Institute of Validation Technology Validation Week- Philadelphia

[ 1 ]CONFIDENTIAL

Institute of Validation Technology

Validation Week- Philadelphia

Tanya Fletcher-Scott

Validation Manager- Greenville SC Solutions Facility

[email protected]

October 24, 2012

Session 4: Best Practice to Implement Process

Validation in Device Manufacturing Enterprise-

wide

[ 2 ]

Agenda

Getting Started-Overview

Process Validation

Enterprise wide Roll Out of Process Validation

Interactive Exercise

Look out for

the

Best

Practice

[ 3 ]


o The Rules- Review of Standards and Guidances for

Process Validation of Devices

o Tools- Risk Assessments and Statistics

o The Team- Don’t go it alone!

o The Docs- Documenting the process validation

activities

[ 4 ]


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

[ 5 ]


The Rules- Review of Standards and Guidances for Process


• 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

[ 6 ]


The Rules- Review of standards and guidances for Process


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).

[ 7 ]




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.

[ 8 ]




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

[ 9 ]




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.

[ 10 ]


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

[ 11 ]



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.

[ 12 ]


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

[ 13 ]



Risk Management Tools

• Preliminary Hazard Analysis (PHA) is a technique that

can 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 safety

engineering, early in the development stages, for the

identification and prioritization of hazards and

hazardous situations as well as for analyzing adverse

events.

[ 14 ]



Risk Management Tools

• Failure Mode and Effects Analysis (FMEA) and Failure

Mode, 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 Hazard

Analysis 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.

[ 15 ]


The Team- Don’t 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.

[ 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+L’s 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:


The Team- Don’t go it alone!

Best

Practice:

Project Managers

are key to any

success tech

transfer

[ 17 ]


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.

[ 18 ]




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

[ 19 ]






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

[ 20 ]






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

[ 21 ]






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 it’s all done, generate the final report summarizing all

requirements, results, issues and conclusions

[ 22 ]

Agenda


Process Validation



[ 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?

[ 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.

[ 25 ]

Process Validation

Creating a strategy/validation plan

B+L’s validation systems does not require validation strategies for smaller, less

complex 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

<Let’s review the sample validation strategy in your bonus material>

[ 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.

[ 27 ]

Process Validation


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

[ 28 ]

Process Validation


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

*<Let’s review the sample control plan in your bonus material>

[ 29 ]

Process Validation

[ 30 ]

Process Validation


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

<Let’s review the sample readiness form in your bonus material>

[ 31 ]

Process Validation

[ 32 ]

Process Validation


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).

[ 33 ]

Process Validation


Existing Products

B+L’s global change management software tracks all changes for

existing 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.

[ 34 ]

Process Validation


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 to

generate data

• Cost of material/product that may need to be scrapped

It’s a Risk decision

[ 35 ]

Process Validation

Runs and Samples

How many runs do we need???

[ 36 ]

Process Validation

Runs and Samples


How many samples do we need to take???

[ 37 ]

Process Validation

Runs and Samples



Can we runs this concurrent with production???

[ 38 ]

Process Validation

Runs and Samples



Can we runs this concurrent with production???

It depends on the scope, level of risk and confidence we have in the

process. It’s a question of risk!

[ 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.

[ 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 what’s important to your process.

Let’s illustrate this point with the validation of Product XYZ

[ 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

CQA’s. They

define what’s

important

[ 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

[ 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

[ 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

[ 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.*

[ 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?

[ 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

[ 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

[ 49 ]

Agenda


Process Validation



[ 50 ]


o Enterprise-wide policies and procedures

o Quality System standardization, design management, change

management and validation

o Train personnel

[ 51 ]


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.

[ 52 ]



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 company’s position on process validation

• Capitalize on best practices at each site.

• Ensures alignment to guidances, standards and industry best

practices

Best

Practice:

In addition to policies

and procedures,

templates provide

consistency

[ 53 ]



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

[ 54 ]


Quality System standardization, design management, change


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)

[ 55 ]




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.

[ 56 ]




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 site

location, manufacturing platform, products manufactured

• Presents to regulators the company’s position on key quality systems

• Ensures alignment to guidances and standards

<Reference a sample global final report template in bonus material>

[ 57 ]

Agenda


Process Validation



[ 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?


[ 59 ]

• 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.


[ 60 ]

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


[ 61 ]

Questions???

Documents

Institute of Validation Technology Validation Week- Philadelphia