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Title: OVERVIEW OF ITFGIPACRS COLLABORATION FOR PRESENTATION TO THE ADVISORY COMMITTEE FOR PHARMACEUTICAL S


1
OVERVIEW OFITFG/IPAC-RS COLLABORATIONFOR
PRESENTATION TO THEADVISORY COMMITTEE
FORPHARMACEUTICAL SCIENCE Presented by Harris
Cummings, PhD15 November 2000Rockville, MD
2
The Inhalation Technology Focus Group (ITFG) of
the American Association of Pharmaceutical
Scientists is comprised of pharmaceutical
scientists who seek to foster and advance the art
and science of pharmaceutical aerosol products,
aerosol technology and related processes The
International Pharmaceutical Aerosol Consortium
on Regulation and Science (IPAC-RS) is an
association of companies that develop and
manufacture orally inhaled and nasal products for
local and systemic treatment of asthma, chronic
obstructive pulmonary disease (COPD), rhinitis,
as well as new products for non-respiratory
disease indications such as diabetes and migraine
3
DRAFT GUIDANCES FOR OINDP
Draft Guidances for Industry 1) Metered Dose
Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug
Products Chemistry, Manufacturing, and Controls
Documentation 2) Nasal Spray and Inhalation
Solution, Suspension, and Spray Drug Products
Chemistry, Manufacturing, and Controls
Documentation and 3) Bioavailability and
Bioequivalence Studies for Nasal Aerosols and
Nasal Sprays for Local Action
4
  • ITFG and IPAC-RS
  • share FDAs goal of assuring highest levels of
    safety, efficacy and quality for orally inhaled
    and nasal drug products (OINDP) and making these
    products available to patients expeditiously
  • recognize value of having OINDP guidance
    documents to facilitate development and approval
    of new medications, but believe that differing
    views exist concerning CMC and BA/BE issues in
    draft OINDP Guidances
  • agree that certain sections of draft Guidance
    documents need to be modified to be consistent
    with todays drug development technologies and
    capabilities
  • believe that additional interactive,
    science-based dialogues need to occur to provide
    full opportunity to discuss all important issues
    in depth in order to achieve meaningful and
    necessary changes in OINDP draft Guidances

5
ITFG/IPAC-RS COMMITMENT TO ADDRESS OINDP ISSUES
  • Following Publication of Draft Guidances, ITFG
    and IPAC-RS Submitted Extensive Written Comments
    to FDA Docket
  • (February 1999, August 1999, September 1999)
  • ITFG and IPAC-RS Organized and Implemented
    Extensive Data-Driven Collaboration to Address
    Issues in Draft Guidances
  • (January 2000-Present)
  • ? Collected and Analyzed Relevant Databases
  • ? Proposing Scientifically Justified
    Modifications to Draft Guidances
  • Collaboration Participated in first OINDP
    Subcommittee Meeting
  • (April 2000)
  • ? Committed to Collecting Relevant Data
  • ? Described Plans to Prepare Data-Based Technical
    Reports on Issues in Draft Guidances for
    Submission to Agency and OINDP Subcommittee
  • Collaboration Submitted Four Technical Reports to
    FDA

6
STEERING COMMITTEE
TECHNICAL TEAMS
CMCTESTS AND METHODS
CMC SUPPLIER QUALITY CONTROL
CMC LEACHABLES EXTRACTABLES TOXICOLOGY WG
BA/BE IN VITRO AND IN VIVO TESTS
CMC SPECIFICATIONS
DCU WG
PSD WG
7
Over 100 individuals from more than 25
companies/institutions are participating in the
ITFG/IPAC-RS Collaboration
Aradigm AstraZeneca Aventis Bespak BI
Roxane Boehringer Ingelheim Celltech-Medeva Dura
Pharmaceuticals Eli Lilly Glaxo Wellcome Inhale
Therapeutic Systems Inspire Pharmaceuticals IVAX
Kos Pharmaceuticals Lovelace Respiratory
Institute Magellan Laboratories Microdrug Pfeiffer
Pfizer Presspart Primedica Schering-Plough 3M
Pharmaceuticals Trudell Medical University of
Rhode Island Valois
8
ITFG/IPAC-RS TECHNICAL TEAMS
  • Technical Teams Are at Different Stages
  • Some Have Collected and Analyzed Data and
    Submitted Initial Assessments to Agency
  • Others Are Analyzing Data and Preparing to Submit
    Technical Reports to Agency and OINDP
    Subcommittee
  • Today Technical Team Leaders Will
  • Review Work of Each Technical Team to Date
  • Describe Collaborations Data-based Conclusions
  • Explain Plans for Further Work

