2010 Tide Conference Final DGWu

Regulatory Considerations on Setting Impurity Specification for Peptide Drug Products

2010 TIDESOligonucleotide and Peptide

Technology and Product DevelopmentBoston, MA

April 25-28, 2010

Duu-Gong Wu, Ph.D.Executive Director

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Topics To Be Discussed

IntroductionReviewers’focus on impuritiesImpurities and specifications at different

stages of drug developmentQualification of impuritiesSetting specifications for impuritiesCurrent regulatory issues on peptide

impuritiesConclusion

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CMC and Drug Development CycleD

isco

very

/Scr

een

Dis

cove

ry/S

cree

n

SYNTHESSYNTHESPURIFICATIONPURIFICATION

ANIMAL TESTINGANIMAL TESTING

LongLong

ShortShort

Phase Phase II

IIIIIIIIII IVIV

PrePre--ClinicalClinicalResearchResearch Clinical StudiesClinical Studies NDA/BLA ReviewNDA/BLA Review PostPost--MarketingMarketing

ADVERSEADVERSEREACTIONREACTIONREPORTREPORT

18 Month ?18 Month ? AVG: 2AVG: 2--5 YEARS5 YEARS 6 Months6 Months10 Months10 Months

INDIND NDA/BLANDA/BLA APPROVALAPPROVAL

POSTPOST--APPROVALAPPROVALCHANGESCHANGES

CM

CC

MC

Safety Safety & Efficacy Safety, Efficacy & Consistency

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FDA-Regulated Peptide Products

Peptide definitionPolypeptides with <40 amino

acids (21 CFR 601.2)Type of products:Therapeutic peptides,Peptide vaccines,Diagnostic peptide products

Sources:Synthetic PeptidesNatural peptides: Secretin,

glucagonrDNA-derived peptides: PTH,

teripartide, glucagon

AprotininBayer

TeduglutideNPS

Glucagon Novartis

Vassopressin Park Davis

OxytocinWatson Lab

Calcitonin, SalmonSandoz

Calcitonin, humanCiba_Geigy

Leuprolide acetateAtrix Lab

Desmopressin Ferring

AbarelixPraecis

Lanreotide acetateIPSEN

TeriparatideLilly

SecretinFerring

Pramlintide acetateAmylin

Peptide_NameCompany

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Common Problems With Peptide Impurities

Generic specifications by CMO in early phase do not support the late phase development- methods and acceptance criteria.

High purity of drug substance at phase 1 could not be duplicated for larger scale; program is delayed due to impurity issues

Changes in impurity profiles after scale-up, change in process, and site.

Forced degradation studies were not performed to identify degradation products and improve analytical method.

Tight acceptance criteria were set without adequate dataAnalytical methods were not evaluated early.No reserved samples were kept for comparability testing.Formulation development was not performed early enough. Interactions with the regulatory agency were inadequate.

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Definition of Impurities

Any component of the new drug substance:which is not the chemical entity defined as the new drug

substance (ICHQ3A) which is not an excipient in the product (ICHQ3B)which is not the chemical entity defined as the drug

substance, an excipient or other additives to the drug product (ICHQ5C, Q6B)Any adventitiously introduced materials ( e.g. chemical,

biochemical or microbial species) not intended to part of the manufacturing process of the drug substance or drug product (contaminants, ICH Q6B)

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Type of Peptide Impurities

Process-related impuritiesStarting materialsSolventsReagents, and catalysts

Product-related impuritiesStarting materials,

intermediates, and by-products

Variants /degradation productsReactants with excipients

Container closure systemGlass, plastic, and rubber

components

Leachables and extractables

Process-related impuritiesFermentation and cell culture

media components (e.g. antibiotics, buffers)

Residual cellular proteins Residual DNAColumn materials

Product-related impurities Aggregates, deamidated and

oxidized forms Other peptide variantsDegradation products

Others Container closure compnentsBacteria, fungi, mycoplasma and

viruses

Chemical Synthesis Fermentation/cell culture

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Potential Impurities in Synthetic Peptides

Toxic reagents and solvents used in synthesis

Diasteromeric(racemized) peptides

Isomerization Deletion (incomplete

coupling) peptides Truncated peptides

Reaction by-products, e.g. incomplete deprotection

Deamidation peptides Oxidation peptides

Disulfide exchange products

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FDA Reviewers’Perspectives on Impurities

What are the expected impurities?How are the impurities identified and controlled?When do the impurities need to be reported,

identified and qualified? How are the impurities controlled at different

phases of drug development?How are the impurities qualified? How are impurity specifications set, and justified? How are the impurity issues handled after

manufacturing changes?

