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

2. Process Stages
Typical Process Flow for an Aseptically Processed Vial Formulation

4. 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

5. 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

6. 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

7. 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

8. 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

9. 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.

10. 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

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

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

13. 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

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

15. Depyrogenation Tunnel

16. Depyrogenation Tunnel
Tunnel Air Flow

17. 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

18. 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

19. 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
8. Drying
9. Unloading

20. 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

21. 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

22. Process Stages - Autoclave

23. 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)

24. 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)

25. 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

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

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

28. 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

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

30. Rolling Diaphragm Pump Technology

31. 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)

32. 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

33. 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

34. 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

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

36. 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