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PubMed | SkyePharma, Sofotec GmbH, S5 Consulting, Consulting Inc. and 3 more.
Type: Comparative Study | Journal: AAPS PharmSciTech | Year: 2016

Fine particle dose (FPD) is a critical quality attribute for orally inhaled products (OIPs). The abbreviated impactor measurement (AIM) concept simplifies its measurement, provided there is a validated understanding of the relationship with the full resolution pharmacopoeial impactor (PIM) data for a given product. This multi-center study compared fine particle dose determined using AIM and PIM for five dry powder inhaler (DPIs) and two pressurized metered-dose inhaler (pMDI) products, one of which included a valved holding chamber (VHC). Reference measurements of FPD


Evans C.,Catalent Pharma Solutions | Cipolla D.,Aradigm Inc. | Chesworth T.,Astrazeneca | Agurell E.,Swedish Medical Products Agency | And 22 more authors.
Journal of Aerosol Medicine and Pulmonary Drug Delivery | Year: 2012

The purpose of this article is to document the discussions at the 2010 European Workshop on Equivalence Determinations for Orally Inhaled Drugs for Local Action, cohosted by the International Society for Aerosols in Medicine (ISAM) and the International Pharmaceutical Consortium on Regulation and Science (IPAC-RS). The article summarizes current regulatory approaches in Europe, the United States, and Canada, and presents points of consensus as well as ongoing debate in the four major areas: in vitro testing, pharmacokinetic and pharmacodynamic studies, and device similarity. Specific issues in need of further research and discussion are also identified. © 2012 Mary Ann Liebert, Inc.


Sandell D.,S5 Consulting | Mitchell J.P.,Consulting Inc.
Journal of Aerosol Medicine and Pulmonary Drug Delivery | Year: 2015

Background: The choice of analytical test methods and associated statistical considerations are considered for the laboratory testing of pressurized metered dose inhaler-spacer/valved holding chamber (pMDI-S/VHC) combinations for in vitro bioequivalence (IVBE). Methods: Four scenarios are presented for comparing TEST ("second entry" or "generic") versus REF ("innovator"): (1) innovator and second entry product pMDI alone without any S/VHC (baseline comparison); (2) innovator and second entry pMDI product with the same S/VHC; (3) innovator pMDI product with existing S/VHC and second entry product with a different S/VHC; and (4) introduction of a second, different S/VHC to be used with a given innovator pMDI product. The following aspects should be reviewed in the preparatory stage of designing experiments to establish IVBE: (a) the inclusion of delayed inhalation; (b) the utilization of age-appropriate flow rates; and (c) the use of anatomically appropriate face models for evaluation of devices with a facemask. Statistical considerations that fit in with such experimental methods include: selection of pMDI batches and S/VHC lots; choice of sample size and acceptance criteria; bracketing or worst case approaches; and balanced/paired designs. A stepwise approach for selection of impactor stage groupings is presented, and an approach to determine realistic acceptance criteria based on REF product characteristics is suggested. Results: An example of an efficient statistical design of experiment is provided for each scenario, together with alternate approaches for calculation of confidence intervals for the mean TEST/REF relationship. It is important to appreciate that the optimal design depends on balancing numerous considerations and will thus likely differ from case to case; hence, the designs presented here should be seen as illustrations rather than the only option available. More effective approaches may be found that suit a particular case at hand. Conclusions: The information provided will assist in developing correlations in support of IVBE for these add-on devices. © Copyright 2015, Mary Ann Liebert, Inc. 2015.


Hauck W.,Sycamore Consulting LLC | Sandell D.,S5 Consulting | Larner G.,Pfizer | Bergum J.,BergumSTATS LLC | And 2 more authors.
Pharmacopeial Forum | Year: 2016

The zero tolerance criterion (ZTC) in the test for uniformity of dosage units (Uniformity of Dosage Units <905>) states that no values are allowed outside a certain range with a sample size (N) of 30. The proper application of this criterion for larger samples has been the subject of much debate, and in particular, the opinion that the ZTC applies to any sample size has been questioned. The United States Pharmacopeia (USP) has previously clarified that the ZTC only applies to the sample size of the compendial test where it is described, but has not provided any guidance about how to manage situations with larger samples sizes. Resolution of this issue is pertinent, especially as sample sizes greater than 30 typically are required for proper statistical batch release testing and the ZTC could act as a hindrance in such situations. This Stimuli article describes how to determine the acceptable numbers of results outside the interval for sample sizes greater than 30 and proposes text for inclusion in USP as part of a new informational-only chapter. The criteria presented will provide a tool to judge, when collecting a large sample of results, whether that sample is consistent with the ZTC of <905>.


