Bioequivalence of Orally Inhaled Drug
Products (OIDP)
Gustavo Mendes Lima Santos
Coordinator of Therapeutic Equivalence
General Office of Medicines
IV Simposium SINDUSFARMA – IPS/FIP – ANVISA
June 22, 2015
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Why discuss OIDPs?
• Asthma: over 300 million affected in the world;
• In Brazil it is estimated that 10% of the population has asthma;
• OIDPs were included in the programme Farmácia Popular;
• Farmácia Popular budget in 2012 was approximately USD 3 billion;
• Number of diseases treated by OIDPs has increased.
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Orally Inhaled Drug Products
• Intended for drug delivery to the sites of action in
the lung;
• Lower Doses → Greater Effect;
• Limiting factors: Pulmonary Deposition and Drug
Delivery From Device;
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Pulmonary Deposition
• Influence the amount of drug available in the site of action;
Taburet A.M., Schmit B. Pharmacokinetic optimisation of asthma treatment. Clin Pharmacokinet. 1994 May; 26(5): 396-418.
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Pulmonary Deposition
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Pulmonary Deposition
Lippmann, M. Respiratory System. ILO Encyclopaedia: http://www.ilocis.org/documents/chpt10e.htm#JD_Ch10_19
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Drug Delivery From Device
• Influence the amount of drug delivered;
• Most Common Delivery Systems:
– Pressurized Metered Dose Inhalers (pMDI);
– Nebulizers;
– Dry Powder Inhalers (DPI)
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Pressurized Metered Dose Inhalers
(pMDI)
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Pressurized Metered Dose Inhalers (pMDI)
Source: http://www.globalasthmareport.org/management/inhalers.php
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Pressurized Metered Dose Inhalers (pMDI)
• Advantages:
– Cost;
– Transportation;
– Conservation.
• Disadvantages:
– Coordination of the inhalation movement;
– Only 10% to 20% of the dose is delivered in the site of action
(due to the particle size and speed);
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Nebulizers
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Nebulizers
Source: https://en.wikipedia.org/wiki/Nebulizer#
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Nebulizers
• Jet and Ultrasonic Nebulizers;
• Advantages:
– Formulations without conservants (single dose flasks);
– Breath sync not required;
– Patients with handling problems (children, arthritis).
• Disadvantages:
– Price;
– Transportation (power supply required);
– Variability of particle size: only 4,2% of labeled dose is available for
inhalation (Hickey and Evan, 1996);
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Dry Powder Inhalers
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Dry Powder Inhalers
• Single Unity Dose Devices (Inhaled Capsules):
Source: https://www.imgbusddy.com
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Dry Powder Inhalers
• Multi-Dose Devices (Diskus):
Source: http://www.wikihow.com/Use-an-Inhaler#
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Dry Powder Inhalers
• Multi-Dose Devices (Diskus):
Source: www.admit-online.info
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Source: www.mims.com
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Dry Powder Inhalers
• Advantages:
– Transportation;
– Conservation;
– Drug Characteristics for Formulation.
• Disadvantages:
– Capacity to deliver the drug (particle size and device related);
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Therapeutic Equivalence for OIDPs
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Challenges for Demonstration of Therapeutic
Equivalence for OIDPs
• Classical bioequivalence approach is considered inadequate;
• Unharmonized regulatory requirements among countries;
• Devices Similarity;
• Acceptance criteria for In vitro comparability tests;
• Adequate in vivo models to demonstrate efficacy and safety.
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Regulatory Requirements for Therapeutic
Equivalence of OIDPs in US and EU
Lee et al. Regulatory Considerations for Approval of Generic Inhalation Drug Products in the US, EU, Brazil,
China, and India. The AAPS Journal. 2015 May 23.
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Regulatory Requirements for Therapeutic
Equivalence of OIDPs in Brazil
• Resolution RDC nº 37, August 3rd 2011:
– Solutions  in vitro tests only
– Suspensions and Powders  in vitro and in vivo tests
• Specific guidance not issued: Technical Note n° 01/2013, 25
march 2013 (only for in vitro tests);
• Case-by-case analysis;
• Theme included in Anvisa’s Regulatory Agenda 2015-2016.
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Regulatory Requirements for Therapeutic
Equivalence of OIDPs in Brazil
• Device Comparability:
– Does the operation mechanism of the device exacerbate differences
in patients’ efforts and handling?
– Does the shape and dimension of the device exacerbate differences in
patients’ efforts and handling?
– Evidence of similarities could be demonstrated in patient handling
studies
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Regulatory Requirements for Therapeutic
Equivalence of OIDPs in Brazil
• In vitro Comparability:
Lee et al. Regulatory Considerations for Approval of Generic Inhalation Drug Products in the US, EU,
Brazil, China, and India. The AAPS Journal. 2015 May 23.
