EDQM & European Pharmacopoeia: State-of-the-art Science .
EDQM & European Pharmacopoeia:State-of-the-art Science for Tomorrow’s MedicinesInternational Conference organised by the European Directoratefor the Quality of Medicines & HealthCare (EDQM),Council of Europe19-20 June 2019, Strasbourg, France1 2019 EDQM, Council of Europe. All rights reserved.Workshop on Finished Product MonographsModeratorDr Tobias Gosdschan, Outgoing Chair of the European Pharmacopoeia Commission2 2019 EDQM, Council of Europe. All rights reserved.
Experience of the U.S PharmacopeialConventionBruk AlemayehuSenior vice president, Chemical MedicinesTopics Trusted resources Development and scope ofStandards Ongoing commitment Partner with us
Our missionTo improve globalhealth through publicstandards and relatedprograms that helpensure the quality,safety, and benefit ofmedicines and foods.4 2018 USP
USP and FDA USP: Private Not-For-Profit Organization– Engaged in the development and revision ofcompendial standards for drugs (and otherproducts)USP & FDA WorkTogether to ProtectPublic Health– Public standards related to identity, strength,purity, quality, packaging, labeling US FDA: Government Agency– Engaged in the promulgation andenforcement of drug (and other product)regulatory requirements– Safety, Efficacy, NDA/ANDA (private license)approvals for marketing, manufacturingprocesses, etc.We work globallyUSP-SINGAPOREUSP site ANAUSP siteUSP-NIGERIALagosUSP-USRockville, MDFrederick, MDWashington, DCUSP-CHINAShanghaiAccraUSP-ETHIOPIAUSP-INDIAAddis selUSP-BRAZILSao Paulo6 2018 USP
USP – public standardsUSP standards used in over 140 countriesHello, userGo to https://online.usppf.com to access the PF7 2018 USPUSP–NF Documentary and Reference StandardsUSP 42 - NF 37General Chapters364Total Monographs4990Substance Monographs2227Product Monographs2763PF 44 (1-6)New General Chapter22Revised General Chapter40New Monographs100Revised sUSP Reference StandardsCurrent CatalogNew to Catalog in 20183815918 2018 USP
For quality standards to be impactful, consider Aligned withPublic health and patientsafety priorities Adapted & ImprovedFor technology andevolution of healthcareDeveloped byIndependent expertsPractical for- Users of the standard- Enforcers of the standardInformed byMeasured byPublic health impact indicatorsReal world implications forpatients and practitioners9 2018 USPScientific experts and volunteers develop our standards
Developing standards11 2018 USPAnatomy of drug product monographTitleDEFINITIONStates the required APIs and requiredpercentages of the labeled amountsIDENTIFICATIONA. (Are the actives present?)B. (Are the actives present?)ASSAY(Are the required percentages of the labeledamounts present?)o Solvents and Mobile phaseo Stock, System suitability, Standard, and Samplesolution preparationso Chromatographic system descriptiono System suitability requirementso Calculationo Acceptance criteriaPERFORMANCE TESTSDissolution 711 (Are the release requirements met?)o Dissolution conditionso Analytical procedure (see Assay for an example)o TolerancesUniformity of Dosage Units 905 (Are the requirements met?)IMPURITIESOrganic Impurities(Are impurities sufficiently controlled?)o Analytical procedure (see Assay for an example)o Acceptance criteriaADDITIONAL REQUIREMENTSPackaging and StorageLabelingUSP Reference Standards 11 12 2018 USP
How do we build a monograph?Supported by:Validation package(s)Specifications and SOPsLetter of approval Additional supporting data(such as CoAs, stability data) 13 2018 USPRequired supporting information Shelf life specifications along with current US FDA approval status (NDA, ANDA, etc.) Analytical procedureso Modern system suitability requirementso Representative chromatographic and/or spectral datao All tests as described in general chapters 1 to 5 including Performance tests such as 711 and 905 Validation data for all analytical procedureso Requirements per 1225 and current FDA/ICH guidelineso Brands of chromatographic columns used in validationo Forced degradation / stability data Specific tests such as Microbial tests 61 & 62 ; Bacterial endotoxin 85 ; pH 791 Batch records / Certificates of Analysis for at least 3 batches Chemical information: names, structures, molecular formula, molecular weight Packaging and storage requirements Labeling requirements Reference material candidate materials needed to support the testing: supply and/or source of supply Rationale and data are required to support requests for revision to an official monograph Description and Solubility information for drug substance monographs14 2018 USP
