Title: David Radspinner, Ph.D.,
1Bioequivalence 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
2ITFG 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
3Background
- 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)
4Objective
- 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
5CMC Issues Addressed by ITFG/IPAC-RS
- Dose Content Uniformity
- Particle Size Distribution
- Tests and Methods
- Leachables and Extractables
6Dose 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
8Foundation 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
9Parametric 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.
11Particle 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
18Leachables and Extractables
- Presented by
- James Blanchard, Ph.D.,
- Rockville, MD
- 19 July 2001
19Leachables 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
20Points 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
21Contacts 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
22Individual 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
23Leachables 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
24Consideration 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
25Bioequivalence Studies for Locally Acting Nasal
Drugs
- Presented by
- Joel Sequeira, Ph. D.
- Rockville, MD
- July 2001
26BA/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
27Dose-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.
28Traditional 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
29Further Work Needed
- Further work needed to
- develop robust clinical protocols,
- identify reliable metrics,
- establish relevant in vitro test platforms
30Case 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
31Steps 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.
32Risk 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
33Conclusion
- 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
34Extra Slides on LE
35Extraction Solvents for Dosage Forms/Components
(Table 1)
36Identification and categorization of extractables
(Table 2)
37Thresholds for extractables (Table 3)
38(No Transcript)
39- 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)
40Leachables 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
41- 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)
43Leachables 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