Best Practices in Device Manufacturing -- Strategies ... · PDF fileCONFIDENTIAL [ 1 ] Best...

[ 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

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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

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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.


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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.


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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


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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


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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

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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.

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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…


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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…


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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.


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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.


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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…

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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

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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.


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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…


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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.

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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.


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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


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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.


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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.


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Options and Tools

Prospective validation/qualification tools:

User requirements,

Functional requirements,

Design specs,

Product transfer,

Risk assessments

Manuals,

DOEs

Engineering evaluations

Etc…


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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


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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


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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


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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.

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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


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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


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Questions and Answers

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