Quality by Design I: Application of Failure Mode Effect Analysis (FMEA) and Plackett–Burman Design of Experiments in the Identification of “Main Factors” in the Formulation and Process Design Space for Roller-Compacted Ciprofloxacin Hydrochloride Immediate-Release Tablets

Abstract

As outlined in the ICH Q8(R2) guidance, identifying the critical quality attributes (CQA) is a crucial part of dosage form development; however, the number of possible formulation and processing factors that could influence the manufacturing of a pharmaceutical dosage form is enormous obviating formal study of all possible parameters and their interactions. Thus, the objective of this study is to examine how quality risk management can be used to prioritize the number of experiments needed to identify the CQA, while still maintaining an acceptable product risk profile. To conduct the study, immediate-release ciprofloxacin tablets manufactured via roller compaction were used as a prototype system. Granules were manufactured using an Alexanderwerk WP120 roller compactor and tablets were compressed on a Stokes B2 tablet press. In the early stages of development, prior knowledge was systematically incorporated into the risk assessment using failure mode and effect analysis (FMEA). The factors identified using FMEA were then followed by a quantitative assessed using a Plackett-Burman screening design. Results show that by using prior experience, literature data, and preformulation data the number of experiments could be reduced to an acceptable level, and the use of FMEA and screening designs such as the Plackett Burman can rationally guide the process of reducing the number experiments to a manageable level.

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“…[24][25][26] The results of FMEA are represented in Table 2 in the form of risk priority numbers (RPNs) which can be used to rank the risk. It is calculated as mentioned below: …”

Quality by design approach to protein PEGylation: a review

“…The ease at which a failure mode can be detected defines the parameter D. The more measurable a failure mode is, the lesser risk process holds. Multiplying these values would result in the risk priority number (RPN) [15].…”

Quality-by-Design II: Application of Quantitative Risk Analysis to the Formulation of Ciprofloxacin Tablets

“…The mixing, roller compaction, and tableting stages are shown with the process parameters for each stage listed below and the output parameters shown above the stages in italics study, two separate DOEs were performed to identify the design space: study 1, a small-scale study with a 0.5 kg batch size that examined only processing variables, and study 2, a larger-scale study with a 3.6 or 1.0 kg batch size that examined both processing and formulation variables and their interactions. The base formulation and process conditions, which studies 1 and 2 are built around, are given in Table I, and are based upon our previous study (4). The numerical values for the DOE conditions and results for studies 1 and 2 are given in an Excel® spreadsheet that is provided as supplemental spreadsheet for this manuscript; in this spreadsheet, formulation F5 is the base formulation of Table I.…”

“…The Carr Index (CI) was calculated as follows: Granule size was measured by laser diffraction using the Malvern Mastersizer (Malvern Inc., Worcestershire, UK) with a sample size of 5 g operated at an air pressure of 20 psi and a feed rate setting of 2.5. The average mean particle size was D [4,3] and the span, (D 90 -D 10 )/D 50 ; the reported values for these parameters are the average of three replicates.…”

“…The goal of this paper is to continue our illustration of how qualitative and quantitative risk tools can be used in quality-by-design approaches to rationally guide the balance between too many and too few experiments during product development, and to target resources to the factors that can have the greatest impact on patient health (4). This study extends the previous qualitative study and illustrates the use of quantitative Monte Carlo techniques to define the design space and quantitate the uncertainty associated with the design space boundaries.…”