itfg/ipac collaboration overview of itfg/ipac collaboration presented by: harris cummings, phd 26...

ITFG/IPACCollaboration

OVERVIEW OF

ITFG/IPAC COLLABORATION

Presented by: Harris Cummings, PhD

26 April 2000Rockville, MD


ITFG

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

Introduction


IPAC

The International Pharmaceutical Aerosol Consortium (IPAC) 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, and migraine, as well as new products for non-respiratory disease indications such as diabetes

Introduction


DRAFT FDA 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 ActionIntroduction


PERSPECTIVE OF ITFG and IPAC ITFG and IPAC:

•share FDA’s goal of assuring the highest levels of safety, efficacy and quality of OINDP and making these products available to patients expeditiously

•recognize the value of having OINDP guidance documents to facilitate the development and approval of new medications, but believe that differing views surround CMC and BA/BE issues

•believe that these differences need to be resolved through the process of a science-based dialogue so that the OINDP Guidances can bring maximum value to regulators and industry, and most of all, to patients and physicians

Introduction


BACKGROUND ON THE COLLABORATION

June 1999: AAPS/FDA/USP Workshop on OINDP Regulatory Issues

•IPAC presents a Statement proposing a consensus building process

•The ITFG endorses IPAC’s Statement

•The Agency agrees to consider IPAC’s proposal further

September 1999: ITFG and IPAC agree to undertake a data-driven collaborative effort

The objectives of the Collaboration are to:

•utilize the combined expertise and experience of scientists from IPAC Member Companies and AAPS Inhalation Technology Focus Group

•expand the knowledge base of the relevant science of OINDP

•facilitate common Understanding on CMC and BA/BE issues in order to provide the Agency and the Subcommittee with timely technical reports and recommendations for consideration during the Subcommittee’s deliberations

Introduction


FRAMEWORK OF ITFG/IPAC COLLABORATION

TECHNICAL TEAMS(Representatives of ITFG and IPAC)

BA/BE

IN VITRO

AND IN

VIVO

TESTS

CMC SPECIFICATIONS

DOSE CONTENT UNIFORMI

TY

PARTICLE SIZE

DISTRIBUTION

CMC SUPPLIE

R QUALITY CONTRO

L

CMC LEACHABLE

S AND EXTRACTBLE

S

CMC TESTS AND

METHODS

STEERING COMMITTEE(Representatives of ITFG and IPAC)

Introduction


PARTICIPATION IN THE COLLABORATION

3M PharmaceuticalsAgouronAradigmAstraZenecaAventisBespakBI RoxaneBoehringer IngelheimDura PharmaceuticalsEli Lilly Glaxo WellcomeInhale Therapeutic Systems

Inspire PharmaceuticalsIVAXKos PharmaceuticalsLovelace Respiratory InstituteMagellan LaboratoriesPfeifferPresspartPrimedicaSchering-PloughTrudell MedicalUniversity of Rhode IslandValois

Approximately 85 individuals and more than 20 companies are participating in the ITFG/IPAC Collaboration. Participants are from the following companies/institutions:

Introduction


WORK OF TECHNICAL TEAMS

In separate presentations today, leaders of the ITFG/IPAC Technical Teams will:

• provide an overview of the work of each Technical Team

and

• describe the Collaboration’s commitment to contribute constructively to the deliberations of the OINDP Subcommittee and the Agency’s development of the OINDP Guidance documents

Introduction


RECOGNITION OF AGENCY’S COMMITMENT TO IMPROVING QUALITY OF

OINDP

• ITFG and IPAC recognize and appreciate the significant effort made by the Agency to issue the draft product quality OINDP Guidances

• ITFG and IPAC strongly support the creation of the OINDP Subcommittee and are pleased to be able to participate in today’s meeting

• We thank the Subcommittee and the Agency for considering our comments and proposals

Introduction


ITFG/IPAC TECHNICAL TEAM: BA/BE IN VITRO AND IN

VIVO TESTS

Presented by: Stephen Farr, PhD



BA/BE: IN VITRO TESTS

BA/BE: IN VITRO TESTS

BA/BE: IN VIVO TESTS

BA/BE: IN VIVO TESTS

Working Proposition

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 BE approval without establishing in vivo BE.

