best practice to implement process validation in device manufacturing enterprise
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GoodTRANSCRIPT
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[ 1 ]CONFIDENTIAL
Institute of Validation Technology
Validation Week- Philadelphia
Tanya Fletcher-Scott
Validation Manager- Greenville SC Solutions Facility
October 24, 2012
Session 4: Best Practice to Implement Process
Validation in Device Manufacturing Enterprise-
wide
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[ 2 ]
Agenda
Getting Started-Overview
Process Validation
Enterprise wide Roll Out of Process Validation
Interactive Exercise
Look out for
the
Best
Practice
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[ 3 ]
Getting Started-Overview
o The Rules- Review of Standards and Guidances for
Process Validation of Devices
o Tools- Risk Assessments and Statistics
o The Team- Dont go it alone!
o The Docs- Documenting the process validation
activities
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[ 4 ]
Getting Started-Overview
The Rules- Review of Standards and Guidances for Process
Validation of Devices:
21 CFR 820 Quality System Regulators
ISO, EN ISO 13485 Medical devices- Quality management systems- Requirements for regulatory purposes
ISO, EN ISO 14971 Medical devices-Application of risk management to medical devices
ISO, EN ISO 9001 Quality management systems Requirements
Best Practice:
Know your
regs and
guidances
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[ 5 ]
Getting Started-Overview
The Rules- Review of Standards and Guidances for Process
Validation of Devices:
GHTF, Global Harmonization Task Force- Quality management Systems-Process Validation Guidance*
SOR/98-282 Canadian Medical Regulators
93/42/EEC Medical Device Directive
*Copy provided as bonus material
Best Practice:
Know your
regs and
guidances
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[ 6 ]
Getting Started-Overview
The Rules- Review of standards and guidances for Process
Validation of Devices:
21 CFR 820 Quality System Regulators
Sec. 820.70 Production and process controls.b-Production and process changes. Each manufacturer shallestablish and maintain procedures for changes to a specification,method, process, or procedure. Such changes shall be verified orwhere appropriate validated according to 820.75 (ProcessValidation), before implementation and these activities shall bedocumented. Changes shall be approved in accordance with 820.40(Document controls).
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[ 7 ]
Getting Started-Overview
The Rules- Review of standards and guidances for Process
Validation of Devices:
Sec. 820.75 Process Validation.a- Where the results of a process cannot be fully verified by
subsequent inspection and test, the process shall be validatedwith a high degree of assurance and approved according toestablished procedures. The validation activities and results,including the date and signature of the individual(s) approvingthe validation and where appropriate the major equipmentvalidated, shall be documented.
b- Each manufacturer shall establish and maintain procedures formonitoring and control of process parameters for validatedprocess to ensure that the specified requirements continues tobe met.
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[ 8 ]
Getting Started-Overview
The Rules- Review of standards and guidances for Process
Validation of Devices:
ISO, EN ISO 13485 Medical devices- Quality management systems-
Requirements for regulatory purposes
7 Product realization, 7.1 Planning of product realization
The organization shall plan and develop the processes needed for product
realization. Planning of product realization shall be consistent with the
requirements of the other processes of the quality management system. In
planning product realization, the organization shall determine the following, as
appropriate:
a) quality objectives and requirements for the product;
b) the need to establish processes, documents, and provide resources specific to
the product;
c) required verification, validation, monitoring, inspection and test activities
specific to the product and the criteria for product acceptance;
d) records needed to provide evidence that the realization processes and
resulting product meet requirements
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[ 9 ]
Getting Started-Overview
The Rules- Review of standards and guidances for Process
Validation of Devices:
ISO, EN ISO 13485 Medical devices- Quality management systems-
Requirements for regulatory purposes
7.5.2 Validation of processes for production and service provision
The organization shall validate any processes for production and service
provision where the resulting output cannot be verified by subsequent monitoring
or measurement. This includes any processes where deficiencies become
apparent only after the product is in use or the service has been delivered.
