Overview of ASTM E2500

In 1998, the International Society for Pharmaceutical Engineering (ISPE) initiated an effort to develop its Commissioning and Qualification baseline guide to help manufacturers focus and prioritize their qualification efforts using this risk assessment tool. More recently, a task team was formed through ISPE, which worked with the American Society of Testing and Materials (ASTM) committee E55.03 on a new consensus-based standard. The standard (ASTM E2500) was voted upon and approved at the end of May 2007.

ASTM E2500 - “A Standard Guide for Specification, Design, and Verification of Pharmaceutical and Biopharmaceutical Manufacturing Systems and Equipment”

This standard applies to all elements of pharmaceutical and biopharmaceutical manufacturing capability; from the actual manufacturing systems, equipment, and automation systems, to manufacturing facilities, process equipment, process control, utilities and laboratory and information systems. It applies to new manufacturing systems and existing systems and equipment. The standard is applicable throughout the product life cycle, from concept to retirement.

Benefits of ASTM E2500 include reduced validation testing redundancy, leveraging start-up and installation testing, concentrating efforts on direct impact equipment and systems. This enables reduced project cost, less qualification paperwork, reduced qualification time and faster time-to-market.

Enable ASTM E2500 standards through ValGenesis

ValGenesis complements any existing framework and can be configured to match the risk-based qualification, or a hybrid of traditional and risk-based approaches. Adopting ValGenesis to implement ASTM E2500 standards helps to enforce policies and procedures for risk assessment and verification standards. In addition helping to enforce policies and procedures that are typically buried in procedures and policies documentation.  ValGenesis employs a number of modules and they help to implement ASTM E2500 standards, as described in the following process flow.

Risk-based Approach

The Planner Module (PM) provides a framework wherein verification requirements can be enforced based on the risk level. The PM also helps to enforce structured and disciplined steps and ensures control and compliance in the verification process by enforcing specification, design, operational and performance verification phases in sequence.

The PM supports a discrete verification approach. Several types of verification plans, with different risk levels, are combined to manage the complex requirements efficiently. This is an advantage for companies requiring different verification approaches with different risk levels, as they can incorporate combinations of entities, such as computerized systems, general laboratory systems and production systems. Different types of system can be categorized and further classified into sub-categories and various verification requirements with different risk levels can be enforced, as needed, for specific categories and subcategories.

This module provides the following features to enforce compliance and consistency in corporate qualification processes:

• Establishes the critical elements for any GxP system to be fully verified.
• Risk assessment with level of verification requirements can be managed and approved through configurable workflows.
• Enforces the compliance requirements.
• Approved plans are living documents for any entity until it is retired and will require revision when requirements change. Approved plans can be revised and again routed for approval as part of an effective verification process.
• Helps to create detailed, manageable verification projects based on the approved verification plans.
• Assists with the creation of a clear hierarchy of GxP systems to be verified, with appropriate phases and required protocols/deliverables with precedence requirements.
• Assists with the project summaries that can include project status, recommendations and test incidents.

Science-based Approach 

The reference function in ValGenesis provides links to product and process information including critical quality attributes (CQAs), critical process parameters (CPPs) and process control strategy information throughout the Life Cycle of the Verification Process.

Critical Aspects of Manufacturing Systems 

In ValGenesis, critical aspects of manufacturing systems are captured through collaboration in the Requirements Manager Module (RMM). This function allows users to remotely share their scientific and product understanding. Each aspect of the manufacturing system is maintained with Severity detectability and Likelihood of Occurrence, system takes care of dynamically calculating Risk class and Risk Priority number based on the predefined formula configured by the users. Any changes to the critical aspect of the manufacturing system will be subjected to subject matter expert’s (SME) review and approval.

Verification steps to test the critical aspect of manufacturing systems are documented in the Developer Module (DM) by designated SMEs.  Review and approval of the steps are accomplished in a collaborative manner, where each reviewer and approver in the approval workflow has the ability to comment and reroute to the initiator for revision. ValGenesis is equipped with controlled and configurable approval workflows and with serial and parallel approval options; this eliminates delays associated with paper-based approval workflows.

Quality by Design 

During the specification design process, critical aspects are captured, documented and approved by SMEs in the Requirements Manager Module.  The approved critical aspects of the design, and associated acceptance criteria, are linked and planned for a structured verification through a dynamically generated traceability matrix function.  The traceability matrix function provides one-to-many, many-to-one, plus forward and backward traceability features. When a change control is required for a critical aspect of the manufacturing process, this traceability functionality provides an accurate assessment of its impact by identifying related specifications, design elements, and verification steps. Traceability functions help to scope the regression testing clearly and accurately.

This trace matrix also assists in root-cause analysis. During verification testing, the deviations observed in the verification steps can be tracked and traced back to the associated design elements and specification, which helps to analyze the deviation impact, associated risks and required steps to rectify the impact.

Good Engineering Practice 

ValGenesis enforces Good Engineering Practice throughout the life cycle of GxP systems from planning to specification, design, verification, acceptance and maintenance. Documentation for the verification plan is created in the planner module and routed for review and approval to SMEs. Approved plans are living documents for GxP systems until they are retired, and will need revision when requirements change. Approved plans can be revised and again routed for approval as part of an effective plan. The Validation Planner Module within ValGenesis helps to enforce requirements for risk assessment, verification standards and procedures that are typically buried in SOPs and policies in the manual process.

