Co-Processed Excipients

In some sections of the pharmaceutical industry, there appears to be a conflict between the advantages co-processed excipients can bring and the perceived increased regulatory burden they could cause. 

Co-processed excipients are defined by the International Pharmaceutical Excipients Council of the Americas Coprocessed Excipient Guide (2017) as “a combination of two or more compendial or non-compendial excipients designed to physically modify their properties in a manner not achievable by simple physical mixing, and without significant chemical change.” These combinations can improve functionality over simple blends of the individual excipients’ components. This improved functionality may relate to drug product manufacture and/or in vitro or in vivo drug product performance. 

But despite the proven advantages of co-processed excipients, parts of the pharmaceutical industry remain reluctant to embrace co-processing, in part because of an ill-informed perception that use of a co-processed excipient increases the regulatory risk, and that the regulatory authorities will demand extra safety testing. Co-processed excipients have been around for many years. One of the first—designed for oral solid dosage forms—was Ludipress® (BASF), in 1985. Silicified microcrystalline cellulose was launched in 1996. In the past 25 years, the number of co-processed materials and grades has increased significantly. 

In some instances, the use of co-processed excipients has improved the robustness of the finished product and reduced the incidence of product failure. For example, in one tablet formulation of a poorly compactible bulk active (API), each batch had to be inspected for damaged tablets, and the amount of damaged, rejected tablets was around 15–20%. Using a co-processed excipient, which was comprised of excipients already in the formulation, eliminated the damaged tablets by improving the compactibility of the formulation. The manufacturer was then able to eliminate the manual inspection, and thus reduce costs. More importantly, the formulation and process were more robust. There are also examples from the nutraceutical sector, where using co-processed excipients has led to more robust tablet formulations of high dose, poorly compactible nutritional supplements using lower amounts of excipients, thus making for more patient-friendly smaller tablets. 

With the increased interest in continuous manufacturing of pharmaceutical finished products—particularly for oral solid dosage forms—there has been a move to limit the number of components because of limitations in the number of excipients that can be fed into the continuous manufacturing equipment trains at any one time. In my opinion, this, in turn, has led to an increase in overly simplified formulations. 

“Things should be kept as simple as possible, but not simpler.” (Einstein ca. 1950 quoted in NY Times) 

This quotation from Prof. Einstein is relevant to the discussion of continuous manufacturing. If we oversimplify formulations, we run the risk of failure due to unanticipated changes (special cause variation). For example, some years ago, one tablet product on the market had a very simple formulation: drug, microcrystalline cellulose and magnesium stearate that was manufactured by direct compression. After its commercial launch, there was an unanticipated change in polymorphic form of the drug to a more stable form, which led to dissolution failures. The company was unable to manufacture the original polymorphic form. What to do? Fortunately, a higher-strength version existed. Because of its larger tablet size, this version had less microcrystalline cellulose, but included a superdisintegrant. This product did not result in dissolution failures after the change in the polymorphic form of the active drug. The lesson? For immediate-release oral solid dosage forms, relying on the relatively weak disintegrant properties of microcrystalline cellulose can be problematic, and a recognized disintegrant should always be included in the formulation, regardless of the processing method.

If formulation and process robustness are not sufficiently accounted for in the development of products and processes for continuous manufacturing, the benefits of continuous manufacturing may not be realized, because of increased failures to meet specifications. The restriction on the number of material feed hoppers in a given manufacturing train can be problematic; it limits the number of materials that can be fed into the equipment train at any one time. 

One solution? Include a pre-blending step, which would allow for extra feeding systems. However, this means integrating at least one extra unit process and associated feeders. That would increase capital and development costs. 

For an oral solid dosage form continuous manufacturing line, an alternative could be to use a co-processed excipient, such as a co-processed combination of a filler and superdisintegrant, or a combination of a filler, superdisintegrant, and compaction enhancement. This would require fewer material feeders for the drug product manufacturing process, and thus allow for a simpler manufacturing equipment train. There are grades of coprocessed excipients available comprising such combinations of materials for both pharmaceutical and nutraceutical use. 

