Pharmaceutical Reference Standards: Overview And Role In .

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Matthew Borer, Ph.D., AdvisorPharmaceutical Reference Standards:Overview and Role in GlobalHarmonization3rd DIA China Annual MeetingBeijing, China, 16 - 18 May, 2011

What is a PharmaceuticalReference Standard?A highly purified sample of a particularcompound that has been characterizedso that an accurate content can bestatedUsed as the basis for quantitative andqualitative testingif 100%SAMPLEM. Borer, May 2011, 3rd DIAChina MeetingCopyright 2011 Eli Lilly and Companythen 90%2

Reference Standard MaterialsM. Borer, May 2011, 3rd DIAChina MeetingCopyright 2011 Eli Lilly and Company3

Reference Standard InformationCertificateProtocolM. Borer, May 2011, 3rd DIAChina MeetingDataPackageCopyright 2011 Eli Lilly and Company4

Reference Standard UsesQuantitative calibrationIdentity comparisonTest of systemysuitabilityyPeak markerFingerprintingVisual comparisonM. Borer, May 2011, 3rd DIAChina MeetingCopyright 2011 Eli Lilly and Company5

Types of Reference StandardsReference StandardCompanyLaboratory-basedOfficialReference Standard Reference Standard Reference StandardPrimaryReference StandardPrimaryReference StandardSecondaryReference StandardOtherReference StandardM. Borer, May 2011, 3rd DIAChina MeetingCopyright 2011 Eli Lilly and Company6

M. Borer, May 2011, 3rd DIA China MeetingCopyright 2011 Eli Lilly and Company7

The Role of Reference Standards in aPharmaceutical Control SystemReference Standards are developed as part ofthe analytical control strategy for each drugproductEach reference standard has a control strategyof its ownReference Standards play a central role inassuring the quality of medicines for patientsduring cGMP testing and release activitiesM. Borer, May 2011, 3rd DIA China MeetingCopyright 2011 Eli Lilly and Company8

Simplified Product Control StrategyWhat themeasurementmeans How tomeasure What tomeasure Basis of the measurement M. Borer, May 2011, 3rd DIA China MeetingCopyright 2011 Eli Lilly and CompanyWhen tomeasure 9

Reference Standard Control StrategyM. Borer, May 2011, 3rd DIA China MeetingCopyright 2011 Eli Lilly and Company10

Regulations Governing RSOperationsFood and Drug Administration (FDA)–––––CFR Title 21 – Food and Drugs GMP, 211.194(c), 211.160(b)(1) and 299.5(c)ICH Guidelines Q7, Q6BVarious FDA Guidance DocumentsFDA regulatory observations (Warning Letters, 483’s)United States PharmacopeiaEuropean Agency for the Evaluation of Medicinal Products (EMEA)––––EU GMP 32, Annex 18 (transcription of ICH Q7)EU Quality Guideline 32 (regulatory submission requirements)ICH Guidelines Q7, Q6BEuropean PharmacopoeiaJapan Ministry of Health Labor and Welfare (MHLW)– Japan Pharmacopoeia Technical Information (JPTI) 1995, section 2– ICH Guidelines Q7, Q6B– Japan PharmacopoeiaM. Borer, May 2011, 3rd DIA China MeetingCopyright 2011 Eli Lilly and Company11

Additional Sources of GuidanceISO Guidelines 31, 32, 34WHO Technical Report Series (TRS) 885, 902,and 908Published Warning Letter CitationsBenchmarking of Findings at Other FirmsAudit Near MissesInternal QA/QC AuditsM. Borer, May 2011, 3rd DIA China MeetingCopyright 2011 Eli Lilly and Company12

Reference Standard vs Drug ProductReference StandardGMP for Human Consumption1.9.Intended use – laboratory controlLimited regulatory requirementsLimited registration commitmentClosed system of usersInfrequent manufacturingOverprotective packagingOverprotective storageSterility typically unimportantDocumentation is critical!9.Intended use – human dosingExtensive regulatory requirementsExtensive registration commitmentOpen system of patientsRoutine manufacturingPackaging optimized for costStorage optimized for convenienceSterility typically vitalDocumentation is critical!10.s I S p Q : Strength and Identity10.S i s P Q : Safety and Purity are1.2.3.4.55.6.7.8.are most critical2.3.4.55.6.7.8.most criticalSafety, Identity, Strength, Purity, QualityM. Borer, May 2011, 3rd DIA China MeetingCopyright 2011 Eli Lilly and Company13

