Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

Quality by Design in Pharmaceutical Development and Manufacturing

Neha Sanghavi (Abschlußjahr: 2015)

Summary
Language: English
The 'traditional' approach to pharmaceutical development is discussed and the Quality by Design (QbD) approach to pharmaceutical development is introduced with a description of the key elements of QbD and a comparison of the two approaches to development.
A theoretical developmental plan is presented for the development by QbD of generic desloratadine 5 mg immediate release (IR) tablets.
The quality target profile is defined based upon the properties of the drug substance, characterization of the reference listed drug (RLD), consideration of the RLD label and the intended patient population. The identification of critical quality attributes is based on the severity of harm to the patient (safety and efficacy) resulting from a failure to meet that quality attribute of the drug product. The critical quality attributes (CQAs) of the drug product that could be impacted by changes to the drug product formulation or manufacturing process are identified as assay, content uniformity, dissolution and degradation products.
Desloratadine is classified in the Biopharmaceutics Classification System(BCS) as a Class I i.e highly soluble and highly permeable compound. The recommended FDA dissolution method for desloratadine is to be investigated for its capability in differentiating between formulations having different desloratadine particle size distributions and to predict their vivo performance in a pilot BE study.
Risk assessment is used to identify potential high risk formulation and process variables and to determine which studies are necessary to achieve product and process understanding in order to develop a control strategy. Each risk assessment is updated to reflect the reduced risk level based upon the improved product and process understanding gained during the course of the developmental studies.
A desloratadine particle size distribution of d90 ≤ 30 μm is selected on the basis of in silico simulation carried out to determine the effect of drug substance particle size simulation on the ratio of Cmax and AUC for the developmental formulation and the reference listed drug (RLD). Wet granulation is the process selected for the manufacture of generic desloratadine tablets, 5 mg. Generic desloratadine film coated tablets are low dose drugs and wet granulation generally fixes the drug in the granule. The process selected for the manufacture of generic desloratadine film coated tablets is fluid bed granulation followed by fluid bed drying. For the manufacture of generic desloratadine tablets 5 mg, excipients identical or similar to those of the RLD are chosen with grades suitable for wet granulation. In addition excipient binary mixture compatibility studies are performed.
Two formulation development design of experiments (DOE) are proposed. The first (DOE) will evaluate the impact of drug particle size distribution and intragranular dibasic calcium phosphate dihydrate/microcrystalline cellulose ratio and the disintegrant(s) level on drug product CQAs. The second DOE will investigate the effect of extragranular lubricant talc levels on drug product CQAs. The formulation composition will be finalized based upon knowledge obtained from these two DOE studies.
Critical process parameters that can impact on drug product CQAs are identified on the basis of an initial risk assessment and investigated by appropriate design of experiments (DOE). Mill impeller speed and mill screen size i.e. Mesh are identified as critical process parameters for milling and acceptable ranges are to be identified through DOE. The impact of talc specific surface area and number of revolutions on drug product CQAs will be investigated and an acceptable range for tablet compression force is to be identified during tablet compression. The film coating process will be optimized using design of experiments.
Scale-up principles are presented for the proposed scale-up to pilot and commercial scales especially for wet granulation, final blending and tablet compression. The final operating ranges for the identified critical process parameters are presented and will be qualified and undergo continuous verification during routine commercial production.
A control strategy is proposed that includes material attributes and process parameters identified as high risk variables during the initial risk assessment, inprocess controls and finished product specifications. The control strategy will be adjusted based upon enhanced product and process understanding gained during the product life-cycle.
Finally the advantages of the development by QbD of generic desloratadine film tablets 5 mg are presented with suggestions for an ‘enhanced’ QbD approach to development. The current challenges to QbD adoption in the pharmaceutical industry from an industry perspective are presented along with the business case and critical factors for the success of the business case for QbD.
Pages : 91