EU GMP Annex 1
EU GMP Annex 1 -
Impact on cleaning and disinfection
by 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.
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, an holistic CCS for a sterile
pharmaceutical has three inter-related pillars for success.
Product Quality &
Patient Safety
Prevention Remediation Monitoring & CI
• Process Design • Cleaning & Disinfection • Data Trending
• Facility Design • Decontamination • Early warning
• Qualification & Validations • Sterilization • Feedback
• Testing & Release • Investigation & CAPA • Employee Trainings
• Employee Training
CONTAMINATION CONTROL STRATEGY (CCS)
PHARMACEUTICAL QUALITY SYSTEM (PQS)
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.
EU GMP Annex 1
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
EU GMP Annex 1
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 programme 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
 EU GMP Annex 1

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/