Justin C. Iovino is the director of business development at CimQuest, Inc., 35 East Uwchlan Avenue, Exton, Pennsylvania 19341, USA. Tel. +1 610 363 0422 Fax +1 610 363 0422 iovino@cimquest.com

Justin C. Iovino

This article discusses an updated perspective concerning the issues to consider when implementing an electronic batch recording system, based on recent US Food and Drug Administration policy announcements regarding enforcement of the 21 CFR Part 11 regulation.

Paper batch records have been used for decades to record procedures, the type and quantity of each material used, and the status of each step in the manufacturing process for both pharmaceuticals and medical devices. Although paper batch records are less complicated to implement than their electronic counterparts, and the controls required for data recording and archival are well understood, a paper batch record system is laborious to maintain and prone to human error, which increases the compliance risk. Additionally, batch records have become bulky and more time consuming to prepare and review, particularly as manufacturing operations become increasingly complicated. Advances in technology and science have created a more competitive climate in life science industries than ever before, causing the need for manufacturers to reduce costs and time-to-market, and improve their ability to satisfy the compliance requirements of US Food and Drug Administration (FDA) regulations. The use of electronic batch recording systems (EBRS) and electronic batch records (EBR) offers one solution. 	

During the last several years, technological evolution has seen discrete instruments/control systems featuring paper batch records being replaced with computerized systems and custom information technology (IT) software applications, which are used in good manufacturing practice (GMP) areas. Examples include a spreadsheet to calculate in- process control (IPC) values and the use of enterprise resource planning (ERP) systems to manage master batch records or bills of material (BOMs).				

At the same time, there has also been a trend towards more complex business practices and the need to manage electronic data across many platforms and functional areas within an enterprise, such as process control, plant management, enterprise management and supply chain management systems. Manufacturing automation systems, for example, have increased in complexity to the point where a typical system now includes hardware, control logic software, human machine interface (HMI) for monitoring, and/or manual control of the process and data acquisition functionality. This situation has evolved such that a single batch record may contain data from hundreds of separate sources. (Figure 1).	

In many cases, batch records have evolved into "hybrid" records; that is, electronic data produced by computerized systems are being used to create paper records, which are then signed by hand. This fragmented form of GMP information increases the risk of non-compliance, does not significantly reduce the chance of error and increases batch record review times causing a delay in product release. To date, the results indicate that there is no real net gain, relative to traditional paper records, by applying IT in this way. What is needed is a way to consolidate and integrate fragmented GMP data to reduce the compliance risk, improve performance and increase profitability.		

Figure 1 Possible batch record data sources.	

Because computerized systems have become so prevalent, FDA has worked closely with industry to prepare guidelines and regulations governing electronic records and signatures. In 1997, it enacted 21 CFR Part 11 - a regulation that defines the criteria by which the agency will accept electronic records and electronic signatures in lieu of paper records and handwritten signatures when submitted or used to support submitted records, as required by existing predicate rules. All computerized systems that produce GMP relevant electronic data or records must comply with Part 11 requirements. 				

During February, in an effort to provide clarification for interpreting Part 11, FDA announced the withdrawal of all previous draft guidance, as well as its compliance policy guide regarding Part 11, and issued a single draft guidance for industry. The key elements of the new guidance are	

a more narrow focus of which records will be considered subject to Part 11

enforcement discretion regarding legacy systems.

Batch record data are integral to tracking and maintaining the quality, safety and efficacy of the product(s) and should be considered high risk. Therefore, all data contained in an EBR that are required by the predicate rules would be subject to the requirements of Part 11. It is unlikely that the good electronic data management methods defined in Part 11 will be modified by FDA. 	

Currently, the industry is faced with the challenge of integrating functionality between applications with seamless connectivity across many different platforms and consolidating fragmented GMP data, while complying with the regulatory requirements of Part 11. Implementing an EBRS is one way of meeting these challenges and there are many benefits by doing so.	

EBRS is not simply a documentation system; it also addresses issues related to the work flow of the operations being performed. Although this article focusses on manufacturing operations, the benefits derived from an automated electronic records system can be realized elsewhere in the product life cycle including research and development, and clinical trials.				

