A major goal of the new regulatory environment is encouraging manufacturers to adopt new technological advances to enable high quality and efficient manufacturing. Many companies are investigating “operational excellence” programs to create a “lean manufacturing” environment with optimized controls for superior product quality. Supply sites have been challenged to reduce costs and gain efficiency through critical assessment of systems. Most resource headcounts at the supply sites are remaining static, thus moving forward, the gains in efficiency, cost, and error reduction will be achieved through investment in automation and technology.

For QC laboratories, management of data means that analysts input data into paper-based notebooks, worksheets, log books, spreadsheets, LIMS, and chromatography data systems (CDS). For the most part, hybrid systems consist of paper-based records that either stand alone or are combined with electronic records. This approach requires redundant checks, peer review, and time-consuming manual systems to maintain data integrity and compliance with regulatory requirements. Since most of the records are paper-based, they require additional efforts for archival and retrieval.

The approaches that many pharmaceutical labs worked on were born out of Y2K initiatives with the goal of going completely electronic. There were many systems identified during Y2K that were capable of generating and/or storing electronic records. The key issue to be resolved is the integration of all QC/QA lab equipment and IT systems so that management of the data, as a whole, is compliant, organized, complete, and capable of streamlining data and workflow throughout the operation. Leading companies are adopting a new approach to “automating compliance” that is, utilizing innovative technologies and building quality directly into the compliance infrastructure (SOPs, work instructions, analytical methods, data sheets, batch records, and more). 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 will discuss the current situation in pharmaceutical quality laboratory operations relative to compliance initiatives, manufacturing challenges, and “method-centric” software, designed for the analyst, to electronically execute and manage lab testing protocols, yielding significant reductions in operational costs while improving productivity.

Industry productivity challenges

The pharmaceutical and biotech industries are challenged to improve product quality, productivity, and assure regulatory 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 five years and vulnerable new product pipelines with ever increasing costs to discover new chemical and molecular entities. Many companies are taking stock of the entire product life cycle (discovery research, development, and manufacturing) and realize all areas must be streamlined. Today, most laboratory operations rely on the ubiquitous use of paper-based “systems” to capture and catalog data. This is particularly evident in the quality control labs where paper notebooks, binders, and data work sheets are used and are fraught with potential human — generated errors requiring constant “checking” and manual verification steps. These processes add no value to the operations and significantly contribute to the costs. Complying with cGMP requirements is an added 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 in 1997. Part 11 has recently been modified to lesson the total enforcement 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 the data’s impact on human health. The QA/QC activities within the pharmaceutical production arena clearly fall into this high-risk definition. Systems that generate electronic records include analytical instruments (chromatography data systems, balances, pH meters, titrators, and spectrophotometers, etc.), office applications (Microsoft Word and Excel) used for documentation, and laboratory information management systems (LIMS). In addition, the data can be used in higher-order systems such as ERP/MRP systems.

The paperless QC lab

Automation initiatives in production are typically driven by the need to precisely control synthetic reactions or bioprocess conditions and cut operational costs. That paradigm is now being further enhanced by reviewing the costs associated with non-value added tasks. An identified area is the large amount of paper processes still used in manufacturing, particularly quality control and quality assurance functions. The key non-valued added functions are the analysts’ records of method execution and the re-typing of data into IT systems such as LIMS or ERP systems. This paper process requires significant review and audits to check the data and assure compliance with the SOP and expected process norms. To investigate an analytical value further complicates the situation as the source data is inside a paper notebook and/or binders that must be manually found and reviewed. If one could capture and catalog all the data and metadata at its source and drive it direct to a database, the entire process could go totally electronic and significantly reduce any manual processes. These “e-manufacturing” initiatives have received attention as one of a small number of critical-path issues that, if solved, will yield significant cost savings for decades.

An automated data capture software application embedded within a company’s existing SOPs or test methods captures all the critical data and metadata created during the process of implementing a method on the lab or process floor. Data elements include method preparation data (reagent info, weighing operations, metrology, etc.), analytical instrument data (chromatography and spectroscopy), and analyst or operator observations (color, texture, shape, etc.).

Electronic software systems take existing written protocols (methods or SOPs) and present it as an electronic version with embedded data capture technology. It is essentially a “method-under-glass” with direct connection to all the lab instruments. These systems allow analysts and operators to interact with the digitized test method or SOP through PCs or hand-held tablet PCs that force sequential data entry and capture either manually or automatically (direct from instruments). The technology can be thought of as a GMP electronic notebook.

