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

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

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

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

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

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

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

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

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

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

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

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)

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