BASi Contract Research News - February 2008

Incurred Sample Reproducibility – Crystal City Update

The latest bioanalytical meeting in the “Crystal City” series was held 7-8 February 2008 in Alexandria, VA. The intent of this meeting was to show how laboratories are demonstrating method reproducibility as applied to study samples from preclinical and clinical studies. Several case studies were presented.

The initial request for reproducibility assessment was made at the May 2006 Crystal City meeting, where FDA representatives presented studies showing wide disagreement in some initial and repeat analysis study sample results, even though the calibration standard and quality control samples looked consistent.

BASi staff have followed this issue closely by participating in a number of meetings since the May 2006 meeting, including the Applied Pharmaceutical Analysis “Regulated Bioanalysis” meetings in September 2006 and September 2007, the 10th Annual Symposium on Chemical and Pharmaceutical Structure Analysis in October 2007, the Delaware Valley Drug Metabolism Discussion Group meeting in April 2007, and the 17th International Reid Bioanalytical Forum in Surrey, UK.

Last summer we drafted an SOP which required that we look at incurred sample reproducibility once per “analytical situation.” For example, a method for the analysis of a drug in dog K₂EDTA plasma would be assessed once by using pooled samples not traceable to individual study samples. We were concerned about mixing PK repeat requests with incurred sample retesting and thought pools would be cleaner. We also felt at the time that any reproducibility results should be connected to the method validation rather than specifically attached to a study.

Those plans, however, changed after presentations at the 2007 Applied Pharmaceutical Analysis meeting in Boston, where it was clear that a method could not simply be tested once and then trusted. Speakers showed that a good method could demonstrate poor reproducibility intermittently, which was later traced to factors such as instability/metabolism, analyst techniques, sample collection, and chromatography variations. The “mechanics” of doing reproducibility testing also became clearer with acknowledgement from agency speakers that incurred sample reproducibility could be separated from PK repeat requests.

BASi then changed direction in drafting its SOP for Incurred Sample Reproducibility assessment from pools to individual samples. We decided to do 10% on each study, up to a maximum of 150 samples. We decided to select randomly across all samples in a study, but only from those samples that initially tested between the low and high QC’s or from those that could be diluted into that range. We decided that at least 2/3’ds of the re-assays must test within 20% of the original result. The retest data will stay with the study and be tabulated separately in the study report. A sponsor can opt out of the re-analysis by written request. Should the study fail the reproducibility testing, we will investigate for cause to resolve the differences and determine the best means to improve the quality of the results. The sponsor will be informed and involved at each step of the process. The BASi SOP went live on 1 January 2008, and in is very much in line with the recommendations of the Crystal City meeting last week.

FDA’s Dr. Viswanathan also made it very clear to attendees that it was time for companies to institute SOP’s and start looking at the reproducibility of their methods. Future inspections will address this.

If you have questions about the new BASi SOP, please contact me at 765-497-5861. We will be happy to share our experiences in this new process and can probably provide you a copy of our SOP upon request (all in the spirit of building a consensus position!).

Ron Shoup, Chief Scientific Officer

Fentanyl Method in Serum

BASi has validated a number of opioid-class drugs for analgesia and pain relief, including morphine, oxycodone, hydrocodone, naltrexone, and non-steroidal anti-inflammatory drugs like acetaminophen, ibuprofen, and naproxen. Our fentanyl method was recently revalidated to 96-well format, using deep-well plates and liquid-liquid extraction. Measurement range in human serum was from a lower limit of 50 pg/mL up to 10.0 ng/mL, based on a 300 µL sample. The assay could have been validated to a lower LLOQ if necessary. For more information, please contact BASi Client Services.

Chromatogram of Blank Matrix

Chromatogram of Low Calibration Standard

Inter-Assay Quality Control Sample Statistics

Assay List Update

Those searching the web for methods will find the BASi assay list, updated monthly, near the top of their hit lists. This web page puts over 400 non-proprietary methods at your fingertips, with the type of instrumental analysis, sample matrix, and lower limit of quantitation. The BASi Standard Analytical Procedure document number is also given. We can send you a validation report in most cases that will describe the performance of the method. We also monitor more recent stability data, after the validation, across all three sites, with our PDS system, and we can pull up the most recent global stability data for methods validated after 2005.

BASi has been validating methods for bioanalysis since 1991, and our standards have been pretty consistent over the past 10 years. Older methods may need some re-validation in a few areas. We can review our validation reports and advise you whether the method will need any new supporting data. In most cases, the restart of an older method gives opportunity to easily add the new experiments.

BASi actually has validated over 900 methods. Since most of our work is for biotechs, large and mid-size pharmas, our methods generally are part of proprietary IND and NDA packages. We have solved some sticky problems over the years. Let us put our expertise to work for your next program.

View the Current List of Assays
 

BASi Report Format Now Standardized

Many of our projects take more time in reporting and Q-review than the actual lab work requires. FDA recently set guidelines for the ECTD format for reports in NDA’s and IND’s.

BASi has now standardized its bioanalytical validation and sample analysis report formats to reflect recently updated SOP’ s. All tables, sections, and figures are bookmarked for the ECTD mandate. A complete analytical run is embedded in the PDF format document as an active link. The document currently shows ink signatures, but all parties will soon be signing electronically from our document management system. For a sample report, please contact your BASi Principal Investigator or Business Development. Other reports from BASi will follow in this format.

Society of Toxicology Meeting

The annual Society of Toxicology meeting will be held at the Washington State Convention and Trade Center in Seattle March 16-19. If you attend, be sure to visit with the BASi staff at booth #2215. BASi staff will be happy to discuss your preclinical toxicology, bioanalytical, clinical, Culex^® or ADME/PK data requirements. Also at the ToxExpo, BASi Product Manager Natasha Nikolaidis will conduct a session on Automated In Vivo Sampling using the Culex^® on Wednesday, March 19, from 8:30 to 9:30 a.m. at the Convention and Trade Center. This is your opportunity to learn more about how this instrument collects blood samples 24/7 from awake and freely-moving rats and mice for studies in pharmacokinetics, drug metabolism and toxicology.