Managing excipient variability is an essential element in designing and manufacturing robust solid oral drug products and is an integral task in when applying quality-by-design (QbD) principles. The article examines factors in assessing excipient variability, the associated challenges developers need to address to design and manufacture solid oral drug products, and solutions for such challenges.
Assessing excipient variabilityPharmTech: What are key considerations in assessing excipient variability and what are the associated challenges developers need to address to design and manufacture solid oral drug products?
Robertson (Colorcon): Understanding the effects of normal excipient variability is important to ensure that potential risks to drug-product quality are effectively managed. With an increasing focus on QbD, both innovator and generic-drug developers will be required to demonstrate excipient risk management in relation to the drug products' critical quality attributes. So, while it is the developer's responsibility to demonstrate robust formulation design and manufacture, it is important that all stakeholders collaborate early in the product lifecycle to ensure mutual success. Often, knowledge and tools to proactively assess the effects of excipient variability upon drug-product quality are available. Of course, this not only provides sufficient development but, importantly, supports implementation of an effective control strategy for subsequent commercial manufacture.
So one may ask, why are excipients variable, and what are the sources of variability? Well, excipients used within the pharmaceutical drug products are diverse in terms of their chemistry, origin, manufacture, and also control. Broadly speaking, we could consider two classes of excipient products. Those described as natural or naturally derived, and those described as synthetic or semisynthetic. The natural or naturally derived excipient products and factors, including the crop source along with environmental variables, such as the growing and processing conditions, can all affect the physicochemical properties of the resultant excipient product. Even for synthetic or semisynthetic excipient, differences in the feedstock, such as the organic and inorganic components from crude oil or gas, along with variability in chemical processing, will all contribute to the overall variability of the excipient product itself.
For an individual manufacturer of an excipient product, there may be lot-to-lot variability of the physicochemical properties. Often, a manufacturer may make related products, such as different physical or chemical grades, or even supply different industries. Therefore, different manufacturing campaigns may be adopted, which can lead to variability associated with switchover, start-up, or shutdown upon a single production line.
Indeed, between the multiple manufacturers of an excipient, it is likely there will be differences in the raw materials and the production process used, the scale of manufacture, and location, all which can contribute to the variability of an excipient product's physicochemical properties.
I think it's also important to recognize the variability in the controls used. Although excipients are required to meet the appropriate pharmacopeia standards, there may be differences in the excipient specifications from vendor to vendor. This can include the ranges specified within standard tests as well as the inclusion of noncompendial physicochemical property tests.