9
NEED FOR SCIENCE-BASED DIALOGUES
  • We Respectfully Request that the Advisory
    Committee For Pharmaceutical Science
  • Support the Importance and Value of Continuing
    Scientific Dialogue on Important CMC and BA/BE
    Issues for Orally Inhaled and Nasal Drug Products
    Before Draft Guidances Are Finalized
  • Endorse Our Request That Opportunities Be
    Identified for a Continued Dialogue Between FDA
    and ITFG/IPAC-RS Collaboration Regarding the
    Collaborations Technical Papers and Data-based
    Proposals to Modify the Draft Guidance Documents

10
RECOGNITION OF AGENCYS COMMITMENT TO IMPROVING
QUALITY OF OINDP
  • ITFG and IPAC-RS Recognize and Appreciate
    Agencys Efforts in Issuing Draft Product Quality
    OINDP Guidances and Agencys Initial Steps
    Towards a Scientific Dialogue
  • ITFG and IPAC-RS Strongly Support Agencys
    Creation of the OINDP Subcommittee and Believe
    That the Subcommittee Should be Given an
    Opportunity to Deliberate Substantively on OINDP
    Issues
  • We Thank the Advisory Committee for
    Pharmaceutical Science and the Agency for
    Considering Our Comments and Proposals and Are
    Pleased to be Able to Participate in Todays
    Meeting

11
ITFG/IPAC-RS TECHNICAL TEAM BA/BE IN VITRO AND
IN VIVO TESTSPresented by Lars Borgström,
PhD 15 November 2000Rockville, MD
12
  • Commitments made at 26 April OINDP Subcommittee
    Meeting
  • To Develop Position Statements on BA/BE Studies
  • To Respond to FDAs BA/BE Questions from 26 April
    OINDP Subcommittee Meeting
  • Status
  • Prepared Two Technical Papers, Submitted to FDA
    on 30 August 2000
  • Technical Paper on FDAs Bioavailability and
    Bioequivalence Questions Presented at 26 April
    2000 OINDP Advisory Subcommittee Meeting

13
BA/BE IN VITRO TESTS
BA/BE IN VIVO TESTS
In vitro testing is essential for pharmaceutical
product equivalence and should be included as
part of BA/BE Guidance for all nasal and oral
inhalation products, but is not currently
sufficient for determining BE without
establishing in vivo BE.
For BE approval, BA/BE Guidance documents for
nasal and oral inhalation drug products for local
action should require use of validated human
models for in vivo testing for local and systemic
exposure, efficacy and safety.
14
  • Teams BA/BE recommendations apply to locally
    acting drugs only (per the current draft BA/BE
    Guidance)
  • Teams comments apply to both orally inhaled and
    nasal drug products, but the dosage forms should
    be treated in separate Guidances
  • Scientific and clinical bases for developing
    BA/BE Guidance are evolving
  • Teams BA/BE position statements reflect only the
    current state of knowledge

15
BA/BE TEAMS FINDINGS IN VITRO TESTS
  • In vitro tests described in the draft BA/BE
    Guidance are not necessarily more relevant or
    discriminating than clinical studies for BE
    assessment
  • The assumption that in vitro studies alone are
    sufficient for BE of solutions is unfounded. The
    draft BA/BE Guidance should not distinguish
    between nasal suspensions and solutions for in
    vivo BE
  • Based on the available literature, current in
    vitro tests may predict lung deposition, but the
    utility of those tests to demonstrate clinical
    equivalence of inhaled drug products has not been
    shown

16
BA/BE TEAMS FINDINGS IN VIVO TESTS
  • Systemic PK/PD estimates systemic exposure (i.e.,
    safety) but does not estimate local delivery
    (i.e., efficacy and local tolerance)
  • Efficacy assessments alone cannot establish in
    vivo BE since they will not assure comparable
    safety (systemic exposure)
  • Lung deposition studies are a promising new
    technique, but currently cannot replace the local
    delivery requirement
  • In vitro data, regional deposition data, PK/PD
    studies, and clinical efficacy studies are needed
    to establish relationships and to characterize
    the formulation when a new inhaled drug is
    developed
  • Reduction of testing requirements for a new
    formulation of an approved drug should therefore
    be negotiated between the sponsor and the Agency
    depending on available data for each particular
    drug

