This document discusses nasal and pulmonary drug delivery systems. It provides details on nasal spray and metered dose inhaler platforms, including their advantages over other delivery methods. Regulatory considerations for these products include specifications, in vitro bioequivalence testing, and characterization studies. Analytical techniques are described for measuring parameters like aerodynamic particle size, droplet size distribution, spray pattern, and plume geometry. The nose and lungs provide non-invasive routes for both local and systemic drug administration.

1. Nasal and Pulmonary Delivery System
Nainesh Patel
Email :naineshp@glenmarkpharma.com
(M) +919158659501
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2. Nasal Delivery Platforms
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3. Nasal Delivery System.
 The nasal route is commonly used
for the delivery of drugs to alleviate
a number of local disorders such as
sinus congestion and allergic
rhinitis.
 It is also begging utilized as an
alternative to oral and injection
methods for the systemic delivery
of a variety of drug including
vaccines, proteins and peptides.
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4. Advantages of Nasal delivery.
 The large surface area for absorption in the nose ,coupled with the
high density of blood vessels, enables efficient absorption into the
blood stream.
 Rapid onset of action compared to oral delivery.
 Avoiding enzyme degradation of the drug with in the GI tract and
first pass hepatic metabolism.
 Painless delivery compared to Injection delivery.
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5. Targeting the Nose
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6. Regulatory /Analytical Application for Nasal spray.
 CMC specifications for Nasal spray
 Bioequivalence In vitro test
 One time characterization study
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7. CMC specifications for Nasal spray.
 Appearance  Osmolality,
 Identification
 Viscosity
 Assay
 Pump delivery
 Related substance
 Spray content uniformity
 Particulate matter
 Spray pattern
 Microbial limits
 Net content  Plume geometry
 Leachable and Exactable  Droplet size distribution.
 Weight loss on stability  Particle size distribution.
 pH
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8. Bioequivalence In vitro test
 Appearance
 Priming and Repriming
 Spray pattern
 Plume geometry
 Small droplet size by Cascade Impactor
 Droplet size distribution by Laser Diffraction
 Microscopy for suspension.
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9. One time characterization study.
 Appearance
 Priming and repriming in various orientations
 Device robustness ( Shaking, Dropping, Vibrating )
 Effect of dosing orientation (60°,75°and 90°)
 Profiling of sprays near container exhaustion (tail off
characteristics)
 Preservative effectiveness
 Photo stability
 Cleaning instructions
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10. Test and Related method/Instrument
 Appearance- By visual method
 Identification- By FTIR/HPLC/TLC
 Assay- By HPLC
 Related substance- By HPLC
 Particulate matter- By visual/By Instrument
 Microbial limits- By Micro
 Net content- By Analytical balance
 Leachable and Exactable By HPLC/GC/GC MS
 Weight loss on stability- By Analytical balance
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11. Test and Related method/Instrument
 Pump Delivery -By NSP UA actuator
 Spray pattern -By ADSA-Spray view
 Plume geometry -By ADSA-Spray view
 Droplet size -Spraytec-Malvern
 Small droplet size by ACI -Expansion chamber with ACI
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12. pMetered Dose Inhaler
&
Dry Powder Inhaler Delivery Platforms.
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13. pMDI & DPI Delivery System.
 Inhaled drug product are becoming
increasingly popular means of local
or systemic therapy via lungs.
 (a) locally(directly) to treat lung
diseases such as asthma and chronic
obstructive pulmonary
diseases(COPD) and to deliver
locally-acting drugs such as
antibiotics and antiviral directly to
the lungs to curb infection.
 (b) systemically, for example in
pain relief and anesthetic
applications.
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14. Advantage of pMDI & DPI Delivery
System.
 Pulmonary delivery offers a number of advantages compared to
the more traditional oral and parental routes.
 Directly targets the lung.
 Rapid onset of drug action.
 Drug effective in relatively low doses.
 Fewer side effects.
 Avoids hepatic metabolism.
 Injection-free administration.
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15. Regulatory /Analytical Application for pMDI
& DPI.
 CMC specifications for Metered Dose Inhaler
 Bioequivalence In vitro test
(Till date no draft/Finial guidance for In vitro study.)
 One time characterization study
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16. CMC specifications for pMDI &DPI.
