EU Guidance / Q&A. Greg McGurk, GMP Manager (acting) GMP Conference. 7 February 2017 Dublin

Transcription

1 EU Guidance / Q&A Greg McGurk, GMP Manager (acting) GMP Conference 7 February 2017 Dublin

2 TPN Manufacture Q&A

3 TPN Guidance Proposed at IWG that working group be formed to draft guidance Several adverse events associated with total parenteral nutrition (TPN) manufacture in various EU member states which have resulted in patient harm or in some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

4 TPN Guidance TPN Guidance Collaborative work programme Ireland, UK, France, & Denmark Aim to provide some consistency in approach within EU

5 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,

6 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

7 TPN Guidance Process design Visual inspection Labelling QA Release & distribution Stability Q&A document developed Awaiting guidance from GMDPIWG on next steps

8 Production of WFI through RO & Biofilm Q&A

9 Production of WFI by non-distillation method (Reverse Osmosis) Revision to WFI Monograph 169 (proposed wording) 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

10 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)

11 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

12 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

13 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 Q for finalization of draft and publication on EMA website

14 Sterilisation of Primary Packaging

15 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

16 Sterilisation of primary packaging Supporting documentation for such variations: Certification that the sterilisation has been conducted and validated in accordance with the following applicable ISO standards: I.S. EN ISO 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 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 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 Sterilization of health care products -- Moist heat I.S. EN ISO 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 Sterilization of Health Care Products - Radiation - Part 2: Establishing the Sterilization Dose I.S. EN ISO Sterilization of Health Care Products - Radiation - Part 3: Guidance on Dosimetric Aspects

17 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

18 Disinfectant Efficacy

19 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

20 Disinfectant Efficacy studies EN 1276 / EN EN Chemical Disinfectants and Antiseptics - Quantitative suspension test for the evaluation of bactericidal activity of chemical disinfectants used in food, industrial, domestic and institutional areas Evaluation of sporicidal activity of chemical disinfectants EN 1650 / EN EN EN Evaluation of fungicidal activity of chemical disinfectants Quantitative suspension test for the evaluation of virucidal activity of chemical disinfectants and antiseptics used in human medicine Bactericidal EN Yeasticidal

21 Disinfectant Efficacy studies EN 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 Quantitative test method for the evaluation of bactericidal and yeasticidal activity on non- porous surfaces with mechanical action employing wipes in the medical area

22 Disinfectant Efficacy studies Parameters that may be modified: Contact time Organisms Water quality Temperature Surfaces Acceptance criteria Inoculum

23 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 (Surface) - Fungi - 3 log, Bacteria - 4 log EN (Suspension) - Spores 3 log USP <1072> (Surface) - Bacteria - 3 log, Spores - 2 log PDA 1 log

24 Aseptic Process Risk Assessment

25 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

26 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

27 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

28 Questions