new annex 15 - gmp consultants, validation · eu gmp guide annex 15 ‘qualification &...
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New Annex 15 –Updated Requirements & Approach to ValidationPresented by Ashley Isbel10th August 2015
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EU GMP Guide Annex 15 ‘Qualification & Validation’2001 Current version of Annex 15 published
Nov 2012 Concept paper from the EMA outlined various reasons for the revision of Annex 15.
Feb 2014
Draft Annex was released for public comment
Mar 2015
Final version released
Oct 2015
Implementation in EU and automatic PIC/S adopters
??? TGA implementation has not yet been announced
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Drivers for the revision
Key drivers:
• ICH Q8, Q9, Q10, and Q11
‒ Indirectly, FDA process validation guidance
• Advancements in manufacturing technology (eg. PAT)
• Changes to other Chapters, Sections and Annexes
• Industry standard practice
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Drivers for the revision
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Overview of changes
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Overview of changes
Key Updates:
• Significant additional guidance on Planning and documentation • Added information on the qualification stages for equipment,
facilities
• Major revision for Process Validation
• Major revision for Cleaning Validation
• New topics added, including verification of transport and method validation
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Planning & Documentation for Qualification & Validation
8 clauses expanded to 18 in new Annex 15 – Focus on clarity and removal of ambiguity
Explicit permission to utilize vendor and third party testing and documentation – provided ‘appropriate personnel at the manufacturing site confirm suitability and compliance …’
Risk management approach mandated, including life cycle approach to risk assessment
Data integrity is also mentioned were ‘appropriate checks’ needs to be built into qualification and validation tasks ‘to ensure the integrity of all data obtained’
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Documentation & Qualification stages
Now Mandatory
Now expectedFor complex/novelsystems
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Process Validation
Annex 15 ‘required’ to be used with relevant’ PV guidelines
Explicit reference to all three phases described in FDA PV guidance (although little information on process development phase)
Detailed information on various aspects of PV – batch sizes, tech transfer, bracketing, use of CQA and CPP, etc.
Clear instructions on retrospective validation (no longer acceptable) and concurrent validation …
New section on ‘Ongoing Process Validation’ included (equivalent to ‘Continued Process Verification’ in FDA guidance.
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Process Validation
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Process Validation
Design Space
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New sections
Entirely new sections:
• Ongoing Process Verification during Lifecycle (phase 3)
• Verification of Transportation
• Validation of Packaging
• Qualification of Utilities
• Validation of Test Methods
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Cleaning Validation
‘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’
Risk Assessment
Meet Acceptance Criteria
ProofAppropriate Number
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Cleaning Validation
• ‘Visually clean’ not generally acceptable on its own
• ‘Limits should be based on a toxicological evaluation’ and refers to the EMA Guideline on setting health-based exposure limits.
‘Limits for the carryover of product residues should be based on a toxicological evaluation. The justification for the selected limits should be documented in a risk assessment which includes all the supporting references.’
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Cleaning Validation
‘Therapeutic macromolecules and peptides are known to degrade and denature when exposed to pH extremes and/or heat, and may become pharmacologically inactive.
A toxicological evaluation may therefore not be applicable in these circumstances. If it is not feasible to test for specific product residues, other representative parameters may be selected, e.g. total organic carbon (TOC) and conductivity’.
Also where a cleaning process is ineffective or is not appropriate for some equipment, ‘dedicated equipment or other appropriate measures should be used for each product’ .
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Cleaning Validation
• No longer looks for ‘3’ consecutive batches
• ‘Concurrent’ validation not acceptable for process, but may be acceptable, in some form, for cleaning validation.
‘It is recognised that a cleaning validation programme may take some time to complete and validation with verification after each batch may be required for some products’
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Take Home Points
New Annex 15 is more descriptive and has been developed with current industry behaviors in mind
Approach is easily aligned with 3 stage FDA PV guidance, while remaining easily relatable for current Annex 15 users.
For most companies, new requirements should not pose a dramatic shift
Instruction now available for activities previously not addressed
We are one step closer to harmonization …
Cleaning validation implementation is a significant challenge
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Thank you for your time.
Questions?
Ashley Isbel
Lead Consultant
www.pharmout.net