Is Three Still the Magic Number for Process Validation?

In January of this year, FDA published its new guidance for process validation, and drug manufacturers are still grappling with its implications. Until now, the industry has adhered to the tradition of producing three batches of product to validate its manufacturing processes. The new guidance does not prescribe any number of batches that is necessary for compliance, however. As a result, companies have been wondering how many batches they must produce to validate their processes.

But this might be the wrong question to ask. “The number of batches should not be considered as an acceptance criterion,” says Hal Baseman, COO of ValSource and coleader of the of Parenteral Drug Association’s process-validation interest group. “Instead, it should be considered as a means to acquire the samples and information needed to ensure process control.”

Unlike the 1987 guidance, the new document takes a life-cycle approach to validation and places great emphasis on data and statistical analysis. “You need to demonstrate statistically that you are in control and the process is working as it’s supposed to work,” says Steve Ostrove, president of Ostrove Associates.

Along with statistical analysis and the science of the process, an evaluation of risk to the patient will help manufacturers determine how many validation batches are required. Companies will have to determine which parts of the process entail risk and how great the risk is. Understanding the type of risk at issue is also crucial. “Is the risk patient death, or is it that somebody’s going to get an upset stomach?” asks Ostrove.

As in the past, the number of batches required to validate a process will depend on the company’s process understanding, as well as on the type and variability of the process. “Validation with fewer than three batches will require good statistical and scientific justification,” says John Krewer, global validation director of Catalent Pharma Solutions. “The less documented knowledge there is about a process, the greater the number of validation batches that will be required.”

The more time and effort a company invests into process design, the easier it will be to qualify and verify the process later on. “If a company develops a product following quality by design principles, there may be sufficient scientific justification for using three batches for validation, depending on the amount of data that is gathered during development,” says Margaret M. Szymczak, an independent pharmaceutical consultant and chair of the Product Quality Research Institute’s Manufacturing Technical Committee. Early in development, drugmakers should ask statisticians to design the experiments in a way that will increase confidence in the process, she adds.

“Another approach a company may take is to make three validation batches prospectively, review the data and release the lots for commercial use, then continue to manufacture validation batches concurrently until robustness is assured,” says Szymczak. At that point, the manufacturer could reduce the amount of testing it requires for release of the product. This approach could be used for products in low demand or those used for niche therapies.

Drug manufacturers have made progress toward understanding their critical process parameters (CPPs) and their products’ critical quality attributes, but work remains to be done. “A lot of companies, in my experience, develop the product, and then almost go into the process-validation part,” says Ostrove. “A lot of times what I see is that they don’t really understand the impact of their CPPs or why they’re controlling to these points,” he adds.

On the other hand, most firms are complying with the section of the guidance that relates to process qualification, according to Ostrove. And, by including a review of in-process testing in their annual product reviews (alongside a review of equipment, the production process, and process changes), many companies also are carrying out the continued process verification that the guidance recommends. Although manufacturers may still have unanswered questions about the new guidance, the industry at large is on its way toward gaining the process and product understanding that FDA has been recommending.