Heed wk 3

Validation Overview

Global Regulatory and Legal Requirements of Quality

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Learning Objectives

1. Provide an overview of various types of validation: product, process, cleaning, equipment, test methods, and software.

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In Common to Pharma and Device

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Why Validate?

• Before any batch from the process is commercially distributed for use by consumers, a manufacturer should have gained a high degree of assurance in the performance of the manufacturing process such that it will consistently produce APIs and drug products meeting those attributes relating to identity, strength, quality, purity, and potency.

• The assurance should be obtained from objective information and data from laboratory-, pilot-, and/or commercial scale studies.

• Information and data should demonstrate that the commercial manufacturing process is capable of consistently producing acceptable quality products within commercial manufacturing conditions.

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What does Success Look Like?

• A successful validation program depends upon: – Information and knowledge from product and process development

– Basis for establishing an approach to control of the manufacturing process

– Results in products with the desired quality attributes

• Manufacturers should: – Understand the sources of variation

– Detect the presence and degree of variation

– Understand the impact of variation on the process and ultimately on product attributes

– Control the variation in a manner commensurate with the risk it represents to the process and product

– Assess the validated state of the process on an ongoing basis

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Validation Success

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Validation Master Plan

• Validation Master Plan

– Document that describes how and when the validation program will be executed in a facility.

– It is the document that outlines the principles involved in the qualification of a facility, defines the areas and systems to be validated and provides a written program for achieving and maintaining a qualified facility with validated processes.

– It is the foundation for the validation program and should include process validation, facility and utility qualification and validation, equipment qualification, cleaning and computer validation.

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Assuring Equipment Performance

• Installation Qualification (IQ)

– Simply put…is everything installed correctly.

– Consider…

• Equipment design features

• Installation and Environmental Conditions

• Safety features

• Supplier documents, Calibration, preventative maintenance and spare parts.

• Operational Qualification (OQ)

– Challenge process parameters to assure the process will result in product that meets requirements.

– Things to consider…

• Determine process control limits

• Material specifications and handling

• Process change control and training

• Determine potential failure modes, action levels and worst case scenario

• Perform software Validation and verification for intended use

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Producing Good Product

• Performance Qualification (PQ)

– Demonstrate the process will consistently produce acceptable product under normal operating conditions.

– Things to consider… • Approved procedures and limits from OQ

• Acceptable product

• Simulate actual manufacturing conditions

• Is the process repeatable and stable long term

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Medical Devices

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Device Development “Waterfall Model”

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For more complicated

devices, development work needs to be conducted in parallel, not

in sequence

Adapted from the FDA Guidance on Design Controls

Assuring Product Design

• Design Qualification (DQ) – Design qualification (DQ)- Demonstrates that the proposed design (or the

existing design for an off-the-shelf item) will satisfy all the requirements that are defined and detailed in the User Requirements Specification (URS).

– Satisfactory execution of the DQ is a mandatory requirement before construction (or procurement) of the new design can be authorized.

• Good product design is dependent on robust “inputs” – Research

– Comparison against predicate products

– Patient focus groups – Human Factor Studies

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Assuring Product Design

• Verification

– Quality System Regulation - Definitions 21 CFR 820.3 (aa) • Verification means confirmation by examination and provision of objective

evidence that specified requirements have been fulfilled.

– The product functions as it was intended

• Validation

– Quality System Regulation - Definitions 21 CFR 820.3 (z) • Confirmation by examination and provision of objective evidence that the

particular requirements for a specific intended use can be consistently fulfilled.

– The product meets user needs

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Pulling it All Together

15 MQ is not a common term, and refers to Maintenance Qualification

Pharmaceuticals

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Approach to Process Validation

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• Process validation has three stages:

– Stage 1 for Process Design • Commercial manufacturing process is defined during this stage based on

knowledge gained through development and scale-up activities

– Stage 2 for Process Qualifications • Process design is evaluated to determine if the process is capable of

reproducible commercial manufacturing

– Stage 3 for Continued Process Verification • Ongoing assurance is gained during routine production that the process

remains in a state of control

Stages of Process Validation

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• Process Validation: Stage 1 – Process Design – Goal of this stage is to design a process suitable for routine commercial

manufacturing that can consistently deliver a product that meets its quality attributes

– Build and capture process knowledge and understanding

• Design of Experiment (DoE) studies to help develop process knowledge

• Risk analysis tools to screen potential variables

• Use of computer simulations can provide process understanding and help avoid problems at commercial scale

– Establish a strategy for process control

• Reduce input variation, adjust for input variation during manufacturing, or combine both approaches

• Use of Process Analytical Technology (PAT) to provide higher degree of process control

Stages of Process Validation

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• Process Validation: Stage 2 – Process Qualification (PQ) – Goal of this stage is to determine if the process design is capable of

reproducible commercial manufacture (tech transfer, scaleup and validation)

– Design of a facility and qualification of utilities and equipment

• Selecting utilities and equipment construction materials, operating principles and performance characteristics (IQ and OQ)

– Process Performance Qualification (PPQ)

• PPQ combines actual facility, utilities, equipment and trained personnel with the commercial manufacturing process, control procedures and components to produce commercial batches

– PPQ protocol and report

• Written protocol that specifies manufacturing conditions, controls, testing and expected outcomes

Stages of Process Validation

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• Process Validation: Stage 3 – Continued Process Verification – Goal is for continual assurance that the process remains in a state of control

during commercial manufacture

– State of control is a condition in which the set of controls consistently provides assurance of continued process performance and product quality (ICH Q10)

In Common to Pharma and Device

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Validation Life Cycle – Device and Pharma

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Form Validation

Team

Plan approach and define parameters

Identify and describe process

Create Validation

Master Plan

Specify process parameters and outputs

Select methods and tools

Perform Design Qualification

(DQ/DOE)

Determine Process Controls

Create Protocols

Perform Installation

Qualification (IQ)

Perform Operational

Qualification (OQ)

Perform Process Performance

Qualification (PPQ)

Prepare Final Report

Monitor and Control Process

Revalidate as Appropriate

Pharma PQ

Adapted from Global Harmonization Task Force: Guidance for Industry - Process Validation: General Principles and Practices

Production and Process Changes

• Establish and maintain procedures for changes to a specification, method, process or procedure.

• Such changes shall be verified or where appropriate validated

• Change Control: – If changes are needed (equipment, new facility, components and materials,

test methods, etc.), the “new” needs to be equivalent to the “original” • Otherwise, there is a break in what was used to demonstrate the product’s safety and quality

(breaks link to clinical trial data!)

• Need to have scientific data to support change

• Need to have a cross-functional group review the change for impact

– Changes may require FDA notification and/or pre-approval

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Revalidation

• When changes or process deviations occur, the manufacturer shall review and evaluate the process and perform revalidation where appropriate. These activities shall be documented.

• Examples of Reasons for Revalidation – Change(s) in the actual process

– Negative trend(s) in quality indicators

– Change in product design that affects process

– Transfer of process to another facility

– Change of the application of the process

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Let’s take a Break!

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