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Multilayer tablets can be challenging, but meeting regulatory expectations is crucial. We speak with Vilayat Sayeed from the FDA, to find out more about the critical factors that need to be fully understood.
Improvement in the understanding of the material science (physical, chemical and mechanical) and the engineering of the tabletting machine to control weight of individual layer/s, total tablet weight and compression factors for the layers are responsible for the advancement in pharmaceutical technology of the multilayer tablets.
Vilayat A. Sayeed, Ph.D, is Director, Division of Chemistry III, FDA/CDER/OPS/OGD.Critical factors can be broadly divided into material attributes and process parameters. Material attributes such as: compatibility, compressibility, compactability, adhesion, tensile strength, flow properties, porosity, density, layer relaxation during shelf-life and storage and propensity for in-vitro and in-vivo delamination are some of the factors a manufacturer must understand in producing a multilayer tablet. The process parameters includes impact of lubricant in each blend, tamping force for initial layer (s) compression, final compression force for tabletting, and press speed. Both of these factors have to be fully understood for making a quality multilayer tablet.
Regulations are written to address and capture the safety, efficacy and quality concerns, regardless of how the product is designed and manufactured. It is the responsibility of the sponsor to study, understand and establish controls in the process to ensure that the manufacture of a drug product can provide the intended product performance and clinical outcome over its shelf life. There are no specific regulations for multilayer tablets or any other pharmaceutical dosage form, but 21 CFR 314 and 21 CFR 320 address the various issues that should be addressed in the submission.
Quality by Design can be used to comprehensively put forth the understanding of the product formulation (drug substance inherent properties, excipient properties and variability) and manufacturing process on product performance. The design elements should be based on prior knowledge, risk assessment and process controls in achieving the multilayer tablet of desired quality. To further enhance the understanding where applicable, the manufacturer should conduct design of experiment studies to develop and identify critical to quality attributes and process parameters. This systematic approach of building quality by having a mechanistic understanding of variables and their impact on the manufacturing process and the performance of the product with limited dependence on the end-product testing should be the focus and the intended use of Quality by Design.
The knowledge gained by applying the scientific principles and risk management tools during the pharmaceutical development must be fully discussed and those functional relationships that are linked to product performance must be clearly presented in the regulatory submission. In addition to providing a complete mechanistic understanding supported by data developed through the application of scientific and quality risk management tools, the applicant should also provide the relevance and justification of the product design to the product performance and clinical outcome. The established controls and specifications should be based on the sound scientific principles, ICH and regulatory agency guidance, and should be fully justified.