LGC CPhI 2015 presentation Dr Christian Zeine - Amazon S3 · PDF fileWhat are primary (reference) standards? • Pharmaceutical context: Primary reference standard is a standard whichstandard

Reference standards in Pharma QC: Limitations of pharmacopoeial materials,p p ,and alternative solutions

Christian Zeine CPhI Madrid 14 October 2015Christian Zeine, CPhI Madrid, 14 October 2015

ScienceSciencefor a safer world

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Topics of today‘s talkTopics of today s talk

• Background

• What are primary standards? And how are they used?

• What are the advantages of LGC‘s primary standards?

• Special cases: Impurity standards

• Final remarks

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Background: Official pharmacopoeial

• From BP EP USP and others

reference standards

• From BP, EP, USP and others

– Are „special“ primary standardsAre „special primary standards• From an officially recognised source• Can be used without further testing

A id l t d• Are widely accepted

– But ...• No certificates of analysis, no expiry dates,

restricted application only• For claiming official status, must be used as mentioned in theo c a g o c a status, ust be used as e t o ed t e

pharmacopoeial methods• Otherwise no official status anymore,

responsibility lies with user, andresponsibility lies with user, andpharmacopoeia commissions reject responsibility

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Background: Official pharmacopoeialreference standards

• Limitations to the official status

– USP General Chapter <11> :• „When approved as suitable for use … in the USP, USP RS also

assume official status and legal recognition in the US. Assessmentg gof the suitability for use in other applications rests with the user."

– General text 5 12 Ph Eur :General text 5.12., Ph. Eur.:• „If a European Pharmacopoeia reference standard is to be used for

any purpose other than that for which it has been established, its suitability for the new use has to be fully demonstrated Anysuitability for the new use has to be fully demonstrated ... . Any value assigned to a reference standard is valid for the intended use and not necessarily for other uses."

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Worst case possible:Overreaction of regulation authority

• Client asked if we can provide further identity data forreference standard from pharmacopeiareference standard from pharmacopeia

– Reason: RS was used for non-official purposeReason: RS was used for non official purpose– German BfArM did not acknowledge official status of

pharmacopeia standard for client‘s purpose– Demand of additional identity data (CofA)– Pharmacopeia refused to disclose data (according to policy)

• First time we saw a pharmacopeial materialchallenged for its identity by regulatory bodyg y y g y y

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Background: Official pharmacopoeialreference standards

• What to do when the official standards do not work?What to do when the official standards do not work?

• See ICH Q7 (GMP Guide):( )– Quote:

Where a primary reference standard is not available from an officially recognized source an “in house primary standard”officially recognized source, an in-house primary standard should be established.(Guideline Q7, GMP Guide for Active Pharmaceutical I di t )Ingredients)

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• Background




• Final remarks

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What are primary (reference) standards?What are primary (reference) standards?

• Pharmaceutical context: Primary reference standard is a standard whichstandard which …– … properties (usually identity, very often also purity/assay

values) have been extensively characterized

• It is set up without comparison to any other standard of the same kindthe same kind

• Basically in pharmaceutical quality controlBasically, in pharmaceutical quality control, measurements in release testing (e.g. of finished dosage forms) need to be traceable to a primary standard ) y

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What are primary (reference) standards?What are primary (reference) standards?

• Traceability to a primary standard means, in simple y p y pterms:– For the measurement of the item to be released (the API itself, or

a medicine containing the API) the calibration of thea medicine containing the API) the calibration of the measurement system must relate back to the primary standard

• Can be done by using the primary standard itself for that calibration– Or by using a secondary standard, that was compared to the

primary one

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What are primary (reference) standards?at a e p a y ( e e e ce) sta da ds

• Definitions ICH (Guideline Q7 GMP Guide for Active• Definitions ICH (Guideline Q7, GMP Guide for Active Pharmaceutical Ingredients)

– Reference Standard, Primary• A substance that has been shown by an extensive set of analytical

tests to be authentic material that should be of high purity. This standard can be: (1) obtained from an officially recognised source, or(2) prepared by independent synthesis, or(3) obtained from existing production material of high purity or(3) obtained from existing production material of high purity, or(4) prepared by further purification of existing production material.

– Reference Standard SecondaryReference Standard, Secondary• A substance of established quality and purity, as shown by

comparison to a primary reference standard, used as a reference standard for routine laboratory analysis.y y

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What are primary (reference) standards?at a e p a y ( e e e ce) sta da ds

• Obtained from an officially recognised source? Whatdoes that mean?

– No specification in ICH Q7 directly– Official pharmacopoeial commissions:

United States Pharmacopeia (USP), European Pharmacopoeia,British Pharmacopoeia etc.