Validation shall demonstrate the ability of these processes to achieve planned
results. The organization shall establish arrangements for these processes
including, as applicable
a) defined criteria for review and approval of the processes,
b) approval of equipment and qualification of personnel,
c) use of specific methods and procedures,
d) requirements for records and
e) revalidation.
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[ 10 ]
Getting Started-Overview
Tools- Risk Assessments and Statistics
Statistics
Sec. 820.250 Statistical techniques.
(a) Where appropriate, each manufacturer shall establish and maintain
procedures for identifying valid statistical techniques required for
establishing, controlling, and verifying the acceptability of process
capability and product characteristics.
(b) Sampling plans, when used, shall be written and based on a valid
statistical rationale. Each manufacturer shall establish and maintain
procedures to ensure that sampling methods are adequate for their
intended use and to ensure that when changes occur the sampling
plans are reviewed. These activities shall be documented.
Best
Practice:
Use your
statisticians
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[ 11 ]
Getting Started-Overview
Tools- Risk Assessments and Statistics
ISO 13485
8 Measurement, analysis and improvement, 8.1 General
The organization shall plan and implement the monitoring, measurement,
analysis and improvement processes needed
a) to demonstrate conformity of the product,
b) to ensure conformity of the quality management system, and
c)to maintain the effectiveness of the quality management system.
This shall include determination of applicable methods, including statistical
techniques, and the extent of their use.
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[ 12 ]
Getting Started-Overview
Risk Assessments
ISO 14971 Medical devices Application of risk management
to medical devices
The ISO Standard defines risk as
combination of the probability of
occurrence of harm and the
severity of that harm
Tools- Risk Assessments and StatisticsRisk Analysis
Risk Evaluation
Risk Control
Evaluation of overall
residual risk acceptability
Risk Management Report
Production and post-
production information
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[ 13 ]
Getting Started-Overview
Tools- Risk Assessments and Statistics
Risk Management Tools
Preliminary Hazard Analysis (PHA) is a technique thatcan be used early in the development process to
identify the hazards, hazardous situations, and events
that can cause harm when few of the details of the
medial device design are known.
Fault Tree Analysis (FTA) is especially useful in safetyengineering, early in the development stages, for the
identification and prioritization of hazards and
hazardous situations as well as for analyzing adverse
events.
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[ 14 ]
Getting Started-Overview
Tools- Risk Assessments and Statistics
Risk Management Tools
Failure Mode and Effects Analysis (FMEA) and FailureMode, Effects and Criticality Analysis (FMECA) are
techniques by which an effect or consequences of
individual components are systematically identified and is
more appropriate as the design matures.
Hazard and Operability Study (HAZOP) and HazardAnalysis and Critical Control Point (HACCP) are typically
used in the latter stages of the development phase to
verify and then optimize design concepts or changes.
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[ 15 ]
Getting Started-Overview
The Team- Dont go it alone!
The types of products manufactured in the
Greenville facility are lens care solutions.
When we are conducting a process validation
to support a product transfer or significant
formulation change, we need the support of a
cross functional group inclusive of corporate
and site wide subject matter experts.
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[ 16 ]
Quality Assurance* Engineering* Manufacturing* Laboratory (Chemistry and Microbiology)* Technical Services Research & Development* Regulatory Affairs* Clinical Engineering Purchasing/Planning Process Excellence / Statistician* Project Manager*
*B+Ls typical team core members for major process validation projects
The Global Harmonization Task Force- Quality Management Systems Process Validation Guidance suggests the following subject matter team
members:
Getting Started-Overview
The Team- Dont go it alone!
Best
Practice:
Project Managers
are key to any
success tech
transfer
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[ 17 ]
Getting Started-Overview
The Docs- Documenting the process validation activities
Sec. 820.75 Process Validation.
a- Where the results of a process cannot be fully verifiedby subsequent inspection and test, the process shall bevalidated with a high degree of assurance andapproved according to established procedures. Thevalidation activities and results, including the date andsignature of the individual(s) approving the validationand where appropriate the major equipment validated,shall be documented.
