My last blog focused on the industry trends concerning cleaning validation verification. Through a quick poll we found that out of twenty-three respondents, approximately fifty (50) percent are doing a standard protocol driven requalification of their cleaning circuits on frequency based intervals, approximately twenty (20) percent are doing some form of continuous monitoring of the process, and shockingly thirty (30) percent are doing nothing after initial cleaning performance qualifications. This week we will focus on the Agency Expectations and what makes practical, achievable and scientifically sound sense.
Knowing that some form of monitoring of the cleaning process effectiveness is an expectation, what does a manufacturer chose? The answer often becomes, whatever the regulators want, of course. There is safety in following the herd and not sticking one’s neck out too far such that greater scrutiny follows. And that mentality is generally regarded as safe, or is it? Certainly inspecting regulators are used to seeing a requalification program with frequency based protocols and justifications of worst-case soils and cleaning circuits. Some regulators have even been known to expect three runs per protocol much like the initial cleaning process qualification. Those expectations are based on the premise that the manufacturer is demonstrating control during the prior months and grants them a license to operate for the forthcoming months until a requalification protocol will again be written and executed with successful results. However, the 2011 FDA Guide on Process Validation, does not simply call for a periodic requalification, it clearly states that a “continual assurance that the process remains in a state of control” is the expectation. Furthermore, guidance states that “data should be statistically trended and reviewed by trained personnel.” If this data is only collected on an annual basis, it would take years or decades until a statistically significant data set would exist from which adverse trends could be spotted and proactively addressed. Although requalification and continued process verification are both called for by regulatory agencies, which delivers greater process knowledge, demonstration of control, and ensures the safest product?
Practical, achievable and scientifically sound sense
Annual requalification has been an element of many manufacturer’s cleaning program for years. So an argument can be made that they are certainly practical, achievable and scientifically sound. But are they? Does continuing to do annual requalification protocols execution of a single worst-case soil and circuit really constitute an industry best practice? When a requalification is done annually and only on one circuit, the expectation is that it is a representative of the other lesser challenging circuits and soils within that family group. But what happens if there is a cleaning failure during that annual, single run execution? Is that failure an isolated event or does it now call into question everything manufactured on that piece of equipment or manufacturing process train or the family grouping which that circuit represents? Moreover, the burden of protocol generation and in-field execution by validation or technical personnel is a costly endeavor which often requires staff augmentation and countless hours of deviation/non-conformance and product impact resolution when non acceptable results are found. If instead, manufacturing operations collected post cleaning samples or better yet process analytical technologies were employed to collect, analyze and confirm cleaning efficacy with each and every run, would the capacity of that data not speak volumes to the scientific acceptability of the equipment and process in terms of safety to proceed with the next manufacturing batch or campaign?
So what did my client end up choosing to demonstrate continued cleaning effectiveness? Well, let’s just say that being in the middle of the herd of requalifying manufacturers is no way to lead an industry best practice effort. Regressing from doing frequency based requalification efforts to doing nothing is not an option. So what is the future evolving towards? Continued process monitoring will provide a safer, less labor arduous, and more compliant program for this manufacturer who is willing to make that bold move, confident that the future is sparkling and bright.
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