Validation of Pharmaceutical

Packaging
S. P. Manek

Ph.D ( Tech )

08-10-2011

Validation : Regulatory Compliance

Validation a Key requirement of all GMP Guidelines

Process Validation
Cleaning Validation
Analytical Methods Validation
Computer systems validation
Facility / Equipments Validation / Qualification ( IQ/OQ/PQ )

Packaging Validation :
to confirm that the resulting product from a specified
packaging process consistently conforms to product
attributes & requirements.

A risk-based approach - focusing on processes that

have the greatest potential risk to product quality
provides a rational framework for developing an appropriate
scope for validation activities.
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Validation : Packaging Operations

US-FDA and EMEA Regulatory compliance
equipment must be suitable for its intended use.
need to validate packaging machines / their various component

Validation process: technically complex, time consuming, costly

Key Elements :
Qualification of equipments : all relevant sub-systems are
thoroughly tested and documented to provide the information
that is essential for successful validation.
Validation of a Product Packaging operation
PQ : verification of facility, utilities, equipment performance,
components, trained personnel and processes
Evaluation of variance & Assessment of impact on Critical Product
Quality attributes

Cleaning validation : Part of Packaging Validation

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Validation
Qualification or Validation?
Qualification and validation are essentially components of
the same concept
The term qualification is normally used for equipment,
utilities and systems : A system must be qualified to operate
in a validated process

The term validation is normally used for processes

In this sense, qualification is part of validation, e.g. you
qualify an autoclave, whereas you validate a sterilization process

Qualification should be completed before process validation

is performed
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Validation : Packaging Operations

A validated process: enables consistent packaging of
products to meet the product / market requirements - Quality
attributes/consumer needs - in a cost effective & an efficient
process with minimum down time, rejects and errors.

Consistency & Cost effectiveness - key business

considerations, a validation activity should be seen not as a
regulatory requirement but as a business necessity

Multi-disciplinary effort: equipment engineers, packaging

technologists and quality teams must plan and work through
a validation program together in order to create a robust
operation & ensure consistent Quality packaging
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Packaging
Packaging : the art, science and technology of preparing
goods for sale in a cost effective manner.

Filling, Sealing, Inspection, Labeling, Final Packaging

In the context of pharmaceuticals, the packaging must:

preserve the product - from degradation or contamination

contain the product - to avoid leakage
identify the product - providing traceability,
security - against tampering and counterfeiting
information on use - an aide memoir for compliance
convenience in use - for medical staff or patient

All this must be ensured for the life of the product and
achieved within a complex regulatory environment.
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Packaging Validation : Pre-requisites

Key areas impacting the robustness of a packaging
process - should be considered in validation:
Packaging equipment & Line Layout / Facility space
Packaging materials
SOPs : Equipment Operation, Maintenance, Cleaning
Calibration Program
Operator Training
Master Validation Plan
Packaging Equipment IQ/OQ/PQ & Validation Protocols
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Validation :Packaging Line Layout

The design and layout of equipment has major impact on
the efficiency of the packaging line.

Line Layout :
Design for a line layout should include the ability to manage
quick change-over, perform line clearance between batches of
product and clean the line in an easy and controlled manner.

The majority of problems on packaging lines are related in

some way to poor line clearance - important to design these
problems out.
Devices will normally be located in critical positions on the line
to detect presence or otherwise of the materials.
The layout should provide easy access for operators and the
engineers for adjustments and or maintenance
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Validation : Packaging Line Equipment

Well designed equipment will lend itself to efficient
packaging of a consistent standard , ensuring that the
machine, as supplied and installed:

Meets Product Packaging expectations.

Performs according to Packaging design intentions
Complies with GMP standards
Is provided with a record of key features and components
as initially installed.
Is provided with information to enable safe, effective and
consistent operation and maintenance.
Has it systems tested and verified as being in correct
working order, to enable validation to be performed.

Validation : Packaging Line Equipment

Validation strategy 1st step : important to define the topology
of the system - defines the scope of the project.

Detail the packaging line system within the validation protocol

Identify and list the system functionality, the Software and
Hardware of the system
Identify the critical measuring devices that need calibration
e.g. pressure gauges, thermocouples, hygrometers etc..

Assess the GMP risk : define if the system has the capability
to impact on the Product in terms of Quality, Strength, Identity
or Purity, leading to product withdrawal / recall.
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Validation : Packaging Lines

GMP risk
Incorrect or contaminated pharmaceutical product
Incorrect assembly of the unit of dose carrier (blister, bottle, vial..)
Incorrect packaging component in the final assembly (incorrect
carton, missing/incorrect label /leaflet)
Incorrect or illegible lot or batch identification

Business and operational risk

Poor packaging quality (cosmetic defects)

Excessive machine down time
Machine damage or wear
Excessive change-over times / Slow speed of operation
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Packaging Materials
Variety of Packaging Materials
Moisture-impermeable containers (Vials /bottles - glass / plastic,
Alu-Alu blisters , Blister strips ( multi layered foils )
Moisture-permeable containers ( PVC blisters, LD/HDPE containers )

Multiple suppliers for same packaging item

An efficient production line needs consistent

materials
The storage and handling of components is as vital in this respect as
their specification to maintain consistency.
Fiber-based materials, such as leaflets (inserts), cartons and labels
can be adversely affected by temp/RH changes.
Supplier / Material qualification, audits, rigorous packaging material
specifications Specifications - should include thickness and
permeability coefficient
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Packaging Validation : SOPs

To manage a packaging line, adequate standard
operating procedures (SOPs) will be required.
Vital to ensure SOPs provide clear and
unambiguous instructions on
how to operate, adjust, and maintain each piece of
equipment
detail how a batch is packaged,
explains how each material is received on the line
and checked for correctness, quantity,
Details of In Process Control (IPC) tests
Procedure for Line clearance / change-over,
including details of cleaning operations to avoid
cross-contamination
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Packaging Validation : Training

The supplier should identify training needs and provide
appropriate training.