In ValGenesis, critical aspects of manufacturing systems are captured in the Requirement Manager Module and verification steps associated with each parameter are documented and approved by SMEs in the Developer Module. Approved verifications steps of critical aspects of the manufacturing process are tested in the Executor Module electronically, achieving a 100% paperless verification process. Issues related to paper-based verification processes such as physically storing documents, manipulating executed documents, losing or misplacing executed test scripts, and scanning executed verification documents to an electronic format are completely eliminated with electronic execution. Executed verification documents are stored electronically in a secured central location for easy retrieval. In addition, ValGenesis improves communication between executors, reviewers and approvers of verification documents. Spelling mistakes and illegible data entries during the execution are totally eliminated.

One of the most important features of ValGenesis, and the executing of verification documents electronically, is the fact that it is fully compliant with FDA regulations. The user ID and date and time stamps are captured for each test case row individually. ValGenesis enforces accountability during the entire execution process, from task assignment to approvals. Screen shots, or any supporting documents, can be attached as hyperlinks at the test case row level. Any number of files can be attached with each test case row. These attachments are available during the review and approval process as hyperlinks.

Compliance requirements such as GxP, 21 CFR Part 11 and other industry standards and statutory requirements are tagged at the category, sub-category, or system level.  Required specification, design and installation activities to meet compliance requirements are enforced in the Planner Module in ValGenesis. The system will be available for production only after completing all these verification requirements. ValGenesis helps to automatically enforce these compliance requirements that are typically documented in procedures and policies in the manual process.

Life-Cycle Documentation

ValGenesis creates documented evidence for planning, specification, design, verification, installation, acceptance and maintenance by SMEs. SMEs can author, peer review, review and approve these life cycle documents in a collaborative manner. Approved life cycle documents are stored in the Library Module with adequate security to protect the integrity of the documents.

An appropriate degree of oversight and control

Because the evidence functionality is built into the system it closely follows a paper-based process and allows for a second user to sign-off, verifying the test results. The ability to adopt the evidence requirement is completely configurable by the system administrator at the protocol level and can be adopted for specific GxP entities and/or qualifications. A high degree of oversight and control is achieved by routing the specification, design, installation, operational and performance verification documents to peer review, review and approval through controlled workflows. Until all the required verification documents are approved by assigned and relevant SMEs, as reviewer and approver, the associated system can not be released for production.

Subject Matter Experts

Verification of manufacturing systems can be managed as projects. At the project level, relevant SME’s can be assigned to develop product and process information including critical quality attributes (CQAs), critical process parameters (CPPs) and process control strategy information, with prior production experience. The developed product and process information can then be routed to the relevant SMEs for review and approval requirements.

Use of Vendor Documentation

Vendor documents can be imported into ValGenesis through a simple import function. Justification and risk assessment to use vendor documents can be documented in the verification plan and project functions. The imported vendor document can be approved by SMEs and by a quality unit, through configurable approval workflows in ValGenesis. If the vendor documents are inadequate, relevant SMEs can update the vendor provided documents for additional verification checks, or to apply other controls, rather than repeating vendor activities and replicating vendor documentation.

Continuous Improvement Periodic Review Scheduler

Periodic review schedules can be created easily in the Scheduler Module. Responsible and relevant SME Groups are alerted of upcoming, or delayed, periodic review tasks automatically through the corporate email system. Each periodic review schedule created is highly configurable, allowing a SME to specify the due dates, frequency of the periodic review, grace period, alert notification, and approval workflow. Once a periodic review schedule has been created in the schedule, it is routed through a configurable approval workflow. Upon approval of the schedule it will automatically be written into the validation calendar.

ValGenesis eliminates the possibility of failing to meet the periodic review of critical GxP entities. Approval workflow improves the communication among various groups involved in the revalidation tasks, this minimizes the impact on production schedules, or other planned tasks.

Change Control Process

Change control is a foundation for the continuous improvement. Change control and validation are intertwined in order to achieve a completely closed-loop quality management process.  The change control module within ValGenesis can be configured to enforce risk based approach, while providing users with the flexibility to configure the change control process to meet their existing business processes.  Through ValGenesis change control process, users are not only able to manage the change control process but they are also able to see the document deliverables required as result of the change.  Required document deliverables are authored and executed within ValGenesis. At the time of final closure of the change request, all the impacted approved validation documents will be available for change request approvers to finally close the change control process.

Summary

The traditional validation activities have become centered around documentation, instead of ensuring quality. Current validation process requires a high degree of manual effort for tracking and reporting and the execution of most validation protocols takes place on paper. Traditional validation activities with paper- and manual-based validation processes stifle innovation, cause compliance risk and compromise a life science firm’s ability to bring products to the market on time.

The current resource intensive manual and/or hybrid validation process, coupled with the introduction of Risk-based validation approaches such as ASTM2500 and FDA’s Quality by Design initiatives make the adoption of electronic validation management systems inevitable.  Adopting ValGenesis to implement ASTM E2500 standards in the corporate validation process helps to enforce the risk-based approach, removes the inefficiencies that plague paper-based validation process and enforces polices and procedures for qualification processes that are typically buried in procedures and policies documents. In addition, ValGenesis helps to enforce consistency, enhances compliance and reduces the cycle time of the corporate validation process.