QUALITY OF PHARMACEUTICAL INGREDIENTS

APPLYING LEARNING TO PRACTICE

PHARMACOPIEL HARMONISATION- INDIAN

PERSPECTIVE& CHALLENGES

Dr. Vinay G NayakPresident, Technical OperationsAlembic Pharmaceuticals Limited

PharmacopoeiasPharmacopoeias followed by the generic manufacturers –

The United States Pharmacopoeia (USP)

The European Pharmacopoeia (EP)The Japanese Pharmacopoeia (JP)The British Pharmacopoeia (BP)

e t s a acopoe a ( )International Pharmacopoeia (Ph.Int.)The Chinese Pharmacopoeia (ChP)

The Indian Pharmacopoeia (IP)

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Wh I P bli St d d I t t?Why Is a Public Standard Important?Ensure a consistent approach to quality for innovator and generic productsinnovator and generic productsAssess the quality of drug products in commerceProvide specifications that new manufacturers

can targetMonitorMonitor

for counterfeit and substandard productsthe quality of imported drug products

Providethe quality of imported drug products information for compounding pharmacists

DEFINATIONHarmonized: A pharmacopeial general chapter or otherHarmonized: A pharmacopeial general chapter or other pharmacopeial document is harmonized when a pharmaceutical substance or product tested by the d t’ h i d d bli h d i EP JPdocument’s harmonized procedure as published in EP, JP and USP yields the same results, and the same accept/reject decision is reached.Harmonized by Attributes: If a monograph or general chapter is not completely harmonized with the corresponding texts of the Japanese Pharmacopoeia and gthe European Pharmacopoeia, it is considered to be harmonized by attributes. Definition of Harmonization

Pharmacopoeial Harmonisationp

•Monographs and general methods of analysis proposed byMonographs and general methods of analysis proposed bynational associations of manufacturers of pharmaceuticalproductsTo ensure rapid publication of signed off texts the PDGTo ensure rapid publication of signed-off texts, the PDGprocedure has been woven into the Ph. Eur. procedureTexts are published in Pharmeuropa and approved by the

•

•Ph. Eur. CommissionPriority of pharmacopoeias according to EU legislation Ph Eur > national pharmacopoeia > third country

•Ph. Eur. > national pharmacopoeia > third country pharmacopoeias, e.g. USP, JP

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Benefits of HarmonisationAvoid divergent future requirements through harmonisation of g q gGeneral chapters, Monographs, Reference standards.

Help drug regulators to assess quality on a common benchmark.

Encourage the implementation and integration of commonstandards.

Easier, faster and economical adoption of standards bymanufacturers.

To facilitate the adoption of new or improved technical research and development approaches which updatepractices.

replace current

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Harmonization By AttributeA li d t ti l h t bl t b h dApplied retrospectively when agreement was unable to be reached on specific tests in a monograph, or parts of a General Chapter.Instituted as a means to move items forward where there was agreement on the main attributes (i.e. assay, identification) as g ( y, )opposed to delaying entire monograph or chapter.Attributes may have been determined to be non-harmonized byPDG for the following reasons–(1) Differing regulatory or legal requirements–(1)–(2)–(3)

Differing regulatory or legal requirementsNon-harmonized methodology for proceduresDifferences in scientific expert opinions

PDG have committed to work transparently in clearly identifyinghi h ifi tt ib t i h h t h i dwhich specific attributes in a monograph or chapter are harmonized.

PDG have committed to working on eliminating non-harmonized attributes where possible.

LIST FOR HARMONISATIONMethylcelluloseMethylcelluloseButyl, Ethyl, Methyl, PropylParabenPolysorbate 80P id

CarboxymethylcelluloseCarboxymethylcelluloseCroscarmelloseSodiumCrospo idone Povidone

SaccharinSaccharin CalciumSaccharin Sodium

CrospovidoneCellulose, MicrocrystallineCellulose, PowderedCellulose Acetate

Sodium ChlorideSodium Starch GlycolateStarch, CornStarch Potato

Cellulose Acetate PhthalateCitric Acid, AnhydrousCitric Acid, MonohydrateEthylcellulose Starch, Potato

Starch, RiceStarch, WheatStearic Acid

EthylcelluloseHypromelloseHypromellose Phthalate,Lactose, Anhydrous

Magnesium Stearate

SucroseTalc

GENERAL CHAPTERSFOR HARMONIZATION

Analytical SievingBulk Density and Tapped D it

peptide mappingPolyacrylamide Gel El t h iDensity

Gas Pycnometric Density of SolidsPowder Flow

ElectrophoresisExtractable VolumeResidue on IgnitionParticulate Matter

Tablet FriabilityOptical MicroscopyPowder FinenessSpecific Surface Area

SterilityDissolutionDisintegrationUniformity of Content/MassSpecific Surface Area

