Issue link: https://www.e-digitaleditions.com/i/1524818
24 August 2024 Inhalation standards and controls of the pre-HFA 1980's and early 1990's). ere were no compelling technical, clinical or economic drivers to update the largely empirical approaches to MDI development and testing during that era. Today there are Quality by Design (QbD), International Council on Harmoni- zation (ICH) and FDA Guidance applicable to many aspects of product design, development characteriza- tion, testing and control, which did not exist prior to the CFC phase-out during the 1990's. Overall, these allow for steadily modernized technical methods and a more a mechanistic, non-empirical understanding of MDI performance. All these factors combined to create an overall con- text for MDIs where requiring new NDAs for every MDI made very good sense, whether it was a refor- mulation of the same active ingredient or formula- tion with a new active entity in an MDI product. e so-called contemporary era of HFA-based MDI products was born through these efforts to achieve licensure by the new NDA route. Compare and contrast the current to next generation propellant switch: General technical considerations ird generation propellants HFA-152a and HFO- 1234ze(E) are considered to have low global warming potential whereas HFA-134a and HFA-227 do not [10]. Generally during the pre-1990's, the approach for success had been to define a strictly controlled narrow path for all aspects of MDI ingredient quality, manufacture and testing. While that worked in terms of product consistency (to the extent measured), this narrow pathway approach was not a realm where advances in MDI quality and innovation were readily As an example, large differences in CFC to HFA sol- vent power rendered useless the elastomers for valve components as metering and canister seals, due to altered swelling (formulation leakage and mechanical issues) and extraction characteristics. e increased solubility of water (for example) also led to corro- sion problems for aluminum and some stainless-steel MDI components that were previously stable with CFC formulations. As a result, for the CFC to HFA propellant switch of the 1990's, new formulations had to be entirely re-developed, and new materials of construction for the valve and canister were necessary to achieve a safe, effective and quality HFA-based MDI drug product [12]. e targeting of every aspect of MDI design, manufacture, testing and assessment of product per- formance (e.g., aerodynamic particle size distribution (APSD) and delivered dose uniformity (DDU)) had to be redeveloped from the ground up—and impor- tantly, in a dearth of relevant scientific data and reg- ulatory precedent. Also, during the 1990's, there were independently growing scientific and regulatory concerns regarding toxic, irritating or mutagenic nitrosamines, polyaro- matic hydrocarbons, etc. a [13, 14] from elastomeric and plastic materials of MDI construction. ese con- cerns were heightened by three factors for MDIs. e target asthma and COPD populations are known to have hyperactive airways, the manufacturing quality of elastomers was uncertain and the corresponding drug product testing for extractables and leachables (E&L) were generally not considered to be sufficient for the then-emerging situation of the 1990's. In addition to E&L testing, the general state for eval- uating MDI quality was already aging (by the quality Propellant Generation and Status Molecular Formula Boiling Point ºC Density g/mL Dipole Moment debye Solubility of Water in Propellant ppm CFC-11 1st discontinued CFCl 3 23.7 1.49 0.45 100 CFC-12 1st discontinued CF 2 Cl 2 -29.8 1.33 0.51 90 HFA-134a 2nd current CF 3 -CFH 2 -26.2 1.23 2.06 3,200 HFA-227 2nd current CF 3 -CFH-CF 3 -16.5 1.41 1.46 610 HFA-152a 3rd next CF 2 H-CH 3 -24.7 0.91 2.26 2,200 HFO-1234ze(E) 3rd next CF 3 -CH=CHF -18.9 1.29 1.44 225 Table 1 Selected Physicochemical Properties of 1st, 2nd and 3rd Generation MDI Propellants a. Carbon black (prepared by the "impingement" or "channel" process). e Commissioner of Food and Drugs, in order to protect the public health, hereby terminates the provisional listing of carbon black (prepared by the impingement or channel process) for use in food, drugs, and cosmetics [13].