17
  • Teams Review Paper Was Intended to Highlight
    Areas in Draft BA/BE Guidance Where Scientific
    Basis Is Uncertain and Where More Scientific
    Discussion and Debate Are Needed
  • Agency's Questions to OINDP Subcommittee on 26
    April Underscore the Agency's Concerns With Some
    of the Positions in the Draft BA/BE Guidance
  • We Encourage the Agency to Solicit Further
    Scientific Discussion on These Positions Before
    Finalizing Current Draft or Issuing Further
    Guidance Documents


18
  • Requesting Opportunity to Meet with Agency to
    Discuss Teams Findings
  • Willing to Address Further Questions Raised by
    Agency

19
ITFG/IPAC-RS BA/BE TECHNICAL TEAM RESPONSES TO
AGENCYS BA/BE QUESTIONS RAISED AT OINDP
SUBCOMMITTEE MEETINGPresented by Les Harrison,
PhD 15 November 2000Rockville, MD
20
ITFG/IPAC-RS COLLABORATION FDA QUESTION
EVALUATION
  • Small Working Groups Formed to Research Each
    Question
  • Scientific Data (Literature and Company
    Experience) Used to Prepare Answers
  • Answers Reviewed by Entire BA/BE Technical Team
  • Consensus Required for All Answers

21
OVERVIEW OF COLLABORATION RESPONSES
  • FDA Raised Difficult Technical Issues at April 26
    Meeting
  • Most Issues Are Still Open
  • Collaboration Committed to Address Questions in
    Order to Complement OINDP Subcommittee's
    Discussion
  • Collaboration Collected and Analyzed Scientific
    Data to Help Resolve Uncertainties
  • Collaboration has Provided Additional Scientific
    Substantiation to Subcommittees Answers
  • Collaboration has Provided Responses Where
    Subcommittees Answers Were Limited

22
IN VITRO BA/BE TESTING A. Profile Analysis (1)

QUESTION 1. Should all stages, including the
inlet (throat) of the cascade impactor (CI) be
considered in a comparison of test and reference
products? SUMMARY OF ANSWER Yes, All Stages
Should Be Considered for Products With
Polydisperse Particle Size Distributions
23
IN VITRO BA/BE TESTING A. Profile Analysis (2)
  • QUESTION
  • 2. Should a statistical approach rather than a
    qualitative comparison be used for profile
    comparisons? If yes, does the chi-square
    comparative profile approach seem appropriate?
  • SUMMARY OF ANSWER
  • Yes, a statistical approach should be used
  • The chi-square approach may be appropriate for
    particle size comparisons further assessment is
    needed
  • Guidance should define equivalence limits
    (extent to which two profiles can differ and
    still be considered equivalent)

24
IN VITRO BA/BE TESTING B. In Vitro Tests for
DPIs Comparability (1a)
  • QUESTION
  • 1. Prior to doing in vivo studies to establish
    equivalence of a test DPI product, a firm would
    need to design its product to have the best
    likelihood of being found equivalent in these in
    vivo studies.
  • a. What design features of the device and
    formulation and what parameters should be
    considered in determining pharmaceutical
    equivalence?
  • SUMMARY OF ANSWER
  • Equivalence in all of the following categories
    should maximize the likelihood of being
    equivalent in vivo studies
  • formulation
  • device elements
  • chemical, physical and in-vitro characteristics
    that demonstrate the performance of the assembled
    system

25
IN VITRO BA/BE TESTING B. In Vitro Tests for
DPIs Comparability (1b)
  • QUESTION
  • b. What comparative in vitro tests should be
    conducted to help support bioequivalence?
  • SUMMARY OF ANSWER
  • delivered dose amount and delivered dose
    uniformity
  • aerodynamic particle size distribution of
    delivered dose, and of carrier or excipient
    materials characteristics of dispersing the
    formulated powder to desired particle size
    distribution across a physiologically relevant
    range of airflows and environmentally realistic
    range of temperatures and humidities
  • microbiological burden in the powder formulation
  • chemical, physical and microbiological stability
    of contained formulation
  • chemical and physical composition of device,
    including extractive materials
  • reliability of device throughout the defined use
    period