Working Proposition

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.

WORKING PROPOSITIONS

BA/BE Technical Team


WORKING ASSUMPTIONS

The Team’s BA/BE recommendations apply to locally acting drugs only (per the current draft BA/BE Guidance).

The Team’s 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.

The Team’s BA/BE working propositions reflect only the current state of knowledge.BA/BE Technical Team


CONCLUSIONS TO DATE• Based on the available literature, current in vitro tests may

predict lung deposition but BE predictability has not been shown

• In vitro tests described in current draft BA/BE Guidance are not necessarily more relevant or discriminating than clinical studies for BE assessment

• 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).

• Because all of the preceding statements apply equally to solutions and suspensions, the assumption that in vitro studies alone are sufficient for BE of solutions is unfounded. The Guidance should not distinguish between nasal

suspensions and solutions for in vivo BE. BA/BE Technical Team


BA/BE TEAM’S COMMITMENTS

Team is committed to prepare a technical paper on the BA/BE issues in the draft BA/BE Guidance.

The purpose of the paper will be to:

• Highlight areas where there is sufficient data to draw conclusions and where there is not enough data at present

• Review technical documentation related to BA/BE issues addressed by the Team

Team expects to complete the paper by end of June 2000

BA/BE Technical Team


ITFG/IPAC TECHNICAL TEAM: CMC SPECIFICATIONS

Presented by: Bo Olsson, PhD



CMC SPECIFICATIONS TECHNICAL TEAM

Focus on •Dose Content Uniformity (DCU)

•Particle Size Distribution (PSD)


ICH: HARMONIZATION

OINDP are amenable to the principles set forth by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH).

The ICH Harmonized Tripartite Guideline on

"Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances" (Q6A) provides a process for establishing specifications.


ICH Q6A: SPECIFICATIONS

“The justification [of specifications] should refer to relevant development data, pharmacopoeial standards, test data for drug substances and drug products used in toxicology and clinical studies, and results from accelerated and long term stability studies, as appropriate.

Additionally, a reasonable range of expected analytical and manufacturing variability should be considered.

It is important to consider all of this information.”

(62 Fed Reg 62892)


DCU

Hypothesis:

The current state of OINDP technology may not allow general compliance with the DCU specifications in the draft FDA CMC Guidances.

To date, more than 12 companies have initiated the process to collect a world-wide blinded database of more than 45 products to examine actual DCU capability of OINDP

Initial assessment by July 31


DCU

ITFG/IPAC position:

The specifications in the draft Guidances should be based upon sound statistical practices such that they can be translated into quality requirements.

Investigate, using database, alternate DCU specifications

• ICH Q4 (Pharmacopoeial Harmonisation) draft proposal • Dr. Walter Hauck's Approach• ISO 2859-1 Approach• Other Approaches


PSD

To date, more than 12 companies have initiated a process to collect a world-wide blinded database of more than 40 products to examine actual PSD capability of OINDP

Initial assessment by July 31

Purpose of PSD survey• 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.


ITFG/IPAC TECHNICAL

TEAM:

CMC TESTS & METHODS

Presented by: Carole Evans, PhD



OVERALL POSITION ON DRAFT CMC GUIDANCES The need for certain tests should be driven by

evaluation of data generated during the development phase of each product.

In many instances, the language in the draft CMC Guidances is ambiguous.

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.

The Team is prepared to work with the OINDP Subcommittee and the FDA to facilitate harmonization of FDA, USP, and ICH.

CMC Tests and MethodsTechnical Team


MDI TESTS

• Water (Moisture) Content

• Spray Pattern

• Impurities & Degradants

• Pressure Testing

• Plume Geometry

• Particle Size Distribution

• Dose Content UniformityCMC Tests and MethodsTechnical Team


• The Team developed working position statements for these tests.

• Members plan to collect and evaluate data regarding many of these working position statements.

TEAM’S APPROACH



TEAM’S COMMITMENT•The Team will prepare technical papers

containing any recommendations regarding MDI tests, in the next 3-4 months.

•The Team would like to suggest alternate language for the draft CMC Guidances to make testing criteria specific to particular dosage forms.

