We have been discussing the effects of supply-chain difficulties even before the COVID-19 pandemic “nuked” the multi-country behemoth. While I’ve been concentrating on security (counterfeiting/substitution) and methodology to speed up production, I would now like to shine a light on consistency of product, from country to country.

There are two major sources of product quality/delivery time problems:

1. Multiple delivery points/sources. Timely deliveries of materials for just-in-time production were iffy, even before the pandemic disrupted transportation. Late or undelivered supplies can cause both delays and force a company to employ substitute raw materials to make delivery dates. These materials can come from non-qualified vendors for expediency’s sake.
2. Local quality variations. The majority of solid pharmaceutical dosage forms consist of multiple ingredients, namely bulking materials, disintegrants, lubricants and binders. Since each location within every country uses multiple suppliers, it’s difficult for a smaller (generic/CMO) to perform both qualification tests and make adjustments to the mixes to emulate the “ideal” formulation (a.k.a., PAT). So, even vetting a vendor for compliance with GMP, sterility, etc., there is no guarantee that the physical properties are all interchangeable in a process. And, most smaller companies don’t have the resources to do validation of products being made from disparate sources. Thus, the generic or CMO uses standard compendial testing in combination with a certificate of analysis from the vendor.

Some of my experiences of trusting incoming materials and relying on compendial tests immediately come to mind:

1. Caffeine, a component (although, for this product is not listed as an API) in our multi-API analgesic tablet. Caffeine was always a difficult ingredient to disperse evenly, even though the other three APIs were well blended. The vendor sold several grades as 80, 100 and 120 mesh, but, while doing a NIR particle size study, it was found that all mesh sizes were actually micronized and only clustered for mesh analysis by static electricity. [Ans: Sieving with the talc broke the charge and CU became quite good.]
2. As we were validating our newly-minted qualitative NIRS software (c. 1984; we were the beta site), we tested and failed a freshly accepted lot of sodium pentobarbital by our new equation. Upon visually inspecting the spectra, the slope of the spectra was seen to be almost flat vs. a 30-40° slope seen in granular samples. It also turned out to be micronized, not 100 mesh. But, the USP only requires “less than 1% is retained on the given screen.” So, it “passed” the compendial test.

With less than optimum tests being available, smaller companies rarely have the resources to do extensive analyses (external to USP, JP, EP, etc.), both chemical and physical, of every lot of every incoming material. This would be a good time to make a pitch for PAT/QbD and even continuous manufacturing, since all routinely test and make allowances for materials variations.

Fortunately, if you want to have consistent products but not spend large amounts of money on testing, it is convenient to have a reputable, multi-country third-party supplier who could do the up-front work of assessing and blending excipients and supply the blended base for a product. This would assure consistency over time and at all locations making similar products.

One solution to these problems came to my attention recently. I’ve been working with JRS Pharma, LP and their director of R&D, Tony Carpanzano, and he showed me one of their best-selling products, which I referred to as “Bisquick.” As I learned more about it, I saw it as one neat way to overcome country to country variability in finished products.

This “Bisquick” (called Prosolv EASYTab) is a co-processed composite made up of a binder, disintegrant, glidant and lubricant—the four basic components found in most immediate release tablets. Co-processing these components (typically by co-spray drying) imparts a tableting functionality that outperforms a physical blend of the component parts across measures of:

1. Flow
2. Homogeneity
3. Compactibility
4. Mechanical integrity
5. Tablet disintegration

The blend was developed to include these components in proportions that provide the most robust characteristics to the in-process blend as well as the finished dosage form. Tablets can be compressed after simply blending with the API. Being a co-processed composite, its composition remains unchanged even when subjected to high-shear mixing conditions that may be encountered in continuous processing applications.

Formulation
EASYtab provides greater compactibility, lower ejection force, and no impact on dissolution in the examples shown (Figures 1-3) for a 40% paracetamol formulation. A company’s generic or proprietary APIs can be blended with Prosolv EASYtab and the resulting blend compressed into tablets. In most cases, this means that the lubricant level does not have to be modified and, being a part of the composite, there is no danger of over-lubrication due to over-blending.




Clinical development
For companies looking at new drug entities (NDEs) that have completed toxicity studies and need to conduct preliminary evaluations in vivo before a final formulation is not yet defied, blending the new drug candidate with EASYtab is quick and simple. The dosage form contains only two ingredients, lessening the regulatory (QA) load, and where an analytical or clinical placebo is needed, the plain EASYtab contains everything within the active formulation except the API, at exactly the right proportions.  This also makes the perfect analytical placebo for conventional (wet, as in HPLC) methods development and, when carefully compacted, for spectroscopic methods, such as near-infrared.

Continuous processing applications
Achieving a satisfactory blend uniformity is essential for any tableting process, whether be it batch (cGMP) or continuous manufacturing. In continuous processes, blending is particularly demanding because dwell-times in the blender are limited (much shorter).  The ease of blending with Prosolv co-processed, high-functionality excipients and their unique surface structure, enable good homogeneity even for low dose APIs, via interactive blending. 

Using a multi-component composite significantly reduces the complexity of the continuous manufacturing process. It brings down the number of powder feeders from four to one and provides a continuous feed of exactly the same composition of excipient ingredients. This leads to consistent functional performance (blending, blend flow, compaction, and tablet characteristics). It also provides a means of delivering into the process ingredients that may not feed consistently, or at all individually, such as the lubricant or glidant. 

With respect to today’s supply chain
The co-processing of the components in Prosolv EASYtab capitalizes on the synergies of the ingredients and obviates variabilities that may otherwise show up as shortcomings in the performance of the single ingredients as sourced individually/locally. Ordering, receiving, quarantining, QC analysis, and release of what was four (or more) separate excipients needed for a formulation can now be reduced to just one.

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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.