26
IN VIVO BA/BE TESTING A. Clinical Studies for
Local Delivery of Nasal Aerosols and Sprays (1)
  • QUESTION
  • 1. Three study designs have been proposed in the
    draft guidance for drugs intended to have local
    action traditional treatment study day(s) in
    the park study, and environmental exposure unit
    study. These study designs are based on seasonal
    allergic rhinitis (SAR). Is it feasible to
    demonstrate a dose-response for locally acting
    nasal drugs? If not, what other approaches can
    be relied upon to establish equivalent local
    delivery?
  • SUMMARY OF ANSWER
  • Studies proposed in draft Guidance are useful for
    determining comparability
  • Their value for establishing clinical equivalence
    and substitutability is unproven
  • Traditional treatment study is most appropriate
    study design for assessing nasal drug products
    intended for local delivery
  • Statistical requirements must be proposed if
    clinical studies are to be used for equivalence
    testing
  • Current study designs are not adequate to
    confidently establish dose-response relationships
    nor is there an alternative method available

27
IN VIVO BA/BE TESTING A. Clinical Studies for
Local Delivery of Nasal Aerosols and Sprays (2)
  • QUESTION
  • 2. Can bioequivalence be established based on SAR
    assure bioequivalence for other indications such
    as recurrence of nasal polyps, or other non-SAR
    conditions?
  • SUMMARY OF ANSWER
  • A pre-existing indication for nasal polyps or
    other non-SAR condition at same dose should be
    transferable from Reference to Test product if
    all BE requirements for SAR met
  • To transfer a pre-existing indication for use in
    children, it should be shown that the studies
    conducted to assess systemic safety are
    predictive of this subgroup.

28
IN VIVO BA/BE TESTING B. Clinical Studies for
Local Delivery of Orally Inhaled Corticosteroids
(ICS)

QUESTIONS 1. A number of approaches have been
proposed to assess bioequivalence of ICS (e.g.,
clinical trials, bronchoprovocation tests,
steroid reduction model, trials with surrogate
measures such as exhaled nitric oxide (eNO),
etc. Are any of these study designs proven to
offer better discrimination in terms of
dose-response sensitivity? 2. What other in vivo
approaches (e.g., surrogate markers) might be
sufficiently sensitive and validated to establish
in vivo BA and BE for inhaled corticosteroids?
29
IN VIVO BA/BE TESTING B. Clinical Studies for
Local Delivery of Orally Inhaled Corticosteroids
(ICS)
  • SUMMARY OF ANSWER
  • Comparative dose-response trial with pulmonary
    function measurements as the primary analysis
    parameters remains the method of choice.
  • However, variability is large, and metrics
    sensitive enough for BE with trial designs that
    are practical from subject number and length of
    study are not yet available.
  • No alternative design has been sufficiently
    validated.

30
IN VIVO BA/BE TESTING c. PK or PD Studies for
Systemic Exposure of Locally Acting Drugs
  • QUESTION
  • Are there situations where in vitro data plus
    systemic PK and systemic PD data can be relied on
    to assure local drug delivery for either nasal or
    inhaled drugs?
  • SUMMARY OF ANSWER
  • Yes, there could be situations where in vitro
    data plus systemic PK and systemic PD data may be
    relied upon for BE.
  • If a predictive in vitro/in vivo correlation can
    be documented, the sponsor should have the
    opportunity to discuss the possibility of waiving
    clinical studies.
  • Post-approval changes to manufacture of approved
    Reference or approved Test products may not
    require extensive testing, but such changes are
    outside the scope of this draft Guidance.

31
  • Questions Posed by FDA on the Draft BA/BE
    Guidance have Underscored a Number of Open Issues
  • BA/BE Team Collected a Substantial Body of
    Information that Merits Examination by the Agency
    and OINDP Subcommittee
  • BA/BE Team Encourages Further Scientific
    Collaboration and Consideration of Key BA/BE
    Issues by Agency Utilizing Existing Avenues
  • OINDP Subcommittee
  • PQRI
  • AAPS/FDA/USP Workshop
  • Dialogue with ITFG/IPAC-RS Collaboration
  • Federal Research Grants
  • We Hope the Agency is Receptive to Our Comments
    and Continues to Dialogue With Public Before
    Finalizing Current Draft or Issuing Further
    Guidances


