1. Validation of Pharmaceutical Packaging
S. P. Manek Ph.D ( Tech )

2. 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.

3. 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

4. World Health Organization
19 April, 2017
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
4. Relationship between validation and qualification
Validation and qualification are essentially components of the same concept.
The term qualification is normally used for equipment, utilities and systems,
and validation for processes. In this sense, qualification is part of validation.

5. 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

6. 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.

7. 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

8. 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

9. 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.

10. 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.

11. 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

12. 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

13. 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

14. 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

15. Validation Master Plan (VMP)
World Health Organization
Validation Master Plan (VMP)
19 April, 2017
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
change control process - Any validation activity is only as good as the change control process used
8. Validation master plan
The validation master plan (VMP) should refl ect the key elements of the
validation programme. It should be concise and clear and contain at least
the following:
— a validation policy
— organizational structure of validation activities
— summary of facilities, systems, equipment and processes validated and
to be validated
— documentation format (e.g. protocol and report format)
— planning and scheduling
— change control
— references to existing documents.

16. 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.

17. 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.

18. 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.

19. 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
The nature of the changes that require revalidation should be stated in the VMP. If any of the following are changed the process becomes invalid and in some agencies’ view, the process is out of control, even if the finished product meets the marketing authorization specifications for finished products:
Software changes, changes in controllers (eg temperature controllers), site changes, operational changes.
Changes that are likely to require revalidation are:
Changes of starting materials (physical properties such as density, viscosity, particle size distribution may affect the process or product).
Transfer of processes to another site.
Change of starting material manufacturer.
Changes of packaging material (e.g. substituting plastic for glass).
Changes in the process (e.g. mixing times, drying temperatures).
Changes in the equipment (e.g. addition of automatic detection systems). Changes of equipment which involve the replacement of equipment on a 'like for like' basis would not normally require a revalidation. For example, a new centrifugal pump replacing an older model would not necessarily mean revalidation.
Production area and support system changes (e.g. rearrangement of areas, new water treatment method).

20. 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 )

21. 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
Number of tablets
Detection, counting
Pilfer-proof
Labeling

22. 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

23. 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

24. 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, 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.

25. 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.

26. Validation Quality is designed and built into the
process/method/equipments/premises
Functionality, consistency and repeatability
is confirmed by
Validation
The WHO GMP Guidelines state (Section 5.1):
“Validation studies are an essential part of GMP and should be conducted in accordance with predefined protocols. A written report summarizing recorded results and conclusions should be prepared and stored. Processes and procedures should be established on the basis of a validation study and undergo periodic revalidation to ensure that they remain capable of achieving the intended results. Particular attention should be accorded to the validation of processing, testing, and cleaning procedures.”

27. 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.

28. Thank you for your attention.