 Appearance and color  Dose content uniformity
 Identification through container life.
 Microbial limits  Particle size distribution
 Water or Moisture content  Microscopic evaluation.
 Assay of Dehydrated  Spray pattern
Alcohol(if used as co  Plume geometry
solvent)  Leak rate
 Net content  Pressure Testing
 Assay (drug content)
 Valve delivery (shot weight)
 Related substance  Leachable and Exactable
 Dose content uniformity.
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17. One time characterization study.
 Determination of Appropriate storage conditions.
 Stability of primary(unprotected)package.
 Temperature cycling.
 Effect of resting time.
 Priming and repriming in various orientations.
 Effect of storage on the particle size distribution.
 Drug deposition on mouth piece and/or Accessories.
 Cleaning instructions.
 Profiling of sprays near container exhaustion (tail off characteristics).
 Plume geometry.
 Microbial challenge.
 In vitro Dose Proportionality.
 Effect of varying flow rate.
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18. Instrument and various technique used for Nasal
Spray, Metered Dose Inhaler, Dry Powder Inhaler.
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19. Basic set up for determination of
Aerodynamic particle size.
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20. Aerodynamic particle size by Anderson
Cascade Impactor.
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21. Aerodynamic particle size by Anderson Cascade
Impactor.
 Anderson cascade impactor is mimic of the pulmonary track and
Lungs.
 Cascade impactor testing is the principal technique and key parameters
for determining metrics that describe Aerodynamic particle size
distribution of Orally Inhaled Products. Like MDI,DPI and Nasal
spray.
 Based on Aerodynamic particle size distribution data, we can
predicted and optimized of drug deposition characteristic in the human
respiratory tract.
 Cascade impactor operates on the principle of internal impaction.
i.e separation is provided on the basis of difference in inertia –a function
of particle size and velocity.
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22. Aerodynamic particle size by NGI
Next generation Impactor.
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23. Aerodynamic particle size by NGI
Next generation Impactor.
 Next Generation Impactor (NGI) is mimic of the pulmonary track
and Lungs.
 Next Generation Impactor (NGI) testing is advanced technique and key
parameters for determining metrics that describe Aerodynamic
particle size distribution of Orally Inhaled Products. Like MDI,DPI
and Nasal spray.
 Based on Aerodynamic particle size distribution data, we can
predicted and optimized of drug deposition characteristic in the human
respiratory tract.
 Cascade impactor operates on the principle of internal impaction.
i.e separation is provided on the basis of difference in inertia –a function
of particle size and velocity.
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24. Moisture content by coulometer with
Automated actuation.
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25. Basic Actuation system for Nasal
spray and pMDI.
• Reduce operators induced subjectivity.
•Actuation parameters relevant to patient use.
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26. Droplet size Distribution by Spraytec-
Malvern UK.
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27. Droplet size Distribution by Spraytec-
Malvern UK.
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28. Droplet size Distribution by Spraytec.
 A typical nasal spray formulation consists of a bottle with a
metered spray pump, containing the drug suspended or dissolved
in a aqueous medium.
 Pump actuation by the patient delivers drug laden droplets in to
the nasal cavity.
 Most nasal spray pumps produces droplets in the size range from
20 µm to 120 µm. It is critically important that the droplets are of
a size that enables their deposition within the nasal passages.
 If droplet are too small (< 10µm), particle/droplet may pass
through the nasal passages and deposit in the lungs. Potentially
allowing deposition of drug and Excipients not approved for
pulmonary absorption. If droplet are too large, particle/droplet
may trapped in nostril.
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29. Spray pattern and Plume geometry by
ADSA-Innova system-US
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30. Spray pattern and Plume geometry by
ADSA-Innova system-US
Spray pattern Plume geometry
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31. Spray pattern and Plume geometry -Theory
 Automated testing of nasal spray pumps yields test data that are more
reliable than the data that result from manual methods. That is because
spray patterns depend so heavily on actuation velocity and acceleration.
For example:
• High actuation velocity and acceleration produce smaller droplets in a
more atomized cloud.
• Low actuation velocity and acceleration levels produce larger droplets
in more stream-like sprays.
 The FDA requires these two tests spray pattern and plume geometry in
submissions for approval of drugs.
