Lean Process Improvements for the GMP Laboratory

Lean Process Improvements for the GMP Laboratory

ITRODUCTIO Pharmaceutical manufacturing costs the industry approximately $90 billion each year and represents twice the expenditure of research and development. 1 A 2001 study conducted by the MIT Pharmaceutical Manufacturing Initiative (PHARMI) indicated that significant time was spent conducting quality control (QC) testing and documenting QC results during the manufacturing process. 2 Eroding profit margins from stiff competition, increasing product defects, 1,3 and the FDA s focus on a quality by design model has led the industry to reevaluate manufacturing efficiency. Recently, the industry has begun adopting both Lean Manufacturing and Six Sigma to achieve the efficiency and quality gains achieved by other industries. 4-6 IT solutions will play a significant role in managing QC standard operating procedure (SOP) documentation during the focus on Lean and Six Sigma to eliminate waste, improve workflows, improve quality, and reduce variability. QC operations represent an expensive component of the manufacturing process. GMP regulations require maintaining thorough documentation to ensure strict compliance with established SOP s during product testing. Thus, maintaining documentation using paper dramatically increases QC result turnaround time. Hence, completing paper documents and ensuring their authenticity creates a burdensome bottleneck in the QC laboratory. Electronic SOP form and worksheet systems, like Waters ugenesis SDMS Intelligent Procedure Manager, present an opportunity to create a semi-automatic Lean Process during the SOP documentation, thereby boosting productivity and accuracy in this largely labor-intensive component of the QC testing laboratory. 2

BOTTLEECK IDETIFICATIO The MIT Pharmaceutical Manufacturing Initiative identified QC testing and documentation as taking up a significant portion of total manufacturing time. 2 Relocating some QC testing to the manufacturing floor represents one solution to the testing lag time and Process Analytical Technology (PAT) represents a tangible solution for real-time testing. Additionally, the pharmaceutical industry s adherence to GMP FDA regulations such as 21 CFR Part 11, requires authentic, accurate, and complete recordkeeping. The regulations pertaining to documentation apply to the entire manufacturing process. When paper-based systems are used, this creates a major bottleneck during the QC testing process because every aspect of the testing requires documentation. Many QC laboratories employ a mixture of electronic data systems and paper. For example, chromatography data systems (CDS) manage the separation experiments and the Laboratory Information Management Systems (LIMS) handle the testing requests and result collection; while paper forms and notebooks capture instrument calibrations, solvent preparation, and other SOP s. The combination of electronic and paper systems results in a disjointed data and documentation process, where data are not readily accessible for real-time process monitoring. This disjointed process directly impacts product quality, variability, and QC turnaround time. Bottleneck resolution An electronic SOP documentation system offers the opportunity to address the three major tenets of Lean Process manufacturing: eliminate waste, improve workflows, and improve quality. To address the three tenets of Lean Process manufacturing, an electronic system must include the following properties: n Compliant-ready to fulfill 21 CFR Part 11, Annex 11 and electronic records requirements to ensure that electronic records are equivalent to paper documents. n Intelligently guide an analyst through laboratory workflows to ensure SOP fidelity. n Interface with common laboratory instruments and systems (balances, ph meters, CDS, LIMS, etc.) to eliminate transcription errors and duplication of efforts. n Capture both document and instrument data into one searchable location to aid searching. n Perform automated calculations in a 21 CFR Part 11 compliant-ready shell to reduce errors and maintain quality. Figure 1 illustrates a simplified workflow highlighting the interface between a LIMS and laboratory instruments with the electronic SOP system. A system comprised of compliant-ready, intelligent SOP s, system inter-operability, and database warehousing offers the potential to streamline the QC documentation process. GMP lab space Manufacturing Line Laboratory Information Management System (LIMS) Laboratory Instruments Figure 1. The GMP laboratory space. An electronic SOP system directly interfaces with test requests arising from a LIMS and with laboratory instrumentation to efficiently conduct and document GMP laboratory testing. System interfacing and professional services Scripted interface Electronic SOP System Data Document Database QC laboratories contain a heterogeneous mixture of laboratory instruments and data management systems. Hence, QC data and results exist in multiple electronic systems that complicate workflows. Lean Process manufacturing demands easy access to QC test results in order to control quality throughout the manufacturing process. Therefore, data exchange between electronic systems is a primary concern for QC operations implementing Lean Process manufacturing. Direct exchange of information between information systems is highly desirable, but due to the multi-vendor landscape of QC operations and the complexity of the electronic systems, a direct link is often not feasible. Hence, exchange of information between systems is often accomplished by utilizing an import/export interface utility. While a manual input/output may be useful for occasional data exchanges, a more automated approach that maintains compliance is necessary. Many IT solutions provide a procedural scripting utility for conducting automated data exchange and procedural operations such 3