SummaryReference Standards are an integral part of a pharmaceuticalproduct control strategyReference Standards have their own unique control strategyThere are some external regulations and more external guidanceassociated with pharmaceutical reference standardsReference Standards are not drugs (have a different intendeduse) and thus have unique attributesReference Standard Quality Systems must bedesigned with regulations, guidance, unique attributes,and intended use in mindM. Borer, May 2011, 3rd DIA China MeetingCopyright 2011 Eli Lilly and Company14

M. Borer, May 2011, 3rd DIA China MeetingCopyright 2011 Eli Lilly and Company15

Lilly RS Quality SystemGlobal Quality Standard – Reference StandardsLocal Procedures Establishment and MaintenanceAcquisition and Management of Materials and ComponentsProduction RecordsFinishing OperationsInventory ManagementStorage Facility RequirementsProcessing, Dispensing, Transferring, and ShippingComplaints and WithdrawalsQuality Unit ResponsibilitiesM. Borer, May 2011, 3rd DIA China MeetingCopyright 2011 Eli Lilly and Company16

Example:Reference Standard CharacterizationReference standard characterization must becustomized to support its specific intended useICH Q3a, IV Reference standards used in the analytical procedures for control of impurities shouldbe evaluated and characterized according to their intended uses.usesWHO, Annex 3, Technical Report Number 885,3 It is necessary to consider all data obtained from testing the material by a wide varietyof analytical methods. When taken as a whole, this will ensure that the substance issuitable for its intended use.use The extent of the analyses required depends on thepurpose(s) for which the chemical reference substance is to be employed, and mayinvolve a number of independent laboratories.ISO 34, 4.1.1 It should be recognized that a reference material needs to be characterized mainly tothe level of accuracy required for its intended purposeM. Borer, May 2011, 3rd DIAChina MeetingCopyright 2011 Eli Lilly and Company17

Example:Inventory ManagementMaterial receiptCycle countingInventory segregationDisaster recovery Active, Inactive, HoldRemoval from inventoryyMaterial movesM. Borer, May 2011, 3rd DIA China MeetingCopyright 2011 Eli Lilly and Company18

M. Borer, May 2011, 3rd DIA China MeetingCopyright 2011 Eli Lilly and Company19

Example: Legal Basis forUnited States PharmacopeiaAccording to the FD&C Act Section 501 and21CFR299(c), a drug marketed in the United Statesmust comply with compendial standardsFD&C Act SEC. 501. [21 U.S.C. 351]A drug or device shall be deemed to be adulterated(b) If it purports to be or is represented as a drug the name of which is recognized inan official compendium, and its strength differs from, or its quality or purity fallsbelow, the standards set forth in such compendium. Such determination as tostrength, quality, or purity shall be made in accordance with the tests or methods ofassay set forth in such compendium, §299.5 Drugs; compendial name.(c) A statement that a drug defined in an official compendium differs in strength,quality, or purity from the standard of strength, quality, or purity set forth for suchdrug in an official compendium shall show all the respects in which such drug sodiffers, and the extent of each such difference.M. Borer, May 2011, 3rd DIA China MeetingCopyright 2011 Eli Lilly and Company20

Verified in Guidance to InspectorsCompliance Program Guidance Manualfor FDA Staff: Drug Manufacturing InspectionsProgram 7356.002PART III – INSPECTIONAL C.C SystemS tInspectionIti CoverageC LABORATORY CONTROL SYSTEM For each of the following, the firm should have writtenand approved procedures and documentation resultingtherefrom - reference standards; source, purity and assay, and tests to establishequivalency to current official reference standards as appropriateM. Borer, May 2011, 3rd DIA China MeetingCopyright 2011 Eli Lilly and Company21

