1. Manufacture of Sterile Medicinal Products: ‘Annex 1’ - DRAFT
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Dr.-Ing. Stephan Roenninger
Amgen (Europe) GmbH Director, External Affairs

2. Sterile Manufacturing
GMP According to Annex 1 Applies for Manufacture of Drug (medicinal) Products
GMP-Part II (ICH Q7)
Annex 1
GMP-Part I
Raw Material
API starting material
Drug (medicinal) Product
Finished Product
API
Patient t
Sterile Manufacturing
New structure & Size 16 pages -> 50 pages; Covers terminally sterilized products, aseptic preparation, the variations of sterilization including filtration and finishing of sterile products and the variations of sterilization including filtration
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Annex 1 draft, Chapter 1

3. Regulatory filing Manufacturing Process and IPC testing is approved
Principle: Minimize Risks of Microbiological, Particulate and Pyrogen Contamination – Contamination Control Strategy
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Facility, Equipment and Process design
Must be optimized qualified and validated
Processes and Monitoring Systems
Designed, commissioned, qualified & monitored, e.g. qualify particle counters including sampling tubing
Personnel: Protect the sterile product
Must have appropriate skills, training and attitudes (hygiene)
Regulatory filing Manufacturing Process and IPC testing is approved
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Ensure protection and control of the product from potential extraneous sources of particulate and microbial contamination such as personnel, materials and the surrounding environment
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GMP
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Dossier
Annex 1 draft, Chapter 2,4

4. Different Equipment Exists and Can be Operated in Compliance
Design and qualification requirements for Premises, Equipment and Utilities (water, air and vacuum) are described – Barrier technology
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Required equipment and/or other materials that may come into contact with a product or influence it directly
Water systems
Steam used for sterilization
Compressed gas and vacuum
Cooling systems
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Glove-Box
Clean room classifications (ISO 14644) and their qualification
Measure particles equal to or greater than 0.5 μm
Maintained in recommended limits for the monitoring of non-living particles
conventional line
PDA letter, June 2019, p.34; based on the PDA research Survey 2017.
RABS-Unit
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Annex 1 draft, Chapter 5, 6, 7

5. The Pharmaceutical Quality System (PQS) Need to Have Additional Controls and Measures to Ensure Quality: QRM to Prevent Contamination
Identify, assess, eliminate (where applicable)
Container integrity
Prevent, monitor and detect contamination
Ensure the safety, quality and efficacy of sterile manufactured product
Assurance of sterility
Minimize microbial contamination
Effective Quality Risk Management System
Basics
Sufficient knowledge and expertise
Root Cause Analysis and CAPA
Quality release
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Sufficient knowledge and expertise
Products manufactured and the manufacturing methods employed
Root cause analysis & Corrective an preventive actions
Procedural, process or equipment failure
Quality release
Access to manufacturing and quality information (registered specification
Annex 1 draft, Chapter 3

6. Integrated Risk-based Controls of Microbial Contamination From Raw Material Until the Final Product Release
Examples
Raw Materials
Facility
Process Controls
DP Testing
- Pest Control
- Facility Cleaning and sanitization
- Gowning
- Clean Utilities
- Material Flow and Cleaning
Media Hold Validation
Engineering controls tested per lot
Environmental Monitoring Program
Media Fill and Airflow Visualization Study
Endotoxin
Sterility
Annual Stability Program
Campaign post process Environmental Monitoring
- Supplier Qualification Program
- Raw Material Controls

7. Annex 1 Lists ‘How to Do’ Requirements for Production and Specific Technologies
Aseptic and terminal sterilization processes
For Products, equipment and packaging components
Approaches to sterilization
Lyophilization
Form-Fill-Seal (FFS), Blow Fill Seal (BFS), Single Use Systems (SUS)
Different technologies
Setting of alert limits and reviewing trend data
Aseptic Process Simulation (APS) [= media fill]
Viable and non-viable environmental and process monitoring
Quality Control
Testing is only the last step in a series of control measures
Representative samples Bioburden assay on each batch
Environmental monitoring data part of batch record
Rapid microbial methods
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Annex 1 draft, Chapter 8, 9, 10

8. QRM: Protecting Patients can Follow a Holistic View Taking into Account Elements Described in Different Documents
Guidance documents are intended to be read in its entirety regardless of the nature of the activities being conducted to fully understand the linkages between certain sections and successfully implement appropriate GMPs at all stages of the supply chain.
According to the ICH Q7-IWG Q&A
QRM: Quality Risk Management
Aknowledgement: Elizabeth Meyers, Myrta Atiles and Kris Evens, Enid Marin-Vallejo Amgen & Gabriele Gori, GSK