EMA Draft Process Validation Guidance - PharmOut · A physical, chemical, biological or...
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EMA Draft Process Validation Guidance Presented by Marc Fini 21 May, 2013
Transcript of EMA Draft Process Validation Guidance - PharmOut · A physical, chemical, biological or...
EMA Draft Process Validation Guidance
Presented by Marc Fini
21 May, 2013
Slide 2 © PharmOut 2013
EMA Draft Guideline on PV
Draft released: 15 March 2012
End of Consultation: 31 October 2012
Will Replace:
• Note for Guidance on Process Validation
• 10 page Guide with 8 Sections
Slide 3 © PharmOut 2013
EMA Draft Guideline on PV
Alignment with ICH Q8, Q9 and Q10
An alternative approach to process validation in which manufacturing process performance is continuously monitored and evaluated
Continuous Process Verification
Documented evidence that the process remains in a state of control during commercial manufacture
Continued Process Verification
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EMA Draft Guideline on PV
Continuous Process Verification should be based on:
Knowledge management is critical to validation success
Knowledge from the product and process development studies
Previous manufacturing
experience
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What is process validation?
Process validation can be defined as 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
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EMA Draft Guideline on PV
Intended to apply to data generated to validate manufacturing process of the intended commercial dosage form only.
Applies to medicinal products for human and veterinary use.
Applicable for biological products, however considered on a case-by case basis.
Provides guidance on the information to be considered for dossier submission.
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EMA Draft Guideline on PV
Continuous Process Verification
• confirm that the control strategy is sufficient to support the process design and quality of the product
• provides more information & knowledge and might help facilitate improvements.
The approach
• A hybrid approach where traditional process validation and continuous process verification mechanisms are combined
• Stand alone continuous process verification can be adopted
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Process validation
Process validation is not a one off event
Process validation must fit a lifecycle approach that ties together:
Product development
Validation of the
commercial manufacture
process
Maintaining the process in
a state of control
throughout routine
operations
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Process validation
The EMA guidance document emphasises that validation needs to be integrated across a product’s lifecycle:
• Remember, no procedures should be in place without the appropriate validation effort.
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Process validation
The validation effort should translate into:
SOPs
Training programs
Risk based methodologies
Investigations into product and process failure
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Traditional process validation
For the regulator to consider:
• Manufacturing processes should be validated before a product is available on the market
• Process validation should verify the adequacy of the control strategy
• All products should undergo process validation to demonstrate the adequacy of the process at each site
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What is a control strategy?
A planned set of controls, derived from current product and process understanding that ensures process performance and product quality.
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)
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What is a 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)
Critical Quality Attribute (CQA):
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)
Critical Process Parameter (CPP):
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Process validation and the control strategy
• Process validation should focus on the control strategy including the critical process parameters
• The ongoing aim is to demonstrate that the process is capable of delivering the desired product quality
• This refers to when the process is in commercial manufacture
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Three golden batches
The number of process validation batches should be based on:
The variability of the process
The complexity of the product and process
The manufacturer’s
experience
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Three golden batches
The three batch concept remains acceptable in this context, however, the guidance also states that the number of batches chosen for the validation effort may be more if needed…
When determining whether three or more batches are needed, consider a risk based, commensurate approach.
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Scale up
• Scale up and the subsequent technology transfer must be carefully managed.
• Scale up will introduce variables that may impact ongoing process and product performance.
• These variables should be the focus of the scale up process.
• The scale up factor must be less than 10.
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Hybrid approach
• The hybrid approach may use a combination of the traditional process validation or continuous process verification for different steps in the process
• The justification for the hybrid approach should be included in the submitted documents and detail which approach applies to each part of the manufacturing process
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Continuous process verification
“Continuous Process Verification (CPV) is an alternative approach to traditional process validation”.
“Manufacturing process performance is continuously monitored and evaluated (ICH Q8)”.
