Bioequivalence Studies and Other Recommendations for Orally Inhaled and Nasal Drug Products: Work of the ITFG/IPAC-RS C

1. Bioequivalence Studies and Other Recommendations for Orally Inhaled and Nasal Drug Products: Work of the ITFG/IPAC-RS Collaboration Presented by David Radspinner, Ph.D., Carole Evans, Ph.D. James Blanchard, Ph.D., and Joel Sequeira, Ph.D. Rockville, MD 19 July 2001

2. ITFG and IPAC-RS 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. Background • ITFG and IPAC-RS formed a collaboration in 2000 to address CMC and BA/BE issues in FDA draft Guidances • ITFG/IPAC-RS Technical Teams previously presented their concerns with regulatory science issues of OINDP and made commitments to gather and analyze relevant data and submit technical reports - 26 April 2000 (OINDP Subcommittee) - 15 November 2000 (Advisory Committee)

4. Objective • Update committee members on work and proposals of ITFG/IPAC-RS CMC Technical Teams • Present views of ITFG/IPAC-RS BA/BE Technical Team on dose-response studies

5. CMC Issues Addressed by ITFG/IPAC-RS • Dose Content Uniformity • Particle Size Distribution • Tests and Methods • Leachables and Extractables

6. Dose Content Uniformity Presented by David Radspinner, Ph.D., Rockville, MD 19 July 2001

7. DCU Update • Collected and analyzed DCU database and submitted findings to FDA in July 2000 Initial Assessment of the ITFG/IPAC-RSDose Content Uniformity Databaseby the CMC Specifications Technical Team of the ITFG/IPAC-RS Collaboration • At November 2000 meeting reported results to this Committee: 68% of analyzed products do not comply with one of FDA test requirements • Met with FDA in November 2000 and May 2001 to discuss findings and plans for future work • Developed improved DCU test

8. Foundation for New DCU Test • Parametric tolerance interval approach proposed by Dr. Hauck • Test design concepts proposed by ICH • Quality standards implied by FDA draft Guidances • Capabilities of modern inhalation technology

9. Parametric Tolerance Interval Testfor Improved Control of DCU in OINDP • Parametric tolerance interval approach • Increased efficiency in using sample information • Improved consumer protection (in statistical sense) • Improved producer protection • Quality: proportion of doses in batch that fall within target interval • Acceptance criteria on sample mean, sample standard deviation and acceptance value • Consistent quality standard, flexible testing schedule • Single test for control of within-unit and between-unit variability • Sample size on average is increased

10. DCU Next Steps • Draft report currently under review. Anticipate submission to FDA in fall 2001 • Anticipate meeting with FDA to discuss new test.Recommend that new test replace that in current draft Guidances.

11. Particle Size Distribution Tests and Methods Presented by Carole Evans, Ph.D. Rockville, MD 19 July 2001

12. Particle Size Distribution - Mass Balance (1) Key Concern: 85-115% LC mass balance is not appropriate as a drug product specification • Mass balance attempts to measure emitted dose, which is appropriately controlled by a separate specification (DCU) • Could be appropriate as part of system suitability control, but not as a release specification for finished drug product • Limits should be determined from validation studies and not set arbitrarily • Label claim is not necessarily defined by the mass of drug collected on all stages and accessories • Compliance in general is not feasible, as demonstrated by database analysis

13. Particle Size Distribution - Mass Balance (2) Update • Collected and analyzed industry data • Submitted report to FDA in August 2000 Initial Assessment of the ITFG/IPAC-RS AerodynamicParticle Size Distribution Databaseby the CMC Specifications Technical Team of the ITFG/IPAC-RS Collaboration Next Steps • Submitted proposal to PQRI

14. Particle Size Distribution as In Vitro BE Test (1) Key Concern PSD Profile Comparisons based on chi-square differences of Test and Reference profiles may not be most appropriate method • Chi-square method was developed for one particular product type and specific particle sizing equipment. Applicability to other products and PSD methods may be limited • Critical equivalence limit is set arbitrarily

15. Particle Size Distribution as In Vitro BE Test (2) Update • Carried out initial investigations of alternate approaches (e.g.,based on bootstrapping) Next Steps • Submitted proposal to PQRI

16. Tests and Methods (1) Key Concern • CMC QC tests for drug product should be selected based on development data, and should provide meaningful information about product quality Update • Collected and analyzed industry data • Submitted report to FDA in May 2001 Recommendations forTests and Methods

17. Tests and Methods (2) Recommendations for Tests and Methods Paper - Water Content - Pressure - Shot Weight - Particle Size Distribution - Spray Pattern - Dose Content Uniformity - Plume Geometry - Impurities and Degradants Next Steps • Will consider submitting proposals to PQRI

18. Leachables and Extractables Presented by James Blanchard, Ph.D., Rockville, MD 19 July 2001

19. Leachables and Extractables Key Concerns • Appropriate reporting/identification/qualification thresholds for leachables and extractables • Definition of correlation; critical component Update • Collected and analyzed industry data • Submitted report to FDA in March 2001 Leachables and ExtractablesTesting: Points to Consider

20. Points to Consider Paper • Controlled Extraction Studies • Definition of critical components • 1 g/g reporting threshold and 100 g/g identification threshold (confirmed structures) for extractables • Leachables Study • Toxicological evaluation should be performed only on leachables • Definition of correlation • 0.2 gtotal daily intake (TDI) reporting threshold and a 2 g (TDI) identification threshold (confirmed structures) for each leachable • Routine Extraction Studies • Purpose is to ensure that extractables profiles of components used in commercial manufacture remain consistent with profiles of components used in pivotal development studies