Integrated control strategyOfficial drug products are prepared “from ingredients that meetUSP or NF standards.” [General Notices 3.10.] Drug product monographs rely on drug substance monograph controls for:– Identification and tests for counterions [prevents formulation (excipient) relatedfalse positives]– Process impurities [non-degradants, including non-degradant stereo isomers]15 2018 USPFlexible monograph approach Address differences in drug substance, ingredient, or product attributes– Polymorphic forms– Impurity profiles– Product-specific dissolution tests Labeling Different tests or acceptance criteria as approved by the US FDA Flexible approach is not used for Assay16 2018 USP
Formulation-specific critical quality attributesUSP uses the flexible monograph approach Multiple tests for the same quality attribute are individually numbered; additional textmay aid the user in determining whether the test is applicable.Dissolution, Test 2: If the product complies with this test, the labeling indicates thatit meets USP Dissolution Test 2Organic Impurities, Procedure 2 [Use Organic Impurities, Procedure 2 if Assay,Procedure 2 is used.] Drug product labeling must identify the test number used, generally when a test otherthan Test 1 appliesLabeling: The labeling states the Dissolution test used only if Test 1 is not used.The labeling indicates which test for Organic Impurities is used only if Procedure 1is not used.17 2018 USPFlexible monographs - examplesExample monographs with multiple dissolution tests Diltiazem HCl ER Capsules – 20 tests Metformin ER Tablets – 16 tests Nifedipine ER Tablets – 12 tests Theophylline ER Capsules – 10 tests Tamsulosin HCl Capsules – 10 tests Olmesartan Medoxomil Tablets – 4 tests18 2018 USP
Challenges to establishing standardsLack of access to critical information for monograph developmentPrior to Public Comment PeriodDuring/Post Public Comment Period Partnering with stakeholders to help Working with stakeholders to get moredevelop new standards and bringexisting standards Up-to-Date Identifying relevant impurities andappropriate limits, especially if USPlaboratories are developing and/orvalidating Up-to-Date analyticalprocedures Coordinating multiple performance testsclarity / specificity in PF comments How to resolve statements indicating theproposed specifications are notappropriate for the public standard Identifying contacts with FDA-approvedapplications to ensure they are engagedand the proposals are suitable19 2018 USP
2020-2025 Expert Committees21 2018 USP
301-816-8369 ktm@usp.org
Finished Product MonographsPerspective of a Regulatory AuthorityAndrea Cseh-PálosNational Institute of Pharmacy and Nutrition, HungaryEDQM and Europen Pharmacopoeia, 19-20 June 2019, StrasbourgOverview IntroductionAssessment issues, challengesExamplesProposalsPotential advantages2
INTRODUCTION3Finished Product (FP) monographsGoal: provide harmonized standards in Ph.Eur.also for finished products (FP) that contain an API for which a Ph.Eur.monograph exists (or on the work program) that have been authorized in at least one ofits member states that have a high public health interest4
How to read and apply FPmonographs General principles for Monographs onFinished Products (FPs) containingchemically defined active substances https://www.edqm.eu/sites/default/files/general principles for monographs on finished products june 2017 e.pdf shall be read in conjunction with the Ph. Eur. General Notices, relevant dosage form monograph and general monograph on Pharmaceutical Preparations.5ASSESSMENT ISSUESCHALLENGES6
Suitability of the FP monographspecifications (methods and acceptance criteria)to adequately control the quality of theproduct needs to be demonstrated in themarketing authorisation application (MAA) assessment of these data is part of themarketing authorisation procedure.7FPMs are legally binding The same set of parameters and limits arenot necessarily appropriate for differentproducts (different excipients, packagingmaterials, FP manufacturing method, clinicalbatches) All products on the market should becovered Potential for unnecessary wide limits –lowest common denominator/lowering ofstandards8
