One of the most time-consuming and costly tasks in a regulated laboratory is periodic qualification of instruments. For laboratories to improve productivity and reduce costs while also meeting regulatory requirements, they need to find processes that reduce the time spent on performing the instrument qualification and paperwork, minimize human error, and streamline recordkeeping and review steps. iPads (Apple Inc., Cupertino, CA) and PC paperless, universal protocols with built-in calculation engines provide a solution for regulatory burdens by reducing person-hours and streamlining qualification processes for a variety of lab instruments, including HPLC, LC-MS, GC-MS, UV-VIS spectrophotometers, dissolution apparatus, and microplate readers.
Paperless lab protocols
A paperless, universal, and automated qualification protocol enables labor-saving automation that is not possible with paper protocols. Paperless protocols include:
- Validated arithmetic engines for calculating results, eliminating the use of calculators and nonvalidated spreadsheets while relieving scientists or engineers from performing these cumbersome and error-prone calculations
- Automatic PASS/FAIL results highlighted in each step of testing, allowing for quick analyses of test results and identification of problem areas, while also eliminating the need to cross-check results with accepted parameters
- A Summary Report that is generated automatically and offers a quick overview of completed results for reviewers and auditors in a format that highlights test failures
- A single protocol that can be used for a variety of instrument configurations by automatically adding or eliminating tests based on the selected instrument’s attributes
- Both electronic and print archiving capabilities, including electronic signatures and time-and-date stamp features compliant with 21 CFR Part 11.
The automation embedded within the paperless protocols, coupled with safeguards minimizing human error, in most cases reduces by half the person-hours required to perform qualification. Additional timesavings accrue outside the realm of actual testing when streamlining of documentation processes is considered.
Simplified document processes with paperless protocols
Typically, many pharma, biotech, and other regulated laboratories employ a variety of paper protocols for qualifying the same type of instruments simply because the instruments came from different manufacturers. However, when protocols are created based on the type of instrument, rather than the brand name, one protocol can be used for all instruments of the same type, requiring fewer protocols.
“Harmonization” further simplifies qualifications in that it makes the traceable tools, standards, and reagents used uniform as well. Less obvious, but perhaps more important, a consistent qualification document creates efficiencies during document reviews for final approval and during audits.
The new iPad- and PC-based protocols are designed to qualify all instruments, regardless of manufacturer, embodying the concept of harmonization through universal formats. However, using unique “smart” features, these digital protocols add yet another dimension to the concept of “universal.”
Figure 1 – Automatic reconfiguration of an HPLC paperless protocol based on selected tests and components. The test section for wavelength accuracy for detector 2 is blocked with a message displayed indicating no test is performed due to the fact that the detector is either an ELSD or RID. Otherwise, the field entries would be available if detector 2 is a DAD or UV-VIS. A separate test section will be displayed if detector 2 is an FLD.
Unencumbered by the physical limitations of paper, iPad- and PC-based protocols have the ability to reconfigure fields, tests, and calculations to match an instrument’s installed components, making the paperless protocols truly “universal.” For example, if an HPLC includes only an isocratic pumping system, then the field entries for gradient composition accuracy and linearity test are automatically blocked with a message indicating that the pumping system is isocratic and no test is required. The protocol automatically configures for selected single or dual detectors (UV-VIS, diode array detector [DAD], fluorescence detector [FLD], refractive index detector [RID], and evaporative light scattering detector [ELSD]), autosampler, column oven, and other modules, and only tests for the selected modules. This protocol can be performed as shown in Figure 1.
Similarly, for GC-MS qualification, the protocol displays only the tests related to selected single or dual detectors (flame ionization detector [FID], thermal conductivity detector [TCD], electroconductivity detector [ECD], nitrogen phosphorus detector [NPD], flame photometric detector [FPD], and mass spectrometer detector [MSD]), injector for each inlet (automated liquid sampler, headspace sampler, and manual injection), inlets, and GC oven temperature tests.
In effect, a single digital protocol can be used for all HPLCs regardless of vendor or configuration. Similarly, a single protocol can be used for all GC-MS systems with single or dual detectors, various injection modules, and other related components The automatic protocol configuration feature extends to the protocols for other lab instruments.
This ability of a “smart” paperless protocol to reconfigure fields, tests, and calculations to suit the instrument being tested is a clear advantage over a static paper protocol. In turn, the “smart” protocols reduce the person-hours spent developing and cataloging protocols for each instrument with varied configurations, while meeting all of the required leading industry standards and GLP, GMP, USPAIQ (Analytical Instrument Qualification), and other international regulatory guidelines.
Use of a paperless protocol with an iPad or PC
Paperless qualification protocols can be used with an iPad or PC. Using the iPad option is easy and intuitive. The protocol is simply uploaded onto the iPad, similar to other files, and entries are made using the built-in virtual keyboard or with a Bluetooth keyboard, as shown in Figure 2. The keyboard entry capabilities allow quick and accurate data entry while eliminating issues over illegible handwriting. In addition, drop-down menus eliminate excessive keyboard entries.
All standard features of the iPad—including zooming and unzooming the page by fingers, portrait or landscape display of protocol by rotating the tablet, and page advancing by swiping the finger over the screen to the left or right—can be used with these paperless protocols. The protocols can also be used with a PC, allowing the user to select the preferred format: iPad or PC.
Paperless protocol “smart” features
Figure 2 – Paperless qualification of a UV-VIS spectrophotometer on an iPad. Data entries are made using the built-in virtual keyboard or with a Bluetooth keyboard. In this case, PASS/FAIL results for wavelength accuracy for UV and VIS ranges are displayed automatically based on selected acceptance criteria.
