In this article, Hervé Sibillat, general manager, ADM-SIO, discusses the important considerations in managing the natural variability of plant-based pharmaceutical ingredients.
Sowing seeds
Variations in the composition and physicochemical properties of pharmaceutical ingredients can have a significant impact on the safety and performance of the final drug product. A failure to properly manage the process has been the root cause of several recent recalls by the US Food & Drug Administration (FDA). Indeed, ‘variability reduction’ is identified as a key objective of the ICH Q10 Pharmaceutical Quality System.
Meanwhile, manufacturers are continuing to innovate with active pharmaceutical ingredients (APIs) and excipients for pharmaceutical products. Highly purified, injectable-grade oils from vegetable origins, for instance, hold promise in applications ranging from large volume emulsions for parenteral nutrition, to use as excipients to address the solubilisation hurdles associated with lipophilic drugs.
However, the safety, quality and stability of vegetable oils is not easy to control. With the starting materials subject to diverse cultivation techniques, weather conditions and soil characteristics, a full risk assessment should always be carried out to identify the attributes that could impact the performance of the final dosage form. From material sourcing and categorisation, through to purification process design and stability studies, managing variability across the supply chain is critical to ensuring consistent plant-based pharmaceutical ingredients.
Starting with the source
ADM-SIO oil drops
Highly purified pharmaceutical oils are normally derived from either crude (solvent-extracted, such as soybean oil) or virgin oil (pressure-extracted, such as olive oil). Right from sourcing of the raw material, there are a number of product variability parameters to take into consideration when working with naturally-derived substances for use in pharmaceutical applications. Taking vegetable oils as an example again, the fatty acid composition is influenced by factors as challenging as sowing density, rainfall levels and soil structure. The way the crop is stored can also impact on quality, with poor conditions leading to the presence of mycotoxins, while an inappropriate drying environment may result in the formation of polycyclic aromatic hydrocarbons such as benzo(a)pyrene.
To guarantee a certain fatty acid profile, it is important to select a supplier that works with the correct crop cultivar. Limiting sourcing to some months of the year, nonetheless, can help to achieve characteristics including a specific UV absorbance. However, ensuring quality and consistency does not stop there. Systems need to be in place throughout the extraction and production processes to avoid issues such as cross-contamination.
Purification process design
When working with vegetable oils, potential contaminants include pesticides, heavy metals and residual solid particles — all of which could negatively impact the quality attributes of the refined product. Conversely, some compounds — such as tocopherols, the antioxidants that naturally occur in most vegetable oils — are beneficial and need to be preserved as much as possible during processing.
It is for this reason that — in line with a good manufacturing practice (GMP) approach — the starting material received from the supplier for purification should always be tested to identify the different substances present. A careful analysis of the vegetable oil at this stage also allows the purification process to be adjusted depending on the variability of each batch. In-process controls (IPC) and real-time monitoring can then be used to fine tune conditions and guarantee the best batch-to-batch consistency. Out of trend (OOT) stability results will also immediately identify any process deviation.
Alongside a knowledge of the critical product parameters, understanding the link to the process parameters is the key to minimising fluctuations in the quality of nature-based pharmaceutical ingredients. External contamination, for instance, can be avoided by conducting the purification steps in a closed environment with a high vacuum, which will remove residual oxygen and limit oxidation of the fatty acids. Nitrogen blanketing, meanwhile, can prevent oil oxidation and improve shelf life stability, while maintaining the optimal process temperature will help to avoid oil degradation and maintain the natural antioxidant content.
Completing the supply chain
Once the highly-purified vegetable oils have been produced, stability studies are essential to provide evidence of how the quality of an API or excipient varies with time. During storage and transport, performance can be influenced by environmental factors, such as temperature, humidity and light. Here, ICH Q1A gives useful guidance, for instance, it recommends that tests are conducted with pharmaceutical ingredients kept in storage conditions similar to the climate of the region where the final drug product will be shipped.
Process management is of critical importance in controlling the variability of naturally derived pharmaceutical ingredients. The major challenge for pharmaceutical laboratories is to carefully select suppliers that have the capacity to apply strict criteria throughout the sourcing, manufacturing and transportation of products.
As a global supplier of highly purified pharmaceutical oils, ADM-SIO, has a network of cGMP compliant manufacturing facilities, enabling it to implement full management of the natural variability of plant-based pharmaceutical ingredients across the value chain, including from the sourcing of the raw materials. Additionally, it is working with both the European and US Pharmacopoeias to establish new monographs and develop advanced analytical techniques, in particular for injectable oils.