the status of qualification & validation - session 1 · pdf filethe status of...
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The Status of Qualification & Validation - Session 1Presented by Ashley Isbel12 May, 2014
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This Session
This session will cover
A recap of the ICH guidelines and US FDA PV Guidance
A refresher on CQAs, CPPs, Control Strategy & other key terms
An overview of the EU PV Guideline (reg submissions)
A summary of the draft EU Annex 15 update
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A paradigm shift
Ahead? …. Or here?
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A paradigm shift
What has brought us here?
• Last decade has seen several “new thinking” movements within the industry and from regulators
• Core to these new ways of thinking have been
• ICH guidelines
• US FDA “GMPs for the 21st Century”
The end result is that we have new guidances and (will soon have) new GMPs for qualification and validation
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A paradigm shift
The new direction pushes us towards a:
• Science-Based
• Risk-Based
• Cost Effective approach
to ensuring patient safety & product quality during pharmaceutical development and manufacturing
It’s worthwhile revisiting the key drivers …
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ICH Q8 Pharmaceutical Development
Critical Quality Attributes
Risk Assessment
Design Space
Control Strategy
Lifecycle Management & Continual Improvement
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ICH Q9 Quality Risk Management
“The evaluation of the risk to quality should be based on scientific knowledge and ultimately link to the protection of the patient.”
“The level of effort, formality and documentation of the QRM process should be commensurate with the level of risk.”
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ICH Q10 Pharmaceutical Quality System
“To establish, implement and maintain a system that allows the delivery of products with the quality attributes appropriate to meet the needs of patients…”
“To develop and use effective monitoring & control systems for process performance and product quality, thereby providing assurance of continued suitability and capability of processes”
“To identify & implement appropriate product quality improvements, process improvements, variability reduction, innovations and pharmaceutical quality system enhancements, thereby increasing the ability to fulfil quality needs consistently.”
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US FDA “CGMP’s for the 21st Century”
• Encourage the early adoption of new technological advances
• Facilitate industry application of modern quality management techniques
• Encourage implementation of risk-based approaches that focus both Industry and Agency attention on critical areas
• Ensure that regulatory review, compliance and inspection policies are based on state-of-the-art pharmaceutical science.
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Goals of Process Validation Based on Current Guidance
• Design & Develop well understood proceduresScience
• Focus on what is critical to patient safety & product qualityRisk
• Quality by Design approachDesign
• Q&V activities to ensure a capable processValidation
• Establish an appropriate Control StrategyControl
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Quality Target Product Profile (QTPP)
“A prospective summary of the quality characteristics of a drug product that ideally will be achieved to ensure the
desired quality, taking into account safety and efficacy of the drug product”.
(ICH Q8)
Define the Quality Target Product Profile
(QTPP)
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Quality Target Product Profile (QTPP)
Pharmaceutical Development goals are to design a quality product.
Establish pre-defined objectives and document the summary as a QTPP:
• Summarise the quality attributes that ensures safety and efficacy.
• QTPP should align with the requirements defined in the TPP.
• Starting point for understanding and assessing criticality of product quality attributes.
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Quality Target Product Profile (QTPP)
Tablet Attribute* Tablet QTPP
Dose 500mg PharmOdol® tablet
Subjective properties Appearance, uniform, no off taste or odour
Patient safety – chemical purity
Impurities and / or degradation products below ICH or to be qualified
Patient safety –biological purity
Acceptable level of non-pathogenic microorganisms, free from yeast or moulds or below the specified limit
Patient efficacy – particle size distribution (PSD)
PSD that does not impact bioperformance or pharmaceutical processing
Chemical and drug product stability:2 year shelf life, below 30˚C
Degradation products below ICH or to be qualified and no changes in bioperformance over expiry period
*Only a few PharmOdol® TPPs discussed here
Example: 500mg PharmOdol® tablet
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Critical Quality Attributes (CQA)
“A physical, chemical, biological or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality”.
(ICH Q8)
Identify the CQAs
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Critical Quality Attributes (CQAs)
• Could be for Raw Materials, Excipients, Drug Substance, intermediate, container closure components.
• Developed from extensive product development & understanding.
• May only have limited information at early Stage 1, so first set of CQA’s may be based on prior knowledge & experience
• Decisions on criticality should be identified using a scientific evidence and a risk-based approach.
• Identify items that impact Safety, Quality, Identity, Potency, Purity (SQuIPP).
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Critical Quality Attributes (CQAs)
• Attributes not defined as critical could still be monitored during the Development phase.
