Life-science companies have

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1 FOCUS ON... INFORMATION TECHNOLOGY Building an Electronic Batch Record System Part 1: Fitting into an Existing Software Environment by Ronald R. Davenhall Life-science companies have always put significant effort (both time and resources) into compiling and reviewing batch records and device histories. Electronic batch records (EBRs), which could significantly reduce workloads and increase accuracy, have been around for many years. However, a lack of clarity on regulatory requirements for electronic records along with the absence of suitable off the-shelf software has meant that very few companies have actually implemented EBR systems (1). Although many pharmaceutical companies have already computerized the weigh-out process, that is normally intended to reduce errors rather than to automate batch records. Typically, a record of the weigh-out is printed and included as an attachment to a manual batch record to be reviewed in the normal way. For most companies, compiling and reviewing batch records/device histories is still almost totally manual: A weighty paper document (or series of smaller documents) accompanies each batch of product as it moves through the manufacturing process. Operators or technicians sign the record to document compliance with defined process steps. They also record batch- or device-specific data such as material lot numbers, test results, equipment identifications, yield calculations, and count reconciliations (1). ILLUSTRATION BY CHRISTINA PRIER STEFFY USING PHOTO BY ROBERT KYLLO ( BENEFITS OF EBR Clearly, software can check accurately and efficiently for results within limits, omissions, correct sequences of events, calculation accuracy, and even equipment and materials status. Software that can interrogate data at the point of entry and perform such logic checks could dramatically improve RFT (right-first-time) performance. The automated continuous review inherent with an EBR can dramatically improve RFT performance, which would allow for a much more consistent and shorter release time, which in turn would allow stocks to be reduced and service levels to be improved (1). A properly constructed and implemented EBR system should be expected to significantly improve RFT performance; improve batchrelease lead-time; significantly reduce manufacturing errors, exceptions, and deviations; and lower the headcount associated with review and processing of deviations (1). Development Initiative: Cambrex has several API and biotechnology manufacturing sites. Most of them are served by a common enterprise resource planning (ERP) software package, which we ve validated to comply with cgmp and 21 CFR Part 11 regulations (2, 3). Some of the sites expressed interest in including an EBR in this process. Because our existing ERP software did not include an EBR, we initiated a development program to provide one to serve both API and biotechnology manufacturing. 24 BioProcess International APRIL 2005

2 The full text of any section of Title 21 of the US Code of Federal Regulations is available at fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm. Adapted from 21 CFR 211 Section 186 Master Production and Control Records must ensure uniformity from batch to batch and include each batch size. The records must be prepared, dated, and signed by one person and independently checked, dated, and signed by another person. They must be prepared according to a written procedure. The Master Production and Control Records shall include The name and strength of the product and a description of the dosage form. The name and weight or measure of each active ingredient per dosage unit or per unit of weight or measure of the drug product and a statement of the total weight or measure of any dosage unit. A complete list of components designated by names or codes sufficiently specific to indicate any special quality characteristics. An accurate statement of the weight or measure of each component, using the same weight system for each component. Reasonable variations may be permitted, however, in the amount of components necessary for the preparation in the dosage form, provided they are justified in the Master Production and Control Records. A statement concerning any calculated excess of component. A statement of theoretical weight or measure at appropriate phases of processing. A statement of theoretical yield, including the maximum and minimum percentages of theoretical yield beyond which investigation is required. A description of the drug product containers, closures, and packaging materials, including a specimen or copy of each label and all other labeling signed and dated by the person responsible for approval of such labeling. Complete manufacturing and control instructions, sampling and testing procedures, specifications, special notations, and precautions to be followed. Adapted from 21 CFR 211, Section 188 Batch Production and Control Records shall be prepared for each batch of drug product produced and shall include complete information relating to the production and control of each batch. These records shall include An accurate reproduction of the appropriate master production and control record, checked for accuracy, dated, and signed. APPLICABLE REGULATIONS Documentation that each significant step