Identification Of Critical Process Parameters Research Articles

Quality by Design in Action 1: Controlling Critical Quality Attributes of an Active Pharmaceutical Ingredient

The importance of Quality by Design (QbD) is being realized gradually, as it is gaining popularity among the generic companies. However, the major hurdle faced by these industries is the lack of common guidelines or format for performing a risk-based assessment of the manufacturing process. This article tries to highlight a possible sequential pathway for performing QbD with the help of a case study. The main focus of this article is on the usage of failure mode and effect analysis (FMEA) as a tool for risk assessment, which helps in the identification of critical process parameters (CPPs) and critical material attributes (CMAs) and later on becomes the unbiased input for the design of experiments (DoE). In this case study, the DoE was helpful in establishing a risk-based relationship between critical quality attributes (CQAs) and CMAs/CPPs. Finally, a control strategy was established for all of the CPPs and CMAs, which in turn gave rise to a robust process during commercialization. It is noteworthy that ...

Understanding pharmaceutical quality by design.

This review further clarifies the concept of pharmaceutical quality by design (QbD) and describes its objectives. QbD elements include the following: (1) a quality target product profile (QTPP) that identifies the critical quality attributes (CQAs) of the drug product; (2) product design and understanding including identification of critical material attributes (CMAs); (3) process design and understanding including identification of critical process parameters (CPPs), linking CMAs and CPPs to CQAs; (4) a control strategy that includes specifications for the drug substance(s), excipient(s), and drug product as well as controls for each step of the manufacturing process; and (5) process capability and continual improvement. QbD tools and studies include prior knowledge, risk assessment, mechanistic models, design of experiments (DoE) and data analysis, and process analytical technology (PAT). As the pharmaceutical industry moves toward the implementation of pharmaceutical QbD, a common terminology, understanding of concepts and expectations are necessary. This understanding will facilitate better communication between those involved in risk-based drug development and drug application review.

Quantitative high throughput analytics to support polysaccharide production process development

The rapid development of purification processes for polysaccharide vaccines is constrained by a lack of analytical tools current technologies for the measurement of polysaccharide recovery and process-related impurity clearance are complex, time-consuming, and generally not amenable to high throughput process development (HTPD). HTPD is envisioned to be central to the improvement of existing polysaccharide manufacturing processes through the identification of critical process parameters that potentially impact the quality attributes of the vaccine and to the development of de novo processes for clinical candidates, across the spectrum of downstream processing. The availability of a fast and automated analytics platform will expand the scope, robustness, and evolution of Design of Experiment (DOE) studies.This paper details recent advances in improving the speed, throughput, and success of in-process analytics at the micro-scale. Two methods, based on modifications of existing procedures, are described for the rapid measurement of polysaccharide titre in microplates without the need for heating steps. A simplification of a commercial endotoxin assay is also described that features a single measurement at room temperature. These assays, along with existing assays for protein and nucleic acids are qualified for deployment in the high throughput screening of polysaccharide feedstreams. Assay accuracy, precision, robustness, interference, and ease of use are assessed and described. In combination, these assays are capable of measuring the product concentration and impurity profile of a microplate of 96 samples in less than one day. This body of work relies on the evaluation of a combination of commercially available and clinically relevant polysaccharides to ensure maximum versatility and reactivity of the final assay suite. Together, these advancements reduce overall process time by up to 30-fold and significantly reduce sample volume over current practices. The assays help build an analytical foundation to support the advent of HTPD technology for polysaccharide vaccines. It is envisaged that this will lead to an expanded use of Quality by Design (QbD) studies in vaccine process development.

Evaluation of critical process parameters for intra-tablet coating uniformity using terahertz pulsed imaging

The purpose of this study was to evaluate the intra-tablet coating uniformity and the identification of critical process parameters in an active pan coating process using terahertz pulsed imaging (TPI). A design of experiments (DoE) was performed with drum load, drum speed, spray rate, run duration and spray pressure as factors. Different measures of intra-tablet uniformity were investigated: the average thickness on the individual tablet faces, spatial variation in layer thickness over the tablet surface, and the coefficient of variation (CVintra). Data analysis revealed that the process parameters in the investigated parameter space had hardly any influence on the difference in layer thickness of the tablet faces and centre band. No increase or decrease in layer thickness – as described in the literature – was found towards the edges of the tablet face. In overwetted process conditions a higher layer thickness at the centre band edges could be observed. Still, the highest variability in coating thickness was found along the circumference of the centre band rather than the height. In general, higher CVintra of layer thickness were found on the centre bands in comparison with the tablet faces. The analysis of the DoE model revealed that the run duration had the highest influence on the CVintra on the tablet faces. TPI showed high potential in the assessment of intra-tablet uniformity and layer thickness distributions over the whole tablet surface. It was successfully used to identify critical process parameters regarding intra-tablet coating uniformity.