Paperless IQ OQ protocols include entries for all necessary data, which in essence provide a checklist ensuring that all required data are recorded, including: company information, instrument information, required calibrated qualification tools, reagents, standards, detailed test procedures, explanation of equations used for all tests, and final results. The protocol automatically alerts the user if any information is missing. Also, test instruction and equations used in arithmetic engines are included when and where required without the need to consult additional documents. Once the information about the company and instrument is entered on the first page of the protocol, the data repopulate throughout the document and are automatically displayed at the bottom of each page, ensuring document integrity.
Next, the protocol guides the user through the tests, including onscreen tool tip instructions that explain the purpose of each field and what information is needed. Fields requiring information are also color-coded, enabling users to quickly identify them. Data entry fields are identified by a dark yellow background that changes to light yellow after entering data. Color-coding fields offers visual cues so that users can quickly identify missing or failing data, which is also a boon during the review process.
Figure 3 – If any data fields are left blank, the field background color turns to dark yellow (caution); at the same time, a “Missing Data” message with a light red background appears in the related PASS/FAIL results field. The PASS/ FAIL status and calculated test results will not be displayed until the related data field information is entered. Note tool tip instruction for field entry.
If any data fields are left blank, the field background color turns to dark yellow (caution) and at the same time, a “Missing Data” message with a light red background appears in the related PASS/FAIL results field. The PASS/FAIL status and calculated test results will not be displayed until the related data field information is entered, as shown in Figure 3. As a safeguard, entries for numerical values only accept numbers. If an entry is invalid or does not fall within the valid range, a warning sign is displayed until a valid value is entered. Safeguards like these are featured throughout the protocol, minimizing the chance of missing or incorrect data entry.
Of special interest are the fields reserved for “results,” which are filled out automatically by the protocol itself. As noted above, the protocol performs all necessary calculations and then determines the PASS/FAIL status for each test, relieving the user from these cumbersome and error-prone tasks. All fields corresponding to calculated values, PASS/FAIL results, labels, and test procedures are color-coded and cannot be accessed or altered by the user. They are filled in by the protocol itself based on the automatic calculations and acceptance criteria.
Figure 4 – The electronic signature feature of paperless protocols ensures that the protocol is reviewed and e-signed by the initial reviewer and tester prior to performing the tests. The paperless protocols can be made “Read Only” after signing by the tester, except for the field used by the final reviewer(s) to approve the document.
Streamlined reporting and review
Once testing is complete, the protocol automatically generates a Summary Report providing a quick overview of completed results for reviewers and auditors. Once again, color-coded fields visually cue reviewers as to out-of-scope results, enabling faster review.
The protocol also includes space to enter information regarding attachments: certificate of calibration for various tools, certificate of analysis for standards and reagents used, certificate of training of the person who performs the qualification, raw data generated by the instrument, and other documents. The final paperless qualification protocol includes the PDF attachments for these documents and automatically displays the total number of pages of the protocol including the attachments, ensuring document integrity.
Of great interest and regulatory importance are the e-signature and time-and-date-stamp features for approvals before and after testing. The protocols can be sent as an e-mail attachment for initial review and approval prior to performing the qualification, and then returned with an e-signature. After testing is complete and all attachments are included, the protocol is e-signed by the tester and sent to the final reviewer. The e-signatures can include the name of the signer, the date and time of the signature, and comments.
Figure 5 – Qualification of an Agilent Series 1100 HPLC system using the HPLC paperless universal IQ OQ protocol in <2 hr. This includes performing the actual tests, data entry, and preparing the report.
As part of the e-signature feature, the entire document can be made “Read Only” after signing by the tester, except for the fields used by the final reviewer(s) to approve the document, as shown in Figure 4.
Once the final reviewer e-signs the document, the protocol locks, becoming “Read Only.” At this point, no changes can be made to the document, ensuring its integrity. The entire document can then be printed or digitally archived as a PDF, with all fields locked and inaccessible. The final document in PDF format meets the requirement of 21 CFR Part 11 compliance.
Conclusion: Proof of concept
Qualifying lab instruments by employing an iPad- or PC-based protocol enables remarkable cost-savings because these paperless and automated protocols reduce human errors and reduce—by hours—the time it takes to qualify an instrument. Figure 5 highlights the qualification of an Agilent Series 1100 HPLC system (Agilent Technologies, Santa Clara, CA) using the HPLC paperless universal IQ OQ protocol in less than 2 hr. This includes performing the actual tests, data entry, and preparing the report. In comparison, it typically takes 8–12 hr to perform the standard test procedures using a paper protocol based on vendor procedures. The same paperless IQ OQ protocol can be used for HPLC systems from Waters (Milford, MA), Shimadzu (Columbia, MD), PerkinElmer (Shelton, CT), Thermo Fisher Scientific (Waltham, MA), and other vendors with a similar configuration.
With savings of 6–8 person-hours on just one HPLC, it is clear that companies can dramatically accelerate their savings when paperless, universal protocols are employed on HPLCs throughout the organization. When other instruments are added, these automated, paperless protocols can have a significant impact on productivity and cost reductions, introducing a significant antidote for the costs of regulatory compliance.
Joe Tehrani, Ph.D., is President and co-Founder, Lab Compliance Solutions, 2647 Gateway Rd., Ste. 105-460, Carlsbad, CA 92009, U.S.A.; tel.: 760-707-2974; e-mail: joe.tehrani@LabComplianceSolutions.com; www.labcompliancesolutions.com.