EU GMP Annex 1 – Impact on Cleaning and Disinfection

By Karen Rossington

Cleaning and microbial contamination control are critical focus areas in pharmaceutical and medical device industries. Robust cleaning and disinfection programs are needed to meet the required cleanroom microbial grades, to prevent cross contamination and subsequent microbial contamination of products.

An inadequate microbial control program can cause significant risk to patient safety, at the very least product recall, and financial loss to the company. Control of microbiological contamination and root-cause investigation are among the top 10 most observed deficiencies by the FDA since 2012. A similar situation is observable in Europe based on MHRA deficiencies reported.

The manufacture of both human and veterinary medicines in the EU is governed by EudraLex Vol 4 Good Manufacturing Practice -“The rules governing medicinal products in the European Union“. Each country in Europe takes this legislation into their own country specific legislation: Rules and Guidance for Pharmaceutical Manufacturers and Distributors in the UK, Guide des Bonnes Pratiques de Fabrication (BPF) in France and GMP-Leitfaden zur “Guten Herstellungspraxis“ in Germany. Annex 1 of EU GMP specifically covers the Manufacture of Sterile Medicinal Products.

Annex 1 Manufacture of Sterile Medicinal Products

EU Annex 1 which specifies guidance for the manufacture of sterile medicinal products was first issued in 1971, revised in 1996 with partial updates in 2003 and 2007. With no complete review of the annex having been carried out for over 10 years, a complete review and rewrite was needed. The annex needed to catch up with both changes in sterile manufacturing technology (RABS, isolators, rapid microbiological and significant updates in regulatory expectation, the introduction of ICH Q9 for Quality Risk Management, ICH Q10 which describes Pharmaceutical Quality Systems, and the changes regarding the production of Water for Injection to include methods other than distillation. As Annex 1 has come to be used beyond sterile manufacturing, the scope of the new draft was also modified to reflect this.

A rewrite and not a revision was necessary, and in August 2022 the European Commission published an updated 59 page document. A working group of 16 representatives including the Pharmaceutical Inspection Cooperation Scheme, (PIC/S), WHO and EMA, in total 52 authorities including the FDA, Japan, Australia, Canada, EDQM & ICH were involved.

Each topic has been significantly expanded, new topics have been included and the concept of risk management is embedded throughout the document. Published in August 2022, GMP compliance to the revised Annex 1 is expected within 12 months. apart from compliance with point 8.123 (sterilization of manual lyophilizers) which has a deadline of 24 months.

General summary of changes

There are now over 300 different clauses, increased from 100 in the previous version. Many of these have been expanded on. The new sections include single use technologies, aseptic operator qualification, application of Quality Risk, disinfectant qualification for cleanroom surfaces, process water systems, including the manufacture of Water-for-Injection, other utilities and closed manufacturing systems.

One of the main documentary requirements of the new draft is the requirement for a holistic contamination control strategy (CCS).

Contamination Control Strategy

This document, either in one master document or separate related documents will reflect a site-wide strategy for minimizing contamination. Whichever way is chosen, it must be a “living” document, which is kept up to date throughout the life cycle of the facility.

As illustrated in the PDA image below, a holistic CCS for a sterile pharmaceutical has three inter-related pillars for success.

A Contamination Control Strategy is referenced many times in Annex 1. In the published version there are now approximately 45 times the annex states that a particular requirement, measurement or validation should be documented in a site’s CCS. For established facilities it probably already exists, even if across separate documents, and the manufacturer should try to include links and references in order not to rewrite all qualification documents. New facilities should start the CCS as early in the process as possible, it should ideally form part of the design process and be included in URS and DQ documents.

The Annex states that “A contamination control strategy (CCS) should be implemented across the facility in order to define all critical control points and assess the effectiveness of all the controls (design, procedural, technical and organisational), and monitoring measures employed to manage risks to medicinal product quality and safety. The combined strategy of the CCS should establish robust assurance of contamination prevention. The CCS should be actively reviewed and where appropriate, updated and should drive continuous improvement of the manufacturing and control methods.”

The CCS should describe the control measures and steps to minimize the risk of contamination from microbial, endotoxin/ pyrogen and particle contamination. It should include a series of interrelated events and measures which even if they assessed, controlled and monitored individually their collective effectiveness should be considered together.

The main elements will include:

• Design of plant and process
• Personnel
• Raw material controls
• Vendor approval
• Process risk management
• Preventative maintenance
• Validation of the sterilization process
• Management of outsourced activities
• Prevention mechanism (trend analysis, investigations, CAPA)
• Utilities
• Product container/closures
• Process validation
• Cleaning and disinfection
• Monitoring systems

And continuous improvement based on the information captured from the above.

Cleaning and disinfection

The references to cleaning and disinfection have been expanded. The word disinfection has been used to replace sanitation as the title of the section. The terminology of “cleaning” has been replaced with “cleaning and disinfection”. The text notes that “For disinfection to be effective, prior cleaning to remove surface contamination should be performed.”