– FDA quotation:Reference standards can often be obtained from the USP and may also be available through the European Pharmacopoeia, Japanese Pharmacopoeia, World Health Organization, or National Institute of Standards and Technology.(FDA Guidance for Industry on Analytical Procedures and Methods Validation for Drugs and Biologics July 2015)Biologics, July 2015)

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How are they used?o a e t ey used

• First answer: Should be used correctly, as much aspossible!

• And that is only half a joke really!

• Primary standards can come …– … from the official sources

• But there are pitfalls with those from the official sources, remember slides seen before!remember slides seen before!– Also: Do not use official identity standards

for own quantitative methods– Consider independent sources, like LGC

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• Background




• Final remarks

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What are the advantages ofLGC‘s primary standards?

• Compared to official pharmacopeial standards:

– Detailed certificate of analysis (CofA), see next slides• Satisfying EP recommendations for primary standards• Developed with top pharmaceutical manufacturersDeveloped with top pharmaceutical manufacturers

– Much more suitable for universal use:A i t b b l t l ti l t h i ( NMR• Assay assignment by an absolute analytical technique (qNMRwhenever possible)

• qNMR specificity close to that of 100% method• Assay assigning technique is also accredited under

ISO specifications

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What are the advantages of

• Compared to other standard

LGC‘s primary standards?Compared to other standardmanufacturers / vendors:

– First one with catalogue rangefor primary standards

– We really know this business!

– Our production site:• Accredited to ISO Guide 34 and

ISO/IEC 17025:„Comparable“ to GMP resp. GLP for theproduction of reference materials

• Successfully audited by multiple top pharmaceutical companiesSuccessfully audited by multiple top pharmaceutical companies

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What are the advantages ofLGC‘ i t d d ?LGC‘s primary standards?

• Recommended approach for primary RS (see also EP G l t t 5 12 h 4 1 ) f ll dEP General text 5.12., paragraph 4-1.), followedclosely by LGC‘s primary standards

– Full characterization and documentation of• Identity (with several qualitative techniques: NMR, MS, IR,

UV/VIS, elemental analysis (CHN), further if necessary)• Purity (with HPLC => impurity profile)

... continued

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What are the advantages ofLGC‘ i t d d ?LGC‘s primary standards?

• Recommended approach for primary RS (continued)

– Full characterization and documentation of• Residual solvents by GC-Headspace methodsResidual solvents by GC Headspace methods• Water content by Karl-Fischer titration• Loss on drying (sum of water and residual solvents)

M lti i t ( h it /id tit i f ti )• Melting point (rough purity/identity information)• Sulphated Ash (inorganic impurities)

• Assay, for primary RSs from purity calculation (with the resultsfrom all relevant examinations) plus at least one additional independent method (e.g. qNMR, titration), other approachesaccepted as well

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Certificates – Primary pharmaceutical reference standards

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• Background




• Final remarks

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Impurity reference standardsImpurity reference standards

• The facts stated before also apply to the impuritystandards from pharmacopoeias

Al ffi i l i t d d– Also official primary standards– With the same limitations as mentioned before

(remember case study from start of lecture)( y )– So also here, use of a more universal standard with detailed

CofA makes sense

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Remember: Worst case possibleRemember: Worst case possible

• Client asked if we can provide further identity data forreference standard from pharmacopeiareference standard from pharmacopeia

– Reason: RS was used for non-official purposeReason: RS was used for non official purpose– German BfArM did not acknowledge official status of

pharmacopeia standard for client‘s purpose– Demand of additional identity data (CofA)– Pharmacopeia refused to disclose data (according to policy)

• First time we saw a pharmacopeial materialchallenged for its identity by regulatory bodyg y y g y y

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Impurity reference standardsImpurity reference standards

• Further things to keep in mind

ICH id li i iti t id dditi ll t– ICH guidelines on impurities to consider additionally torelated substances testing in monographs (not discussed today)

• Often not enough to test just according to the monographsg j g g• Additional testing on impurities required

– Change of pharmacopoeial monographs– Change of pharmacopoeial monographs• Risk of unavailability of impurity standard (see next two slides)

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Pharmacopoeial monograph changesPharmacopoeial monograph changes

• Monographs are constantly developing– Normally due to technical progress– Or regulatory changes

• At the same time, pharmacopoeias accomodate their sourcing issues for impurities theresourcing issues for impurities there– Diminishing the unit sizes– Switch from neat materials to materials like ‘XY for peakSwitch from neat materials to materials like XY for peak

identification / system suitability’– See examples next slide

• So, best not to specify explicitly USP / EP neat impurity standards in your dossier until you have to

Wh t d d i t id d i ht f i– When standard is not provided any more, you might face issues when specified in your non-pharmacopoeial method 32