Some think that the FDA will require extra safety testing for co-processed excipients, according to their 2005 Guidance on nonclinical testing of new excipients, because of the risk of formation of new co-valent compounds. This is not correct! It is possible to demonstrate the absence of a new covalently bonded material using a battery of analytical techniques. This was demonstrated by Tobyn et al. (1998) for silicified microcrystalline cellulose. This general approach could be adapted as necessary and used for other co-processed excipients to demonstrate the absence of novel covalently bonded entities after co-processing. This, in turn, would allow bridging to the safety data, and/or history of safe use, for the component excipients in the co-processed excipient, which would save considerable expense and time. 

Another regulatory issue has arisen in Europe. Some regulators believe that co-processing circumvents current good manufacturing practices (cGMPs). It can be argued that such thinking runs contrary to the European regulations. The European Falsified Medicines Directive (FMD) brought excipients under the auspices of the European medicines’ regulations, and included a requirement that the drug product manufacturer undertake a formalized risk assessment on the appropriateness of the good manufacturing practices applied to the manufacture of their excipients. A Guideline on the formalized risk assessment procedure was published in 2015. Thus the excipient user must evaluate the excipient manufacturer’s application of GMPs to determine if the standard of GMP applied is appropriate for the intended use of the excipient. The attitude of these regulators seems to imply that excipient GMPs are inferior to finished product GMPs. This is not the case. Globally recognized GMP standards are available for excipients (see e.g., ANSI 363, WHO Annex 5 and EXCiPACT). 

By way of an example that may explain the contradiction, consider the scenario of a tablet formulation, made by direct compression, and comprising the drug, a filler (e.g., microcrystalline cellulose) and a lubricant (e.g., magnesium stearate). (This would be similar to the example above concerning oversimplification.) Providing that the marketing application is acceptable, there is no reason why this formulation could not be approved for marketing. Consider then a tablet formulation, also made by direct compression, and comprising a drug, a co-processed filler (e.g., silicified microcrystalline cellulose) and a lubricant (e.g., magnesium stearate). Somehow, according to those certain regulators’ thinking, this formulation should not be approved, because it contains a co-processed excipient, which those regulators consider is manufactured to a lesser standard of cGMP. The excipient manufacturers making silicified microcrystalline cellulose also manufacture microcrystalline cellulose, and, most likely produce both excipients to the same standard of GMP. How is it, then, that microcrystalline cellulose would be acceptable in this application, but silicified microcrystalline cellulose would not? 

In summary, co-processed excipients have tremendous potential to enhance the robustness of pharmaceutical products and processes. Also, they have the potential to facilitate more robust and simpler continuous manufacturing of pharmaceutical finished products. However, to realize that potential, both the pharmaceutical manufacturers and regulatory authorities must accept that co-processed excipients do not present an undue regulatory risk, and are legitimate additions to the excipient armamentarium. The developers and manufacturers of co-processed excipients will need to undertake the necessary studies to demonstrate that the co-processed excipient is safe, effective and stable within the context of the particular application. 

References 

1. Certification standards for pharmaceutical excipient suppliers, Issue 2, EXCiPACT asbl, Brussels, BE, 2017. 

2. Directive 2011/62/EU of the European Parliament of the Council of 8 June 2011 (Falsified Medicines Directive). 

3. Guidance for Industry: Nonclinical studies for the safety evaluation of pharmaceutical excipients, US FDA, CDER and CBER, Silver Spring MD May 2005. 

4. Guideline of 19 March 2015 on the formalized risk assessment for appropriate good manufacturing practice for excipients of medicinal products for human use. (2015/C 95/02). 

5. Co-processed Excipient Guide for Pharmaceutical Excipients, The International Pharmaceutical Excipients Council of the Americas, Arlington, VA and The International Pharmaceutical Excipients Council of Europe, 2017. 

6. NSF/IPEC/ANSI 363-2019 Good Manufacturing Practices (GMP) for Pharmaceutical Excipients, American National Standards Institute, Washington, DC. 

7. Tobyn MJ, McCarthy GP, Staniforth JN and Edge S, Physicochemical comparison between microcrystalline cellulose and silicified microcrystalline cellulose, Int J Pharm, (1998) 169, 183-194. 

8. WHO Technical report Series, No. 885, Annex 5 – Good manufacturing practices: supplementary guidelines for the manufacture of pharmaceutical excipients, World Health Organization, Geneva, CH, 1999