Porosimetry by Mercury IntrusionX-Ray powder diffraction

Uniformity of Content/MassMicrobial ContaminationLaser Diffraction MeasurementParticle SizeB t i l E d t iAmino acid determination

Capillary electrophoresisIsoelectric focusingProtein determination

Bacterial EndotoxinsWater-Solids Interaction

Protein determination

Pharmacopoeial Harmonisation

• Starting point: Industry is developingmore & more products intended formore & more products intended for submission worldwid•Aim: “single set of global secifications”•Aim: single set of global secifications(see ICH Q6A Guideline objective)• Avoid redundant testing by suppliers andg y pppharmaceutical industry to meet differingstandards

Benefits of HarmonisationAvoid divergent future requirements through harmonisation of g q gGeneral chapters, Monographs, Reference standards.

Help drug regulators to assess quality on a common benchmark.

h l d f

Encourage the implementation and integration of commonstandards.

Easier faster and economical adoption of standards by

Easier, faster and economical adoption of standards bymanufacturers.

To facilitate the adoption of new or improved technical researchd d l t h hi h d t replace current and development approaches which update or

practices.replace current

: f. 8

Pharmacopoeial HarmonisationpThree major pharmacopoeias

Japanese Ph E Ph iJapanesePharmacopeia

Governmental

Ph. Eur.

EDQM,Council of Europe

USPharmacopoeia

Independent ofGovernment

Inter-governmentalGovernment

Mrs C. Vielle, ©2010 EDQM, Council of Europe,All rightsreserved

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PHARMACOPOEIAL DISCUSSION GROUPIn response to proposals from industry:In response to proposals from industry:PDG was formed in 1989PDG is an informal body and consists of representatives from–United States Pharmacopeia (non-governmental)–European Pharmacopoeia, (European Directorate for thep p , ( pQuality of Medicines in the Council of Europe)–Japanese Pharmacopoeia (Ministry of Health, Labour andWelfare)Welfare)

The PDG: its missionDrives InternationalHarmonization ofrequirements in parallel and in corequirements in parallel and in coco-ordination with the ICH activityHas focused on:

E i i t• Excipients• General Chapters

EuropeanPharmacopoeiaPharmacopoeia(Ph. Eur.)P t ti bli h lth l• Protecting public health - one common compulsory

standard• The Ph. Eur. is the official pharmacopoeia in Europe –p p pcomplemented by national pharmacopoeias for texts ofinterest to only one Member State

M d t t th d t i 36 M b St t (C E)• Mandatory at the same date in 36 Member States (CoE) and the EU (decision of Ph. Eur. Commission).• Legally binding quality standards for ALL medicinalg y g q yproducts inthe EU, i.e. raw material, preparations, dosage forms, containers must comply with the Ph Eur requirementscontainers must comply with the Ph. Eur. requirementswhen they exist.

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Fats Radiopharm.

Herbals

Dosageforms Human

vaccines

The Ph Eur today Vet.VaccinesyPlastics

Bloodderiv.Antibiotics•Active substances (organic, inorganic)

Excipients

Chemicals Gases

Homeopathy

Biological••

Excipients ys

Substances of biological origin and biotechnologysomatropin...)

(insulin,

Herbal drugs, essential oils and fats, preparationsRadiopharmaceuticals

•••Vaccines sera (human veterinary) blood derivatives•••

Vaccines, sera (human, veterinary), blood derivativesHomeopathic preparationsGeneral monographs on dosage forms

•g p g

General texts on quality issues and standard analytical methods⇒ More than 2300 monographs

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Reference StandardsReference Standards

•Most monographs require at least onestandard

referencestandardThe reference standard underpins the•

•quality standard

Established and monitored by the EDQM Laboratory••

Established and monitored by the EDQM LaboratoryProducedDivision

and distributed by theReference

Standards

⇒ 2200 reference standards

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PDG & Harmonisation (1)( )

••

Pharmacopoeial Discussion Group (PDG) set up in 1990Drives international harmonisation of pharmacopoeial requirementsDrives international harmonisation of pharmacopoeial requirements among the world’s three major pharmacopoeias, the Ph. Eur., JP and USP - a single set of global specifications.Scope: general methods of analysis and excipient • p g y pmonograph, Aims:•– Avoid redundant testing by suppliers and pharmaceutical industry

totomeet different standardsReduce the overall cost of pharmaceutical research world-wide by avoiding duplication of work (preparation of dossiers and