•The Team will develop position statements and repeat this process for other dosage forms



The Team would like the opportunity to share our recommendations with the OINDP Subcommittee and the Agency

TEAM’S COMMITMENT



ITFG/IPAC TECHNICAL TEAM: CMC LEACHABLES AND

EXTRACTABLES

Presented by: Kaushik J. Dave, R.Ph, PhD



LEACHABLES AND EXTRACTABLESTECHNICAL TEAM

The Team recognizes that control of extractables and leachables is important for ensuring the safety and quality of inhalation drug products

CMC Leachables and Extractables Technical Team


DEFINITIONS

Extractables:Compounds that can be extracted from the elastomeric or plastic components, or coatings of the container closure system when in contact with appropriate solvent(s).

Leachables:Compounds that leach into the formulation from the elastomeric or plastic components, or coatings of the container and closure system as a result of direct contact with the formulation.



TEAM’S FOCUSThe Team has identified four key areas of the draft

CMC guidances for clarification and/or further investigation:

• Analytical Characterization of Extractables (Control Extraction Studies)

• Analytical Characterization of Leachables

• Safety Qualification of Leachables

• Routine Extractables Testing



TEAM’S TOPICS FOR STUDY

1. Analytical Characterization of Extractables (Control Extraction Studies)

The Team requests clarification and will propose alternate language with respect to the specific requirements for control extraction studies (e.g., determination of which critical components are required for extractables analysis )



2. Analytical Characterization of Leachables

How is a correlation with extractables established?

The Team will prepare a review of available leachables data and examine it for correlation with the corresponding extractables data. A working definition of correlation will be proposed based on an examination of the data.




3. Safety Qualification of Leachables

What are current industry practices for establishing safety of leachables?

The Team’s Working Group on Toxicology will survey current industry practices and will propose a strategy for safety qualification of leachables based on best practices (e.g., What are the qualification criteria? Does ICH apply?)




4. Routine Extractables TestingIs quantitative testing of extractables appropriate for control of composition of all components?

The Leachables and Extractables Team, in collaboration with Supplier QC Team, will propose a control strategy combining appropriate scientific practices, cGMP controls and supplier qualification systems for ensuring the relevant performance and safety characteristics of critical components




TEAM’S APPROACH AND COMMITMENT

The Team is committed to offer data-based technical reports and recommendations to the Agency and the OINDP Subcommittee within 3-4 months.

The Team is available to evaluate any extractable and leachable issue which the Agency and the OINDP Subcommittee request.



ITFG/IPAC TECHNICAL TEAM: SUPPLIER QUALITY

CONTROL (QUALIFICATION)

Presented by: Gordon Hansen



SUPPLIER QUALITY CONTROL TEAM

Team membership is comprised of representatives from 9 pharma companies and 5 key component manufacturers.

CMC Supplier Quality ControlTechnical Team


SUPPLIER QUALITY CONTROL TEAM

A core theme of the draft CMC guidances with respect to component, excipient, and raw material suppliers is summarized below:

Tight standards and extensive testing by the pharma manufacturer are required in order to assure batch to batch quality of components and excipients.



TEAM’S THESIS

The qualification and control of critical components (in the areas of performance related physical testing, extractables and leachables) and excipients should be achieved by a combination of appropriate scientific practices, cGMP controls and supplier qualification systems.



TEAM’S APPROACH: cGMP SURVEY

A survey of suppliers was conducted to evaluate quality and compliance practices at all stages of component, excipient, raw materials, and active drug substance manufacture

•Survey requested assessment of performance related to 31 specific cGMP elements

•Circulated to all companies represented on Team

•Information obtained on 53 suppliers, from raw materials through finished component manufacture




Results:

• Highest level of compliance is evident with active ingredient suppliers

• Level of cGMP awareness and compliance in the component and raw material supply chain is increasing, but needs to be improved

• Specific cGMP program elements remain to be generally accepted and implemented, especially early in supply chain




Results:

•No generally accepted cGMP guidelines exist for the component supply chain

•cGMP guidelines have been drafted by IPEC (International Pharmaceutical Excipients Council)



PROPOSALS AND COMMITMENTS

• The Team endorses the IPEC Guideline for the control and cGMP compliance of excipients

• The Team proposes that an industry-wide initiative be established to develop a cGMP guideline for component suppliers



PROPOSALS AND COMMITMENTS

The Team requests that the Agency partner with the pharma industry and component suppliers by:

• Formally recognizing the value of a cGMP guideline for component suppliers by acknowledging in the guidance documents that if sufficient supplier control mechanisms are in place, appropriate reductions in testing will be considered.