Identification of critical process parameters and its interplay with nanosuspension formulation prepared by top down media milling technology – A QbD perspective

The purpose of this study was to optimize the process parameters of a poorly soluble drug by top down media milling process using different polymer systems. Process parameters including agitation rate (RPM), size of grinding media and drug content were studied through a Quality by Design (QbD) approach, using three different polymeric stabilizers (HPMC 3 cps, PVP K-30 and HPC-EXF) with the addition of Vitamin E TPGS as a surface active agent. From the statistical analysis, the RPM of the media milling was determined to be the most significant process parameter with respect to influence on particle size. The effects of varying the size of grinding media or drug content were not found to be as significant as the effects of RPM. Finally, the polymeric stabilizer played an important role in the production of nanoparticles. Among the different polymers, HPMC stabilized systems demonstrated superior results with regards to the consistency in producing successful nanoparticles and inhibition of crystal growth during storage. This study established the interplay among the formulation parameters in order to select the design space, which helped us in the identification and rank ordering of critical and noncritical variables related to the quality attributes of nanosuspension formulation during the early phase of product development.

The way to a design space for an animal cell culture process according to Quality by Design (QbD)

Background The strategy of implementation of the QbD (Quality by design) approach in upstream processing of therapeutic proteins consists of the identification of critical process parameters (CPPs) that have a statistically significant influence on the critical quality attributes (CQAs) of a specific process. By applying the acceptance criteria to the CQAs, proven acceptable ranges (PARs) for the CPPs can be deduced from experimental data. The multidimensional combination of these ranges form the design space and thus assures the quality of the product. The QbD approach according to the ICH guidelines Q8, Q9 and Q10 may be subdivided in the work packages scale down model qualification, risk analysis, process characterization and range studies. The foundation of the QbD approach is represented by the scale down model. Several different scale down criteria were applied and adapted until a satisfactory match of scale down to commercial scale data was achieved. The scale down model is then used to investigate cause effect relationships between process parameters and quality attributes of the production process. Since a standard cell culture process from thawing of the vial up to the final production fermenter can comprise up to 100 process parameters, a risk based approach is helpful to filter the most important ones. Those parameters are then experimentally investigated to verify their criticality for the quality attributes of the process. This approach relies on design of experiment (DoE) to reduce the number of required experiments to a manageable number while maintaining meaningful results. During the range studies, those critical parameters will be investigated with the help of a high resolution DoE matrix in order to be able to reveal possible interactions and higher order effects.

A novel conico-cylindrical flask aids easy identification of critical process parameters for cultivation of marine bacteria

A polymethylmethacrylate (PMMA) conico-cylindrical flask (CCF) with an inner arrangement consisting of eight equidistantly spaced rectangular strips mounted radially on a circular disk to provide additional surface area for microbial attachment and ports to allow air supply was employed for melanin production by Shewanella colwelliana and antibiotic production by Pseudoalteromonas rubra. The design allowed comparison of production between (1) CCF with hydrophobic surface (PMMA-CCF), (2) CCF with hydrophilic glass surface (GS-CCF), and (3) standard unbaffled Erlenmeyer flask (EF). Melanin production in the PMMA-CCF was higher by at most 33.5% and growth of S. colwelliana by at most 309.2% compared to the other vessels. Melanin synthesis was positively correlated with reactor surface area and hydrophobicity, suspended cell growth, and biofilm formation. Antibiotic production in the EF was higher by at most 83.3%, but growth of P. rubra was higher in the PMMA-CCF by at most 54.5% compared to the other vessels. A hydrophilic vessel surface, abundant air supply, but low shear stress enhanced antibiotic production. The CCF together with the EF allowed identification of the crucial parameters (vessel surface characteristics, growth, biofilm formation, and aeration) influencing productivity, knowledge of which in the initial stages of process development will facilitate informed decisions at the later phases.

Fatigue Failure of Extrusion Dies: Effect of Process Parameters and Design Features on Die Life

Analysis of die failure plays an important role in the prediction and prevention of die failure, and subsequently in improving economics of any metal-forming process. Industrial experience has shown that fracture is the most common mode of failure in the case of hot aluminum extrusion dies. The purpose of the present work is to implement fatigue damage models in a Finite Element code for identification of critical process parameters and die design features in the case of fatigue being the dominating failure mode. For the maximum number of billets extruded by the die before fatigue crack initiation (fatigue life cycles in extrusion), Morrow’s stress- and strain-life damage models are implemented for axisymmetric flat extrusion die. With the help of finite element software ABAQUS, extrusion process is simulated and dynamic stress and strain values were obtained by first identifying the potential fatigue location in the die. The evaluation of applicability of the damage models is done for specific hot extrusion die made of H13 steels with Al-6063 as billet material. By considering temperature and strain rate as process parameters and bearing length and fillet radius of the die as geometric features, different simulation runs are performed to investigate the effect of process and design features on the useful die life. Morrow’s stress life model shows a good correspondence between computed and actual failure of dies. By establishing correlations of die life with process and design parameters under different conditions, it was shown that the present investigation is a useful guideline at die design and extrusion process stages.