Of the many changes the draft Annex contained, this article looks particularly at the impact the draft had on the requirements for cleaning and disinfection, and whether the latest version (Annex 1 v.12 February 2020) has changed the guidance significantly in this respect.
It is true that what is in the latest draft may change again following the consultation period. However, the direction of travel for the guidance is reasonably clear. The first draft encouraged contamination control and steps taken to minimise the risk of contamination (which includes cleaning and disinfection) to be considered holistically. This has now been amended in v.12 to state that they should all be considered 'together' within a documented contamination control strategy (CCS).
It would be considered prudent for sterile manufacturers to compare the proposed changes in the draft to the procedures and practices at their own sites to determine if adjustments to site CCS will be needed in order to remain compliant.
Cleaning vs disinfection
4.36 The disinfection of cleanrooms is particularly important. They should be cleaned and disinfected thoroughly in accordance with a written programme. For disinfection to be effective, prior cleaning to remove surface contamination should be performed. Cleaning programmes should effectively remove disinfectant residues.
5.4 The [equipment] cleaning process should be validated to:
I. Remove any residue or debris that would detrimentally impact the effectiveness of the disinfecting agent used.
II. Minimize chemical, microbial and particulate contamination of the product during the process and prior to disinfection.
It has been accepted for some time that the terms 'cleaning' and 'disinfection' should be considered as two distinct terms, and it can often be helpful to consider them as two distinctly different processes when they are carried out within cleanroom environments.
The Annex 1 section previously called 'Sanitation' had already been renamed 'Disinfection' and had been expanded in the Annex draft issued in 2017, indicating that this was an area of increased focus. The separation of these two processes is now clearly stated.
V.12 highlights that disinfectants used in Grade C and D may also be required to be sterile
The process of cleaning is to remove physical dirt, soiling or disinfectant residues from a surface that could otherwise present a risk of physical, chemical or particulate contamination to the cleanroom area or products being manufactured within it. The presence of dirt, soil or residues on a surface could also present a physical barrier impeding the contact of any disinfectants that may be applied to a surface or to any microorganisms present, potentially impacting the disinfectant efficacy.
Cleaning of gross levels of dirt or soil are usually performed using appropriate (HEPA filtered) vacuums, or by wet wiping or mopping with water of appropriate quality or a cleanroom specific detergent designed to wet and/or emulsify the soil to aid its dispersal and removal.
By contrast, disinfection refers to the application of a chemical with a known antimicrobial activity or effect, for a specific contact time to reduce any bioburden present to an acceptable level.
There has been concern for some time about disinfectant residues that remain on surfaces post-application, and there are numerous examples of pharmaceutical companies receiving observations and citations for the presence of visible residues in the cleanroom environment.
The presence of visible residues has often been seen in the past as an indication that a cleaning and disinfection process is not fully in control, as the activity itself is leaving a 'contaminant' on the surface. The Annex draft now goes further, raising the concern that the residues themselves can have some hidden effects.
Rotational disinfectant use
4.36 The disinfection of cleanrooms is particularly important. They should be cleaned and disinfected thoroughly in accordance with a written programme... More than one type of disinfecting agent should be employed to ensure that where they have different modes of action and their combined usage is effective against all bacteria and fungi. Disinfection should include the periodic use of a sporicidal agent. Monitoring should be undertaken regularly in order to assess the effectiveness of the disinfection program and to detect changes in types of microbial flora (e.g. organisms resistant to the disinfection regime currently in use).
4.38 Disinfectants and detergents used in Grade A zone and Grade B areas should be sterile prior to use (disinfectants used in Grade C and D may also be required to be sterile). Where the disinfectants and detergents are made up by the sterile product manufacturer, they should be monitored for microbial contamination. Dilutions should be kept in previously cleaned containers and should only be stored for defined periods. If the disinfectants and detergents are supplied "ready‐made" then results from certificates of analysis or conformance can be accepted subject to successful completion of the appropriate vendor qualification.
Disinfectants are usually divided into either broad‐spectrum disinfectants or sporicides (these are usually more aggressive, oxidising chemistries capable of penetrating and killing bacterial endospores).
Whilst the requirement to rotate a broad‐spectrum disinfectant with a sporicide 'in accordance with a written programme' (i.e. not using sporicides only reactively) remains, the Annex draft v.12 issued in February 2020 has changed slightly. It now appears to imply the use of two different (possibly broad spectrum) disinfectants with different modes of action in addition to the periodic use of a sporicidal agent, however, this needs clarification.
The concept of acquired rather than innate resistance has been a contentious point for years
Though this practice is still sometimes seen, there may be little value in rotating two broad-spectrum disinfectants that are exerting an effect on a similar spectrum of organisms. Having two broad-spectrum disinfectants that need to be rotated can also increase complexity in terms of SOPs, and procedures, and increase the burden of validation and control of materials on site.
