The benefits of quality by design (QbD) concepts related to both product (ICH Q8)1 and drug substance (ICH Q11)2 are well-established, particularly in regards to the potential to use knowledge to affect process changes without major regulatory hurdles, i.e., revalidation/regulatory filing, etc. Less wellestablished, but potentially of significant value, is the application of the same concepts to analytical methods.

Analytical methods play an obvious key role in establishing the quality of final product as they establish conformance with product acceptance criteria (i.e., specifications) and indicate the integrity of the product through indication of product stability. Analytical methods are validated, like manufacturing processes, but what if the operational ranges could be established during method validation when demonstrating fitness for purpose?

Would it be possible to drive method improvement, especially post validation in the same way that the concept of continuous improvement is a key driver for manufacturing processes? Despite this attractive “value proposition”, there is to date little evidence that as an industry this is being practically realized.

The result is that many methods used in a QC environment lag well behind technical developments in the analytical field, often leading to the use of suboptimal procedures that impact adversely on the efficiency within the laboratory. The challenge is to create an environment whereby such changes can be made efficiently and effectively.

One approach is to apply the principles of ICH Q8−10; delivering a science and risk based approach to the development and validation of analytical methods, establishing a method operable design region (MODR) within which changes can be made. Such a framework is illustrated in Figure 1.



This starts with a definition of the effective requirements of the method, an analytical target profile (ATP), this taking the specific form of acceptance criteria for method performance. Such a process can be used to not only establish effective analytical methods but is also supportive of continual improvement, specifically within the MODR. However, such a concept is potentially limited in that the expectation is that changes are restricted to within the MODR.

Such restrictions may inhibit continuous improvement. A prime example is change of stationary phase or a change from HPLC to UPLC; both fall outside of the original MODR. Historically such changes have been notoriously difficult and often therefore avoided unless imperative. A recent publication13 examined this, presenting a method enhancement concept that would allow minor changes outside of the MODR. This is based on the realization that performance of any analytical method is based on the conduct of a system suitability test (SST); such tests ensure the method’s fitness for purpose.

Karlsson et al. stated that changes outside of the initial MODR may be possible provided that the method principle is unchanged, failure modes are the same, and the SST is capable of detecting these, both for the original method and for any method changes that fall outside of the original MODR. Put simplychanges can be made provided the SST criteria are passed. A change from HPLC to UPLC was used to illustrate this. Revalidation of the method is still required, but critically such changes do not require regulatory interaction but can be managed through internal quality systems.

1 ICH Q8 Pharmaceutical Development. http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q8_
(2) ICH Q11 – Development and Manufacture of Drug Substances
(Chemical Entities and Biotechnological/Biological Entities) Q11.http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q11/Q11_Step_4.pdf (Aug 2009).