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Pharma Water Systems: Regulatory compliance, best practice & system qualification

Gordon FarquharsonMay 2019

3-May-19 ©2019

Water systems agenda?

n Pharma Water Systems: Regulatory compliance, best practice & system qualification:¨Regulatory requirements – what the GMPs say.¨Non-distillation WFI – Q&A paper & Draft Annex 1.¨Best sources of guidance.¨Applying Annex 15, and the 3-phase approach to PQ.

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Regulatory requirements –What the GMPs say

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Eudralex Vol iv – This is all we have today!n 3.43 Distilled, deionised and, where appropriate, other water pipes should

be sanitised according to written procedures that detail the action limits for microbiological contamination and the measures to be taken.

n Annex 1 - 59. Water treatment plants and distribution systems should be designed, constructed and maintained so as to ensure a reliable source of water of an appropriate quality. They should not be operated beyond their designed capacity. Water for injections should be produced, stored and distributed in a manner which prevents microbial growth, for example by constant circulation at a temperature above 70°C.

n 60. All equipment such as sterilisers, air handling and filtration systems, air vent and gas filters, water treatment, generation, storage and distribution systems should be subject to validation and planned maintenance; their return to use should be approved.

n 72. Water sources, water treatment equipment and treated water should be monitored regularly for chemical and biological contamination and, as appropriate, for endotoxins. Records should be maintained of the results of the monitoring and of any action taken.

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Lots more GMP Water regulatory guidance elsewhere

n EMA¨ 13th November 2018 Draft – Guideline on the quality of water

for pharmaceutical use n EMA/CHMP/CVMP/QWP/496873/2018 n Consultation ends 15th May 2019n Whole focus is on application of water quality specs from Ph.Eur

¨ Questions and answers on production of water for injections by non-distillation methods – reverse osmosis and biofilms and control strategies EMA/INS/GMP/443117/2017 GMP/GDP Inspectors Working Group.

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Lots more GMP Water regulatory guidance elsewhere

n WHO good manufacturing practices: water for pharmaceutical use -https://www.who.int/medicines/areas/quality_safety/quality_assurance/GMPWatePharmaceuticalUseTRS970Annex2.pdf

n What I always thought should be the bases of anEudralex Annex. Seems to be needed.

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Ph.Eur changes - impactn Ph.Eur Monographs (0169) & (1927)

¨Following a decision taken by the European Pharmacopoeia (Ph. Eur.) Commission at its 160th session (March 2018), the monograph for Water, highly purified (HPW) will be suppressed on 1 April 2019 from the Ph. Eur.

n Note: The monograph suppression is a consequence of the recent revision of the monograph for Water for injections (0169), which now allows for purification processes equivalent to distillation for producing water for injections (WFI), in addition to distillation. Hence, the HPW monograph is a duplication of the WFI monograph in terms of quality requirements and production methods, and as such became redundant.

n Therefore firms using references to (1927) HPV must manage this change.

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Non-distillation WFI

PhEur April 2017 & April 2019EMA Q&A paperDraft Annex 1 –New utility guidance

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Non-distillation WFI – a big deal !

n In EU/PIC-s we have a bit of a GMP vacuum at the moment.

n Worldwide many regulators simply don’t accept the principle of non-distillation based WFI production in spite of the EP, USP & JP accepting it.

n One MHRA inspector said distillation is more abusable! I would prefer to say more robust.

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Ph.Eur and the EMA GMP guidance

n Ph.Eur monograph (0169) brings the Ph. Eur. more closely in line with the US Pharmacopeia and the Japanese Pharmacopoeia which allow for production of WFI by distillation or a purification process proven being equal or superior to distillation, and by distillation or reverse osmosis followed by ultrafiltration, respectively.

n Any non-distillation technology for producing WFI should be equivalent in quality to that produced by distillation, where equivalence in quality does not simply mean compliance with a specification but also takes into account the robustness of the production method.

n This is why the ongoing general revision of Annex 1 ‘Manufacture of sterile medicinal products’ to the EU Good Manufacturing Practice (GMP) guidelines will include new guidance on production methods for WFI. In order to ensure the necessary guidance was available when the revised WFI monograph (0169)came into force, a Q&A document was published by the GMP/GMDP Inspectors Working Group of the EMA.

