Validation master planning for compliance and efficiency
Thoughtfully developing and implementing a VMP can enhance quality systems, simplify validation and verification processes, and support operational excellence.
Thomas Dzierozynski and Thomas Ciesliga
While a validation master plan (VMP) may not be specifically required by FDA, its use has become common practice in the medical device and diagnostic industries in defining objectives, methodologies, and a basis for product and process acceptance and summary. In the product life cycle, the VMP provides a structured approach to testing requirements that are defined during the design phase, and provides a means to document the rationale used to prove a product is acceptable based on its requirements and risk. The overall objective of a plan is to identify and set out the approach for validating products and manufacturing processes within a company’s quality system to ensure requirements for intended use are consistently met. To this end, a VMP will also define the approach for validation of equipment, processes, test methods, computerized systems, and facilities used to produce the commercial goods. (However, some companies are known to establish separate VMPs for certain activities; i.e., product, processes, test methods, and facility.)
The VMP is crucial from a quality and regulatory-compliance standpoint, and with input and buy-in from stakeholders, it can decrease the time it takes to bring a device through the design-control process to market introduction. A typical VMP (different from a site VMP) is written on a project-to-project basis and establishes roles, responsibilities and accountabilities of stakeholders and team members, project scope, prerequisites and activities, and criteria for acceptance.
When the plan is applied holistically, it can serve as a way to prioritize activities that have the greatest effect on speed of project execution, such as product-requirement definition, risk management, integration with quality systems (change control, document control, deviations, etc.), and review and approval for project phases and deliverables. This view and application of the VMP can also improve consistency of validation throughout an organization, bolster efficiency in application of best practices and continuous improvement, and build confidence for regulatory submission and inspection.
This article examines the importance of a VMP to manufacturers of IVDs in developing and delivering safe and effective products that are compliant and profitable. It provides specific points in the design of and approach to validation by incorporating key attributes of the quality system, such as risk management and change control, and providing a means to communicate activities and requirements to stakeholders.
Validation activities regarding medical devices and IVDs are performed throughout product development, design transfer, and commercialization as part of a company’s quality system to ensure that products meet their intended use, and that equipment, processes, and facilities consistently create a product meeting its predetermined specifications and quality attributes. Validation can no longer be seen in isolation and needs to be adapted to and imbedded in best practices as a means for a company to achieve regulatory compliance and financial benefit.
The overall philosophy and approach taken to validate products, processes, and facilities should be documented in a VMP and supported by validation procedures that define specific content and testing governance. This VMP is best developed as requirements are being defined to ensure requirement attributes are testable and measurable; provide traceability at the start; and establish activities, resources, and timelines for completion. In addition, as most manufacturers compete in a global marketplace, this plan needs to ensure that both domestic and international requirements are achieved through a harmonized approach.
More companies are employing engineering models and experimental design to provide scientifically sound and statistically valid data that not only validate requirements but also validate interactions between requirements. As a result, these models improve the robustness of testing and define boundaries and quality attributes of products. The use and application of these models need to be defined in the plan.
In addition, certain types of changes and improvements to an IVD product’s design are often avoided because of regulatory requirements and potentially excessive implementation time that includes validation. This is usually the result of a lack of clear understanding of validation requirements or a failure to apply risk management and traceability to requirements that result in the imposition of overly stringent validation processes. To a manufacturer of marketable devices, this avoidance carries with it significant cost considerations. Defining clear validation requirements and process removes the ambiguity of what is required to validate changes and improvements, and reduces the time to implement them.
The regulatory expectations for validation continue to mature as regulatory bodies apply more focus on a product’s safety and effectiveness from a user’s perspective. Requirements drawn from risk-management activities need to define the rigor of validation testing for products and processes, and regulatory bodies are expecting manufacturers to clearly define and present their cases in regulatory filings or with compliance issues for stating a product is safe and effective based on its intended use and quality attributes. In addition, regulatory bodies are also recognizing the use of consensus standards. The use of these standards needs to be based on their applicability to products and processes in consideration of intended use and requirements. How a company adopts these principles needs to be defined in the VMP.
Validation master planning should not be a burdensome process that imposes restrictions on a manufacturer’s ability to do business effectively. When validation is approached as a business process with a well-defined VMP, it can improve cost and compliance, improve speed to market, limit risk, and achieve harmonization across products and international requirements and practices.
The content and detail that goes into a VMP will depend on the product, equipment, processes, facility, or project for which the plan is written. At a minimum, a VMP will include the following sections.
Introduction and scope. A description of the facility and manufactured products whose validation requirements are defined under the plan. For new products or facilities, a clear definition of what is not included is recommended.
Roles, responsibilities, and accountabilities. A definition of the roles and responsibilities of department and project core team members, and delineation of who is accountable for decisions and deliverables.
Description. A definition of products, processes, and facilities within the scope of the plan, and a description of each.
Validation strategy. A provision of strategy for how equipment, products and processes, and facilities will be validated, and a rationale for each strategy—especially for instances in which no validation will be performed. A definition of test methods, test coverage, tools and techniques, statistical techniques, and use of compliance standards should be included.
Validation deliverables. For a facility that is manufacturing marketable devices, this section may include all validation activities that have currently been performed, as well as a schedule of planned activities. For new facilities or projects, this section should include all of the deliverables that are required by the validation strategy. These could be both verification and validation activities for equipment, facilities, processes, test methods, etc.
Criteria for acceptance. A definition of the criteria that must be met to consider the product, process, or facility within the scope of the plan validated and fit for its intended use.
