Last update on November 8, 2024
The acceptable intake (AI) of nitrosamines in pharmaceutical products are established by regulatory agencies to ensure patient safety.
The FDA also acknowledges the challenge posed by limited compound-specific data for NDSRIs. This lack of data has led to applicants conducting unnecessary studies or even discontinuing drug products from the market. Drug shortages have ensued, impacting patient access to medications. For that reason, the guide addresses these challenges and aims to strike a balance between safety assessments and uninterrupted drug supply.
To calculate the acceptable limits of nitrosamines in pharmaceutical products, you can use the following template. This template involves calculating the acceptable daily intake (ADI) based on toxicological data, typically using the threshold of toxicological concern (TTC) approach for nitrosamines. The template includes steps for determining the maximum allowable concentration in the drug product based on daily dosage .
N-Nitrosamine impurities, including nitrosamine drug substance-related impurities (NDSRIs), have challenged pharmaceutical industry and regulators alike and affected the global drug supply.
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Set an appointmentThe Importance of Predicting Carcinogenic Potency and AI Limits for Nitrosamines in Pharmaceuticals
1. Health and Safety Concerns
- Carcinogenic Risk: Nitrosamines are a class of compounds known to be potent carcinogens in animal studies, and their presence in pharmaceuticals can pose significant cancer risks to humans. Accurate prediction helps in assessing and mitigating this risk by calculating the Acceptable Intake (AI) limits, which represent the maximum daily exposure to nitrosamines that is unlikely to pose a significant cancer risk over a lifetime.
- Exposure Limits: Establishing AI limits ensures that the levels of nitrosamines in drugs are within safe exposure limits, reducing the risk of long-term adverse health effects for patients.
2. Regulatory Compliance
- Regulatory Requirements: Agencies like the FDA, EMA, and WHO have stringent guidelines regarding the permissible levels of nitrosamines in pharmaceuticals. Predicting carcinogenic potency and AI limits helps pharmaceutical companies comply with these regulations, avoiding legal and financial repercussions.
- Product Safety and Market Approval: Adherence to regulatory limits on nitrosamines is essential for market approval of pharmaceutical products. Predictive tools facilitate early detection and control of nitrosamine levels during drug development and manufacturing processes.
3. Public Health importance
- Risk Management: Proactive identification and control of nitrosamine contaminants protect public health by minimizing exposure to potentially carcinogenic compounds in medicinal products.
- Trust in Pharmaceutical Products: Ensuring that pharmaceutical products are free from harmful levels of nitrosamines maintains public trust in medication safety and efficacy.
4. Scientific and Technological Advancements
- Improved Predictive Models: Advancements in AI and computational models enhance the ability to predict the carcinogenic potency of nitrosamines more accurately. This allows for better risk assessment and management strategies.
- Cost and Time Efficiency: Predictive modeling reduces the need for extensive in vivo testing, saving time and resources in the drug development process.
Calculating Acceptable Intake (AI): Step-by-Step Methods
Determine which nitrosamines could potentially be present in your drug product or API. Common nitrosamines include N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA).
Determining the Permissible Daily Exposure (PDE) for nitrosamines involves identifying the specific nitrosamines present, referring to regulatory guidelines to find the PDE values, and ensuring that these values are not exceeded in the pharmaceutical product. Using the provided sources, you can obtain accurate and up-to-date PDE values for various nitrosamines to ensure compliance and safety.It is important for calculating the Acceptable Intake (AI) limits.
Identify Nitrosamine Compounds
Identify the specific nitrosamines present or potentially present in the pharmaceutical product. Common nitrosamines include:
- N-nitrosodimethylamine (NDMA)
- N-nitrosodiethylamine (NDEA)
- N-nitroso-N-methyl-4-aminobutyric acid (NMBA)
- N-nitrosodipropylamine (NDPA)
- N-nitrosomethylphenylamine (NMPA)
Refer to Regulatory Guidelines : Regulatory bodies provide specific PDE values for various nitrosamines. The following sources can be referred to for these values: FDA Guidance on Nitrosamine Impurities: FDA Guidance Document , EMA Q&A on Nitrosamines: EMA Guidance Document , ICH M7(R1) Guideline: ICH Guideline .
