Guidance for Industry 

 
Pharmaceutical Components 

at Risk for Melamine 

Contamination 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

Center for Veterinary Medicine (CVM) 

August 2009 

 
Current Good Manufacturing Practice (CGMP) 
  Contains Nonbinding Recommendations 
 
 
Guidance for Industry 

 
Pharmaceutical Components 

at Risk for Melamine 

Contamination 

 
Additional copies are available from:  

 
Office of Communications  
 
Division of  Drug Information, WO51, Room  2201 

 Center for Drug Evaluation  and Research 
 
Food and  Drug Administration 

10903 New Hampshire Ave.  

Silver Spring, MD 20993 
  
Phone: 301-796-3400;  Fax: 301-847-8714 
  
druginfo@fda.hhs.gov 
  
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm  
  
 
and/or 
 
 
Communications Staff, HFV-12 

Center for Veterinary Medicine  

Food and  Drug Administration 

7519 Standish Place 

Rockville, MD  20855 
 
Phone: 240-276-9300 

http://www.fda.gov/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/default.htm  
 
 
 
 
 
U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

Center for Veterinary Medicine (CVM) 

August 2009 

 
Current Good Manufacturing Practice (CGMP) 
  Contains Nonbinding Recommendations 
 
TABLE OF CONTENTS 
 
 
I.   INTRODUCTION............................................................................................................. 1 
 
II.   BACKGROUND ............................................................................................................... 2 
 
III.   REQUIREMENTS AND RECOMMENDATIONS ...................................................... 3 
 
IV.   EXAMPLES OF AT-RISK PHARMACEUTICAL COMPONENTS ........................ 3  

 
  Contains Nonbinding Recommendations 
 
 
1
 
GUIDANCE FOR INDUSTRY
 
 
Pharmaceutical Components 

at Risk for Melamine Contamination 

 
 
 
This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic.  It 
does not create or confer any rights for or on any  person and does not operate to bind FDA or the public.  
An alternative approach may be used if such approach satisfies the requirements of the applicable statutes 
and regulations.  If you want to discuss an alternative approach, contact the FDA staff responsible for 
implementing this guidance.  If you cannot identify the appropriate FDA staff, call the appropriate 
number listed on the title page of this guidance.  
 
 
 
 
I.  INTRODUCTION  
 
This guidance is intended to alert pharmaceutical manufacturers of finished products, pharmacy 
compounders, repackers, and suppliers to the potential risk of melamine2 contamination in 
pharmaceutical components.  In September 2008, FDA received reports from China about food 
articles contaminated with melamine, which have resulted in thousands of hospitalizations for 
kidney problems and at least three deaths.  As of the date of this guidance, FDA is not aware of 
any pharmaceuticals that have been contaminated with melamine.  However, because of the 
potential risk of drug contamination, it is important that manufacturers take steps to ensure that 
susceptible components are not contaminated with melamine. 
 
This guidance provides recommendations that will help pharmaceutical manufacturers of  
finished products, repackers, other suppliers, and pharmacists who engage in drug compounding 
better control their use of at-risk components3 that might be contaminated with melamine.  FDA 
                                                 
1  This  guidance was developed by the Office of Compliance in the Center  for Drug Evaluation and Research  
(CDER) in cooperation with the Center for Veterinary Medicine (CVM)  at the Food and Drug Administration. 
 
2 Melamine is a nitrogen-based compound that is characterized by its high  nitrogen content.   It is also  known by  
other chemical names, such as triaminotriazine, cyanuramide, and cyanuric acid amide.  Melamine is an industrial 
chemical used in the manufacturing of resins for surface laminates and adhesives in the production of  wood-based  
panels. Melamine or its resins are also  used in making  melamine dinnerware, additives for textiles, and as flame-
retardant additives for foam  mattresses.  For the purpose of this guidance, we use the term  melamine in the following  
sections to mean melamine and related analogs (e.g., melamine and cyanuric acid). 
 