as performing statistical calculations and trending. Writing scripts can be challenging especially while maintaining compliance, so many solution providers provide professional services to write automation and interface scripts. Waters offers professional services for systems such as Empower and ugenesis SDMS to facilitate workflow optimization, system validation, and system-to-system interfacing. VALUE STREAM MAPPIG The first step in developing a Lean GMP Laboratory Process is to map out the current state. The current state process map serves to establish a clear view of the process bottlenecks and acts as a baseline to track future process improvements. Figure 2 illustrates a current and future state process map for a Laboratory. Current Paper-based laboratory Paper-based laboratory LIMS LIMS Test Test CDS CDS Select SOP Select SOP ph Meter ph Meter Assign Test Assign Test Conduct Test Conduct Test Electronic Balance Electronic Balance Capture & Catalog Analytic Data Other Instruments Other Instruments Capture & Catalog Analytic Data Generate COA Generate COA Finalize SOP Document Finalize SOP Document Testing Complete Testing Complete Return Return Solvents Standards Reagents Solvents Standards Reagents Futrue Laboratory Laboratory SDMS SDMS LIMS LIMS Test Test CDS CDS Select SOP Assign Test Select SOP Conduct Test Instrument fit-for use inventory ph Meter Instrument fit-for use inventory ph Meter Assign Test Electronic Balance Electronic Balance Conduct Test Scripted/intelligent interface Generate COA Other Instruments Other Instruments Figure 2. A value stream map highlighting the current state QC laboratory documentation process that includes a mixture of manual processes, paper documentation, and electronic systems. The future state replaces manual system interfacing and documentation with an electronic SOP system to streamline QC testing and information capture. 4 Generate COA Capture & Catalog Finalize SOP Analytic Data Document Scripted/intelligent interface Scripted/intelligent interface Capture & Catalog Finalize SOP Analytic Data Document Reagent inventory Testing Complete Testing Complete Return Return Solvents Standards Reagents Scripted/intelligent interface Reagent inventory Solvents Standards Reagents

Detailed analysis of the current state map may provide a toplevel view of inputs and outputs, bottlenecks, sources of error and variability, and provide an indication of the complexity of the process. The future state process map in Figure 2 illustrates compartmentalization of the laboratory process into three parts: LIMS, an SOP electronic documentation system, and the analytical instrumentation. This new process organization allows the highly-skilled analyst to focus on conducting analytical testing, while the LIMS and/or SOP electronic documentation system handles the non-value added paper and data management. FLOW CHART MAPPIG Figure 3 illustrates a detailed workflow covering a single analytical test and highlights an HPLC dissolution workflow. Each rectangle in the flowchart represents a documentation step. This workflow consists of 10 documentation steps and a report step with content consolidated from the documentation steps, plus test results. This HPLC dissolution workflow demonstrates the degree of documentation required to conduct a relatively straightforward test such as dissolution in a compliant laboratory. To further demonstrate the documentation burden, consider that QC laboratories may also conduct UV based dissolution, content uniformity, assay, and impurity testing. Hence, all of these tests require approved SOP forms as well as complete and accurate documentation during testing to ensure compliance. An electronic SOP system captures all necessary documents and guides the analyst through the testing workflow, while managing necessary system interfaces. Start Mobile Phase? Prepare Mobile Phase Solvent Mixture? Prepare Solvent Mixture Standard? Prepare Dissolution Bath Internal Standard? Prepare Internal Standard Solution Prepare Standard Setup HPLC Standard Stock Solution? Run on HPLC Ready? Prepare Standard Stock Solution Prepare Set Complete? Plot Report End Figure 3. Flowchart of HPLC dissolution workflow. The diamonds represents decision points within an electronic SOP system, and the rectangles represent documentation events. This workflow consists of 10 documentation steps. 5

ERROR PROOFIG PROCEDURES Go to ext Step Prerequisites Solvent bottle: Bottle volume Mobile Phase? Mobile phase 1000 ml Figure 4 demonstrates the initial step from the HPLC dissolution workflow shown in Figure 3. If the analysts need to prepare a mobile phase, they are methodically guided through the preparation protocol. The prerequisite step directs the analyst to obtain the necessary solvent bottle and then Step 1 confirms that the solvents are available by interfacing with a reagent inventory system and automatically logs them into the worksheet. Step 2 provides the mobile phase preparation protocol. Intelligent Guidance Step 1 Description: Locale water, methanol, and glacial acetic acid from inventory and record identifying information. Component Batch no. Source Expire date Water Methanol Glacial acetic acid Step 2 Description: Prepare the mobile phase by mixing, methanol, and glacial acetic acid in a ratio of 69:28:3. (See table for required volumes of each). ote: For safety, add the acid last. Solvent Volume Units Water 690 ml Methanol 280 ml Glacial acetic acid 30 ml Figure 4. First documentation step in a HPLC dissolution study. Enforced workflow and automated interfacing to reagent inventory systems provides a method for error proofing the QC documentation process. 6

