EU GMP

WHAT ARE
THE NEW
CHALLENGES
IN STERILITY
ASSURANCE?

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 DEFINITION
EUDRALEX OF CLEANROOM
VOLUME 4
ANNEX 1:
MANUFACTURE OF
STERILE PRODUCTS
DRAFT PROPOSAL
FOR REVIEW “A room designed, maintained, and
controlled to prevent particulate and
microbial contamination of drug
products. Such a room is assigned
and reproducibly meets an
appropriate air cleanliness level.“

(EU GMP Annex 1)

“Room within which the number concentration

of airborne particles is controlled and
classified, and which is designed, constructed
and operated in a manner to control the
introduction, generation and retention of
particles inside the room.“

(ISO 14644-1: 2015)

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 EUDRALEX VOLUME 4
THE RULES GOVERNING
is the collection of rules and
regulations governing medicinal MEDICINAL PRODUCTS
IN THE EUROPEAN UNION

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products in the European Union.

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consists of 10 volumes.
ANNEX 1
UPDATES FROM THE LAST VERSION

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The annex 1 draft, circulating for review of involved stakeholders,

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has changed dramatically from the last version issued in 2008,
VOLUME 4 following the evolving changes in GMP environment, both

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regulatory and scientifically based.
of "The rules governing
medicinal products in the
European Union" contains 6
guidance for the 18 pages More than 50 pages
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interpretation of the
principles and guidelines of
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good manufacturing
practices for medicinal
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Main
products for human and changes on
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veterinary use. its content

are here
reported:
Includes other areas,
besides sterile products,
to which it can be applied
ANNEX 1 Classification vs. monitoring of clean
is focused on the room and clean air device (classification
manufacture of sterile is required to be performed according
medicinal products. EN ISO 14644-1)
More detailed guidance (in accordance
with FDA) on media simulations
Bioburden monitoring prior to sterilization
Detailed guidance on primary packaging

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 EUDRALEX
VOL. 4,
ANNEX 1
SCOPE
To provide guidance for the
manufacture of sterile products
using the principles of Quality Risk
Management (QRM).

Some principles, such as

contamination control strategy,
design of premises, cleanroom
classification and qualification,
monitoring and personnel
gowning, also apply to non-sterile
products (e.g. creams, certain
liquid or intermediates) where the
control and reduction of microbial,
particulate and pyrogen
contamination is considered
important.

DRAFT
The second draft of GMP Annex 1 has been recently
released and the issue date for the new revision is
finally approaching. The document, a milestone
standard for all the sterile manufacturers, has been
widely revised and extended, with important insights
and implementations for the sterility assurance of the
finished products. Should all the manufacturers get
ready to be compliant with the approaching news
from Annex 1? Absolutely YES!

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 The 2020 Annex 1 draft results to be widely expanded
in many sections, and the added news are many and
significant. One first aspect, catching the eye of any
interested reader, is the strong attention paid to PQS
and Quality Risk Management: ICH Q9 and Q10 are
now globally accepted and implemented.
Manufacturers, now more than ever, are requested to
improve their management system for risk assessment,
investigations, CAPAs implementation and monitoring.
And most of all, they are requested to improve their risk
ANNEX 1 assessment approach, extending it to every aspect of
sterile manufacturing. This new global, site-wide

IMPLEMENTATIONS: approach to the contamination risk assessment is

reflected in the strong focus on the implementation of
Contamination Control Strategy: a newly requested
Let’s see the main document where any aspect, having an impact on the
sterility assurance of sterile products, must be assessed
implementations, with with a holistic approach: cleanroom design, material/
personnel flows, closed systems implementation,
respect to the current environmental monitoring and data trend, disinfection,
utilities management, and so on.
Annex 1 edition. The new Annex 1 draft requests the sterile
manufacturers to re-think their cleanrooms layout, with
new approaches to the design of environmental
monitoring plans of the critical areas, changing rooms,
HVAC system and cleanroom qualification. And new
technologies are now mentioned for the protection of
the most critical steps of aseptic processing: the
implementation and use of RABS, isolators and
closed systems is now dramatically encouraged.

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 Most of all, aseptic processing is approached with deeper insights In conclusion, the new Annex 1
on the most critical aspects for microbial contamination containment. is going to request manufacturers
Manufacturers are now requested to be aware of their need for to adopt an overall risk
(just to mention the most relevant ones): assessment approach and build
a robust and scientifically-based
a strong sterile personnel training and qualification program management system for the
sterility assurance of their
a risk-based approach to sterility assurance and environmental monitoring products. A lot of operational
aspects of sterile production are
a scientific justification for time controls on sterile processing now much more detailed and
cleared, and new challenges are
a close control to material and operators flows in and out from cleanrooms arriving for sterile manufacturers
to get compliance with GMP
guidelines, not only related with
equipment and cleanrooms but
But the list doesn’t stop here. Because the new draft Annex 1 also also with their quality personnel
introduces important news about aseptic process simulation (aka skills and background.
media fill). The requirements for media fill execution are much more
detailed in terms of acceptance criteria, performance parameters and
operational aspects to be challenged. Manufacturers are thus forced to
have, or gain, deeper knowledge and skills on every aspect of their
aseptic processing.

Visual Inspection is another production step poorly detailed in the

previous edition and now much better defined: critical defects must be
listed, monitored and trended, and dedicated personnel is now
requested to be qualified and periodically assessed for their ability to
reliably detect such defects. And last but not least, in a list that could
be much longer, alternative rapid microbial methods are now
mentioned and their adoption foreseen: such methods (not only
for environmental monitoring and sterility test) show important
advantages, with respect to the currently used ones, but need strong
and skilled efforts for their set-up and validation, to be reliably applied.