in the manufacture, processing, packaging, or holding of the batch was accomplished, including Dates Identity of individual major equipment and lines used Specific identification of each batch component or inprocess material used Weights and measures of components used in the course of processing In-process and laboratory control results Inspection of the dispensing, manufacturing, packaging, and labeling area before and after use A statement of the theoretical yield and a statement of the percentage of theoretical yield at appropriate phases of processing Complete labeling control records, including specimens or copies of all labeling used Description of drug product containers and closures Any sampling performed Identification of persons performing and directly supervising or checking each significant step in the operation Any investigation made Results of examinations made in accordance with those investigations. Adapted from 21 CFR 211, Section 192 All drug product production and control records, including those for packaging and labeling, shall be reviewed and approved by the quality control unit to determine compliance with all established, approved written procedures before a batch is released or distributed. Any unexplained discrepancy (including a percentage of theoretical yield exceeding the maximum or minimum percentages established in master production and control records) or the failure of a batch or any components to meet any of its specifications shall be thoroughly investigated, whether or not the batch has already been distributed. The investigation shall extend to other batches of the same drug product and other drug products that may be associated with the specific failure or discrepancy. A written record of the investigation shall be made and include the conclusions and follow-up. Adapted from Guidance for Industry, Part 11, Electronic Records, Electronic Signatures, Scope and Application, August 2003, prt11elect.pdf Production records may be in electronic format. Approved systems may use electronic signatures or electronically executed signatures. Procedures may be in electronic format. Dates may be recorded electronically. Data may be recorded electronically. Investigation records may be in electronic format. 26 BioProcess International APRIL 2005

3 What did we need in our EBR? We decided that it should contain all current ERP system functions and operate within the existing system be 21 CFR Part 11 compliant comply with 21 CFR , , and comply with other applicable predicate rules match the needs of our businesses be a complete set of instructions for manufacturing a batch of intermediate or finished product serve as documentation of the manufacturing process once complete support a validated manufacturing process. Process stages define the STEPS a process will go through and the RECIPES that can be used. Part 1 of this article discusses how our existing ERP software organizes data because we designed the EBR to work inside our existing system. Part 2 will describe the EBR system we developed. The first task of our development team was to determine what information should be included in the prototype. As one would expect, the sites were using traditional paper batch sheets. All plants are governed by a variety of predicate rules (21 CFR 210, 211, 610, 820; ICH Q7a, Q6b; and the European Directives). We first looked to 21 CFR 211 Sections 186, 188, and 192 for definitive help. We also checked other regulations where appropriate (see the Applicable Regulations box). Guidance for development of the Cambrex EBR focused mainly on the regulations and other commonly accepted cgmp practices. We were also guided by precepts from the ISA S88 guidelines for batch control (4 6). EXISTING ERP SOFTWARE FUNCTIONS Within our existing ERP system (irenaissance from Ross Systems, Inc., process specifications represent manufacturing s product formulations and equipment routings. It is each site s responsibility to ensure that process specifications realistically depict how a product is made. The process specification is the equivalent of the master production and control record discussed in 21 CFR 211 Section 186. A process specification is used for defining how products are made, standard costing, creating jobs, job costing and variance analysis, job scheduling and work-center loads, and yield reporting. Process specifications are created to deal with predetermined batch sizes. Depending on the validation, these quantities may be scaled up or down for varying job sizes. Each process specification includes one or more process stages: a generic, logical, or physical function in a production process. A recipe describes how one stage in a manufacturing process is completed: Each stage has an associated recipe. The recipes define the material inputs consumed; labor used; equipment used; miscellaneous costs, as applicable; quality control requirements (in-process testing and QC laboratory testing), as applicable; byproducts produced; and intermediate or finished products produced (including coproducts). Process stages define the steps a process will go through and the recipes that can be used. The valid recipes are, in turn, linked by the relationships of the stages in a process specification. Depending on the validation, an unlimited set of alternative recipes can be defined for each stage