“It is a science and risk-based real-time approach to verify and demonstrate that a process that operates within the predefined specified parameters consistently produces material which meets all its Critical Quality Attributes (CQAs) and control strategy requirements”.
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Continued process verification during the lifecycle
“Subsequent to process validation and during commercial manufacture, companies should monitor product quality to ensure a state of control is maintained throughout the commercial part of the product lifecycle.
This will provide assurance of the continued capability of the process and controls to produce product that meets the desired quality and to identify changes that may improve product quality or performance”.
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Continuous Process Verification
Sufficient knowledge and understanding of the process is required to support continuous process verification
The regulatory submissions must include
• The suitability and feasibility of continuous process verification strategy
• Process parameters and analytical methods
The manufacturer needs to define the stage the product is considered validated, with justification.
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Continuous process verification
Detail and document the continuous process verification plan and rationale for what to verify.
What are the pre approved acceptance criteria for this verification?
Remember, these should be based on CQAs and CPPs
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Continuous process verification
Monitor product quality to ensure a state of control throughout commercial manufacture
Provides assurance of quality and identifies changes that might improve process – how will these changes be evaluated?
Relevant process trends will help verify the original process validation or identify changes to the control strategy
The extent and frequency of ongoing process validation should be reviewed. If appropriate, enhanced sampling & monitoring may help process understanding.
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Continuous process verification
Continuous verification should provide assurance that the process outputs are in a state of control and the process is stable.
• The level of verification will be based on the knowledge of the process and the control strategy feedback
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Activity – Continuous verification
• Discuss the question below with your groups
• Contribute to group discussion
Discuss the factors that may influence the data gathered during continuous
verification?
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Activity – Continuous verification
• Knowledge and understanding of product and process performance during the development phase
• The level of sophistication and complexity in the automation and in process controls
• Complexity and novelty of the product and process
• These all need to be defined and documented
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EMA Process Validation Guidance
• The assessment of a manufacturing process during a batch using on line and in process verification methods
• Continued process verification can be used to ‘augment’ or replace traditional process validation
Continued Process Verification
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Methods of manufacture
Non-standard MoM
• Specialised dose forms
• New technology in conventional processes
• Highly specialised or highly complex processes
• Non-standard methods of sterilisation
Highly specialised or highly complex
• Includes processes such as lyophilization and aseptic manufacture, real time release (parametric release)
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Standard v Non-standard MoM:
Needs to be justified on a “case-by-case” basis considering the appropriate development data or by reference to similar products.
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EMA process validation guidance
• Leverage development phase activities to drive product understanding and development of validation strategies
• Development phase activities may include:
Design space
Pilot scale production
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Similarities to the US FDA process validation guidance
• Incorporates product life cycle, QRM and efficient quality system practices (ICH Q8, Q9 & Q10)
• Emphasis on continued process verification through analysis of pre and post release data to provide confidence of an ongoing valid process
• Acknowledgement and provision of scope to emerging processing technologies, such as PAT, to assist the validation effort
• Enhanced detail to provide understanding of regulator expectation on what constitutes an appropriate validation effort
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Differences to the US FDA process validation guidance
EMA: “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.”
US FDA: “the collection and evaluation of data, from the process design stage throughout production, which establishes scientific evidence that a process is capable of consistently delivering quality product.”
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Differences to the US FDA process validation guidance
• The EMA draft guideline states “a minimum of three consecutive batches”, with justification to be provided (there are some exceptions to this statement).
• The US FDA guidance states that the number of batches must be sufficient to provide statistical confidence of the process. It is a subtle, but important distinction in the approaches.
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Impact of this Guide:
The EMA and the
Pharmaceutical Inspection
Cooperation Scheme (PIC/S)
are closely aligned.
PIC/S may adopt the guidance in full, or develop
its own guidance based on the
EMA document.
Regulatory guidance from the EMA has relevance for PIC/S aligned
countries.
