Validation of Pharmaceutical Packaging

Validation is a process of establishing documentary evidence demonstrating that a procedure,

process, or activity carried out in production or testing maintains the desired level of compliance
at all stages. In Pharma Industry it is very important apart from final testing and compliance of
product with standard that the process adapted to produce itself must assure that process will
consistently produce the expected results. Here the desired results are established in terms of
specifications for outcome of the process. Qualification of systems and equipment is therefore a
part of process of validation. It is a requirement of food and drug, pharmaceutical regulating
agencies like FDA's good manufacturing practices guidelines. Since a wide variety of
procedures, processes, and activities need to be validated, the field of validation is divided into a
number of subsections including the following:

• Equipment validation
• Facilities validation
• HVAC system validation
• Cleaning validation
• Process Validation
• Analytical method validation
• Computer system validation
• Packaging validation
• Cold chain validation

Similarly, the activity of qualifying systems and equipment is divided into a number of
subsections including the following:

• Design qualification (DQ)

• Component qualification (CQ)
• Installation qualification (IQ)
• Operational qualification (OQ)
• Performance qualification (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.

• 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.

• Cleaning validation: Part of Packaging 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. youqualify an autoclave, whereas
you validate a sterilization process

• Qualification should be completed before process validation is performed.

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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.
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.
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

Validation: Packaging Line Layout

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

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 • 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.

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 Hardwareof 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 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.
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.
– How a batch is packaged.

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 – 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.

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.

Validation Master Plan (VMP)

Any validation exercise must start with a detailed Validation Master Plan, will include key
elements of the validation program.

– Company’s 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.

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Change control process - Any validation activity is only as good as the change control process
used
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.
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.
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.

Validation: Change Control

Changes that require revalidation
• Software changes; Controllers.
• Site changes; Operational changes.

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 • Change of source of material.
• Change in the process.
• Significant equipment change.
• Production area changes.
• Support system changes.
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.)

Illustrative variables of tablet packagin:

Process step Control or manipulate Measured responses or

(independent) variables output (dependent) variables

Blistering Machine speed Leak testing

Machinability of blister Appearance
material Minimum information is legible
Forming temperature Yield
Forming pressure
Sealing temperature
Sealing pressure

Bulk packing Tablet counter Number of tablets

Incomplete tablets Detection, counting
Machine speed Pilfer-proof
Labeling
Yield

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 • PQ – ExamplesAmpoule / Vial Filling & Packing :
– Filling :
– Fill volume variation: fill accuracy.
– Splashing, spillage, container damage.
– De-oxygenate, if required (assay).
– Seal quality: aesthetics, seal test (leak test).
– Labeling / information overprinting.
– Inspection: manual, automatic, bar code reading.
– Line speed.
-Product viscosity.
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.

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).

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 • Detect, understand sources & degree of variation, it’s 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.
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.

Quality is designed and built into the Process/method/equipments/premises.

Functionality, consistency and repeatability are confirmed by Validation.
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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