32
ITFG/IPAC-RS TECHNICAL TEAM CMC
SPECIFICATIONSPresented by Bo Olsson,
PhD15 November 2000Rockville, MD
33
DOSE CONTENT UNIFORMITY (DCU)
Teams Hypothesis The current state of OINDP
technology may not allow general compliance with
the dose content uniformity specifications in the
draft FDA CMC Guidances. Questions Raised by the
Agency at OINDP Subcommittee Meeting Should
there be a single content uniformity standard for
all orally inhaled and nasal drug products
(OINDPs)? Should the FDA continue development of
the proposed statistical approach to evaluating
content uniformity? Teams Approach Collect
Worldwide Database to Investigate Actual DCU
Capabilities and Appropriate Statistical
Approaches
34
DCU WORKING GROUP STATUS REPORT
  • Collected Worldwide DCU Database Containing Data
    From 10 Companies on 77 Orally Inhaled and
    Intranasal Drug Products (Currently on the Market
    and Under Development) With a Total of 46,016
    Individual Observations
  • Analyzed Collected Data, Prepared and Submitted
    Initial Assessment of DCU Database to FDA on 31
    July 2000
  • Developed Proposed Plan for Stage 2 Analysis of
    DCU Database and Submitted it to FDA on 22
    September
  • Meeting With Agency on 20 November to Discuss
    Initial Assessment of DCU Database and Proposed
    Plan for Stage 2 Analysis of DCU Database

35
DCU WORKING GROUP FINDINGS
  • Key Requirement of Draft Guidance Specification
    for DCU
  • Reject a batch if a DCU determination outside
    75-125 of the Label Claim (LC) is obtained
  • Findings From DCU Database
  • Main analysis showed that
  • Grand Mean Dose Content is 100 LC
  • 68 of all products show results outside 75-125
    LC

36
CONCLUSIONS FROM INITIAL ASSESSMENT OF DCU
DATABASE
  • The Initial Assessment of the DCU Database
    Supports the Hypothesis That Orally Inhaled
    Products Do Not in General Comply With the DCU
    Specification in the FDA Draft CMC Guidances.
  • The Relatively Large Difference Between Products
    and Between Product Types Suggest That a Single
    Content Uniformity Specification for All Orally
    Inhaled Products Is Not Suitable.

37
PLAN FOR FURTHER ANALYSIS OF DCU DATABASE
  • In consultation with FDA, DCU Working Group will
    continue analysis of DCU database to investigate
  • Compliance with FDA Draft Guidances Complex
    Criteria
  • ICH Approach
  • Dr. Haucks Approach of Statistical Hypothesis
    Testing
  • Other Approaches

38
PARTICLE SIZE DISTRIBUTION (PSD)
  • Teams Commitment Made at OINDP Subcommittee
    Meeting
  • Examine the relevancy of the mass balance
    requirement as a product specification versus
    system suitability requirement.
  • Investigate if fewer than 3-4 stage groupings can
    provide equivalent control.
  • Teams Approach
  • Collect worldwide database to investigate actual
    PSD capabilities and appropriate statistical
    approaches for control of PSD in OINDP
  • Question Investigated in the Initial Assessment
  • Can the current state of OINDP technology
    generally comply with the mass balance criterion
    in the draft FDA CMC Guidances?

39
PSD WORKING GROUP STATUS REPORT
  • Collected Worldwide PSD Database Containing Data
    From 7 Companies on 35 Orally Inhaled and
    Intranasal Drug Products (Currently on the Market
    or Under Development) With a Total of 3,606
    Individual PSD Determinations
  • Analyzed Collected Data, Prepared and Submitted
    Initial Assessment of PSD Database to FDA on 29
    August
  • Developing Plan for Further Analysis of PSD
    Database
  • Willing to Meet With Agency to Discuss Initial
    Assessment of PSD Database and Plan for Further
    Analysis

40
PSD WORKING GROUP FINDINGS
  • Draft Guidance Mass Balance Specification
  • Total mass of drug collected on all stages and
    accessories during particle size testing should
    be within 85-115 LC on a per actuation basis
  • Main Finding from PSD Database
  • Only 4 of 35 products showed no results outside
    85-115 LC

41
CONCLUSION FROM INITIAL ASSESSMENT OF PSD DATABASE
  • Initial Assessment of the PSD Database Indicates
    that
  • Orally Inhaled Products Do Not in General Comply
    with the Proposed Mass Balance Requirement in the
    Draft CMC Guidances (85-115 LC)
  • The Proposed Requirement Is Not Suitable As a
    Drug Product Specification but Could Be
    Appropriate As a System Suitability Test Defined
    on a Case by Case Basis

42
PLAN FOR FURTHER ANALYSIS OF PSD DATABASE
  • PSD Working Group will Continue Analysis of PSD
    Database to
  • investigate further relevance of the mass balance
    criterion as a product specification versus
    system suitability requirement
  • compare different metrics and sets of criteria
    for characterizing PSD of OINDP
  • PSD Working Group Is Willing to Meet With Agency
    to Discuss Results of Initial Assessment and
    Plans for Further Analysis of PSD Database

