Urban Legends and Misconceptions

We tend to “fool” ourselves. I am overweight and, therefore, try to avoid mirrors. When I sit and watch football, I like to think I can still play (and I was born when Truman was president). Are these bad things to believe? No. They just make life more pleasant.

We also tend to go along with some ideas because someone who knows someone told him/her that he heard it from someone else. (For instance, “I heard that the XYZ instrument could/couldn’t do the ABC test at another location, so why bother asking about it or checking our facts?”) There are misconceptions and “urban legends” (ULs) that we encounter daily; we avoid seeing that the Emperor is only wearing his “Underoos.” We go along under truths that are true only because they have always been true. Confused?

Let’s start off easy. I recently discovered that assaying 10 tablets isn’t really doing a statistical sampling of a three-million-tablet batch! Stop the presses! This is news to… just about nobody who stops to think about it. Then why do we pass or fail huge, expensive lots of drug product based on such a minute sampling? I have some theories and would love someone to correct me (or quietly agree with me), if I am off center.

Main reason: cost of analysis. To perform a “square root of ‘N’ plus one” analysis would be astronomically expensive and time-consuming. The square root of one million is one thousand. To perform between one and two thousand HPLC assays for every batch produced would destroy a large portion of the batch, engage numerous analysts, take up many instruments, use up many liters of expensive solvent, and give us tank-cars of organic, flammable waste for disposal. For large, proprietary companies, there would be a major cut in profits; for generics, the cost could be deadly. In essence, this one requirement could eliminate generic companies and put the cost of pharmaceuticals beyond the reach of all but the wealthiest Americans.

Needless to say, PAT is slowly correcting this little oversight in a way that does not bankrupt anyone. Not only will batches pass, but will get better and better over time. The actual methodology used in PAT depends on many test points. However, the urban legend that 10 assays are sufficient makes a method using 10,000 points difficult to sell to management.

Another urban legend is contained in the “recovery” step in HPLC method development. We weigh out the active pharmaceutical ingredient (API) in increments from 50 to 150% of label content into volumetric flasks. Then, the excipients are added as per the manufacturing formula. Solvent is added and the flasks shaken or “sonicated.” Then the supernatant is filtered and assayed by HPLC. Spot the urban legend here? That merely pouring the powders into a flask is equivalent to making tablets from 50 to 150% of label and THEN extracting the API. We believe that the API was actually “recovered.”

This little urban legend haunted my group when we attempted to perform a NIR transmission assay of tablets. [1, 2]. The QA department insisted that we actually make tablets over the entire range bounded by HPLC limits. Since the tablets could not physically be made at the 50 and 150% range, we performed the analyses and pooled our results as an “assay” not content uniformity. Then, we were allowed to use 80-120% assay standards for the “range.”

Needless to say, these urban legends continue to haunt PAT. We hear that the FDA wants to monitor all our processes (without black helicopters, even), that they will make PAT mandatory, that they will take established products off the market (if they see inconsistencies through PAT), etc., etc., etc… When I spoke with people at a recent PAT meeting, they candidly stated that their own QA departments were the roadblocks to PAT, not anyone they met in FDA. [The job of QA is to be sure that a company does not deviate from cGMP; to quote Tevye (from “Fiddler on the Roof”), “tradition!” To some in QA, the paperwork is the product, not the tablets or capsules. It is more important to fill in all the spaces and run every test than it is to pass a batch.]

Does the FDA want to monitor our processes? I imagine they would love to limit site inspections through limited access to PAT (real-time) data. Do they wish to force it? I really don’t think they have plans for world domination. Will PAT become mandatory? Well, here I can’t say “no” with any certainty. The EPA tends to change limits as new equipment becomes available, so, maybe… Of course, from where I sit, I can’t understand why a company would want to take six months to make a batch of product, then either pass or fail it on limited tests. And, from a safety point of view, there could be strong arguments for PAT becoming the law and not a suggestion. In that case, it would make sense to get in position and gain experience while it is a suggestion (guidances are just that: suggestions).

In conclusion, I would STRONGLY recommend checking “common knowledge” for future determinations. Speaking to people is one way to avoid erroneous knowledge. The instrument manufacturers and FDA personnel are people, too. The vast majority are rooting for you to be successful. A successful industry means job security for both the Agency and instrument vendors. They are on your side; talk with them and don’t rely so much on “word of mouth” to make decisions.

References

1. E.W. Ciurczak, G. Ritchie, R. Roller, H. Mark, Cindy Tso, and S. MacDonald, “Validation of a NIR Transmission Spectroscopic Procedure, Part A: Validation Protocols,” J. Pharm. Biomed. Anal. 28(2), 251-260 (2002).

2. E.W. Ciurczak, G. Ritchie, R. Roller, H. Mark, Cindy Tso, and S. MacDonald, “Validation of a NIR Transmission Spectroscopic Procedure, Part B: Application to Alternate Content Uniformity and Release Assay Methods for Pharmaceutical Dosage Forms,” J. Pharm. Biomed. Anal. 29(1-2), 59-171 (2002).