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Regulatory Considerations on Setting Impurity Specification for Peptide Drug Products 2010 TIDES Oligonucleotide and Peptide Technology
Regulatory Considerations on Setting Impurity
Specification for Peptide Drug Products
2010 TIDES
Oligonucleotide and Peptide
Technology and Product Development
Boston, MA
April 25-28, 2010
Duu-Gong Wu, Ph.D.
Executive Director
Topics To Be Discussed Introduction Reviewers’focus on impurities Impurities and specifications at different stages of drug
Topics To Be Discussed
Introduction
Reviewers’focus on impurities
Impurities and specifications at different
stages of drug development
Qualification of impurities
Setting specifications for impurities
Current regulatory issues on peptide
impurities
Conclusion
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18 June 2010
CMC and Drug Development Cycle Pre Pre--Clinical Clinical Research Research Clinical Clinical Studies Studies NDA/BLA NDA/BLA
CMC and Drug Development Cycle
Pre
Pre--Clinical
Clinical
Research
Research
Clinical
Clinical Studies
Studies
NDA/BLA
NDA/BLA Review
ReviewPost
Post--Marketing
Marketing
SYNTHES
SYNTHES
Phase
Phase II
PURIFICATION
PURIFICATION
ADVERSE
ADVERSE
REACTION
REACTION
IIII
REPORT
REPORT
ANIMAL
ANIMAL TESTING
TESTING
III
III
IVIV
Short
Short
POST
POST--APPROVAL
APPROVAL
CHANGES
CHANGES
Long
Long
66 Months
Months
1818 Month
Month ??
AVG:
AVG: 22--55 YEARS
YEARS
1010 Months
Months
IND
IND
NDA/BLA
NDA/BLA
APPROVAL
APPROVAL
Safety
Safety & Efficacy
Safety, Efficacy & Consistency
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CMC
CMC
Discovery/Screen
Discovery/Screen
FDA-Regulated Peptide Products Company Peptide_Name  Peptide definition Amylin Pramlintide acetate Polypeptides with <40 amino Ferring
FDA-Regulated Peptide Products
Company
Peptide_Name
Peptide definition
Amylin
Pramlintide acetate
Polypeptides with <40 amino
Ferring
Secretin
acids (21 CFR 601.2)
Lilly
Teriparatide
Type of products:
IPSEN
Lanreotide acetate
Therapeutic peptides,
Praecis
Abarelix
Peptide vaccines,
Ferring
Desmopressin
Diagnostic peptide products
Atrix Lab
Leuprolide acetate
Sources:
Ciba_Geigy
Calcitonin, human
Synthetic Peptides
Sandoz
Calcitonin, Salmon
Natural peptides: Secretin,
glucagon
Watson Lab
Oxytocin
rDNA-derived peptides: PTH,
Park Davis
Vassopressin
teripartide, glucagon
Novartis
Glucagon
Bayer
Aprotinin
NPS
Teduglutide
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Common Problems With Peptide Impurities Generic specifications by CMO in early phase do not support the
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 data
Analytical 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
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 Chemical Synthesis Fermentation/cell culture Process-related impurities Process-related impurities Fermentation and cell culture
Type of Peptide Impurities
Chemical Synthesis
Fermentation/cell culture
Process-related impurities
Process-related impurities
Fermentation and cell culture
Starting materials
media components (e.g.
Solvents
antibiotics, buffers)
Reagents, and catalysts
Residual cellular proteins
Product-related impurities
Residual DNA
Starting materials,
Column materials
intermediates, and by-
Product-related impurities
products
Aggregates, deamidated and
Variants /degradation products
oxidized forms
Reactants with excipients
Other peptide variants
Degradation products
Container closure system
Others
Glass, plastic, and rubber
components
Container closure compnents
Bacteria, fungi, mycoplasma and
Leachables and extractables
viruses
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Potential Impurities in Synthetic Peptides  Toxic reagents and  Reaction by-products, solvents used in e.g.
Potential Impurities in Synthetic Peptides
Toxic reagents and
Reaction by-products,
solvents used in
e.g. incomplete
synthesis
deprotection
Diasteromeric
Deamidation peptides
(racemized) peptides
Oxidation peptides
Isomerization
Disulfide exchange
products
Deletion (incomplete
coupling) peptides
Truncated peptides
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FDA Reviewers’Perspectives on Impurities What are the expected impurities? How are the impurities identified and controlled?