–

y g p (p pstudies)Reduce the time required for medicines to be made available to patients

–

p

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PDG & Harmonisation (2)( )

• Monographs and general methods of analysis proposed by nationalnationalassociations of manufacturers of pharmaceutical productsTo ensure rapid publication of signed-off texts, the PDG procedure has been woven into the Ph Eur procedure

•

procedure has been woven into the Ph. Eur. procedureTexts are published in Pharmeuropa and approved by the Ph. Eur. Commission

•

• Priority of pharmacopoeias according to EU legislationPh. Eur. > national pharmacopoeia > third country pharmacopoeias, e.g. USP, JPp p , g ,

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PDG & H i ti t t d t (4)PDG & Harmonisation: status update (4)

28 of the 35 General Chapters and 41 of the 6128 of the 35 General Chapters and 41 of the 61excipient monographs of the current work programme ha e been harmonisedprogramme have been harmonised.17 General Chapters published in Chapter 5.8

d id d i t h bland considered interchangeable

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“Regulatory Flexibility” in the Pharmacopoeia g y y p(1)

“An article is not of Pharmacopoeia quality unless it compliesith ll th i t t t d i th h Thi dwith all the requirements stated in the monograph. This does

not imply that performance of all the tests in a monograph isnecessarily a prerequisite for a manufacturer in assessing

li i h h Ph i b f l fcompliance with the Pharmacopoeia before release of a product. ...”

“...The manufacturer may obtain assurance that a product is of...The manufacturer may obtain assurance that a product is ofPharmacopoeia quality from data derived, for example, from validation studies of the manufacturing process and from in-process controls ”process controls…..

“Regulatory Flexibility” in the Pharmacopoeia“Regulatory Flexibility” in the Pharmacopoeia (2)

“ P t i l i i t d d“… Parametric release in circumstances deemedappropriate by the competent authority is thusnot precluded by the need to comply with thenot precluded by the need to comply with the Pharmacopoeia.”

(European Pharmacopoeia,

1.1 General Statements)p )

AlternativeMethods“… The tests and assays described are the official ymethodsupon which the standards of the Pharmacopoeia are based With the agreement of the competent authoritybased. With the agreement of the competent authority,alternative methods of analysis may be used for control purposes, provided that the methods used enable an unequivocal decision to be made as to whether compliance with thestandards of the monograph

would beachieved if theofficialstandards of the monographmethods were used…”

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QbD - Demystification

•A systematic approach will facilitate the process to achievequality and should automatically generate more knowledge.quality and should automatically generate more knowledge.Not necessarily new requirements:

•–

Pharmaceutical development has been a requirement inPharmaceutical development has been a requirement inthe EU for a long timeQbD does not require the establishment of e.g., design

l ti l t ti i ht

–

space or real time release testing: a company might decide based on full scientific understanding not to establish a design space or RTR testing.–The level of development will depend on the complexity of the process and product and on the opportunities chosen or wanted by the applicant.y pp

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Revision of Chapter 2.2.40 NIRp(Near Infrared Spectroscopy)

t d t h f “b h t ” t ”i li ”• to accommodate changes from “bench-top” to”in-line”measurements• prepared in close consultation with Joint CHMP/CVMP Quality prepared in close consultation with Joint CHMP/CVMP QualityWorking party• to be aligned with the ongoing revision of the QWP Note for guidance on NIR (e.g. Delete validation requirements)→ published for consultation in Pharmeuropa 23.3, will be adopted in parallel with the revised version of the QWP Note for guidance on NIRparallel with the revised version of the QWP Note for guidance on NIR

Achievements: excipientsp40/62 Excipients monographsHarmonisation by attribute:RecogniseHarmonisation by attribute:Recognise sticking points.(Non-harmonised-attributes)(Non-harmonised-attributes)Publish “core” harmonisation resultCo-operation with Tri-PECp

Achievements: General Chapters

27/35 General Chapters

10 of Q6A general chapters10 of Q6A general chapters

6 bi t h l h t6 biotech general chapters11 powder characterisation general11 powder characterisation general chapters

Why evaluation by ICH EWG Q4B ?G ffDespite PDG efforts general chapters remained

effectively unharmonizedImplementation of sign off texts as agreed ? NeedImplementation of sign-off texts as agreed ? Need for formal declaration of regulatory acceptance to be expedited, to facilitate achieving truebe expedited, to facilitate achieving trueharmonization in practiceConsidered critical to attain full utility of ICH Q6A GLIndustry and regulators promoted such greater cooperation to ICH SC 2003cooperation to ICH SC 2003

PDG Achievements in Brussels Sign OffTopics – GeneralChapters/ExcipientsLaser diffraction measurementssize (new) Carmellose (new)

of particlesize (new) Carmellose (new) Dissolution Testing: Rev. 2Bacterial Endotoxin: Rev 1Bacterial Endotoxin: Rev. 1Additional minor revisions

PDG Achievements in BrusselsProcess improvements since Portland: SmallProcess improvements since Portland: Small working group to monitor and communicate PDG topics on a regular basis beneficial for progressDevelopment of online repository of PDGdocuments ongoingg gContinuous Process Improvement as standing agenda item.