Extract PDE Values from Guidelines : Extract the PDE values for each identified nitrosamine from the regulatory guidelines. These values are typically provided in the form of Acceptable Intake (AI) limits. Here are the common PDE values for some nitrosamines:
- NDMA: 96 ng/day
- NDEA: 26.5 ng/day
- NMBA: 96 ng/day
- NDPA: 26.5 ng/day
- NMPA: 26.5 ng/day
Use the PDE Values in Risk Assessment : Incorporate these PDE values into the risk assessment and control strategies for the pharmaceutical product. Ensure that the levels of nitrosamines in the product do not exceed these PDE values.
Establish the maximum daily dose (MDD) of your drug product. This information is crucial as it directly influences the acceptable concentration of nitrosamines.
Step-by-Step Calculation of MDD
1. Identify the Dosage Form and Strength:
- Determine the strength of the active pharmaceutical ingredient (API) in each unit of the dosage form (e.g., mg per tablet, mg per capsule, mg per mL of injection).
2.Determine the Recommended Daily Dosage:
- Refer to the prescribing information to find the recommended daily dosage, which includes the number of doses per day and the amount of API per dose.
3. Determine the Maximum Daily Dose (MDD):
- If the maximum daily dose is specified directly in the prescribing information, use that value.
- If not directly specified, calculate the MDD by using the highest recommended dose within the approved dosage range.
Example Calculation
Scenario
- Dosage Form: Tablet
- Strength of API: 50 mg per tablet
- Recommended Dosage: 1 tablet twice a day (BID)
- Maximum Dosage: Up to 4 tablets per day
Calculation
Total Daily Dose:
Formula: Total Daily Dose = Strength of API × Number of Doses per Day
Example: Total Daily Dose = 50mg/tablet × 2 tablets/day = 100mg/day
Maximum Daily Dose (MDD):
Formula: MDD = Strength of API × Maximum Number of Doses per Day
Example: MDD = 50 mg/tablet × 4 tablets/day = 200mg/day
Using the PDE and MDD, calculate the acceptable concentration limit of each nitrosamine in your product. The formula is:
Acceptable Concentration (ng/mg)= AI Limit (ng/day) / MDD (mg/day)
Let’s take another example and calculate the acceptable concentration of NDMA in a drug product with a maximum daily dose of 500 mg/day.
- Maximum Daily Dose (MDD): 500 mg/day
- AI Limit for NDMA: 96 ng/day
- Acceptable Concentration of NDMA = 96 ng/day / 500 mg/day = 0.192 ppm = 192 ppb
Use validated analytical methods to test your product for nitrosamine levels. Ensure these methods are sensitive enough to detect concentrations at or below the acceptable limits.
Implementing validated analytical testing for nitrosamine levels involves several key steps to ensure accuracy, sensitivity, and compliance with regulatory standards. Below is a detailed guide on how to perform this:
Steps to Implement Analytical Testing for Nitrosamines :
A) Selection of Analytical Methods:
- Choose suitable analytical methods that are validated for detecting nitrosamines. Common techniques include:
- Gas Chromatography-Mass Spectrometry (GC-MS)
- Liquid Chromatography-Mass Spectrometry (LC-MS)
- High-Performance Liquid Chromatography (HPLC) with tandem mass spectrometry (HPLC-MS/MS)
- Ensure the methods are capable of detecting nitrosamine impurities at concentrations at or below the acceptable limits (ng/mg level).
B) Method Validation:
- Validate the chosen analytical methods according to regulatory guidelines to ensure accuracy, precision, specificity, sensitivity, reproducibility, and robustness.
- Key parameters to validate include:
- Accuracy: The closeness of the test results to the true value.
- Precision: The repeatability of the test results.
- Specificity: The ability to unequivocally assess the analyte in the presence of components that may be expected to be present.
- Sensitivity: The lowest amount of the analyte that can be detected but not necessarily quantified.
- Limit of Detection (LOD) and Limit of Quantitation (LOQ): The lowest concentration of the analyte that can be reliably detected and quantified, respectively.
- Linearity: The ability to obtain test results that are directly proportional to the concentration of the analyte.
- Range: The interval between the upper and lower levels of the analyte that have been demonstrated to be determined with precision, accuracy, and linearity.