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Power of the regulator’s Q&A paper?n Why are these happening more & more?

¨A way of adding clarity to unclear requirements:n 2008 Annex 1 issues (PIC/S)n Non-distillation WFI ‘emergency’ patch post 2017 Ph.Eur

monograph change.¨Where updates are required before any planned

GMP revisions are completed.n e.g. the EMA/PIC-S processes can be slow – 5 years.

n Can they be cited during GMP inspections?n Where do the questions come from?

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The big issues at large

n Some of the EMA Q&A paper recommendations are highly controversial ¨Sanitizing techniques including steam sterilization.¨Use of real-time microbial detection in water (e.g. IMD-

W).n Dealing with the suppression of the HPW spec in

Ph.Eur.

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Best other sources of guidanceIndustry associationsISPE

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Industry association generated guidancen ISPE, PDA, etcn Most associations try to get some regulatory endorsement, but this

is getting more and more difficult.n Generally industry trying to develop and promote a consensus

position on how to achieve a high level GMP objective.n These guidance documents have a lot of detail and get out of date

quite quickly.n Latest ISPE Guidance (always check for the latest editions)

¨ Baseline® Guide vol 4 – Water & Steam Systems.¨ Good Practice Guide: Commissioning & Qualification of Pharma Water

& Steam Systems.¨ Good Practice Guide: Ozone Sanitization of Pharma Water Systems.¨ Good Practice Guide: Sampling Pharma Water, Steam, & Process

Gases

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Myths, fables, fantasies, traditionsn Loads out there!

¨ Traditions:n Weir type diaphragm valves are the only acceptable sanitary valves.

¨ Myths & fables:n WFI held at 80 oC is a requirement.n Sanitary pipe connections aren’t permitted; system must be fully

welded.n 6 pipe diameter ‘dead-legs’ are ok. They are not today.n Systems must be passified periodically.

n Fantasies¨ Biofilms are easy to remove.¨ Rouging (nice peoples rust) always causes a water quality problem.

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Water System Qualification

Annex 15The 3-Phase approach

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Qualification & Validation framework – Annex 15

n URSn Design Qualificationn Installation Qualificationn Operational Qualificationn Performance Qualificationn Process validationn Change Controln Regular Review (Annual system review)

n This presentation will not deal with all the normal qualification/validation steps. BUT focus on the special PQ for water systems

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Familiar V-Model applies

User Requirement(i.e What)

Functional Design(i.e. How as Schematic)

Detail Design(i.e How to make)

OperationalQualification

PerformanceQualificationPQ Test Plan

OQ Test Plan

IQ Test Plan

Implementation

(inc. PDI)

(inc. FAT)

Impact Assessment

Design Development

Installation Qualification

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Important background to the approach generally adopted.

n 3-phase approach - Promoted first by US FDA in their High Purity Water System Guidance.

n Endorsed by WHO in the WPU guidance.n Endorsed by ISPE Baseline® and Good Practice

Guides.n Generally applied in industry.

¨Long term tests of 12 months to demonstrate consistent system performance (seasonal variations).

¨Timings are somewhat flexible.