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[ 18 ]
Getting Started-Overview
The Docs- Documenting the process validation activities
The Global Harmonization Task Force- Quality Management Systems Process Validation Guidance suggests the following elements in your
process validation protocols:
Elements Validation
Strategy
IQ OQ PQ PV
Identification of the process to be validated X X X X X
Identification of device(s) to be manufactured
using this process
X X X X X
Objective and measurable criteria for a
successful validation
X X X X X
Identification of operators and required operator
qualification
X XBest
Practice:
Validation
Strategies are a
great tool for big scope projects
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[ 19 ]
Getting Started-Overview
The Docs- Documenting the process validation activities
The Global Harmonization Task Force- Quality Management Systems Process Validation Guidance suggests the following elements in your
process validation protocols:
Elements Validation
Strategy
IQ OQ PQ PV
Length and duration of the validation X
Shifts, operators, equipment to be used in the
process
X X
Any subjective criteria used to evaluate the
product
X X X X
Identification of utilities for the process
equipment and quality of the utilities
X X
Complete description of the process X X X X X
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[ 20 ]
Getting Started-Overview
The Docs- Documenting the process validation activities
The Global Harmonization Task Force- Quality Management Systems Process Validation Guidance suggests the following elements in your
process validation protocols:
Elements Validation
Strategy
IQ OQ PQ PV
Relevant specifications that relate to the
product, components, manufacturing
materials, etc
X X X X
Process parameters to be monitored, and
methods for controlling and monitoring*
X X
Product characteristics to be monitored and
method for monitoring*
X X
Any subjective criteria used to evaluate the
product
X X
*Use of a Control Plan is a great tool and best practice. Example included in bonus material
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[ 21 ]
Getting Started-Overview
The Docs- Documenting the process validation activities
The Global Harmonization Task Force- Quality Management Systems Process Validation Guidance suggests the following elements in your
process validation protocols:
Elements Validation
Strategy
IQ OQ PQ PV
Definition of what constitutes non-
conformance for both measurable and
subjective criteria
X X X X X
Statistical methods for data collection and
analysis
X X X X
Consideration of maintenance and
repairs of manufacturing equipment
X
Criteria for revalidation X
When its all done, generate the final report summarizing all requirements, results, issues and conclusions
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[ 22 ]
Agenda
Getting Started-Overview
Process Validation
Enterprise wide Roll Out of Process Validation
Interactive Exercise
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[ 23 ]
Process Validation
o Creating a strategy/validation plan
o Strategies for new and existing products
o Runs and samples
o When are you done?
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[ 24 ]
Process Validation
Creating a strategy/validation plan
A Validation plan which defines what needs to be validated (i.e.
equipment, systems and processes) and how validation needs will be
met for a given project.
The strategy also provides a roadmap to follow ensuring the
requirements are defined and agreed upon up-front and that all
requirements are met prior to implementation or launchBest
Practice:
Wait until you
have created or
updated your risk
assessment
before generating
a strategy.
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[ 25 ]
Process Validation
Creating a strategy/validation plan
B+Ls validation systems does not require validation strategies for smaller, lesscomplex validation projects whose strategy can be fully detailed within a protocol.
The strategy is useful to communicate completion of validation strategy activities
and results of the testing performed to support product Launch or Design Change
Implementation
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[ 26 ]
Process Validation
Strategies for new and existing products
New Products
Per ISO 9001, all new products must under Design and development
which includes:
Planning Design and development inputs Design and development outputs Design and development review Design and development verification Design and development validation* Control of design and development changes*
*At the completion of the design and development validation and
before the control of design changes, product transfer and process
validation occurs.
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[ 27 ]
Process Validation
Strategies for new and existing products
New Products
During the product transfer process, the product is being evaluated
at the manufacturing site for scale up.