3 For the purpose of this guidance, we use the term  at-risk component to mean those ingredients or raw materials that 
rely on a test for nitrogen content for their identity or  purity or strength, and that contain  nitrogen in amounts greater 
than 2.5 percent.  Such a component can be  derived from source material that might  be contaminated with  
1 
 Contains Nonbinding Recommendations 
 
considers the presence of melamine in any drug (unless specifically approved as an impurity) to 
render that drug adulterated under sections 501(a)(2)(B) and 501(d) of the Act (21 U.S.C. 
351(a)(2)(B) and 351(d)). 
FDA's guidance documents, including this guidance, do not establish legally enforceable 
responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should 
be viewed only as recommendations, unless specific regulatory or statutory requirements are 
cited. The use of the word should in Agency guidances means that something is suggested or 
recommended, but not required. 
 
II.  BACKGROUND  
 
In 2007, FDA learned that certain pet foods were sickening and killing cats and dogs.  FDA 
found that vegetable proteins imported into the United States from  China and used as ingredients 
in pet and livestock food products were contaminated with melamine. 
 
In September 2008, FDA received reports of melamine-contaminated infant formula in China.  
In response, FDA issued a Health Information Advisory to make the public aware of FDAs 
ongoing effort to monitor the safety of the American food supply by testing certain imported 
food ingredients derived from milk.  Pharmaceutical components that are similarly derived from  
milk are also at risk for being contaminated with melamine. 
 
These two incidents share the following similarities: 
 
	   Melamine, a nitrogen-based compound, was apparently added to bolster the apparent 
protein content in foods or in ingredients used in processed food products intended to 
contain protein. 
 
	   Recipients using a test for nitrogen content would not have been able to distinguish 
between melamine and the desired protein. 
 
	   Melamine contamination became public only after numerous adverse health events, 
including deaths, were reported and associated with the use of contaminated products. 
 
These incidents illustrate the potential for drug components to be contaminated with melamine;   
therefore, it is important for drug manufacturers to be diligent in assuring that no component 
used in the manufacture of any drug is contaminated with melamine.4  
 
________________________ 
melamine, or the component itself can be directly contaminated by melamine in an attempt to reduce its quality or 
strength or to substitute for it.  Examples of each type appear in section IV.  
4 The risk assessment for melamine in foods  does not  fully address the risks applicable to  drugs.  At this time, the 
FDA has not  established an appropriate level of melamine in drug  products.  Contamination of any type in drugs can  
result in the loss of active ingredient strength and  potency and can disrupt the processing  of the finished product. 
Contaminants can also affect product or component stability. Any of these results from contamination can lead to  
reduced therapeutic effectiveness.  Decreased  drug effectiveness and possible long-term exposure risks raise serious 
concern over the safety of  drugs contaminated with melamine and its analogs. 
 
2 
 Contains Nonbinding Recommendations 
 
III.  REQUIREMENTS AND RECOMMENDATIONS  

 
The current good manufacturing practice (CGMP) regulations require that all components (i.e., 
ingredients or raw materials) be tested before they are released for use in the manufacture or 
preparation of drug products (21 CFR 211.84).  It is critical that all manufacturers determine 
whether they are using an at-risk component for melamine contamination to manufacture or 
prepare a drug product. Section IV of this guidance lists examples of at-risk components for 
melamine contamination and explains how such components were identified. 
 
The CGMP regulations at 21 CFR 211.84(b) and (d) require that a component testing program  
consider such issues as the need for confidence levels and degree of precision required, as well 
as the past reliability of a supplier. Accordingly, once you have determined you are using an at-
risk component, the Agency recommends that: 
 
1.	   Manufacturers of finished drug products test for melamine in at-risk components before 
they are released for use in the manufacture or preparation of the drug products.   FDA 
has posted assay methods for measuring melamine contamination in foods using liquid 
chromatography triple quadrupole tandem mass spectrometry (LC-MS/MS) and gas 
chromatography/mass spectrometry (GC-MS) (see Analytical Methods for Melamine and 
Triazine Analogs, available at 
http://www.fda.gov/AnimalVeterinary/ScienceResearch/ToolsResources/ucm135002.htm). 
These methods have been evaluated using dry protein materials.5   
   