43
SPECIFICATIONS TEAM CONCLUSIONS
  • Many Unresolved Issues Surround CMC
    Specifications for DCU and PSD. To Address These
    Issues, Team Has Collected and Is Analyzing DCU
    and PSD Data
  • Team Strongly Encourages Continued Discussion by
    All Interested Parties Before CMC Draft Guidances
    Are Finalized
  • Developing Statistically Sound Specifications
    Based on Real Data Is Essential to Creating
    Scientifically Credible Program of Product
    Quality Control


44
ITFG/IPAC-RS TECHNICAL TEAM CMC TESTS AND
METHODS Presented by Carole Evans, PhD 15
November 2000 Rockville, MD
45
TEAMS OBJECTIVE
  • The Team Would Like to Assist the Agency in
    Developing CMC Testing Requirements That Provide
    Valuable Information About Product Quality

46
TEAM POSITION ON DRAFT CMC GUIDANCES
  • To Clarify Testing Requirements for Each of the
    Four OINDP Dosage Forms, the Draft Guidances
    Should Be Edited or a Separate Guidance Should Be
    Developed for Each Dosage Form
  • In Some Instances, the Language in the Draft CMC
    Guidances Is Ambiguous
  • The Need for Certain Tests Should Be Driven by
    Evaluation of Data Generated During the
    Development Phase of Each Product

47
PRESENTATION TO OINDP SUBCOMMITTEE
  • Approach and Commitments
  • The Team Developed Position Statements on the
    Following MDI Tests
  • -Water
  • -Spray Pattern
  • -Plume Geometry
  • -Particle Size Distribution
  • -Shot Weight
  • -Impurities and Degradants
  • -Dose Content Uniformity
  • -Pressure

48
TESTS METHODS TEAM STATUS REPORT
  • Collected and Analyzing Data to Investigate the
    Teams Position Statements for the Following MDI
    Tests
  • -Water
  • -Spray Pattern
  • -Plume Geometry
  • -Temp/ Relative Humidity in Particle Size
    Distribution Testing
  • -Shot Weight
  • Drafted Comments on MDI Requirements for
  • -Impurities and Degradants
  • -Dose Content Uniformity

49
TESTS METHODS TEAM PRELIMINARY FINDINGS ON MDI
TESTS
  • Collected Data Show That for Many Products, the
    Tests for Spray Pattern, Water Content, and Shot
    Weight Do Not Provide Meaningful Information
    About Product Performance
  • There Exists a Wide Body of Literature that Lends
    Support to the Use of Validated and Suitable
    Alternate Methods for Determining Particle Size
    Distribution
  • Literature Data Suggests That for Mixed
    Propellant/co-solvent Formulations, Pressure
    Testing During Development Is Not a Reliable
    Means of Measuring Propellant Mixture Ratio.
    Integrity of the Propellant-Alcohol Mixture Is
    Better Controlled by Alcohol Content Analysis

50
FURTHER WORK OF TESTS METHODS TECHNICAL TEAM
  • Team Will Submit Technical Paper Containing
    Conclusions and Recommendations to Agency
    (Expected Submission - December 2000)
  • Team Will Collect and Analyze Data on Non-MDI
    Dosage Forms in Early 2001
  • Team Will Request Opportunity to Meet with Agency
    to Discuss Teams Findings
  • Willing to Address Further Questions Raised by
    Agency


51
ITFG/IPAC-RS TECHNICAL TEAMS CMC LEACHABLES AND
EXTRACTABLES ANDCMC SUPPLIER QUALITY
CONTROLPresented by Gordon Hansen15
NovemberRockville, MD
52
TEAM POSITION ON DRAFT CMC GUIDANCES
  • Team Supports Efforts of Agency in Drafting
    Guidance Documents Which Address Requirements for
    Leachables and Extractables for Orally Inhaled
    and Nasal Drug Products
  • Team Believes That Current Draft Guidances Could
    Be Enhanced by Clarification in Specific Areas
  • Team Has Identified Key Areas of Draft Guidances
    Which Would Benefit From Further Investigation
    and Dialogue With Agency
  • Team Is Prepared to Work With OINDP Subcommittee
    and FDA

53
STATUS REPORT OF LEACHABLES EXTRACTABLES TEAM
  • Key Issues for Clarification and Agency Dialogue
  • What are appropriate reporting/identification
    thresholds for leachables extractables?
  • How is a correlation between leachables and
    extractables established?
  • What are appropriate practices for establishing
    safety of leachables?
  • Is extractables profiling appropriate for
    control of component composition?
  • Which critical components should be subject to
    routine extractables testing?
  • Process Employed to Investigate Key Issues

