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 Reviewersfocus 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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CMC and Drug Development Cycle

Pre-Clinical Research
Discovery/Screen
SYNTHES PURIFICATION

Clinical Studies Phase I

NDA/BLA Review Post-Marketing

II
ANIMAL TESTING
Short Long

ADVERSE REACTION REPORT

III

IV
POST-APPROVAL POSTCHANGES

18 Month ?

AVG: 2-5 YEARS 2-

IND
Safety

NDA/BLA
Safety & Efficacy

6 Months 10 Months

APPROVAL

Safety, Efficacy & Consistency

CMC

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FDA-Regulated Peptide Products

Company Peptide_Name Pramlintide acetate Secretin Teriparatide Lanreotide acetate Abarelix Desmopressin Leuprolide acetate Calcitonin, human Calcitonin, Salmon Oxytocin Vassopressin Glucagon Aprotinin Teduglutide

Peptide definition
Polypeptides with <40 amino acids (21 CFR 601.2)

Amylin Ferring Lilly IPSEN Praecis Ferring Atrix Lab Ciba_Geigy Sandoz Watson Lab Park Davis Novartis Bayer NPS
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Type of products:
Therapeutic peptides, Peptide vaccines, Diagnostic peptide products

Sources:
Synthetic Peptides Natural peptides: Secretin, glucagon rDNA-derived peptides: PTH, teripartide, glucagon

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 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
Process-related impurities
Starting materials Solvents Reagents, and catalysts

Fermentation/cell culture
Process-related impurities
Fermentation and cell culture media components (e.g. antibiotics, buffers) Residual cellular proteins Residual DNA Column materials

Product-related impurities
Starting materials, intermediates, and byproducts Variants /degradation products Reactants with excipients

Product-related impurities
Aggregates, deamidated and oxidized forms Other peptide variants Degradation products

Container closure system

Glass, plastic, and rubber components Leachables and extractables

Others
Container closure compnents Bacteria, fungi, mycoplasma and viruses
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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 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 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

FDAprimary objectives in reviewing an IND are, in all s phase of the investigation, to assure the safety and rights of subjects, FDAreview of Phase 1 submissions will s 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 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 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 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 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 Animal and clinical studies Reference to other studies and FDA findings s [(505(b)(2)] Literatures [rarely, 505(b)(2)] Generic Drugs Specified levels in Monographs Literature data

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, 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 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/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 CMC Review Practices on Synthetic Peptides s

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 Action Threshold Reporting Threshold Minimal Identification and Characterization Range Full Identification and Characterization Threshold Qualification of Individual Impurities Threshold Qualification of Total Impurities Threshold 0.2% 0.2 to <0.5% 0.5% 1.0% 3.0% In Vivo Diagnostic Vaccines In Vitro Diagnostic

Peptide-Related Impurity Level 0.3% 0.3 to <1.0% 1.0% 2.0% 5.0% 0.5% 0.5 to <2.0% 2.0% 5.0% 10.0% 1.0% 1.0 to <5.0% 5.0% None None

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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 Limit Reporting threshold >0.1% Identification Qualification threshold 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

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 Reporting Maximum Daily Threshold Dose 2 g/day > 0.05 % Identification Threshold Qualification Threshold

> 0.10 % or 1.0 > 0.15 % or mg/day(whiche 1.0mg/day ver is lower) (whichever is lower) > 0.05 % > 0.05 %

> 2 g/day

> 0.03 %

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 0.1% 0.05% Identification Thresholds 1.0% or 5 TDI, whichever is g lower 0.5% or 20 TDI, whichever g is lower 0.2% or 2 mg TDI, whichever is lower 0.10%

g 1 >1 g
Maximum Daily Dose < 1mg 1 mg - 10 mg > 10 mg 2g > 2g

*Thresholds may be lower for highly toxic impurities

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Impurity in New Drug Product

Maximum Daily Dose Qualification Thresholds

< 10 mg 10 mg - 100 mg > 100 mg 2g > 2g

1.0% or 50 TDI, whichever is g lower 0.5% or 200 TDI, whichever is g lower 0.2% or 3 mg TDI, whichever is lower 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), 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 WellCharacterized, 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 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 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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Thank You
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