2010 Tide Conference Final DGWu
-
Upload
digedagalchemist -
Category
Documents
-
view
30 -
download
1
Transcript of 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
Page 2
18 June 2010
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
Page 3
18 June 2010
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
Page 4
18 June 2010
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
Page 5
18 June 2010
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.
Page 6
18 June 2010
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)
Page 7
18 June 2010
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
Page 8
18 June 2010
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
Page 9
18 June 2010
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?
Page 10
18 June 2010
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)
Page 11
18 June 2010
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
Page 12
18 June 2010
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)]
Page 13
18 June 2010
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).
Page 14
18 June 2010
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
Page 15
18 June 2010
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.
Page 16
18 June 2010
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
Page 17
18 June 2010
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
Page 18
18 June 2010
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
Page 19
18 June 2010
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
Page 20
18 June 2010
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.
Page 21
18 June 2010
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
Page 22
18 June 2010
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).
Page 23
18 June 2010
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
Page 24
18 June 2010
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
Page 25
18 June 2010
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
Page 26
18 June 2010
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
Page 27
18 June 2010
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
Page 28
18 June 2010
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
Page 29
18 June 2010
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
Page 30
18 June 2010
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
Page 31
18 June 2010
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]