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32. Spray pattern and Plume geometry -Theory
 The FDA recommends that test labs use automated actuation
systems to reduce variability in these measurements due to
operator factors. Automated actuation also increases measurement
sensitivity, in order to detect differences among products.
 During product development, analysts can use these
measurements to design a delivery system that accounts for the
properties of the fluid that carries the drug. Automated testing also
helps to find acceptable tolerances for variables of interest during
stability testing. Lastly, quality control of release grade products
requires highly consistent test methods and sensitive measurement
technologies.
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33. Emitted dose by Glass Twin Impinger.
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34. Emitted dose by Glass Twin Impinger.
 Glass Twin impinger developed at GSK lab.UK and it is recognized
as apparatus A in Ph.Eur.2.9.18.
 It is designed such that at a flow rate 60.0 L/min through the
impinger.
 The particle cut off diameter is 6.4 microns. Particle smaller than
6.4 microns pass in to the lower impingement chamber.
 The value of the Glass Twin impinger, particularly with respect to
routine quality control application.
 Glass Twin impinger used for routine QC applications.
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35. Delivered Dose by DUSA.
(Dose Unit Sampling Apparatus)
For pMDI/ DPI For Nasal spray
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36. Delivered Dose by DUSA.
(Dose Unit Sampling Apparatus)
 The Delivered dose is the total amount of drug emitted from the
medical device and hence available to the patient/user.
 It is used to perform those tests specified in the pharmacopoeia
relating to Delivered or emitted dose namely “Delivered Dose
Uniformity and Delivered Dose Uniformity over the Entire
contents.
 It is designed such that at a flow rate 28.3 L/min including filter
and inhaler..
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37. Small Droplet size by Anderson
cascade Impactor.
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38. Small Droplet size by ACI.
 A two-liter or larger induction port (expansion
chamber) is preferred to this test.
 The total mass of drug below the top stage is of primary
interest.
 The total mass of drug collected on all stages and
accessories is recommended to be between 85 and 115
percent of label claim on a per actuation basis.
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39. Brief Summary of Sophisticated
Instrument.
Instrument/Make Application
Anderson Cascade Impactor- Aerodynamic particle size Distribution
Westech Scientific Instruments- for MDI,DPI and Nasal spray.
UK/Copley Scientific ,UK
Next Generation Impactor- Aerodynamic particle size Distribution
Copley Scientific ,UK for MDI,DPI and Nasal spray.
Aerosol Drug Spray Determination of Spray pattern and
Analyser(ADSA) Plume geometry for MDI and Nasal
Innova system ,USA, spray.
SPRAY VIEW® -Image Therm, Determination of Spray pattern and
Proveris Scientific,USA. Plume geometry for MDI and Nasal
spray
Spraytec-Malvern, UK. Droplet size distribution by laser
diffraction for MDI and Nasal spray
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40. Brief Summary of sophisticated
Instrument.
Instrument/Make Application
Glass Expansion chamber- Determination of Small droplet size
Westech Scientific Instruments-UK/Copley for Nasal spray.
Scientific ,UK
Delivered Dose Uniformity Apparatus.(DUSA)- Determination of Uniformity of
Westech Scientific Instruments-UK/Copley Delivery
Scientific ,UK
Glass Twin Impinger.- Determination of Emitted dose
Copley Scientific ,UK./Westtech Delivery
Instrument.
New High Capacity Pump Model HCP5. Common Utilities for Testing.
Westech Scientific Instruments-UK/Copley
Scientific ,UK.
Copley Inhaler Testing Data Analysis Software. To calculate MMAD and GSD.
(CITDAS –V-3.00)
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41. Regulatory bodies.
 ANVISA (Brazil) : Pharmaceutical Equivalence and Bioequivalence of
Nasal Spray and Aerosol Drug.
 EMEA (Europe) -Nasal spray-inhalation-suspension 2006.
 Health Canada (Canadian guidelines)-Nasal spray-inhalation
November 2003.
 CDER (US): Nasal Spray and Inhalation Solution, Suspension, and Spray
Drug Products - Chemistry, Manufacturing, and Controls Documentation.
 CDER (US): Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI)
Drug Products Chemistry, Manufacturing, and Controls Documentation.
 US Pharmacopeia :601-Aerosole, Nasal sprays, Metered Dose Inhalers
and Dry powder inhalers.
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43. Thank You!
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