FDA ニトロソアミン類不純物のguideを発出の解説

FDAは、10月2日に、webセミナーで9月1日発出したガイダンス“Control of Nitrosamine Impurities in Human Drugs”を解説した。








Root Causes of Nitrosamine Contamination

Cause 1;Process Related

▪ Physicochemical properties of the starting materials, intermediates or Drug Substance

▪ Specific process conditions

▪ Impurities in or reactions with raw materials

Action: Development and Control Strategies







Cause 2: Supply Chain

▪Use of recovered or recycled materials or other intermediates (including of excipient) contaminated with nitrosamines

▪Cross-contamination in multi-purpose facilities

Action; Quality Oversight




アクション; 品質の監視

Cause 3; Stability

▪ Stability: Drug Substance or Drug Product

▪Excipient compatibility

Action; Quality Oversight

原因3; 安定性



アクション; 品質の監視


Recommendations to API Manufacturers

• Optimize design of process in route of synthesis “ROS”

➢ Related reaction conditions

➢ Amine bases

➢ Amide solvents – use caution

➢ Replace nitrites with other quenching agents for azide decomposition processes

➢ Control reaction sequence/conditions








• Audit/monitor supply chain

• Avoid cross-contamination



•交叉汚染を防ぐ (再生溶媒・触媒からの交叉汚染)、

Control of Nitrosamine impurity in APIs

➢ Case 1, nitrosamine level is more than LOQ and less than Acceptable Intake (AI):

▪ control strategy (including specifications)

➢Case 2, Nitrosamine level is more than AI:

▪ The batches should not be released unless with FDA agreement to prevent/mitigate drug shortages









Recommendations to Drug Product Manufacturers

• Collaborate with API manufacturers

➢If risk is detected, continuously test API lots until verified to be without unacceptable levels of nitrosamines

• Evaluate all pathways (including degradation) during manufacture and storage





• Control of nitrosamines in drug products

➢Case 1, nitrosamine level is more than LOQ and less than Acceptable Intake (AI):

▪ control strategy (specification); also necessary if risk is inherent from API or drug product

➢ Case 2, Nitrosamine level is more than AI:

▪ batches should not be released;

▪ contact FDA regarding batches on the market



▪管理戦略を立案(規格設定を含む)。 APIまたは医薬品にリスクが内在する場合にも必要




▪ FDA may exercise regulatory discretion when warranted to prevent/mitigate drug shortages. ▪FDAは、欠品を防止/軽減することが正当化される場合、規制上の裁量を行使する場合がある。


このガイダンスの工程表 Timeline: Three-Step Implementation


• Approved/marketed drug products

1. Risk assessment would be completed within 6 months from guidance publication (March 1st, 2021)



2. Confirmatory testing

Once risk is identified, Confirmatory testing should immediately start for high risk products



3. Submission of changes to FDA

Last two steps would be concluded within 3 years of guidance publication, any change should be submitted to FDA. (September 1st, 2023)


最後の2つのステップは、ガイダンスの公開から3年以内に終了します。変更がある場合は、FDAに提出すること。 (期限;2023年9月1日)


未承認薬の対応Implementation for Pending Applications


▪ Risk assessment and also confirmatory testing if at risk should be conducted.

▪ Changes may be submitted in amendment if not included in the original submission





➢Pending with FDA:

▪ Risk assessment and also confirmatory testing if at risk should be conducted.

▪ The applicant should report to FDA if nitrosamine level would be more than AI,

▪In the case nitrosamine level is more than LOQ and less than Acceptable Intake (AI), Applicant should submit their amendment to FDA with control strategy (including specifications)








This guidance describes

• Potential root causes of nitrosamine impurities in APIs and drug products

• Established AI limits

• Recommendations on the steps to take for prevention or mitigation of this issue

• Timeline for the implementation

• Expectations in DMFs/applications at various stages






•さまざまな段階でのDMF /申請書における(対応、修正)期待





• Harmonization with other international regulators;• EMA/EDQM/OMCL • HSA/TGA/HC

➢Systemic approaches of three-step mitigation strategy

➢Timeline for implementation of three-step strategy (EMA)

➢Acceptable Intake Limits

➢Analytical methods and criteria

• Benefits – APIs/drug product manufacturers and applicants can evaluate and address risks in consistent approaches globally

•他の国際規制当局;•EMA / EDQM / OMCL/ シンガポール保健省HSA /オーストラリア TGA / カナダHC と協調して進めている





•メリット-API /医薬品の製造業者と申請者は、一貫したアプローチでリスクを評価し、グローバルに対処可能