Process Stages Typical Process Steps Dispensing and Weighing Compounding Sterile Filtration Container Preparation Stopper Preparation Filling and Stoppering Capping and Crimping Inspection Packing

Process Stages Typical Process Flow for an Aseptically Processed Vial Formulation

Process Stages 1. Dispensing and Weighing Centralised Dispensing: Solid Actives and Excipients Small Quantities of Liquid Actives and Excipients Key Considerations: Area Classification Cross Contamination Potential Toxic Compounds Decentralised Dispensing: Water and Solvents Key Consideration – Design of Compounding Room(s) where dispensing performed

Process Stages 2. Compounding (Formulation) E.g. Room where product components (Active, Excipients, Solvents etc) are brought together to produce the formulation that will subsequently be filled. E.g. Pooling of premixed product Simple Liquid Mixing Dissolution of solid active Emulsification Key Consideration Utility Requirements Proximity to Filling Point Area Classification Cross Contamination Flow of people, clean and dirty equipment, raw materials, product, waste

Process Stages 3. Sterile Filtration Product is sterile filtered through 0.2m filter(s) to provide a defined reduction in the microbiological concentration prior to filling. Post filtration the product is deemed sterile. Key Considerations Sterilisation of filter in place Post sterilisation pre-production integrity testing Post production integrity testing (in situ) Elimination of Aseptic connections Filter Location

Exercise 2 Compounding and Filtration Product being compounded/ formulated, filtered and filled into mobile 300l vessels. What design features should be considered to mimimise issues such as manual handling/ contamination for: A: Filling Area B: Vessel

Exercise - Answer Filling Area: Manual handling considerations Access to isolation valves Lifting method of filter housings Contamination: All feed lines sloped with no dead legs Minimise joints minimises contamination. Internal finishes polished for ease of CIP/ SIP

Exercise - Answer Mobile Vessel: Manual handling considerations Weight of full vessel and method of transport Access to sight glass/ isolation valves Contamination: All feed lines sloped with no dead legs Minimise joints minimises contamination. Internal finish polished for ease of CIP/SIP.

Process Stages 4. Container Preparation – Cleaning and Sterilisation of Empty product Containers Cleaning Washing and rinsing of containers using suitable grade of water to remove extraneous particles and chemicals Initial rinses can be carried out using Purified water Final rinse must use WFI (Water for injection) Containers blown dry using sterile air Equipment Rotary Washer Linear Washer

Vial Washing Machine - Rotary Washer Bosch RRN 2020 Rotary Washer Bausch & Ströbel FAW 1120 Rotary Washer

Process Stages – Vial Washer IMA/Libra - Hydra - Linear Washer WORKING PROCESS

Process Stages Container Preparation Sterilisation Dry heat Depyrogenation of clean containers to deactiviate bioburden (viable contamination) and degrade endotoxins (non-viable pyrogenic contamination) Heat-up, sterilisation and cooling zones Combination of residence time and setpoint temperature (250oC – 350oC) in sterilisation zone to achieve required degree of depyrogenation Typically 6 log reduction of bioburden required

Process Stages Equipment Tunnel Pressure Profiles Dry Heat Oven Continuous Depyrogenation tunnel Tunnel Pressure Profiles HOT ZONE COOLING ZONE Sterile area

Depyrogenation Tunnel

Depyrogenation Tunnel Tunnel Air Flow

Process Stages 5. Stopper Preparation Stoppers must be sterile as they are in direct contact with the product at some time during storage, handling or use Washing and rinsing to remove extraneous particulates and chemicals Detergent washing sometimes used for endotoxin load reduction Stopper may be siliconised for ease of insertion of stoppers into vials Stoppers must receive a final rinse of WFI Stoppers must be sterilised (typically using clean steam) Stoppers must be dried using sterile air Stoppers must maintain sterility during transfer to filler Equipment Rotating Drum Stopper Processor Fluidised Bed Stopper Processor

Stopper Processor Fedegari (Modified Autoclave) The stoppers are simply and quickly loaded through hatches in the drum The loaded drum is slid into the chamber on its carriage. As the door is hinged shut the magnetically coupled drive engages

Stopper Processor Huber Stopper Processing Cycle 1. Washing/ Detergent Addition 2. CIP System (Patented) 3. Direct Impact Cleaning (Patented) 4. SIP-System (Patented) 5. Rinsing/ Siliconisation 6. Subaqual- Siliconisation 7. Sterilisation to DIN 58.950 8. Drying 9. Unloading

