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[ 1 ]CONFIDENTIAL
Best Practices in Device Manufacturing --
Strategies Prospective and Retrospective
Validations
Jorge A. Cordero-Monroig; BSChE, MBA-GM
Validation Site Leader
B+L Greenville Solutions Plant
[ 2 ]
Agenda:
Concept and Definitions
How to identify Equipment/Process/Systems that requires Prospective vs Retrospective Validations
Prospective vs Retrospective– The Implementation
Interactive Exercise: The application
Using real life examples, participants study how to determine when apply Prospective vs Retrospective qualifications
Q&A
Best Practices in Device Manufacturing -- Strategies Prospective and Retrospective Validations
[ 3 ]
Concept and Definitions
Validation is the process that assures that a system, service, or product meets the intended purpose. Validations are typically a combination of several qualifications
E.g. Manufacturing line validation, product validation, Calibration management Software, etc…
Qualification is the process that demonstrates that an equipment has been installed properly and works as intended meeting the expected acceptance criteria.
E.g. filler, capper, labeler, cartoner, etc…
Three type of validation/qualification: prospective, concurrent and retrospective validation/qualifications.
Best Practices in Device Manufacturing -- Strategies Prospective and Retrospective Validations
[ 4 ]
Concept and Definitions
Prospective validation/qualification is performed prior to release the system/equipment/process for normal operation to ensure that all the functions, critical parameters, and acceptance criteria are met. It is the prefer validation strategy.
E.g. New mix tank qualification and Distribution control system
Concurrent validation/qualification is performed during normal production. This process typically required enhance inspection and held product (as applicable) until final report is approved…
E.g. Product validation in a new line concurrent with the first 3 lots.
Best Practices in Device Manufacturing -- Strategies Prospective and Retrospective Validations
[ 5 ]
Concept and Definitions
Retrospective validation/qualification requires the evaluation of production history on the assumption that composition, integrity, functionalities, procedures, and equipment remain unchanged or meet the acceptance criteria. Only use when prospective or concurrent validation cannot be performed or when equipment /process /system are legacy or never has been validated.
E.g. Legacy HPW, non-validated HVAC
Best Practices in Device Manufacturing -- Strategies Prospective and Retrospective Validations
[ 6 ]
How to identify Equipment/Process/Systems that requires Prospective vs. Retrospective Validations
First step is to develop a method to define the Equipment/System impact criticality (GMP or Non-GMP).
Perform a Systems/Equipment Impact and Criticality Assessment
Systems/Equipment Classifications:
Direct Impact
Indirect Impact
No Impact
Best Practices in Device Manufacturing -- Strategies Prospective and Retrospective Validations
[ 7 ]
Best Practices in Device Manufacturing -- Strategies Prospective and Retrospective Validations
How to identify Equipment/Process/Systems that requires Prospective vs. Retrospective Validations
Direct Impact = GMP Critical
Direct impact in the safety, identity, potency-strength, quality and/or purity of the product.
Direct impact to regulatory aspect such as labeling, and evaluation, generation, archiving, and reporting data that is used for release
Maintain, control, and monitor environmental conditions to preserve product quality
Used to clean, sanitize, or sterilize to preserve product quality
[ 8 ]
Best Practices in Device Manufacturing -- Strategies Prospective and Retrospective Validations
How to identify Equipment/Process/Systems that requires Prospective vs. Retrospective Validations
Indirect/No Impact = Business Critical Elements that affect the ability to manufacture and operate efficiently
such as Boilers, Plant Steam, Compressed Air, Secondary / Tertiary Packaging
Elements that affect customer satisfaction such as cosmetic defects, failures in deliver on time, and missing promotional material
Systems that evaluate and monitor operation efficiencies
Equipment that help to improve operation efficiencies
Must comply with GEP (Good Engineering Practice):
Fitness to purpose, reliable, cost effective
Design follow industries guidance and statutory requirements
Take inconsideration GMP, Safety, Health, Environmental, ergonomic, operational, and maintenance requirements
Proof professional and competent design, construction, installation testing, and commissioning
Appropriate documentation such as design concepts, as build drawings, manuals, certifications, maintenance instructions, and test records.
[ 9 ]
Direct Impact Systems/Equipment shall answer YES to one of the following questions:
Does the Systems/Equipment come in direct physical contact with the product?
Example: Filler, Tanks, Clean Steam, Filtered Compressed Air etc…
Does the Systems/Equipment produce or distribute a material that has direct contact with product?
Example: Bottles/Caps Molding machines, Form Fill & Seal (FFS) Machines, etc…
Is the Systems/Equipment used in cleaning, sanitizing or sterilizing?
Example: Clean Steam, CIP systems, Autoclaves, etc…
Best Practices in Device Manufacturing -- Strategies Prospective and Retrospective Validations
[ 10 ]
Does the Systems/Equipment create or maintain a specified environmental condition required to preserve product quality?
