Sterile Processing
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Transcript Sterile Processing
Process Stages
Typical Process Steps
1.
2.
3.
4.
5.
6.
7.
8.
9.
1
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
2
Typical Process Block Flow Diagram for an Aseptically Processed Vial Formulation
Vials
Vials Shrink
Wrapped
Pallets
Water
for Injection
WFI
Generation
System
Nitrogen
Bulk Drug
Substance
Stoppers
Nitrogen
Storage
Tank
Stoppers
Caps
Caps
(Gamma
Irradiated)
Background Area Classification
Required By Process Step
Warehouse
Warehouse
Cold Store
External
Store at 20C
to 80C
Warehouse
Store
Store
Unclassified
Pharmaceutical Grade
Laminar Flow Zone
Grade D
(Pharmaceutical with
local monitoring)
Grade C
(ISO8 Class 100,000)
Transfer to
Compoundin
g Room
Airlock
Grade B
(ISO7 Class 10,000)
Airlock
Grade A
(ISO5 Class 100)
Compounding
Room
Open Processing
Pool into
Tank
Closed Processing
ISL
Isolator (Class 100)
QC Tests
Filter thru 2
x 0.22µm
filters
Unpack
Stoppers
Caps
Inspection
Formulation
Room
Stopper
Processor
Cold
Store
(2-80C)
Transfer
Container
Filter
(0.22µm)
Inspection
Transfer
Container
Filling
Room
Unpack Vials
Load Vials
Capping
Room
Head Tank
at Fill
Station
Wash Vial
Depyrogenate
Vial
Fill Vial
Load
Stopper
Feed
Station
Cap Seal
Feed Station
Stopper Vial
Seal Vial
with Cap
Inkjet/Tray
Off Room
Warehouse
Cold
Store
(2-80C)
Ink Cartridge
Cold Store
(20C to 80C)
Print Vial
Cap
Tray Off
Vials
Stretchwrap
Pallet
Warehouse
(Quarantine
)
Component Prep Room
3
Release
from
Quarantine
Dispatch
Process Stages
1. Dispensing and Weighing
Centralised Dispensing:
Key Considerations:
Area Classification
Cross Contamination Potential
Toxic Compounds
Decentralised Dispensing: Water and Solvents
4
Solid Actives and Excipients
Small Quantities of Liquid Actives and Excipients
Key Consideration – Design of Compounding Room(s)
where dispensing performed
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.
Key Consideration
5
Pooling of premixed product
Simple Liquid Mixing
Dissolution of solid active
Emulsification
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 0.2m filter(s) to
provide a defined reduction in the microbiological
concentration prior to filling. Post filtration the product
is deemed sterile.
Key Considerations
6
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:
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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
8
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
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Rotary Washer
Linear Washer
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
15
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
Equipment
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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
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
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Stopper Processor
Huber Stopper Processing Cycle
1. Washing/
Detergent
Addition
6. SubaqualSiliconisation
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2. CIP
System
(Patented)
7. Sterilisation to
DIN 58.950
3. Direct
Impact Cleaning
(Patented)
8. Drying
4. SIP-System
(Patented)
5. Rinsing/
Siliconisation
9. Unloading
Stopper ProcessorOperation
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
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Parts Washer
Ultrasonic Bath
Autoclave
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 microorganisms 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.
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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
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SAL= (Initial Bioburden Count)- (LRV)
Process Stages
6. Filling / Stoppering
Key Considerations
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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
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
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Time Pressure Fill (TPF) Technology
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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
28
Rolling Diaphragm Pump Technology
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Used for Many Shear Sensitive Bio-Pharmaceuticals Protein
Products (Considered ‘Gentler’ on Proteins)
Rolling Diaphragm Pump Technology
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Filling Methods – Peristaltic Pumps
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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
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Process Stages
7. Capping and Crimping
Secures the Inserted Stopper into the
Vial Neck Helping to Ensure LongTerm Integrity and Sterility of the Vial
Caps can be Plastic or Aluminium
Key Considerations
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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
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Process Stages
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Inspection:
Vial Integrity Tester (Wilco)
Seidenader Vial Inspection
System
Process Stages
9. Packing
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Protection for transport to
warehouse/ pharmacy/
hospital
May include carton,
booklet, leaflet.
Many forms for Sterile
Products including vials
and syringes