Potential Impact on Cleaning and Disinfection

Karen Rossington - Contec, Inc.

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. Incidents of contaminated product entering the supply chain with devastating consequences have happened in the last 8 years in the USA, UK, France, Italy, South Africa.

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 United States is governed by The Center for Drug Evaluation and Research (CDER) through the Food and Drug Administration (FDA). The quality of these drug products is carefully monitored with the FDA Current Good Manufacturing Practice (CGMP) regulations. CGMP regulations contain minimum requirements for the methods, facilities and controls used in manufacturing, processing and packing of a drug product.

However, any pharmaceutical manufacturer who sells medicinal products in the EU will also have to meet the requirements of the European Union (EU) Good Manufacturing Practice for Medicinal Products: EudraLex Vol 4 Good Manufacturing Practice - “The rules governing medicinal products in the European Union. 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 methods) 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.

Additionally, there were some areas of the current version of the annex which were ambiguous and needed correction or clarification. 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 December 2017 the European Commission via a GMP/GDP working group produced a draft of Annex 1.

The working group of 16 representatives included the Pharmaceutical Inspection Cooperation Scheme, (PIC/S), WHO and EMA, in total 52 authorities including the FDA, Japan, Australia, Canada, EDQM & ICH were involved.

The document has been rewritten, the current 16- page document is replaced with a potential 50-page document. Each topic has been significantly expanded, new topics have been included and the concept of risk management is embedded throughout the document. Thousands of comments were returned from industry and industry groups in response to the draft.

An updated draft, v12 was circulated for targeted comment, to key industry groups in early 2020, with comments returned by July 2020. The IWG met in March 2021 and the current understanding is a final draft was to be sent to WHO, PIC/s and regulators only, by June 2021. It is not known whether this deadline was achieved. After approval of the draft the earliest publication of Annex 1 (still considered a priority by EMA) would be September 2021. It is looking unlikely that this date will be achieved, and some industry groups believe it might be early 2022 until we see publication of the new Annex 1.

General Summary of Changes

There are now over 270 different clauses, increased from 100 in the current 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.

CCS is mentioned numerous times in the draft, and some EU national agencies are already requesting a 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 draft states that “A contamination control strategy should be implemented across the facility in order to define all critical control points and assess the effectiveness of all the controls and monitoring measures employed to manage risks associated with contamination. The CCS should be actively updated and should drive continuous improvement of the manufacturing and control methods.”

The main elements will include:

• Design of plant and process 
• Equipment and facilities 
• Personnel 
• Utilities 
• Raw material control 
• Product containers and closures 
• Vendor approval 
• Process risk management 
• Process validation 
• Preventative maintenance
• Cleaning and disinfection
• Monitoring systems
• Prevention- trending, investigations, CAPA
• Continuous improvement

The draft annex v 12 defines disinfection as “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 judged 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 draft, “Cleaning programs should effectively remove disinfectant residues.”

Within the section on equipment it is highlighted that, “The cleaning process should be validated so that it can be demonstrated that it remove any residues 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 are currently not 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 draft v12. With an additional comment from the previous draft “where they have different modes of action their combined usage is effective against all bacteria and fungi.” In line with other regulatory guidance the phrase “....include the periodic use of a sporicidal agent ” has been added.

Also amended from the previous draft, draft annex v12 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 disinfectant 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.

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 and disinfectant residues.” Cleaning is the removal of non-viable contamination by physical means or by suitable agents to render a surface visibly clean.

For more information on Annex 1 or to request information on Contec’s range of low residue disinfectants and detergents, email [email protected]

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 current version of Annex 1 gives 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 sterilized.” This is repeated in the draft Annex 1, clarifying “...when made up by the sterile product manufacturer”, and the exception for sterile dilutions is removed.

Draft v12 acknowledges that many disinfectants and detergents are brought in ready-to-use from a manufacturer, so “If the disinfectants and detergents are supplied readymade 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.” Draft v12 also adds “(disinfectants used in Grade C and D may also be required to be sterile.)” This would have to be risk assessed and captured in the CCS.

The draft states that it is the disinfection process that should be validated, not just the disinfectant. “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 of prepared solutions.” So 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.

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. Work needs to be carried out to validate the disinfectant on surfaces that reflect those in the facility with high risk surfaces identified by risk assessment.

The disinfectant will need to be effective against house isolates, these could be seasonal, this will be shown by shown by EM trends. Annex 1 now clarifies that “if microorganisms are detected in a grade A or B zone, they should be identified to species level... Consideration should also be given to the identification of grade C and D contaminants” This requirement should be documented and defined in the CCS.

So, What Now?

After approval of the draft the earliest publication of Annex 1 (still considered a priority by EMA) is September 2021. However, this is looking very unlikely with most commenters thinking publication in early 2022 will be more likely. From the point of publication, GMP compliance to the revised Annex 1 would be expected within six months unless specifics items are given an extended implementation time. It would be prudent to plan ahead for any disinfectant validation with these core principles in mind, as it is likely that many will appear in the finished document.

Implications for North American Pharmaceutical Manufacturers

As mentioned previously, all facilities who current market sterile pharmaceuticals to the European Union will have to meet all the requirements of the new Annex 1. The FDA was a key contributor to the draft annex looking to harmonize GMP across Europe and the United States. It is highly likely that changes will follow to the sterile manufacturing guide in the United States as well.. It would be prudent for all pharmaceutical manufacturing facilities to keep a “weather eye” on whatever changes make the published version of EU GMP Annex 1 Manufacture of Sterile Medicinal Products.

Glossary

• CAPA - Corrective Action Preventative Action
• CCS - Contamination Control Strategy
• DQ - Design Qualification
• EDQM - European Directorate for the Quality of Medicines
• EM - Environmental Monitoring
• EMA - European Medicines Agency
• FDA - Food and Drug Administration
• GDP - Good Distribution Practice
• GMP - Good Manufacturing Practice
• ICH - International Council for Harmonization
• IWG - Inspectors Working Group
• MHRA - Medicines and Healthcare products Regulatory Agency
• RABS - Restricted Access Barrier Syste
• URS - User Requirement Specification
• WHO - World Health Organization

Author Biography

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