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 process Forced degradation and stability
Identification of Impurities
Potential impurities based on materials used in
manufacturing process
Forced degradation and stability studies
Impurity characterization
Routine release and in-process tests
Extraction studies (extactables/leacheables)
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Characterization of Impurities (S.3.2) List of potential/theoretical impurities and origins Reagents, solvent, catalysts Starting materials and
Characterization of Impurities (S.3.2)
List of potential/theoretical impurities and
origins
Reagents, solvent, catalysts
Starting materials and intermediates
Degradation products
Description of analytical methods for impurity
identification
Actual impurities detected
Identification by HPLC retention time
Structural characterization
Analytical Results and a list of qualified levels
Description 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
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
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
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 required
New 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
Phase 3 IND Studies
Impurity specifications should be near final based on
the available release and stability data to support
phase 3 clinical studies
Analytical 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 approval Changes in synthesis process Scale-up
Impurities Testing for Manufacturing Changes
Manufacturing changes before and after
approval
Changes in synthesis process
Scale-up
Site change
Changes in formulation
Comparability testing for impurities
Comparative testing (characterization) for impurities
profiles
Assessment of validity of current methods
Qualification of new impurities or higher levels of old
impurities based on qualification decision tree.
Revision of specifications if necessary
Discussion with FDA regarding the change in profiles
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Qualification Studies for New Impurities General toxicity qualification study Two weeks to three months of animal
Qualification Studies for New Impurities
General toxicity qualification study
Two 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
Genotoxicity
In vitro bacterial reverse mutation assay such as Ames
In 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 New Drugs Generic Drugs Animal and clinical studies Specified levels
Qualification- New Drugs Vs Generic Drugs
New Drugs
Generic Drugs
Animal and clinical studies
Specified levels in
Monographs
Reference to other studies
and FDA’s findings
Literature data
[(505(b)(2)]
Literatures [rarely, 505(b)(2)]
Comparison with levels in
reference drugs
Animal studies including
comparative in vitro
genotoxicity studies
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Issues on Setting Impurity Specifications Analytical methods and acceptance criteria (ICH Q6AB) Categories of impurities Organic,
Issues on Setting Impurity Specifications
Analytical methods and acceptance criteria (ICH
Q6AB)
Categories of impurities
Organic, inorganic impurities, and solvents
Analytical method-dependent
Routine tests vs in-process controls
Manufacturing capacity vs safety limits
Acceptance criteria- ranges or limits
Release specifications vs stability specifications
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Approaches Toward Setting Specifications Qualification (safety) levels Manufacturing capability Levels specified in ICH or domestic guidance
Approaches Toward Setting Specifications
Qualification (safety) levels
Manufacturing capability
Levels specified in ICH or domestic guidance
USP monographs
Other existing drug product specifications
Limit tests and values reported
Statistical analysis, if appropriate
Negotiation with the FDA.
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Impurity Release and Stability Specifications Stability specification is regulatory Release specification should include: Each specified identified
Impurity Release and Stability Specifications
Stability specification is regulatory
Release specification should include:
Each specified identified impurity/degradation products
Each specified unidentified impurity/degradation
products
Any unspecified impurity/degradation products
Total impurities/degradation products
Stability specifications only include:
Degradation products
Extractables/leacheables, if detected
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FDA’s CMC Review Practices on Synthetic Peptides Prior to 2004 with ONDC Intercenter Agreement- CDER (ONDC)
FDA’s CMC Review Practices on Synthetic Peptides
Prior to 2004 with ONDC
Intercenter Agreement- CDER (ONDC) for synthetic peptides
1994 Guideline for synthetic peptide; (2004 unpublished
revision)
Consult reviews by designated CMC reviewers
ICH Q3AB exclude peptide products
Different 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 *Withdrawn 2003 drafted unpublished guidance Use Therapeutic In Vivo Vaccines
Proposed Qualification Levels of Peptide-Related
Impurities
*Withdrawn 2003 drafted unpublished guidance
Use
Therapeutic
In Vivo
Vaccines
In Vitro
Diagnostic
Diagnostic
Action Threshold
Peptide-Related Impurity Level
Reporting Threshold
0.2%
0.3%
0.5%
1.0%
Minimal Identification and
0.2 to <0.5%
0.3 to <1.0%
0.5 to <2.0%
1.0 to <5.0%
Characterization Range
Full Identification and
0.5%
1.0%
2.0%
5.0%
Characterization Threshold
Qualification of Individual
1.0%
2.0%
5.0%
None
Impurities Threshold
Qualification of Total Impurities
3.0%
5.0%
10.0%
None
Threshold
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General European Pharmacopeia 2034: Substances for Pharmaceutical use Table 2034.2-Reporting, identification and qualification of organic impurities
General European Pharmacopeia 2034: Substances
for Pharmaceutical use
Table 2034.2-Reporting, identification and qualification of
organic impurities in peptides obtained by chemical
synthesis
Threshold
Reporting
threshold
Qualification
threshold
Limit
>0.1%
Identification
threshold
> 0.5%
>1%
The low administration dose
Typical related substances are non-toxic
Not feasible to reduce impurities to <0.1%
Exposure of of molar concentration is much smaller
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Current CMC Review of Peptide Impurities Quality by Design approaches More upfront works on the impurities
Current CMC Review of Peptide Impurities
Quality by Design approaches
More upfront works on the impurities
Synthetic peptide: ICH Q3A and Q3B, although
excluded from these documents
Recombinant DNA-derived peptide: ICH Q6B,
Appendix 6.2.
