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Today, ASTM standard E, Specification, Design, and Verification of Pharmaceutical and Bio-pharmaceutical Manufacturing Systems and Equipment, 1 elevates risk-based validation as a critical aspect of GMP manufacturing, based on managing risk in a structured approach to segment unit operations and leveraging engineering activities to reduce qualification risk as the process moves from asset acquisition to process implementation.
We describe the challenges inherent in good engineering practices GEPs that lead to what to consider in evaluating risk. By comparing the organizational structures based on the classic validation V-model and contrasting those with the framework for risk-based validation, it is possible to evaluate the pitfalls that would impede the successful implementation of ASTM E Finally, we will outline the business considerations for streamlining project execution in line with cGMPs.
Depending on where your organization is on the pendulum of risk tolerance, there are many benefits to adopting risk-based validation RBV and ASTM E within an overall validation strategy, as long as the organization is structured appropriately.
Risk is defined as the probability of occurrence of harm combined with the severity of that harm that affects all stakeholders. Stakeholders in this case can include the company itself, its shareholders, employees, regulatory bodies, and—most importantly—the public.
When we apply this concept to validation activities, a risk-based approach is intended to lower the overall risk in the overall validation strategy, not add risk to the process by reducing validation activities.
To reduce risk, three elements are essential: 1 the risk must be formally identified and quantified, 2 effective control measures can be implemented to reduce the risk to an acceptable level, and 3 validation can be performed to a level that is commensurate to the risk.
Historically, there has been a steady evolution toward integrating risk-based tools to increase the value and effectiveness of a validation program. The level of validation required could be determined, based on this assessment. However, it takes a significant effort to complete because all system features are validated, regardless of the cost or resources required to achieve a successfully validated system. Furthermore, if a change were to occur midway through the implementation, all relevant test and specification documentation would have to be updated to reflect the change.
As companies became more efficient and more risk-cognizant, RBV became a more attractive approach for streamlining validation activities. The goal of RBV is to use a risk management tool, such as failure mode and effects analysis FMEA , to evaluate the impact, likelihood, and detectability of a failure mode in order to establish the overall risk of each failure mode within a piece of equipment. Risk is then assessed using system impact assessments, where each functional requirement of the system is weighted and tested, based upon its potential impact on the product, process, or quality attributes.
This approach is contrary to the classical validation paradigm, where each functional requirement of the system would be tested equally. In fact, we initially saw this idea coming from the FDA when it introduced its Guidance on Process Validation, 5 which moved away from the prescriptive structure of IQ, OQ, and PQ traditionally used in validation strategies.
Instead, the FDA strongly recommends leveraging risk management principles and scientific understanding as a foundation for demonstrating equipment stability. These concepts drift away from the classic validation paradigm of incorporating repetitive, non-value-added checks and balances as part of the validation of a system.
When comparing a classical validation with an RBV approach, user and functional requirements for each system are generated. In the RBV approach, SIAs are also generated to evaluate and determine the level of validation testing required for each user and functional requirement. In classic validation, every requirement is tested with equal weight, while in a RBV or ASTM E approach, requirements are weighted and tested based upon their impact on the process and product.
With classical validation, a vendor is audited and the system evaluated on its capability to meet all user and functional requirements. By contrast, with a RBV or ASTM E approach, a vendor is audited to gain a high level of confidence that the system is able to meet all critical requirements.
There are some organizational considerations to evaluate first. Validation often has to provide justification on what is important to a system based on the results of the FMEA and SIA, serving as a bridge between engineering and QA. It is equally important that QA has a strong technical understanding of the process CQAs and constraints of the systems being qualified so they can more easily evaluate the rationale for not testing certain system functionality.
Not all system functionality will be validated if a particular feature of a system will not be used and this has been documented and agreed to by the internal stakeholders.
SMEs relied upon much earlier in the project not only for their technical understanding but also for overseeing the quality requirements required downstream. An ASTM E approach also requires engineering to have formalized procedures to manage quality activities.
For example, engineering procedures would be required for activities such as vendor technical assessments, construction inspection, instrumentation verification, and installation verification. Therefore, the typical good engineering practices GEPs frequently used would need to be formalized and used consistently.
However, its implementation does require planning and self-evaluation by organizations before taking the plunge. More time and effort of the SMEs will be required throughout the project life cycle to support critical decision-making. In the classical validation paradigm, SMEs are required at specific points in the project life cycle to provide their input and deliverables.
Once this was delivered, they often moved on to other responsibilities outside of the project. However, the ASTM E approach relies heavily on SME input in the requirements documentation through to the development of the verification plan and testing documentation. This greatly expands upon the role and responsibilities of engineering from the classic validation approach; a robust and adequately staffed engineering team is necessary to meet the needs within an ASTM E methodology.
Michele Levenson specializes in process, equipment, utility, facility, computer, automation validation, and project management in the biopharmaceutical, pharmaceutical, medical device, and diagnostic industries. Her areas of expertise include quality management systems, statistical analyses, process design, and process validation, spanning solid dose manufacturing delivery systems to aseptic biotech processes and drug delivery systems, leading commissioning and qualification mission critical projects for gene therapy, pharmaceutical, and biotechnology companies.
Get more pharma manufacturing insight with our FREE newsletter sign me up. Sign in or Sign-up. Guest Column May 10, By Michele Levenson, Pharmatech Associates Today, ASTM standard E, Specification, Design, and Verification of Pharmaceutical and Bio-pharmaceutical Manufacturing Systems and Equipment, 1 elevates risk-based validation as a critical aspect of GMP manufacturing, based on managing risk in a structured approach to segment unit operations and leveraging engineering activities to reduce qualification risk as the process moves from asset acquisition to process implementation.
Risk Management And Validation Depending on where your organization is on the pendulum of risk tolerance, there are many benefits to adopting risk-based validation RBV and ASTM E within an overall validation strategy, as long as the organization is structured appropriately.
Qualification Guideline ASTM E2500 revised
Techniques For Risk-Based Validation Using ASTM E2500