BUILDIG WORKSHEETS WITH A FORM DESIGER Some manufacturing processes utilize a jig apparatus to boost productivity and add precision to repetitive jobs. A common example of a jig is used during house key duplication. This jig provides rapid and accurate key duplication. In the same manner, SOP forms ensure that information is accurately and rapidly recorded. While an SOP form is quite easy for an analyst to use, creating and tracking revisions of the form is not that easy for the person designing the form. An electronic SOP system should provide form designing functionality that streamlines the process of designing SOP forms. Additionally, the electronic system should maintain electronic signatures and revision histories for all SOP s and provide a facility to publish approved SOP forms to the analyst. Electronic document management systems (EDMS) provide some of this functionality for the form author, such as the ability to track the revision changes and housing documents in a centralized location; however, these systems often lack a convenient mechanism for maintaining 21 CFR Part 11 compliant documents during workflow implementation by the QC analyst. Form designing functionality within an electronic SOP system allows the form author to enforce a workflow while following the protocol within the form, as well as providing a convenient means to interface with other electronic systems, such as LIMS, reagent inventories, CDS, ph meters, and electronic balances (a feature absent from EDMS s). The form shown in Figure 5 makes use of a reagent inventory system and an electronic balance. Finally, the form embeds a QC department validated equation into a compliant-ready application shell (21 CFR Part 11, Annex 11) to ensure authentic and traceable data. Prerequisites Step 1 Step 2 Volumetric flask: Flask volume Description: Mobile Phase 100 ml Locale methanol, and benzoic acid from inventory and record identifying information. Component Batch no. Source Expire date Methanol Benzoic acid Description: Prepare a solution of benzoic acid in methanol containing about 6 mg per ml. Add 20 ml of methanol to the volumetric flask then add the benzoic acid. Swirl flask, then add methanol to volume. Component Desired amount Actual amounts Units Benzoic acid 600 mg Concentration 0 mg/ml Figure 5. Third documentation step of a HPLC dissolution study. This form enforces a workflow, automatically interfaces with an external reagent management system, and performs automated calculations by using formulas validated by the QA department. Cycle-time reduction There is little time differential between transcribing information in a paper form versus electronic form; however, the following examples are dramatically faster in an electronic form: n An electronic form reduces the transcription times by interfacing directly with electronic instruments to pull information directly into the forms, while employing error proofing within the forms. n Quality assurance efforts to assess compliance are reduced by 50-70%, since all documents are housed within a compliant-ready solution. n Direct database-to-database interfaces provide rapid access to chemical reagent and instrument fit-for-use information. n Information reuse dramatically reduces the time to convert measurement data collected in printed instrument reports into usable results or answers. One example comes from a Waters customer in the medical device industry. The company conducted an HPLC dissolution study that collected analytical results by using Empower and then electronically captured the raw reports into ugenesis SDMS. An automation script created by Waters Professional Services reused the multi-day content found in the raw reports to produce a report summary that included statistics and graphs. The automated script converted a two week manual process into a 10-minute semiautomated process. 7

COCLUSIO Eroding profit margins, more product recalls, and the FDA s focus on quality by design has led the pharmaceutical industry to adopt Lean Six Sigma in manufacturing. While QC testing plays a crucial role in guaranteeing the quality, safety, and efficacy of pharmaceutical products, it also represents a significant portion of the product manufacturing time. Ubiquitous documentation steps to satisfy regulations require significantly more time for QC testing. Electronic SOP systems like SDMS Intelligent Procedure Manager offer the potential to eliminate waste, improve workflows, and improve quality thereby addressing the central tenets of Lean process improvement. References 1. L Abboud, Scott Hensley, ew Prescription for Drug Makers: Update the Plants, The Wall Street Journal, A1, September 3, 2003. 2. G K Raju, Pharmaceutical Manufacturing: ew Technology Opportunities, a 2001 presentation to FDA s Science Board, http://www.pharmaceuticalmanufacturing/whitepapers/2004/118.html 3. U.S. Food and Drug Administration Enforcement Reports, 2000-2004. 4. Santiago, Process Excellence in the Manufacturing Value Chain, 2004, http://www.pharmamanufacturing.com/articles/2004/91.html 5. A Shanley, Right the First Time, 2004, http://www.pharmamanufacturing.com/articles/2004/114.html 6. A Shanley, ovartis Goes Lean, 2004, http://www.pharmamanufacturing.com/articles/2004/111.html Waters and ugenesis are registered trademarks of Waters Corporation. Empower and The Science of What s Possible are trademarks of Waters Corporation. All other trademarks are the property of their respective owners. 2008 Waters Corporation. Produced in the U.S.A. September 2008 720002787en PC-PDF Waters Corporation 34 Maple Street Milford, MA 01757 U.S.A. T: 1 508 478 2000 F: 1 508 872 1990 www.waters.com