Analytical Method Execution Automation: PAT for Pharmaceutical QC Laboratory Operations

With the FDA’s increasing focus on modernizing regulation of pharmaceutical manufacturing and product quality, companies are being forced to reexamine whether traditional development and commercialization processes are sufficient. A major goal of the new current Good Manufacturing Practices (cGMPs) initiative and Process Analytical Technologies (PATs) is encouraging the adoption of new technological advances to enable high-quality and efficient manufacturing.

Pharmaceutical development and manufacturing has not changed its fundamental paper-based infrastructure in decades. The principal reason is that regulatory requirements resist change. Until recently, industry and the FDA were not aligned with respect to utilizing innovation and technology to bring manufacturing processes into the twenty-first century. Leading companies are adopting a new approach to automating compliance by utilizing innovative technologies and building quality into the compliance infrastructure (e.g., standard operating procedures, work instructions, analytical methods, data sheets, and batch records). Many of these internal programs are sometimes called “Right the First Time” programs. Their key conclusion is that compliance activities can be automated, creating a new, more compliant paradigm; reducing risk; and providing higher productivity and improved quality.

This paper discusses the current situation in laboratory operations relative to compliance initiatives and manufacturing challenges, and profiles a “method-centric” software platform, designed for the analyst, to electronically execute and manage QC testing protocols, yielding significant reductions in overall product release cycle times. This technology can be defined as PAT (process analytical technology) for QC and process laboratory processes.

Today, the U.S. pharmaceutical industry spends approx. $90 billion on manufacturing. By improving manufacturing efficiency by only 5%, the industry could yield over $4.5 billion annually.1 Leading pharmaceutical companies, generics, and contract research organizations have prioritized programs designed to eliminate the routine, nonvalue-added tasks through automation. Research conducted at VelQuest Corp. (Hopkinton, MA) confirms that in most regulated companies, approx. 70% of laboratory-based resources are focused on compliance-related functions.2 Within the quality operations, the initiative to “go paperless” is expected to create operational benefits resulting in millions of dollars in efficiency gains. This e-manufacturing environment will enable immediate communication between the many disparate data sources, ranging from product and process development, pilot operations, incoming raw materials inspection, in-process monitoring, and process analytical technologies to final quality control laboratory results. Interfacing these data sources and higher-order information management technologies provides a platform for enterprise-wide decision-making to significantly improve batch release cycle times. Going paperless can allow one to manage the data across the entire enterprise—within the plant, plant to plant, or across the entire global operation.

Industry operational challenges

The pharmaceutical and biotechnology industries are challenged to improve product quality, productivity, return on investments, and compliance while at the same time generating an annual 10–15% growth for their stakeholders. This is becoming increasingly difficult due to the large number of branded products coming off patent over the next three years and vulnerable new product pipelines. This means that these companies must roughly double the number of new lead candidates entering the clinical trial phases of the drug approval process, shorten overall time to market, and decrease overall costs. The entire product life cycle (research, development, and manufacturing) must be streamlined. Within this environment, large amounts of data are being generated across the entire enterprise. Today, most laboratory operations rely on the ubiquitous use of paper-based systems that are fraught with potential human-generated errors and require constant checking and manual verification procedures. These processes add no value to the operations and significantly contribute to the costs. Also, complying with cGMP requirements is another challenge for the life science industry, further adding costs stemming from manual activities centered on compliance.

21 CFR Part 11 emerged as a demanding regulation for the pharmaceutical and biotechnology industries. Regulations that affect the overall management of electronic records have added new priorities for the industry. Part 11 has recently been modified to lessen the total scope and provide a more rational framework for implementation; however, the rule still applies if the electronic record is in a high-risk area as defined by impacts on human health. The QA/QC functions within the pharmaceutical production arena clearly fall into this high-risk definition. Systems that generate electronic records required by a predicate rule must be examined, including analytical instruments (chromatography data systems, balances, and spectrophotometers, etc.), office applications (Microsoft® Word™ and Excel™, Redmond, WA) used for documentation, and LIMS. From each QC laboratory across the enterprise, Part 11 significantly impacts good electronic record-management practices.