This clarifies current best practice that cleaning and disinfection are two distinct activities trying to achieve different things. Cleaning is defined as “A process for removing contamination e.g. product residues or disinfectant residues.” Cleaning is the removal of non-viable contamination by physical means or by suitable agents to render a surface visibly clean.

Disinfection is “The process by which the reduction of the number of microorganisms is achieved by the irreversible action of a product on their structure or metabolism, to a level deemed to be appropriate for a defined purpose.” Some disinfection agents are effective only against vegetative microbes, while others possess additional capability to effectively kill bacterial and fungal spores.”

Many common and well used disinfectants, for example amines, amphoterics and quaternary ammonium compounds leave significant residues on a surface, which can subsequently have a detrimental effect on the effectiveness of the disinfectant used. This is acknowledged in the new version, “Cleaning programmes should effectively remove disinfectant residues.”

Within the section on equipment it highlights that, “The cleaning process should be validated so that it can be demonstrated that it remove any residue or debris that would detrimentally impact the effectiveness of the disinfecting agent used.”

There are disinfectants available which do leave minimal to no residue, or which have residues which are free rinsing or easily removable.

Rotation

Regulatory guidelines have not been aligned on the subjection of disinfectant rotation and the number of disinfectants which need to be used. EU GMP Annex 1 previously stated that “more than one type of disinfecting agent should be employed” and this is repeated in the new revision. Additionally, it states why, to ensure that where they have different modes of action, “their combined usage is effective against bacteria and fungi.” In line with other regulatory guidance it also clearly states that disinfection “should include the periodic use of a sporicide.”

The published annex mentions that “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)”.

This is an improvement on the previous wording which appeared to infer there could be acquired resistance to disinfectants at in-use concentrations, rather than innate resistance, which as a theory this has been largely discredited.

If the risk management approach of the rest of the guide is applied, the number & frequency of disinfectants to use, would be decided upon reviewing the trends of the EM program and periodic auditing of the cleaning and disinfection process. Our discussions with the MHRA confirmed that if EM results/trends are under control, there would be no stipulated need to have achieved this using a rotational disinfectant program.

Many facilities will routinely use a broad-spectrum disinfectant in rotation with a sporicide kept for intermittent or action point use. This is mainly due to the corrosive or aggressive nature of many sporicidal biocides rather than any concern over resistance. The more recent availability of highly effective cleanroom sporicides with no classified hazard may change this approach.

Disinfectant qualification

The previous version of Annex 1 gave some clear guidance about the use of disinfectants and detergents. “Disinfectants and detergents should be monitored for microbial contamination; dilutions should be kept in previously cleaned containers and should only be stored for defined periods unless sterilised.” This is repeated in the new version clarifying “...when made up by the sterile product manufacturer”, and the exception for sterile dilutions is removed.

The new annex acknowledges that many disinfectants and detergents are brought in ready-to-use from a manufacturer, so “If the disinfectants and detergents are supplied ready-made then the results from C of A or C of C can be accepted subject to suitable vendor qualification.”

It continues to state that “Disinfectants and detergents used in Grades A and B should be sterile prior to use.” It additionally requests that consideration should be given to disinfectants used in Grade C and D areas also being sterile prior to use, this would be decided via risk assessment and documented in the CCS.

Annex 1 states that it is the disinfection process that should be validated, not just the disinfectant. “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 on the type of surface material, or representative material if justified...” High risk surfaces will need to be identified and documented in the CCS.

Validation will need to relate to the manner in which the disinfectant is used, whether by spraying, wiping, using a presaturated wipe, not just standard suspension testing of the disinfectant.

Annex 1 also states that the validation work carried out “should support the in-use expiry periods of prepared solutions.” This will be relevant not only for dilutions made from concentrate but also ready-to-use trigger sprays and presaturated wipes. Efficacy testing will be required for not only the unopened product at end of shelf life but also for the product during its in-use period.

Environmental monitoring should be carried out to assess the effectiveness of the disinfectant program and be suitable to detect any changes in the type of house isolates identified. For instance, the microbial flora in a facility can change dependent on external factors such as local building work being carried out, seasonal changes and changes in staff. Annex 1 now clarifies that “Microorganisms detected in the grade A and B areas should be identified to species level…Consideration should also be given to the identification of microorganisms detected in grade C and D areas.” This requirement should be documented and defined in the CCS.

In Summary

There is more emphasis on separate cleaning and disinfection steps, which reflects current best practice. The periodic use of a sporicide is specified which brings the guidance into line with other regulatory documents. The removal of disinfectant residues is mentioned more than once so consideration needs to be given to “no residue” disinfectants, or disinfectants with easily removable residues. There is no definition of what a “low residue” disinfectant is, if the low amount of residue still builds up and is difficult to remove is the “low residue” relevant.

It is the disinfectant process which needs to be validated. Disinfectant efficacy needs to be proven on specific facility equipment, surfaces and associated processes. Disinfectant products need to be validated that they are efficacious for the whole duration of use but data from a qualified vendor can be used. All decisions need to be made based on Quality Risk Management and Environmental Monitoring trends and captured within the facility’s Contamination Control Strategy.

More information can be found here.

https://www.contecinc.com/annex-1-update/