Title: OVERVIEW OF ITFGIPACRS COLLABORATION FOR PRESENTATION TO THE ADVISORY COMMITTEE FOR PHARMACEUTICAL S
1OVERVIEW OFITFG/IPAC-RS COLLABORATIONFOR
PRESENTATION TO THEADVISORY COMMITTEE
FORPHARMACEUTICAL SCIENCE Presented by Harris
Cummings, PhD15 November 2000Rockville, MD
2The 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
3DRAFT 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draft OINDP Guidances - agree that certain sections of draft Guidance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
5ITFG/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
6STEERING 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
7Over 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
8ITFG/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
9NEED 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
10RECOGNITION 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
11ITFG/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
13BA/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
15BA/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
16BA/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
19ITFG/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
20ITFG/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
21OVERVIEW 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
22IN 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
23IN 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)
24IN 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
25IN 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
26IN 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
27IN 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.
28IN 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?
29IN 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.
30IN 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
32ITFG/IPAC-RS TECHNICAL TEAM CMC
SPECIFICATIONSPresented by Bo Olsson,
PhD15 November 2000Rockville, MD
33DOSE 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
34DCU 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
35DCU 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
36CONCLUSIONS 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.
37PLAN 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
38PARTICLE 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?
39PSD 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
40PSD 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
41CONCLUSION 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
42PLAN 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
43SPECIFICATIONS 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
44ITFG/IPAC-RS TECHNICAL TEAM CMC TESTS AND
METHODS Presented by Carole Evans, PhD 15
November 2000 Rockville, MD
45TEAMS OBJECTIVE
- The Team Would Like to Assist the Agency in
Developing CMC Testing Requirements That Provide
Valuable Information About Product Quality
46TEAM 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
47PRESENTATION 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
48TESTS 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
49TESTS 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
50FURTHER 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
51ITFG/IPAC-RS TECHNICAL TEAMS CMC LEACHABLES AND
EXTRACTABLES ANDCMC SUPPLIER QUALITY
CONTROLPresented by Gordon Hansen15
NovemberRockville, MD
52TEAM 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
53STATUS 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
54STATUS 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
55KEY 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
56TOXICOLOGY 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
58STATUS 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
59ITFG/IPAC-RS COLLABORATION CONCLUDING
REMARKSPresented by Cynthia Flynn, PhD15
November 2000Rockville, MD
60COMMITMENT 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
61DATA-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
62SUMMARY 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
63ILLUSTRATIONS 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
64CONSIDERATION 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
65SCIENCE-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
66REQUEST 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