Opening the door to the paperless laboratory

The automation initiatives in production over the last decade were driven by the need to precisely control production processes and cut costs. That environment is now being further modified by reviewing the costs associated with nonvalue-added tasks. An identified area is the large amount of paper processes used in manufacturing, particularly quality control and quality assurance functions. These e-manufacturing initiatives have received attention as one of a small number of critical path issues that, if solved, will provide significant cost savings for decades. Some key insights obtained from a research survey conducted by VelQuest Corp. in 20022 are revealing: “Our company has a priority initiative to delegate decision-making, enrich jobs and create accountability for delegated decisions. We see paperless labs as a tool to empower analysts to fulfill this charter. We also want to reduce the time lab supervision spends on review and investigations, so they can work on process improvement. . . . We believe [that through paperless labs] real-time feedback enables analysts to reduce errors, minimize rework loops and correct ambiguous results immediately.”

The main issues mentioned here are decreased review times, reduced operator error, minimization of rework and investigations, and ultimately enhancement of the work experience for well-trained analysts and operators. All of these issues contribute to costs and product release cycle times and, if minimized, will significantly affect an operation’s bottom line.

The patented SmartLab™ software was developed to embed an automated data capture software application within a company’s existing standard operating procedures (SOPs) or test methods (VelQuest Corp.). In doing this, the software presents only the approved method to the analyst and captures all the critical data and metadata created during the process of implementing a method on the laboratory or process floor. Data elements include method preparation data (reagent information, weighing operations, metrology, etc.), analytical instrument data (chromatography and spectroscopy), and analyst or operator observations (color, texture, shape, etc.).

Figure 1 - A digital version of a standard operating procedure (or method) is presented to an analyst with automatic capture of critical method-based data. This process eliminates transcription errors associated with paper-based notebooks.

Figure 2 - After a method is completed, all data are presented to reviewers with visual flags for all specifications and materials expiration requirements along with instrument calibration dates, audit trails, annotations, e-signatures, and direct “drill-down” links to the raw data sources at the click of a mouse.

The software takes existing written protocols (methods or SOPs) and presents them in an electronic version with embedded data capture technology. Analysts and operators interact with the digitized SOP through PCs or handheld tablet PCs that force data entry and capture either manually or automatically (directly from instruments). The technology can be thought of as a QA/QC Operation e-Notebook. At the end of the process all of the data are aggregated in a reviewer screen (see Figures 1 and 2) with all data flagged for specifications and a direct link to the original data source. Review times are typically reduced by a factor of 50% or more. Raw data files are automatically captured and organized in a secure repository for future needs.

Access to the SmartLab platform is controlled via a secure privilege grid with full audit trail and electronic signature capability providing compliance with the FDA’s 21 CFR Part 11 regulations. The resulting data are accessible to any authorized member of the QA review or management team. Customized reports, including certificates of analysis for batch release documents, can then be automatically created and approved. Data and trending reports can also be exported to other inhouse IT infrastructure requirements such as a LIMS or Enterprise Resource Planning/Manufacturing Resource Planning (ERP/MRP) system. In many respects, this technology represents the process analytical technology applied to the QC laboratory processes. Just like physical manufacturing processes, the laboratory environment utilizes method processes conducted by analysts, and through embedded method-centric software (SmartLab), the PAT philosophy can be applied to the laboratory with equivalent productivity improvements and significant returns on investment.

Conclusion

The pharmaceutical industry is seeking to control costs as a result of questionable new product pipelines and the erosion of business due to the large number of products coming off patent over the next few years. For decades, most of the data management processes in QA/QC have been paper based, requiring numerous nonvalue-added manual checks to ensure that data integrity and product quality standards have been met. In today’s modern computer-based environments, technology can be adapted to totally eliminate these paper systems and replace them with a fully all-electronic method execution and data capture and review system. An example of such a system is the SmartLab platform, which is designed to present approved SOPs in a digital form and embed software to automatically prompt analysts and operators to follow the procedure as written and automatically capture and catalog all the method data and outcomes in a secure repository. This process eliminates operator method error or transcription issues in working with a paper-based notebook process. The data are automatically grouped and presented to a QA reviewer with color-coded flags for specification verification, e-signatures, and full audit trail of activity. This process can typically reduce review times by over 50% and reduce rework and internal investigation processes, resulting in overall operational QA/QC laboratory cost improvements of over 20%. This technology can be viewed as PAT technology for the laboratory environment.

References

  1. Pharmaceutical Processing Dec 2003:20.
  2. Laboratory IT-Enabled Solutions Research Report. VelQuest Corp., Nov 2002.

Mr. Helfrich is Director, Laboratory Automation Programs, VelQuest Corp., 25 South St., Hopkinton, MA 01748, U.S.A.; tel.: 508-497-0128; fax: 508-497-2396; e-mail: [email protected].