It is at this stage that the use of statistician can help evaluate
process capability and readiness for process validation. Also
helpful with defining acceptance criteria, number of
samples, etc.
Risk analysis can be a great tool in defining worse
case conditions a process can potential see in routine
manufacturing. These failure modes can be tested
in product evaluation and/or validation trials.
(reference validation strategy risk mitigation table)
Best
Practice:
During the product
transfer stage there
needs to be high
engagement with site
validation
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[ 28 ]
Process Validation
Strategies for new and existing products
New Products
Process Validation Readiness should include the following:
Design review confirms process is capable
All prerequisite validations are complete (e.g. equipment, facility, software, etc.)
Process control plan has been created or updated*
Risk analysis has been updated
*
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[ 29 ]
Process Validation
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[ 30 ]
Process Validation
Strategies for new and existing products
New Products
Process Validation Readiness should include the following:
All procedures, batch records, inspection plans, specifications, drawings are updated and approved.
All impacted personnel are trained on procedure, batch records, inspection plans, etc.
All raw materials are procured and in approved status
All new suppliers are in approved status
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[ 31 ]
Process Validation
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[ 32 ]
Process Validation
Strategies for new and existing products
Existing Products
Existing products are defined as validated products that
have been transferred to the manufacturing site for routine
manufacture. For validations involving any existing product,
B+L follows a global change management process.
Sec. 820.70 Production and process controls.b-Production and process changes. Each manufacturer shall establishand maintain procedures for changes to a specification, method,process, or procedure. Such changes shall be verified or whereappropriate validated according to 820.75 (Process Validation), beforeimplementation and these activities shall be documented. Changes shallbe approved in accordance with 820.40 (Document controls).
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[ 33 ]
Process Validation
Strategies for new and existing products
Existing Products
B+Ls global change management software tracks all changes forexisting products.
Depending on the scope of the change; a limited, extensive or full
revalidation may need to be conducted. A key element of change control
is the impact analysis. The impact analysis considers the impact of the
change to the risk management file. Best Practice:
A Validation
representative
needs to evaluate
changes impacting
validated state.
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[ 34 ]
Process Validation
Strategies for new and existing products
Existing Products
A useful tip is to work with your Research and Development group
or Technical Services group to evaluate the capability of the
product device after proposed change.
Pros:
Better process understanding Greater confidence in the process to pass when you go into live
validation.
Cons:
May require additional equipment, line time, resources, lab support togenerate data
Cost of material/product that may need to be scrapped
Its a Risk decision
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[ 35 ]
Process Validation
Runs and Samples
How many runs do we need???
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[ 36 ]
Process Validation
Runs and Samples
How many runs do we need???
How many samples do we need to take???
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[ 37 ]
Process Validation
Runs and Samples
How many runs do we need???
How many samples do we need to take???
Can we runs this concurrent with production???
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[ 38 ]
Process Validation
Runs and Samples
How many runs do we need???
How many samples do we need to take???
Can we runs this concurrent with production???
It depends on the scope, level of risk and confidence we have in the
process. Its a question of risk!
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[ 39 ]
Process Validation
Runs and Samples
For the number of runs, we use 3 as a starting point. We let our risk
assessment drive the number of runs needed. Example:
There is a process change that will impact the manufacturing of a
formulation in 2 different tanks. Our engineering data indicates that although
the 2 tanks are the same size they are both designed differently and have
different heating and agitation profiles. A risk analysis indicates that heating
and agitation may have significant impact on product acceptance. For this
process validation a minimum of 6 runs (3 runs/tank) may be recommended
in addition to engineering trials to confirm capability of the formulation.
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[ 40 ]
Process Validation
Runs and Samples
In sampling, we target confidence level of at least 90%. We also let our
risk analysis drive the number and type of samples needed. There
needs to be an understanding of whats important to your process.
Lets illustrate this point with the validation of Product XYZ
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[ 41 ]
Runs and Samples
Overview of product and manufacturing process for Product XYZ
Raw Materials:
Sterile Water
NaCL
Raw Material A
Raw Material B (new)
Excipients
Critical Quality Attributes (CQAs).
