Testing for Melamine Contamination

Are your starting materials at risk?

By Jeffery C. Basham

As the FDA moves to protect consumers from accidental and nonaccidental adulteration of pharmaceutical products, the agency has issued a non-binding recommendation to pharmaceutical manufacturers of finished products, pharmacy compounders, repackers and suppliers concerning the risk of melamine contamination in starting materials.

Our industry’s push to become more global and use cost-controlling suppliers from all over the world has opened the door to risks from which we have historically been (somewhat) protected. As we continue to work with global companies, it is very likely that the FDA will continue to issue recommendations for protecting consumers of pharmaceutical products. For example, testing of elemental metals may be the agency’s next recommendation.

In response to this particular non-binding guideline, the industry has begun to lay the groundwork for ongoing testing of specific products for melamine contamination. This includes suppliers, analytical testing laboratories and contract manufacturers, as well as pharmaceutical companies.

The FDA recommendation follows two separate but widespread incidents of melamine contamination in consumable products. In both incidents, starting materials were manufactured in China and exported to the U.S., where they were used to make pet food and baby formula.

By itself, melamine is no more toxic than common table salt. But in the presence of cyanuric acid, it loosely associates to form a melamine-cyanuric acid complex, which accumulates in the body, leading to kidney failure.

According to the FDA, melamine was added to starting materials to bolster their apparent protein content — thus making them appear more nutritious than they actually were. The contamination became public only after numerous adverse health events were reported and associated with the use of contaminated products.

These incidents demonstrate the ease with which one can receive melamine-contaminated starting materials and miss detecting it. The FDA identified at-risk components derived from milk or animal products. The FDA also recommended testing starting materials that contain more than 2.5% nitrogen in the compound by weight.

The following are examples of at-risk pharmaceutical components:

• Adenine (USP)
• Albumin (IID)
• Ammonium salts
• Calcium pantothenate(USP)
• Caseinate or sodium caseinate (IID)
• Chorophyllin copper complex sodium (USP)
• Colloidal oatmeal (USP)
• Copovidone (USP/NF)
• Crospovidone (USP/NF)
• Dihydroxyaluminum aminoacetate (USP)
• Gelatin (IID)
• Glugan (USP)
• Guar gum (USP.NF)
• Hyalurinidase (USP)
• Imidurea (USP/NF)
• Amino Acids derived from casein protein by hydrolysates
• Lactose (USP/NF, IID)
• Melphalan (USP)
• Povidone (USP/NF)
• Povidone-Iodine (USP)
• Protamine sulfate (USP)
• Protein hydrolysate powder for injection (USP)
• Taurine (USP)
• Thioguanine (USP)
• Urea (USP)
• Wheat bran (USP)
• Zein (USP/NF)

It is important for companies in the supply chain to determine if they are using an at-risk material. If a company finds that materials in use are deemed at-risk, the FDA guidance recommends that manufacturers of finished drug products test for melamine in the starting materials before they are used in the preparation of the final drug product, and that manufacturers know and monitor their supply chain for at-risk materials.

The motivation for melamine contamination testing can be found in how companies have tested starting materials in the past.

To measure the protein content of their starting materials, companies typically have relied on a total nitrogen test such as USP Nitrogen Determination as part of the monograph for release. But melamine is a nitrogen-based compound; companies testing for nitrogen alone will not be able to distinguish melamine content from the protein content they desire.

The FDA has also released suggested analytical methods for melamine that were developed by the agency’s Office of Regulatory Affairs in response to the initial melamine contamination in pet and baby food. The FDA has warned that these methods can produce varying results.

Many methods can be developed to support the required level of detection. A simple HPLC separation method with UV detection is suitable for determining melamine down to the recommended limit of 2.5 parts-per-million.

In an effort to manage these extra testing costs, our method is designed to be simple in principle and easily adaptable to additional sample matrices as needed. For added reliability, sample matrix interferences are evaluated on each sample tested and confirmed to allow acceptable quantitation of melamine within the working range of the method.

To date, gelatin capsule shells — derived from animal collagen — are the most common starting materials we have been asked to test for the presence of melamine. Due to the wide range of color combinations possible in gelatin capsule shells, the presence of various coloring agents means each gelatin capsule presents different challenges for identification and quantitation of melamine at trace levels. The approach Metrics has taken adapts to these differences easily.

To read the full guidance issued by the FDA, “Guidance for Industry Pharmaceutical Components at Risk for Melamine Contamination,” visit the agency’s Web site at www.fda.gov. In addition, companies should contact their suppliers in order to understand the suppliers’ positions and actions related to this guidance.

Source: Guidance for Industry: Pharmaceutical Components at Risk for Melamine Contamination (August 2009). Retrieved January 2010 from: www.fda.gov

Jeffery C. Basham is vice president of business development at Metrics Inc., a provider of formulation development, clinical trial material (Phases I – III) and commercial manufacturing and analytical development/validation services to the pharmaceutical industry.