Verified by 483 ObservationsEastman Chemical Company Review of procedures for handling Reference Standardsshowed that Triacetin working standards are notcompared to or qualified against the USP TriacetinRS Current and draft SOPs for handling referenceRS.standards in general do not clearly indicate what tests ormethods of qualification are to be used for each standardmaterial, or specify how the expiry/re-certification date isestablished; instead it allows any chemist discretion inthese matters.M. Borer, May 2011, 3rd DIA China MeetingCopyright 2011 Eli Lilly and Company22

Reference StandardHarmonization GoalsThe same dose of medicine for every patient aroundthe worldNo difference in property values of a ReferenceStandard only due to measurement variabilityM. Borer, May 2011, 3rd DIAChina MeetingCopyright 2011 Eli Lilly and Company23

The Challenge for a GlobalManufacturerHow to maintainequivalency withmultiple nationalstandards?M. Borer, May 2011, 3rd DIAChina MeetingCopyright 2011 Eli Lilly and Company24

Example: Small Molecule APIStudent t-test results in a P-value of 3.5x10-5,rejecting the null hypothesis that the mean valuesare equivalentComparing ratioof the solutionconcentration tothe peak area ona single HPLCsetupM. Borer, May 2011, 3rd DIAChina Meeting0.84%Copyright 2011 Eli Lilly and Company25

Example: Peptide Drug Product29UCL 28.78Pot. Ann.Avg 28.47LCL 278RS0160RS0160RS0160RS0160RS016028RS0145Shifts incontrol chartcorrelatewith newcompendialreferencestandardsRef StandardM. Borer, May 2011, 3rd DIAChina MeetingCopyright 2011 Eli Lilly and Company26

Ways to Demonstrate EquivalencyComparative AssayEstablish a Secondary RS using the Compendial RS as aPrimary RS per the ICH Q7 definitionOfficial RSSecondary RSM. Borer, May 2011, 3rd DIA China MeetingCopyright 2011 Eli Lilly and Company27

Ways to Demonstrate EquivalencyMass BalanceAssign the in-house RS by another means (e.g., mass balance) andshow that this assignment is equivalent to comparative assay resultsversus the compendial standard(s) (e.g,. mass balance is within the95% confidence interval)Secondary RSM. Borer, May 2011, 3rd DIA China MeetingequivalentOfficial RSSecondary RSCopyright 2011 Eli Lilly and Company28

Why Establish an In-house RS?Pre-compendial support Compendial RSs are not available during development and early commercializationGlobal supply chain An in-house RS can be shown equivalent to more than one Official RSReliable supply It is unacceptable to halt manufacturing waiting for an Official RS to be re-suppliedC t l off frequencyControlfoff bbatcht h replacementlt Official RS batches might be replaced frequently which reduces long-term consistencyUsage rate Agencies typically cannot supply the volume of RSs required by the pharmaceutical industryIntended use An in-house RS can be shown compatible with intended uses beyond monographsSite-to-site consistency When global manufacturing sites use the same RS, there is more assurance or consistencyCost In-house RSs are less expensive to maintain, especially when there are multiple Official standardsM. Borer, May 2011, 3rd DIA China MeetingCopyright 2011 Eli Lilly and Company29

Future ChallengesThe difficulties associated with characterization ofbiomolecule reference standards make harmonization ofmultiple compendial reference standards a challengeNo way to fully define the Potency via physiochemical testing, so they RS defines biologicalgactivityyPrimarybutThe Primary RS has no basis for comparison, so monitoring forchange in Potency is hamperedandBioassay methods are typically highly variable, making itdifficult to measure small changes13-May-2011, M. Borer, et al. 2011 Eli Lilly and Company30

ConclusionsReference Standards are an essential part of cGMPpharmaceutical manufacturingReference Standards are not drugs and thus have a uniqueintended use and unique attributesReference Standard Quality Systems must be designedwith regulations, guidance, unique attributes, and intendeduse in mindIt is a challenge to maintain multiple regional officialstandards that are equivalent, especially for biomoleculesGlobal compendial agencies and manufacturers shouldwork together to maintain equivalencyM. Borer, May 2011, 3rd DIA China MeetingCopyright 2011 Eli Lilly and Company31

May 17, 2011 · Reference Standard Characterization Reference standard characterization must be customized to support its specific intended use ICH Q3a, IV Reference standards used in the analytical procedures for control of impurities should be evaluated and characterized according to their i