Blow-Fill-Seal (BFS)

Technology Guidance

Kenneth H. Muhvich, Ph.D.

Principal Consultant
Micro-Reliance LLC

Pharmaceutical BFSIOA
„ Formed as an interest group in 1989
„ Consisted of companies involved in
advanced aseptic processing using
B/F/S machines, as well as vendors
„ Forum for idea exchange
„ Overarching purpose was to identify &
document best practices for operation
of B/F/S machines

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Pharmaceutical BFSIOA
„ Published “Points to Consider for
Pharmaceutical Blow-Fill-Seal
Manufacturing Operations” in
September of 1993
„ That document described B/F/S
operations and provided more general
information, as well

B/F/S DRAFT Guidance

„ “The Manufacture of Sterile
Pharmaceuticals and Liquid Medical
Devices Using Blow/Fill/Seal
Technology”
„ Originally written by the Pharmaceutical
Blow/Fill/Seal – International Operators
Association (BFSIOA)

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B/F/S DRAFT Guidance
The purpose of the guidance is to…
„ provide a description of current B/F/S

operations and best practices

„ accurately reflect B/F/S manufacturing

on a global basis
„ focus on issues that are specific to

B/F/S technology & aseptic processing

B/F/S DRAFT Guidance

„ Sterile pharmaceuticals
„ Liquid medical devices
„ Aseptically filled products filled only
using B/F/S technology
„ Terminally sterilized products

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BFS Process Outline
„ Polymer granules are melted and extruded
under high pressure to form a plastic tube or
“parison”
„ The container is formed in a cooled mold by
blowing sterile air or via vacuum
„ The container is then aseptically filled and
sealed in a highly controlled environment
„ A diagram of the process is provided in the
DRAFT guidance

Part 5.1 – Advantages of

B/F/S Technology
„ Personnel are not normally present
during aseptic filling
„ Greatest potential source of microbial
contamination removed
„ Containers are formed immediately
before filling and sealing; exposure time
to environment is markedly reduced

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Part 5.1 – Challenges of
B/F/S Technology
„ Potential for leakage of hydraulic or
cooling system fluids
„ Particulate generation
„ Polymer contamination due to handling
and storage
„ High heat output may affect airflow
patterns or cause condensate formation

Part 6.1.2
Container Design
„ An extensive list of characteristics to be
considered when developing a product
to be packaged in a polymeric container
is provided
„ Characteristics described include:
thermal resistance, extractables,
leachables, chemical reactivity, barrier
requirements, opacity, absorption, etc.

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 Part 6.1.2
Container Design
Container development should include
evaluation of the following criteria:
shape, rigidity, frangibility, gas
permeation characteristics, water
vapour transmission rate, light
transmission, dosage requirements
[volume, delivery, inserts], closure type,
labeling, and overwrapping.

Part 6.1.3 - Polymer

„ Chemical properties – compatibility of
resin and product
„ Barrier properties
„ Sterilization properties
„ Processing characteristics

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 B/F/S Equipment Design
„ Much more complex that traditional
aseptic filling equipment
„ B/F/S equipment-related items include:
extruder performance, CIP/SIP of air
and product pathways, filling system
design, blowing & ballooning air, mould
design, utilities, polymer feed system,
deflashing system and leak detection

Part 6.2.2 – Control of

Critical Zone Environment
„ Point of fill has traditionally been considered
to be the critical zone in a B/F/S machine
„ FDA Class 100 (ISO 5)
„ EU “effective Grade A shower”
„ Area between parison cutting and mould
sealing should also be considered a critical
area and should be protected by air of
appropriate quality to prevent microbial
contamination

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Part 6.2.3 Air Shower
„ Localized ISO 5 conditions at the point
of fill are provided via an air shower
that is appropriately designed.
„ Sterilizing grade filter or HEPA
„ Sterilization or sanitization of air shower
surfaces
„ Monitoring viable and non-viable
particulates in critical zones

Other Considerations
Described in the Guidance
„ Product pathway cleaning and
sterilization
„ Mould design
„ Deflashing (cropping) systems
„ Equipment Monitoring
„ Container/Closure System Leak
Detection

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Facility Design
„ Rooms in the Aseptic Processing Area
should meet ISO 14644 Standards
„ Guidance recommends that the B/F/S
machine should be located in an ISO 8
(operational)/ISO 7 (non-operational)
clean room

Polymer Storage
and Distribution
„ Designed to ensure that contamination
does not occur
„ Should require clear procedures for
handling polymer beads supplied in
bags or gaylords [bins]
„ Handling of waste polymer should be
designed to prevent cross
contamination

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Qualification & Validation
Product/Process Validation
„ Leak testing to ensure hermetic seal

„ Wall thickness

„ Container opening

„ Container moulding

„ Fill volume

„ Line stoppages

Equipment Validation
„ Extrusion process – high temperature
and pressure
„ Bacterial endospore challenge
„ Bacterial endotoxin challenge
„ Knowledge of bioburden and endotoxin
levels on incoming polymer
„ Polymer flush volume required for batch
changes

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OPERATIONS
„ In-process Controls
„ Start-up Procedures
„ Interventions – into the filling room,
into the filling machine or into the
critical zone
„ Environmental Monitoring

Equipment Operation
„ Sanitization of “Critical Surfaces”
„ Equipment Cleaning
„ Cooling Systems
„ Extruder Control
„ Maintenance

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Facility Operation
„ Gowning requirements – Grade A/B
clothing should be worn, because the
operator may have to reach into a
critical zone
„ Polymer handling
„ Training

Risk Assessment
„ Product contamination – low risk due to
limited time of product exposure and by
eliminating operator interventions
during product filling
„ Sources of contamination are described
„ Other product quality attributes, e.g.,
ease of opening and expulsion of
contents

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