This article is part of PharmTech's supplement "Solid Dosage and Excipients 2010."
Since the concept of quality by design (QbD) emerged nearly a decade ago, the pharmaceutical industry has been trying to understand
and put into practice a more flexible and risk-based approach to manufacturing. Although the introduction of US Food and Drug
Administration guidances and International Conference on Harmonization (ICH) guidelines—ICH Q 8, 9, and 10—have provided some
details on how QbD can be applied, many questions remain. The development and use of excipients in drug-product formulations
has posed several challenges, including understanding excipient variability and functionality when implementing a QbD-based
To provide some answers and potential solutions to these common challenges, Pharmaceutical Technology gained input from the
following industry experts: William F. Busch of Dow Wolff Cellulosics–Pharmaceutical Excipients, a business unit of Dow Chemical
(Midland, MI), with Tom Frazier, product market manager for Carbowax Sentry, a product line of Dow Chemical; Stuart Porter,
senior director of pharmaceutical research and development at International Specialty Products (ISP) in Wayne, NJ; and John
Langridge, manager of research and development/quality control at DMV-Fonterrra Excipients (DFE) in Goch, Germany. They provide
examples and advice on excipient selection, regulatory expectations, supply-chain considerations, and more.
Can you outline how QbD may be applied in excipient selection and understanding the functionality of the excipient in the
QbD comprises many steps that typically involve the following:
Examining all of the formulation and process parameters, typically by employing a statistical design-of-experiments (DoE)
approach to assess the impact of each parameter and the interaction between parameters on the final product. The outcome of
this approach would be to facilitate effective formulation and process optimization.
- Conducting a risk-assessment analysis of the formulation and the manufacturing process to determine which parameters have
the greatest impact on product quality and characteristics. This analysis involves examining all parameters that are likely
to have an effect, determining what that effect will be, what the likelihood that an event that could have an effect will
occur, how frequent that occurrence might be, and how likely is it that such an event will be observed. For each of these
characteristics, a rating system is used to apply a total score to each parameter. Parameters that receive the highest score
are deemed to pose the highest risk and should be be investigated to reduce that risk to acceptable levels.
- Based on the results of the DoE and risk assessment, a design space can be created that will define the operating ranges (both
formulation and process) within which a product can be manufactured and be expected to consistently meet the required quality
standards and performance attributes.
Ultimately, when this process is established, the goal is to minimize reliance on conventional in-process and post-manufacturing
quality-control testing of samples by implementing an effective process-analytical-technology (PAT) strategy that enables
critical process parameters (CPPs) to be monitored. This process uses tools that have feed-back and feed-forward capabilities,
so that operation within the required design space is assured.
In terms of how QbD implementation might affect excipient selection, there are two key considerations. First, during the application
of statistical DoE, it is likely that the impact (in quantitative and functionality terms) of the excipient will be determined.
As a result of this analysis, selection of a particular excipient may well rest on how sensitive the formulation (and the
ultimate manufacturing process) is to potential variation in that excipient. Such sensitivity should be considered in terms
of the range of excipient content that can be tolerated without having a demonstrably negative effect on the formulation,
and in terms of the likely impact of batch-to-batch variability in that excipient. Potential negative effects should be considered
with regard to how the excipient affects functionality of the dosage form (e.g., drug-release characteristics) as well as
the chemical stability of the active pharmaceutical ingredient (API) in the dosage form.
Second, during the risk-assessment stage, excipient selection may hinge on the size of that excipient's risk factor. For an
excipient supplier, complying with the demands of a pharmaceutical manufacturer during this processes can be troublesome.
The reason for this is that a pharmaceutical manufacturer will often ask for samples of a particular excipient that represent
the extremes of the specification range. Although an excipient supplier will, out of necessity, set a range of specifications
for a particular material, that material is often manufactured to tolerances that are much tighter than those depicted by
the specification ranges. Production processes are then designed to target the middle of that range to avoid out-of specification
production. Hence, it may not be possible to supply samples that represent the extremes of the specification ranges.
We see an increasing trend in customers' application of QbD to excipients. In terms of excipient selection, there is more
interest in matching excipients to processes in addition to traditional excipient selection using preformulation and excipient
compatibility studies. Examples include selection of materials with good recompacting properties for dry-granulation processes
(e.g., roller compaction) and selection of materials with low sensitivity to lubricants and to compaction speed for scale-up.
With regard to understanding functionality, there is a definite trend in testing the ranges of excipient specifications during
the development process. This, of course, depends on the criticality of the excipient for correct performance. Although not
directly relevant to oral solid dosage forms, QbD studies are always applied to carrier lactose for dry-powder inhalers, to
the extent that several customers now frequently request commercial batches, not just trial batches, targeted to a particular
point in the overall particle-size specification.
Additionally, we see more interest in the understanding of how nonspecified properties (i.e., not specified on a certificate
of analysis, or CoA) of an excipient may affect processing. One example is the role of amorphous lactose in the compaction
of spray-dried lactose, and the proper packaging and environmental controls needed to maintain the amorphous lactose. Another
example is the role of viscosity of polymeric disintegrants and the effect of viscosity on granulation and disintegration.