3a Buda Mihaela

8/16/2019 3a Buda Mihaela

http://slidepdf.com/reader/full/3a-buda-mihaela 1/25

Update on the Revision of thePh. Eur. Water for Injections

Monograph

Dr Mihaela Buda

European Pharmacopoeia Department,EDQM, Council of Europe

M. Buda, PDA Pharmaceutical Microbiology, Berlin, 17-18 February 2015 ©2015 EDQM, Council of Europe. All rights reserved. 1



Points to be addressed

q Introductionq History Water for Injections (WFI)

q Ph. Eur. actions

Ø Data gathering: use of membrane technologiesØ Reflection Paper: RO and WFI

Ø Revision of WFI monograph (0169)

q Current status

q Conclusion, timelines

2M. Buda, PDA Pharmaceutical Microbiology, Berlin, 17-18 February 2015 ©2015 EDQM, Council of Europe. All rights reserved.



Ph. Eur. WAT Monographs (1/2)

3

Water, purified(Ph. Eur. 0008)

PW

Water for Injections(Ph. Eur. 0169)

WFI

Water, highly purified (Ph. Eur. 1927)

HPW

Other:

Water for diluting concentrated haemodialysis solutions (Ph. Eur. 1167)

Water ( 15 O) injection (Ph. Eur. 1582)

Tritiated ( 3

H) water for injection (Ph. Eur. 0112)

M. Buda, PDA Pharmaceutical Microbiology, Berlin, 17-18 February 2015 ©2015 EDQM, Council of Europe. All rights reserved.



Ph. Eur. WAT Monographs (2/2)

4

Water, purified

(Ph. Eur. 0008)PW

Water for Injections

(Ph. Eur. 0169)WFI

Water, highly purified

(Ph. Eur. 1927)HPW

Ø for preparation ofmedicines other thanthose that are requiredto be both sterile andapyrogenic, unlessotherwise justified andauthorised

Ø for preparation ofmedicines for parenteraladministration (bulk WFI)and for dissolving ordiluting substances /preparations for parenteraladministration (SWFI)

Ø intended for use wherewater of high biologicalquality is needed,except where WFI isrequired

• distillation• ion exchange

• reverse osmosis• any other suitable

method

• distillation only • double-pass reverseosmosis coupled with

other suitabletechniques such asultrafiltration anddeionisation






q Ph. Eur. actions



q Current status





History Water for Injections (WFI) (1/3)

6

19971973

1983

Ph. Eur. 2nd Edition, 5th Add. – WFIRevision: editorial changes (bulk WFI / sterile WFI)

Distillation only

Ph. Eur. 3rd Edition – WFIRevision: replacement of in vivo

Pyrogens test by LAL (sterile WFI)

1969

Ph. Eur. 1st EditionPu r if ied W a te r

physico-chemical tests

1st Publication WFI

Distillation only

First discussions on RO (double pass):• limited experience• membranes robustness, microbiological control• potential impurities – not detectable by standard methods• no data available from systems using membrane

technique for producing WFI




Ph. Eur. 3rd Edition (Suppl.)

Revision: Production section(Bioburden, TOC, Conductivity)

2000


7

2002

Revision initiated:

further guidance to

allow closer monitoringof the production

1999

Renewed discussions on RO

International Symposium:Need for data & guidance

No evidence to support RO asproduction method for WFI

HighlyPurifiedWater(HPW)

Ph. Eur. 4th Edition

HPW – new monograph

WFI – no modification Adoption by CHMP/CVMP ofNote for Guidance on Quality ofWater for Pharmaceutical Use




8

ü 3 monographs with clear

specifications ü Guidance for use of

different water grades

2008


Regulatory event:

RO used for producing WFI

EMEA/CVMP/2934/2009

Reflection paper on WFIprepared by RO

EMEA/CHMP/CVMP/QWP/28271/2008

Concerns from regulators – Biofilm& microbiological safety

2009 – 135th SessionPh. Eur. Commission:Ph. Eur. requested totake the lead






q Ph. Eur. actions



q Current status





Ph. Eur. Actions: Phase 1

10

Ø Format: questions (supportive data)

• Range of separation for RO

• Validation of production system• Maintenance of production system

• Biofilm formation

• Membrane efficiency

• Additional tests

Objective: GATHER DATA for use ofnon-distillation technologies for

producing water of WFI qualityØ HOW? A survey

Ø Key elements:

• Participation of a maximum number ofcompanies

• Sharing of information and opendiscussion

Survey

2010

Ø OUTCOME:

• data focused on: bioburden,

TOC, conductivity andendotoxins

• no data for other physico-chemical parameters




Ph. Eur. Actions: Phase 1/ Assessment

11

Survey

2010

Ø In favour (statements from companies)

• RO not sufficient – part of purification pathway

• Additional purification modules

• Consider production and distribution systems

• Regular sanitisation needed

• Validation is achievable

Ø Systems used - large diversity:• Degasifier + Water softener + microfiltration + UF

• Filtration + Water softener + RO + EDI + UF

• Water softener + RO + EDI + membrane degasification + UF

• Water softener + microfiltration + (x3)RO

• Double pass RO




Ph. Eur. Actions: Phase 1/Compilation

12

Survey

2010

RO + additional purification modules: whatever the design of thesystem reported, all produce a water meeting current specificationsfor WFI established

Parameter Estimated value

Bioburden 10 CFU / 100 mL

TOC 50 to 350 ppb

Conductivity 0.5 to 2.5 µS.cm-1

Endotoxins 0.25 EU/mL


Ph E A ti Ph 2



Position of the Ph. Eur.Commission:ü Progress in the field of pharmaceutical

water production was acknowledged andhas to be considered.