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Identification of Impurities

Potential impurities based on materials used in manufacturing processForced degradation and stability studiesImpurity characterizationRoutine release and in-process testsExtraction studies (extactables/leacheables)

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Characterization of Impurities (S.3.2)

List of potential/theoretical impurities and originsReagents, solvent, catalysts Starting materials and intermediatesDegradation products

Description of analytical methods for impurity identification Actual impurities detectedIdentification by HPLC retention timeStructural characterization

Analytical Results and a list of qualified levelsDescription of best efforts for some impurities which can not

be characterized

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IND CMC Review Focus

FDA’s primary objectives in reviewing an IND are, in all phase of the investigation, to assure the safety and rights of subjects, … FDA’s review of Phase 1 submissions will focus on assessing the safety of Phase 1 investigations…, [21 CFR, 312.22(a)]…. Although in each phase of the investigation sufficient

information is required … to assure the proper identification, quality, purity, and strength of the investigational drug, the amount of information needed will vary with the phase…, the proposed duration, the dosage form and the amount of information otherwise available”[[21CFR312.23(a)(7)(I)]

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Preclinical and Phase 1 IND Studies

Safety is the sole concern for impurities.Identification of impurities is not required and the profile

can be based on the chromatographic retention time.Impurities are qualified by animal studies to support

phase 1 clinical trials.The impurities in clinical materials should be relevant to

those used in the animal toxicology studies, in term of the species and levels.Acceptance criteria are tentative, and may be based on

known safety levels (e.g. heavy metal and residual solvents), or just report the results (preclinical lots)Analytical methods do not have to be validated, but

qualified (EU requires validation).

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Phase 2 IND Studies

Suitable limits should be established based on existing manufacturing experience, release and stability data, and safety considerations New impurities (e.g., from a change in synthetic

pathway) should be qualified, quantified, and reported, as appropriate. Suitable analytical methods should be developed,

although validation is not requiredNew information on impurities needs to be

submitted to IND in an amendment and discussed during End-Of-Phase 2 meeting

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Phase 3 IND Studies

Impurity specifications should be near final based on the available release and stability data to support phase 3 clinical studiesAnalytical procedures for impurities should be finalized

with ongoing method validation.New impurities should be identified, qualified,

quantified, and reported , as appropriate. Reassessment of impurity profiles for change in

synthetic procedure, scale and sites need to be conducted. Amendments needs to be submitted for such changes.

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Impurities Testing for Manufacturing Changes

Manufacturing changes before and after approvalChanges in synthesis processScale-upSite changeChanges in formulation

Comparability testing for impuritiesComparative testing (characterization) for impurities

profilesAssessment of validity of current methodsQualification of new impurities or higher levels of old

impurities based on qualification decision tree.Revision of specifications if necessaryDiscussion with FDA regarding the change in profiles

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Qualification Studies for New Impurities

General toxicity qualification studyTwo weeks to three months of animal studies

– Based on indication or duration of clinical studies–One most sensitive species likely to maximize potential

to detect toxicity

GenotoxicityIn vitro bacterial reverse mutation assay such as AmesIn vitro Chromosomal Aberration Tests

–Mouse Lymphoma or CHO Assay

Immunogenicity tests for peptide/proteins products

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Qualification- New Drugs Vs Generic Drugs

Comparison with levels in reference drugs

Literatures [rarely, 505(b)(2)]

Animal studies including comparative in vitro genotoxicity studies

Literature data Reference to other studies and FDA’s findings

[(505(b)(2)]

Specified levels in Monographs

Animal and clinical studies

Generic DrugsNew Drugs

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Issues on Setting Impurity Specifications

Analytical methods and acceptance criteria (ICH Q6AB)Categories of impuritiesOrganic, inorganic impurities, and solvents Analytical method-dependent

Routine tests vs in-process controlsManufacturing capacity vs safety limitsAcceptance criteria- ranges or limitsRelease specifications vs stability specifications

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Approaches Toward Setting Specifications

Qualification (safety) levels Manufacturing capabilityLevels specified in ICH or domestic guidanceUSP monographsOther existing drug product specifications Limit tests and values reportedStatistical analysis, if appropriateNegotiation with the FDA.

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Impurity Release and Stability Specifications

Stability specification is regulatoryRelease specification should include:Each specified identified impurity/degradation productsEach specified unidentified impurity/degradation

productsAny unspecified impurity/degradation productsTotal impurities/degradation products

Stability specifications only include:Degradation productsExtractables/leacheables, if detected

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FDA’s CMC Review Practices on Synthetic Peptides

Prior to 2004 with ONDCIntercenter Agreement- CDER (ONDC) for synthetic peptides1994 Guideline for synthetic peptide; (2004 unpublished

revision)Consult reviews by designated CMC reviewersICH Q3AB exclude peptide productsDifferent qualification levels in FDA peptide guidance.

After 2004 following reorganization Product jurisdiction between OBP and ONDQA is less clear Consult reviews are no longer in practice Both 1994 and draft revised peptide guidance (internal use)

were withdrawn.ICH Q3A and B are cited by some reviewers, if not all.More emphasis on immunogenicity (clinical hold issue).

