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 0.2m filter(s) to
provide a defined reduction in the microbiological
concentration prior to filling. Post filtration the product
is deemed sterile.

Key Considerations





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:


7
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.

9
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


10
Rotary Washer
Linear Washer
Vial Washing Machine - Rotary Washer
Bosch
RRN 2020 Rotary Washer
Bausch & Ströbel
FAW 1120 Rotary Washer
11
Process Stages – Vial Washer
IMA/Libra - Hydra - Linear Washer
WORKING PROCESS
12
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
13
Process Stages

Equipment


Dry Heat Oven
Continuous Depyrogenation tunnel
Tunnel Pressure Profiles
HOT ZONE
COOLING ZONE
Sterile area
14
Depyrogenation Tunnel
15
Depyrogenation Tunnel
Tunnel Air Flow
16
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


17
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
18
Stopper Processor
Huber Stopper Processing Cycle
1. Washing/
Detergent
Addition
6. SubaqualSiliconisation
19
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
20
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



21
Parts Washer
Ultrasonic Bath
Autoclave
Process Stages - Autoclave
22
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.

23
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

24
SAL= (Initial Bioburden Count)- (LRV)
Process Stages
6. Filling / Stoppering



Key Considerations





25
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
26
Time Pressure Fill (TPF) Technology


27
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

29
Used for Many Shear Sensitive Bio-Pharmaceuticals Protein
Products (Considered ‘Gentler’ on Proteins)
Rolling Diaphragm Pump Technology
30
Filling Methods – Peristaltic Pumps
31

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
32
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
33

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
34
Process Stages

35
Inspection:

Vial Integrity Tester (Wilco)

Seidenader Vial Inspection
System
Process Stages
9. Packing



36
Protection for transport to
warehouse/ pharmacy/
hospital
May include carton,
booklet, leaflet.
Many forms for Sterile
Products including vials
and syringes