Wednesday, June 3, 2009

PAT TOOLBOX: Quality Systems

Building in Real Time

Doing so can reduce review times by over 50 percent and minimize re-work and internal investigation processes, yielding overall operational QA/QC cost improvements of over 25 percent

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 cGMP initiative, Six Sigma, lean manufacturing and process analytical technologies (PATs) are encouraging adoption of new technological advances to enable high quality and efficient manufacturing.

Pharmaceutical development and manufacturing has not changed its fundamental paper-based infrastructure for decades. The principle reason is that past regulated environments resisted change. Recently, industry and the FDA have become very aligned with respect to utilizing innovation and technology to bring manufacturing processes into the 21st century. Leading companies are adopting a new approach to "automating compliance" by utilizing innovative technologies and building quality into the compliance infrastructure (SOPs, work instructions, analytical methods, data sheets, batch records and more). Many of these internal programs are called "right-first-time" or "operational excellence" programs. Their key conclusion is that compliance activities can be automated, creating a new more productive paradigm, reducing compliance risks and providing higher productivity and improved quality. Automation enables companies to institutionalize these new initiatives.

Published results prove the point [3]. Significant liberation of resources from leaders in the field routinely demonstrate north of 30 percent elimination of the labor from processing, reviewing, and approving tests, translating into faster cycle times, more predictable release times, and higher quality. In addition, analysts, chemists and operators have a better work environment, and can invest newfound time on higher quality activities and increasing capacity within the bounds of the existing operations.

Paper-Based Challenges

The U.S. pharmaceutical industry spends approximately $90 billion on manufacturing. By improving manufacturing efficiency by only 5 percent, 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, non-value added tasks through automation. Research confirms that in most regulated companies, 70 percent 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 yielding 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, process analytical technologies (PAT) and final quality control lab 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.

The pharmaceutical and biotech industries are challenged to improve product quality, productivity, return on investments and compliance, while, at the same time, generating an annual double digit top and bottom line 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 manufacturing and laboratory operations rely on the 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 costs. Also, complying with cGMP requirements is an added challenge for the life science industry, further adding costs stemming from manual paper-based activities centered on compliance with cGMPs'.

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 lesson 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 manufacturing and QA/QC functions within the pharmaceutical production arena clearly fall into this "high risk" definition. Systems that generate electronic records required by rules must be examined, including analytical instruments (chromatography data systems, balances and spectrophotometers etc.), office applications (Microsoft Word and Excel) used for documentation and production equipment.

Fig. 1: A digital version of a standard operating procedure (or method) is presented to QC lab analyst or production floor operators with automatic capture of critical method-based data. This process eliminates transcription errors associated with paper-based notebooks.

Think back to the pre-1970s when the worldwide banking system was paper-based. The scene at local banks included long lines and great difficulty in accessing your money. Transfers, withdrawals, deposits-access was localized and difficult. Today, we have a fully automated electronic banking system. It's easy to gain access to your account through a secure privilege grid (an ATM machine). It's easy to make deposits, withdraw funds, transfer funds, etc. from anywhere in the world. Technology enables the banking industry to automate the "banking regulations", providing end users with dramatic improvements in productivity, cycle times and compliance.

Clearly, there is a similar opportunity for the life science industry.

Automation Initiatives-PAT, Six Sigma and Lean Manufacturing

The automation initiatives in production over the last decade where driven by the need to precisely control production processes and cut costs. Operational excellence programs often utilize Six Sigma and lean manufacturing approaches to identify opportunities to improve manufacturing operations. These approaches have clearly identified significant costs associated with non-value added tasks. One major component for improvement is the large amount of paper processes used in manufacturing and quality control and quality assurance functions. "E-manufacturing" initiatives have received attention as one of the critical-path issues that, if solved, will yield significant cost savings for decades.

It makes sense. Under cGMPs, the industry uses well defined Standard Operating Procedures (SOPs) to govern their internal quality systems. Technologies that automate the processing of these SOP's and institutionalize "best practice" within pharma's quality systems, will clearly yield significant benefits including drastically reduced operator errors, significant acceleration of batch record and test method data review times, and minimizing rework and investigations-ultimately enhancing 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 enhance an operations' bottom line. In 1999, a patented process was developed to embed an automated data capture software application within a company's existing SOPs, batch records, or test methods. The software applications take existing written protocols (methods, batch records, or SOP's) and present them to the analyst/operator as an electronic version with embedded, real-time data capture technology. Analysts and operators interact with the digitized SOP through PCs or hand-held tablet PCs that force data entry and capture either manually or automatically (direct from instruments and equipment). The technology can be thought of as a "QA/QC operation e-notebook." At the end of the process ALL the data is aggregated in a reviewer screen (See Figure 1, 2 and 3) with all data flagged for specifications or expected process norms and a direct link to the original data source.