• Establishing key elements and expectations for a cGMP guideline.

• Participation in reviewing and commenting on draft cGMP guidelines.



ITFG/IPAC COLLABORATION: CONCLUDING REMARKS

Presented by: Cynthia Flynn, PhD



COMMITMENT OF THE ITFG/IPAC COLLABORATION

•More than 85 pharmaceutical scientists from more than 20 companies have been working diligently and constructively to address key concerns in draft CMC and BA/BE Guidance documents

•ITFG/IPAC is committed to collecting and assessing all relevant data available to the Collaboration, and sharing the findings in a timely fashion with the OINDP Subcommittee and the Agency

•ITFG/IPAC anticipates that this information will be useful to 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

Conclusion


TIMEFRAME FOR TECHNICAL TEAM DELIVERABLES

BA/BE Team: technical paper on BA/BE issues will be completed by June 30, 2000

Specifications Team: initial assessment of actual DCU & PSD capabilities of OINDP based on a statistical evaluation of the gathered database by July 31, 2000

Tests and Methods Team: technical paper on key MDI tests will be completed in next 3-4 months

Leachables/Extractables Team: technical reports will be written and recommendations made in next 3-4 months

Supplier Quality Control Team: act as a co-leader in developing a cGMP guideline for component manufacturers with the AgencyConclusion


NEED FOR A SCIENCE-BASED INTERACTIVE DIALOGUE

The ITFG/IPAC Collaboration requests that the Agency:

continue the OINDP Subcommittee process in order to resolve concerns about key CMC and BA/BE issues through a science-based interactive dialogue

Conclusion


ACKNOWLEDGEMENTS

We express our gratitude to the Agency for holding this meeting and allowing us to present the work of the ITFG/IPAC Collaboration

We thank the members of the OINDP Subcommittee for considering our comments and proposals

We acknowledge the hard work, commitment and constructive collaboration of the numerous experts involved in the ITFG/IPAC Collaboration

Conclusion


PARTICIPANTSLex Adjei V.P., Research Kos Pharmaceuticals

Melton Affrime V.P. Clinical Research Schering-Plough

David Alexander Glaxo Wellcome

Lisa Antonino Inhale Therapeutics

James Blanchard Staff Scientist Aradigm

Allan Boksar Sr. Manager Quality Lab. Operations Dura Pharmaceuticals

Lars Borgström Scientific Adviser AstraZeneca

Guillaume Brouet Laboratory Manager Valois of America

Scott Brown Mgr., Pharmaceutical Dev. Schering-Plough

Jean Cao Statistician Schering-Plough

Yung Sung ChengLovelace Respiratory Institute

Eric CoutureDirector, Regulatory Liaison AstraZeneca

Jacqueline Crew Aventis

Harris Cummings Exec. Director Aerosol Product Development Magellan Laboratories

Kaushik Dave Manager Schering-Plough

Sarvajna Dwivedi Dura Pharmaceuticals

Mark Eaves Marketing Director Presspart

Charles EckDir., Inhalation Technologies Primedica

Bruce EkholmBiostatics Section Leader 3M Pharmaceuticals

Michael Eldon Director, Regulatory Affairs Inhale Therapeutics

James ElvecrogMgr. Analytical R&D3M Pharmaceuticals

Elizabeth Erdos Director, Quality Assurance Aradigm

Mark EskesAssociate Scientist Agouron

Richard EvansSr. Director, Pharmaceutical Dev. Inspire Pharmaceuticals

Carole Evans Section HeadMagellan Laboratories

Barbara Falco Dir., Quality Assurance Kos Pharmaceuticals

Stephen FarrV.P., Pharmaceutical Sciences Aradigm

Joseph Ferrara Director, Government Policy Boehringer Ingelheim

Kevin C. Fitzgerald Sr. Assistant Dir., Technical RegulatoryAffairs DepartmentGlaxo Wellcome

