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Cleanroom regulations: An expert opinion

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Rowin Vos, general manager BV at Connect 2 Cleanrooms, a cleanrooms design and manufacture specialist, provided Medical Plastics News editor Laura Hughes with his expert opinion on cleanrooms regulations.

What is the difference between ISO and GMP?

In both guidelines, particle contamination is used for the classification of the environment, both at rest and in operation. One of the main differences between the ISO classification and the EU GMP grades is the addition of microbiological limits of the room in operation. When following EU GMP guidelines, the principles of Quality Risk Management (QRM) should be applied to ensure that microbial, particulate and pyrogen contamination associated with microbes is prevented in the final product, or at least reduced as far as possible. In practice that also means that the facility, equipment and process design must be optimised qualified and validated according to Annex 15 of the EU GMP.

Is it then sufficient to build an envelope where all exposed surfaces are smooth and impervious, without uncleanable recesses, as detailed in EU GMP Annex 1?

No, that is not sufficient to provide complete product protection, as the case studies by Neches have shown. Personnel must have appropriate skills, training and attitudes, with a specific focus on the principles involved in the protection of the product during the aseptic manufacturing and packaging process. Also, the processes and monitoring systems must be designed, commissioned, qualified and monitored by personnel with appropriate process, engineering and microbiological knowledge. In essence, all activities should be managed in accordance with QRM principles that provide a proactive means of identifying, scientifically evaluating and controlling potential risks to quality (GMP draft Annex 1, December 2017).

You mentioned the difficulties that apply to terminal sterilisation of polylactic acid, polyglycolic acid and poly(lactic-co-glycolic acid) implants, but under strictly controlled conditions it can be done. How does that affect the manufacturing conditions?

In general, there are two primary routes of manufacturing sterile products:

But even in the case of terminal sterilisation, the manufacturing objectives are to control and minimise the particulates and bioburden in the product throughout the non-sterile processing stages. That’s why we refer to a “controlled” environment. The envelope, equipment and pre and post-manufacturing processes all need to be governed by Standard Operating Procedures (SOPs) in order to create that “controlled” environment.

Some manufacturers may argue that the contamination risk is far-fetched. Would you agree?

Yes, to some extent I tend to agree, but it is still up to them to assess their risks, based on their materials, process and intended use. Another way of looking at it would be to develop a process of minimal measures and to validate the outcome to a sterility assurance level of 106. Although in practice, that is not very likely to work, as that case would be hard to validate. Validation depends on repeatable results, time after time, which is difficult to do without strict process control.

Industrial pharmaceutical manufacturing sets out new sets of rules. Compare that to a situation where a patient could be expected to freshly prepare and reconstitute lyophilised drugs by aspirating saline from a pre-sterilised container, breaking an ampoule, adding the water, aspirating the solution in the syringe again and injecting intramuscularly. All of that would usually be done standing at the kitchen worktop. The manufacturer who delivers that same syringe in a “ready to use” format will have to build a full EU GMP suite from grade D, cascading all the way down to grade A for sterile filling the syringes.

We have to bear in mind that the Medical Device Directive stipulates that devices must be manufactured in such a way that their use does not compromise the safety of patients. That is all encompassing.

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