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Regulatory Requirements for Therapeutic
Equivalence of OIDPs in Brazil
• Aerodynamic Particle Size Distribution:
Source: http://www.pharmacopeia.cn/v29240/usp29nf24s0_c601_viewall.html
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Aerodynamic Particle Size Distribution (APSD)
Source:
http://fy.chalmers.se/OLDUSERS/molnar/lectures/Measurement%20Methods%20II.htm
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Aerodynamic Particle Size Distribution (APSD)
• Challenges:
– Statistical Approaches (modified chi-quare,
population bioequivalence);
– Acceptance Criteria;
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Regulatory Requirements for Therapeutic
Equivalence of OIDPs in Brazil
• In vivo comparability:
– Efficacy related to pulmonary deposition;
• crossover PK studies, with inhibition of absorption from the gastrointestinal tract
through administration of activated charcoal (if necessary);
– Safety related to total quantity of drug available systemically;
• crossover PK studies, without inhibition of absorption from the gastrointestinal
tract through administration of activated charcoal;
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Pharmacokinetic Studies
• Challenges :
– Are PK studies correlated to the amount of drug available in the lung?
– Are PK studies correlated to the region of deposition of the drug in
lung (central/peripheral)?
– Are PK studies correlated to the amount of time that the drug stays in
the lung?
– Goyal and Hochhaus, 2010: Simulations results correlating AUC to
pulmonary deposition and Cmax to residence time in lung.
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Regulatory Requirements for Therapeutic
Equivalence of OIDPs in Brazil
• If pharmacokinetic studies are not feasible, pharmacodynamic
studies would be acceptable:
– Proposed Endpoints:
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Sputum eosinophilia
Exhaled nitric oxide (eNO)
Bronchoconstriction challenges
Spirometry
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Pharmacodynamic Studies
• Challenges :
– Sensitivity to differentiate products;
• Dose-response relation;
• High variability of the biomarker.
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Final Considerations
• Important to discuss international harmonization of
regulatory criteria;
– PQRI and IPAC-RS
• Stimulation of Research of more biorelavant
techniques;
• Anvisa come to a guidance for industry for
registration of OIDPs.
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References
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Brazil. Ministry of Health. Resolution SAS/MS nº 709 of 17 december 2010. Accessible via
http://portal.saude.gov.br/portal/arquivos/pdf/pcdt_asma.pdf
Brazil. Federal Government. Popular Pharmacy Program. Accessible via http://portal.saude.gov.br/portal/saude/area.cfm?id_area=1095
Brazilian Health Surveillance Agency. 2011. Resolution RDC nº 37, 3 august 2011. Provides information about biowaiver and substitution of
bioequivalence studies. Accessible via http://www.in.gov.br/imprensa/visualiza/index.jsp?jornal=1010&pagina=6&data=05/03/2007
Brazilian Health Surveillance Agency. 2003. Resolution RDC nº 16, 2 march 2007. Provides information about generic drugs registration. Accessible via
http://www.crfrj.org.br/crf/arquivos/file/ConcursoEstagiarios2010/RDC16_2007MODIFICADA.pdf
Panamerican Heath Organization. 2005.Term of Cooperation 37 for Brazilian health surveillance system reorganization. Accessible via
http://new.paho.org/bra/index.php?option=com_content&view=article&id=182&Itemid=610
Brazilian Health Surveillance Agency. 2009. Normative instruction nº 12, 15 october 2009. Provides information about tests for evidence of
pharmaceutical equivalence and bioavailability / bioequivalence for nasal sprays and aerosols controlled dose. Accessible via
http://portal.anvisa.gov.br/wps/wcm/connect/ce6dfe8047458eff9843dc3fbc4c6735/U_IN-ANVISA-12_151009.pdf?MOD=AJPERES
United States Food and Drug Administration. 2013. Draft Guidance on Albuterol Sulfate. Accessible via
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM346985.pdf
United States Food and Drug Administration. 2013. Draft Guidance on Budesonide. Accessible via
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM346985.pdf
European Medicines Agency. Committee for Medicinal Products for Human Use. 2009. Guideline on the requirements for clinical documentation for
orally inhaled products (OIP) including the requirements for demonstration of therapeutic equivalence between two inhaled products for use in the
treatment of asthma and chronic obstructive pulmonary disease (COPD) in adults and for use in the treatment of asthma in children and adolescents.
Accessible via http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003504.pdf
Therapeutic Products Directorate, Health Canada: Guidance to establish equivalence or relative potency of safety and efficacy of a second entry
short-acting beta2-agonist metered dose inhaler. 1999. Accessible via: http://www.hc-sc.gc.ca/dhp-mps/alt_formats/hpfbdgpsa/pdf/prodpharma/mdi_bad-eng.pdf
Therapeutic Products Directorate, Health Canada: Guidance for Industry Pharmaceutical Quality of Inhalation and Nasal Products. 2006. Accessible
via:http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/chem/inhalationnas-eng.php
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References
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Thank you!
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