2.	   Manufacturers of finished pharmaceuticals know and monitor their supply chain for any 
at-risk components, which means knowing the identity and role of the actual 
manufacturer of such components and any repackers and distributors who handle the 
components before receipt by the manufacturer.   Manufacturers should obtain 
certification from the manufacturer of at-risk components that these components are 
tested for the absence of melamine contamination.  Manufacturers should also audit their 
component suppliers to ensure CGMP compliance.  
 
3.	   Distributors of finished pharmaceutical products under their own brand or label obtain 
certification by the manufacturer that the products are tested for the absence of melamine 
contamination if their product contains an at-risk component.  
 
FDA also recommends that compounders who use at-risk components in compounding drugs 
either test the components for melamine or ensure that such testing was properly done by a 
reliable supplier. 
 
IV.   EXAMPLES OF AT-RISK PHARMACEUTICAL COMPONENTS  
 
The following listed components are considered to be at-risk for melamine contamination.  These 
components were identified from a search of the United States Pharmacopeia/National 
                                                 
5 An alternative method or methods can also be qualified for use in screening components for the presence of  
melamine.  The test method used should be suitable for detecting melamine contamination in at-risk components 
down to at least 2.5 parts per million (ppm) to  give a high degree of assurance that they are not contaminated.  
 
3 
 Contains Nonbinding Recommendations 
 
Formulary (USP/NF) monographs and the FDA Inactive Ingredient Database (IID).6  This list is 
not considered to be exhaustive, and it is essential that manufacturers evaluate their drug 
components to determine whether they are vulnerable to melamine contamination.  For each 
compendial component listed, a test for total nitrogen content is specified in the USP 
monograph.7  We have also listed certain noncompendial components that can be derived from  
animal-based materials and that could be tested by methods that are not specific to confirm the 
identity or structure of the material.  
 
   Adenine (USP) 
   Albumin (IID)8  
   Amino acids derived from casein protein hydrolysates8  
   Ammonium salts9  
   Calcium pantothenate (USP) 
   Caseinate or sodium caseinate (IID)8,10  
   Chlorophyllin copper complex sodium (USP) 
   Colloidal oatmeal (USP) 
   Copovidone (USP/NF) 
   Crospovidone (USP/NF) 
   Dihydroxyaluminum aminoacetate (USP) 
   Gelatin (IID)8  
   Glucagon (USP) 
   Guar gum (USP/NF) 
   Hyaluronidase (USP)8  
   Imidurea (USP/NF) 
   Lactose (USP/NF, IID)10  
   Melphalan (USP) 
   Povidone (USP/NF) 
   Povidone-Iodine (USP) 
   Protamine sulfate (USP) 
   Protein hydrolysate (powder) for injection (USP) 
   Taurine (USP) 
                                                 
6 The FDA Inactive Ingredient  Database (IID) is available on the Internet at 
http://www.accessdata.fda.gov/scripts/cder/iig/index.cfm. 
  
7 The nitrogen assay (see USP General Test Monograph for Nitrogen  Determination, USP <461>) converts all 
nitrogen in the sample to ammonia, and then  the ammonia liberated  by distillation is trapped as ammonium and  
measured using a pH titration. 
 
8 The sourced starting material can be derived from animal materials and tested for total nitrogen content to estimate 
protein content.  
  
9 This component includes any ammonium salt that is assayed using a pH titration to measure ammonia. Ammonium  
salts are being included here, in part, because of an  October 2008 reported incident  of melamine contamination in  
ammonium bicarbonate intended for food use.  The ammonium bicarbonate contamination was not found in the 
United States.  
 
10 The sourced starting material can be derived from  milk. 
4 
 Contains Nonbinding Recommendations 
 
   Thioguanine (USP) 
   Urea (USP) 
   Wheat bran (USP) 
   Zein (USP/NF) 
 
 
5