Reliability Evaluation of Nonlinear Design Space in Pharmaceutical Product Development

Hayashi, Yoshihiro; Kikuchi, Shinya; Onuki, Yoshinori; Takayama, K.

doi:10.1002/jps.22734

Cited by 17 publications

(17 citation statements)

References 21 publications

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Section: )mentioning

confidence: 99%

“…The distribution of the border of the design spaces was obtained mathematically from the intersection points of normal lines at given points on the border of the original design space and the borders of the BS design spaces. Although a detailed explanation of each statistical analysis was described fully in previous articles, [20][21][22] for a better understanding, the process for the determination of the conservative border of the design space is shown in Fig. 1 and is described as follows:…”

Section: Measurement Of Response Variablesmentioning

confidence: 99%

“…Although most histograms seemed to be normally distributed, some histograms seemed to be nonnormally distributed because their skewness and kurtosis, which are the indices of the normality of histograms, were not close to zero. 22) Therefore, 95% CIs based on a nonparametric approach were calculated and the polynomial approximation technique was again applied for each 95% CI point. Thus, conservative as well as optimistic borders of design space were obtained, as shown in Fig.…”

Section: Input Variables Hardnessmentioning

confidence: 99%

“…To overcome this drawback, we applied a bootstrap (BS) resampling technique to evaluate the reliability of the design space, [14][15][16][17][18][19][20] and a polynomial approximation method with 95% confidence intervals (CIs) based on either a parametric or a nonparametric approach to determine the conservative border of the design space. 21,22) Applying these techniques, we propose an approach to evaluate the reliability of the design space for practical use.Particularly for the oral formulation manufacturing process, many examples have been reported to establish the design space using a linear response surface model with critical process parameters (CPPs), because the linear response surface model is effective at a certain defined scale with particular equipment.23,24) However, there are always difficulties of scalegap and equipment-gap, which are inevitably problematic for pharmaceutical development studies. …”

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A Novel Approach to Establishing the Design Space for the Oral Formulation Manufacturing Process

Norioka

Hayashi

Onuki

et al. 2013

CHEMICAL & PHARMACEUTICAL BULLETIN

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A novel approach to establishing the design space for the oral formulation manufacturing process was investigated. A response surface method incorporating multivariate spline interpolation was applied to overcome the nonlinear problem, which is always problematic in pharmaceutical development studies, and a bootstrap resampling technique, polynomial approximation technique, and 95% confidence intervals based on a nonparametric approach were applied to estimate the reliability of the established design space derived from the nonlinear response surface model. The critical quality attributes (CQAs) of intermediate material rather than the critical process parameters (CPPs) were chosen as the causal factors for the response variables, which were CQAs of the final product to avoid scale-gap and equipment-gap. This enabled the effective use of data sets accumulated during all pharmaceutical development studies. It was confirmed that a conservative border as well as an optimistic border of the design space for practical use was obtained considering the variability of the border of the design spaces on nonlinear response surfaces. Furthermore, the nonlinear response surface model using CQAs of intermediate material derived from data sets of a laboratory scale study and pilot scale studies could predict the CQA of the final product (2.5 h dissolution of commercial-scale study) with high accuracy. Consequently, the proposed novel approach overcame all of the difficulties for the manufacturing process development of oral formulations and this is the first study to demonstrate the effectiveness of the design space using CQA of intermediate material for the oral formulation manufacturing process.Key words design space; experimental design; response surface method; multivariate statistical analysis; confidence interval; critical quality attribute In recent years, the "quality by design" (QbD) concept has been introduced by the International Conference on Harmonization (ICH) Q8 guideline. This guideline has recommended establishing a science-based rationale in pharmaceutical development studies for both formulation development and manufacturing process development. The guideline also noted that the multidimensional relationships of causal factors that have been demonstrated to provide specified target values of response variables are defined as the design space, and the establishment of the design space based on scientific understanding gained from pharmaceutical development studies and manufacturing experience provides the regulatory flexibility. 1)Therefore, the establishment of the design space is important not only to achieve a higher level of scientific understanding, but also to gain regulatory flexibility.To establish the design space, a design-of-experiments (DoE) approach was used effectively to determine the multidimensional relationships among causal factors and response variables.2,3) A response surface method (RSM) is useful for visual understanding of the derived multidimensional relationships.4-7) However, the m...

