Analysts Present Strategies for Chromatographic Method Development and Validation

AAPS, San Antonio (Oct. 31)-The advantages of ultra-performance liquid chromatography over traditional high-performance liquid chromatographic were the center of the presentation, “Strategies for Rapid Chromatographic Method Development from Preclinical to Phase 3,” by Charanjeet Jassal of Wyeth Pharmaceuticals. Jassal compared the results of several analytical studies involving UPLC and HPLC, emphasizing the methods’ performance, advantages, and concerns. Time for peak resolution was the most apparent difference, and Jassal presented an analysis in which a UPLC technique took 10 min versus the 60-min HPLC analysis. Another major advantage is that some UPLC systems can run at high back pressures (as high as 15,000 psi). “Common problems in gas chromotography detection include dirty syringes, dirty inlets, flow adjustment, headspace problems, and the poor quality of carrier gas, for which I recommend the use of traps,” said Jassal.

Phase-appropriate method validation

Lisa Martin, PhD, associate director of pharmaceutical R&D at Astra Zeneca presented “The Practice of Method Validaiton by Phase Validation,” reviewing a validation approach first presented in the Nov. 2004 issue of Pharmaceutical Technology (S.P. Boudreau et al.,28 (11), 54-66) and based on a workshop on analytical acceptable practices. She reviewed the ICH (International Conference on Harmonization) definitions of method development and method validation as presented at the workshop. Key benefits of the phased validation approach include: it is a less-resource intensive approach; it maintains flexibility; and it helps keep the focus on the science.

Martin also discussed ICH Q2A (now coded Q2(R1)) analytical method validation requirements and the phased validation workshop approach for drug substances. Among the recommendations stemming from the workshop: for the validation protocols and acceptance criteria, manufacturers should avoid setting rigid standard operating procedures (SOPs) and acceptance criteria early in the process, and validation reports should be completed with all data and include summary reports.

Martin provided several examples of how AstraZeneca has so far implemented a phased validation approach and how its team has applied this practice, to various extents, to best meet minimum requirements. For example, in developing a drug substance impurity method, the team conducted several validation studies, including specificity, linearity, and robustness (solution stability), as well as system suitability tests and repeatability. Martin also described AstraZeneca’s approach to drug-substance assay-method validation and a drug-product method for immediate-release tablets, which included assay and impurity tests for linearity at three ranges, accuracy and repeatability tests, specificity, content uniformity, and dissolution. In 2005 representatives from six company sites in three countries began a global proposal for implementing a phased approach of phased validation parameters for organic impurities. Part of the proposal suggests a validation protocol that includes documenting SOPs and other procedures in a laboratory notebook, not requiring acceptance criteria, and developing a validation report that is flexible and summarizes all data. Although the company is still observing variability in the extent of the validation among the six sites, Martin emphasized that the company continues to focus on how to deliver validation requirements.