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 staff comprises experienced and
skilled experts that can support
you in the goal for compliance
with the new arriving Annex 1, in
every aspect of your aseptic
manufacturing: sterility assurance
strategies, quality compliance,
microbial monitoring, cleanroom
design and revamping,
equipment qualification, critical
system validation, analytical
methods selection and
validation, and many others.
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The main and most important
implementations, with respect to the
current Annex 1 edition are:
Quality Risk Management: strong attention
and focus on a site-wide approach to risk
assessment and management
Contamination Control Strategy: a new
holistic approach is requested to assess the
contamination risk and define all the required
control and contamination strategies at every
distinct stage of production
New technologies for the protection of the
product and of the process (e.g. RABS/isolators)
are now strongly recommended
Stronger focus on:
• personnel training and qualification programs
• a risk-based approach to sterility assurance
and environmental monitoring
• a scientific justification for time controls
on sterile processing
• Scientific approach, management and
requirements for media fill execution
• Visual inspection
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 GAPS classification with
ASSESSMENT risk based approach

Remediation activities
REMEDIATION Implementation with “Prioritization approach” Overall assessment of facility compliance readiness

Definition and issue of a Contamination Control

Strategy document

MOCK Simulation of EU GMP inspection focused Application of the risk assessment approach to:
INSPECTION on Annex 1 requirements • Environmental and personnel monitoring
• Cleaning/disinfection strategies
• Raw materials monitoring
• Utilities monitoring
• Media fill definition and execution
WAR ROOM Direct support during real inspection
SUPPORT Environmental monitoring data management:
trending, statistical analysis, microbial identification,
alert/action limits calculation

Container closure integrity:

statistical analysis and risk-based management

PUPSIT: risk assessment for the definition of the most

reliable strategy to implement in-place integrity testing

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 PQE Quality Engineering team can assess
Quality Engineering your existing sterile manufacturing areas in
order to evaluate the necessary revamping
and improvement plan in terms of:
Compliance
Quality Engineering Gap Analysis

Layout revamping according new Annex 1 requirements

Data Integrity & CSV
Cost Estimate for departments revamping

Differential pressure & classification Layout

Equipment & Utilities Qualification Improvement of material, personnel and waste flow

P&ID for HVAC and Utilities

Suppliers selection support for process equipment, RABS, Isolator and Utilities
Project Management Conceptual & Basic Design for brownfield and greenfield projects

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 PQE Compliance team can support your
organization in implementing the most
reliable strategy to comply with the new
Annex 1 requirements in terms of:

Overall assessment of facility compliance readiness

Definition and issue of a Contamination Control Strategy document

• site overview, gap assessment on critical points, definition of a global containment strategy

Application of the risk assessment approach to: PQE can assess the facility with regards to
• Environmental and personnel monitoring
• Cleaning/disinfection strategies
Data Integrity & CSV requirements,
• Raw materials monitoring supporting the customer on the
• Utilities monitoring implementation of the suggested
• Materials not-sterilizable to be used in cleanrooms
remediation actions.
• Media fill definition and execution
• Planning strategy Services in scope:
• Defining of critical interventions
“To be status” Data Integrity & CSV definition
Deviation and CAPA management (aseptic environment):
• Overview of all microbiological deviations and related investigations Supplier selection
• Mitigation plan
• CAPA definition New Systems URS Creation

Personnel training: Data Integrity Governance System Creation

• Aseptic behavior
• Critical points of garments and aseptic gowning
Validation of every GxP System impacted by Annex 1. Such as:
• Non-viable particles monitoring systems
Environmental monitoring data management: • Environmental Monitoring system
• Trending and statistical analysis • Equipment Control systems such as Isolators and/or RABS
• microbial identification plan and data analysis • Equipment Control systems for Sterilization such as Autoclaves and / or depyrogenation Tunnel
• alert/action limits calculation • Equipment Control Systems for CIP (Cleaning in Place ) / SIP (steam in Place) for Vessel,
Purified Water distribution Lines, WFI (Water for Injection) distribution Lines, Equipment
Container closure integrity: statistical analysis and risk-based management Control System for sanitization of Isolators and / or RABS (e.g.VHP)
• Lyophilizers Control Systems
PUPSIT: risk assessment for the definition of the most reliable strategy to
implement in-place integrity testing

SUS (Single Use System):

• Definition, risk assessment and management of the issues

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PQE Technical Qualification team
can support your Validation and
QA departments in performing the
following activities in the context
of sterile facilities:
Skilled professionals, specialized
in PMO, can help your internal
departments in the:
Definition of the overall Annex 1 Project Plan
Suppliers coordination
Project supervision, monitoring and reporting

Validation Master Plan

User Requirements Specification

Quality Risk Assessment

Process Equipment Qualification

• Isolator / RABS / UDAF
• Filling Line
• Environmental Monitoring System
• Autoclave and Depyrogenation Tunnel/Oven CONTACT US TO
• Blow-Fill-Seal (BFS)
• CIP and SIP
KNOW MORE ABOUT
• Visual Inspection Machine ANNEX 1
• Freeze Dryer

Clean Utilities Qualification DON’T WAIT!

• Water and Steam Systems A team will be available to evaluate
• Process Gases the best tailored solutions for your
• Cleanroom and HVAC Qualification business by PQE Group.

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 Choose PQE Group,
we support you
globally, thinking locally.

HEADQUARTERS
Località Prulli, 103/C • 50066
Reggello (Florence) ITALY
T +39.055.5275100 • F +39 055.5275142