WorldWIDE
REGULATORY GUIDANCE
At present, there are no worldwide standards that are specifically applicable to Orally Inhaled and Nasal Drug Products (OINDPs). Below are regulatory agencies by region, a harmonizing organization, and selected recommended guidelines for safety, quality and efficacy.
The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) is a unique organisation consisting of representatives from the regulatory authorities in the European Union (EMA), Japan (MHLW) and the USA (FDA), and experts from the pharmaceutical industry in the three regions, in a single forum. ICH has concentrated on the preparation of the following quality related guidelines:
In the USA, the regulatory function is performed by the Food and Drug Administration (FDA) through two centers, the Center for Drug Evaluation and Research (CDER) in respect of medicines and the Center for Devices and Radiologic Health (CDRH) in respect of medical devices.
The FDA’s relevant current thinking for orally inhaled and nasal drug products is reflected in the following Regulatory Guidances for Industry:
- (CDER 2018), Metered Dose Inhaler (MDI) & Dry Powder Inhaler (DPI) Products – Quality Considerations Guidance for Industry”, Pharmaceutical Quality/CMC Documentation – Draft
- (CDER 2017), Bioequivalence Summary Table for Metered Dose Inhaler Products, Technical Specifications Documentation
- (CDER 2003), Bioavailability and bioequivalence studies for nasal sprays for local action, Biopharmaceutics – Draft
- (CDER 2003) Bioequivalence summary tables related to the in vitro tests recommended in “Bioavailability and Bioequivalence Studies for Nasal Aerosols and Nasal Sprays for Local Action
- CDER (2002), Nasal Spray and Inhalation Solution, Suspension and Spray Drug Products, Chemistry, Manufacturing and Controls
- CDER (2003), Integration of Dose-Counting Mechanisms into MDI Drug Products, Clinical Medical
- CDER (2001), Sterility Requirements for Aqueous-Based Drug Products for Oral Inhalation, Small Entity Compliance Guides
- CDER (2018), ANDA Submissions — Amendments to Abbreviated New Drug Applications Under, Generics
- CDER (2011), Process Validation: General Principles and Practices Guidance for Industry, Good Manufacturing Practices
- CDER (2004), Process Validation Requirements for Drug Products and Active Pharmaceutical Ingredients Subject to Pre-Market Approval
The FDA’s current thinking and expectations on how to develop generic drug products therapeutically equivalent to specific reference listed drugs is reflected in the following Product-Specific Guidances:
- (CDER 2013; Revised Jun 2013; Dec 2016), Draft Guidance for Albuterol Sulfate, Inhalation, Aerosol, Metered
- (CDERJun 2015; Revised Nov 2018, Feb 2019), Draft Guidance for Azelastine Hydrochloride and Fluticasone Propionate, Nasal, Spray
- (CDER 2019), Draft Guidance for Beclomethasone Dipropionate, Inhalation, Aerosol, Metered
- (CDER 2018), Draft Guidance for Beclomethasone Dipropionate, Nasal, Aerosol, Metered
- (CDER 2019), Draft Guidance for Budesonide, Nasal, Spray, Metered
- (CDER 2015), Draft Guidance for Budesonide; Formoterol Fumarate Dihydrate, Inhalation, Aerosol, Metered
- (CDER 2014; Revised Dec 2016), Draft Guidance for Buprenorphine Hydrochloride; Naloxone Hydrochloride, Oral, Sublingual Tablet
- (CDER 2019), Draft Guidance for Dihydroergotamine Mesylate, Nasal, Spray, Metered
- (CDER 2019) Draft Guidance for Fluticasone Furoate, Nasal, Spray, Metered
- (CDER 2015; Revised 2019), Draft Guidance for Fluticasone Propionate, Inhalation, Aerosol, Metered
- (CDER 2019), Draft Guidance for Fluticasone Propionate; Salmeterol Xinafoate, Inhalation, Aerosol, Metered
- (CDER 2015), Draft Guidance for Ipratropium Bromide, Inhalation, Aerosol, Metered
- (CDER 2015), Draft Guidance for Levalbuterol Tartrate, Inhalation, Aerosol, Metered
- (CDER 2015; Revised 2019) Draft Guidance for Mometasone Furoate, Nasal, Spray, Metered
- (CDER 2017), Draft Guidance for Naloxone Hydrochloride, Nasal, Spray
- (CDER 2016), Draft Guidance for Olopatadine Hydrochloride, Nasal, Spray, Metered
- (CDER 2012; Revised 2012; 2018) Draft Guidance for Sumatriptan, Nasal, Spray
- (CDER 2018) Draft Guidance for Talc, Inhalation, Aerosol, Metered
- (CDER, 2016; Revised 2018, 2019), Draft Guidance for Triamcinolone Acetonide, Nasal, Metered, Spray
- (CDER 2014; Revised 2018), Draft Guidance for Zolmitriptan, Nasal, Spray
In Europe, the Committee for Medicinal Products for Human Use (CHMP) is the European Medicines Agency’s (EMA) committee responsible for human medicines.
The main guidance from the EMA relating to Orally Inhaled and Nasal Drug Products is contained in the following guidelines. These guidelines give a comprehensive list of the parameters that are critical to the safety, quality and efficacy of inhalation and nasal products:
- (CPMP 2006), Guideline on the Pharmaceutical Quality of Inhalation and Nasal Products.
- (CPMP 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.
- Matters relating to the “Replacement of chlorofluorocarbons in medicinal products” are also important considerations of quality, safety and efficacy.
In the UK, the Medicines and Healthcare products Regulatory Agency is an executive agency of the Department of Health and Social Care in the United Kingdom which is responsible for ensuring that medicines and medical devices work and are acceptably safe.
In China, the National Medical Products Administration (NMPA) is the Chinese agency for regulating drugs and medical devices (formerly the China Food and Drug Administration or CFDA). Its responsibilities include drafting laws and regulations for drugs, medical devices, and cosmetics, as well as establishing medical device standards and classification systems.
In Brazil, the Health Regulatory Agency, Anvisa, executes sanitary control of the production, marketing and use of products and services subject to health regulation, including related environments, processes, ingredients and technologies.
In Canada, Health Canada reviews drug products to assess their safety, efficacy and quality.
Regulatory guidelines for in vitro testing of OINDPs include general descriptions for characterizing OINDP performance under fixed laboratory conditions to determine certain end-point oriented critical quality attributes (CQA) that drive product quality. Proveris instruments can perform these tests on a range of devices through the life of the device. Below are some of the commonly accepted tests:
- Single Actuation Container (SAC) Through Life
- Aerodynamic Particle Size Distribution (APSD) by Cascade Impaction (NGI, ACI)
- Spray Pattern
- Plume Geometry
- Priming/Re-priming
- Delivered Dose Uniformity
- Valve/Pump Delivery (Shot Weight)
- Drug Particle Size by Microscopy (Suspensions)
- Droplet Size Distribution (DSD) by Laser Diffraction
- Product Wasting for Through Life Testing