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PQ Programme

n Phase 1 -- typical duration 2-4 weeks

¨ Develop appropriate operating ranges

¨ Develop and finalise operating, cleaning and maintenance procedures

¨ Demonstrate production and delivery of product water of the required quality

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PQ Sampling -- Phase 1 (Slide 1)

n Sample after each step in treatment processn Sample at each point of usen Sample incoming feed water -- verify feed water

qualityn US FDA Water Guide suggests daily sampling --

alternate may be acceptable

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PQ Sampling -- Phase 1 (Slide 2)

n Chemistry testing specific to unit processn Microbiological testing for each unit processn At completion SOPs for operation, maintenance and

trouble shooting finalised

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PQ Test Programme -- Phase 1 (Slide 3)

n Alarm response/action levels verifiedn Test failure modes

¨Define failure events¨ Is failure localised? (specific location)¨Define handling of different failure types

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PQ Test Programme Objectives Phase 2

n Typical duration 2-4 weeks¨ Demonstrate consistent operation within established

ranges¨ Demonstrate consistent production and delivery of water

of the required quality when system operated to SOPs

n Sampling scheme / duration same as Phase 1

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PQ Sampling Program Objectives Phase 3

n Typical duration balance of one year¨Demonstrate extended performance

¨Ensure that potential seasonal variations are evaluated and treated

¨Sample locations, frequencies and tests based on established procedures

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Re-qualification n Important:

¨ We are not validating a batch process.¨ Water systems are continuous processes requiring on-going

system monitoring and water quality testing to verify the system is in control.

n We don’t need to requalify systems periodically.n Requalify all or part of systems after major system

changes - Determined via the change control processn Periodic revalidation/requalification is not requiredn Perform periodic system reviews

¨ Response to system feedback -- not revalidation -- is essential (perform regular review)

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And finally - Re-qualification examples n Replacing a system component – like for like.

¨ Limited testing.¨ Prove set-up and physical performance is re-established as for the original

component.¨ Instigate some additional relevant water quality testing (chemical & micro).¨ Go back into operation.

n Adding a user point to a system loop.¨ Controlled install.¨ Passivate, clean & fill.¨ Prove flow rate equivalent to before.¨ Test quality.¨ Go back into operation.

n Upgrading a system component.¨ Likely to have a bigger impact – depends on where and what is changed.¨ Assess risk.

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references

n Eudralex Vol iv relevant clauses.n Guideline on the quality of water for pharmaceutical use -

EMA/CHMP/CVMP/QWP/496873/2018n EMA Q&A Non-distillation WFI - EMA/INS/GMP/443117/2017 GMP/GDPn WHO - WHO good manufacturing practices: water for pharmaceutical use -

https://www.who.int/medicines/areas/quality_safety/quality_assurance/GMPWatePharmaceuticalUseTRS970Annex2.pdf

n Ph.Eur Monograph (0169) - 1st April 2017 – permitting non-distillation WFI.n Ph.Eur suppression of Monograph (1927) – 1st April 2017 – removes highly

purified water (HPV).n US FDA Guide to inspection of high purity water systems (7/93) 2002/2016.

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references n Advances in vapor compression technology for the production of

USP WFI. Gsell, Nunez, and Smith-Palmer. ISPE Pharmaceutical Engineering March/April 2013, Vol 33, N0 2.

n Methods of producing WFI. Brush and Zoccolante. ISPE Pharmaceutical Engineering July/August 2009, Vol 29, No 4.

n Water systems utilizing mutiple effect and vapor compression technologies compared. George Gsell. ISPE Pharmaceutical Engineering March/April 2004, Vol 24, No 2.

n EMEA (now EMA): Note for guidance on quality of water for pharmaceutical use. CPMP/QWP/158/01 & EMEA/CVMP/115/01; London May 2002.

n Reliability study for membrane processed WFI. Kojima, Okada, Sasaki, Oba, Fujise, Kusuyama. PDA Journal of GMP & Validation in Japan Vol 13, No 2; 2011.

n Background document for revision of monograph Water for injections (0169), based on the Reflection Paper endorsed by the European Pharmacopoeia Commission at its 146th Session, June 2013.

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This presentation has been preparedand delivered by:-

Gordon J FarquharsonPrincipal

Critical Systems LtdConsulting in Safety & Quality Critical Systems

Guildford, Surrey, UKtel +44 (0)1252 703 663

gjf@critical-systems.co.ukwww.critical-systems.co.uk

3-May-19 ©2019

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