• CQAs are subject to change as product and process knowledge develops (Design Space)
• Continue using Quality Risk Management
• CQAs are usually linked to test specifications
• All CQAs should be fully understood and defined before moving to Stage 2
Input Process Output
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Design Space
“The multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters
that have been demonstrated to provide assurance of quality. Working within the design space is not considered as a
change. Movement out of the design space is considered to be a change and would normally initiate a regulatory post approval change process. Design space is proposed by the
applicant and is subject to regulatory assessment and approval.”
(ICH Q8)
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Design Space
• Development of a Design Space is optional but can be described in a Regulatory Submission
• Should be adopted by development teams as it results in better process understanding and the knowledge supports the control strategy
• Understanding of the relationship between process inputs and CQAs
• Useful to understand the edge of failure for material attributes or process parameters
• Could be applied to part of a process
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Design Space
Knowledge Space
Design Space
Operational Space
Previous Experience
Literature
First PrinciplesTechnology
Transfer
Material Attributes
Process Parameters
CQAs & CPPs
Risk Assessment
Experimental Design
Facility, Systems & Equipment
Understanding
Scale-up
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PharmOdol® From QTPP to CQAs
Paracetamol Product
PharmOdol QTPP* Translation to CQA
Dose 500mg tablet Identity, Assay, Uniformity of Dosage Units
Subjective properties
Appearance, uniform, no off taste or odour
All blisters filled, correct number of strips in pack, unit Integrity and other characteristics
Patient safety – chemical purity
Impurities and/or degradation products below ICH
Appearance and other characteristics Absence of defects
Patient safety – biological purity
Acceptable level of non-pathogenic microorganisms, free from yeast or moulds or below the limit
Acceptable degradation product levels at release, appropriate manufacturing environment controls, input raw material quality. Degradation controlled by packaging.
*Only a few PharmOdol ® QTPPs included here
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Process for manufacture of 500mg PharmOdol®
Dispensing Blending Granulation Drying Milling Lubrication Compression Packing
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Overall Process Assessment
CQA
Dis
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Ble
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Gra
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Dry
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Mil
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Co
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Pa
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Identity
Appearance
Assay
Content Uniformity
Purity
Hardness
Friability
Dissolution
Known or Potential impact to CQA
Potential impact to CQA
No impact to CQA
Define the highest risk parameters and identify the CPPs
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Critical Process Parameters (CPPs)
“A process parameter whose variability has an impact on a critical quality attribute and therefore should be monitored or
controlled to ensure the process produces the desired quality”.
(ICH Q8)
Define Process Steps & CPPs
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Critical Process Parameters (CPPs)
• Quality Risk Management critical at several stages of Stage 1 Process Design
• Subject Matter Experts (SMEs) from various departments
• Provide documented rationale
• A “Cause and Effect Diagram” to identify process input parameters where variability may have largest impact to product quality/process performance
• As knowledge develops, other assessment tools are useful
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Defining CPPs
Process Variable
Can variable be
controlled?
NO
Process Performance
Attribute
Product Quality Attribute
OR
Process Input
YES
Potential Impact to
CQAs?
NOYESPotentially
a CPPPotentially NOT a CPP
Risk Assessment.
CQA?
YESCritical Process Parameter
NO
Key Process Parameter
Non-Key Process Parameter
OR
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Control Strategy
“A planned set of controls, derived from current product and process understanding that ensures process performance
and product quality.”
(ICH Q10)
(definition continued on next slide)Create a Control Strategy
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Control Strategy
“The controls can include parameters and attributes related to drug substance and drug product materials and
components, facility and equipment operating conditions, in-process controls, finished product specifications, and the
associated methods and frequency of monitoring and control”.