There are many benefits to incorporating an electronic notebook system. At the end of the process all the data is aggregated in a reviewer screen (Figures 1 and 2) with all data flagged for valid method norms and a direct link to the original data source. Review times are typically reduced by a factor of 50% or more. Instrument data files are automatically captured and organized in a secure repository for future needs. Access to the 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 result data is accessible to any authorized member of the QA review or management team. Tailored reports, including certificates of analysis for batch release documents, can then be automatically created with on-line review and approval. Data and trending reports can also be exported to other in-house IT infrastructure requirements such as a LIMS or ERP system. In many respects, this technology represents the “process analytical technology” (PAT) applied to the QC laboratory processes. Just like physical manufacturing processes, the lab environment utilizes “method processes” conducted by analysts and through embedded “method-centric” software the PAT philosophy can be applied to the lab with equivalent productivity improvements and significant returns on investment.

Operational excellence–productivity metrics in use

Many top pharmaceutical, biotech, CRO, and generic organizations have fully validated or are in process of implementing a GMP electronic notebook system. Each year key managers from these companies convene at the International Meeting on Automated Compliance Systems (IMACS)1 and report on their results and plans. The following summaries outline several reports:

Top 10 Large Pharmaceutical Company
A GMP electronic notebook system was rolled out in conjunction with a scheduled LIMS deployment. A single product in manufacturing was converted to an all electronic operation. Analysis of data for the year in this single product was reported as follows:

• Time Savings — three hour savings in analyst time for an assay/content uniformity method. The method required many calculations that are now automated. This translated into approximately 30 hours per week gained by the lab and data review for a single method. A total savings of approximately 79 hours of analyst time per week based on multiple batches or product per week.
• Error reduction (documentation, transcription, calculation) — errors were reduced to zero.
• Data Review — Reviewers benefited by having all of the data centralized and in electronic format for review. 

As a result, the QA labs were able to eliminate the need for planned head count additions in support of product testing. Overall this system has saved the operation several hundred thousand dollars per year for a single product.

Mid-tier Pharmaceutical Company
This company reported that it had multiple manufacturing sites and installed an electronic notebook system in a European plant. This plant produces several products for worldwide distribution. The Director of Quality Control reported the following:

• The system was installed as an alternative to a planned LIMS implementation and did everything required in terms of traditional LIMS capabilities while providing an electronic notebook for GMP operations.
• The timeliness of final lot release documentation significantly reduced the “quarantine value” for operations. Estimated impact on over $20M/year of product.
• Eliminated “silly errors” and automatically checks for data completeness and has built-in compliance flags for atypical data collections (if made by analysts).
• Percent savings varied depending on activity and complexity but in general they reported a 30—50% reduction in testing time and 50—70% reduction in review and approval time. 

Large Pharmaceutical Company — New Plant Installation
This large pharmaceutical company installed an electronic system at their main development facility and is expanding the capability to a production plant involved in production and delivery of time-sensitive imaging products. The Senior Research Investigator reported the following:

• Estimated resource liberation of 1 FTE on a base of 8 FTE’s in the quality operation.
• 16 analytical methods, 19 instruments, a LIMS and CDS interfaced to the method-centric system and GMP “golive” in less then six months.
• Analysts and reviewers saved significant time with removal of manual calculations and transcriptions. Eliminated the need for Excel for one method.

Conclusions

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 non value-added manual checks to insure data integrity and product quality standards have been made. In today’s modern computerbased environments, technology can be used to totally eliminate these paper systems and replace them with a fully all electronic method execution and data capture and review system. This process eliminates operator method error or transcription issues in working with a paper-based notebook process. The data is automatically grouped and presented to a QA reviewer with compliance flags for specification verification, e-signatures, and full audit trail of activity. Systems have been implemented in GMP labs with significant operational excellence reports given at the annual IMACS conference. This process can typically reduce review times by over 50%, reduce re-work and internal investigations yielding overall operational QA/QC cost improvements of hundreds of thousands of dollars/product line. This technology can be viewed as operational excellence technology for the GMP QC/QA lab environment.

References:

1. IMACS 2005 – International Meeting on Automated Compliance Systems, May 18-19, 2005, Princeton, NJ (www.imacs-world.com).

John P. Helfrich is Director, GMP Automation Programs, VelQuest Corporation, 25 South Street, Hopkinton, MA 01748; 508-497-0128; John.helfrich@velquest.com.