eu guidance / q&a...production of wfi by non-distillation method production of wfi by...

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Proposed at IWG that working group be formed to draft guidance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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• 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


• 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


• 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:


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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•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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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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• Contact time

• Organisms

• Water quality

• Temperature

• Surfaces

• Acceptance criteria

• Inoculum

Parameters that may be modified:

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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


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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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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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

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