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Proposed Qualification Levels of Peptide-Related Impurities

None10.0%5.0%3.0%Qualification of Total Impurities Threshold

None5.0%2.0%1.0%Qualification of Individual Impurities Threshold

5.0%2.0%1.0%0.5%Full Identification and Characterization Threshold

1.0 to <5.0%0.5 to <2.0%0.3 to <1.0%0.2 to <0.5%Minimal Identification and Characterization Range

1.0%0.5%0.3%0.2%Reporting Threshold

Peptide-Related Impurity LevelAction Threshold

In Vitro Diagnostic

VaccinesIn Vivo Diagnostic

Therapeutic

Use

*Withdrawn 2003 drafted unpublished guidance

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General European Pharmacopeia 2034: Substances for Pharmaceutical use

The low administration doseTypical related substances are non-toxicNot feasible to reduce impurities to <0.1%Exposure of of molar concentration is much smaller

>1% > 0.5%>0.1%Limit

Qualification threshold

Identification threshold

Reporting threshold

Threshold

Table 2034.2-Reporting, identification and qualification of organic impurities in peptides obtained by chemical synthesis

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Current CMC Review of Peptide Impurities

Quality by Design approachesMore upfront works on the impurities

Synthetic peptide: ICH Q3A and Q3B, although excluded from these documentsRecombinant DNA-derived peptide: ICH Q6B,

Appendix 6.2.Peptides of natural origin: 1997 Premarin

Memo0.1% and above need to be identified and quantified

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Impurity Thresholds in New Drug Substance

•Thresholds may be lower for highly toxic impurities•number of decimal digits: two below 1.0 %, one above 1.0 %•application of conventional rounding rules

> 0.05 %> 0.05 %> 0.03 %> 2 g/day

> 0.15 % or 1.0mg/day (whichever is lower)

> 0.10 % or 1.0 mg/day(whichever is lower)

> 0.05 %≤2 g/day

Qualification Threshold

Identification Threshold

Reporting Threshold

MaximumMaximum Daily Dose

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Impurity in New Drug Product

*Thresholds may be lower for highly toxic impurities

0.10%> 2g

0.2% or 2 mg TDI, whichever is lower

> 10 mg –2g

0.5% or 20 g TDI, whichever is lower

1 mg - 10 mg

1.0% or 5 g TDI, whichever is lower

< 1mg

Identification ThresholdsMaximum Daily Dose

0.05%>1 g

0.1%≤1 g

Reporting ThresholdsMaximum Daily Dose

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Impurity in New Drug Product

*Thresholds may be lower for highly toxic impurities

0.15 %> 2g

0.2% or 3 mg TDI, whichever is lower> 100 mg –2g

0.5% or 200 g TDI, whichever is lower

10 mg - 100 mg

1.0% or 50 g TDI, whichever is lower

< 10 mg

Qualification ThresholdsMaximum Daily Dose

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Guidances and Guidelines for Impurities

ICH GuidanceICH Q3A(drug substance), B (drug product), C (residual

solvents), Q6A (specifications for NCE), Q6B (biotech)Q1AR(stability, NCE), Q5C (stability, biotech)ICH Q 2A (analytical methods)

Domestic Guidance/guidelinesContent and Format of Investigational New Drug Applications

(INDs) for Phase 1Studies of Drugs, Including Well-Characterized, Therapeutic,Biotechnology-derived ProductsINDs for Phase 2 and Phase 3 Studies: Chemistry,

Manufacturing, and Controls InformationFDA's Policy Statement For The Development Of New

Stereoisomeric Drugs. 5/1/92

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Guidance and Guideline For impurities (cont’d)

Domestic Guidance/guidelinesANDAs: Impurities in Drug SubstancesANDAs: Pharmaceutical Solid Polymorphism

Chemistry, Manufacturing, and Controls InformationGenotoxic and Carcinogenic Impurities in Drug

Substances and Products: Recommended ApproachesSafety Assessment of Pharmaceutical ExcipientsContainer Closure Systems for Packaging Human Drugs

and Biologics

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Conclusion

FDA reviewers are currently applying ICH guidance for setting peptide impurity specifications.

Detection and identification of impurities needs to be planned from the early development stage and continued throughout the development cycle.

Acceptance criteria need to set based on safety levels and manufacturing capability or based on QBD principles.

Comparability testing and re-qualification of impurities need to be incorporated into development timeline.

Analytical methods require re-evaluation after manufacturing changes.

The levels specified in ICH guidances only provide information on the levels required to be reported, characterized and qualified, not mandatory quality standards.

T h a n k Y o u

Contact Information

Duu-Gong Wu, Ph.D.Executive Director, PharmaNet Consulting

504 Carnegie CenterPrinceton, New Jersey 08540

Tel: +1 609-580-8142Fax: +1 [email protected]