Validation of Pharmaceutical Packaging S. P. ManekPh.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.
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
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
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
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. • 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 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.
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 • 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
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 • Definesnature & 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
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 • 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 )
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
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). • 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 is 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.