S5 Consulting

Lund, Sweden

S5 Consulting

Lund, Sweden
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Hauck W.,Sycamore Consulting LLC | Sandell D.,S5 Consulting | Larner G.,Pfizer | Bergum J.,BergumSTATS LLC | And 2 more authors.
Pharmacopeial Forum | Year: 2017

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〉. [NOTE-This Stimuli article was previously published in Pharmacopeial Forum 42(5) [Sept.-Oct. 2016]. It is being published again to correct errors in Table 3 in the Proposal section. Table 3 as presented here contains the correct values. Further, it is clarified in this republication that although the discussion focuses on content uniformity for assessing uniformity of dosage units, the uniformity can be demonstrated equally well, in certain cases, using weight variation following the same procedure as used for content uniformity. The proposal put forward herein is thus equally applicable to weight variation when used for sample sizes larger than 30].


Capen R.,Nonclinical and Pharmaceutical science Statistics | Capen R.,Merck And Co. | Christopher D.,Nonclinical and Pharmaceutical science Statistics | Forenzo P.,Novartis | And 10 more authors.
AAPS PharmSciTech | Year: 2012

This article proposes new terminology that distinguishes between different concepts involved in the discussion of the shelf life of pharmaceutical products. Such comprehensive and common language is currently lacking from various guidelines, which confuses implementation and impedes comparisons of different methodologies. The five new terms that are necessary for a coherent discussion of shelf life are: true shelf life, estimated shelf life, supported shelf life, maximum shelf life, and labeled shelf life. These concepts are already in use, but not named as such. The article discusses various levels of product on which different stakeholders tend to focus (e.g., a single-dosage unit, a batch, a production process, etc.). The article also highlights a key missing element in the discussion of shelf lifea Quality Statement, which defines the quality standard for all key stakeholders. Arguments are presented that for regulatory and statistical reasons the true product shelf life should be defined in terms of a suitably small quantile (e.g., fifth) of the distribution of batch shelf lives. The choice of quantile translates to an upper bound on the probability that a randomly selected batch will be nonconforming when tested at the storage time defined by the labeled shelf life. For this strategy, a random-batch model is required. This approach, unlike a fixed-batch model, allows estimation of both within- and between-batch variability, and allows inferences to be made about the entire production process. This work was conducted by the Stability Shelf Life Working Group of the Product Quality Research Institute. © 2012 American Association of Pharmaceutical Scientists.


Sheth P.,Recipharm | Sheth P.,Cirrus Pharmaceuticals Inc. | Sandell D.,S5 Consulting | Conti D.S.,U.S. Food and Drug Administration | And 5 more authors.
AAPS Journal | Year: 2017

Metered dose inhalers (MDIs) are complex drug-device combination products widely used to treat pulmonary disorders. The efficacy, driven by aerosol performance of the products, depends on a multitude of factors including, but not limited to, the physicochemical properties of drug and nature and amount of excipient(s). Under the quality by design (QbD) paradigm, systematic investigations are necessary to understand how changes in critical quality attributes (CQAs) of formulation, device, and manufacturing process influence key product performance parameters, such as delivered dose (DD) and fine particle dose (FPD). The purpose of this work is to provide a better understanding of the effects of different levels of excipients and drug particle size distribution on the aerosol performance of MDI products, while using two fundamentally different MDI products as relevant model systems, Proventil® HFA (albuterol sulfate suspension) and Qvar® (beclomethasone dipropionate solution). These MDI products, as model systems, provided mid-points around which a design of experiments (DOE), consisting of 22 suspension and 9 solution MDI formulations, were defined and manufactured. The DOE included formulations factors with varying ethanol (2 to 20% w/w and 7 to 9% w/w for the suspension and solution, respectively) and oleic acid concentrations (0.005 to 0.25% w/w and 0 to 2% w/w for the suspension and solution, respectively) and drug volumetric median particle size distribution (PSD D50, 1.4 to 2.5 μm for the suspension). The MDI formulations were analyzed using compendial methods to elucidate the effect of these formulation variables (ethanol, oleic acid, and PSD D50) on DD and FPD. The outcomes of this study allowed defining design spaces for the formulation factors, such that DD and FPD would remain within specific pre-defined requirements. The systematic approach utilized in this work can contribute as a QbD tool to evaluate the extent to which the formulation factors govern the aerosol performance of MDI drug products, helping to design MDI formulations with desired product performance parameters. © 2017 American Association of Pharmaceutical Scientists


Sandell D.,S5 Consulting | Tougas T.,Boehringer Ingelheim Pharmaceuticals
Statistics in Biopharmaceutical Research | Year: 2012

The quality of a commercial pharmaceutical product is set by a well-designed, understood, and executed manufacturing process using high-quality raw materials. In addition, this built-in quality is verified at release and its stability is assured by random sampling and testing of critical product characteristics against established specifications. There are several approaches to how this verification testing is designed, depending on the underlying quality philosophy employed. This article explores different common approaches and briefly discusses the pros and cons of each. In the most general sense, quality can be defined as the extent to which a product meets customer expectation. The common practice in the pharmaceutical industry is to specify test acceptance criteria without clearly defining or relating these criteria to an underlying quality statement about the product. Fundamental to constructing such a quality statement is an assumed definition of what is meant by drug product in this context, that is, batch, individual dosage units, or some other basic unit. As a result, it is not always fully clear what a reasonable customer expectation is. In contrast to current practices, we propose that a transparent quality statement should be formulated for every pharmaceutical product and that the test(s) to verify that the required performance (as defined by the quality statement) should be designed using established statistical techniques. © 2012 Copyright Taylor and Francis Group, LLC.


Nichols S.C.,OINDP Consultant | Mitchell J.P.,Consulting Inc. | Sandell D.,S5 Consulting | Andersson P.U.,Astrazeneca | And 4 more authors.
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 FPDPIM were made by each organization using either the full-resolution Andersen 8-stage non-viable impactor (ACI) or Next Generation Impactor (NGI). FPDAIM was determined for the same OIP(s) with their choice of abbreviated impactor (fast screening impactor (FSI), fast screening Andersen (FSA), or reduced NGI (rNGI)). Each organization used its validated assay method(s) for the active pharmaceutical ingredient(s) (APIs) involved. Ten replicate measurements were made by each procedure. The upper size limit for FPDAIM varied from 4.4 to 5.0 μm aerodynamic diameter, depending upon flow rate and AIM apparatus; the corresponding size limit for FPDPIM was fixed at 5 μm in accordance with the European Pharmacopoeia. The 90% confidence interval for the ratio [FPDAIM/FPDPIM], expressed as a percentage, was contained in the predetermined 85–118% acceptance interval for nine of the ten comparisons of FPD. The average value of this ratio was 105% across all OIPs and apparatuses. The findings from this investigation support the equivalence of AIM and PIM for determination of FPD across a wide range of OIP platforms and measurement techniques. © 2016, American Association of Pharmaceutical Scientists.


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.


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.

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