Clean it up: How the GMP Draft Annex 1 will impact cleaning and disinfection

Karen Rossington from Contec discusses how a new good manufacturing practice regulation is set to impact cleaning programmes within the pharmaceutical industry. 

Cleaning and microbial contamination control are critical focus areas in the pharmaceutical industry. Robust cleaning and disinfection programmes are needed to meet the required cleanroom microbial grades, to prevent cross contamination and microbial contamination of products. Indeed incidents of contaminated products entering the supply chain with devastating consequences have happened in the last eight years.

The manufacture of medicines in the EU is governed by EudraLex Vol 4 Good Manufacturing Practice and each country in Europe takes the legislation into their own guidance.

Annex 1 manufacture of sterile medicinal products

EU Annex 1 specifies guidance for the manufacture of sterile medicinal products and was first issued in 1989. With no complete review of the annex having been carried out for over 10 years, a complete rewrite was needed. The annex needed to catch up with both changes in sterile manufacturing technology and significant updates in regulatory expectation.

Therefore, in December 2017 the European Commission via a GMP/GDP working group produced a draft of Annex 1.  The document was completely rewritten and now features new and expanded topics, with the concept of risk management embedded throughout. Thousands of comments were returned from industry and industry groups in response to the draft.

Contamination control strategy

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

This document, either in one master document or separate related documents will reflect a site-wide strategy for minimising contamination. Whichever way is chosen, it must be a “living” document, which is kept up to date throughout the life cycle of the facility. 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. Ideally it would 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 assess the effectiveness of all the control and monitoring measures employed.” The main elements will include amongst others, design of plant and process, equipment and facilities, process risk management and cleaning and disinfection.

Cleaning and disinfection

The references to cleaning and disinfection have been expanded. The terminology of “cleaning” has been replaced with “cleaning and disinfection”. The text notes that “for disinfection to be effective, cleaning to remove surface contamination must be performed first”. This clarifies current best practice that cleaning and disinfection are two distinct activities trying to achieve different things. Cleaning is the removal of non-viable contamination and disinfection is “the process by which surface bioburden is reduced to a safe level or eliminated.”

Many common and well used disinfectants 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 programmes should be effective in the removal of disinfectant residues.” 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 rotation and the number of disinfectants which need to be used. The US FDA, Japan and the Brazilian Health Regulatory Agency don’t specify and expect it to be based on a review of EM data. EU GMP annex 1 previously stated that “more than one type of disinfecting agent should be employed” and this is repeated in the draft. In line with other regulatory guidance the phrase “….include the periodic use of a sporicidal agent ” has been added.

If the risk management approach of the rest of the guide is applied, the number and frequency of disinfectants to use would be decided upon reviewing the trends of the environmental monitoring programme and periodic auditing of the cleaning and disinfection process rather than an edict to rotate two different disinfectants. Discussions with two MHRA inspectors confirmed that if environmental results/trends are under control, there would be no stipulated need to have achieved this using a rotational disinfectant programme.

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 draft version of Annex 1 gives some clear guidance about the validation of disinfectants;  “Disinfectants should be shown to be effective for the duration of their in-use shelf life….” This will be relevant not only for dilutions made from concentrate but also RTU trigger sprays and presaturated wipes. Efficacy testing will be required for not only the unopened product at the end of shelf life but also for the product during its in-use period. It’s expected that work will be carried out on isolates and surfaces that are specific to the individual facility. The draft annex includes the phrase “….taking into consideration appropriate contact time and the manner in and surfaces on which they are utilised.”

This point is reinforced further: “Disinfectants should be shown to be effective when used on the specific facilities, equipment and processes that they are used in.” As well as standard lab testing on EN surfaces and with ATCC organisms, it is now clearly stated that work needs to be carried out on surfaces from the facility. The disinfectant needs to be shown to be effective against house isolates, these can change seasonally but will be 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 defined in the CCS.” It continues to state that “Disinfectants and detergents used in Grades A and B should be sterile prior to use.”

So what now?

The annex is still at a draft stage and there has been a call for a further consultation phase. The Implementation Working Group (IWG) met in September and it is likely that an amended draft will be sent out for another consultation phase in some form or another.  However, there is a widely held view that the general direction of travel shown in the document will not change. It would be prudent to plan ahead with any disinfectant validation with these core principles in mind as it is likely that many will appear in the finished document.