# Presentation: 658824

## OVERVIEW OFITFG/IPAC-RS COLLABORATIONFOR PRESENTATION TO THEADVISORY COMMITTEE FORPHARMACEUTICAL SCIENCE Presented by: Harris Cummings, PhD15 November 2000Rockville, MD

**OVERVIEW OF****ITFG/IPAC-RS COLLABORATION****FOR PRESENTATION TO THE****ADVISORY COMMITTEE FOR****PHARMACEUTICAL SCIENCE** Presented by: Harris Cummings, PhD15 November 2000Rockville, MD

## 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

## DRAFT GUIDANCES FOR OINDP

- 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*

**DRAFT GUIDANCES FOR OINDP**

## ITFG and IPAC-RS:

**ITFG and IPAC-RS:**
- share FDA’s 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- agree that certain sections of  draft Guidance documents need to be modified to be consistent with today’s drug development technologies and capabilities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

## ITFG/IPAC-RS COMMITMENT TO 

- 	(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
- 	(July and August 2000)

**ITFG/IPAC-RS COMMITMENT TO **
**ADDRESS OINDP ISSUES**

## TECHNICAL TEAMS

**STEERING COMMITTEE**

**TECHNICAL TEAMS**

**CMC  SUPPLIER QUALITY CONTROL**

**CMC****TESTS AND METHODS**

**CMC  SPECIFICATIONS**

**DCU WG**

**PSD WG**

**CMC LEACHABLES & EXTRACTABLES **
**TOXICOLOGY WG**

**BA/BE IN VITRO AND IN VIVO TESTS**

## Over 100 individuals from more than 25 companies/institutions are participating in the ITFG/IPAC-RS Collaboration

**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**

## 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 Collaboration’s Data-based Conclusions
- Explain Plans for Further Work
- Describe Data-based Proposals to Modify Draft Guidances

**ITFG/IPAC-RS TECHNICAL TEAMS**

## NEED FOR SCIENCE-BASED DIALOGUES

**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 Collaboration’s Technical Papers and Data-based Proposals to Modify the Draft Guidance Documents **

**NEED FOR SCIENCE-BASED DIALOGUES**

## RECOGNITION OF AGENCY’S COMMITMENT TO IMPROVING QUALITY OF OINDP

- ITFG and IPAC-RS  Recognize and Appreciate Agency’s Efforts in Issuing Draft Product Quality OINDP Guidances and Agency’s Initial Steps Towards a Scientific Dialogue
- ITFG and IPAC-RS Strongly Support Agency’s 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 Today’s Meeting

**RECOGNITION OF AGENCY’S COMMITMENT TO IMPROVING QUALITY OF OINDP**

## ITFG/IPAC-RS TECHNICAL TEAM BA/BE IN VITRO AND IN VIVO TESTSPresented by: Lars Borgström, PhD 15 November 2000Rockville, MD

- ITFG/IPAC-RS TECHNICAL TEAM BA/BE IN VITRO AND IN VIVO TESTSPresented by: Lars Borgström, PhD 15 November 2000Rockville, MD

## Commitments made at 26 April OINDP Subcommittee Meeting

- To Develop Position Statements on BA/BE Studies
- To Respond to FDA’s BA/BE Questions from 26 April 		OINDP Subcommittee Meeting
**Status**
- 	Prepared Two Technical Papers, Submitted to FDA on 30 August 2000
**	**
***Technical Paper on FDA’s Bioavailability and Bioequivalence Questions Presented at 26 April 2000 OINDP Advisory Subcommittee Meeting***
***Review of In Vivo and In Vitro Tests in FDA’s Draft Guidance on Bioavailability and Bioequivalence Studies for Nasal Aerosols and Nasal Sprays for Local Action and  Anticipated Forthcoming Guidance for Orally Inhaled Drugs***

## 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.

**BA/BE:  IN VIVO TESTS**

- 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.

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

- 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
- Team’s BA/BE position statements reflect only the current state of knowledge

## BA/BE TEAM’S FINDINGS: IN VITRO TESTS

**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**

**BA/BE TEAM’S FINDINGS: IN VITRO TESTS**

## BA/BE TEAM’S FINDINGS: IN VIVO TESTS

**BA/BE TEAM’S 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**
- R**eduction 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**

## Team’s 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

## Requesting Opportunity to Meet with Agency to Discuss Team’s Findings

**Requesting Opportunity to Meet with Agency to Discuss Team’s Findings**
**Willing to Address Further Questions Raised by Agency**

## ITFG/IPAC-RS BA/BE TECHNICAL TEAM RESPONSES TO AGENCY’S BA/BE QUESTIONS RAISED AT OINDP SUBCOMMITTEE MEETINGPresented by: Les Harrison, PhD 15 November 2000Rockville, MD

- ITFG/IPAC-RS BA/BE TECHNICAL TEAM RESPONSES TO AGENCY’S BA/BE QUESTIONS RAISED AT OINDP SUBCOMMITTEE MEETINGPresented by: Les Harrison, PhD 15 November 2000Rockville, MD

## 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

## 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 Subcommittee’s Answers
- Collaboration has Provided Responses Where Subcommittee’s Answers Were Limited
- Need More Opportunities to Consider these Difficult Questions
- Agency Should Continue to Dialogue with Public