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Section: )mentioning

confidence: 99%

Section: Measurement Of Response Variablesmentioning

confidence: 99%

Section: Input Variables Hardnessmentioning

confidence: 99%

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confidence: 99%

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A Novel Approach to Establishing the Design Space for the Oral Formulation Manufacturing Process

Norioka

Hayashi

Onuki

et al. 2013

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…[3][4][5][6][7][8][9][10][11][12] LAC is used as a filler-binder and CS as a filler and possible disintegrating agent. 13) MCC is a filler and used mostly as a binder for direct compression.…”

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Optimization of Premix Powders for Tableting Use

Todo

Sato

Takayama

et al. 2018

CHEMICAL & PHARMACEUTICAL BULLETIN

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SummaryDirect compression is a popular choice as it provides the simplest way to prepare the tablet.It can be easily adopted when the active pharmaceutical ingredient (API) is unstable in water or to thermal drying. An optimal formulation of preliminary mixed powders (premix powders) is beneficial if prepared in advance for tableting use. The aim of this study was to find the optimal formulation of the premix powders composed of lactose (LAC), cornstarch (CS), and microcrystalline cellulose (MCC) by using statistical techniques. Based on the "Quality by Design" concept, a (3,3)-simplex lattice design consisting of three components, LAC, CS, and MCC was employed to prepare the model premix powders. Response surface method incorporating a thin-plate spline interpolation (RSM-S) was applied for estimation of the optimum premix powders for tableting use. The effect of tablet shape identified by the surface curvature on the optimization was investigated. The optimum premix powder was effective when the premix was applied to a small quantity of API, although the function of premix was limited in the case of the formulation of large amount of API. Statistical techniques are valuable to exploit new functions of well-known materials such as LAC, CS, and MCC.Key words tablet; direct compression; premix powder; quality by design; simplex lattice design; thin-plate spline Chemical and Pharmaceutical Bulletin Advance PublicationA compressed tablet is one of the most popular and widely used dosage forms for drug administration. They are easy to swallow and the proper dose is countable by the number of tablets. Compared with the other solid dosage forms such as powders, granules, and capsules, tableting requires rather long and complex manufacturing process, i.e., milling, sieving, mixing, granulation, drying, and compression via a tableting machine. Direct compression is the simplest method and a popular choice to prepare the tablet. 1)In addition, direct compression is easy to adopt when the active pharmaceutical ingredient (API) is unstable in water or to thermal drying.2)It is beneficial if we can provide the optimal formulation of preliminary mixed powders (premix powders) in advance for tableting use. Such knowledge can be applicable to the development of an initial trial of tablet formulation containing APIs.The aim of this study was to find the optimal formulation of the premix powders composed of lactose (LAC), cornstarch (CS), and microcrystalline cellulose (MCC) by using a series of statistical techniques. [3][4][5][6][7][8][9][10][11][12] LAC is used as a filler-binder and CS as a filler and possible disintegrating agent. 13)MCC is a filler and used mostly as a binder for direct compression. 14)These components are the most common and effective tableting materials. 15) In recent years, the application of statistical techniques to pharmaceutical product development has been implemented to allow the "Quality by Design" concept proposed by the International Council for Harmonization of Technical Requirements for Pharm...

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Fast-track to A Solid Dispersion Formulation Using Multi-way Analysis of Complex Interactions

Berg

Søgaard

et al. 2013

Journal of Pharmaceutical Sciences

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Reliability Evaluation of Nonlinear Design Space in Pharmaceutical Product Development

Cited by 17 publications

References 21 publications

A Novel Approach to Establishing the Design Space for the Oral Formulation Manufacturing Process

A Novel Approach to Establishing the Design Space for the Oral Formulation Manufacturing Process

Optimization of Premix Powders for Tableting Use

Fast-track to A Solid Dispersion Formulation Using Multi-way Analysis of Complex Interactions

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