Document zdKRE0RKp4J1v6VjG2KowmbX6

EUROPEAN MEDICINES AGENCY SCIENCE MEDICINES HEALTH 1 30 March 2023 2 EMA/CHMP/83033/2023 3 Committee for Medicinal Products for Human Use (CHMP) 4 Questions and answers on data requirements when 5 replacing hydrofluorocarbons as propellants in oral 6 pressurised metered dose inhalers 7 8 Agreed by Rheumatology and Immunology Working Party February 2023 Adopted by CHMP for release for consultation 30 Mar 2023 Start of public consultation April 2023 End of consultation (deadline for comments) 9 10 31 May 2023 Comments should be provided using this template. The completed comments form should be sent to @ema.europa.eu 11 Keywords question and answer, oral pressurised metered dose inhalers, hydrofluorocarbon replacement and propellant 12 Official address Domenico Scarlattilaan 6 1083 HS Amsterdam The Netherlands Address for visits and deliveries Refer to www.ema.europa.eu/how-to-find-us Send us a question Go to www.ema.europa.eu/contact Telephone 6000 An agency of the European Union European Medicines Agency, 2023. Reproduction is authorised provided the source is acknowledged. 13 Table of contents 14 1. Introduction ............................................................................................ 3 15 2. General principles.................................................................................... 3 16 3. Questions and answers on data requirements when replacing 17 hydrofluorocarbons as propellants in oral pressurised metered dose 18 inhalers ....................................................................................................... 3 19 3.1. What are the quality data requirements? .................................................................3 20 3.2. What are the non-clinical data requirements? ..........................................................4 21 3.3. What are the data requirements to address safety/tolerance aspects of a novel 22 propellant?.................................................................................................................5 23 3.3.1. Data requirements on local tolerance ...................................................................5 24 3.3.2. Data requirements on clinical safety.....................................................................5 25 3.4. What are the data requirements to address possible changes to the exposure to the 26 active substance(s)? ...................................................................................................6 27 3.4.1. Step 1 - In vitro................................................................................................7 28 3.4.2. Step 2 - Pharmacokinetics..................................................................................7 29 3.4.3. Step 3 - Pharmacodynamic data .........................................................................8 30 3.5. What are the data requirements for children and adolescents? ...................................8 31 3.6. Are there any specific considerations related to the product information following a 32 change in propellant? ..................................................................................................8 33 Questions and answers on data requirements when replacing hydrofluorocarbons as propellants in oral pressurised metered dose inhalers EMA/373361/200523 Page 2/9 34 1. Introduction 35 There is an increased awareness about the global warming potential of certain hydrofluorocarbons 36 (HFCs) used as excipients (propellants) in pressurized metered dose inhalers (pMDIs). Therefore, the 37 European Commission has taken an initiative aiming at phasing out the use of HFCs in pMDIs in favour 38 of low global warning potential propellants (LGWP). Additionally, companies have taken initiatives 39 towards replacing the existing propellants with LGWPs by asking for scientific advice on product 40 development. As such, propellant replacement constitutes a major change to the finished product 41 formulation with potential impact also on the construction of the inhaler; therefore, data confirming 42 maintenance of adequate finished product performance need to be provided for each modified product. 43 In addition, data addressing possible toxicity and local tolerance of novel propellants need to be 44 provided. This questions and answers document aims at providing advice regarding data requirements 45 for such replacements. It applies to all medicinal products irrespective of the legal basis for marketing 46 authorisation. 47 2. General principles 48 Propellants could be introduced in a medicinal product either as part of an initial marketing 49 authorisation application (approved via either full or abridged applications), as a part of an extension 50 application or as replacements of existing propellants via a variation procedure for an approved 51 medicinal product. The data requirements depend on whether the propellant is regarded as novel (i.e., 52 not previously used in any approved medicinal product with the same route of administration) or 53 established. If a certain propellant has already been used in an approved medicinal product for the 54 same route of administration, the data requirements for including the said propellant in another 55 medicinal product can be reduced when sufficient data, including pharmacovigilance data, have been 56 collected. 