Solution is safe and effective for intended purpose (attribute or go/no-go)
Batch is homogeneous (variable data)
Raw Materials A and B must meet label claim (attribute or go/no-go)
Process Validation
Best
Practice:
A key to the
sampling rationale
is found in the
CQAs. They define whats
important
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[ 42 ]
Runs and Samples
Product XYZSterile
Filling
Bulk
Compounding
Packaging
Step 1
Purified Water
Add Excipents
Heat sterilize mixture
CPPs=batch temp,
agitation speed
Step 2
Mix, dissolve and Sterile filter excipents
CPP=batch temp, mix time
Step 3
Mix and Sterile filter Raw Materials A and B
CPP=batch temp, mix time
Step 4
Mix dissolve and Sterile filter NaCL and excipients
CPP=batch temp, mix
time
19,000 L
Tank
CPP=Critical Process Parameter
19,000 L
Tank
Process Validation
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[ 43 ]
Runs and Samples
Sterile
Filling
Bulk
Compounding
Packaging
19,000 L
Tank
CPP= Line length,
product conditioning
volume, filling speed, etc.
Process Validation
Product XYZ
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[ 44 ]
Runs and Samples
Sterile
Filling
Bulk
Compounding
Packaging
Case Study- Process Validation for Product XYZ
Our product and process risk assessment identified both the bulk compounding and sterile filling process steps as having the highest potential risk. Critical Quality
Attributes (CQAs). Solution is safe and effective for intended purpose (most likely impacted in bulk
compounding and sterile filling process)
Batch is homogeneous (most likely impacted in bulk compounding)
Raw Materials A and B must meet label claim (most likely impacted in bulk compounding)
We focused more effort (sampling and runs) on these high risk process steps during scale up and process validation
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[ 45 ]
Runs and Samples
Sterile
Filling
Bulk
Compounding
Packaging
Process Validation
Based on historical data and information from our risk assessments, the heaviest use of statistics (sampling) was focused on the bulk compounding and sterile filling
processes as we needed to demonstrate a high level of assurance at these stages.
We used process capability data from similar products and development work to establish standard deviations for Raw Materials A and B.
Our sample size was based on the use of standard deviations from engineering trials, 90% Confidence
For batch and bottle homogeneity we demonstrated with 90%Confidence that batch and bottle sample sets were homogeneous.*
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[ 46 ]
Process Validation
When are you done?
Now that the execution is complete with your
Process Validation and Final Report has been
written and approved,
Are You Done?
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[ 47 ]
Process Validation
When are you done?
According to GHTF - Quality Management Systems Process
Validation Guidance, you should maintain a state of
validation:
Monitor and control
Changes in processes and/or product
Continued state of control
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[ 48 ]
Process Validation
When are you done?
Most companies including B+L are using the product quality review
process to confirm medical device products are maintained in a state of
control. Key attributes include:
In process and final product manufacturing trend data
Complaints
Non-conformances
Corrective Preventive Actions
Stability
Changes and subsequent validations
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[ 49 ]
Agenda
Getting Started-Overview
Process Validation
Enterprise wide Roll Out of Process Validation
Interactive Exercise
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[ 50 ]
Enterprise wide Roll Out of Process Validation
o Enterprise-wide policies and procedures
o Quality System standardization, design management, change
management and validation
o Train personnel
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[ 51 ]
Enterprise wide Roll Out of Process Validation
Enterprise-wide policies and procedures
The CFR requires established procedures to conduct process validation and support monitoring and control of process parameters.
Sec. 820.75 Process Validation.a- Where the results of a process cannot be fully verified by subsequent
inspection and test, the process shall be validated with a high degree ofassurance and approved according to established procedures. Thevalidation activities and results, including the date and signature of theindividual(s) approving the validation and where appropriate the majorequipment validated, shall be documented.
b- Each manufacturer shall establish and maintain procedures formonitoring and control of process parameters for validated process toensure that the specified requirements continues to be met.
