Andy Cooper

The uniformity of delivered dose, or dose content uniformity, was assessed to understand the performance of the Sirdupla generic product versus the Seretide Evohaler innovator product.

	Analytical method development and validation are performed using a generic quality-by-design (QbD) framework for lifecycle management (1-3). This approach is analogous to the framework recommended for product development in the International Council on Harmonization (ICH) guidelines (4) and is a regular practice within the pharmaceutical industry (5-11). All methodology has a defined analytical target profile (ATP), which is a set of predefined objectives that defines performance requirements and is subject to risk management and continuous improvement processes.

	The methodology for uniformity of delivered dose (UoDD)/dose content uniformity (DCU) is a critical quality attribute (CQA) of orally inhaled and nasal drug products (OINDP). In line with the QbD paradigm, this critical variable was assessed by designed experiments to understand the performance of the Sirdupla (Mylan) generic product versus the Seretide Evohaler (GlaxoSmithKline) innovator product (salmeterol/fluticasone propionate, 120 actuations).


	Two Sirdupla product strengths were evaluated: a high-strength (HS) product in respect to Seretide Evohaler 25/250 mcg/actuation salmeterol/fluticasone propionate, 120 actuations; and a medium-strength (MS) product in respect to Seretide Evohaler 25/125 mcg/actuation salmeterol/fluticasone propionate, 120 actuations. Samples were prepared at the start, middle, and end of the pressurized metered dose inhaler (pMDI) container life (SOL, MOL, EOL) using unit spray collection apparatus (USCA), in accordance with the 

) guidelines (12,13). Two actuations were collected per test sample. While priming and collection actuations were performed manually, an MDI FD-10 instrument (InnovaSystems, New Jersey, US) was used to automate the waste actuations between the stages of container life. Samples were then analyzed by high-performance liquid chromatography-ultraviolet detection (HPLC-UV) methodology validated in accordance with ICH guidelines (14), quantifying amounts of salmeterol xinafoate (SX) and fluticasone propionate (FP). Dose proportionality was demonstrated for these actuations for all studies. In this article, only FP data are shown. Critical method parameters are listed in 

	The lifecycle management tools supplement the traditional approach to method development/validation. Initially, the pre-prepared generic versions of the ATP and risk assessment (RA) for the methodology are reviewed, with any specific product considerations factored in. The generic assay ATP can be broadly described as accurate, precise, and robust quantification of the active substances over their specification range. More specifically for this Sirdupla UoDD method, the ATP requirements were that the average dose was within 85-115% of Seretide Evohaler label claim (15), with acceptable test variability (e.g., relative standard deviation not more than 10%) for both APIs. It is imperative for generic products that there is this ATP prerequisite for accuracy. Such pre-defined objectives are peer-reviewed and define the method development (MD) end point. The RA uses suitable risk management tools such as fishbone diagrams, cause-and-effect matrices, and failure mode effect analyses. These tools define appropriate controls and identify required MD and method validation (MV) experimentation for each method variable, and are again peer-reviewed. MD/MV experimentation includes appropriate robustness/ruggedness studies to understand and control critical variables and define design space, as outlined in detail in this publication.

There are multiple variables that can influence UoDD data as shown in 

. Aside from the product-related factors, risk assessments of the other variables are required. While some parameters have no impact if they are suitably controlled (e.g., cleaning), other more critical parameters require experimentation to determine their effects (e.g., shake/fire parameters for suspension pMDIs). Further risk assessments were required to determine the critical shake/fire parameters the experimentation would focus on.

	Firstly, screening experiments were performed for the automated waste actuations to define appropriate settings for shake speed and depression hold time. Other high-risk parameters were then assessed, particularly for their effects on container EOL data (see 

). Actuation force and post actuation delay were not found to be statistically significant in their effect on UoDD at EOL. A number of main effects were statistically significant: temperature, number of shake cycles, and post-shake delay (data in red). The settings for these parameters were optimized to minimize potential for through container life trends (e.g., sedimentation will be slower at a lower temperature with a reduced post-shake delay). As well as these statistically significant main effects, there are a number of statistically significant interactions present involving all five parameters, highlighting the importance of conducting experiments in a balanced design. As there are significant interactions involving actuation force and post-actuation delay, which were not highlighted as significant main effects, these parameters are also appropriately controlled. It should be noted that no main effect or interaction was of large practical significance (all affect dose by less than 5%), demonstrating reasonable robustness over the entire experimental design space. In practice, a more constricted control space is applied for these parameters, which will therefore contribute significantly less than 5% to the overall test variability. All experiments on the waste actuations were performed with the MS Sirdupla product.  

	Next, a risk assessment was conducted to determine the shake/fire parameters to be assessed for the priming/collection actuations, performed manually by the analysts. Four parameters in total were chosen for experimentation. Screening experiments were performed using the HS product to define boundaries for optimization studies with both product strengths. The screening experiments, and the subsequent optimization tests, showed that shake speed and post actuation delay were not practically significant. Only depression hold time and post-shake delay were shown to be practically significant parameters, and are minimized to reduce sedimentation of the API and potential enrichment of the dose. As shown for the waste actuation studies, and for other products (16), post-shake delay is shown to be significant and requires tight control (see 

). In practice, a zero second post-shake delay cannot be achieved. It is, therefore, important to consider the control that can be accomplished in a robust and rugged manner day after day by different analysts.  

	Lastly, control space settings were chosen from the experimental design space evaluated for both the waste actuations and the priming /collection actuations. These optimized settings were verified/validated as shown in 

	The data generated were shown to be comparable with data generated for the Seretide Evohaler product. Data will continue to be assessed as part of the method review process, completing the lifecycle loop.


	Analytical method development and validation was performed using a generic QbD framework for lifecycle management. UoDD methodology was assessed using QbD tools such as risk assessments, ATP, and designed experiments to understand the performance of the Sirdupla generic product versus the Seretide Evohaler innovator product. Suitable control of the shake/fire parameters for priming, collection, and waste actuations is critical for the analytical method.

	This control is delivered via use of automation for the waste actuations onlyautomation could be extended to the priming/collection actuations, and even the sample recovery process, to exercise greater control. The optimized methodology demonstrates that the Sirdupla generic product generates comparable UoDD data to the Seretide Evohaler innovator product. This methodology is considered appropriate for the product lifespan, although it will be subject to continuous improvement processes in line with the QbD paradigm.

Sirdupla is a trademark of Mylan Inc. Seretide and Evohaler are registered trademarks of GlaxoSmithKline Group.


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	When referring to this article, please cite it as A. Cooper, "A QbD Method Development Approach for a Generic pMDI," 

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Application for Sirdupla Uniformity of Delivered Dose Methodology