July 28, 2022
Markus Greulich (MG): Unlike orally administered products, such as tablets and capsules, that pass through the intestine, which is designed to prevent foreign contaminants from foods from entering the bloodstream, parenteral products are delivered directly into the bloodstream, where human bodies are really vulnerable. Only the immune system can fight bacterial contamination. As such, these applications are considered to be high-risk, and there are significant regulations and strict controls for parenteral drugs and parenteral drug manufacturers.
It is essential to ensure that parenteral products are sterile. For some products, sterilization can take place at the very end of the production process. However, many drug products cannot withstand sterilization conditions, so other measures, such as sterile filtration, must be used in combination with strict control measures to ensure product quality and to prevent the introduction of contamination at every possible step.
MG: There are many ways in which bacteria might get introduced into a drug product. One is from the environment in which the manufacturing takes place. Therefore, there are strict regulations regarding in the surrounding environment. Personnel are a second source, as they can bring bacteria into the manufacturing environment. Because the equipment is constantly in contact with the product, it also presents a contamination risk. The water used in manufacturing processes is also critical, because whenever water is present, there is always the potential for bacterial growth. Last but not least, the raw materials used to produce the drug product can be a source of microbial contamination. This last point is the critical one for excipient suppliers.
MG: A key principle of good manufacturing practice is that using only a single control measure is rarely a very reliable approach to ensuring sterility and quality. A terminal sterilization method, for instance, may have a capability threshold, and a high bioburden may exceed the quantity of microorganisms that can be removed. The bioburden must be determined before terminal sterilization to ensure that it is not too high for the technique being used. Testing after sterilization can also be an issue, as sterility assays also have limitations in terms of specificity and sensitivity.
In addition, a high bioburden creates a risk for endotoxin contamination, because endotoxins originate in bacterial cells. Even if the bacteria are killed, subcellular components may still be present in the formulation, leading to unacceptable levels of endotoxins and pyrogenic compounds in the final drug product. For these reasons, terminal sterilization is really not an effective solution on its own. A comprehensive approach to ensuring sterility is much more effective and reliable.
Furthermore, for many products, terminal sterilization via steam treatment is not possible, because the drug substances and/or other ingredients in these formulations are heat sensitive. Sterile filtration is often the only answer for these products.
Lars Albermann (LA): The regulatory landscape reflects what Markus just said about the limits to manufacturing processes. There are risks associated with higher bioburden early on in the process. Assuring sterility is therefore not something that can be thought of only at the end –– it must be considered throughout the entire process.
LA: There is guidance in the EU on what you have to do for excipients –– i.e., the Guidelines of 19 March 2015 on formalized risk assessment for ascertaining the appropriate good manufacturing practice for excipients in medicinal products for human use (2015/C 95/02), but it is not very prescriptive. It establishes the requirements for assessing the risks associated with the use of excipients and how to consider the different dimensions of those risks. The appropriate level of GMP (Good Manufacturing Practice) needed is determined by the excipient type and how it is used in a formulation. The risks associated with the excipient manufacturer must also be assessed. Any gaps that are identified must be addressed during the qualification processes for an excipient, and ongoing assessment of supplier performance must be pursued. It is also necessary to establish a proper system for change notifications to keep customers up to date.
While these requirements are much stricter than they were even 10 years ago, they are still not particularly prescriptive. They identify what must be looked at, but not how to do it exactly. That is one of the reasons why industry standards and voluntary certifications continue to have high merit.
MG: For some materials that formulators use in parenteral products, more guidance is needed with respect to acceptable bioburden and endotoxin limits. There are bioburden limits in pharmacopeias, but those general limits are pretty high, because they are not geared toward aseptic processes as such but are general requirements for substances for pharmaceutical use.
In addition, the responsibility for assuring quality is ultimately in the hands of the marketing authorization holder. Of course, drug manufacturers need to rely on their suppliers to provide materials that meet their requirements.
LA: That is an interesting question. The voluntary industry standards evolved because of the absence of direct regulatory requirements. The industry came to the conclusion that standards are required, and because little was coming from state agencies or authorities, it was necessary for industry to take the initiative and develop them.
In general, there are differentiated levels of regulatory requirements depending on the type of material. Medicinal products have the most comprehensive regulations, followed by drug substances / APIs, because they are the key active ingredient in formulated drug products. Excipients fall into the third tier; they can impact drug performance (controlled release or targeted delivery, for instance), but do not have their own pharmaceutical activity.
This tiered system makes sense when patient exposure is considered. However, excipients often comprise the majority of a medicinal product. From that perspective, proper GMP and general product quality requirements are essential; otherwise, there is a real risk of having an incorrect or non-functional medicinal product or even one that can harm patients.