Validation governance. The VMP should reference or contain aspects of how the effort will maintain configuration management, traceability, modifications to plan, entry criteria to testing, retesting, data collection, and issue reporting and resolution.
Plan closeout and turnover. The final element to a validation plan is the closeout and turnover. This verifies that all criteria have been met and that the plan is suitable for turnover to the end user. A definition of the review and approval that is required at each phase or for each deliverable of a project—not just the final VMP requirements—should be included.
VMP: Product Development
Verification and validation are required activities under 21 C.F.R. 820.30(f)(g) during the product development life cycle. They are based on requirements, design, and intended uses. Design validation shall confirm through the provision of objective evidence that the physical, functional, and performance product requirements, intended uses, and user needs can be consistently fulfilled. A VMP for a product should address the following:
Traceability to inputs:
Use cases and scenarios
Warnings and instructions for use
The validation-testing approach:
Definition of production-equivalent device
Regression testing: Selective retesting of a system or component to verify that modifications have not caused unintended effects and that the system or component still complies with its specified requirements under IEEE 90.
Human factors and usability testing: Usability studies, which include workflow and user interface under the context of the actual use conditions, are conducted
Safety assurance testing and dependability: Detailed arguments and reasoning that justify claims about the safety integrity of a given system
Links to clinical testing
VMP: Equipment, Process, and Facilities
The equipment, processes, and facilities that manufacture products require validation, and the VMP must address the approach taken.
Validation of equipment and faculties shall provide evidence that equipment is installed per user requirements, consistently and properly operates through functional requirements, and performs within defined operating ranges. Equipment validation should address the following actions.
Identification—equipment and components are identified appropriately
Inspection and installation—verification against drawings and specifications
Configuration—equipment, machines, and controls configuration are per specifications
Utilities—required utilities are supplied per specifications
Environmental requirement—appropriate for equipment and components
Product contact materials—compatible with product
Facility finishes—meet room-classification requirements
Calibration—for critical instruments
Normal operation testing—verification against functional requirements
Alarms, safety devices, and interlocks
System failure and recovery
Spare parts and preventive-maintenance programs
Testing under anticipated production conditions
Assurance production of product that will meet requirements
Facilities meet temperature, humidity, differential pressure requirements
Facilities meet environmental requirement
Process validation, which is required by the medical device QSR in 21 CFR § 820.75, must demonstrate that a process will consistently result in a product meeting designed quality characteristics. These studies should be performed under normal operating conditions using approved procedures or work instructions by trained operators. This is the final activity that provides documented verification that a finished product can consistently be produced meeting all specifications and required characteristics.
Quality Systems and Regulatory Pathways
Quality systems elements that, when defined in the VMP, can support cost, compliance, and time to market include the following.
Risk management (ISO 14971). Define a process that identifies hazards associated with the device in order to estimate and evaluate risk, control the risks, and monitor the controls effectiveness. This applies through all stages of the medical device life cycle.
Design control. Reference existing design control procedures that are used throughout the design and development process, and define any changes to those procedures that might be followed. This applies to new, modified, or improved devices as well as manufacturing processes, and should cover the entire life of a device. Design control does not end when production of a device starts. The process should cover design input, design output, design review, design verification, design validation, design transfer, design changes, and the design history file (DHF).
Integration with quality systems. Define how validation is integrated in to quality systems such as records control, document control, change control, production and process controls, and equipment and facility control. Show how and when during the life cycle these controls and systems will be implemented, as well as any departures from procedures.
Premarket submission and registration requirements. Define requirements that must be met for premarket submissions or registration requirements, and explain how these will be met. Also state review and approval requirements for project phases and deliverables.
Continuous improvement. Describe continuous improvement processes that are in place and how validation will be performed.
Benefits of a VMP for IVDs
Following this approach for developing and implementing a VMP offers IVD manufacturers numerous benefits. For example, from a quality and compliance standpoint, a VMP can present documented evidence that a manufacturer’s validation process is under control and follows a well-defined strategy and that it should benefit the company during an FDA or quality system inspection (such as ISO: 13485 or ISO: 9001). The VMP can also advance business efficiency by improving productivity and preventing potential process and product failures.
A VMP should result in simplification and standardization of validation and verification processes. By clearly defining validation strategy and requirements and defining how risk management will be implemented, a manufacturer’s validation process should become more simple.
A VMP should also help support operational excellence. By applying a plan holistically, that plan will define up front how the validation process is integrated into the quality system, how risk management will be applied, and how validation of continuous improvement will be handled. It also defines how validation will be performed throughout the project life cycle and through regulatory submissions and other phased approval.
By implementing the approach outlined here, a manufacturer should see the benefits described along with the most significant benefit: improved cost of quality. For an IVD manufacturer, the cost of quality is not just creating a quality product, which can result in scrap, rework, repeated inspections, and repeated tests. It can also be the time cost of taking a device from definition of requirements to market. The dollar cost of creating a poor-quality product will vary; however, in almost all cases, it is safe to assume that spending the time up front to implement a VMP will cost far less in the long run.
In summary, the need for a VMP is not specifically noted in any FDA regulations; however, its use has become common practice in the medical device and diagnostic industries for demonstrating that the validation process is under control. The overall objective of a plan is to identify and set out the philosophy for how products, processes, and facilities will be validated within the quality system to ensure the requirements for intended uses are consistently met. The VMP’s benefit has been demonstrated in driving a structured approach in product development, verification and validation, and manufacturing efforts, and in providing a means to document rationale for validation decisions.
When applied holistically, a VMP will simplify and standardize validation processes, facilitate continuous improvement and operational excellence, ensure smooth integration into quality systems, support design control and the device life cycle, and improve the overall cost of quality.