Annex 1 - Final Version and its Impact - Live Online Conference
14/15 December 2022
Course No. 20687
Speakers
Arjan Langen
GE Healthcare
Dr. Ingrid Walther
Pharma Consulting Walther
Werner Hofstetter
Octapharma
Roland Koch
Gasporox
Dr. Philip Hörsch
Vetter Pharma-Fertigung
Dr Rainer Gnibl
GMP Inspector
Dr. Bettina Rietz-Wolf
Regierungspräsidium Tübingen
Dr Jean-Denis Mallet
Former Head of the Pharmaceutical Inspection Dpt. AFSSAPS
Walid El Azab
QP Pro Services
Luigi Scaffidi
Boehringer Ingelheim Pharma
Dr Simone Biel
Merck
Stephan Löw
CSL Behring
Dr. Johannes Rauschnabel
Syntegon Technology
All times mentioned are CET.
Objectives
This conference offers you a unique possibility to become acquainted with the new regulatory requirements of the revised final Annex 1, the impact on aseptic manufacturing and the challenges relating to quality aspects.
Authority speakers as well as representatives from pharmaceutical industry and experts from technical suppliers will provide you information about their thinking about the new requirements. They will discuss the statements of the new Annex 1 on topics like Quality Risk Management, Process Simulation/Media Fills well as the challenging topics of PUPSIT and the use of Single Use Materials.
The widely discussed topic of Contamination Control Strategy will also be discussed and the updated ECA Guide will be presented in support.
Subsequently, classical topics of contamination control like environmental monitoring and cleaning and disinfection are considered in the light of Annex 1.
Background
The Annex 1 “Manufacture of Sterile Medicinal Products” was published for the first time in 1971. During the following years it was updated several times, as example to align classification table of clean rooms, to include guidance on media simulations and bioburden monitoring in 2005 and 2007 or relating to capping of vials in 2010.
At the end of 2017, the first draft of a fundamental revision was published, which was intended to focus on more structured guidance, including state-of-the-art principles such as quality risk management and the consideration of new technologies and innovative processes. The draft now contained new sections, e.g. for utilities, and extended sections on topics such as production and specific technologies or on the requirements of Aseptic Process Simulation (APS).
During the subsequent public consultation, over 6000 comments were submitted to EMA, which were then processed alongside the challenge of moving to Amsterdam. This resulted in the current document, which was published on 20 February 2020 for a second, restricted consultation. After reviewing the approximately 2,000 comments submitted, the Inspector Working Group (IWG) finalised the report at the beginning of 2022 and forwarded it to the responsible bodies of the European Commission for final approval.
The long-awaited revised Annex 1 on the manufacture of sterile medicinal products was finally published by the European Commission on August 25, 2022 (1). The main reason for the update was to reflect changes in the regulatory environment and manufacturing, which includes a significant shift towards the application of quality risk management principles. The new Annex 1 will enter into force on August 25, 2023.
Target Group
This conference is of interest to professionals from pharmaceutical and biopharmaceutical manufacturers, authorities and suppliers with responsibilities in
Aseptic Manufacturing
Quality Assurance
Quality Control, Auditing
Inspections
who are involved in
Contamination Control
Monitoring
Qualification and Validation
Self Inspection
Quality Affairs
Process Simulation/Media Fill
Technical Requirements
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Introduction – Revision, Consultaion and the Annex 1 Task Force of RCA/EQPA
The Drivers for Updating the Annex 1 and the Major Changes Introduced
Introduction of Annex 1
Overview of drafting process
Major changes introduced
Contamination Control Strategy - Inspector´s View on an Overarching Strategy
Requirements
Expectations & Interpretations
ECA CCS Guideline: Example in Documenting the CCS and Future Challenges to Evaluate CCS Performance
Present the ECA guideline and Approach
Share example of elements to add in a CCS document using ECA template
Key information to have in a CCS
Future challenge: use of statistic and novel software to achieve holistic assessment approach
Structure and Design – Practical Aspects for a CCS
How to develop the strategy
How to have your documents available and accessible
Process Simulation – Annex 1 Requirements
Requirements
Expectations & Interpretations
Aseptic Process Simulation (APS /Media Fill) – Industrial Point of View
Different Designs / Simulation long filling times
Risk-based approach for interventions
Sterile Filtration – Pre-Requisites, must Haves, and Exceptions
The revised Annex 1 describes requirements when validating and utilizing a membrane filter to sterilize a medicinal product. There are still open questions such as
Redundant filtration – the extra piece of mind?
PUPSIT required – but exceptions allowed?
Filter inside or outside the isolator?
PUPSIT – Annex 1 - Application of Risk Management
PUPSIT: Risk Assessment for PUPSIT and Considerations of Associated Risks in Established Processes
Risks of flaw masking and filter damage
Product and process evaluations
Risk - Benefit analysis
CCIT – In the Light of the New Annex 1
Requirements for CCIT in finishing of sterile products
Overview of CCIT Methods
Applicability of the different technologies for the final containers
EudraLex Annex 1 Vol. 4 (August 2022) - Impact for Cleaning and Disinfection
Regulations relating to cleaning, disinfection
Impact to disinfectant selection and regime design
Challenges of disinfectant residue management
Qualification of a Disinfection System Complying Annex 1 - Industrial Experiences
Case study for qualification of disinfectants
Efficacy – how to control?
Annex 1’s “Specific Risks Associated with Single-Use Systems”
Challenges when using Single-Use Systems (SUS) in sterile manufacturing
Annex 1’s expectations, such as supplier qualification, extractables evaluation, verification of integrity throughout the process, incoming control, operator training
SUS and closed systems
Quality Risk Management in the Manufacture of Sterile Medicinal Products – Inspector’s Experiences
QRM in the Annex 1, more than CCS
Inspectors expectations on implementation of QRM principle
Best and worst case examples
Quality Risk Management in Sterile Manufacturing
Dos and don’ts
Practical examples
Key steps in executing a risk assessment
Enhanced Requirements on Facilities and Utilities
Utilities: water, steam and gases
Facilities: airlocks and pass-boxes ; insertion of barrier technologies
Implicit requirements
Barrier Systems – the Current Way
What makes a real barrier?
What are the limitations of isolators, of RABS?
Are Isolators less “performant” than RABS?
Isolators and Annex 1 – Technical and Practical Challenges
Personnel - Behaviour and Access into Cleanrooms
Requirements for personnel in new Annex 1
Developments since version 2008 of Annex 1
Comments of inspector on implementation
Environmental & Process Monitoring - Inspector´s View
Summary of Requirements from entire Annex 1
Essentials for Inspection
Optimizing your EM Program as per Revised Annex 1
Traditional vs Rapid Methods
EM risk assessment
Recovery studies
Data integrity
Annex 1 in The Age of Digitization: Re-imagining Contamination
TCCS and its parts – from MSC up to Monitoring
The benefits o a risk-based system- from DI up to trending
Takeaway Tools
Digitization in quality management and contamination control
Remote and hybrid work
Integrated Metrics
Process flow metrics and KBIs
Comparison of Annex 1 with Other Relevant
Documents
Clean Room Grades
Gowning
Monitoring
Trending
Annex 1: Industry Assessment after the two Rounds of Consultation
Short discussion of selected paragraphs
What could be achieved in the consultation?
What to look out for in future inspections?
What stumbling blocks have remained?
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Seminar Programme as PDF