Example: HVAC, Class A / ISO 5 rooms, etc…
Does the Systems/Equipment produce, monitor, evaluate, store or report data used to accept or reject product or GMP materials or data used to support Regulatory Compliance-Practices?
Example: PCS, EMS, Delta V, e-Batch Records, etc…
Does the Systems/Equipment perform a critical process step or operation in the manufacturing, processing, packaging, labeling testing or holding of the product?
Example: Inspections Systems, Vision Systems, Vacuum Systems, etc…
Best Practices in Device Manufacturing -- Strategies Prospective and Retrospective Validations
[ 11 ]
Indirect Impacts Systems/Equipment shall answer YESto the following question:
Is the Systems/Equipment linked or support a direct impact systems?
Example: DI Water Systems, Chillers, Boilers, etc…
No Impact Systems/Equipment answer NO to all previous questions.
Example: Cooling Towers, Sand Filters, Office HVAC Units, OEE Systems, Palletizer, etc…
No impact Systems/Equipment are not critical for the product quality but for business.
Best Practices in Device Manufacturing -- Strategies Prospective and Retrospective Validations
[ 12 ]
How to identify Equipment/Process/Systems that requires Prospective vs. Retrospective Validations
Prospective validation/qualification it is required on:
New equipment/systems classified as direct impact
Changes in existing direct impact equipment/systems
Driven by new projects, improvement process, change control, non-conformance, etc…
E.g. Adding a check-weigher to the manufacturing line, Installation of a new walk-in refrigerator.
Best Practices in Device Manufacturing -- Strategies Prospective and Retrospective Validations
[ 13 ]
Best Practices in Device Manufacturing -- Strategies Prospective and Retrospective Validations
How to identify Equipment/Process/Systems that requires Prospective vs. Retrospective Validations
Retrospective validation/qualifications it is required on:
Existing direct impact equipment/systems
Driven by Plant Inventory Assessment
Perform an assessment of all the equipment of the plant
Divide the assessment by departments (e.g.)
Bulk
Filling
Packaging
Laboratories (Micro/Chemistry)
Utilities
Receiving and Inspection
Warehouse
Etc…
[ 14 ]
How to identify Equipment/Process/Systems that requires Prospective vs. Retrospective Validations
After perform the inventory by area and classify each system/equipment, we need to determined the status of each system/equipment.
System/Equipment Status:
Validated
Legacy
No validated
Strategies Prospective and Retrospective Validations
[ 15 ]
How to identify Equipment/Process/Systems that requires Prospective vs. Retrospective Validations
Validated System/Equipment:
Meet all current regulatory and local requirements
Validation/qualification is not older than XX years (Depend on how mature in validation has been your company)
Periodic reassessments and/or requalification demonstrate that the equipment/systems still meeting the validated state.
Legacy System/Equipment:
Equipment/systems with validation/qualification older than XX years and no periodic reassessments and/or requalification performed.
No validated System/Equipment:
System/equipment with no evidence of previous validation/qualification.
Best Practices in Device Manufacturing -- Strategies Prospective and Retrospective Validations
[ 16 ]
Prospective vs. Retrospective Validations– The Implementation
Tools to track the prospective and retrospective validation after identify them.
Site Validation Master Plan (SVMP)
SOPs
Flash Reports
Capital Projects
Remediation Projects
Etc…
Best Practices in Device Manufacturing -- Strategies Prospective and Retrospective Validations
[ 17 ]
Best Practices in Device Manufacturing -- Strategies Prospective and Retrospective Validations
Prospective vs. Retrospective Validations– The Implementation
Site Validation Master Plan Role
Site Validation Master Plan (SVMP) summarize the what, why, when, and how equipment and systems are validated and qualified in your facility.
SVMP also provide a list of systems/equipment that require validation during the year including prospective and retrospective validations.
SVMP is the primary document showed to the FDA and any other regulatory agency to present the site validation program.
The SVMP is a living document that is typically updated annually.
[ 18 ]
Prospective vs Retrospective – The Implementation
SOP Role
Standard Operations Procedures (SOPs) are the local documents developed to ensure that an operation can be performed consistently by any qualified person.
The validation SOP provides the local rules to develop, perform, and report validation activities.
The purpose of the validation SOP is to establish a procedure to conduct prospective or retrospective validations/qualifications of critical systems / equipment. Also, validation SOP should provide the minimum requirements for each type of system/equipment as well as what type of validation/qualification should be used.
Best Practices in Device Manufacturing -- Strategies Prospective and Retrospective Validations
[ 19 ]
Prospective vs. Retrospective Validations– The Implementation
Capital Projects and Remediation Flash Reports Role
Keep tracking of all the validation required for the year
Keep resources with a similar work load.
Maintain an effective communication between validation group, upper management and user areas
Keep updated the progress in each validation
Best Practices in Device Manufacturing -- Strategies Prospective and Retrospective Validations
[ 20 ]
Prospective vs Retrospective – The Implementation
Responsibilities – Who and When
Who:
Validation site leader – ensure that the plant inventory and system/equipment classification assessment reflect the actual status of the equipment, systems, and processes. Also, ensure that the SVMP reflect the any deficiency or gap found during the plant inventory and system/equipment classification assessment
Validation Engineers and/or Technicians – perform the prospective and retrospective validation/qualification activities, as applicable.