Stopper Processor Operation WSSD processor (Getinge) Wash, Siliconize, Sterilize, Dry processing, in the sequence below Docking of transfer container Wetting of closures Washing (optionally with detergent) Rinsing Siliconization Sterilization Drying Pressurization for transfer & storage De-docking of transfer container Any combination of Wash, Siliconize, Sterilize, Dry may be performed

Process Stages Contact Parts Preparation Equipment parts which come into contact with either the product or container closure components must be cleaned and sterilised before each batch, e.g. product filling vessel, filling pumps, stopper feed tracks Washing and rinsing with detergent to remove product residues Initial rinses with purified water Final rinse(s) with WFI Sterilised using steam in pass through autoclave Equipment Parts Washer Ultrasonic Bath Autoclave

Process Stages - Autoclave

Process Stages - Sterilisation Sterility Assurance Level (SAL) The probability of any given unit being non-sterile after exposure to a validated sterilisation process. Autoclaves generally obtain an SAL of 10-6 (i.e. assurance of less than one chance in a million that viable micro-organisms are present in the sterilised article) To calculate the SAL for an autoclave, you need to know:- A: Starting bio-burden B: Log Reduction Valve (LRV) must be known. The LRV is the number of logarithmic reductions in initial count brought about by the autoclave (sterilisation method)

Process Stages - Sterilisation LRV = t/D Where: t = Sterilising Time, mins D = Length of time to reduce the number of viable organisms by 1 log reduction (or 90%) at a specified temperature SAL= (Initial Bioburden Count)- (LRV)

Process Stages 6. Filling / Stoppering Key Considerations Sterile filtered product is dosed into the washed and sterilised depyrogenated containers and then containers are stoppered Critical Process Step – Exposure time minimised to further reduce contamination risk Key Considerations Grade A / Class 100 / ISO 5 Conditions required Fill accuracy of equipment Product container contact surfaces should be of a suitable material and finish to prevent contamination Design of critical area should support an optimal laminar flow pattern Ease of changeover between batches and batch sizes

Filling and Stoppering Machine Bosch MLF 3002 IN Bausch & Ströbel FVF 5060

Time Pressure Fill (TPF) Technology Most Common System Supplied Today Tank feeds manifold feeds pinch valve feeds filling needle

Piston Pumps Technology Until recently the most common system supplied Tank feeds manifold feeds pump feeds filling needle Unfavorable for shear sensitive products as small gap between piston and cylinder

Rolling Diaphragm Pump Technology Used for Many Shear Sensitive Bio-Pharmaceuticals Protein Products (Considered ‘Gentler’ on Proteins)

Rolling Diaphragm Pump Technology

Filling Methods – Peristaltic Pumps Gentle Transfer Action Suitable for Protein Usually in Hazardous Product Application (No Metallic Contact) Quick Change-Over (Product Contact Tubing Disposed)

Stoppering Application of Stoppers Usually by Means of Pick & Place Device Vibratory Bowl Used to Sort Stoppers Track-Feed Stoppers to Pick & Place Device Key Considerations Grade A / Class 100 / ISO 5 Condition Required Stopper / Closure Contact Surfaces should be a a Suitable Material and Finish to Prevent Contamination Movement & Stoppers and Vibratory Bowl make this an Area of Risk

Process Stages 7. Capping and Crimping Secures the Inserted Stopper into the Vial Neck Helping to Ensure Long- Term Integrity and Sterility of the Vial Caps can be Plastic or Aluminium Key Considerations Capping Machines are Contaminant producers as They Release Particles During Crimping Capper and Filler Usually in Different Rooms to Avoid Contamination Bosch

Process Stages 8. Inspection Filled Containers of Paranteral Product Should be Inspected Individually for Extraneous Contamination or Other Defects such as: Foreign Matter Fill Volume Container Integrity Product Clarity / Colour Inspection can be Manual, Semi-Automatic or Fully Automatic

Process Stages Inspection: Vial Integrity Tester (Wilco) Seidenader Vial Inspection System

Process Stages 9. Packing Protection for transport to warehouse/ pharmacy/ hospital May include carton, booklet, leaflet. Many forms for Sterile Products including vials and syringes