Pharmaceutical Validation: Solving the Problem or Merely Addressing the Issue?

Photo Credit: CoreDESIGN/Shuttestock.comIncognito focuses on a big challenge in regulated analytical chemistry laboratories.

To put the title another way—why suture the wound when you can stop the bleeding with a tourniquet?

Well that works fine until the tourniquet is removed!

I have so many conversations about separation issues that end up with the other person glazing over when I start to explore the actual cause of the problem, which is typically something to do with chemistry.

Frankly, so many of us are just interested in finding a fix for the problem we have right now, to get the results out of the door, and who cares if the method is flawed; I just need the results for this batch (and who cares about the poor sap who has to run this method the next time—because I’m going to avoid it like the plague).

With problematic chromatographic methods such as these, just releasing the batches where the quality controls (QCs) manage to squeeze through the acceptance criteria and repeating system suitability tests until they fall within the specification is not the answer. I’m aware that companies are tightening up on repeated system suitability testing and initiating investigations where out of specification (OOS) results are caused by poor repeatability (agreement) of QC samples, but show me a laboratory where methods don’t have to be “tuned” or “equilibrated” or “system flushes” inserted to get them to work, and I’ll show you a rare laboratory indeed. Further, “investigations”, “root cause analysis”, and “CAPA (corrective and preventative action)” analysis are fine—if you actually know something of the root causes, the fundamentals, and the first principles on which the techniques operate.

So many laboratory staff are chromatography users rather than chromatographers these days (1) and I wonder how many are able to identify the root cause of the problem in the chemistry of the separation, the susceptibility of the column chemistry, the poor design of the eluent system, the bad injection solvent, and the nonrobust nature of the eluent pH selected? How many of your recent investigations actually identified the root cause and implemented a truly preventative measure? I would suggest that where problems with the separation are concerned, if no chemistry is involved in the investigation, then the root cause probably hasn’t been addressed.

When I ask the glazed correspondent what the chemistry of the analyte is, the majority state that they have no idea. Therefore, they probably have little chance of really solving many of the issues we are having. How dispiriting! Perhaps ignorance leaves them blind to the futility of this situation.

The look of disappointment when I can’t suggest a “quick fix” involving a slight tweak to the operating conditions, a clever way to equilibrate or flush the column, or an “allowable adjustment” to help system suitability criteria to be met frightens me. Some analytical methods are old, some are poorly designed, and some should never have been properly validated. These methods need to be redesigned in order for them to work to the requirements of a modern regulated laboratory environment (and I’m not just talking about pharmaceutical laboratories by the way). I can’t give you a tourniquet and frankly you don’t know how to suture, and even if you did it appears they are too expensive.

So, your method is validated and registered, but this really doesn’t mean it’s any good. I can cite you many methods (particularly legacy methods using old column technology, ion pairing reagents, sacrificial bases) that made it to manufacturing process control or QC and are absolutely horrible. There are also methods using older technology (columns as well as instrumentation) that would be much more “fit for purpose” if they were updated to use new column technology, new instrumentation, and new detector technology with advanced settings.

I’ve heard a thousand times about the “totally prohibitive costs” to redevelop, revalidate, and reregister methods, which is a massive barrier to making a bad method better. Why are we in this position? Why should we live with poor methods because it costs so much to change them in highly regulated environments? Surely, we have just priced ourselves out of quality improvement? We need to address this issue, and it needn’t herald the loss of control and method “fiddling” that so concerns quality assurance (QA) departments and regulators—we need to start this debate and we need to start it now.

I also hear often that “Bob” (the chromatography expert who used to work in the laboratory but left, or got laid off, or transferred) did some work on this method “back in the day”, but no one can remember what it was that he did, or can remember what the problem was, but the issue seems to have appeared again. So, Bob is gone, you don’t know what he did to solve the problem, and the laboratory manager is pushing for results, and even they are of an age now that they may not have the depth of knowledge or experience in chromatographic science that would allow them to help. Your investigational analysis team has been outsourced to China or India and you need to get some release testing (raw material analysis, cleaning validation, stability analysis) done and there is literally no one that can help. I can see you reaching for the tourniquet as we speak. It’s not your fault. It’s a product of the situation in which we find ourselves: of increasing instrument complexity and inaccessibility, increasing regulatory burden, decreasing focus on analytical science in higher education, and an industry attitude that chromatography is a support service where button pushers produce data that allows us to release product. What a sorry state.

In summary, the issues with solving an ongoing analytical problem in a regulated laboratory environment include:

A huge amount of pressure to get the results out of the door;
A poor understanding of analyte and separation chemistry and the fundamental principles of chromatography, which is hampering any root cause analysis using first principles;
A prohibitively large cost barrier to redeveloping and reregistering methods and therefore little chance of properly addressing issues in the short term
The chromatography expert left and the investigational analysis team has been offshored because chromatography is now an ancillary service, which is almost fully industrialized, and therefore expensive experts are not required locally to support this function.

We are running out of tourniquets, no one knows how to suture, and to be honest, even the sticking plasters are a little thin on the ground.

What are we going to do about it?

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