Peptides of natural origin: 1997 Premarin
Memo
0.1% and above need to be identified and quantified
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Impurity Thresholds in New Drug Substance Maximum Maximum Daily Dose ≤2 g/day Reporting Identification Qualification Threshold
Impurity Thresholds in New Drug Substance
Maximum
Maximum Daily
Dose
≤2 g/day
Reporting
Identification
Qualification
Threshold
Threshold
Threshold
> 0.05 %
> 0.10 % or 1.0
mg/day(whiche
ver is lower)
> 0.15 % or
1.0mg/day
(whichever is
lower)
> 2 g/day
> 0.03 %
> 0.05 %
> 0.05 %
•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
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Impurity in New Drug Product Maximum Daily Dose Reporting Thresholds ≤1 g 0.1% >1 g 0.05%
Impurity in New Drug Product
Maximum Daily Dose
Reporting Thresholds
≤1 g
0.1%
>1 g
0.05%
Maximum Daily Dose
Identification Thresholds
< 1mg
1.0% or 5 g TDI, whichever is
lower
1 mg - 10 mg
0.5% or 20 g TDI, whichever
is lower
> 10 mg –2g
0.2% or 2 mg TDI, whichever
is lower
> 2g
0.10%
*Thresholds may be lower for highly toxic impurities
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Impurity in New Drug Product Maximum Daily Dose Qualification Thresholds < 10 mg 1.0% or 50
Impurity in New Drug Product
Maximum Daily Dose
Qualification Thresholds
< 10 mg
1.0% or 50 g TDI, whichever is
lower
10 mg - 100 mg
0.5% or 200 g TDI, whichever is
lower
> 100 mg –2g
0.2% or 3 mg TDI, whichever is lower
> 2g
0.15 %
*Thresholds may be lower for highly toxic impurities
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Guidances and Guidelines for Impurities ICH Guidance ICH Q3A(drug substance), B (drug product), C (residual solvents),
Guidances and Guidelines for Impurities
ICH Guidance
ICH 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/guidelines
Content and Format of Investigational New Drug Applications
(INDs) for Phase 1Studies of Drugs, Including Well-
Characterized, Therapeutic,Biotechnology-derived Products
INDs for Phase 2 and Phase 3 Studies: Chemistry,
Manufacturing, and Controls Information
FDA'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/guidelines ANDAs: Impurities in Drug Substances ANDAs: Pharmaceutical Solid
Guidance and Guideline For impurities (cont’d)
Domestic Guidance/guidelines
ANDAs: Impurities in Drug Substances
ANDAs: Pharmaceutical Solid Polymorphism
Chemistry, Manufacturing, and Controls Information
Genotoxic and Carcinogenic Impurities in Drug
Substances and Products: Recommended Approaches
Safety Assessment of Pharmaceutical Excipients
Container 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
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.
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T h a n k Y o u Contact Information Duu-Gong Wu, Ph.D. Executive Director, PharmaNet
T h a n k
Y o u
Contact Information
Duu-Gong Wu, Ph.D.
Executive Director, PharmaNet Consulting
504 Carnegie Center
Princeton, New Jersey 08540
Tel: +1 609-580-8142
Fax: +1 609-720-7995
dwu@pharmanet.com