Reviewing data is an important part of an OOS investigation. Raw data review includes:
ARL’s data reviewer checks all the calculations recorded in the laboratory notebooks and ensures the arithmetic is accurate. The laboratory examines water content and molecular weight calculations for transcription errors of active pharmaceutical ingredient standards.
Chromatograms and Spectra
Our laboratory also reviews the chromatograms and spectra to ensure the data passes quality requirements:
- peak shape (width and symmetry)
- peak height
- proper elution
The data reviewer evaluates the retention time (RT) to confirm the sample API peak comes out at the same time as the standard API peak in the chromatogram.
Standards and Reagents
During review, ARL verifies the correct standard was used. It is important correct standards are used as different forms of APIs may have different retention times. ARL uses USP grade material as the standard for non-cGMP work and USP reference standards for cGMP work, if available. The data reviewer makes sure the standard did not contribute to the out of specification result.
We also ensure the reference standard was stored properly. If standards are kept in abnormal storage conditions, results can trend high as the standard degrades.
Any other required procedures such as evaluating water content or drying was conducted properly on the reference material are reviewed during OOS investigations.
Trends can occur at the instrumentation, sample, or analyst level.
An instrumentation failure occurs when an instrument is giving bias results. ARL’s metrology department ensures all laboratory instruments are calibrated and comply with method requirements. If an instrument is not regularly serviced, API residue can build up in the instrument’s loop and cause high results.
Sample trends refer to getting results either always low or always high. If a sample is resulting low, our laboratory reviews the extraction procedure and chemist trends. If a sample is always high, our laboratory reviews the standard. Data reviewers also look at client sample trends to see if the preparation has a history of out of specification. In stability studies, results should follow a high-to-low trend. Low-to-high trends may indicate sample preparation or vehicle/matrix issues. Evaporation in some formulations can also cause low to high trends due to specific excipients and/or container integrity.
Analyst trends look at sample and standard preparation. ARL analysts are trained by an experienced chemist and must pass proficiency tests. If an error occurs at the analyst level, samples are re-tested, and the chemist determines the root cause with a corrective action to prevent future errors.
After a raw data review, our analysts perform visual inspections to see if there is a visible reason a sample may be out of specification due to particulate matter or binding of API within the vehicle. Our analysts may also contact clients before re-testing as sometimes samples are sent for testing because the client suspects the sample may be OOS.
ARL’s out-of-specification investigations use a hybrid approach to review data, formulations, and tests. Our data reviewers consult with ARL’s scientific directors and clients to ensure we provide a 360-view investigation and evaluate all aspects of the laboratory, data, and client and analyst trends. Typical investigations are concluded within one week or within 4 business days after the due date.
For more information on OOS investigations, contact ARL 800-393-1595 or firstname.lastname@example.org