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FDA is implementing Pharmaceutical Quality/ Manufacturing Standards/ Current Good Manufacturing Practice (CGMP) guidance for the control of nitrosamine impurities in human drugs without prior public comment because the Agency has determined that prior public participation is not feasible or appropriate. FDA made this determination because of the importance of providing timely information to manufacturers regarding risk assessments, testing, and other appropriate actions they should take to reduce and mitigate nitrosamine impurities in active pharmaceutical ingredients (APIs) and drug products. This guidance document is being implemented immediately, but it remains subject to comment in accordance with the Agency’s good guidance practices.

This guidance recommends steps manufacturers of APIs and drug products should take to detect and prevent unacceptable levels of nitrosamine impurities in pharmaceutical products. The guidance also describes conditions that may introduce nitrosamine impurities.
 

General Root Causes for the Presence of Nitrosamine Impurities in APIs

1. General Conditions That Lead to Nitrosamine Formation
2. Sources of Secondary, Tertiary, and Quaternary Amines That Can Form Nitrosamines
3. Contamination in Vendor-Sourced Raw Materials
4. Recovered Solvents, Catalysts, and Reagents as Sources of Contamination
5. Quenching Process as a Source of Nitrosamine Contamination
6. Lack of Process Optimization and Control
    

Recommendations

Acceptable Intake Limits: FDA recommends the following acceptable intake (AI) limits for the nitrosamine impurities.

These limits are applicable only if a drug product contains a single nitrosamine. If more than one of the nitrosamine impurities identified in the Table is detected and the total quantity of nitrosamine impurities exceeds 26.5 ng/day (the AI for the most potent nitrosamines) based on the maximum daily dose (MDD), the manufacturer should contact the Agency for evaluation. For drug products with an MDD of less than 880 mg/day, a recommended limit for total nitrosamines of 0.03 ppm is not more than 26.5 ng/day and is considered acceptable. For drug products with an MDD above 880 mg/day, the limit for total nitrosamines should be adjusted so as not to exceed the recommended limit of 26.5 ng/day.
 

API and drug product manufacturers should take the following steps to mitigate nitrosamine impurities in their products:

1. Assess the risk of nitrosamine impurities in APIs, marketed products, and products under approved and pending applications. Risk assessments should be conducted in a timely manner based on the prioritization of drugs. Manufacturers do not need to submit risk assessment documents to the Agency, but they should retain these documents so that they are available if requested.

2. Conduct confirmatory testing when there is any risk for the presence of nitrosamine impurities. Due to nitrosamines’ physiochemical properties (low molecular weights, some volatility, and high toxicity), the analytical methods for nitrosamines need to have specificity, excellent chromatographic separation, and highly sensitive detection capability.

3. Report changes implemented to prevent or reduce nitrosamine impurities in APIs and drug products to FDA. This includes submission of any drug master file (DMF) amendments in accordance with 21 CFR 314.420(c) and changes to approved applications as required under 21 CFR 314.70 and 314.97 and pending applications under 21 CFR 314.60 and 314.96.
 

Recommendations to API Manufacturers:

1. API manufacturers should optimize the design of the manufacturing process for APIs during route of synthesis (ROS) development to minimize or prevent the formation of nitrosamine impurities. API manufacturers should refer to the recommendations in ICH M7(R1) and the ICH guidances for industry Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients (September 2016) and Q11 Development and Manufacture of Drug Substances (November 2012) in this respect.

2. API manufacturers should consider removing quenching steps (when there is a risk of nitrosamine formation, e.g., using nitrous acid to decompose residual azide) from the main reaction mixture to reduce the risk of nitrosamine formation.

3. API manufacturers should audit their supply chains and monitor them for any at-risk raw materials, starting materials, and intermediates.

4. To avoid cross-contamination when recovered materials such as solvents, reagents, and catalysts are used in the manufacturing process, recovered material should be used only in the same step or in an earlier step (if there is sufficient purification) of the same process from which it was collected.

5. API manufacturers should be aware that potable water used in API manufacture may contain low levels of nitrite and even nitrosamines from environmental contamination.

6. API batches may be re-processed or reworked to control the level of nitrosamine impurities as provided in ICH Q7 for amending and controlling such operations. If a batch is found to contain nitrosamine and is reprocessed or reworked in any way, these operations should be conducted under the oversight of the quality unit.
 

Recommendations to Drug Product Manufacturers

Drug product manufacturers should conduct risk assessments to determine the potential for nitrosamine impurities in drug products. A risk assessment should involve collaboration with the API manufacturer to aid in the identification of the API ROS or other process conditions of the API’s manufacture that put the drug product at risk for nitrosamine impurities. The risk assessment should also include evaluation of any pathway (including degradation) that may introduce nitrosamines during drug product manufacture or storage. If the risk assessment determines that there is no potential for nitrosamine impurities, there is no need to take further action. If a risk of nitrosamines in a drug product is identified, confirmatory testing of batches should be conducted using sensitive and appropriately validated methods. If a nitrosamine impurity is detected, manufacturers should investigate the root cause and implement changes in the manufacturing process to mitigate or reduce nitrosamine impurities.
 

Reporting Changes to FDA

Drug manufacturers must report changes implemented to prevent or reduce nitrosamine impurities in accordance with FDA regulations (21 CFR 314.60, 314.70, 314.96, and 314.97). If an API DMF holder makes process changes in the ROS as a result of the risk assessment and confirmatory testing, the DMF holder must submit amendments and inform each drug product manufacturer that references the DMF (including pending and approved applications), in accordance with 21 CFR 314.420(c). If the API is manufactured by the applicant and not covered by a DMF, the manufacturer must report such ROS changes in the application in accordance with 21 CFR 314.70 and 21 CFR 314.97. If a batch of API is found to contain a nitrosamine and is reprocessed or reworked in any way, these operations should be reported in the DMF or application (as applicable).