ü Commission gave mandate to the Ph. Eur.Water Working Party

t o r e v iew the

p roduc t i on sec t i on of the Water forInjection monograph (0169) to considerthe inclusion of currently availabletechnologies and evaluate whetheradditional online monitoring is needed.”(Press Release November 2011, 141st Session Ph.Eur. Commission)

OBJECTIVE:

• Sufficient data to re-open the debate inorder to introduce non-distillationsystems for WFI production?

• Built communication channels.

• Discussion platform for regulatorsand companies.

• Possible need to initiate a revision ofWFI monograph?


Summary report of the Expert Workshop organised by the EDQM in March 2011

Survey2010

ExpertWorkshop

2011,

EDQM


Ph E A ti Ph 3




Survey2010

ExpertWorkshop

2011

Ph. Eur.WAT WP

Points for further consideration

§ WFI monograph (0169):Ø Can non d i s t il la t i on techn iques be

cons ide red sa fe enough ?

- Current parameters: adapted to non-distillation techniques?

- Change/Update limits for existing parameters?- Add new parameters?

- Include new control methods?

- Modify/Update existing control methods?

§ Impact on other water monographsØ Ph. Eur. 0008 – Purified water

Ø Ph. Eur. 1927 – Highly purified water

(Ph. Eur. WAT WP, 2013)




Reflection Paper on WFI (1/2)

15

ü summarises current status of alternative methods forproducing water of WFI quality, based on scientific datareceived from the enquiry on non-distillation technologies

ü reviews all evidence to support a revision of the WFImonograph to allow non-distillation technologies forproducing WFI to be included in addition to distillation




Reflection Paper on WFI (2/2)

16

Ø recognises concerns about microbiological safetyà not necessarily an issue, provided that microorganisms aresuitably controlled and final quality of water is appropriate:

• Properly operated membrane systems

• Initial water pre-treatment

• Additional purification modules

• System designs to minimise biofilm formation

• Regular maintenance/sanitisation

• Continuous in-process control, fixed interval sampling

• Continuous measurement of physico-chemical parameters (TOC,conductivity, temperature, pressure) à risk mitigation

(based on general statements from companies )




WFI monograph (0169)- Request for Revision-

17

146th Session of the European Pharmacopoeia Commission,June 2013

ü Endorsement of Reflection Paper on WFI

ü Agreement to work on the revision of the monograph on W ate r fo r

in jec t ions

(0169) (WFI) to allow non-distillation technologies for theproduction of WFI to be included in addition to distillation

ü Acknowledgement that design, failure mode and maintenance of waterproduction systems play an important role in ensuring that appropriate waterquality is established and maintained

necess i ty to d i scuss ro les and

r e spons ib i li t i es w i th GM P / GDP In spec tor s W o rk i ng G roup and J o i n t

C H MP / C VMP Q ua li ty W o rk i n g P a rt y






q Ph. Eur. actions



q Current status





Water for Injections (0169)cu r ren t s t a tus

19

Ph. Eur.WFI monograph

•

Quality standard• Defines quality of WFI in terms of microbiological and

physico-chemical requirements

PRODUCTIONsection

revision:

Ø include reverse osmosis coupled with suitabletechniques for producing WFI in addition todistillation;

Ø a requirement for ‘regular total organic carbonmonitoring ’ is added to further emphasise thespecific test controls required.

System design,operation, maintenance

(validation and monitoring)

→GM P r equ ir emen t s

Consequence: Highly Purified Water (1927) → deleted from Ph. Eur.


R i i WFI M h



L ia i son with work undertaken by the GMP/GDP InspectorsWorking Group with a view to updating the GMP guidance

Revision WFI Monograph





‘…changes that may require n e w

G M P g u id an ce include those forthe revision to the Ph. Eur.monograph on methods otherthan distillation for theproduction of water for injection.’

Concept paper on the revision of annex 1 of the guidelineson good manufacturing practice – manufacture of sterilemedicinal products (EMA/INS/GMP/735037/2014)

Re ision WFI Timelines



22

European Pharmacopeia CommissionDecision on work program – 146th Session, June 2013

WAT Working PartyPreparation of draft revision – 7th Meeting, October 2014

Public consultation on Pharmeuropa 27.2 (April 2015)(Comments by 30 June 2015)

Revision WFI – Timelines (2/3)




23

I. Revised WFI monograph(with Explanatory Note)

II.Reve r se Osm os i s f o r P roduc t i on o f W FI

(supportive document for monograph revision)


Revision WFI Timelines



24

Public consultation on Pharmeuropa 27.2 (April 2015)(Comments by 30 June 2015)

WAT Working PartyExamination of comments

European Pharmacopeia Commission Adoption (implementation 1 year after)

Revision WFI – Timelines (3/3)




Acknowledgments

25

• Ph. Eur. WAT Working Party• Dr Ged Lee, Chair of the Ph. Eur. WAT Working Party

• Dr Stephen Wicks, EDQM

3a Buda Mihaela

Documents

Transcript of 3a Buda Mihaela