Hatley R.H.M.,Philips | Von Hollen D.,Philips | Sandell D.,S5 Consulting | Slator L.,Philips
Journal of Aerosol Medicine and Pulmonary Drug Delivery | Year: 2014

Background: Use of a valved holding chamber (VHC) in conjunction with a pressurized metered dose inhaler (pMDI) can reduce issues relating to poor actuation-inhalation coordination and potentially improve the lung deposition of aerosol, compared with use of a pMDI alone. However, the performance of a VHC is influenced by different device-related factors, including the size and shape of the VHC and the material it is manufactured from (conventional versus antistatic). This study aimed to provide an in vitro characterization of an antistatic VHC, the OptiChamber Diamond VHC, comparing the aerodynamic particle size distribution of aerosol delivered via this VHC with results from a second antistatic VHC and a conventional VHC. Methods: The pMDI drug formulations (albuterol, suspension; beclomethasone dipropionate, solution) were connected to a Next Generation Impactor, either directly (pMDI alone tests) or via a VHC (VHC tests). The pMDIs were actuated (×10 per product pair) and tested at extraction flow rates of 15 L/min and 30 L/min, without any time delay between actuation and inhalation. Dose delivery using the two pMDI drug formulations was compared, and is presented with reference to key aerodynamic particle size parameters. Results: Compared with tests on pMDIs alone, use of a VHC increased the dose of aerosol within the respirable range, particularly at a 15 L/min flow rate. Between-VHC comparisons indicated that the two antistatic VHCs were equivalent. Delivery of albuterol appeared to be influenced by the VHC used, but beclomethasone dipropionate seemed unaffected. Conclusions: The two antistatic VHCs were equivalent for both pMDI brands. Aerosol delivered from the antistatic VHCs at 15 L/min had a higher proportion of fine particles compared with the conventional VHC. © 2014, Mary Ann Liebert, Inc.


Slator L.,Philips | Von Hollen D.,Philips | Sandell D.,S5 Consulting | Hatley R.H.M.,Philips
Journal of Aerosol Medicine and Pulmonary Drug Delivery | Year: 2014

Background: Valved holding chambers (VHCs) are accessory devices for pressurized metered dose inhalers (pMDIs). Use of a VHC may help overcome coordination issues associated with drug delivery via the pMDI alone. Previous work has established that aspects of VHC use, including the time between actuation and inhalation (inhalation delay) and inhalation flow rate, can influence the amount of drug available to inhalation. This study compared the impact of inhalation delay and flow rate on the in vitro delivery of aerosol from different VHC brands. Methods: A custom-built inhalation delay test rig, which enabled automation of controlled inhalation delays (0, 5, or 10 sec), was developed. Extraction air flow was set to 5, 15, or 30 L/min. Delivery of albuterol (ProAir HFA 90 μg) to a filter (emitted dose) was assessed using three commercially available VHC brands (one conventional, two antistatic). Emitted dose under 27 different combinations of inhalation delay, flow rate, and VHC brand was determined in order to assess the effects of inhalation delay and flow rate. Pairwise comparisons of the different VHC brands with different inhalation delay/flow rate combinations were conducted to assess in vitro equivalence. Results: Emitted dose increased with flow rate and decreased with longer inhalation delays. Dependence on flow rate was similar for the two antistatic VHCs and more pronounced for the conventional VHC. The two antistatic VHCs showed equivalent results for the emitted dose of albuterol, across a range of flow rates and using different inhalation delays; the relation between the two antistatic VHCs fell within the±15% acceptance interval criteria for in vitro equivalence. Conclusions: The different inhalation delays and flow rates had similar effects on the delivery of drug via the three VHCs. The two antistatic VHCs were shown to be equivalent in vitro in terms of emitted dose of albuterol. © 2014, Mary Ann Liebert, Inc.


Sandell D.,S5 Consulting | Tougas T.,S5 Consulting | O'Connor D.,S5 Consulting | Horhota S.,S5 Consulting
Pharmaceutical Technology | Year: 2011

Considerable opportunity exists to improve the drug-development process without compromising the safeguards that currently mitigate risk to subjects in clinical trials. The authors outline some areas that would benefit from additional consideration and the development of harmonization. These areas include step-wise modifications of test products, the concept of representative, genotoxic impurities, specifications and acceptance criteria, and stability studies.

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