Benefits of Risk-Based Validation: A Suite of Case Studies

Three companies, three stages of development, and one key strategy can benefit them all: risk-based validation.

By Moria Feighery-Ross, Pharmatech Associates

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Three companies, three stages of development, and one key strategy can benefit them all: risk-based validation. With it, all three companies will save time and money in their present stage of evolution; all three will have a stronger sense of the meaningful steps in their development and production processes and the ability to focus their future efforts and investments where it counts.

Risk-based validation is a validation philosophy in which qualification and validation processes are streamlined by an honest assessment of the risks to product quality (and/or identity, purity, potency and safety) posed by an equipment feature, process step, or process capability. For instance, a widely used commercial off-the-shelf software system is much less likely to contain unknown critical flaws than a custom coded automation routine upon initial installation. Risk-based validation provides a documentation framework to demonstrate that the qualification strategy for the commercial software was considered, and decided to be less risky and therefore to need less attention during the qualification or validation. 

The direct benefit of risk-based validation is that it provides the tools to make informed decisions about where—and why—to focus current validation activities. Even better, it provides the rationale and documentation to back up that decision to regulatory bodies. It is easy to see how this will benefit each of the following companies:

•Company A is a small, pre-clinical device company that has just acquired an existing facility to support a clinical production line. It is currently qualifying the facility’s existing features and will soon begin its first foray into process validation. 

•Company B is the mid-sized acquisition of an offshore company. It has built a new facility for its evolution from clinical to commercial production of a drug-device combination product. It is currently focused on qualifying the large, custom-built pieces of equipment that will anchor the production line.

•Company C is a mid-sized subsidiary of a large U.S, company. It is expanding and has built a large new facility to house its existing commercial production lines. Commissioning activities for the facility are completed and its focus is to determine the risk posed to the validated state of the process by picking it up and moving it elsewhere. 

Using risk-based validation, beginning with an assessment of what they have, and a well thought out User Requirements document describing what they need, Company A is gaining a highly detailed understanding of the benefits and drawbacks of its choices in process development. It is also saving money by using a process that results in both the validation of the important process steps and the documentation that will show regulatory bodies that all avenues have been explored and due consideration paid to the risks.

Company B benefits from its choice to use risk-based validation by decreasing the time required to qualify its shiny new production line and get to market. The newly built facility will continue to drain capital from the company until it makes its own, therefore minimizing delays is crucial to capturing shareholder confidence and market share.

Company C has probably the largest immediately visible benefit from its continuing use of risk-based validation. This is mostly because they are now reaping the benefit from previous uses of risk-based validation, as discussed in the next section, but is partially because some changes to equipment are being made to allow the company to continue production in its original location until the new facility is approved. The company uses risk-based validation to determine which of these changes merely requires minor revision to the procedures, and which need more substantial revalidation. Significant savings in time, effort and cost can be realized in this way.

The less-obvious benefit of risk-based validation comes later for all three companies, and although it is somewhat more difficult to predict precisely how it will manifest in a nebulous future, it is not hard to see that it will benefit. This value shows up when problems arise, or when processes evolve, or simply as the company grows its business. A risk-based validation system in place will aid a company in its response to those types of challenges, because the current process will have been thoroughly analyzed (see the Company C example). 

Company A will reap the rewards of risk-based validation when—for instance—it develops a new process step that allows it to streamline production. The company can easily determine what subsequent process steps may be affected by the implementation of the new step, what will need revalidation and, more importantly, what will not. It is quite frequently not necessary to revalidate the entire downstream process, and a company already well versed in risk-based validation will find it easy to determine the path forward at this point. Company A will save much of the time it takes to decide what to do, as well as the time and resources it would take to perform unnecessary revalidation activities. 

Company B, because it is scaling up from clinical to commercial production, may find that after the initial settling-in period of commercial production, the in-process reject rate is still higher than acceptable. The company is making good product and selling it to satisfied customers, but production is a little more wasteful than it should be and the bottom line can be improved. Review of the process Failure Modes and Effects Analysis (FMEA) that was created during initial validation will point troubleshooters toward those risks that were not fully mitigated at the time; one of these may be contributing to the problem and can be addressed to reduce the severity of its impact. In this case, the reward is time: less time spent chasing down the problem, and less rejected product leads to production goals quickly met.

Company C is reaping these future benefits now, from its previous use of risk-based validation. It has revisited its previous validation activities, and is able to successfully leverage effort and money already spent to reduce costs and man-hours required to validate the new production line. It is now easy for the company to determine which processes are now required to be validated due to regulatory changes and company policy evolution; reviewing the previous documentation will point the way.

Risk-based validation has immediate and future benefits that are easy to demonstrate for these three companies, but what about your company? Risk-based validation can aid a company in any phase of its lifecycle. Pre-clinical Company A is getting into formal validation earlier than many others. By choosing to build this strategy right into the foundation, this young upstart is giving itself an advantage by not allowing company culture to develop the all-too-common mindset of validation as a hassle imposed by outside forces, as well as the other benefits that follow to companies further ahead in their evolution. A company in clinical trials probably has the most to lose – and the most to gain – using the tools of risk-based validation, especially an honest, highly participatory and well followed-through FMEA, could make or break success at this time. 

Companies moving into commercial production, like Company B, will be able to use risk-based validation as a tool to shorten to-market timelines. Even more importantly, by assessing risks at each possible change during the scale-up and tech-transfer processes, such companies will be less likely to adopt process conditions that could negatively impact the final commercial process. Companies continuing commercial production, like Company C, benefit most by an increased ability to respond to changing conditions that affect product validation.
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