C) Sample Preparation:
- Prepare the pharmaceutical product samples for analysis following standardized procedures to ensure consistency.
- Include sample extraction, purification, and concentration steps to isolate nitrosamines from the matrix.
D) Quality Control:
- Use control samples, including spiked samples with known concentrations of nitrosamines, to verify the accuracy and precision of the testing process.
- Implement routine quality control checks to ensure ongoing reliability of the analytical methods.
E) Testing and Data Analysis:
- Conduct the testing using the validated methods on prepared samples.
- Analyze the data to quantify nitrosamine levels in the pharmaceutical product.
- Ensure that the detection limits of the methods are adequate to meet the regulatory acceptable limits.
F) Documentation and Reporting:
- Document all steps of the analytical testing process, including method validation, sample preparation, and testing procedures.
- Report the findings in a detailed and transparent manner, including the levels of detected nitrosamines and their comparison to the acceptable limits.
- Maintain records for regulatory review and compliance audits.
G) Regular Monitoring and Revalidation:
- Continuously monitor nitrosamine levels in pharmaceutical products through periodic testing.
- Revalidate analytical methods whenever there are significant changes in the process, formulation, or regulatory requirements.
Develop a robust control strategy to monitor nitrosamine levels throughout the production process. This can include:
- Regular testing of raw materials and final products.
- Optimizing manufacturing processes to minimize nitrosamine formation.
- Implementing quality control measures to detect and address any deviations.
FAQs and Additional Resources for Acceptable Intake (AI)
Q 1> What are nitrosamines, and why are they harmful?
Nitrosamines are chemical compounds that can form in pharmaceuticals and are known to be potentially carcinogenic.
Q 2> How can nitrosamines form in drug products?
They can form through chemical reactions involving nitrites and secondary amines, often during manufacturing or storage.
Q 3> Where can I find regulatory guidelines for nitrosamines?
Guidelines are available on the websites of regulatory agencies like the FDA and EMA.
Q 4> What should I do if nitrosamine levels exceed acceptable limits?
If nitrosamine levels exceed acceptable limits, it is important to investigate the source of contamination, implement corrective actions to reduce the levels, and consult with regulatory bodies for guidance. Engaging with health authorities ensures that appropriate steps are taken to protect patient safety and compliance with regulatory standards is maintained.It is important for calculating the Acceptable Intake (AI) limits.
Conclusion
The FDA’s final guidance on nitrosamine impurities represents a milestone in the pharmaceutical industry’s journey towards enhanced safety and patient care. By addressing the challenges associated with NDSRIs and setting AI limits, the FDA and EMA are taking significant steps to protect public health. Pharmaceutical manufacturers, in collaboration with regulators, are now equipped to navigate these changes and provide safe and effective drug products to patients worldwide.
calculating the Acceptable Intake (AI) limits of nitrosamines involves understanding regulatory guidelines, precise calculations based on PDE and MDD, and rigorous testing and control measures. By following these steps, you can ensure that your drug products remain safe for consumers and comply with regulatory standards.
Referenzen
- https://www.fda.gov/drugs/drug-safety-and-availability/information-about-nitrosamine-impurities-medications
- https://www.ema.europa.eu/en/human-regulatory-overview/post-authorisation/pharmacovigilance-post-authorisation/referral-procedures-human-medicines/nitrosamine-impurities
- ICH M7 Assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk – Scientific guideline | European Medicines Agency (europa.eu)
- Health Canada updates guidance on nitrosamine impurities in medications – Canada.ca
- Nitrosamine impurities in medications: Overview – Canada.ca
- https://www.pmda.go.jp/files/000241927.pdf
Sagar Pawar
Sagar Pawar, a Quality Specialist at Zamann Pharma Support, brings over 11 years of experience in Quality domain for the pharmaceutical and medical technology industries. Specializing in qualification, validation, Computer System Validation (CSV), and Nitrosamine activities, Sagar is currently focused on enhancing the Zamann Service portfolio by developing and implementing robust strategies to address Nitrosamine-related challenges. Outside of work, Sagar enjoys trekking and cooking. Connect with Sagar on LinkedIn to discuss topics related to equipment qualification, GMP Compliance and Nitrosamine-related challenges.