54
STATUS REPORT OF TOXICOLOGY WORKING GROUP
  • Questions Investigated
  • What are current practices for establishing
    safety of leachables?
  • What recommendations should be made on safety
    evaluation of leachables?
  • Status
  • Reviewed Current Practices of Safety Evaluation
    of Leachables
  • Proposing Strategy for Safety Qualification of
    Leachables
  • Toxicology Strategy will be Incorporated into
    Points to Consider

55
KEY POINTS TO CONSIDER LEACHABLES EXTRACTABLES
TEAM
  • A Leachables Study Is a One-time Development
    Study
  • A Correlation Is Established Between Leachables
    and Extractables When Each Leachable Can Be
    Linked Qualitatively to a Corresponding
    Extractable
  • Once a Correlation Is Established, Leachables Are
    Controlled Through Routine Extractables Testing
    of Critical Components Which Contact the
    Formulation or Patients Mouth or Nasal Mucosa
  • The Final Guidances Should Include Reporting,
    Identification, and Qualification Thresholds for
    Leachables


56
TOXICOLOGY EVALUATION PROPOSAL
  • Add Separate Section to Each Guidance to Describe
    the Toxicology Evaluation Process, Including a
    Flowchart
  • Toxicological Qualification Should Be Performed
    Only on Leachables and Only on Leachables That
    Occur Above a Data-supported Threshold
  • Guidelines Should Distinguish Between Genotoxic
    and Non-genotoxic Leachables
  • For component suppliers, USP lt87gt and lt88gt may
    have utility for extractable testing. However
    for a pulmonary drug product, USP lt87gt and lt88gt
    are not necessary when a more comprehensive
    in-vivo toxicological evaluation is available

57
LE TEAMS NEXT STEPS
  • Will Submit Points to Consider
  • Will Request Opportunity to Meet with Agency to
    Discuss Teams Findings and Consider Appropriate
    Strategy for Establishing Toxicology Threshold
  • In Collaboration with the Supplier Quality
    Control Technical Team, Will Propose a Control
    Strategy (Including Appropriate Testing Criteria)
    for Ensuring Relevant Performance and Safety
    Characteristics of Critical Components
  • Willing to Address Further Questions Raised by
    Agency


58
STATUS REPORT OFSUPPLIER QUALITY CONTROL
TECHNICAL TEAM
  • Question Investigated
  • What is current status of compliance in
    component supplier industry?
  • Status
  • Conducted Survey of Suppliers to Evaluate Quality
    and Compliance Practices at All Stages of
    Component, Excipient, Raw Materials, and Active
    Drug Substance Manufacture
  • Concluded that No Generally Accepted cGMP
    Guidelines Exist for Component Supply Chains
  • Endorsed IPEC Guideline for Control and cGMP
    Compliance of Excipients
  • Proposed Industry-wide Initiative to Develop cGMP
    Guideline for Component Suppliers
  • Next Steps
  • In Consultation with FDA, Undertake Development
    of cGMP Guideline for Component Suppliers

59
ITFG/IPAC-RS COLLABORATION CONCLUDING
REMARKSPresented by Cynthia Flynn, PhD15
November 2000Rockville, MD
60
COMMITMENT OF ITFG/IPAC-RS COLLABORATION
  • More Than 100 Pharmaceutical Scientists From More
    Than 25 Companies and Institutions Have Been
    Working to Address Key Concerns in Draft CMC and
    BA/BE Guidance Documents
  • ITFG/IPAC-RS Is Committed to Assessing All
    Relevant Data Collected by the Collaboration, and
    Sharing Findings in a Timely Fashion With OINDP
    Subcommittee and Agency
  • ITFG/IPAC-RS Anticipates That Its Data-based
    Conclusions and Proposals Will Be Useful to the
    OINDP Subcommittee in Its Deliberations and the
    Agency in Its Preparation of Final CMC and BA/BE
    Guidances That Will Benefit Patients and the
    Pharmaceutical Industry

61
DATA-BASED CONCLUSIONS TO DATE
  • Based Upon Data Collected and Analyzed, Members
    of the ITFG/IPAC-RS Technical Teams Have
    Concluded That Certain Aspects of the Draft
    Guidances Should Be Revised
  • As Described in the Earlier Presentations, the
    Technical Teams Have Prepared or Will Prepare
    Specific Data-based Proposals for Modifying the
    Draft Guidance Documents