FPMs are legally binding EU (CHMP, QWP) guidelines will be lessefficient tool for assessment (these guidelines are the basis for acommon assessment approach) Will it be possible to ask for tightening?9Dissolution testing procedure(test conditions, acceptance criteria)If specified in the FP monograph: shall be mandatory unless otherwisestated in the monograph (“unless otherwisejustified and authorised”).BUT: should be sufficiently discriminatory toassure batch-to-batch consistency and whereappropriate, consistency with those batches forwhich satisfactory evidence of efficacy has beendemonstrated.10
Dissolution limit & method based on results of in vivo studies different for each individual product establishing a common FPM dissolutionmethod and specifications for genericproducts is challenging.11If the product is not adequatelycontrolled by the respectivemonograph To be evaluated whether the proposedspecifications and analytical methods areadequate for the specific product Feedback from authorities to the Ph.Eur. COM valuable information for review and potentialrevision of the monographQuestions: When? During assessment or after approval? What will be the legal position for the product inthe interim period?12
Impact on existing products Need for variations – to demonstrate thecompliance even if in-house method is moreappropriate Need for demonstrating that the in-housemethod is „at least equivalent” – validation, crossvalidation Associated workload for applicants and NCAs If „not comply” – what to do? – withdraw?suspend ?– it was already authorized!13Questions How to handle if the applicant does notsubmit a variation application to implementthe FP monograph in time? Which type of variation? Until now no Category for that in the“Classification Guideline”. The following two categories were agreed byEMA via CAPs. Type IB: B.II.d.1.z. – Control of finished product (Conformance toPh.Eur. new drug product monograph ) Type IB B.III.2.z. (Change to comply with Ph. Eur. or with a nationalpharmacopoeia of a Member State, (Drug Product)14
EXAMPLES15Case 1The product was approved just after theimplementation date of FPM with: wider limit for total impurities (0.5% instead of0.2%) in-house HPLC method for related substancesNo variation since the approval The analytical method is different as described inthe monograph No demonstration that the in-house method is atleast equivalent to the FP monograph16
Justification of the applicant The limit for total impurities does not take intoaccount any specified impurities The drug product specification includes twospecified impurities both with a limit of nmt 0.2%(in line with ICH Q3B (R2) and maximum dailydose of 100mg/day.) Total impurity limit for the corresponding API isnmt 0.5%, higher than the total impurity limitfor finished product. The product is other salt (or base) of the API the monograph does not apply17Case 2Change to align with the Ph.Eur. monographPresent: Include only individualdegradants 0.1% inthe calculation of totaldegradants. The sum of all individualdegradants TotaldegradantsProposed Include only individualdegradants and processimpurities 0.1% in thecalculation of the totalimpurities. The sum of all individualdegradants and processimpurities TotalImpurities18
Related substances testFP monographs limit degradation products arising duringmanufacture and shelf-life of the finishedproduct, (including those impurities of synthesis thatare also degradation products).FP monographs are not designed to control impurities of synthesisthat are not degradation products. necessarily take account of all possibleimpurities in future products.19Case 2the proposed calculation for total impuritiesincludes individual degradation products andprocess impurities which exceed the reportingthreshold of 0.1%.The variation was accepted without anyquestions/comment!Questions: Unspecified impurities – only degradation productsor any? Total – should include also process impurities?20
Case 3Change to align with the Ph.Eur. monographOnly one (shelf-life, wider) specification isimplemented removal of separate, (tighter, accepted release)specification for impuritiesWas it really necessary?21PROPOSALS22
