Key Formulation Factors
There are several formulation and manufacturing challenges that need to be addressed when working with multilayer tablets,
but meeting regulatory expectations is crucial. Pharmaceutical Technology speaks with Vilayat A. Sayeed, PhD, director of the Division of Chemistry III at the US Food and Drug Administration, Center
for Drug Evaluation and Research, Office of Pharmaceutical Science, Office of Generic Drugs, to find out more about critical
FDA's Vilayat A. Sayeed
PharmTech: How have advances in pharmaceutical manufacturing technology influenced the development of multilayer tablets?
Sayeed (FDA): Improvement in the understanding of the material science (physical, chemical, and mechanical) and the engineering of the
tableting 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.
PharmTech: What critical factors do manufacturers need to be aware of when producing multilayer tablets?
Sayeed (FDA): 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 tableting,
and press speed. Both of these factors have to be fully understood for making a quality multilayer tablet.
PharmTech: Which regulations, in particular, are applicable to determining these critical factors?
Sayeed (FDA): 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.
PharmTech: How can manufacturers best use a quality-by-design approach to support the development of a new multilayer tablet?
Sayeed (FDA): 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.
PharmTech: Are there any other issues specific to multilayer tablets that companies will need to address in regulatory submissions?
Sayeed (FDA): 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.