LA: Safety requirements are spelled out in quite some detail in the U.S. guidances, but the FDA (U.S. Food and Drug Administration) also does not have a very prescriptive approach when it comes to GMP, even less so than the EMA (European Medicines Agency). The overall requirements are comparable, but there is no detailed guidance in terms of GMP requirements provided.
MG: There has been a recognition in the last 10–15 years that controlling the quality of excipients is important, because they are critical for the final formulation. The question is whether the burden of assuring excipient quality should fall on the drug manufacturer or whether GMP regulations should be implemented for excipient manufacturers.
I believe that the former was chosen because the latter option places too much of a burden on both authorities (in terms of inspections) and excipient manufacturers, many of whom do not produce excipients as primary products. The way the excipient is used in the formulation and the process involved also influences the final quality, safety, and efficacy of the product. In fact, sales for many of these companies in the pharmaceutical sector are very small relative to other sales in other markets. Many excipients were initially designed for use in other applications where the quality requirements can be quite different. It would therefore be very challenging to establish mandatory GMP guidelines. Only drug manufacturers know the specifics of their process and application and are therefore the only ones to be able to decide on appropriate excipient quality.
That leaves the responsibility with the drug manufacturers, which obviously also creates difficulties. They cannot simply buy from authority-inspected, qualified GMP excipient manufacturers, because such suppliers don’t exist. Yet drug manufacturers must assure that quality requirements are met and that their products do not pose any patient risk due to inadequate quality. Achieving that goal requires the development of controlled processes and systems for ensuring that raw materials and raw material suppliers meet expectations, which in turn requires the participation of raw material suppliers, including excipient manufacturers. Indeed, excipient supplier qualification is very important to assure raw material quality.
With its SAFC® Raw Materials portfolio, MilliporeSigma is dedicated to helping support drug makers with products and information they need to perform proper risk assessments and thus effective decision making.
MG: Many excipients are not that critical per se. Mineral salts and many buffer components, for instance, present low risk for microbial contamination. Others, such as those derived from plant sources, require much stricter control. Ultimately, although the majority of excipients generally present a low risk, it is still essential to implement an appropriate level of control.
LA: I would add that there are a few excipients that are very hygroscopic or have a tendency to accommodate bacteria. Those excipients obviously require a higher level of control.
MG: Excipient manufacturing processes are very diverse because of the differences in their chemical structures. However, the quality requirements are similar. It is important to extensively train operators and pay close attention to the manufacturing environment in order to be fully compliant with the guidelines outlined in the EXCiPACT® standard and the Joint IPEC (International Pharmaceutical Excipients Council)–PQG Good Manufacturing Practices guide. Basically, we apply these quality guidances, which include performance of risk assessments, for all of the excipients that are covered by our Emprove® brand.
One of our goals is to help our customers perform their own risk assessments. Manufacturers need a lot of information from suppliers to be able to properly assess an excipient with respect to quality and quality performance from batch to batch. The lack of specific requirements does make it challenging for drug makers, and it is our objective to provide as much support as possible so customers can properly conduct their risk assessments.
LA: The overall risk assessment for use of the excipient in the medicinal product has to be performed by the drug manufacturer, because only the formulator fully understands the role of the excipient in the product and the associated risks. Excipient manufacturers aren’t privy to this type of information. What we can do — and aim to do — is provide our customers with a set of information that will enable them to easily perform their risk assessments using the same level of information for each and every excipient they buy from us.
We have developed a template for providing this information so that customers purchasing SAFC® excipients get a comprehensive set of data when they do their qualifications and do not have to come back to MilliporeSigma looking for missing information. With the template, customers know where to look for specific pieces of information and can use the same process for each and every new SAFC® excipient from MilliporeSigma that is qualified. That is hugely appreciated by customers.
MG: I think the benefit that we offer with our SAFC® portfolio is that, with our Emprove® Expert range, our customers can rely on having bioburden/microbiological specifications for each of those products that also include endotoxin limits. Plus, our portfolio is fairly large and covers all of the types of ingredients used in parenteral products, which makes it possible for customers to find the optimal products for their specific products and processes.
The portfolios of other excipient suppliers are often much smaller and typically do not include such a wide range of ingredients. For instance, they may offer mineral sources or buffers, but not both. With the competition, it can also be difficult to identify products that meet the criteria for parenteral manufacturing. MilliporeSigma’s Emprove® Expert offering is very transparent, and documentation is readily available. That makes it easier to perform risk assessments and make more rapid decisions.
LA: In addition, one thing for which customers have expressed appreciation with the Emprove® offering is the consistency that exists across the portfolio. Customers always know where to find which type of information, regardless of the type of material.
