation must be managed with the same attention to detail. This is achieved by implementing strict protocols. Daw has detailed levels of protocol which start with safety wear, not only on arrival on site, but through to installation teams in full cleanroom garb. HEPA vacuum cleaners need to be used at all times. To ensure all the requisite protocols are maintained, inductions are carried out for all staff and the total area is policed. Any violation is documented and appropriate action taken. These records naturally form part of the IQ audit trail. As part of the IQ, Daw confirms the installation process has met all predetermined quality parameters. This applies equally to all installed material and systems, such as controls and process equipment. Once the team is happy that the IQ meets the DQ, which is in turn referenced back to the URS, the Operational Qualification (OQ) phase of the project may be entered. This includes both in-house and third party testing to ensure the predetermined parameters agreed by all parties during the preparation of the URS, and formalised and approved during the DQ, are met. Once this has been completed successfully, the facility can be handed over to the end user to complete "in-house testing" of Performance Qualification and process validation activities. Regulatory and operational compliance cannot be completed without all of the foregoing activities being completed and "signed off" as approved in a timely manner. Lastly, a full operation and maintenance manual must be issued to complement all the DQ, IQ, OQ and PQ documentation. This will include technical data for all equipment supplied as part of the project, as built drawings and recommended maintenance and cleaning regimes. When this stage is complete the facility meets the requirements of the authority. Without completing the steps outlined here, all you will have is a box, not a cleanroom.