**14. Concluding remarks**

When we consider the critical role that analytical method development, qualification and validation play in the biopharmaceutical industry, the importance of a well designed strategy for the myriad analytical activities involved in the development and commercial production of biotechnology products becomes evident.

The method qualification activities provide a strong scientific foundation during which the performance characteristics of the method can be assessed relative to pre-established target expectations. This strong scientific foundation is key to long-term high performance in a Quality environment, following the method validation, which serves as a critical pivotal point in the product development lifecycle. As noted previously, the method validation often serves as the point at which the Quality organization assumes full ownership of analytical activities. If done properly, these activities contribute to operational excellence, as evidenced by low method failure rates, a key expectation that must be met to guarantee organizational success. Without the strong scientific foundation provided by successful method development and qualification, it is unlikely that operational excellence in the Quality environment can be achieved. As analytical technologies continue to evolve, both the biotechnology industry and the regulatory authorities will need to continuously develop concepts and strategies to address how new technologies impact the way in which the Quality by Design principles inherent in the analytical lifecycle approach are applied to the development of biopharmaceutical products. The basic concepts are described in ICH guidelines Q8, Q9 and Q10 (ICH 2005; ICH 2008).

130 Analytical Chemistry

methods.

**14. Concluding remarks** 

change in the output of the analytical method can be linked to the target expectations for the precision of the method, which are derived from the Horwitz equation (Horwitz 1982; Horwitz and Albert 1997; Horwitz and Albert 1997). Recently a number of software packages have become available to assist with the design and data analysis (Turpin,

Remediation of validated analytical methods is typically triggered by the need to improve existing methods used for disposition of commercial products. The improvement may be required due to an unacceptable rate of method failures in the GMP environment, lengthy run times, obsolete instruments or consumables, the changing regulatory environment for

We anticipate that technological advances will continue to drive analytical methods toward increasing throughput. In this context, it appears that many release methods are destined for change as soon as the product has been approved for commercial use (Apostol and Kelner 2008; Apostol and Kelner 2008). This is due to the fact that it takes more than 10 years to commercialize a biotechnology drug, resulting in significant aging of the methods developed at the conception of the project. Therefore, the industry and regulators will need to continuously adjust strategies to address the issue of old vs. new methods, particularly with respect to how these advances impact product specifications (Apostol, Schofield et al. 2008). Frequently, old methods have to be replaced by methods using newer technologies, creating a significant challenge for the industry in providing demonstration of method equivalency and a corresponding level of validation for the

When we consider the critical role that analytical method development, qualification and validation play in the biopharmaceutical industry, the importance of a well designed strategy for the myriad analytical activities involved in the development and commercial

The method qualification activities provide a strong scientific foundation during which the performance characteristics of the method can be assessed relative to pre-established target expectations. This strong scientific foundation is key to long-term high performance in a Quality environment, following the method validation, which serves as a critical pivotal point in the product development lifecycle. As noted previously, the method validation often serves as the point at which the Quality organization assumes full ownership of analytical activities. If done properly, these activities contribute to operational excellence, as evidenced by low method failure rates, a key expectation that must be met to guarantee organizational success. Without the strong scientific foundation provided by successful method development and qualification, it is unlikely that operational excellence in the

Lukulay et al. 2009; Jones and Sall 2011; Karmarkar, Garber et al. 2011).

**13. Challenges associated with validated methods** 

specifications or stability testing, or for other business reasons.

production of biotechnology products becomes evident.

The ICH Q2 guideline requires that an analytical method be validated for commercial pharmaceutical and bio-pharmaceutical applications. Frequently, validation is done only once in the method's lifetime. This is particularly of concern when the future testing is performed on an instrument with different technical characteristics, in different geographic locations within the company and/or at contract laboratories around the world, using different consumables, different analysts, etc. This concern is exacerbated by the requirement for modern pharmaceutical and biopharmaceutical companies to seek regulatory approval in multiple jurisdictions, where the instrumentation, consumables, and scientific staff experience at the testing location may be very different than that present in the place where the drug was developed. These considerations raise questions about the value of the current format of the validation studies conducted by the industry. Moreover, it is not clear how the validation data obtained using existing methodologies should or even could be used toward the assessment of the uncertainty of the future results, given the many factors that contribute to the uncertainty.

Perhaps the time is right for the industry to consider the use of a combination of sound science and reasonable risk assessment to change the current practice of the retrospective use of method validation to the new paradigm of live validation of purity methods based on the current information embedded in the chromatogram. Laboratories that work in a GMP environment are required to produce extensive documentation to show that the methods are suitable. Pharmaceutical and biopharmaceutical companies thoroughly adhere to these requirements, inundating industry with an avalanche of validation work that has questionable value toward the future assessment of uncertainty. The predication of uncertainty provides an alternative that has the potential to reduce the work required to demonstrate method suitability and, in turn, provide greater assurance of the validity of the results from the specific analysis in real time.

The establishment of qualification target expectations can be considered as a form of Quality by Design (QbD), since this methodology establishes quality expectations for the method in advance of the completion of method development. Also, the analytical lifecycle described here covers all aspects of method progression, starting with method development, the establishment of system suitability parameters, and qualification and robustness activities, culminating in method validation, which confirms that the method is of suitable quality for testing in Quality laboratories. The entire analytical lifecycle framework can be considered as a QbD process, consistent with evolving regulatory expectations for pharmaceutical and biopharmaceutical process and product development.