Pharmacopoeial monograph changesPharmacopoeial monograph changes

• Examples for diminishing unit sizes / withdrawn materialsExamples for diminishing unit sizes / withdrawn materials

– First 25 reference standards from European Pharmacopoeia from catalogue no. 40 (issued 2004), compared to material currently available

• Acebutolol Imp I, from 20 mg (neat) to 0.004 mg (‘lyophilised’)p , g ( ) g ( y p )• Aceclofenac Imp F, from 50 mg to 20 mg (both neat)• Aceclofenac Imp H, from 25 mg to 10 mg (both neat)

Aciclovir Imp A 30 mg (neat) withdrawn replaced by peak• Aciclovir Imp A 30 mg (neat), withdrawn, replaced by peak identification and system suitability mixtures (‘lyophilised’)

– Extrapolation over the whole EP range (approx. 1650 CRS in 2004) ld lt ( ti hi h t i t !) iwould result (caution, high uncertainty!) in

• 198 impurity standards with diminished unit sizes• 66 impurity standards being withdrawn

– How to ract to these „threats“? Consider safe supply with impuritystandards from LGC, with detailed CofA! 33

CofA: Impurity RSCofA: Impurity RS

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Why replacement with LGC d t ?

• Experienced manufacturer of reference standards

products?

– First hand data from our customersthrough customised projects20+ years experience in reference standards manufacturing– 20+ years experience in reference standards manufacturing

• Unique position as National Metrology Institute in theq p gyUK for chemistry and biochemistry– Experiences and philosophies from that function

t i t f b ienter in any part of our business processes

• Attractive discount scheme in placeAttractive discount scheme in placefor range of primary standards, storing options (warehouse) possible!– See also customised services at end

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For whom can thisi f ti b f i t t?• The quality control (product release testing)

information be of interest?

department– The stability testing department– The analytical R&D department– The analytical validation department (often incorporated in

the R&D group)t e & g oup)– The regulatory department– The purchase department

• Of major / minor pharmaceutical (generics) manufacturermanufacturer– Of contract manufacturer organistions (CMOs)– Of contract research organisations (CROs)O co t act esea c o ga sat o s (C Os)– Of analytical contract laboratories

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Closing remarksClosing remarks

• LGC Standards is part of LGC group

S i & I ti ti• Science & Innovation section of LGC acts as NMI for chemical and biochemicalfor chemical and biochemical measurement in the UK (comparable to NIST in the US)( p )

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Closing remarksClosing remarks• Manufacturing of pharmaceutical reference materials

F API d i iti 3 500 t d d– For APIs and impurities, approx. 3,500 standards– Constantly new developments (e.g. primary standards)

• Brochure of 320 impurity standards available with reference to p ythe USP description, in most cases less expensive price-per-mg compared to USP, plus the CofA!

– ISO 34 and ISO 17025 accreditedISO 34 and ISO 17025 accredited– Customised services

• Production of solvents– For HPLC applications in pharma

industryE t l f id l i– Extremely pure for residue analysis

• DistributionPharmacopoeial reference standards phytochemical materials– Pharmacopoeial reference standards, phytochemical materials

– CRMs/RMs from LGC, IRMM, NMIA, NIST etc. for all purposes 38

Service modules

Process steps based on internal quality standards; ISO 17025 or ISO Guide 34

1 2 3 4 5 6 7 8Sourcing Quality

ControlRAW-

material Packaging Characte-risation

Certifi-cation Storage Distribution

Supplementary processes for stability monitoring and re-testing

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S i f t h ti lServices for two pharmaceutical World Top 10 companiesp p

1 2 3 4 5 6 7 81Sourcing Quality

ControlRAW-

material

4Packaging Characte-

risationCertifi-cation

7Storage

8Distribution

1Sourcing

2Quality Control

3RAW-

material

4Packaging

5 Characte-

risation

6 Certifi-cation

7Storage

8Distribution

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Services over the whole chain1

Sourcing

2Quality Control

3RAW-

material

4Packaging

5Characte-

risation

6Certifi-cation

7Storage

8Distribution

St Qability

Monit+

C

BatchMonito+o

ring

+ oring+

• For several top generic / ethical companies• Depending on the extent of the service, price per unit canp g p p

go down to less than 30 EURO41

THANK YOU!THANK YOU!QUESTIONS?• christian zeine@lgcgroup com• [email protected]• At our LGC booth, 3G101,

today from 16 30 to end of daytoday from 16.30 to end of day

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Documents

LGC CPhI 2015 presentation Dr Christian Zeine - Amazon S3 · PDF fileWhat are primary (reference) standards? • Pharmaceutical context: Primary reference standard is a standard whichstandard