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Process Stages

1. Dispensing and Weighing2. Compounding3. Sterile Filtration4. Container Preparation5. Stopper Preparation6. Filling and Stoppering7. Capping and Crimping8. Inspection9. Packing

Typical Process Steps

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Process Stages

Typical Process Flow for an Aseptically Processed Vial Formulation

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UnpackStoppers

Caps

Typical Process Block Flow Diagram for an Aseptically Processed Vial Formulation

Formulation Room

Load Stopper

Feed Station

Stopper VialFill Vial

Cap Seal Feed Station

Seal Vial with Cap

Ink Cartridge

Tray OffVials

Warehouse

Wash VialLoad VialsStretchwrap

Pallet

Warehouse (Quarantine

)

Release from

Quarantine

Dispatch

Inspection

Head Tank at Fill

StationUnpack Vials

Component Prep Room

Filling Room

Depyrogenate Vial

Cold Store (20C to 80C)

Filter(0.22µm)

Print Vial Cap

Capping Room

Inspection

Inkjet/Tray Off Room

TransferContainer

Stopper Processor

TransferContainer

WFI Generation

System

Waterfor Injection

Warehouse

Transfer to Compoundin

g Room

Pool into Tank

Bulk Drug Substance

Nitrogen Storage

Tank

Nitrogen

Filter thru 2 x 0.22µm

filters

QC Tests

Vials Shrink Wrapped Pallets

Vials

Warehouse

Stoppers Caps

CompoundingRoom

Cold Store

(2-80C)

Cold Store

(2-80C)

Airlock Airlock

Store Store

Warehouse

Caps(Gamma

Irradiated)Stoppers

Store at 20C to 80C

Cold Store

Background Area Classification Required By Process Step

External

Unclassified

Pharmaceutical Grade

Grade D(Pharmaceutical with local monitoring)

Grade C(ISO8 Class 100,000)

Grade B(ISO7 Class 10,000)

Grade A(ISO5 Class 100)

Laminar Flow Zone

Open Processing

Closed Processing

ISL Isolator (Class 100)

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Process Stages1. 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 Stages2. 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 Stages3. 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 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 Stages4. 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 WasherIMA/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 ProfilesHOT

ZONECOOLING

ZONE

Sterile area

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Depyrogenation Tunnel

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Depyrogenation Tunnel

Tunnel Air Flow

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Process Stages5. Stopper PreparationStoppers 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

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

Fedegari (Modified Autoclave)

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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

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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

OperationStopper Processor

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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-burdenB: 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/DWhere:

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 Stages6. 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

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

7. Capping and Crimping

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Process Stages

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

8. Inspection

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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