Micro and Chemistry Department – provide trend analysis and personnel as applicable to support retrospective validation/qualifications.
Maintenance/Metrology – provide PMs and calibration certificate reports to support the prospective and retrospective validation/qualifications.
Best Practices in Device Manufacturing -- Strategies Prospective and Retrospective Validations
[ 21 ]
Prospective vs Retrospective – The Implementation
Responsibilities – Who and When
When:
Prospective validation is performed on new system/equipment/process, when changes to systems/equipment/process are required, and when new components and/or products are introduced. Prior distribution or equipment/system release.
Concurrent Validation/qualification is performed when test is performed with product during normal operation and the risk of adulterate the product or affect product quality is considered low.
Retrospective validation/qualification is performed when system/equipment/process has been in operation and the validation/qualification are too old or never have been validated/qualified.
Best Practices in Device Manufacturing -- Strategies Prospective and Retrospective Validations
[ 22 ]
Prospective vs Retrospective – The Implementation
Options and Tools
Prospective validation/qualification tools:
User requirements,
Functional requirements,
Design specs,
Product transfer,
Risk assessments
Manuals,
DOEs
Engineering evaluations
Etc…
Best Practices in Device Manufacturing -- Strategies Prospective and Retrospective Validations
[ 23 ]
Prospective vs Retrospective – The Implementation
Options and Tools
Retrospective validation/qualification tools:
Manual /Drawings
Trend analysis:
Microbiology trend reports,
Chemistry trend reports
History data:
Fill volume
Torque
Temperature trend and charts
Batch records:
Interventions
Jams
Rejects
Best Practices in Device Manufacturing -- Strategies Prospective and Retrospective Validations
[ 24 ]
Prospective vs Retrospective – The Implementation
Options and Tools
Retrospective validation/qualification tools:
Maintenance and Metrology Programs
Out of calibration (OOC), and
Broken/damage instruments (DBI),
Compare unplanned work orders, (OOC), and (DBI) with previous evaluation period
Process Excellence:
Historical Statistical data
PFMEA’s
Best Practices in Device Manufacturing -- Strategies Prospective and Retrospective Validations
[ 25 ]
Prospective vs Retrospective – The Implementation
Pros and Cons
Prospective Validation:
Pros:
Ensure that the equipment/systems is suitable for intended use before put the equipment/system into service.
Avoid on-hold product
Avoid product waste, if failures occurs
Highly degree of assurance that the equipment/system will meet the expectation during normal production
Cons:
Require downtime of the manufacturing lines
Require suspension of the legacy equipment/systems and non-validated equipment/systems until validation is completed (in use equipment)
Increase in validation cost
Best Practices in Device Manufacturing -- Strategies Prospective and Retrospective Validations
[ 26 ]
Best Practices in Device Manufacturing -- Strategies Prospective and Retrospective Validations
Prospective vs Retrospective – The Implementation
Pros and Cons
Retrospective Validation:
Pros:
Lower validation cost than prospective validation.
Less downtime required than prospective validation
Only option on existing systems that cannot be stopped
Cons:
Validation failures may put at risk the product manufactured
It is not the prefer option by regulatory agencies
Create unexpected workload on team.
High cost due to recalls or corrective actions if the validation/qualification fails.
[ 27 ]
Summary of how implement
Define the concept and process of prospective and retrospective validation/qualification in local SOPs
Develop a method or follow existing method of equipment/system classification, GMP Critical or Non-GMP (Business) Critical
Perform an inventory of all equipment and systems of the plant and classify them between GMP Critical (Direct Impact) and Business Critical (Indirect Impact/No-Impact)
Based on equipment inventory, define the status of all the GMP critical equipment/system: Validated, Legacy, and Non-validated.
Following local SOPs define what validation/qualification type is required for the legacy and non-validated equipment/system and for any new and changes in equipment/system.
List the prospective and retrospective validation in the SVMP.
Define the strategy to follow, tools, and options
Best Practices in Device Manufacturing -- Strategies Prospective and Retrospective Validations
[ 28 ]
Interactive Exercise:
Using real life examples, participants study how to identify Prospective and Retrospective Validation/Qualification
Classify the following equipment / system, define the type of validation and establish the strategies of how validate/qualify them:
New Autoclave
Legacy HPW and Clean Steam Systems
Replacement of Environmental Monitoring Systems
Non-Validated Lab. Refrigerators/Incubators
Non-Validated Boilers
Update of Labeler PLC
Adding a new configuration to a Casepackers (Tertiary packaging)
New Mix Tank
Best Practices in Device Manufacturing -- Strategies Prospective and Retrospective Validations
[ 29 ]
Questions and Answers
?
Best Practices in Device Manufacturing -- Strategies Prospective and Retrospective Validations