57 When documenting a formulation with a novel propellant, there are two aspects to cover pertaining to 58 the efficacy and safety of the product, i.e., issues related to the safety/tolerance aspects of the novel 59 propellant (see question 3.3) and changes to the formulation with impact on the aerodynamic particle 60 size distribution of the active substance in the product as well as on other properties of the emitted 61 cloud. The latter point might have clinical implications as the local and systemic exposure of the active 62 substances could be impacted as discussed in question 3.4. below and needs to be addressed for all 63 product formulations also in case of established LGWPs. 64 3. Questions and answers on data requirements when 65 replacing hydrofluorocarbons as propellants in oral 66 pressurised metered dose inhalers 67 3.1. What are the quality data requirements? 68 When replacing the propellant in a medicinal product, quality data should be provided as for any other 69 variation or extension application. 70 With regards to the control of excipients (propellant), in case of novel propellants, full details should be 71 provided as outlined in the Guideline on excipients in the dossier for application for marketing 72 authorisation of a medicinal product (EMEA/CHMP/QWP/396951/2006), under the section novel 73 excipients. For an established LGWP section 3.2.P.4 should be provided as standard; of note, a 74 specification, including relevant tests, e.g., identification, physical characterisation (e.g., boiling point, 75 vapor pressure, relative density), appearance, assay, acidity, total residue, moisture content, related Questions and answers on data requirements when replacing hydrofluorocarbons as propellants in oral pressurised metered dose inhalers EMA/373361/200523 Page 3/9 76 impurities and unrelated impurities (e.g., CO, N2, O2), is needed. However, a change of propellants 77 may have a significant impact on the finished product functionality and performance and the following 78 quality data requirements are to be taken into account: 79 All relevant pharmaceutical development studies described in the Guideline on the 80 pharmaceutical quality of inhalation and nasal products (EMEA/CHMP/QWP/49313/2005 81 Corr). 82 For all the indicated patient populations, propellant aspects which may impact the 83 usability of the product such as expelling pressure, taste, feeling in the mouth and 84 flammability. 85 Re-evaluation of the finished product specifications, at release and at the end of shelf- 86 life, in view of the results of the batches used in the studies pivotal for demonstrating 87 therapeutic equivalence and safety, and proposed in line with the finished product 88 specification(s) section for inhalation products described in the Guideline on the 89 pharmaceutical quality of inhalation and nasal products (EMEA/CHMP/QWP/49313/2005 90 Corr). When no clinical studies have been conducted, the critical quality attributes limits 91 should not be substantially changed. 92 Discussion and justification of device related changes (e.g., in the device components 93 such as valve and canister), taking into consideration the requirements described in the 94 Guideline on quality documentation for medicinal products when used with a medical 95 device (EMA/CHMP/QWP/BWP/259165/2019) and related documents. 96 Pressurised metered dose inhalers are considered as a critical dosage form. Hence, 97 adequate manufacturing method validation and stability data should be provided. Stability 98 data for at least two batches, packed in the commercial container closure system, stored at 99 long-term conditions and in different orientations for a sufficient time should be provided to 100 conclude similar stability profile. The batches should preferable be of production scale, 101 however, pilot scale may be sufficient, if justified. Stability data for the new propellant in 102 other finished products could be seen as supportive. 103 In addition to characterisation of the finished product with the new propellant, in vitro data should be 104 used as the first step to establish therapeutic equivalence between the reformulated product and its 105 reference, see question 3.4. 106 3.2. What are the non-clinical data requirements? 107 Excipients are not expected to have any intended pharmacological activity; therefore, primary and 108 secondary pharmacology studies are not warranted. Consequently, the non-clinical requirements for a 109 novel excipient are limited to toxicology and pharmacokinetics. Safety pharmacology data might be 110 obtained in toxicology studies obviating the need for stand-alone safety pharmacology studies. 111 However, a lack of these data needs to be justified. 112 Full details as outlined in the Guideline on excipients in the dossier for application for marketing 113 authorisation of a medicinal product (EMEA/CHMP/QWP/396951/2006) should be provided and 114 adequate non-clinical data in accordance with ICH M3 (R2) as for any new substance. To support the 115 use of novel excipients in a paediatric population (question 3.5.), ICH S11 may also apply. 116 Questions and answers on data requirements when replacing hydrofluorocarbons as propellants in oral pressurised metered dose inhalers EMA/373361/200523 Page 4/9 117 3.3. What are the data requirements to address safety/tolerance aspects 118 of a novel propellant? 