ProposalsA binding general text specifically forFPs would be useful The existing „General principles ”* documentshould be amended/completed (see next slide)and moved into the General Notices https://www.edqm.eu/sites/default/files/general principles formonographs on finished products june 2017 e.pdf23Proposals for General NoticesFlexibility should be kept – the productshould be assessed on its own meritClear procedure is needed: in case wider limit or a better analyticalmethod is authorized based on soundjustification on notification procedure of the COM andproposal for revision of FPM 24
Proposals for General NoticesLimits for impurities: to be introduced„unless otherwise justified andauthorized”For alternative methods: the statement„In the event of doubt or dispute, the methods ofanalysis of the Ph.Eur. are alone authoritative” –for FP should not be valid!25Introduction of a General Chapter Similarly to General Chapter 5.10. As a guidance/help for proper interpretation of therequirements The status of the dissolution methods andrequirements should be clarified (mandatory orexample) Limits for impurities: Clarification is needed – (any individual and totalvs. only any or total degradation products,reporting threshold .) General monograph of „Pharmaceutical Preparations”(2619) should refer to this general chapter.26
POTENTIAL ADVANTAGES27Potential AdvantagesAt present: ICH Q3B and ICH Q6A: strictly applicable only for„new drug products” legally more binding requirements(mandatory), for existing products as well ICH Q3B: no limit only thresholds for degradationproducts possibility to ask for tighter limit as proposed bythe applicant (in case it is unnecessarily wide andnot properly justified by stability data at the timeof authorization)28
Long term advantages Early development of the product(generics): the already existing monographcan be a good starting point – targetrequirements – easier assessment Analytical method validation - in case(only) the monograph method(s) are used,assessment of the validation document iseasier – as only verification is needed29Thank you for yourkind attention!30
Finished product monographsPerspective of an OMCLBRENIER CharlotteHead of Chemical Medicines and other Health Products Physicochemical departmentLaboratory Controls Division19-20 June 2019EDQM International conference, StrasbourgPresentation of the French OMCLFR ANSM The French OMCL FR ANSM is the Laboratory Controls Division of theFrench Competent Authority ANSM (French National Agency for Medicinesand Health Products Safety) This Laboratory Controls Division (CTROL) is located on three sites inFrance: Saint-Denis: control of biological products Lyon: control of vaccines in collaboration with the 2 other sites Montpellier-Vendargues: control of chemical medicines, API, medical devicesand gene therapy products. The laboratory Controls Division is involved in: Market SurveillanceBatch releaseElaboration of standards (participation in EDQM working and expert groups)ANSM1
French OMCL FR ANSMQuality management – ISO 9001ANSM was audited according to ISO 9001:2015 at the end of 2018and received the attestation in January 2019 in the scope of: Surveillance of health products, Handling of high risk situations Control of health products InspectionANSM2French OMCL FR ANSMQuality management – ISO 17025The laboratory control division, as part of the OMCL network, isregularly audited through MJA (Mutual Joint Audits) coordinated byEDQM. Ongoing attestations (EN ISO/IEC 17025 version 2005) :Last audits carried out respectively in December 2015, May 2017 and inJune 2017 for Saint-Denis, Montpellier-Vendargues and Lyon sites.Audited activities: batch release for vaccines and technics for marketsurveillance on all health products.The attestations of compliance obtained are valid until June 2020 forSaint-Denis site and October 2021 for Montpellier-Vendargues and Lyonsites. Ongoing processThe laboratory control division is engaged in the implementation of thenew version of the standard (ISO/ IEC 17025:2017).ANSM3
French OMCL FR ANSMControl of chemical medicines (market surveillance) Context of controls Annual market surveillance program Includes reference and generic products Based on a risk based approach for the selection of products Concerns national products, MRP/ DCP, CAP Emergency requests (about 20% of the batches controlled) Suspicion of quality defect, emerging subjects of concern, newimpurities Pharmacovigilance, inspection feedbacks Suspicion of falsification Judicial requisitionsANSM4French OMCL FR ANSMControl of chemical medicines (market surveillance) Methods used for controls Methods from MA files ANSM methods (market surveillance methods applied to genericseries) EDQM/ OMCL network methods (market surveillance methods for MSSstudies) Ph. Eur. monographs Other methods from USP, BP, scientific publications Typical results obtained (2018, 526 batches including API) 6% of non compliance within the market surveillance program 30% of non compliance for batches controlled on emergency requestsANSM5