MG: There is always evolution. The Material Qualification Dossier provides customers with the basic information needed to make a first evaluation. In the Quality Management Dossier, we provide a level of detail and data geared toward supporting risk assessments, including self-assessment results and audit summaries — relevant supply chain information that is increasingly important.
We always want to keep up with regulatory requirements and customer expectations. For instance, when the regulations relating to elemental impurities changed, we added this information into the Operational Excellence Dossier to support our customers’ compliance efforts. Regulations are always changing, and we stay up to date with them so that we can be one of the leading suppliers in the context of the regulatory landscape — to stay ahead of what our customers might need for their risk assessments.
LA: I would add that we do know that our dossiers cannot always address all of the questions that customers have. So, of course, we have a dedicated customer service group and quality and regulatory experts ready to investigate and answer customer questions. We look at these questions, analyze them, identify clear additional information needs, and develop a means for incorporating that information into the dossiers and testing its value. If found to be warranted, that information is then brought into the dossiers permanently.
MG: There are roughly 400 products overall in the Emprove® portfolio. The majority of our excipients are in the Emprove® Essential range, because oral administration is the most common delivery route, and there are therefore more ingredients in this category. But with over 100 excipients available in the Emprove® Expert range, designed for parenteral formulation, customers have a high likelihood of finding excipients that will provide optimal formulations for their parenteral drug products.
MG: One problem in the industry is the introduction of novel excipients. From a regulatory point of view, detailed safety and CMC (chemistry, manufacturing, and controls) information on a novel excipient must be submitted as part of the registration dossier for the final drug product. There is no separate approval pathway for excipients on their own. That creates added risk for the drug formulator on top of the high risk that already exists for new drug development. As a result, drug manufacturers are reluctant to use novel excipients, and therefore very few make it to the market.
LA: I agree that there is a certain barrier to excipient innovation, because the effort with documentation –– in terms of the data that you have to provide –– is really high for novel excipients. Essentially, a data set similar to what is required for a new drug substance is expected. There are examples, of course, because there are novel drug substances for which no existing excipient will work. The mRNA vaccines against COVID-19 are a great example. There were no established excipients that could protect and target the mRNA to the right cells, so new excipients for formulations encapsulating mRNA in lipid nanoparticles were developed. It was a lot of effort, obviously, but that effort made it possible to create novel and effective vaccines.
MG: I would say that there is a need for improved surfactants for parenteral applications, particularly new surfactants with the right safety profiles. At present, there is only a very limited number available on the market. If those surfactants don’t work, then there are three to five other excipients that might provide the desired performance. If those cause problems, there is little other choice.
There are also growing challenges associated with bioavailability and solubility, because more and more of the drug substances in development have very poor solubility. There are different approaches based on different ingredients that could be very interesting.
We are also seeing increasing use of technologies, such as hot-melt extrusion, spray drying, and so on, that could benefit from excipients designed specifically for use in those processes. Right now, formulators are using compendial excipients, even though they are not optimal for the drug substance given its physicochemical properties or the special formulation/delivery technology employed. I think there is a lot of innovation potential not yet leveraged because of this roadblock against novel excipients.
LA: The fact that the FDA launched their pilot program in 2021 to look at a different way to handle novel excipients, especially those intended for use in drug products that meet a high medical need, is encouraging. Of course, a separate pathway for excipient approvals would require investment of significant effort and therefore significant resources, which are always in short supply.
Another issue that we see in Europe is that there is no such thing as a drug master file (DMF) for excipients. Excipients that require more thorough regulation –– because they are novel or are lipid excipients for which the documentation requirements are higher and no monograph exists in any pharmacopoeia –– face not only approval challenges, but also intellectual property issues. Again, the burden is on the marketing authorization holder (drug manufacturer), and there is a lot of additional information required from the excipient supplier. It would be much clearer and easier if a mechanism was established for the filing of DMFs for excipients by excipient manufacturers in Europe as well.
With such a mechanism and clearer guidelines for novel excipients being established, it would considerably ease the effort to bring the final drug product to the market. In addition, this would open up opportunities for the use of novel excipients helping to address especially demanding formulation challenges with these novel approaches. Either way, a close collaboration between the authorization holder and excipient supplier will continue to be critical. The quality of the product and the provided information is key for success in general and especially for high-risk formulations.
Originally a molecular biologist, Lars Albermann received his PhD from the University of Münster, Germany. For the last 14 years he has been working in several regulatory positions in pharmaceutical industry as well as contributing to a number of industry associations, joining Merck KGaA, Darmstadt, Germany, in 2012. Currently, he is responsible for a team of regulatory experts in Life Science Regulatory Management. The team is working on regulatory topics mainly related to APIs and excipients, supporting a number of manufacturing sites as well as global activities.
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