Ensuring API Quality—A Pharmacopeia Perspective

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Pharmaceutical Technology spoke with Ed Gump, VP Small Molecules at the US Pharmacopeia (USP) about API quality from the standards perspective.

Pharmaceutical Technology spoke with Ed Gump, VP Small Molecules at the US Pharmacopeia (USP) about API quality from the standards perspective.

PharmTech: How crucial is it for pharma manufacturers to ensure the safety of APIs?

Gump (USP): To ensure the quality (and by extension, the safety) of their products, it is crucial that pharma manufacturers ensure the quality of their drug product ingredients—the API as well as excipients. In the [United States] (and in many other countries), the legal burden to ensure the quality of each ingredient, including excipients, is on drug manufacturers.

Unlike APIs, excipients are often not pure and tend to be complex in nature and can be sourced from natural (animal, plant, mineral), synthetic, and semisynthetic origins. And many (if not most) excipients have uses beyond pharma, so it is especially important for manufacturers to test the quality of their excipients and ensure they are fit for pharmaceutical use.

PharmTech: What are the steps an API manufacturer and sponsor must take to ensure quality throughout the development and manufacture of an API?

Gump (USP): Manufacturers should manufacture their products under CGMPs [current good manufacturing practices], adhering to all regulatory requirements at the federal, state, and local level.

When ordering APIs from suppliers, manufacturers shouldqualify their suppliers, perform regular quality audits of their suppliers’ facilities, develop specifications to ensure that API is fit for use in their product formulations and that API conforms to USP standards, ensure the quality of the API they receive such as by testing the API against the USP monograph and reference standard.

PharmTech: What has the industry learned from the nitrosamine contamination problems in blood pressure medications?

Gump (USP): We have learned that it is not just blood pressure medications that are at risk of nitrosamine contamination.

Nitrosamines can form in a lot of different ways, based on fairly simple chemistry. Changes in manufacturing processes, ingredients (including excipients), ingredient sources, and even the API (sometimes referred to as the drug substance) itself can all be sources for nitrosamine to form.

Many recent drug recalls are due to a specific sub-category of nitrosamine impurities known as drug substance-related nitrosamine impurities (DSRNIs), a class of nitrosamines sharing structural similarity to the API.


DSRNIs (and nitrosamines in general) can form in several different ways. One of the most common reactions is when an API molecule has what’s known as secondary amine group in its structure, and when (1) nitrite and (2) acidic conditions are present. Under these conditions, the API molecule with a secondary amine can react to form a nitrosamine.

For example, excipients such as Sodium starch, Crospovidone, Povidone, Lactose, Croscarmellose, etc. are used in various pharmaceutical formulations as solubilizing agents, binders, disintegrants, etc. The presence of nitrate and nitrites has been found in these excipients at parts per million levels.

Nitrites from excipients could react with amines in APIs, or low molecular weight amine impurities. Because excipients are generally the greatest component of medicinal products, sufficient amounts of nitrite could be present as a reaction partner.

However, this is not the only chemical route that can potentially lead to formation of a nitrosamine.

Given that there are a variety of possible routes, it's critical for manufacturers to understand what medicines and associated manufacturing processes are at risk to form nitrosamines, confirm if they are forming, at what levels, and how they can establish controls to ensure they are not present at levels that could be harmful.

It’s also important for manufacturers to make sure that when risks exist, they are establishing control strategies using tests which are ‘fit for purpose’ for their products so that they can reliably detect and control nitrosamines. Establishing safeguards like these at appropriate checkpoints within the global medicines supply chain will mean patients have access to the safe medicines they need, when they need them, and that the medicines will deliver the intended therapeutic benefit.

PharmTech: Have regulators and industry resolved the nitrosamine problem or is it continuing?

Gump (USP): It is continuing, but now that regulators and industry are aware of the problem there is an incredible amount of effort being focused on fixing the problem. Every new recall is actually a sign of progress and shows that industry and regulators are working hard to identify nitrosamines in their products and when they are finding them at unsafe levels, they are recalling those products.

The discovery of nitrosamine impurities in some drugs over the past four years has prompted major efforts by regulators and industry to reduce or eliminate their presence in the medicines supply chain. FDA now expects drug manufacturers (for drugs approved in the US market) to assess on a regular basis the risk of any nitrosamine impurity formation in their products.