I have spent the last few columns dealing with the transfer of methods throughout a greatly extended supply chain. We discussed both assuring that methodology is standardized and performed properly by contracted CROs and CMOs and, of course, various venues within a corporation, from the next building to the next continent. After you have navigated the tricky and often murky waters of method/methodology transfer, we discussed whether the methods being transferred actually did what we expected, to give useful information, not just data.

It would appear that we are finally attempting to characterize the materials we place into a pharmaceutical process—beyond the archaic USP, etc. monographs—such that our PAT/QbD projects have a fighting chance to succeed. That is, we are measuring the morphology, crystallinity and particle size/density to assure proper blending and granulations for the QbD process. These data allow us to establish and maintain a proper design space for our operators to be able to modify the process to obtain quality products.

However, even the most diligent screening or characterization program is often still after-the-fact lab-based, using retain samples, and is designed to either use or reject an ingredient after it has been delivered and stored in the warehouse. While this vigilance is admirable, it begs the question of what do we do with materials we deem not suitable for our process yet not returned to the vendor? We could just dispose of them—something as inexpensive as lactose is no problem, but some drug substances are very, very expensive—or try to return them for credit.

Disposing of any material is a waste of money and, unless there is a preexisting agreement with a vendor, good luck trying to return a lot of raw material for credit. The not-so-secret secret is that most suppliers of excipients and APIs do not bend their production parameters to our needs for several reasons:

1. The pharma/biopharma industry may generate an awful lot of income, but they do it on a relatively low amount of raw materials. We are small potatoes in the line of customers who purchase these excipients.
2. Unfortunately, pharma companies are all paranoid. When a company formulates its dosage forms, despite all the reverse engineering tools available to generic competitors, they treat the excipients, APIs and their ratios and, of course, the mechanics themselves as state secrets, never to be discussed outside their walls.
3. Sadly, most pharma companies actually don’t know which parameters they want their APIs and excipients to possess. This is principally because the majority of pharma/biopharma companies do not have an active PAT or QbD/continuous manufacturing program in place.

Since it is never my intent to simply point out problems, I have some suggestions that might help. While I do not formulate or make solid dosage forms, I have observed and helped formulate, produce and analyze them for nearly five decades. I look at this situation an opportunity to advance PAT, QbD and continuous manufacturing.

This may seem like heresy to many of you, but why not include the suppliers in some of your PAT/QbD committee meetings or pre-formulation/formulation discussions? Not the ones that are about a new API manufacturing technique or financial considerations, but the ones with the formulators and production staff. You could simply refer to an API as the active and disclose a few details, such as the crystallinity, particle size, percent of formulation, hydration state and some processing traits, like shape and flowability. If and when the vendors are aware of what their excipients must do in a mixture, they can work with us, not just be a passive supplier supplying us with a take it or leave it attitude.

Just how would the new partnership work? Well, several changes could be instituted in the way we buy/specify materials. I previously stated that suppliers will favor the bigger spenders—food/confectioners—and the smaller volume buyers, such as pharma, gets what it gets. But, as the saying goes, money talks. So I will offer several suggestions for change:

1. If the originator, CMO/CRO or generic company spells out what is needed, for example, specific material specs, to produce a dosage form and the vendor has been privy to the formulators’ reasoning, the supplier can monitor their lots for ones having specs that the buyer wishes.
2. If the monitoring adds a cost to production, the buyer can agree to paying a premium for lots that are in the sweet spot of their QbD requirements for a working design space. These could either be deliberately produced—adjustments to the spray dryer for lactose—or, when the supplier does product QC to generate a certificate of analysis (CoA), he sets aside any batches that fulfill the desires of the company. Perhaps the company will need to purchase one or two extra batches per year, but that is preferable to a hit or miss purchasing program, as we have now, where lots are either returned or destroyed.

For this concept to work we will need a paradigm shift. Currently, by the time an established product is farmed out to a CMO or picked up by a generic house, there is almost zero desire to streamline the process. It is far simpler to assume that shipping the old process to a CMO in a country with lower labor costs is a good idea.

That may not work for long, due to the fact that wages and costs are rising in many developing countries. And, as my dad used to say, “What’s cheap is cheap.” He was speaking about food, furniture and tools, but it pertains to drug products as well. Making a tablet/capsule the way it was made 17 years ago is mostly like making an auto the way it was made 17 years ago. Personally, while I enjoy classic cars, I don’t want a 1999 Ford as a new car. I prefer more than 13 mpg in my car. Similarly, a dosage form, made by an old method, doesn’t get the best mileage.

When a company understands what makes the existing as well as new product shine, batch after batch, a number of things happen:

1. The CMO doesn’t need as long for process transfer. As with product scale-up, getting the new location or the full-sized batch up to speed could take a year or more, especially considering that the CMO will have a different supply chain, meaning different raw materials and APIs from the ones used to originally develop the product.
2. As hinted at in the above paragraph, the costs of production could fall low enough for the originator to continue selling the product under its own name. The difference is that the wholesale price could be dropped, making it competitive with generics. This could be permanent or a stopgap until your CMO is up to speed.
3. Lastly, generating a QbD for an existing product with tons of production and QC data will allow a company to practice for its newer products. In truth, most companies only have a few recipes for solid dosage forms, so understanding an older product will lead to having a step up on the next new formulation.

So it makes good business sense to detail your old car—existing product—before putting it out on the market—assigned to a CMO. You make a better product and make a few more dollars. 

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Emil W. Ciurczak
DoraMaxx Consulting

Emil W. Ciurczak has worked in the pharmaceutical industry since 1970 for companies that include Ciba-Geigy, Sandoz, Berlex, Merck, and Purdue Pharma, where he specialized in performing method development on most types of analytical equipment. In 1983, he introduced NIR spectroscopy to pharmaceutical applications, and is generally credited as one of the first to use process analytical technologies (PAT) in drug manufacturing and development.