119 3.3.1. Data requirements on local tolerance 120 Data on the local tolerance of the propellant alone (without active substances involved) should be 121 generated by two studies: 122 a) Data on ciliary function should be preferably collected from a study in non-smoking healthy 123 volunteers as this is deemed the most sensitive population to detect differences between the 124 new and the reference propellant. There is no established and validated "golden standard" 125 method (currently, April 2023) and thus a thorough justification for the choice of the design is 126 needed. A scintigraphy evaluation would be an acceptable option if statistical aspects such as 127 pre-specification of a primary endpoint with a non-inferiority margin at a relevant level can be 128 justified. 129 b) Data on possible airway sensitivity reactions should be collected by studying lung function 130 in asthmatic patients. A cross-over design using a supratherapeutic propellant dose is 131 recommended where FEV1 (AUC0-15min) is investigated. A younger population may be more 132 sensitive to detect bronchoconstrictive effects, hence an upper age limit of, e.g., 45 years is 133 advised. As possible effects of the chosen comparator propellant might not be known, it is 134 recommended to conduct a pilot study to support the choice of the study size and of the non- 135 inferiority margin. 136 3.3.2. Data requirements on clinical safety 137 The clinical safety of any novel propellant should be supported by at least one safety study. The main 138 objective of this study is to collect adverse events such as bronchoconstriction, hoarseness, and cough. 139 Study duration should be at least 3 months. A study size of approximately 300 subjects in each 140 treatment arm would allow an adequate estimation of common adverse events. 141 The pMDI product at investigation should ideally be a vehicle version of the final formulation to allow 142 detecting adverse effects of the novel propellant while minimising the risk that these are masked by 143 the active substance(s) (thereby compromising any extrapolation of the conclusions to other products). 144 For instance, bronchoconstriction could be masked by 2-agonists and hoarseness and cough are 145 known side effects from glucocorticoids, complicating the evaluation. The subjects to be included could 146 then be either healthy volunteers or patients (who are else using dry powder devices for maintenance 147 treatment). 148 Nevertheless, as 3-month studies investigating an excipient might prove difficult to conduct in practice, 149 it would be acceptable to use a final finished product formulation indicated for daily maintenance 150 treatment, preferably a mono-component product such as a glucocorticoid. The included subjects 151 should preferably have a low risk of need for concomitant treatment (besides reliever medication, 152 which needs to be allowed). 153 A comparator product which is an approved pMDI product supported by a full dossier should be 154 included. This could, e.g., be a pMDI product for which the marketing authorisation is intended to be 155 varied (or a placebo version of the same). 156 As the amounts of a propellant included in the medicinal product (referring to daily exposure) might be 157 of relevance for the safety profile, in the case that the study is conducted with a medicinal product 158 containing an active substance, it is recommended to choose a product/strength where the number of 159 actuations needed is in the higher range. Questions and answers on data requirements when replacing hydrofluorocarbons as propellants in oral pressurised metered dose inhalers EMA/373361/200523 Page 5/9 160 3.4. What are the data requirements to address possible changes to the 161 exposure to the active substance(s)? 162 For each strength of the pMDI product for which the marketing authorisation is to be varied due to a 163 change of propellant, data must be provided showing that the local and systemic exposure of the 164 active substance(s) is not impacted by the change. Therapeutic equivalence should be confirmed as 165 outlined in the guideline on the requirements for clinical documentation for orally inhaled products 166 (OIP) (CPMP/EWP/4151/00 Rev. 1) with related documents. This guideline is under revision, and it 167 should be interpreted as a stepwise procedure to establish therapeutic equivalence between two 168 products as outlined in Figure 1 below. Data should be provided both with and without spacer/holding 169 chamber. 170 For hybrid or generic medicinal products, the comparator product should be the reference medicinal 171 product irrespective of the propellant used in the said reference medicinal product. 172 Figure 1 Schematic overview of the three-step approach for showing therapeutic equivalence for orally 173 inhaled products. 