Conclusion


PARTICIPANTSCynthia Flynn Dir., Worldwide Drug Product Pharmaceutical Quality Analysis Aventis

Igor Gonda V.P., R&D Aradigm

William Gore Dir., Analytical Sciences Boehringer Ingelheim

Bernard Greenspan Dir., Aerosol Technology Dura Pharmaceuticals

Kristi Griffiths Senior Statistician Eli Lilly

Gordon Hansen Associate Dir.Analytical Sciences Boehringer Ingelheim

Lester I. Harrison Sr. Research Specialist 3M Pharmaceuticals

Stephen Horhota Research & Development Boehringer Ingelheim

Paul Kovach Sr. Research Scientist Eli Lilly

Robert L. KunkaGroup Leader, Clinical Pharmacology Glaxo Wellcome

Susan Lanham Regulatory ManagerEli Lilly

Nicholas J. LicatoSr. Manager, QC Dura Pharmaceuticals

Alice Loper V.P., Pharmaceutical DevelopmentSchering-Plough

Andrea McPhillips Section Head, Product Development BI Roxane

Fiona MillarHead, Product DevelopmentIVAX

Jolyon Mitchell Scientific Director Trudell Medical

Matthew Moran Sr. Regulatory Affairs SpecialistAgouron

John MorganDirector, Regulatory Affairs Glaxo Wellcome

Thomas E. NeedhamApplied Pharmaceutical Sciences University of Rhode Island

Steven Nichols Aventis

Daniel Norwood Sr. Principal Scientist Boehringer Ingelheim

Jay Occulto Dir., Regulatory Affairs Pfeiffer of America

Bo Olsson Scientific Adviser AstraZeneca

Kevin Ostrander Mgr., Formulation Development NanoSystems

Terry Pait Manager, Quality Control Glaxo Wellcome

Rajni Patel Assoc. Dir., Pulm. Analy. Dev. Boehringer Ingelheim

Björn Persson Dir., Analytical Development AstraZeneca

Judith R. Plon Director, Regulatory Affairs Aventis

Conclusion


PARTICIPANTSEric Plummer Dir., Advance Sciences Bespak

John N. PritchardGlaxo Wellcome

Ann Purrington 3M Pharmaceuticals

Nats RajagopalanBiopharm. Project Dev.Eli Lilly

Michael T. Reibe Dir., Inhalation Product Development Glaxo Wellcome

Shashank Rohatagi Drug Metobolism/Pharmacokinetics Aventis

Darlene Rosario Assoc. Dir., Regulatory Affairs Dura Pharmaceuticals

Colin Rowlings Agouron

Dennis Sandell Principal Research Scientist AstraZeneca

Julie SatterwhiteRes. ScientistEli Lilly

David Schultz Research Specialist 3M Pharmaceuticals

Jeff Schuster Dir., Aerosol Technology Dev. Aradigm

Christopher J. Sciarra Vice President Sciarra Laboratories

Joel Sequeira Sr. Associate Director Schering-Plough

Sam Shum Analytical R&D Kos Pharmaceuticals

Ann Smith Operations CMC Strategy Manager AstraZeneca

Edmundo Stahl Dir., Pulmonary Dpt. IVAX

Susan Tiano Sultzbaugh Pharmaceutical R&D Schering-Plough

Yosyong Surakitbanharn, Research Scientist Pharmaceutical DevelopmentAgouron

Terrence Tougas Assoc. Dir, Analytical Sciences Boehringer Ingelheim

Keith Truman Mgr., Dry Powder Development Group Glaxo Wellcome

Steven Viti Assoc. Dir., Regulatory Affairs IVAX

Ed Warner Dir., Statistical Support Schering-Plough

Tomas P. WeberSr. Manager, Product Development Dura Pharmaceuticals

Tony West Aventis

Steve White Technical Leader Inhale Therapeutics

David Whitman Inhalation Analytical Scientist3M Pharmaceuticals

Ronald Wolff Sr. Research ScientistEli Lilly

Bruce Wyka Dir., Physical & Analytical Chemistry Schering-Plough

Harold Yeager Eli Lilly

Conclusion

itfg/ipac collaboration overview of itfg/ipac collaboration presented by: harris cummings, phd 26...

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