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[ 52 ]
Enterprise wide Roll Out of Process Validation
Enterprise-wide policies and procedures
Best practices for a multi-site / global company to deploy process validation
procedures is Enterprise-wide policies and procedures:
Pros:
Provides clear instruction for how things are done. Offers consistent approach to validation to train to and follow regardless of
site location, manufacturing platform, products manufactured
Presents to regulators the companys position on process validation Capitalize on best practices at each site. Ensures alignment to guidances, standards and industry bestpractices
Best
Practice:
In addition to policies
and procedures,
templates provide
consistency
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[ 53 ]
Enterprise wide Roll Out of Process Validation
Enterprise-wide policies and procedures
Cons:
Difficult to gain consensus with multiple sites who have always done it their way.
Procedures and templates may not be flexible to meet needs of different products, manufacturing platforms
Learning curve and time to implement
Tips for Enterprise-Wide roll out are:
Getting engagement and feedback from stakeholders at the manufacturing site. Feedback should be from each type of
manufacturing site.
Deploy procedures and templates on a trial basis to validate its use. Allow extended phase in period (60-90 days) for training
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[ 54 ]
Enterprise wide Roll Out of Process Validation
Quality System standardization, design management, change
management and validation
The success of any Validation Program is contingent on a healthy Quality System.
ISO 9001 identifies the some of the Quality Systems evaluated during management review:
5.6.2 Review input- The input to management review shall include information
on:
a) results of audits, (Internal and External Audits)
b) customer feedback, (Complaints)
c) process performance and product conformity, (NonConformance Management)
d) status of preventive and corrective actions, (NonConformance Management)
e) follow-up actions from previous management reviews,
f) changes that could affect the quality management system, and (Change Mgmt)
g) recommendations for improvement. (Continuous Improvement)
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[ 55 ]
Enterprise wide Roll Out of Process Validation
Quality System standardization, design management, change
management and validation
ISO 9001 state the following responsibilities of Management Review:
5.6.3 Review output- The output from the management review shall include any
decisions and actions related to:
a) improvement of the effectiveness of the quality management system and its
processes,
b) improvement of product related to customer requirements, and
c) resource needs.
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[ 56 ]
Enterprise wide Roll Out of Process Validation
Quality System standardization, design management, change
management and validation
Standardization of key quality systems like design management, change management and validation ensures:
Provides clear instruction for how things are done.
Offers consistent approach to train and follow regardless of sitelocation, manufacturing platform, products manufactured
Presents to regulators the companys position on key quality systems
Ensures alignment to guidances and standards
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[ 57 ]
Agenda
Getting Started-Overview
Process Validation
Enterprise wide Roll Out of Process Validation
Interactive Exercise
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[ 58 ]
Firm is rebranding a legacy medical device product in a
new bottle.
Product is a sterile liquid. Bottle is being sourced from a
new supplier. Bottle requires a different sterilization
method. New equipment will be needed to run this bottle.
Validation needs to be conducted to launch to new product.
What will the validation strategy be?
Interactive Exercise
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Product ABC is currently filled in an oval and opaque HDPE. New bottle is round, transparent (without colorant) HDPE
Sterilization Method for current bottle is Ethylene Oxide. New bottle will require gamma irradiation
Bottle will be filled in Fill Room C. Fill Room C only has change parts for oval bottles.
Instead of using the checkweighing system, the firm would like to use fill volume sensors that were always integrated on Fill Room C
but never used because firm uses opaque bottles.
Original validation for Product ABC was conducted 15 ago.
Interactive Exercise
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Each team, take 5-10 minutes to develop a validation strategy.
Demonstrate the use of the following:
Success criteria
Team Members
Any necessary pre-work (engineering, develop studies, etc.)
Training
Proposed risk analysis
Proposed statistics
Process steps to focus validation effort
Interactive Exercise
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Questions???