The process of producing batch records by implementing an EBRS and the benefits derived can be stated simply as automate, validate, reduce errors and streamline the review process. However, there are many factors to consider when implementing an EBRS. In addition to the business needs described earlier, consideration must be given whether to upgrade an existing system or install a new system (either to replace or to supplement the existing system), and the validation impact of the system architecture selected. User and functional requirements should be defined early in the project by a multidisciplinary team, which should include representatives from the quality assurance (QA), IT, validation and manufacturing departments.	

 Deciding whether to upgrade or replace a manufacturing automation system depends on whether the system architecture has a Part 11 compliant upgrade available. Although it may be more cost-effective to upgrade than to replace, not all legacy systems can be made Part 11 compliant.		

Figure 2 Required system architecture and data.	

Installation of a new process control system (PCS) that includes a supervisory control and data acquisition (SCADA) package could incorporate EBRS functionality. Although replacing an existing system with newer technology may provide a compliant solution, it may be more cost-effective to move the data and create the EBR on another platform such as a SCADA or manufacturing execution system (MES), particularly when the cost of validating the replacement system and the downtime required for installation are taken into consideration. In situations where a SCADA system already exists as part of the PCS, the EBRS functionality may be added, although an upgrade of the software is often required. Another solution is to incorporate the EBRS functionality into an MES system. In addition to providing production unit management and work order execution, this technology also has the ability to integrate data from ERP, electronic document management (EDMS) and laboratory information management (LIMS) systems. 	

The validation impact is reduced by the use of commercial off-the-shelf (COTS) products compared with custom-developed solutions because many of the standard functions must be tested by the vendor and are often considered validated or certified. However, application specific configurations or software customization will require additional validation. Although many new products claim to be Part 11 compliant, it is worth noting that compliance can only be achieved when the configured system has been properly installed, tested and appropriate procedures and policies regarding the configuration and system use are in place.	

Figure 2 shows a typical system architecture and the data required for a Part 11 compliant EBR. The database(s) should be designed with all of the requisite controls for electronic records such as secure time-stamped audit trials and authority checks to ensure only authorized individuals can access the system. Attributes that are inherent in manual paper-based recording systems must be designed into an EBRS. The issues that should be addressed when designing an EBRS are discussed below.				

 Converting from paper batch records to an EBR provides an opportunity to review record content and determine what can be eliminated. Frequently, paper batch records require the signature of the person who performs each task. If electronic data are obtained automatically, numerous manual entries, including those that verify entries by others, can be eliminated. During the requirements and design phases of the project, it should be decided whether to replicate the existing paper batch record in electronic form or to streamline the batch record.	

 Batch records contain many types of data that must be available throughout the entire retention period and, therefore, must be archived. This data includes raw data, entered data, calculations, signatures and metadata (that is, data contained in the EBR such as file name and date).	

Other design issues include where the archived data will be stored (for example, the local system, a centralized server or a data warehouse) and which medium will be used. Furthermore, the integrity of the archived data has to be maintained, and security issues such as system access and chain of custody must also be considered. Procedures will need to be developed that define the archival and retrieval functions.	

 There are many possible design solutions when implementing an EBRS. The network topology, the number of workstations, the number of servers (such as database server, application server and a server to interface with other applications) and the location of these components are critical to successful implementation. An important issue to consider when making these decisions is whether or not the infrastructure and the GMP relevant data it contains are secure. If the existing infrastructure is an "open system," then the proper controls, such as secured access to the data, document encryption and digital signature standards, must be in place.  The segment of the network containing the GMP batch data could be isolated through the use of routers or firewalls to protect against unauthorized access. Decisions regarding where the data are stored and how it came to be stored has a significant impact on validation because, previously, non-GMP systems that now contain GMP-relevant data must be qualified and some software applications may now require validation.	

 Assigning user access rights, and where they will be managed and applied are other considerations. Who needs access to the EBR?  Typically this includes production, supervision management, quality control (QC) and QA personnel. When these personnel require access to the record, the purpose for the access and the various access locations, such as a QC laboratory or QA office, must be identified and incorporated into the system. The status of the batch must be tracked within the system as well because batch status will change during various operational, review and approval steps.	