of a process specification. Our ERP system allows multiple resource inputs for each recipe. Each recipe can also include quality control information. Within a manufacturing job, users can record actual values and compare them with the standards for a recipe. If a recipe is modified, all process specifications containing stages linked to it are reactivated to check the validity of the recipes and stages. A recipe can be driven either from a given set of inputs or for a specific set of outputs. An inputdriven recipe (and hence process) assumes that at the time the process is begun the input quantities are known and the final outputs are not. An output-driven process assumes that the required output quantities are known and that, therefore, the inputs required for the process can be determined. Recipe Details: Each recipe contains a set of line records that identify the resources required or determine the outputs of the manufacturing process. Recipe line types are given values of one to five, which correspond to the following resource or output types. Material Input (Line Type 1, Source I or P) is used for any material input required for a recipe. This includes materials that come from inventory, work-in-progress inventory, purchasing, or a previous stage in the manufacturing process. Material Input (Line Type 1, Source C) is used for any comments or instruction input required for a recipe. Direct Labor (Line Type 2) is used for labor input directly traceable to the manufacturing process job in which a recipe is being used. The actual time and costs are recorded and included in costing the output products. Machine Input (Line Type 3) includes all inputs defined as machines. This may include items such as vessels, conveyor systems, pipe lines, or any other item of capital equipment used in a process that has time and related costs directly attributable to manufacturing a product. Machine records are essential to the operation of a manufacturing system and should be used to represent any capital equipment used and for which time/costs are scheduled, costed, or recorded. 28 BioProcess International APRIL 2005

4 Miscellaneous Costs (Line Type 4) include all costs not related to running a machine or labor resource and not regarded as material. They do, however, represent direct costs that can be measured and attributed to a manufacturing process. Examples include items such as subcontract or external processing costs (tolling) and clean-outs. Outputs (Line Type 5) represent all outputs from operation of a recipe. These include finished products destined for inventory, work inprogress inventory, or a customer and byproducts and processed outputs destined for the next stage in a manufacturing process. There is no limit to the number of output recipe lines. A flag on the line distinguishes byproducts from final products. All final products and interstage outputs are regarded as coproducts by the recipe. If a recipe is used in the final stage of a process specification, however, it cannot contain any interstage outputs. Output recipe lines also include a cost allocation percentage. It determines how the costs accumulated to that stage in the process specification are allocated among the outputs. Output(s) from a recipe have several destination types. Type S: An interstage output is assumed to be going to the next stage in the process. Interstage outputs exist only in transitory form. However, they are important because they form a link with recipe inputs when process specifications are defined. Type W: Work-in-progress inventory is assumed to be held on the work-in-progress inventory master. Type I: Inventory contains all items held by the warehouse. Type C: Direct to-customer items are assumed to go directly from the manufacturing system to an external party without passing through inventory or sales-order processing. Quality control details are test codes that identify tests to be performed when a recipe line is used in a job. One or more can be held against each recipe line or header. A quality control test defines a range of acceptable results and whether the results are numeric or text. Test codes are organized into test groups that, in turn, make up test specifications. Sampling instructions are outlined in specific test procedures. QC tests may be used to record in-process testing results and the characteristics of final products. The activation routine carries out all essential validation checks on the structure and network links within a process specification. Until it is done, a process specification cannot be used. The activation routine ensures that the link structure is valid. This includes ensuring that the process is not circular and that its structure begins and ends with valid recipes. checks all interstage inputs and outputs to ensure that they relate correctly, so no interstage products appear from nowhere or disappear without being accounted for in the next recipe. sets up all records used for costing and scheduling the process specification. validates that alternative recipes have the correct interstage inputs and outputs. ensures that the principal product is valid. ensures that process lines use consecutive machine and labor codes. Authorization of a process specification uses employee and department codes to determine which process specifications an employee is allowed to