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Electronic batch record systems (EBR) are increasingly commonplace in pharmaceutical and biotechnology manufacturing environments. EBR systems are used for the automation of the execution of a batch record; they can be interfaced with many different types of systems, equipment, and instruments. Control of the batch record use when manufacturing pharmaceutical and biotechnology products is a regulated process of critical importance to assure product quality and patient safety. Therefore, the implementation strategy, validation, and on-going control of EBR is of utmost significance and interest to regulatory authorities when they perform inspections of manufacturing facilities. This paper discusses current topics, considerations, and controls necessary for the implementation and validation of EBR.
Improvements and innovation in manufacturing execution systems through technological breakthroughs in system design have been critical to the development of systems that automate complex regulated processes in the industry. Automation of complex regulated processes provides efficiency, cost reduction, and increased compliance. EBR systems represent one example of these technological improvements, and they are capable of a high degree of integration with different types of systems and equipment, including both manufacturing automation equipment (e.g., distributed control system, programmable logic controllers) and business systems, such as enterprise resource planning systems. EBR systems provide critical functionality that help ensure a high-level of efficiency, consistency, and reproducibility. Because of these factors and the increased quality provided by EBR systems for pharmaceutical and biotechnology products, their use within these types of manufacturing environments is increasing.
During the implementation of EBR systems, project teams face many challenges that can have a negative impact on business and compliance. Some of these challenges are related to the attempts to automate an inefficient and cumbersome manual batch record process. A lack of understanding of the technology capabilities, limitations, and constraints of the batch record process may create unrealistic expectations by the system owner. Many times, EBR project teams lack the knowledge and understanding of the applicable regulatory requirements found in Code of Federal Regulations (CFR) Title 21 Part 11, 211.186, 211.188, and 211.192. These regulatory requirements are critical to implementation of EBR, and they need to be clearly understood to avoid compliance issues and unnecessary cost. The applicable regulations cannot be ignored or misinterpreted by the project team. These regulations need to be seen as critical user requirements that can be implemented by the technical team. Implementation best practices will be discussed later in this paper.
One of the main challenges for the validation team is having adequate time in the project schedule to test critical requirements that can have a negative impact on product safety and quality. It can be quite challenging if the technical team is also responsible for validation because they may lack the regulatory knowledge and understanding of the critical aspects of the system. Inadequate knowledge of the critical aspects may lead to the validation team excluding items that are critical to the manufacturing process and decisions made by the EBR system from the validation functions and calculations. These challenges can be avoided by having a solid validation strategy that is based on the results of risk assessments that were performed to identify and mitigate high-risk requirements. Qualified resources are needed as part of a project team, which must have both a solid technical and validation understanding of the applicable regulatory requirements. Validation best practices will be discussed later in this paper.
Implementation Best Practices
When implementing EBR systems, one of the major challenges is attempting to automate an inefficient and cumbersome manual process. Another challenge is managing the resistance from the users and system owners with regards to changing their current paper process before moving batch records to an electronic format. These challenges can have a negative impact on the implementation and expected return of investment (ROI) of the technology. It is strongly recommended that companies invest their time in redesigning their paper batch record to eliminate inefficiencies and unnecessary steps in the process that will add cost to the EBR implementation. Process-mapping activities should be performed to identify and eliminate waste prior to the EBR implementation. An assessment of the applicable regulatory requirements should be performed to ensure that all steps implemented in the redesigned process are compliant with regulatory expectations. Companies should avoid implementing requirements that exceed regulatory expectations because this could lead to an inefficient and expensive implementation that will have a negative impact on the ROI. Electronic record requirements related to data integrity, security, and user access are critical to the EBR implementation and validation. Electronic signature and audit trail requirements are critical, and they need to be addressed in the user requirement specification and verified during validation.
The following implementation best practices should be considered during the implementation of EBR systems in the pharmaceutical and biotechnology industry:
- Process-map current process
- Redesign paper process to eliminate waste and inefficiencies
- Perform assessment of applicable regulatory requirements and their impact to the process (21 CFR Part 11, 211.186, 211.188, 211.192)
- Identify key requirements based on the process redesign and assessment of applicable regulations
- Translate applicable regulatory expectations into user requirements.