The Annex draft v.12, perhaps disappointingly, continues to reference organisms 'resistant' to the disinfection regime. The concept of acquired rather than innate resistance occurring at a site has been a contentious point for years, with little evidence of this phenomenon forthcoming.
The requirement for disinfectants to be effective against the typical flora encountered, and the idea that the efficacy of the disinfectants used, and the types of organisms encountered should be kept under review, is sound. This is the purpose of having periodic use of a sporicide, to ensure that the disinfectant rotation used has a full spectrum of activity, including against bacterial endospores.
The requirement for disinfectants and detergents used in Grade A zone and Grade B areas to be sterile prior to use (termed Grades A and B areas in Annex 1 2008 and in the 2017 draft) and for solutions to be monitored for microbial contamination, remains in place.
Interestingly, Annex 1 draft v.12 highlights that disinfectants used in Grade C and D may also be required to be sterile. This is again an indication that QRM principles must be applied. The use of sterile products in lower grade areas should not be ruled out if a contaminant present in a disinfectant could detrimentally impact on a production area and/or the products being manufactured within that area.
In-house preparation
4.38 ...Where the disinfectants and detergents are made up by the sterile product manufacturer, they should be monitored for microbial contamination. Dilutions should be kept in previously cleaned containers and should only be stored for defined periods. If the disinfectants and detergents are supplied "ready‐made" then results from certificates of analysis or conformance can be accepted subject to successful completion of the appropriate vendor qualification.
Concentrate versions of disinfectants have long been used and are considered by many to be a practical and cost‐effective means of producing large volumes of disinfectant for use. However, the Annex 1 draft issued in 2017 made it clear that there were increased considerations around filtration processes, including minimising the number of aseptic manipulations (including non‐intrinsic aseptic connections), filtration process conditions, filter integrity testing, validation pre and post use, in‐use filter pressures, bacterial retention and filter management that all impacted on disinfectants being prepared and filtered into sterile areas.
End-users of disinfectants should carefully consider contact times, surface materials and methodology used to validate them
Initially, the Annex 1 draft 2017 required that a 'worst-case location' water sample be taken each time the system is used for manufacturing and manufacturing processes. This has now been toned down significantly in the v.12 draft.
Despite the reduced requirement for water testing in the latest draft, end-users should still consider the 'total cost' of preparation of disinfectants from concentrates with the increased scrutiny of their preparation and filtration. The additional training, documentation and monitoring required for the process should also be factored in.
Validation of efficacy
4.37 The disinfection process should be validated. Validation studies should demonstrate the suitability and effectiveness of disinfectants in the specific manner in which they are used and should support the in‐use expiry periods of prepared solutions.
4.38 Dilutions should be kept in previously cleaned containers and should only be stored for defined periods. If the disinfectants and detergents are supplied "ready‐made" then results from certificates of analysis or conformance can be accepted subject to successful completion of the appropriate vendor qualification.
The Annex is clear that the effectiveness (efficacy) of disinfectants should be validated, and that the validation should be representative of the specific way they are used. This reinforces that end-users of disinfectants should carefully consider the contact times, surface materials and methodology used to validate disinfectants.
It also requires that the 'in‐use expiry' or hold time of a disinfectant solution is demonstrated through validation. This may involve a validation study to determine the length of time that a concentrate or a dilution prepared from a concentrate remains effective, stable and uncontaminated after opening. This may represent a further increased burden on users preparing detergent or disinfectant products from concentrate rather than using "ready‐made" or ready‐to‐use products. Here the Annex draft concedes that certificates of analysis or conformance from approved vendors may be sufficient, negating the need to validate.
Key points of v.12
The revised version 12 of the Annex 1 draft issued February 2020 retains much of the 'direction of travel' of the 2017 draft with regards the guidance for cleaning and disinfection as an integral part of a Contamination Control Strategy (CCS).
Some of the key areas of focus in both the 2017 draft and the latest version (v.12) are now:
- The Annex raised the concern that residues can have some hidden effects.
- Implies the use of two different broad-spectrum disinfectants with different modes of action in addition to the periodic use of a sporicidal agent is required / desirable.
- The requirement for disinfectants and detergents used in Grade A zone and Grade B areas to be sterile prior to use remains in place.
- The potential use of sterile disinfectants in Grade C and D cleanrooms, based on QRM.
- Disinfectant efficacy validation should be representative of the specific way disinfectants are used.
- 'In‐use expiry' or hold time should also be demonstrated through validation if disinfectants are prepared in‐house.
The final version of the Annex will invariably still contain some text that may be open to interpretation and will of course never be able to be a perfect guide for all readers. Further public consultation is underway, with a select number of relevant industry groups and organisations poised to provide further comments, suggest clarifications and amendments to the rapporteur.
It is hoped that this shorter consultation period, with a more focused range of groups and organisations, could deliver a final version of Annex 1 in 2020.
