Understanding the effect of excipients’ material attributes on the final drug product is integral to quality by design (QbD). The authors examine the effect and interaction of variations in the material properties of hypromellose on powder flow, the physical attributes of tablets, and in vitro drug-release profiles from two model formulations of extended-release hydrophilic matrix tablets using QbD principles.
Quality by design (QbD) is a systematic approach to designing and developing pharmaceutical formulations and manufacturing processes to ensure predefined product quality (1). In the case of hydrophilic matrix tablets, it is important to consider potential variability in material attributes of the rate-controlling polymer in addition to variability in the API properties and processing conditions (2–4). This proactive and enhanced understanding supports efficient pharmaceutical product development.
This study examines the effect and interaction of variations in hypromellose physicochemical properties on powder flow, the physical attributes of tablets, and in vitro drug-release profiles from two model formulations of extended-release (ER) hydrophilic matrix tablets using QbD principles. This article presents a QbD approach to determine the effect of material attributes on both the physical properties and in vitro drug-release performance of the matrix tablets.The excipient hypromellose United States Pharmacopeia (USP) substitution type 2208 (Methocel K15M Premium CR, Dow Chemical) was used as the rate-controlling polymer for two case studies with a soluble drug (propranolol hydrochloride [HCl]) and slightly soluble drug (theophylline). Normal variation of Methocel material attributes (apparent viscosity, percent hydroxylpropoxyl (HP) substitution, and particle size) was studied at polymer concentrations of 15% w/w and 30% w/w. The study demonstrated consistent physical properties for direct-compression blends and subsequent tablet cores, irrespective of the Methocel concentration or drug included. In vitro drug release, however, showed greater sensitivity to material-attribute variability at lower polymer concentration.
The importance of QbD
QbD is a systematic approach to pharmaceutical development that results in increased quality and reduced costs. QbD means designing and developing formulations and manufacturing processes to ensure predefined product quality (1). Adoption of QbD principles for new-chemical-entity and generic-drug products is becoming an expectation by regulatory agencies to better ensure that high-quality medicines are available to the end-user, namely the patient. Building quality into drug products by design also benefits developers. Successful first-cycle approval, reduction of postapproval changes, and the potential of real-time release could offset initial investment associated with QbD implementation.
Importantly, enhanced understanding of the product and manufacturing process also can lead to the elimination of production rejects and recalls due to quality issues. Before FDA introduced QbD into the chemistry, manufacturing, and controls (CMC) review process in 2004, the amount of product waste due to manufacturing mistakes was reported to be as high as 50% (5). Clearly, for the end-user, the patient, drug-product recalls associated with quality issues, and potential shortages of medicines are a risk to health. For the manufacturer, these problems can lead to severe financial penalties due to loss of market share and even litigation. Needless to say, adverse publicity also can erode consumer confidence and damage a manufacturer's reputation.
The foundations of QbD for drug-product development are contained within the International Conference on Harmonization (ICH) quality guideline ICH Q8 (R2) Pharmaceutical Development (R2) (6). This guideline for pharmaceutical development includes "determining the critical quality attributes (CQA) of the drug substance (and) excipients and selecting the type and amount of excipient to deliver drug product of the desired quality" (6). This determination is of particular importance for designing drug products for ER applications, where the performance of the rate-controlling excipient is crucial to precisely deliver the required amount of drug over time. Typically, for ER technologies, such as hydrophilic matrices, barrier membrane-coated multiparticulates and osmotic delivery systems, the dose of the drug within a single unit is much greater than in an immediate-release product. Understanding the primary rate-controlling excipients' physiochemical properties (i.e., material attributes) is important to ensure robustness of the finished product and to mitigate any risk of batch-to-batch variability and/or potential premature drug release that could impact the patient.