Consider the specific packaging methods,

Machine operating techniques, hardware/software to be used,
Selection / identification of packaging materials
Product packaging requirements

Records of relevant training and experience should be

maintained & available as part of the project documentation.
The requirement is for classroom training with notes and a
test to be made at the end, in both theory and practice.
Training Module for retraining / training new operators
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Validation Master Plan (VMP)

Any validation exercise must start with a detailed Validation
Master Plan, will include key elements of the validation
program.
Companys validation policy
organizational structure of validation activities
summary of facilities, systems, equipment and
processes validated/to be validated. All critical
equipment, systems, devices, software must be
identified and listed
Defines nature & extent of testing, test procedures
documentation format (e.g. protocol and report)
planning and scheduling
change control process - Any validation activity is only
as good as the change control process used
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Qualification Protocols
A classical approach to validation : prepare protocols for DQ, IQ,
OQ and PQ.
test each piece of equipment in the line and to test the interaction
between different pieces of equipment /systems.
designed to test all the critical steps, providing a list of tests which are
to be performed and the acceptance limits for each test.

Tests must demonstrate that the system is able to:

do what is expected within the operating range required for the

process.
Test beyond the normal operating range to provide information on the
system behaviour, which can be used to finalize operational limits.

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Validation Protocols
Short description of the process with a summary of the
critical processing steps or critical parameters to be
monitored during validation.
Additional testing intended to be carried out (e.g. with
proposed acceptance criteria and analytical validation as
appropriate).
Sampling plan where, when, how and how many
samples are taken ( more sampling than normal IPC ).
Details for recording and evaluation of results.

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Performance Qualification
PQ, the last stage in validation, should reflect the real
production environment, using production materials in a
normal daily operation.

The exercise should extend over a time period sufficient to

ensure that shift working patterns and normal lunch breaks
etc. are included and to certify that the systems are
challenged for stop/start, batch changes etc.

It is important to document the rationale for a matrix

approach in the VMP - what and why it will be done.
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Validation : Change Control

Changes that require revalidation

Software changes; Controllers

Site changes; Operational changes
Change of source of material
Change in the process
Significant equipment change
Production area changes
Support system changes

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PQ - Examples
Blister Packing :
Speed & Temperature settings / range
Different materials
Different suppliers
Different products

Need to package at extreme temps &

evaluate its impact on Quality
Sealing Quality
Pack appearance ( Aesthetics )
Product Quality ( Stability, purity, assay etc )
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Illustrative variables of tablet packaging

Process step

Control or manipulate
(independent) variables

Measured responses
or output (dependent)
variables

Blistering

Machine speed
Machinability of blister material
Forming temperature
Forming pressure
Sealing temperature
Sealing pressure

Leak testing
Appearance
Minimum information is
legible
Yield

Bulk packing

Tablet counter
Incomplete tablets
Machine speed

Number of tablets
Detection, counting
Pilfer-proof
Labeling
Yield
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PQ - Examples
Ampoule / Vial Filling & Packing :
Filling :
Fill volume variation : fill accuracy
Splashing, spillage, container damage
deoxygenate, if required (assay )

Seal quality : aesthetics, seal test ( leak test )

Labeling / information overprinting
Inspection : manual, automatic, bar code reading
Line speed
Product viscosity
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Common Issues
Packaging process validation is often supplemented by
100% inspection online - firms take the approach that it is
the way to go & have inspectors set up offline to sort out /
rework unacceptably packaged product.
Cause : Packaging process variables are not adequately
identified, studied / not observed to nail it through the
validation.
Solution :
Validate packaging process by optimizing the packaging process
variables and making three runs.
A statistically valid sampling plan implemented & samples tested per
the finished product specifications.
Critical variables impacting quality identified & controlled
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Tips & Hints

Understand thoroughly the packaging system and its critical steps.
Never under estimate the amount of time needed to develop plans - more
time you spend in design of the protocols, the less you will waste in
resolving issues and investigating failures.
Develop a good sound sampling plan - IPC tests are meaningful and
provide useful data on the line performance (samples should reflect the
normal operating conditions).
Detect, understand sources & degree of variation, its impact on product
attributes and control variations
Finally, any validated system is as good as the associated change control
process.
make sure all changes are fully assessed and documented.
the impact of the change on the validation status of the system must
be fully assessed before any changes are made.
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Summary
Industry
Constantly challenged to reduce costs
New markets and new packs add complexity to the operation
An ever changing regulatory environment demands compliance.

To ensure pack integrity, manage complexity, maximize

efficiency and minimize costs; appropriately designed packs,
running in validated packaging lines, are a business
necessity rather than a regulatory requirement.

If validation is well planned and documented, then GMP

compliance will naturally follow.

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Quality is designed and built

into the
process/method/equipments/premises
Functionality, consistency and repeatability
is confirmed by

Validation

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Importance of Validation : Cost of Quality

Visible costs, e.g., waste,
returned / recalled goods
..

Invisible/Hidden costs,
e.g., wrong decisions
( machine, change part ),
non-trained workers,
Non-standardized process,
low yield, maintenance / idle
machine time, unsuitable
packaging material etc.
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Thank you for your attention.

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