(ICH Q10)Create a Control Strategy
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Control Strategy
• Important output of Stage 1
• Will ensure that the process remains in control
• Created based on process knowledge gained and the application of science and risk-based approaches and techniques
• Encompasses all elements of each unit operation of the manufacturing process
• All product attributes and process parameters should be in a complete Process Control Strategy
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Control Strategy for Blending
CQA Process Step Parameter Specification Control
Uniformity of Dosage Units
Blending Time (min) 4-16 mins 5-8 mins
Uniformity of Dosage Units
Blending Speed (rpm) 10-15 rpm 12-14rpm
Uniformity of Dosage Units
Blending Load (Kg) 900-1200 Kg 1000-1100 Kg
*Only one PharmOdol ® Control Strategy example included here
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Control Strategy
Control Strategy Elements Rationale
Raw Materials Control of input variability
Test Specifications Related to product safety/efficacy
In-Process Controls Monitor the process
Performance Parameters Cannot be controlled but are indicators
Set Points & Ranges Known acceptable variability
Process Monitoring Data collection for all Stages
Processing & Hold Times Time limits impact product quality
Process Analytical Technology (PAT) Real-time monitoring/release
Other Control Strategies and their rationale might include:
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Process Design Completion
Stage 1 output should be a Report that justifies the Control Strategy:
• Defined CQAs
• Risk Assessments
• Process Information (Inputs & Outputs)
• Parameters and Ranges
• Design Space Information (if applicable)
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Process Design Completion
Knowledge Space
Design Space
Operational Space
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US FDA and EU “Process Validation”
Process Design
Process Qualification
ContinuedProcess
Verification
Continuous Improvement “Lifecycle”
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Process Validation Lifecycle
Stage 2
Process Qualification
Stage 1
Process Design
Stage 3
Continued ProcessVerification
Evaluate / Confirm
Distribute
Design of Facilities & Qualification of Equipment and
Utilities
Process Performance Qualification
(PPQ)
Stage 3a
Heightened sampling & testing
until variability understood
Stage 3b
Routine monitoring program
Commercial Manufacturing
FDA Product Life Cycle – Process Validation
Changes
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FDA (& EU) PV Stages
Stage 1 – Process Design: The process is defined during this stage based on knowledge gained through development and scale-up activities.
Stage 2 – Process Qualification: During this stage, the process design is evaluated to determine if the process is capable of reproducible commercial manufacturing.
Stage 3 – Continued Process Verification: Ongoing assurance is gained during routine production that the process remains in a state of control.
Identify sources of Variability
Control of Variability
Monitoring Variability-remains “in control”
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EU Guideline on Process Validation
• Draft released under this name in Feb 2012
• Final version published in Feb 2014 under the title “Guideline on process validation for finished products – information and data to be supplied for regulatory submissions”
• This is not a process validation guideline. It is a guideline on regulatory submission data requirements, however:
• It is a useful resource regarding regulatory positions on scale up, as well as adding clarity to complexity/novelty considerations
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EU GMP Guide Annex 15 “Qualification & Validation”
Concept Paper from the EMA (Nov 2012)outlined various reasons for the revision:
• ICH Q8, Q9, Q10 and Q11
• Advancements in manufacturing technology
• EMA draft Guide on Process Validation
• Changes to other Chapters, Sections and Annexes
Draft published in March 2014
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EU GMP Guide Annex 15 “Qualification & Validation”
Main Changes:
• Cross-reference made to Annex 11 Computerised systems
• Planning and documentation for Qualification and Validation
• Added information on the qualification stages for equipment, facilities and utilities
• Major revision of the Process and Cleaning Validation sections
• New sections added
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EU GMP Guide Annex 15 “Qualification & Validation”
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EU GMP Guide Annex 15 “Qualification & Validation
Design Space
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EU GMP Guide Annex 15 “Qualification & Validation”
Cleaning Validation
• Definition now "will remove all traces of the previous product used in the equipment."
• “Visually clean” not acceptable on its own
• “Limits should be based on a toxicological evaluation to determine the product specific permitted daily exposure (PDE) value"
• No longer looks for “3” consecutive batches
• Cleaning verification may be used when manufacturing batches infrequently or for IMP’s
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EU GMP Guide Annex 15 “Qualification & Validation”
“Typically, the cleaning procedure should be performed an appropriate number of times based on a risk assessment and meet the acceptance criteria in order to prove that
the cleaning method is validated ”
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EU GMP Guide Annex 15 “Qualification & Validation”
New sections on:
• Ongoing Process Verification during Lifecycle
• Verification of Transportation
• Validation of Packaging
• Qualification of Utilities
• Validation of Test Methods
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Process Validation Definitions
• The documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce a medicinal product meeting its predetermined specifications and quality attributes
PIC/S & EU
• The collection and evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality product.
US FDA
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Number of Runs
• “3 consecutive runs”
• New rationale based on:
• Understanding the process
• Design & development phase
• Experience from similar processes
• > or < 3 runs?
• Decision should be based on:
Knowledge, Statistics & Risk!
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Activity 1: EU Draft Annex 15
Please complete the Blue Sheets as a group and return them to us
Please assign a Speaker/Scribe at
each table
If there are any questions, please ask!
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Thank you for your time.Questions?
Ashley Isbel
Lead Consultant
www.pharmout.net