Introduction

It is worth taking a moment to review the road that led to the long-awaited update of Annex 1 of EudraLex Volume 4 - Good Manufacturing Practice (GMP) guidelines.

In 1989 the first edition of the guide ‘EudraLex The Rules Governing Medicinal Products in the European Union’ which amongst its volumes included Volume 4 ‘EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use’ was published, and included an annex on the manufacture of sterile medicinal products.

A second edition was published in 1992, and further updating and re-structuring of the guide followed.  Annex 1 was also revised during the 2000s, but no complete review of the annex has been carried out since the last revision issue in 2008 – over 10 years ago. A complete rewrite has therefore been long overdue.



Relevance of Annex 1 beyond the EU

As stated in the EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use – Introduction: “The pharmaceutical industry of the European Union maintains high standards of Quality Management in the development, manufacture and control of medicinal products…Manufacturing authorisations are required by all pharmaceutical manufacturers in the European Union whether the products are sold within or outside of the Union.”

Pharmaceutical manufacturers within the EU, or manufacturers supplying products to the EU are therefore required to conform to EU GMPs.

EudraLex Vol.4 Annex 1 is common to the member states of the EU, but also the participating authorities of (PIC/S). As of June 2018, 48 countries have acceded as state members of PIC/S.

Updates or revisions to EudraLex Vol.4 Annex 1 therefore impacts on the GMP standards in use globally and has significant and wide-reaching consequences.



How the draft Annex evolved

An indication that a draft edition of a revised and updated version of the 2008 version of Annex 1 was imminent was given by the European commission in January 2015 via a ‘Concept Paper’. This was then followed by several notices that a change would be forthcoming in due course. 

On December 20th, 2017 the European Commission produced a draft of a revised Annex 1. Following the publication, there was a period of public consultation that ran from 20th December 2017 to 20th March 2018. 

The draft revision had attempted to reflect many of the advances in sterile manufacturing technology that had occurred in the preceding 10 years since the Annex had been updated, particularly with regards to RABS, isolators and single use technologies. There were therefore some significant changes relating to these areas, but also updates to the guidance on operator training and qualification, qualification of disinfectants for cleanroom surfaces and their in-use expiry periods, process water systems, other facility utilities and closed manufacturing systems. There was an acceptance and alignment with ICH Q9 (Quality Risk Management) and ICH Q10 (Pharmaceutical Quality System) and the new draft implicitly encouraged using the principles of Quality Risk Management (QRM), with numerous references to QRM made throughout the document.



The impact of the Annex 1 update on cleaning and disinfection

Of the many changes the draft Annex contained, this article will look 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 - now 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 versus disinfection and the focus on disinfectant residues

Annex 1 v.12 February 2020

“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 programs 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 within cleanroom environments.

The Annex 1 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. 

The process of cleaning is to remove physical dirt, soiling or disinfectant residues from a surface which 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 on 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 an 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.

Rotation and use of disinfection agents

Annex 1 v.12 February 2020

“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 se (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 broad-spectrum disinfectants or sporicides (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.

Whilst this practice is 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 phenomena 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 daft 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 of disinfectant from concentrates

Annex 1 v.12 February 2020

“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.

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 disinfectant efficacy and in use expiry periods

Annex 1 v.12 February 2020

 “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.

Conclusion:

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 organizations 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 organizations could deliver a final version of Annex 1 in 2020.