Overcoming the Challenges of Phyto-API Supply

By Andrew Badrot, CEO C2 PHARMA

Phytochemical active pharmaceutical ingredients (APIs) come from plants, and each has unique properties and considerations f

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Phytochemical active pharmaceutical ingredients (APIs) come from plants, and each has unique properties and considerations for pharmacological use in humans. C2 PHARMA manufactures and distributes niche phytochemical and ophthalmic APIs with a focus on sustainable and reliable supply chains. Here, the supply of digoxin is overviewed.

Natural and Synthetic Phytochemical Considerations
Plants contain complex chemical substances that impart unique properties, such as resistance to attack by microbes and other predators. Many of these compounds are also pharmacologically active in humans, providing significant therapeutic effects. Indeed, many important active pharmaceutical ingredients (APIs) – such as the anti-cancer drug taxol – have originally been isolated from plants.
In some cases, such as for taxol, despite the complex structures of these small molecules, synthetic routes have been developed to manufacture them reliably. For others, however, synthesis is not practical.
The Digoxin Example
The heart disease treatment digoxin (a long series of saccharides with a wide range of functional groups), which is on the WHO essential medicines list,cannot be synthesized economically. This makes securing the supply chain challenging because phytochemical concentrations in plants are highly influenced by growing conditions like soil nutrients, temperature and moisture/humidity. Plants grown in different geographic locations on plantations that use diverse fertilization practices will have variable compositions of phytochemicals. If there are extended periods of unusual weather conditions like excessive drought or rain, there can be a large impact on the level of the phyto-API and similar compounds in the plant. 
Siting plantations in locations with ideal growing conditions and implementinggood agricultural and collection practices(GAcP)can help increase the production of the desired phyto-API. The timing of the harvest also affects the phyto-API and other compound content from batch to batch of plant material. Many batches are required because the concentrations of phyto-APIs in plants tend to be relatively low, requiring large amounts of dried plant material to produce measurable quantities of purified API.
Furthermore, extraction of the desired compound from dried plant material is often just the first step in the production of natural product APIs. In most cases, the desired compound is obtained along with numerous other phytochemicals, many of which have very similar structures. For a low-concentration phyto-API like digoxin, the concentration may be like that of the other compounds present in the extracted mixture.
Concentration Synergies
Within one plant, there can be multiple phytochemicals with a synergistic effect that results in more potent extracts. These structural analogs are considered in the design of the extraction and purification process, as is elimination of any phytochemicals that do not have a positive impact on the effectiveness of the end phyto-API. The need to retain select structural analogs and separate others can be complicated.
Due to its high toxicity, digoxin also poses additional problems and its production requires highly specialized expertise. Separation and purification are achieved via a series of extraction, concentration and recrystallization steps.
Manufacturing process parameters are also essential throughout each step of extracting and purifying digoxin to ensure maximum yields and quality and minimize variability.Final processing is crucial, as the appropriate particle size distribution must be achieved to ensure that each micro-dosed tablet of digoxin will dissolve evenly in the stomach.
Partnering for Redundancy for Reliability
In the past, shortages of digoxin occurredregularly due to a lack of focus by the incumbent manufacturer in both the manufacturing technology as well as in the supply reliability of the Digitalis lanata plant.Depending on the severity, a shortage could mean life-threatening consequences for patients that rely on them.
C2 PHARMA set out investments in both manufacturing and plantation of Digitalis lanatato create a redundant supply chain to overcome any risk of shortage. The plant is grown across various fields and locations in Europe adhering to stringent GAcP regulations and a dedicated state-of-the-art drying facility has also been built to handle optimal drying of the leaves. In parallel, a program has been pursued with one of Germany’s leading universities to continue breeding more productive varieties of Digitalis lanata.
A cutting-edge production facility was established in Vizag, India and is operated by contract manufacturing partner Laurus Labs. An alternativedigoxin product portfolio manufactured at a production facility in Poland was acquired from Nobilus Ent, which inherited its own digoxin manufacturing technologyfrom Roche/Galenus Mannheim; and the company remains a manufacturing partner and releasing entity for this API.C2 PHARMA also partners with logistics experts for the handling and of highly potent APIs and temperature-sensitive products, such as digoxin.
Both the Indian and European manufacturing sites for C2 PHARMA’s Digoxin API have been audited by regulatory authorities in the US, Europe, and Asia. While there are slight differences in impurity profiles in the digoxin products produced in India and Poland, both meet US and European Pharmacopeia specifications. Access to two sources of digoxin API with separate supply chains for the D lanata leaves enables C2 PHARMA to ensure a unique and redundant supplyfor this API.