62
SUMMARY OF COLLABORATIONS TECHNICAL PAPERS
Specifications Team Initial Assessment of the
ITFG/IPAC Dose Content Uniformity (DCU) Database
(Submitted to FDA in July 2000) Initial
Assessment of the ITFG/IPAC Aerodynamic Particle
Size Distribution Database (Submitted to FDA in
August 2000) BA/BE Team Technical Paper on
FDAs Bioavailability and Bioequivalence
Questions Presented at 26 April OINDP Advisory
Subcommittee Meeting (Submitted to FDA in July
2000) Review of In Vivo and In Vitro Tests in
FDAs Draft Guidance on Bioavailability and
Bioequivalence Studies for Nasal Aerosols and
Nasal Sprays for Local Action and Anticipated
Forthcoming Guidance for Orally Inhaled Drugs
(Submitted to FDA in July 2000) Tests and
Methods Team Leachables and Extractables
Team Data-based Technical Reports Expected to be
Submitted in December 2000
63
ILLUSTRATIONS OF PROPOSED CHANGES TO DRAFT
GUIDANCES
  • BA/BE Team Draft BA/BE Guidance Contains Areas
    Where Scientific Basis Is Uncertain Further
    Scientific Dialogue Is Needed
  • Specifications Team Initial Assessment of DCU
    Database Indicates That OINDP Do Not in General
    Comply With DCU Specification in Draft CMC
    Guidance Initial Assessment of PSD Database
    Indicates That OINDP Do Not in General Comply
    With Proposed Mass Balance Requirement in Draft
    CMC Guidance (85-115 LC)
  • Test and Methods Team Collected Data Show That
    for Many Products, the CMC Draft Guidances MDI
    Tests for Spray Pattern, Water Content and Shot
    Weight Do Not Provide Meaningful Information
    About Product Quality
  • Leachables/Extractables Team Draft CMC Guidance
    Should Recognize That a Leachables Study Is a
    One-time Development Study CMC Guidance Should
    Include Reporting, Identification and
    Qualification Thresholds for Leachables

64
CONSIDERATION OF DATA-BASED PROPOSALS FOR
MODIFIYING GUIDANCES
We Believe It Is Important That the
Collaborations Data-Based Conclusions and
Proposals for Modifying the Draft OINDP Guidance
Documents Be Given Full Consideration Before the
Guidances Are Finalized
65
SCIENCE-BASED DIALOGUES NEEDED
  • The Collaboration Strongly Recommends That the
    Agency Continue to Work Towards Resolving These
    Important CMC and BA/BE Issues by Utilizing
    Existing Avenues for In-Depth Interactive,
    Scientific Dialogues, Including, as Appropriate
  • OINDP Subcommittee
  • PQRI
  • AAPS/FDA/USP Workshop
  • Dialogue with ITFG/IPAC-RS Collaboration
  • Such Dialogues Will Ensure That the OINDP
    Guidances Bring Maximum Value to Regulators and
    Industry, and Most of All, to Patients and
    Physicians

66
REQUEST TO ADVISORY COMMITTEE FOR PHARMACEUTICAL
SCIENCE
  • Participants of the ITFG/IPAC-RS Collaboration
    Respectfully Request That the Advisory Committee
    for Pharmaceutical Science
  • Support the Need for Continuing Scientific
    Dialogue on Important CMC and BA/BE Issues for
    Orally Inhaled and Nasal Drug Products Before
    Draft Guidance Documents Are Finalized
  • Endorse Our Request That Opportunities Be
    Identified for a Continued Dialogue Between FDA
    and the ITFG/IPAC-RS Collaboration Regarding the
    Collaborations Technical Papers and Data-based
    Conclusions

67
  • We Express Our Gratitude to the Agency for
    Holding This Meeting
  • We Appreciate the Opportunity to Present the Work
    of the ITFG/IPAC-RS Collaboration to the Agency
    and the Members of the Advisory Committee for
    Pharmaceutical Science
  • We Thank the Agency and the Members of the
    Advisory Committee for Pharmaceutical Science for
    Considering Our Comments and Proposals
  • We Hope That Our Past and Future Submissions and
    Interactions Will Assist the Agency, the Advisory
    Committee for Pharmaceutical Science and the
    OINDP Subcommittee in Their Work to Finalize
    These Important Guidance Documents Based on All
    Currently Available Scientific Evidence
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