Fig. 2: A digital version of a standard operating procedure (Method or Batch Record) is presented to QC lab analyst or production floor operators with automatic capture of critical method-based data. Any out of norm entry is immediately "flagged" to the analyst or plant floor operator. The metadata and data capture bar (bottom of screen) is unique for each step that requires data capture (QC test or Process Step).

Fig. 3: After a Batch is completed all data is presented to reviewers with visual "flags" for all specifications or expected process norms 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 button. This review "dash-board" reduces review cycle times by over 50 percent.

Three Layers to Consider

There's a lot to think about. The good news is that many companies have already begun the transformation from the paper-based world to the fully electronic environment. Today, companies have deployed fully validated solutions to change the current paradigm (See IMACS Proceedings [3]). There are three levels of the solution to be considered.

Instrument Connectivity: Real-time data capture at the point of use from human observations, rs232 instruments, and PC-based instruments. It is critical that a software application be a tool for the analyst/operator that completely removes transcriptions, copying paper, and taping or gluing paper printouts. All of these manual operations require checking and rechecking via peer review before approvals. They are a major source of errors and difficulty in finding critical data during investigations and audits. Today, there are hundreds of instrument connections available off-the-shelf inclusive of their validation protocols. The world of instrument connections should be viewed like connecting printers to a Windows system, pull from the list and load the drivers.

Method Execution: The secret to a fully compliant cGMP operation is the quality systems approach governed by a company's standard test methods, batch records and SOPs. An organization should ask, "who is the end user/customer for new technology?" Most companies agree that modern pharmaceutical operations document the majority of their work in paper notebooks, log books, and data sheets and use a pen and a calculator as the most modern tools for their employees. Clearly companies can see that in other parts of their organization, computer based tools have revolutionized their business process, i.e. Microsoft Word vs. a typewriter, Excel vs. paper ledgers. What would the work environment be like if we hadn't modernized today's business office with these tools for the work force?

So, when defining requirements to institutionalize operational excellence programs, companies look to significantly improve operators and analysts work flow by providing them with the right tools. Experts suggest that companies find suppliers who provide tools that focus on end-users doing the day to day physical work, rather than developing customized approaches with large complex "management-focused" deployments.

The method execution layer of system architecture has tremendous potential for operations improvements. When adopting solutions in this area, companies have the ability to build-in most operational excellence and PAT approaches. For example, a simple loss on dry test can be built with best practices. Upon deployment of the method on the manufacturing floor or in the laboratory, this test method will be performed consistently and compliantly as described by the paperless automated test. Today, suppliers to the industry have libraries of methods available for execution with many error prevention techniques avoiding transcription, calculation, and compliance errors.

External System Integration: One of the most common challenges facing life science companies is the number of systems under management and their lack of ability to communicate with each other. It is critical to define the system integration requirements in any automation program. Data is the product of today's quality operation within the pharmaceutical and life science industry and there are many systems that contribute to results. Leaders in the field suggest that system integration be designed to minimize the dependence of separate systems so that as each system is revised the bridge between systems remains valid and intact.

Fig. 4: After a Batch has been run, all the data and results are automatically reported in any format including a digital representation similar to the paper version.

Use caution when assessing the scope of a systems integration project. This is an area that has been more difficult to deploy than as outlined on the "white-board". Experts suggest a detailed scope definition and stepwise deployment as the most successful approach.

Industry Seeking to Control Costs

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 and the production floor have been "paper-based" requiring numerous non value-added manual checks to insure data integrity and product quality standards have been maintained. In today's modern computer-based environments, technology can be adapted to totally eliminate these paper systems and replace them with a fully electronic method execution, data capture, review and reporting system. An example of such a are platforms 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, in real-time, capture and catalog all the 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 is 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 percent and reduce re-work and internal investigation processes yielding overall operational QA/QC cost improvements of over 25 percent.�


[1] Pharmaceutical Processing, December 2003, page 20.

[2] Laboratory IT-Enabled Solutions Research Report, VelQuest Corporation, November, 2002.

[3] Summary Report on International Meeting on Automated Compliance Systems (IMACS) 2005

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