I was pondering which of this month’s editorial “bullet points” I would discuss when an idea hit me. Why not just talk about them all? Namely, for me, Global Outsourcing Strategies, Clinical Trial Supplies, and HPAPI’s (high potency APIs) all work together. In fact, while I could zero in on any single topic, I believe they walk in unison. Much like the Ideal Gas Law, you cannot change one of the parts (P, V, T, or n) without affecting all the others. Just as with an object in motion, no matter how complex the movement, it can be described instantaneously by a simple  X, Y and Z graph. A macro example of this is that the Earth appears flat over a short distance, or completely if you are a cultist, so we lose perspective of the whole picture.

Similarly, most of us are so immersed in our jobs and lives, we only see “now,” “tomorrow,” and, maybe, “the day after tomorrow.” Yes, we may plan for months ahead for birthdays, vacations, etc., but, overall, we seldom look ahead decades in our professional disciplines. While “the future” seems far away, we are all chipping away at the present in unison, affecting the form that the future (next year?) will take. It is human nature to exist in our own silos and not notice what is happening next door until it knocks on, or knocks down, our front door.

More and more, the “big Pharma boys” are slowly and finally responding to the economic pressures of doing everything themselves. When we observe the progression of outsourcing from, say, 1970 through 2000, it went from a few cases within national boundaries to much of what we do with many thousands of miles between sources and sponsor(s). Seldom was long-range planning involved as much as walking along the buffet table, testing ideas willy-nilly. Get our heparin from China, using 1950s tests for drug identity and purity? Sure, why not? What could possibly go wrong?

So, at this point you might ask how all the topics work together. Simply put, we quote the basis of the nuclear arms treaty: “Trust, but verify.” Short of hiring and training tens of thousands of Agency inspectors and having at least one at every production and analytical facility in the world, there are some solutions between that and where we are today.

First, the high potency APIs have some unique properties that need be kept in mind. The amounts of API, simply due to the higher potency (HP), can cause mixing and analysis difficulties. The dosage form itself is probably small, think birth control tablets, and can have on-line measurement difficulties. Methods (HPLC) might have extraction difficulties, e.g., for Assay, where 10-20 tablets are ground and aliquots are weighed into flasks. If Content Uniformity is performed, individual tablets are assayed. Due to the amount of HPAPI, smaller amounts of solvent in order to keep concentrations within analysis limits are used and, with poorly soluble APIs, this could lead to varying levels of extraction.

On-line or near-line measurements, employing chemical imaging (CI), can help with homogeneity problems. Early imaging technologies were good, yet quite slow. As a reminder, CI produced a map of the material, mostly the surface, but can also see more of the internal structure, as well. The thousands of pixels, close to one or just a few particles within the tablet are displayed with their entire NIR spectrum. This 3-D data cube may be used to plot and quantify each component of a mixture: powder blend, tablet matrix, or capsule fill. The spectral plots produced are far better measures of amount and distribution than any traditional, wet method.

Some new on-line NIR equipment is capable of qualifying—density, API-ID, dissolution prediction—and quantifying—% API, capsule fill—up to 100,000 tablets/capsules per line per hour. With this level of control, a dosage form with a small level of active may be made and sold with great confidence. In normal NIR—transmission or reflection—the spectrum is an average of all the ingredients, wherein a trace level of API might not register well. In a CI approach, aided with push-broom and spatially-resolved spectra, thousands of smaller spectra are generated, where the API is a major component in several pixels, allowing an accurate determination, rapidly.

Many HP actives are also poorly soluble. This means the material needs to be in an amorphous form. The traditional batch process methodology for producing tablets can vary by quite a bit. Depending on the physical parameters, even in a PAT regulated program, varying amounts of blending and granulation, as well and varying levels depending on batch size can place varying stress—mechanical, heating—on the API. This warming can potentially transform the API into an even less soluble form, affecting in vivo therapeutic action.

When you remove the variabilities in a production line, you can more easily control the physical conditions experienced by the HPAPI. For example, in a continuous manufacturing suite, all the lots, no matter how many doses manufactured. That is, at any point of the production cycle—weighing, blending, granulating—the amount of material residing at any point is constant and the same for all batches, large or small. With monitors at every point of the process, the integrity of the API can be evaluated. As with the CI above, monitoring the bulk material mitigates smaller percentages of API, allowing continuous analysis at all points.

Now for the interesting part: tying all the points together. With massive numbers of contract organizations “hauling the water” for the large, but shrinking, Pharma companies, the supply chain refers to finished products and clinical supplies/tests, as well as “merely” API synthesis and raw material purchasing. Starting with contract labs/manufacturing/clinical groups (apropos to this magazine, no?), there seems to be a log-jam here. As large companies begin to universally embrace PAT, QbD, and CM, AND they also wish to use outsourcing more often, they are at a crossroad. They cannot produce more and more products via CM while the CMOs do not have or cannot afford the hardware, software and skillsets for CM.

Pfizer has a program where it makes “pre-fab” CM suites, loaded on trailers, delivered to its remote sites, validated, and run as if they were at the location where the product was developed. Clearly, the validation process for a suite that was already validated and merely moved is less arduous than constructing one and validating in place. This concept may clearly be expanded to CMOs and clinical trial sites.

In fact, using smaller, more easily modified processes for clinical work makes sense. If there is any question about varying dosage forms to give different blood levels and extended release performance, then smaller, more agile equipment makes perfect sense. Small batches with varying physical characteristics could be made in rapid order, without tearing down a process line, cleaning, and performing a cleaning validation. In addition, no matter how small a clinical batch, it can represent a “commercial-sized” batch as specified by the FDA for design-of-experiment studies, since a commercial sized batch is simply the CM suite run longer. Thus, the process parameters for a 10,000-tablet batch are identical with a 10,000,000-tablet batch.

As for supply chain problems, this “out-reach” CM program can aid with all of them, as explained by the following:

1. The overall product quality of “Product XYZ” will be the same, whether produced in Michigan or Manilla, since the same equipment, run under the same SOPs, using the same software controls will be producing the product.
2. The inevitable differences in excipients, used at remote locations, may be addressed easily. Since it is not commercially viable for excipients to be shipped from the U.S. to other countries, it is a better idea to use RM testing SOPs, developed for the parent company. These would include NIRS and Raman for qualification for the contents all containers at the warehouse step. This helps keep records for moisture, particle size, etc. for batch records where they are used.
3. The act of qualifying all incoming raw materials de facto also qualifies the suppliers of raw materials. Since there have been problems with relying on certificates of analysis from overseas suppliers, especially in developing countries, data generated by actual container-wise testing of incoming raw materials can help identify which suppliers are conforming to the date on CoA’s. This might lead to avoiding one or more suppliers.

Now, if you put all these topics together (HPAPIs, global outsourcing, and clinical trials), you can see that “homogenizing” the manner of production—CM, NIR and Raman monitoring, 100% raw materials qualified, etc.—will go a long way to obviating constant inspections, rejected lots and recalled lots, and 483’s, and assure customers and Agencies around the world that the quality and availability of the products will be constant and satisfactory.

As Henry Ford and all airlines found out, if you standardize parts, you save money and time, which equals money.

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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.