 Part 11 section 11.10 (b) states that "copies of (electronic) records must be retrievable in both human readable and electronic form." This presents issues not found with paper records. Design issues, such as which technology to use (for example, a PDF file); whether or not this technology would still be viable in the future during the record retention period; and whether to save the formatted report or recreate the report each time from the archived data.	

The elements of an EBRS fall into two categories: content and controls.				

 EBR content is generally defined within the predicate rules, 21 CFR Part 210 and 211 for pharma-ceutical manufactures, and 21 CFR Part 820 for medical device manufacturers. Additional requirements are defined by Part 11.	

Data/metadata. The type of data to be saved in the EBRS includes entries made into the batch record and the data required to support those entries. This includes raw data, such as process parameters; alarms/ events; IPC test data; entered data; and metadata, such as calibration data, file name and file date. One additional requirement is that all related data must be linked to the proper batch record. 	

 User identification and password are required to identify who performs each task within the system. Authentication, review or approval requires an electronic signature to include ID, password, printed name and the purpose of the signature. It should be noted that 21 CFR Part 820 requires signatures in nine places whereas 21 CFR Part 210 and 211 require signatures in only four places; however, company standard operating procedures (SOPs) may require additional signatures.	

 Controls are required to ensure security, integrity and trustworthiness of the data contained in the batch record, and operational system checks are required to enforce permitted sequencing of steps and events. When designing an EBRS the following must be considered:	

 The system should allow for secured access to individual data fields on a display screen for manual data entry. This means that access rights and privileges must be managed and applied at the data level. One feature that should be incorporated into the system is a "line out" capability for all data that are manually entered into the record. The system should provide a method to allow changes to incorrect data in a manner consistent with the audit trail requirements of Part 11 Section 11.10 (e). An optional "comment" field, or "reason code," linked to the entered data field could be used to provide an explanation for the change, thereby simplifying the review process. The system should also provide a mechanism for version tracking/control of such items as master data, SOPs and BOMs to ensure that only the current "approved" version of a document is used at the appropriate time and this information is then captured in the batch record. These documents may be managed in an EDMS or an ERP system that is interfaced with the ERBS. 	

Sequencing. How the manufacturing system responds at the end of each step, operation or input from a QC laboratory or QA function should be designed into the EBRS system, as must a method for tracking batch status. Changes in status (such as in-process, hold and release) that result from events such as a deviation, incident resolution or QA approval, also need to be captured in the batch record.	

 Unlike paper batch records, which can be carried from location to location, an EBRS must be designed to allow electronic signatures to be applied to the record at the appropriate time and location. If repeated signatures by one person are required this will also impact the design of the system. 	

Implementing an EBRS requires careful evaluation and assessment of current practices and will result in significant changes in the daily activities of manufacturing operations. However, there are many benefits to utilizing a properly designed EBRS: documentation errors will be reduced, missing entries are eliminated there is immediate notification of adverse results. These help to reduce the risk of non-compliance. In addition, efficiency will be improved by eliminating paper forms and reduced review times will lower costs, reduce cycle time and increase product throughput, thereby improving product delivery performance and profitability.	

Articles

Paper batch records have been used for decades to record procedures, the type and quantity of each material used, and the status of each step in the manufacturing process for both pharmaceuticals and medical devices. Although paper batch records are less complicated to implement than their electronic counterparts, and the controls required for data recording and archival are well understood, a paper batch record system is laborious to maintain and prone to human error, which increases the compliance risk. Additionally, batch records have become bulky and more time consuming to prepare and review, particularly as manufacturing operations become increasingly complicated. Advances in technology and science have created a more competitive climate in life science industries than ever before, causing the need for manufacturers to reduce costs and time-to-market, and improve their ability to satisfy the compliance requirements of US Food and Drug Administration (FDA) regulations. The use of electronic batch recording systems (EBRS) and electronic batch records (EBR) offers one solution.