1. Manufacture of Sterile Medicinal Products: Practical Examples
Dr.-Ing. Stephan Roenninger
Amgen (Europe) GmbH Director, External Affairs

2. The Pharmaceutical Quality System (PQS) Need to Have Additional Controls and Measures to Ensure Quality: QRM to Prevent Contamination
Effective Quality Risk Management System
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
Basics
Sufficient knowledge and expertise
Root Cause Analysis and CAPA
Quality release
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

3. Integrated Risk-based Controls of Microbial Contamination From Raw Material Until the Final Product Release
Raw Materials
Facility
Process Controls
DP Testing
- Supplier Qualification Program
- Raw Material Controls
- 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

4. Controls at the Supplier and at the Receiving Stage are Established to Reduce Contamination Risks
Supplier Qualification Program
Ensures the quality of Raw Materials
Qualifies and monitors for GMPs compliance and supply materials that meet company's specifications
Pharmaceutical industry have evaluated the use of aseptic connectors as alternatives when traditional systems are not appropriate for the design. The industry deemed that commercial available aseptic connectors can provide higher sterile assurance.
Companies ensures compliance with all regulations regarding connections for sterile operations in a Class A (Grade 5)
Raw Materials
- Supplier Qualification Program
- Raw Material Controls

5. The Supplier Quality Process Qualifies and Monitors for GMP Compliance and Supply Materials
Supplier Selection & Approval
Specification Development
Material Qualification
Supplier & Material Monitoring
Continuous Improvement
Supplier Qualification Program
Quality Agreement template

6. Supplier Quality Management Process: Material Qualification and Approval
High Criticality
High potential to affect product SISPQ
Medium Criticality
Lower potential to affect product SISPQ
Low Criticality
Very low or no potential to affect product SISPQ
New materials are evaluated and classified based on their potential to impact safety, identity, strength, purity and quality (SISPQ)
Materials classified as either High or Medium Criticality are typically placed into groups and subgroups in the ERP system

7. Controls Within the Manufacturing Facility are Established to Avoid Contamination Events
Pest Control Program
Applies to all buildings, their surroundings & the entire Site acreage.
Facility Cleaning and Sanitization Program
The facility-cleaning/sanitization program is established to maintain the cleanliness of the manufacturing facility and therefore to maintain a microbiological controlled environment.
Gowning
Requirements per room classification are established.
Clean Utilities
Purified Water System, Water For Injection (WFI) System, Clean Steam Generation and Distribution, Process Air Generation and Distribution, and Nitrogen Distribution System
Material Flow and Cleaning
No cardboard is allowed in the Manufacturing Facility.
All material must be entered through the Material Airlock Room and a wipe down must be performed
Facility
- Pest Control
- Facility Cleaning and sanitization
- Gowning
- Clean Utilities
- Material Flow and Cleaning

8. The Process and Technology Used During Filling Have Controls in Place to Ensure Sterility of the Products
Validation of connectors with media hold studies
The components used for the product transfer are autoclave or gamma irradiated
Autoclave parts are validated.
Media studies were completed to demonstrate the robustness of the process.
Media Hold studies performed
Environmental Monitoring Program (Viable and Non-Viable)
Provides meaningful information of the quality of the manufacturing environment.
Identifies potential routes of contamination, allowing the implementation of corrective actions to prevent product contamination.
Media Fill Studies
Airflow Visualization Study
Classified Areas Qualification (EMPQ)
Process Engineering controls used per lot
Companies can design the process with controls in place to ensure product transfer is secure and sterility of the product is maintained.
Process Controls
Media Hold Validation
Engineering controls tested per lot
Environmental Monitoring Program
Media Fill and Airflow Visualization Study

9. The Process and Technology Used During Filling Were Designed to Guarantee Sterility
HEPA Filter Certification Program
Isolator (Engineering Controls)
Isolator (Cleaning and Decontamination Process)
Glove Integrity Test
Product Filtration Process
Depyrogenation of Vials/ Sterilization of stoppers/ Vial Components
Syringe, barrels, and plungers ready to use from vendor
Process Controls
Media Hold Validation
Engineering controls tested per lot
Environmental Monitoring Program
Media Fill and Airflow Visualization Study

10. The Final Assurance that the Product is Sterile is a Well-Design- Testing Approach
Release Testing for DP
Bioburden
Sterility
Endotoxin
EM in the Filling Process
Annual Stability Program
DP Testing
Endotoxin
Sterility
Annual Stability Program
Campaign post process Environmental Monitoring

11. Control of Microbial Contamination by Using Appropriate Personal and Additional Testing
Personal – specifics for their function & task
Sufficient appropriate personnel, suitably qualified and experienced
Should receive regular training, qualification
Systems in place for
Disqualification of personnel from entry into cleanrooms
Qualification of outside staff
Personal hygiene and cleanliness - high standards
Appropriate closing
Quality Control
Principle
Testing is only the last step in a series of control measures
Samples taken should be representative of the whole of the batch
Special testing
Microbiological contamination of starting materials
Bioburden assay on each batch
Special expectations
Media used should be tested for its growth promotion capability
Environmental monitoring data are part of batch record
Rapid microbial methods can be used

12. There are sterile APIs and follow Annex 1
API for a Sterile Drug Product Must be Sterile ONLY for Drug Products that Do Not Undergo Sterilization (Pharm. Ru, Categories 1.2.A, 5.2.A)
Manufacturing of Biotech API: Sterilize* 1. Cell culture equipment 2. Culture media 3. Fermentation equipment, as appropiate
API used for sterile manufacturing* 1. Measure microbial load & endotoxin 2. Use of water quality
There are sterile APIs and follow Annex 1
API starting material
Drug (medicinal) Product
API
Russian Pharmacopoeia Tests (Chapter 1.2.B & 5.2.B) might be preformed as IPC and not reported in the CoA of the DS (according to ICH Q7)
*GMP Part II (ICH Q7)

13. When Manufacturing Sterile Products Implement an Effective Risk Management to Prevent Contamination
Control Strategy
Facility & Material Severity +
Qualification/Validation and Quality System Probability +
Analytical Methods & Testing Detection
Aknowledgement: Elizabeth Meyers and Myrta Atiles, Mangen