In our previous blog, we explored the importance of having a reliable, high-quality supply of carbomer excipients to ensure the consistent high quality of finished drug products.
For drug formulators to ensure they select carbomers that are of the highest safety standards, it is important for them to have a deeper understanding of local and global regulatory requirements for drugs and drug components including inactive ingredients. There are no consistent standards across the globe, which makes it more challenging to find and source high-quality carbomers.
However, understanding the regulations in place in key pharmaceutical markets can help ensure the production of high quality end-products ensuring compliance and patient safety compliance This can help maintain access to these economies and even aid access to smaller markets in their regions, since many often follow the regulatory framework of their larger neighbors.
In this blog, we will explore the regulatory requirements governing excipient safety for the United States as an example of best practice to help formulators understand how to select the most appropriate carbomer for their needs.
Understanding the U.S. excipient regulatory landscape
The United States Pharmacopeia (USP) and National Formulary (NF) are recognized as official compendia for drugs marketed in the U.S. under the Federal Food, Drug and Cosmetic Act. The USP is an independent, non-governmental, not-for-profit organization that sets quality, purity and strength standards for drug products (active and inactive ingredients), food ingredients and other products sold in the United States. The FDA works closely with USP to enforce USP’s standards, which are often called monographs.
They contain monographs for drug substances and excipients that explain the minimum standards to which each ingredient must adhere. A monograph includes the name of the ingredient, its definition and specifications, as well as packaging, storage and labelling requirements.
A monograph for a drug substance or excipient is officially added to either compendium only once the U.S. FDA approves a drug containing that material.
If a monograph exists for a material, then under FDA rules, the material used in a drug formulation must comply the monograph’s specifications. The FDA recognizes compliance to other compendia if a monograph for the material does not exist in either the USP or the NF.
In addition to meeting the specifications of a monograph, an excipient must be produced using Good Manufacturing Practice (GMP) guidelines and sourced according to Good Distribution Practice (GDP) principles. In addition, the methods used in their manufacture should conform to the requirements of the USP general chapter <467>, which we will explore in more detail later.
With all of this in mind, a drug formulator developing a product for the U.S. market has some freedom when it comes to selecting a carbomer. However, opting for a carbomer that complies with monographs in multiple compendia, such as Carbopol® from Lubrizol Life Science Health (LLS Health), can help ensure compliance with a range of global regulations.
U.S. requirements for excipient manufacturing
It is important to note that various compendia feature restrictions on the use of solvents in excipient manufacture to ensure the excipient in question complies with its associated monograph.
The choice of solvent plays a central role in excipient quality and safety and, ultimately, on the quality of the finished drug product it is used in. For example, a solvent traditionally used in carbomer production, benzene, is a well-known carcinogen. If there is any residual benzene left in the finished drug, then it could pose a health hazard to any patient taking the product. FDA has recently issued communication to drug manufacturers regarding risk of benzene contamination in certain drugs. This communication was primarily triggered by recent recall of hand sanitizer and aerosol drug products that have been recalled due to benzene contamination. Carbomers (thickening agents) manufactured in benzene have been attributed as a potential source which further highlights the importance of solvents used in the manufacturing process.
The USP general chapter <467> contains requirements to prevent the instance of such toxic residual material in end drug products. It categorizes solvents into three Classes according to their toxicity:
- Class 1 solvents are known – or strongly suspected – to be carcinogenic in humans, or to have Ozone-depleting properties, and should be avoided in excipient manufacture. List of Class 1 solvents – Benzene, Carbon tetrachloride, 1,2-Dichloroethane, 1,1-Dichloroethene and 1,1,1-Trichloroethane
- Class 2 solvents are toxic to animals or are suspected of reversible toxicities in humans, and their use in excipient production should be limited.
- Class 3 solvents have low toxic potential in humans and are safe to use in excipient manufacture.
The European Pharmacopoeia 7.0 (Eur.Ph. 5.4) has similar guidance regarding toxic residual solvents in pharmaceutical excipients, as does the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) Q3C. The ICH Q3C has been adopted by the U.S. FDA, as well as other key global regulators, such as the European Medicines Agency (EMA), the Japanese Pharmaceuticals and Medical Devices Agency (MHLW/PMDA) and the Chinese National Medical Products Administration (NMPA).
Specifically, the ICH Q3C guidance explains that Class 1 solvents such as benzene should not be employed in the manufacture of drug substances, excipients, or drug products because of their unacceptable toxicity. The guidance notes that if benzene use is unavoidable to produce a drug product with a significant therapeutic advance, then its levels should be restricted to 2 parts per million (ppm), unless otherwise justified. The ICH has limits for all class 1 solvents and formulators should be aware of the above to avoid sourcing excipients manufactured using class 1 solvents.
In addition to these requirements on solvents, formulators should ensure that their excipient manufacturer has a qualification program for their suppliers and the materials they receive from them. As part of this, excipient manufacturers must have an agreement in place with their own raw material suppliers to be notified of any significant change to a material they receive.
The search for the right supplier
At LLS Health, we have been manufacturing our high-quality Carbopol® carbomers for 50 years. We have experience supplying safe, high-quality, compliant carbomers to a range of global markets, and understand the regulations in place in the US and other markets to support drug formulators in ensuring compliance. We can provide documentation to demonstrate the quality of our carbomers in line with the above requirements, and regularly invite companies to audit our processes.
Working with us, drug formulators can be confident that they can access carbomers that can support them in delivering compliant end products to the global market.
To find out more about how LLS Health can help you access a reliable high-quality supply of carbomers to meet your needs, contact us today.