The success of the implementation depends on assurance that inefficiencies and waste are eliminated before automating the batch record process. An accurate understanding of the regulatory requirements is needed to reduce the compliance and business risk.
Validation Best Practices
Validating EBR systems can be very challenging; it requires a solid validation strategy that is based on the results of functional risk assessments. These risk assessments are intended to identify and mitigate high-risk requirements that can have negative impacts on the system and product quality. Prior to the risk assessment being performed, the project team needs to identify and document critical user requirements. An assessment of the regulatory requirements applicable to batch records needs to be performed in order to identify critical requirements that must be implemented in the EBR system. The strategy needs to be documented in a validation plan. The validation plan should provide the following information:
- System Description
- Roles and Responsibilities
- Applicable Standard Operating Procedures
- Risk Management
- Validation Deliverables
- Validation Strategy
- Acceptance Criteria
Process-mapping and redesigning the current process provides input to the user requirements needed to implement the EBR system. Additional requirements will be identified as a result of comparing the assessment against the applicable regulatory requirements. Assessing the regulatory requirements found in 211.186, 211.188, and 211.192 helps to identify the requirements related to quality approvals of the batch record, when the identification of individuals is needed and the information is needed in the batch record. It is critical that all the regulatory expectations are translated accurately in the user requirements. Incorrect interpretations of the regulatory requirements can lead to increased compliance risk and implementation of inefficient controls that can have a negative impact on the batch record cycle times.
One of the biggest challenges during the implementation of EBR systems is understanding what is critical and any impact to the batch record process. Technical teams lack the understanding of the process and normally tend to downplay the impact on critical functions such as calculations. This creates a major challenge when the technical team is given the authority to determine the critical aspects of the system. Based on the author’s previous experience, technical teams will underemphasize the criticality of functions in order to reduce the validation effort and deliver the project according the schedule. It is very important that decisions about system critical functions and calculations include the system owner and users of the system. The system owner is the subject matter expert of the process and the most qualified member of the team to determine criticality. Decisions related to criticality should not be influenced by reducing the validation effort; they should be based on functional or requirement risk assessments. These risk assessments should assess the potential failure scenarios of the critical functions, including calculations that are used by the EBR system to make critical decisions about the batch. The entire batch records process workflow needs to be validated during performance qualification to ensure that all controls, required signatures, and approvals have been implemented. Performance qualification should include validation of the entire batch record process; including all functions, calculations, and approvals; to ensure that it meets user requirements. The bottom line is that an EBR system is high-risk; it has direct impact on the product, and a significant amount of its functions include calculations that are critical to the process and should be validated.
For an EBR implementation, the following validation deliverables should be considered:
- System Assessments
- Part 11 Applicability
- System Risk Assessment
- Direct/Indirect Assessment.
- Validation Plan
- User Requirements
- Functional Specifications
- Design Specifications
- Configuration Specifications
- Risk Assessments
- Validation Protocols
- Validation Summary Reports
- System Security and Access Controls.
System Operation and Maintenance
Once the validation is completed, the EBR system changes need to be managed under change control. Changes to functions, requirements, and design require a change control that is assessed by the appropriate SMEs, including the system owner and user groups. Changes to critical calculations should be managed under a change control or procedure that controls the lifecycle of formulas and calculations. Verifications or validation for changes to calculations should include verification that data is being pulled from the correct database locations. This should also include verification that calculated values are accurate and reported to the appropriate number of decimal places. This verification can be performed using test scripts or a protocol.
In addition to controlling changes to the system during the operational phase, procedures need to be established for backup and restore, incident and problem management, disaster recovery, periodic reviews, system security, and user access.
In summary, the considerations for validation of an EBR system are similar to any other computer system used in the industry. However, it is important to understand the process, critical aspects of the system, and the applicable regulatory requirements that will be automated with the EBR system. All of these critical aspects require a solid validation strategy that is based on the results of risk assessments that identify critical functions and calculations of the system. Downplaying the complexity, regulatory requirements, and risk can lead to an implementation that may increase compliance risk. The system complexity and the fact that the process is highly regulated require a significant amount of inspection readiness.