proteinLC method for impurities_range and acuracy determintn

[Pradeep Iyer]

and please try and acknowledge the vast vast difference in a pharmaceutical analytical work and a biopharma analytical work!!!

[danko]

I don’t know where people draw the line between (simply) pharma and biopharma, quality wise, but I’m not completely convinced that there should be any quality rebate for either of the 2.
Why should people inject an inactive or directly harmful drug in their bodies, just because its bio origin? The reason for impure drugs is typically the low quality of purification processes. And this brings me directly to the chromatography part of the matter. Biopharma products are purified by chromatographic means and the typical process consists of a series of chromatographic purification steps (e.g. SEC, IEx, HIC etc.). So, if the manufacturers don’t cut corners (by utilizing lousy chrom. methods, or inadequate number of steps, or taking/keeping too much of the fractions of interest and thus some of the impurities that should’ve been removed etc.) there is no reason for users not to expect the obvious i.e. pure drugs.
That was the general considerations. More concrete, I would agree with HW Mueller that inadequate recovery, uncertainty caused by poor analytical chromatography etc. all adds to the final outcome – which ideally should be safe drugs.
With regards to following guidelines, registered specifications etc. there is always this big gab between what is done, why so and what could/should be done and why so.

Transferring the risk to the users/patients is bad science and self-indulgence.

Best Regards

[Uwe Neue]

We should be clear that the complete characterization of all components of a protein pharmaceutical is a must. This is even more true for protein biopharmaceuticals than for small molecules, but even in the case of small molecules, there have been cases of very serious errors. There is a famous case of the tryptophan produced in a fermentation process by a company outside the US that was contaminated with a tryptophan dimer, when a new strain of the producing bacteria was used. Over 30 people in the US died as a consequence. The analysts either did not see the problem or ignored it. The former is incompetence of the analysts, the second is irresponsibility. I am sure that you can find the details of the story on the internet.

So I would warn everybody in the analysis of complex products to not do such silly things, unless you want to spend the rest of your life in jail for manslaughter.

[Uwe Neue]

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[HW Mueller]

Uwe, it is difficult anymore, here, to find out who really makes the medication if the patent has run out - cost saving measures. I don´t know what a certificate of analysis is worth. A few years ago Kaiser, founder of the Bad Dürckheim chromatography Institute, fielded a stern warning at analytical chemisty and its regulators. With the type of encouragement to substitute assumption for knowing, seen many times recently, one can only hope that nobody oversees a hormonal disruptor, or whatever, in his pills. I consider ourselves to be extremely lucky that not more has happened. There have been other examples of "impurities" causing trouble. Still the known cases are relatively rare, but actually these can never be rare enough.

[Uwe Neue]

Hans: here are a few quotes from the findings of an apparently independent investigator:

From publications by Jos Hoogmartens:

1. Nelfinavir: Analysis of commercial samples. The Int. Ph. sets the limit for any individual impurity not to be more than 0.5% and the sum of impurities not to be more than 1.0% in bulk samples. Seven NFVM samples were analyzed for related substances and results obtained are summarized in Table 5. Sample 2 does not comply for the sum of impurities. All the impurities are expressed as NFVM, using a 0.5% dilution (10.0 _g/ml) of the examined sample.

2. Indinavir: Analysis of commercial samples. The Int. Ph. sets the limit for any individual impurity to be not more than 0.1% and the sum of the impurities to be not more than 0.5% in bulk samples. Six commercial samples of IDV were analyzed for related substances of IDV using the monograph method and results obtained are summarized in Table 8. All samples comply for the sum of impurities whereas samples No. 2, 3 and 6 do not comply for individual impurities. All impurities are expressed as IDV, using a 0.1% dilution (2.0_g/ml) of the examined sample as the reference.

3. Analysis of purity in 19 drug product tablets containing clopidogrel: 18 copies versus the original brand

A high level of impurities was found in many copies; over 60% of the copies contained more than four times the amount of hydrolysis product or R-enantiomer compared to the reference drug product. In addition, 50% of the samples did not comply with the 95–105% limits for content. It should be noted that there is no Pharmacopoeia monograph at the moment of writing this document that would set limits to the impurities and content in clopidogrel bulk substance.
Although most copies passed the dissolution specifications at 30 min, no adequate dissolution profiles were obtained for most of them. Differences in excipients led to different tablet masses and they also had an influence, together with the packaging of the
tablets, on the stability during 3 months under stress conditions. Most of the copies are not of equivalent quality compared to the innovator drug product.

[HW Mueller]

This is probably why the copies are cheaper (price). Now the situation, with which I am more familiar. is even much worse, namely the quality control in nuclear medicine. Here some semi-official TLC methods don´t work at all, it is impossible for them to work. The only thing here is that patients may get questionable stuff only once in a lifetime at usually exceedingly low levels.