## IN VITRO BA/BE TESTING

**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

## IN VITRO BA/BE TESTING

**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)**

## IN VITRO BA/BE TESTING

**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

## IN VITRO BA/BE TESTING

**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

## IN VIVO BA/BE TESTING

**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

## IN VIVO BA/BE TESTING

**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.

## IN VIVO BA/BE TESTING

**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?*

## IN VIVO BA/BE TESTING

**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.

## IN VIVO BA/BE TESTING

**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.

## Questions Posed by FDA on the Draft BA/BE Guidance have Underscored a Number of Open Issues

**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**

## ITFG/IPAC-RS TECHNICAL TEAM CMC SPECIFICATIONSPresented by: Bo Olsson, PhD15 November 2000Rockville, MD

- ITFG/IPAC-RS TECHNICAL TEAM CMC SPECIFICATIONSPresented by: Bo Olsson, PhD15 November 2000Rockville, MD

## DOSE CONTENT UNIFORMITY (DCU)

**Team’s 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?*
**Team’s Approach:**
- Collect Worldwide Database to Investigate Actual DCU Capabilities and Appropriate Statistical Approaches

## 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*

## 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**

## 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.**

## 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. Hauck’s Approach of Statistical Hypothesis Testing
- Other Approaches

## PARTICLE SIZE DISTRIBUTION (PSD)

**Team’s 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.
**Team’s 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?*

## 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

## 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

## 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**

## 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

## SPECIFICATIONS TEAM CONCLUSIONS

**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**

## ITFG/IPAC-RS TECHNICAL TEAM

**CMC TESTS AND METHODS**
**Presented by:  Carole Evans, PhD**
**15 November 2000**
**Rockville, MD**

## TEAM’S OBJECTIVE

- The Team Would Like to Assist the Agency in Developing CMC Testing Requirements That Provide Valuable Information About Product Quality

## 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

## 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
- The Team Committed to Conducting Data-Based Investigations of these Position Statements, where Appropriate

## TESTS & METHODS TEAM STATUS REPORT

- Collected and Analyzing Data to Investigate the Team’s 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
- Compiled Data from the Scientific Literature for:
- Particle Size Distribution -- Investigation of Alternate Methods
- Pressure testing for single propellant/co-solvent mixtures

## 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

**TESTS & METHODS TEAM PRELIMINARY FINDINGS ON MDI TESTS**

## 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 Team’s Findings
- Willing to Address Further Questions Raised by Agency

**FURTHER WORK OF TESTS & METHODS TECHNICAL TEAM**

## ITFG/IPAC-RS TECHNICAL TEAMS CMC LEACHABLES AND EXTRACTABLES ANDCMC SUPPLIER QUALITY CONTROLPresented by: Gordon Hansen15 NovemberRockville, MD

- ITFG/IPAC-RS TECHNICAL TEAMS CMC LEACHABLES AND EXTRACTABLES ANDCMC SUPPLIER QUALITY CONTROLPresented by: Gordon Hansen15 NovemberRockville, MD

## 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

## 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:**
- Collected drug product specific leachables and extractables data in order to investigate the concept of correlation
- Formed Toxicology Working Group to Address Toxicology Issues for Leachables
-  Investigated current supplier practices for control of component composition and extractables profiles

## 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*

## 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 Patient’s Mouth or Nasal Mucosa
- The Final Guidances Should Include Reporting, Identification, and Qualification Thresholds for Leachables

## 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 <87> and <88> may have utility for extractable testing.  However for a pulmonary drug product, USP <87> and <88> are not necessary when a more comprehensive in-vivo toxicological evaluation is available

##  L&E TEAM’S NEXT STEPS

-  **L&E TEAM’S NEXT STEPS**

- Will Submit *Points to Consider*
- Will Request Opportunity to Meet with Agency to Discuss Team’s 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

## STATUS REPORT OFSUPPLIER 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**

## ITFG/IPAC-RS COLLABORATION CONCLUDING REMARKSPresented by: Cynthia Flynn, PhD15 November 2000Rockville, MD

- ITFG/IPAC-RS COLLABORATION CONCLUDING REMARKSPresented by: Cynthia Flynn, PhD15 November 2000Rockville, MD

## COMMITMENT OF ITFG/IPAC-RS COLLABORATION

**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

## DATA-BASED CONCLUSIONS TO DATE

**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

## SUMMARY OF COLLABORATION’S 

**SUMMARY OF COLLABORATION’S**** **
**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 FDA’s 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 FDA’s 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

## ILLUSTRATIONS OF PROPOSED CHANGES TO DRAFT GUIDANCES

**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 Guidance’s 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

## CONSIDERATION OF DATA-BASED PROPOSALS FOR MODIFIYING GUIDANCES

**CONSIDERATION OF DATA-BASED PROPOSALS FOR MODIFIYING GUIDANCES**

- We Believe It Is Important That the Collaboration’s Data-Based Conclusions and Proposals for Modifying the Draft OINDP Guidance Documents Be Given Full Consideration Before the Guidances Are Finalized

## SCIENCE-BASED DIALOGUES NEEDED 

**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

## REQUEST TO ADVISORY COMMITTEE FOR PHARMACEUTICAL SCIENCE

**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 Collaboration’s Technical Papers**** and ****Data-based Conclusions**

## We Express Our Gratitude to the Agency for Holding This Meeting 

- 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