WHO good manufacturing practices considerations for the prevention and control of nitrosamine contamination in pharmaceutical products

The WHO has published a new draft guideline on considerations for the prevention and control of nitrosamine contamination in pharmaceutical products. This guideline applies to all manufacturers of excipients, active pharmaceutical ingredients and finished pharmaceutical products.

The guideline helps manufacturers with questions they should answer regarding risk assessment and root cause analysis. It provides also examples of possible root causes.

There are separate sections for excipients and packaging materials, APIs and finished pharmaceutical products.

Sections on analytical methods and recommendations complete the document.

The WHO’s draft guidance is open for comments until 9 June 2024.

You can download the full document as PDF below.

Introduction

1.1. Nitrosamines and their precursors are found in food products and other consumer products such as processed meats, alcoholic beverages, and cosmetics. In these cases, they are normally present in small quantities.

1.2. Foods such as meats, dairy products and vegetables as well as drinking water may contain low levels of nitrosamines. There is no immediate health risk associated with the use of pharmaceutical products containing levels of a nitrosamine impurity below recommended acceptable intake limits. The actual health risk varies from person to person and also depends on the chemical structure of the nitrosamine contaminant. Nitrosamine impurities may increase the risk of cancer in case of exposure above acceptable levels and over long periods of time (i.e., lifetime intakes below acceptable limit is not expected to significantly increase cancer risks). The risk further depends on several factors, such as:

• the daily dose of the medication;
• how long the medication is taken;
• the level of the nitrosamine impurity in the finished product.

1.3. In recent years, some manufacturers of pharmaceutical products have identified that their products were contaminated with N-nitrosodimethylamine (NDMA), hereafter referred to in general, as nitrosamines). This has led to worldwide recalls of certain products that contained levels of nitrosamines above acceptable limits.

1.4. Nitrosamines is a group or class of compounds which have the chemical structure of a nitroso group bonded to an amine (R1N(-R2)-N=O). The compounds can form by a nitrosating reaction between amines (secondary, tertiary, or quaternary amines) and nitrous acid (coming from nitrite salts under acidic conditions) (1).

1.5. Nitrosating agents include nitrites (e.g. sodium nitrite, NaNO2) and nitrous acid (HNO2), nitric oxide (NO), nitrosyl halides (e.g. ClNO, BrNO), dinitrogen trioxide (N2O3), dinitrogen tetroxide (N2O4) and organic nitrites (e.g. t-BuONO). Some can arise from recycled solvents or reused catalysts from different processes or across manufacturing lines with inadequate control and inappropriate monitoring.

1.6. N-Nitrosamines are a class of substances of concern to international regulators and the pharmaceutical industry. This is because many nitrosamines are highly potent mutagenic agents that have been classified as probable human carcinogens. In order to control the presence of nitrosamines in pharmaceutical products, manufacturers should be familiar with the root causes of nitrosamine impurities in their products. A comprehensive risk management plan should be established and implemented.

1.7. Manufacturers should perform risk assessments to determine whether their products are at risk of containing nitrosamine impurities, and ensure that the levels of impurities do not exceed the acceptable limits. Risk assessment should include the assessment of information relating to excipients, active pharmaceutical ingredients (APIs) and finished pharmaceutical product manufacture. It should cover potential formation and presence of nitrosamine impurities, as well as the potential for contamination of other products from e.g. materials, other products or residue on commonly used equipment.

1.8. New impurities of concern may be identified on an ongoing basis. The following nitrosamine impurities are currently of concern: (Note: This not an exhaustive list)

• N-nitrosodimethylamine (NDMA)
• N-nitrosodiethylamine (NDEA)
• N-nitrosodiisopropylamine (NDIPA)
• N-nitroso-N-methyl-4-aminobutanoic acid (NMBA)
• 1-methyl-4-nitrosopiperazine (MNP)
• N-nitrosoethylisopropylamine (NEIPA)
• N-nitrosodibutylamine (NDBA)

1.9. Materials, equipment and utilities, may contain contaminants that may be carried over into another material, intermediate, excipient or finished product resulting in contamination or in the formation of nitrosamines. This may result in an adulterated product which could be harmful to patients.

1.10. Traces or residue of unwanted substances present in materials, on surfaces of equipment, in the environment, or in carrier material such as water – may be difficult to remove. These may also be difficult to detect through conventional analytical procedures and basic tests.

Validated, sensitive, selective analytical procedures may have to be used to detect these contaminants.

… (you find the complete document as PDF to download below).

See the full draft working document QAS/24.943 on “WHO Nitrosamine Contamination” here

(click the picture to download the working document)

Please submit your comments through the online platform, PleaseReview™
(https://who.pleasereview.net/Main/Default.aspx?action=loaddocument&reviewid=244). If not registered or included in our mailing list, submit your request with full name, email address and organization/affiliation to [email protected].

For any technical questions, you may contact Dr Steve Estevao Cordeiro, Technical Officer, Norms and Standards for Pharmaceuticals, Technical Standards and Specifications ([email protected]), with a copy to Ms Bezawit Kibret ([email protected], [email protected]).

Comments should be submitted through the online platform by 09 June 2024. Please
note that only comments received by this deadline will be considered for the preparation of this document.

Source: WHO, draft working document QAS/24.943:  “WHO Nitrosamine Contamination”