Most excipients have been commonly used for more than fifty years and are still used today. There have been no major alterations made to the excipients specification over the years. There has been no debate about what would occur when our current excipients and/or their specifications are not sustained with the relevant requirements to ensure efficient medicines can be formulated, developed and manufactured on a regular basis. Change is happening.
WE are now in a new era, which consists of the arrival of combinatorial chemistry, high-throughput screening, recombinant technologies and along with better insights of proteins, drug receptor interactions, monoclonal antibodies. Also, we have very advanced tools which allow us to uncover very effective drugs. The innovation of excipients cannot adapt to the drug discovery developments.
Most excipients may be considered as inadequate regarding meeting certain industry requirements. Few excipients do not have satisfactory test methods in place to detect adulteration. This raises a few questions for regulatory agencies, as it is their duty to protect the public from contaminated medicines. Understanding of some excipients is too low to develop strong formulations for some drug molecules. The specifications are not strict enough to ensure that it can be used for the manufacturing of some drug products.
The pharmacopoeias have established more defined monograph specifications over the past few years. This was supported by the partnership of the Pharmacopoeial Discussion Group (PDG) to react to some of the controversies and adversities associated with the official substances (and food items) in recent years which consists of contaminated glycerine in Hati and other countries (ethylene glycol and diethylene glycol), contaminated heparin in Germany and the US (over-sulfated chondroitin sulfate), and contaminated milk in China (melamine). The FDA has requested the United States Pharmacopoeia-National Formulary (USP-NF) to modify all monographs, which consists of a particular identity test (id test) for every official substances, includes excipients. A priority list of excipients has been acknowledged, which does not involve a particular id. test and the analysis are not specific, thus leaving a substance which could easily be contaminated. The USP-NF Expert committees continue to investigate this matter further.
Biotechnology drug formulation (e.g. peptides, proteins and monoclonal antibodies). Biotechnology drug products formulation outlines various requests based on the interpretation and control of the composition of the required excipients.This represents various issues for the formulator (excipient user) and the excipient manufacturer. Excipient users require more information and stricter specifications for the elements involved in the excipient. The manufacturer must assess how to deliver this at an effective cost and without interfering with the excipients performance, which is required by their customers. It must be noted that most excipients are manufactured through continuous processing in large quantities. Pharmaceutical use may be below 10% of the manufacturer’s total output, and the implementation for parental products may be below 10% of the pharmaceutical use, which only requires a very small usage.
User’s requirements (preferred specification requirements) for excipients are applied in the formulation and manufacture of biotechnology drug products may be exceeding the proficiencies of the manufacturing stages and raw material sources. How can we address this evident impasse? It is determined by the excipient in question. A certain amount of excipients may be amenable to simple purification methods. Others may demand the purification of raw materials and reagents before synthesis occurs. However, others may request further safety measures to be carried out beyond the purified starting materials and reagents, for example preventing the formation of by-products, etc. All of these implications have additional financial cost. Biotechnology products usually have a very high price, due to excipients being expensive. The excipient cost per unit is decreased, due to the small quantities used per unit dose.
It is evident that new ideas are necessary for the use, tracking and procurement of excipients for the manufacture of bio-technology developed drug products. There is the possibility that there are particular (enhanced purity or super-refined) grades of some excipients, which should be examined. These grades would have decreased levels of concomitant components. On the other hand, it may mot be easy to develop and introduce to the market. Small quantities are necessary. It is not straightforward to implement this manufacture type on a manufacturing plant, which was constructed to produce ‘000’s of tonnes per annum. The enhanced purity grade may not be suitable for every user as the concurrent components available in the traditional grade may be required for excipient and/or product operations in other applications.
The pharmacopoeias issue should be taken into account. A segment of its existing aims of pharmacopoeia is to reinforce the monographs as it is predominately associated with the detection of adulteration. How do they integrate improved purity grades into a monograph for a specific material? Do these cases provide a potential opportunity?
Let’s take vegetable fixed oils for example. Fatty acid composition alone is not enough to determine contamination, however when it is integrated with sterol composition, they collaborate with one another. This improved purity grades will possibly have a changed fatty acid composition and a decreased content of sterols. Will the criteria of the amalgamated tests be enough to determine contaminated at an adequately low level?
The fixed oils may not be applicable to the formulation of the majority of biotechnology drug products, but fatty acids and related issues apply.
What is the ideal time-frame to wait before; they are applied in a pharmaceutical finished product? How do we integrate them into pharmacopoeias? Must a separate monograph be created or must we explore other options to integrate them into its existing monograph? The time has come for pharmaceutical and biopharmaceutical manufacturers to take excipients seriously.
A&C are at the forefront of custom excipients with full product documentation. The good news is that there are changes with the excipient marketplace. This shows how pharmaceuticals and biopharmaceuticals can reduce costs efficiently.
** This article is written by IPEC Americas. **