21. Leachables and Extractables Testing Process with Reporting Threshold Critical Component Contacts formulation or patient’s mouth or mucosa? YES NO Routine Extraction Studies and other testing, if necessary • Controlled Extraction Studies • Qualitative and quantitative assessment of all peaks > 1-20 g/g Other (not extractables) testing is sufficient (e.g., functional, identity, dimensional, etc. – as necessary). • Design and conduct a Leachables Study on aged registration batches through shelf life to quantify in drug product the extractables identified above • Quantify all peaks > 0.2 g TDI (Reporting Threshold) • Provide identity and quantity of the leachables to toxicologists for assessment Biological Safety Qualification of Leachables TDI = Total Daily Intake

22. Qualification Process with Reporting and Qualification Thresholds Risk Assessment Acceptable? Individual Leachable Above Reporting Threshold (>0.2 g TDI)? YES NO No Additional Evaluation*  5g TDI (some structural info.) > 5g TDI (structureconfirmed) No SAR Concerns SAR Concerns Qualified Collect Toxicological Data, SAR, Literature, and In Vivo Data TDI = Total Daily Intake SAR = Structure Activity Relationships *For certain classes of potential leachables with special toxicological concerns [i.e., nitrosamines, polynuclear aromatics (PNAs), mercaptobenzthiazole, etc.] lower reporting thresholds, dedicated methods, appropriate specifications, and appropriate qualifications and risk assessments may be required. YES NO Qualified Reduce, Remove, or Collect More Data

23. Leachables and Extractables Next Steps • Guidances should incorporate a leachables qualification program, including reporting and toxicological qualification thresholds for leachables • Approach proposed by ITFG/IPAC-RS should be carefully considered by toxicologists and chemists from FDA, industry, and academia • Submitted proposal to PQRI

24. Consideration of OINDP Issues • The ITFG/IPAC-RS Collaboration plans to bring several proposals to PQRI, and continue discussions with the Agency regarding the new DCU proposal • We hope that through the meetings of the OINDP Subcommittee, Advisory Committee for Pharmaceutical Science, PQRI, and other appropriate fora, the work of the ITFG/IPAC-RS Collaboration will be carefully considered • We believe that FDA and industry will be better able to respond to the needs of patients by expediting the availability of new OINDP products while maintaining appropriate standards of safety, efficacy and quality • We are grateful for the Agency’s consideration of BA/BE and CMC issues for OINDP

25. Bioequivalence Studies for Locally Acting Nasal Drugs Presented by Joel Sequeira, Ph. D. Rockville, MD July 2001

26. BA/BE Team’s Work to Date • FDA Presentations • 26 April 2000 OINDP Subcommittee Meeting • 15 November 2000 Advisory Committee for Pharmaceutical Science • Agency Meeting 26 April 2001 • 17 July 2001 OINDP Subcommittee Meeting • Reports Submitted to FDA • 30 August 2000: Technical Paper on FDA’s BA/BE Questions Presented at 26 April 2000 OINDP Advisory Subcommittee Meeting • 30 August 2000: Review of In Vivo and In Vitro Tests in FDA’s Draft Guidance on BA/BE Studies for Nasal Aerosols and Nasal Sprays for Local Action andForthcoming Guidance for Orally Inhaled Drugs • 5 April 2001: On the Risks of Eliminating In Vivo Studies for Nasal Solutions for Local Action

27. Dose-Response of Locally Acting Nasal Drugs • In vitro study designs in draft BA/BE Guidance: useful for determining comparability of products, but unproven value for establishing clinical equivalence and substitutability • We agree with the OINDP Subcommittee’s recommendation of selecting one-dose between Test and Reference in the clinical study, and the inclusion of a placebo.

28. Traditional Treatment Study • Traditional treatment study (TTS) = most appropriate study design for nasal products for local delivery • 2 week duration is appropriate • Weaknesses of TTS include dependence on seasons, measurable placebo effect

29. Further Work Needed • Further work needed to: • develop robust clinical protocols, • identify reliable metrics, • establish relevant in vitro test platforms

30. Case study • Design Issues with a 1999 BE traditional treatment study*: • Hierarchy • Statistical power • Bias *Casale TB., Azzam SM., Miller RE etal., Demonstration of therapeutic equivalence of generic and innovator beclomethasone in seasonal allergic rhinitis. Ann. Allergy Asthma Immunol 1999; 82:435-41

31. Steps to Confirming Correct Study Design • The recommended study design should address the issue of substitutability and not confuse this with comparability • Need to develop statistical requirements for this study design, for comparing Test and Reference products. The Team seeks Agency’s guidance concerning this issue.

32. Risk Management as a Tool • Risk areas present with locally acting nasal products in the context of clinical comparability and substitutability: • Comparability of container/closure system to assure comparable spray delivery • Effect of particle size differences between Test and Reference and the implication for onset of action • Effect of particle size on systemic exposure and local side effects • It cannot be presumed that an in vitro test that correctly correlates with the local actions will also be predictive of the systemic outcome

33. Conclusion • Container/closure and particle size are two key risk areas that remain to be addressed regarding clinical comparability and substitutability. • We agree with Agency and OINDP Subcommittee that particle size is important in development of standards for OINDP • Further consideration of particle size is required because of its effect on: • Systemic absorption • Onset of action