eu guidance / q&a - etouches · pdf fileireland, uk, france & hungary part i...
TRANSCRIPT
EU Guidance / Q&A
Greg McGurk, GMP Manager (acting)
GMP Conference
7 February 2017
Dublin
TPN Manufacture Q&A
TPN Guidance
Proposed at IWG that working group be formed to draft guidance
Several adverse events associated with total parenteral nutrition
(TPN) manufacture in various EU member states which have
resulted in patient harm or in some instances patient deaths
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TPN Guidance
• Collaborative work programme
• Ireland, UK, France, & Denmark
• Aim to provide some consistency in
approach within EU
TPN Guidance
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TPN Guidance
Order receipt & Verification
Minimisation of errors – order entry, verification, manufacture, picking, quality checks, batch
release etc
Documentation – batch and orders
Sanitisation – transfer of materials for processing
VHP surface decontamination
Isolators – Physical controls, transfer hatches, RTPs / DPTEs,
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TPN Guidance
Area classification
Environmental monitoring
Controls for Manual additions
Controls for automated systems
Electrolyte QC Testing
Process simulations / media fills
Sterility testing
Manufacturing process controls – pooling
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TPN Guidance
Process design
Visual inspection
Labelling
QA Release & distribution
Stability
Q&A document developed – Awaiting guidance from GMDPIWG on next steps
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Production of WFI through RO &
Biofilm Q&A
Production of WFI by non-distillation
method (Reverse Osmosis)
• It is produced either :
• by distillation .....
• by reverse osmosis, which may be single-pass or double-pass, coupled with
other suitable techniques such as deionisation and/or ultrafiltration
• Correct operation monitoring and maintenance of the system are essential
• In order to ensure the appropriate quality of the water, validated procedures, in
process monitoring of the electrical conductivity, and regular total organic
carbon and microbial monitoring are applied
Revision to WFI Monograph 169 (proposed wording)
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Production of WFI by non-distillation method
Production of WFI by non-distillation (Reverse Osmosis) &
Biofilm Q&A guidance document
Q&A developed to take account of concerns and expectations
Ireland, UK, France & Hungary
Part I – Production of WFI by non-distillation methods (RO)
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Production of WFI by non-distillation method
Concerns regarding production by non-distillation methods
System Design considerations – Control strategy; Materials of Construction; Pre-Treatment; RO
Membranes; Nanotechnology; Electrodeionisation; Ultra-Filtration; TOC; Conductivity
Sanitisation
Qualification
Sampling and testing requirements
Preventative Maintenance
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Biofilm
Part II of Q&A deals more specifically with Biofilms and control strategies
Overview of Biofilms and their development
Control strategy
Removal of established biofilm
Chemical sanitising agents & Physical methods for cleaning
Detectability of Biofilms
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Q&A Production of WFI by non-distillation method (RO) &
Biofilm Control
Q&A developed and issued for public consultation
Deadline – 29th November 2016
Comments received and under review
Q2 – Q3 2017 for finalization of draft and publication on
EMA website
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Sterilisation of Primary Packaging
Sterilisation of primary packaging
Sterilisation of Primary packaging, used during aseptic processing of the finished product, is a critical process and
the sterility of the primary container is a critical quality attribute to ensure the sterility of the finished product
Not all sites performing sterilisation need be GMP certified by an EU authority
Only those sites involved in terminal sterilisation of API, Excipients and finished product – MIA and / or GMP
certification
Sites performing sterilisation of primary packaging are still expected to be named on the relevant MIA and IMP
authorisations
Variations to MIA and IMP Authorisations, where EU GMP certification is unavailable, to include additional
supporting documentation
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Sterilisation of primary packaging
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• Certification that the sterilisation has been conducted and validated in accordance with the
following applicable ISO standards:
• I.S. EN ISO 20857 Sterilization of Health Care Products - dry Heat - Requirements for the
Development, Validation and Routine Control of a Sterilization Process for Medical Devices
• I.S. EN ISO 11135 Sterilization of Health-care Products - Ethylene Oxide - Requirements for the
Development, Validation and Routine Control of a Sterilization Process for Medical Devices
• I.S. EN ISO 17665-1 Sterilization of Health Care Products - Moist Heat - Part 1: Requirements for
the Development, Validation and Routine Control of a Sterilization Process for Medical Devices,
and, ISO/TS 17665-2 Sterilization of health care products -- Moist heat
• I.S. EN ISO 11137-1 Sterilization of Health Care Products - Radiation - Part 1: Requirements for
Development, Validation and Routine Control of a Sterilization Process for Medical Devices
• I.S. EN ISO 11137-2 Sterilization of Health Care Products - Radiation - Part 2: Establishing the
Sterilization Dose
• I.S. EN ISO 11137-3 Sterilization of Health Care Products - Radiation - Part 3: Guidance on
Dosimetric Aspects.