French OMCL FR ANSMControl of generic medicinesCurrent methodology for the control of generic series (national products, MRP, DCP): Choice of the critical parameters to be controlled depending on the product(example: assay, related substances, dissolution test, pH, ) Choice of the methods involved: For some tests, such as assay or related substances: A common method (typically HPLC) is retained.The compliance is checked against each manufacturer set of specificationsIn case of non compliance: the reference method (MA file) is applied For some tests, such as dissolution, most often the specific methods described in MA files are appliedIn some cases, additional tests using a common dissolution method are carriedout to compare dissolution profiles. Conclusion: the compliance of each batch depends on the specificationsdescribed for shelf-life in each MA file. The set of specifications can bedifferent from a manufacturer to another one.The same methodology is applied for European MSS studies.ANSM6French OMCL FR ANSMInvolvement in the elaboration of Ph. Eur. standards The French OMCL is involved in the elaboration of API and FP Ph.Eur. monographs: Expert/ chair in EDQM groups 10C and 10D Elaboration of API Ph. Eur. monographs Expert in P4 group Elaboration of API monographs Elaboration of FP monographs: Deferiprone tablets (2986) and deferiprone solution (2987) in2017Rivaroxaban tablets 3021 in 2017ANSM7
Example 1 of Market surveillance study:Anticancer drug (solution for in
Standards Reference Standards USP 42 - NF 37 General Chapters 364 Total Monographs 4990 Substance Monographs 2227 Product Monographs 2763 PF 44 (1-6) New General Chapter 22 Revised General Chapter 40 New Monographs 100 Revised Monographs 511 USP ReferenceStandards Current Catalog 3815 New to Catalogin 2018 91. 9
study as per IP, API, Unani, Pharmacopoeia, Homoeopathic Pharmacopoeia, Siddha Pharmacopoeia, BHP, Japanese Pharmacopoeia, Chinese Pharmacopoeia, European Pharmacopoeia, USP (dietary supplements), WHO and EMEA guidelines and ESCOP monographs for medicinal products. 07 Unit-4 Quanti
PHARMACOPOEIA Free access to supportive pharmacopoeial texts in the field of vaccines for human use during the coronavirus disease (COVID-19) pandemic Updated package - October 2020 Published in accordance with the Convention on the Elaboration of a European Pharmacopoeia (European Treaty Series No. 50) Council of Europe Strasbourg
Officially recognized pharmacopoeia (or compendium) Those pharmacopoeias recognized by the Authority, i.e., The International Pharmacopoeia (Ph.Int.), European Pharmacopoeia (Ph.Eur.), British Pharmacopoeia (BP), Japanese Pharmacopoeia (JP), and the
"Pharmacopoeia" may be used to indicate the Pharmacopoeia of the Union. The official texts of the Pharmacopoeia of the Union include general notices, general chapters, monographs, and annexes, which are published in Russian. Monograph is a document that sets out the requirements and statements of the Pharmacopoeia for
New and revised General Chapters in the European Pharmacopoeia Workshop New Technologies European Pharmacopoeia 9
The development of this edition had as domumentation sources the European pharmacopoeia existent at that time, the heroic drugs list elaborated by the International Pharmacopoeia Commission (Bruxelles – 1906) and the American Pharmacopoeia. The heroic drugs in the 1915 edition are ma
5/11/2015 16 Regulatory Considerations in Excipient choice Regulatory Guidancesfor Global Nutrition ‐just a few that must be considered WHO British Pharmacopoeia US Pharmacopoeia European Pharmacopoeia China Pharmacopoeia China GB National standards
previous Pharmacopoeia (limited to part of the Name and Standards for the drugs concerned) may be accepted to conform to the Name and Standards established in the new Pharmacopoeia before and on September 30, 2017. In the case of drugs which are listed in the new Pharmacopoeia (excluding those listed in the previous Phar-