Achievements: General ChaptersAchievements: General Chapters

27/35 General Chapters 10 ofQ6A general chapters

11Q6A general chapters6 biotech general chapters11 powder characterisation general chaptersp

CurrentResidue on

Status of Q4B evaluationIgnition (Annex 1) step 5Residue on

ExtractableIgnition (Annex 1) step 5Volume (Annex 2)

Particulate Matter (Annex 3) step 4Microbial ContaminationMicrobial Contamination (Annexes 4A, 4B, 4C) Disintegration (Annex 6)Uniformity of Dosage Units (Annex 5)y g ( )Dissolution (Annex 7) step 2Sterility (Annex 8)

Indication of Harmonisation StatusIndication of Harmonisation StatusPDG agreement to review previously published harmonised excipientpublished harmonised excipient monographs toindicate harmonisation status highlight residual differencesachieve harmonisation at a higher level

Interaction PDG/Q4BSC d f t Q4B ti itiSC approved future Q4B activities:Tablet friability (PDG Stage 6) Analytical Sieving (PDG Stage 6)y g ( g )Bulk Density and Tapped Density (PDG Capillary electrophoresis (PDG Stage 6)

Stage 6)

Polyacrylamide gel electrophoresis (PDG Stg 6)Polyacrylamide gel electrophoresis (PDG Stg 6)

Interaction PDG/Q4BInteraction PDG/Q4BPossible future PDG activities discussion:

underdiscussion:Chromatography pHpSpectrophotometry (includingWater determination

NIR)

Summary:PDG harmonisation process improvedR l t ti f i ff d bli h d t tRegulatory scrutiny of sign-off and published texts (ICH Q4B) has “sharpened” the processFirst texts “can be used as interchangeable” in the ICH

iregionsScope of Q4B widenedWork on dosage-form general chapters and excipients is the priorityCurrently EP/USP bilateral pilot project on prospectiveAPI harmonisation

Chapter <231> Heavy Metals -Issues

Difficulties in reproducibility–Monitor solutions/standards change with time, recovery issuesDifficulties with reagents –safety issues–All procedures generate H2S (USP via thioacetamide reaction–All procedures generate H2S (USP via thioacetamide reaction with base). H2S more toxic than cyanide–Thioacetamide not allowed in California and several European countries (EP uses Na2S)Nondiscriminatory screening test–Not element specific–Sensitivity varies by element–Only a few elements respond at required sensitivitiesOnly a few elements respond at required sensitivitiesVisual comparison test–Limits based on visual acuity, not toxicology

TOXICOLOGYUSP is proposing an approach to elementalUSP is proposing an approach to elemental impurity control that is both health based and risk basedControl metals that are toxicControl metals that are toxicAt limits that are toxicologically relevantAt all times during a drug product’s shelf lifeWith a risk based approach as to what and when to testWith a risk-based approach as to what and when to test

GLOBAL HARMONISATIONBenefits to stakeholders–Elimination of redundant testing–Multi-compendial complianceMulti compendial complianceBenefits to the pharmacopeias

–Stronger monographs with a global set oft tti d i i t d dexperts setting and reviewing standards

–Specifications (test methods) are representative of the global supply chaing pp y

SUMMARYSUMMARYAs pharmaceutical companies move from Regional to

Global markets there is an increasing trend to move

from diverse to commonly accepted standards.Also the advancements in scienceand tachnology havepromoted meaningful standards of Quality Measurement

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SUMMARYSUMMARYPharmacopoeias are key-players in ensuring safe standardsto protect public healthto protect public healthPharmacopoeias can react quickly to newly arising challengesA li ti f th ICH t i l d iblApplication of the new ICH concepts is already possiblein the present framework of pharmacopoeial requirements, further guidance being developedCh t th t di i tti ifi ti illChanges to the present paradigm in setting specificationsneed to be closely followed by the pharmacopoeias –however: safety first !!

will

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YOU MUST BECOME THE YOU MUST BECOME THE CHANGE YOU WANT TO SEECHANGE YOU WANT TO SEE

Mahatma Gandhi‐Mahatma Gandhi

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Thank youThank you

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