Supporting documentation for such variations:
Sterilisation of primary packaging
Supporting Documentation:
QP declaration
Audit report may be requested as supporting documentation
Additional points to consider:
Site must satisfy themselves that the process for sterilisation and the controls in place at CMO are maintained.
Validation documentation to be made available during inspection , if requested
Robust system in place to confirm the sterility of the packaging components
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Disinfectant Efficacy
Disinfectant Efficacy studies
Leverage data from Vendor regarding initial contact times
Assess various surfaces with environmental isolates
Consider end of shelf-life studies
In use shelf life to be assessed
Grade A & B – Sterile
Monitoring programme
Detailed SOPs for sanitisation – effectiveness assessed
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Disinfectant Efficacy studies
•Chemical Disinfectants and Antiseptics - Quantitative suspension test for the evaluation of bactericidal activity of chemical disinfectants used in food, industrial, domestic and institutional areas
EN 1276 / EN 13697
•Evaluation of sporicidal activity of chemical disinfectants EN 13704
•Evaluation of fungicidal activity of chemical disinfectants EN 1650 / EN 13697
•Quantitative suspension test for the evaluation of virucidal activity of chemical disinfectants and antiseptics used in human medicine
EN 14476
•BactericidalEN 16615
•YeasticidalEN 16615
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Disinfectant Efficacy studies
EN 13697 – Chemical Disinfectants and Antiseptics - Quantitative non-porous
surface test for the evaluation of bactericidal and/or fungicidal activity of
chemical disinfectants used in food, industrial, domestic and institutional areas
NOTE: there is currently no approved surface test method for sporicidal
activity
EN 16615- Quantitative test method for the evaluation of bactericidal and
yeasticidal activity on non- porous surfaces with mechanical action employing
wipes in the medical area
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Disinfectant Efficacy studies
• Contact time
• Organisms
• Water quality
• Temperature
• Surfaces
• Acceptance criteria
• Inoculum
Parameters that may be modified:
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Disinfectant Efficacy studies
A lower log reduction than that specified by the standards
may be acceptable in practice. Acceptance criteria should
be set accordingly and appropriately justified
Typically
• EN 13697 (Surface) - Fungi - 3 log , Bacteria - 4 log
• EN 13704 (Suspension) - Spores – 3 log
• USP <1072> (Surface) - Bacteria - 3 log, Spores - 2 log
• PDA – 1 log
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Aseptic Process Risk Assessment
Aseptic Process Risk Assessment
Use of SMEs
Include Microbiologist
Round table discussions
Observe & critically assess process and control measures
Do not play down the severity rating
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Aseptic Process Risk Assessment
Do not increase the level of detection rating if the issue has
poor or no detectability
Do not decrease the probability of occurrence rating if there is
a trend of the issue occurring. State the facts
Use data where possible to justify
It is better to identify the problem early and fix it
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Aseptic Process Risk Assessment
Environmental Monitoring does not reduce the risk
Identify and acknowledge the fact that risks exist
Goal is to assess those risks not to accept them
Reassessment strategy
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Questions