authorize. Each employee code is associated with a department, and each process specification that must be authorized has a list of departments required to authorize it. If sequencing is in use, the authorizing departments must authorize the process specification in a specific order. Job (Manufacturing) Functions: A job is regarded in the system as an identifiable production activity or batch of production. It is essentially a copy of the original process specification and recipes, appropriately scaled for the quantity of output requested by a user. It provides the basis for calculating standard production costs and recording actual costs and quantities, and it is the basis for the EBR and the batch production and control record. The activation routine carries out ALL essential validation checks on the structure and network links within a process specification. Once a job has been created, it must be ready released and then final released into production before input and output transactions can be recorded against it. Created jobs may use one or more of three available approval mechanisms. The EXEC approval is at job creation, enabling authorization by a party or parties before the job is ready released or final released. Full EXEC approval allows the job to go to final release. The MANUF approval authorizes the input of the job s material inputs. The users on the shop floor are prohibited from making any QC tests or from counting out any output products until their material inputs have been reviewed and approved. The SHIP approval authorizes dispatch of the product. Without this approval, users may not dispatch the product, do a warehouse transfer, or issue material to a job. This can also be used as the QA approval. Any or all of those approval mechanisms can be established at the process specification level, requiring enforcement at the job level. 30 BioProcess International APRIL 2005

5 Job creation allows users to manually create jobs. A user will be asked for material input quantities or material output quantities depending on whether the process specification entered as a basis for creating the job is input- or outputdriven. Jobs that have not been ready- or final-released can be amended, e.g., new input and output lines added, existing ones deleted, or quantities and run rates modified. The most common uses are to change the job start or end dates and to change the job output quantities. It can also change input materials and/or quantities, machine codes, and labor classes, and it can add or remove inputs and outputs. The main function of ready releasing a job is to update inventory quantities for the required materials and final output products: Quantity committed is increased for the materials required by a job, and quantity on order is increased for the output products. A job must be final released before any transactions can be recorded against it within the ERP system. We have modified the jobs creation program to allow for the creation of campaigns of like jobs. Local parameters allow campaigns to be created and specify the maximum number of jobs within a campaign. If a campaign is requested, the user is prompted with the standard batch size and asked to provide the total quantity to be produced. The system will then calculate the number of jobs needed for the campaign. The system gets the job cycle time from the recipes and allows users to amend the cycle time for the campaigned jobs. The system then creates the jobs for the campaign, allowing modification of the start times and dates. 21 CFR PART 11 COMPLIANCE Our ERP software has been modified to include all elements required for 21 CFR Part 11 compliance. The system can capture information required for field auditing, single and double electronic signatures, reports, and inquiries. These functions will also be used within the EBR. This was the system with which we started when we began to create a prototype EBR system. Part 2 of this article will describe in detail the system we developed. REFERENCES 1 Electronic Batch Records (EBR) in the Irish Medical Device and Pharmaceutical Sectors. BSM Ireland Ltd., Galway, Ireland, Summer Davenhall RR. A Case Study of ERP System Validation. BioProcess International, 3(1) 2005: Electronic Records; Electronic Signatures Code of Federal Regulations Part 11, Title ANSI/ISA Batch Control Part 1: Models and Terminology. American National Standards Institute and Instrumentation, Systems, and Automation Society, 5 ANSI/ISA Batch Control Part 2: Data structures and Guidelines for Languages. American National Standards Institute and Instrumentation, Systems, and Automation Society, org. 6 ANSI/ISA Batch Control Part 3: General and Site Recipe Models and Representation. American National Standards Institute and Instrumentation, Systems, and Automation Society, Ronald R. Davenhall is director of business process improvement at Cambrex Corporation, One Meadowlands Plaza, East Rutherford, NJ 07073; , fax ; ron.davenhall@cambrex.com. He holds an engineering degree from the US Merchant Marine Academy and has worked on computer systems and ERP system implementations since Headquartered in East Rutherford, NJ, Cambrex Corporation provides development an manufacturing services; chemical, biological, and cell-based active pharmaceutical ingredients; research products; and testing reagents and services.