Process Stages

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Process Stages
Typical Process Steps

• Dispensing and Weighing
• Compounding
• Sterile Filtration
• Container Preparation
• Stopper Preparation
• Filling and Stoppering
• Capping and Crimping
• Inspection
• Packing

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Process Stages

• Typical Process Flow for an Aseptically Processed
  Vial Formulation

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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

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Process Stages

• 2. Compounding (Formulation)
• 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

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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

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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

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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

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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.

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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

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Vial Washing Machine - Rotary Washer
Bosch RRN 2020 Rotary Washer
Bausch Ströbel FAW 1120 Rotary Washer
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Process Stages Vial Washer
IMA/Libra - Hydra - Linear Washer
WORKING PROCESS
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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

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Process Stages

• Equipment
• Dry Heat Oven
• Continuous Depyrogenation tunnel

Tunnel Pressure Profiles
HOT ZONE
COOLING ZONE
Sterile area
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Depyrogenation Tunnel
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Depyrogenation Tunnel
Tunnel Air Flow
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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

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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
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Stopper Processor
Huber Stopper Processing Cycle
2. CIP System (Patented)
1. Washing/ Detergent Addition
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
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Operation
Stopper Processor

• 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
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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

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Process Stages - Autoclave
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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)

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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)

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Process Stages

• 6. Filling / Stoppering
• 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

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Filling and Stoppering Machine
Bosch MLF 3002 IN
Bausch Ströbel FVF 5060
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Time Pressure Fill (TPF) Technology

• Most Common System Supplied Today
• Tank feeds manifold feeds pinch valve feeds
  filling needle

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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

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Rolling Diaphragm Pump Technology

• Used for Many Shear Sensitive Bio-Pharmaceuticals
  Protein Products (Considered Gentler on
  Proteins)

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Rolling Diaphragm Pump Technology
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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)

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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

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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
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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

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Process Stages

• Inspection
• Vial Integrity Tester (Wilco)
• Seidenader Vial Inspection System

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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