David Radspinner, Ph.D.,

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

• Collected and analyzed DCU database and submitted
  findings to FDA in July 2000
• Initial Assessment of the ITFG/IPAC-RS Dose
  Content Uniformity Database by 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

• 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.

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Particle Size Distribution Tests and Methods

• Presented by
• Carole Evans, Ph.D.
• Rockville, MD
• 19 July 2001

12

• 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

• Update
• Collected and analyzed industry data
• Submitted report to FDA in August 2000
• Initial Assessment of the ITFG/IPAC-RS
  Aerodynamic Particle Size Distribution Database
  by the CMC Specifications Technical Team of the
  ITFG/IPAC-RS Collaboration
• Next Steps
• Submitted proposal to PQRI

14

• 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

• Update
• Carried out initial investigations of alternate
  approaches (e.g.,based on bootstrapping)
• Next Steps
• Submitted proposal to PQRI

16

• 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 for Tests and Methods

17

• 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 Extractables Testing Points to
  Consider

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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 ?g total 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

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Contacts formulation or patients mouth or mucosa?
YES
NO
Other (not extractables) testing is sufficient
(e.g., functional, identity, dimensional, etc.
as necessary).

• Controlled Extraction Studies
• Qualitative and quantitative assessment of all
  peaks gt 1-20 ?g/g

Routine Extraction Studies and other testing, if
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 gt 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
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Individual Leachable Above Reporting Threshold
(gt0.2 ?g TDI)?
NO
YES
No Additional Evaluation
? 5?g TDI (some structural info.)
gt 5?g TDI (structure confirmed)
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.
NO
YES
Qualified
Reduce, Remove, or Collect More Data
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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

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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 Agencys consideration of
  BA/BE and CMC issues for OINDP

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Bioequivalence Studies for Locally Acting Nasal
Drugs

• Presented by
• Joel Sequeira, Ph. D.
• Rockville, MD
• July 2001

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BA/BE Teams 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 FDAs BA/BE
  Questions Presented at 26 April 2000 OINDP
  Advisory Subcommittee Meeting
• 30 August 2000 Review of In Vivo and In Vitro
  Tests in FDAs Draft Guidance on BA/BE Studies
  for Nasal Aerosols and Nasal Sprays for Local
  Action and Forthcoming Guidance for Orally
  Inhaled Drugs
• 5 April 2001 On the Risks of Eliminating In Vivo
  Studies for Nasal Solutions for Local Action

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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 Subcommittees
  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

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Further Work Needed

• Further work needed to
• develop robust clinical protocols,
• identify reliable metrics,
• establish relevant in vitro test platforms

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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 82435-41

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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 Agencys guidance
  concerning this issue.

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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

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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

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Extra Slides on LE
35
Extraction Solvents for Dosage Forms/Components
(Table 1)
36
Identification and categorization of extractables
(Table 2)
37
Thresholds for extractables (Table 3)
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(No Transcript)
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• Clarify that purpose of routine extraction
  testing is to ensure that the extractables
  profiles of components used in commercial
  manufacture remain consistent with profiles of
  components used in pivotal development studies
• Should be performed only on those critical
  components which contact the formulation or
  patients mouth or nasal mucosa
• Not an effective substitute for in-process
  controls and supplier qualification
• Routine control of extractables should be
  dictated by current Good Manufacturing Practices
  (Collaborate with Supplier Quality Control Team)

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Leachables Extractables Team

• Threshold Justification
• ICH guidelines for impurities and degradants
  (Q3B) are inappropriate for setting OINDP
  thresholds for leachables
• Rationale for setting qualification threshold
• When the TDI of an OINDP leachable ?
  qualification threshold, the TDI is so low it
  will not compromise patient safety
• Establish qualification threshold
• Comparison to inhaled dose from ambient particles
• Estimate daily volumes of air inspired by healthy
  and asthmatic adults and children
• Estimate inhaled doses for ambient particles in
  clean US city (PM10 18 ?g/m3)
• Comparison to acceptable TDIs of impurities and
  leachables in MDIs
• Comparison to TDIs of marketed products

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• Findings - Threshold of 5 ?g TDI represents
• Daily dose per leachable of 0.1 1 ?g/kg
• In comparison to inhaled dose of ambient
  particles for healthy and asthmatic persons
• ? 3 of particle dose for persons ?10 yrs
• ? 9 of particle dose for children 1 - ?10 yrs

42

• Findings - Threshold of 5 ?g TDI represents
• In comparison to acceptable TDIs for impurities
  and leachables in MDIs
• 63 of TDI for acceptable level (5 ppm) of total
  unsaturated compounds in HFA134a
• ? 0.3 of TDI for acceptable level of a typical
  valve leachable (2,2,4,6,6-pentamethyl-hept-3-ene)
  
• In comparison to TDIs of marketed products
• 2 of TDI for Atrovent (low drug TDI 216 ?g)
• 0.3 of TDI for Flovent (high drug TDI 1960 ?g)

43
Leachables Extractables Team

• Conclusions from threshold justification
• ICH guidelines for impurities and degradants are
  inappropriate for setting OINDP thresholds for
  leachables
• Qualification threshold of 5 ?g TDI per leachable
  would not compromise patient safety
• Advantages of qualification threshold
• Investigators and reviewers will benefit from an
  appropriate safety standard
• would help to ensure that all products are
  evaluated in a thorough and consistent manner
• Avoids overburdening preclinical evaluation
• Allows for minor changes in product design
  without need for extensive additional preclinical
  assessment