From Laboratory Notebook to. Laboratory Worksheets: Recording. Analytical Data for Stability Testing of Pharmaceuticals by Kimloan C. Huynh-Ba and ...
From Laboratory Notebook to Laboratory Worksheets: Recording Analytical Data for Stability Testing of Pharmaceuticals by Kimloan C. Huynh-Ba and Anne-Francoise Aubry
Abstract
Until the electronic notebook becomes a reality, another alternative to the traditional bound notebook is the laboratory worksheet. Ms. Huynh-Ba R&D Stability Manager DuPont Pharmaceuticals Co. Experimental Station, E353/ 111 P.O. Box 80353 Wilmington, DE 19880-0353, U.S.A. Tel.: 302-695-8335 Fax: 302-695-8665 kirnloart.c.huynh-ba@ dupontpharma. corn
The following case study shows how a laboratory worksheet system was implemented in an analytical R&D department to replace traditional laboratory notebooks. The procedure outlined here was tailored to stability testing in the analytical research & development (R&D) environment, but could easily be adapted to a quality control (QC) laboratory. The main concern in using worksheets is the protection of data integrity. Once this has been addressed, the use of worksheets stands out as a more flexible medium than traditional notebooks for recording data. Until electronic systems are mature enough to be used in the pharmaceutical industry, worksheets seem to be a valid alternative to traditional notebooks.
Dr. Aubry Senior Research Scientist DuPont Pharmaceuticals Co. Experimental Station, E353/ 105 P.O. Box 80353 Wilmington, DE 19880-0353, U.S.A. Tel.: 302-695-9981 Fax: 302-695-8665 anne-francoise. aubry@ dupontpharma.com
n a world that increasingly relies on electronics, the laboratory notebook remains the principal means of recording raw data in the pharmaceutical industry. Although attractive, the electronic notebook
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presents some risks for preserving intellectual and corporate properties. 1-4 On a practical level, a full electronic notebook is not possible until all of the laboratory instruments are computerized and able to communicate with each other. Until the electronic notebook becomes a reality, another alternative to the traditional bound notebook, which may ease the transition to a fully electronic system, is the laboratory worksheet. Laboratory worksheets are preprinted forms on which raw data and other necessary information for a given analytical test are recorded. 5 Because a blank field is present for each required piece of information, analysts are less likely to forget to record any data. Once filled, the worksheets form a complete and independent package that can be easily reviewed, audited, and filed. Unlike notebooks, however, worksheets are not physically bound together and
Key Words: raw data, electronic data, notebook, worksheet, documentation
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therefore need to be strictly controlled to avoid any falsification or destruction of data." Even though the use of worksheets is widespread in other industries, such as environmental, it has found limited application in the pharmaceutical industry. An informal survey of companies in the U.S. and Europe conducted by the authors' group in 1998 indicated that the use of worksheets was mostly limited to QC laboratories and contract research organizations (CROs). For CROs, worksheets are often the best way of maintaining confidentiality. Why are worksheets unpopular in analytical R&D departments? One reason may be that they lack the flexibility that notebooks have for recording development or validation work and nonroutine analyses. However, even in an R&D environment, worksheets are a valid option later in drug development, particularly for recording stability data. As the drug development progresses to Phases II and III, formulations are being finalized and analytical methods are usually well established. Facing the large volume of stability samples in support of regulatory submissions, worksheets seem to be a more efficient way to record data than bound notebooks. The worksheet system described in this article was developed at DuPont Pharmaceuticals for the Pharmaceutical Stability Testing Laboratory. Content of the worksheets A typical worksheet packet consists of several pages secured together in a report cover. The information entered in the worksheets is no different than what was traditionally recorded in notebooks; only the format is different. The information is organized in a logical fashion and blank fields are reserved for the
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Prenumbered paper
0001392 Worksheet number Workbook 123DISS -
STABILITY TESTING LABORATORY RECORD
Page 11
TESTING: METHOD NUMBER: SPECIFICATION: ALERT LEVEL: SAMPLE ID:
DISSOLUTION 123DISSOLUTION.01 123SPECIFICATION.01 Mean NLT 80% at 30 minutes
EQUIPMENT INFORMATION: Balance ID Batch ID Autosampler ID Filter Type Thermometer ID Dissofil ID pH Meter ID/Reading HPLC System TD/Channel #
Timer ID Stopwatch ID Aliquot Start Temp:
Testing information
Blank fields completed by analyst
°C °C End Temp: Degassed YES or NO
Figure 1 Example of a worksheet.