174 Questions and answers on data requirements when replacing hydrofluorocarbons as propellants in oral pressurised metered dose inhalers EMA/373361/200523 Page 6/9 175 176 3.4.1. Step 1 - In vitro 177 All pharmaceutical requirements specified in the Guideline on the requirements for clinical 178 documentation for orally inhaled products ((CPMP/EWP/4151/00 Rev 1) section 5.2 should be 179 evaluated for the modified product. Data should be provided irrespective of whether all criteria are 180 fulfilled or not. 181 3.4.2. Step 2 - Pharmacokinetics 182 In the case that therapeutic equivalence cannot be established based on in vitro data, PK data to 183 address systemic safety and lung deposition / local availability with and without a spacer need to be 184 provided. As surrogate marker for safety, total exposure (AUC0-t and Cmax) should be used. For 185 products where the contribution from the gastrointestinal tract to the systemic exposure following 186 inhalation is negligible (<5%), the systemic safety study could also be used to compare lung 187 deposition. In the case that the contribution from the gastrointestinal tract is not negligible, local Questions and answers on data requirements when replacing hydrofluorocarbons as propellants in oral pressurised metered dose inhalers EMA/373361/200523 Page 7/9 188 exposure as a surrogate marker for efficacy could be either exposure (AUC0-t and Cmax) following 189 charcoal administration or (in case of rapidly absorbed substances) AUC0-30 min (together with Cmax). 190 3.4.3. Step 3 - Pharmacodynamic data 191 In the cases where comparable local and systemic bioavailability between test and reference products 192 cannot be confirmed, concerns about efficacy and/or safety raised due to the differences recorded 193 could be addressed with targeted PD studies. It is acknowledged though that it is difficult to design 194 such studies with adequate assay sensitivity and for some substance/combination of substances 195 adequate PD models are not available. Therefore, it is recommended to make a request for scientific 196 advice before conducting any PD study. The possibility of reformulation could be considered in the case 197 that comparable local and systemic bioavailability with and without charcoal (as applicable) cannot be 198 confirmed. 199 3.5. What are the data requirements for children and adolescents? 200 The conclusion from studies supporting safety of a novel propellant as outlined in question 3.3. above 201 can be extrapolated to children and adolescents even though the studies are conducted in adults 202 only. 203 If, with reference to question 3.4, therapeutic equivalence between the test product and its reference 204 is confirmed at step 1 (i.e., in vitro data only), the same age limit as for the reference product can be 205 applied. 206 It is also acceptable to extrapolate the conclusion on therapeutic equivalence demonstrated by 207 pharmacokinetic (and if applicable pharmacodynamic) studies in adults to adolescents as long as the 208 reference product is approved for this age group. 209 According to the guideline on the requirements for clinical documentation for orally inhaled products 210 (CPMP/EWP/4151/00 Rev 1), extrapolation of pharmacokinetic (and if applicable pharmacodynamic) 211 data in adults to children would not be straight forward as small differences between products that are 212 not detected as a difference in exposure in adults could still be of concern in children due to the 213 smaller size of their airways and their different breath pattern. Nevertheless, it might be acceptable to 214 keep the age limit currently approved for the product subjected to the change of propellant also, in the 215 case that therapeutic equivalence is established based on PK data in adults, i.e., in the absence of 216 specific data in children, because retained positive benefit/risk balance in this population is 217 anticipated. 218 3.6. Are there any specific considerations related to the product 219 information following a change in propellant? 220 Name of the product: changes in the qualitative composition of excipients do not require any change in 221 the name of the product. 222 Inclusion of statements such as `HFC free' on the label: As a general principle, the Summary of Product 223 Characteristics (SmPC) is the basis of information for healthcare professionals on how to use the 224 medicinal product safely and effectively. There is no ground or need to include additional information 225 on elements which are not included in a medicinal product (i.e., absence of a component in the product 226 or in a container), as the information may become extensive and confusing. Therefore, such 227 promotional statement is not allowed. Questions and answers on data requirements when replacing hydrofluorocarbons as propellants in oral pressurised metered dose inhalers EMA/373361/200523 Page 8/9 228 Flammability warning: Depending on the propellant and product formulation, a warning on flammability 229 may be necessary. Inclusion of warnings on use near an open flame, lit cigarette or some devices 230 (e.g., hairdryers) should be considered. In accordance with the European Commission Guideline on 231 Summary of Product Characteristics, any warning necessary for excipients should be included in the 232 SmPC at the end of section 4.4. The warning should also be reflected in section 2 of the package leaflet 233 under <X contains {name the excipient(s)}>. 234 Special storage conditions: Any subsequent special storage conditions should be reflected in section 235 6.4 of the SmPC, section 9 of the Annex IIIA - Labelling, and section 5 of the package leaflet. 236 Questions and answers on data requirements when replacing hydrofluorocarbons as propellants in oral pressurised metered dose inhalers EMA/373361/200523 Page 9/9