information that the analysts have to enter. This is extremely helpful when it comes to information related to which pieces of equipment were used in the testing and their status (i.e., calibration, performance verification,etc.). Electronic worksheet templates customized to specific test methods are used to prepare the worksheets. The worksheet template can cover a
The use of worksheets should be acceptable to regulatory agencies as long as the documents are controlled, traceable, and provide all necessary analytical information. single test or several tests and can be used for single or multiple samples. For example, for dissolution testing, samples are tested individually and a worksheet is generated for each sample (Figure 1). For other tests, such as assay by HPLC, a set of
samples is usually tested in the same HPLC run together with standards. The worksheets will then contain data for the complete set of samples. Regardless of the testing, the worksheets must include the following information: the tests to be performed with a reference to the test methods and the current specifications; the identification of the sample(s) being tested; and testing information including equipment used, solvent preparation, standard, and sample preparation. Worksheets also allow different tests to be performed simultaneously by different analysts, while still allowing the data to be kept together as a packet following testing. In the modern laboratory, most data are collected electronically and calculations are often made by computer. Analysts using a traditional notebook must cut and paste these printed data in their notebook. 1 It is this cumbersome activity that led Dabek and Orndorff to call the laboratory notebook a "medieval artifact in an electronic world". 1 Inaworkshetym,da available on small pieces of paper, such as balance or pH me-
ter printouts, equipment information, and sample labels, may still need to be pasted. However, any data that can be printed on standard-size (81/2 x 11 in.) paper is treated as an attachment to the worksheets. Once the testing is completed, the number of pages attached must be recorded on the worksheets to protect data integrity, and each attachment must reference the worksheet number in case it is misplaced. Controlling the worksheet system Although the Federal Register requires that "laboratory records shall include complete data derived from all tests necessary to assure compliance with established specifications and standards,"6 it does not require that data be kept in a bound notebook. The use of worksheets should be acceptable to regulatory agencies as long as the documents are controlled, traceable, and provide all necessary analytical information. However, in the highly regulated pharmaceutical environment, the most challenging issue remains the control of the worksheets so that substitution or destruction of raw data can be avoided. To overcome this issue, a series of controls can be implemented: 1. Worksheet templates may be modified at any time when project methods are revised. All versions are tracked by a version number appearing on every worksheet. The active worksheet templates are available to analysts as read-only documents on a dedicated computer and printer. All electronic versions of templates are stored and backed up in a secured server. 2. The worksheets are printed on blank prenumbered sheets purchased from an outside supplier. These sheets are used in
numerical order, exclusively for the preparation of worksheet packets. All pages, including accidentally unused or misused pages, must be accounted for. In addition to the preprinted number, every worksheet packet is assigned a unique reference number that is recorded on each page of the worksheet packet. 3. Analysts are responsible for preparing their own worksheet packet by following a standard operating procedure. They assign a worksheet number to the set of samples to be tested and record the worksheet number in a logbook. The logbook serves as a very important part of the control system. It tracks the prenumbered sheets used in the preparation of the packet, the worksheet number, the sample identification, the initials of the analyst who created the packet, and the date.
The use of worksheets can save precious analyst time for routine analysis, even in an R&D setting. Expect the unexpected Even with an established and fully validated method, there may be occasions when something goes wrong during the testing. Documenting method deviations, repeat analysis, or investigations on preprinted worksheets is not practical. Since good record-keeping is essential, each worksheet packet contains a few blank pages that can be used to record additional information, from a simple observation to a full-blown investigation of an out-of-specification result. For even more flexibility, additional sheets of prenumbered paper can be
added to the worksheet packet if necessary. The new pages are simply logged in to the same set of data and worksheet number. Conclusion It has been shown that the use of worksheets can save precious analyst time for routine analysis, even in an R&D setting. Worksheets also allow the laboratory to manage data more efficiently by keeping test results together in a central location and making data more easily accessible to auditors or regulatory inspectors. The main disadvantage of worksheets is that they use unbound pages, which makes them more difficult to secure than traditional notebooks. However, there are several ways to control the worksheet system to preserve the integrity of the records: • Develop an easy-to-follow system to create, file, and archive worksheets • Implement clear and precise standard operating procedures (SOPs) describing the use, format, and control of worksheets: "Regardless of style, length, language or method of distribution, it is important to note that any SOP, once written and approved, must be followed as written"' • Develop a program for training analysts on their responsibilities regarding the worksheets • Organize periodic QA audits of the systems. Moving forward, the current worksheet system will be integrated to a LIMS. This will eliminate the need for prenumbered paper, a dedicated computer, and the logbook. Eventually, a totally paperless system to record laboratory data may be achievable, which will allow us to take the laboratory data to the next step, where technical
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information is accessed remotely and shared globally. 4
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References 6. 1. Dabek, R.A.; Orndorff, J. "Laboratory Notebooks: A Medieval Artifact in an Electronic World"; Chemtech 1999, 29(3):6-12. 2. Pharr, D.Y.; Settle, F.A. "Implementation of an Electronic Laboratory Notebook"; Am. Lab. 1996, 28(14): 35. 3. Ramaseshan, S. "The Computer as a Laboratory Notebook"; Curr. Sci. 1996, 70(11):950. 4. Rooney, T.A. "Electronic RecordKeeping has Real Advantages for Remote and Team Access"; To-
day's Chemist at Work 1999, Aug. (15). Krull, I.; Swartz, M. "Laboratory Notebook Documentation"; LC•GC 1997, 15(12):1122. Federal Register, CFR 21 Part
211.194, "Laboratory Records," 1999. 7.
Nilsen, C.L. "Writing SOPs: Keep it Simple"; Pharmaceutical Formulation & Quality 1999, Jan./Feb. (21).
Authors Ms. Kimloan C. Huynh-13a received a Bachelor's degree in Chemistry and Mathematics from Millersville University of Pennsylvania (Millersville, PA) and a Master's of Science degree in Analytical Chemistry from Villanova University (Villanova, PA). She was previously a Senior Analytical Chemist at ICI Americas. She joined DuPont Pharmaceuticals in 1991, has held various positions in the Pharmaceutical R&D Department, and currently is an R&D Stability Laboratory Manager: Dr. Anne Francolse Aubry received her Doctorate in Pharmacy from the University of Mon, France, in 1986 and her Ph.D. from the University Pierre et Marie Curie, Paris, in 1990. She worked as a postdoctoral fellow at St Jude Research Hospital in Memphis, 'IN, and McGill University in Montreal. She has held various faculty and industrial positions in Canada. She joined DuPont Pharmaceuticals in 1996, and is currently a Senior Research Scientist in the Pharmaceutical R&D Department
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