By Phil Crooker, VP – Technical, Regulatory & Access, Parexel
I have written previously about general points to consider in managing the submission of information with regulatory applications related to the control of potentially mutagenic impurities based on written advice that the U.S. Food and Drug Administration (FDA) had published (see the blog post here. I also wrote a companion piece about the CGMP compliance and enforcement trends that could be gleaned from Warning Letters issued to firms involved in the synthesis and manufacture of active pharmaceutical ingredients (API) and drug products where the presence of nitrosamine-related impurities had been detected (see the blog post here). More recently I wrote about the after-action report in the wake of the nitrosamine-related impurities issues in Europe that the European Medicines Agency had written that has broad implications for not just API at-risk for nitrosamine contamination but broader and more comprehensive regulation of API manufacture (you can find that blog here).
Now the FDA has joined the fray with a substantial new guidance document. On September 3, 2020 the agency published the Guidance for Industry - Control of Nitrosamine Impurities in Human Drugs. You can find a copy of the guidance document and the Federal Register notice here). Three quick points about how seriously FDA views this new guidance document:
- The guidance was not published in draft form but rather for immediate implementation because of the public health importance in sharing the information.
- COVID-19 has forced FDA to put a moratorium on most guidance development not related to the pandemic, and this is one of the few non-COVID19 related guidance documents to be published since early this year.
- And the FDA Small Business & Industry Assistance (SBIA) will broadcast a free webinar to discuss the implementation of the recommendations in the guidance in October. You can find more information about how to register for the webinar here.
The guidance document is chock full of information. Here’s how I have unpacked the critical points raised in the guidance.
- The FDA notes that the unexpected findings of nitrosamine impurities in several classes of drugs has made clear the need for a risk assessment strategy for potential nitrosamines in any pharmaceutical product at risk for their presence. At first blush this appears to be a more limited and different approach that the EMA has taken that required firms to evaluate all API chemically synthesized and drug products formulated using those API for the presence of nitrosamine impurities (you can find the detailed information from EMA here.
- However, later in the guidance document FDA states that the recommendations in the guidance apply to all chemically synthesized API and to drug products containing chemically synthesized API and to drug products at risk due to other factors described in the guidance. This is more closely aligned with the EMA approach, and FDA confirms that it has been collaborating with other international regulators on this issue, including EMA.
Types of Nitrosamine Impurities
- The FDA has identified seven nitrosamine impurities that theoretically could be present in drug products but only five of them have been detected in API or drugs products. These five are: (1) (2) NDMA; (3) NDEA; (4) NMPA; (5) NIPEA; and (6) NMBA. Structures and nomenclature are found on page 4 of the guidance.
General Root Causes for Presence of Nitrosamine Impurities in API
The agency outlined 6 root causes of the presence of nitrosamine impurities in API based on information it has gathered (such as through inspections, testing and research, application review and industry responses to general advice and information request letters).
- General reaction conditions.
- Sources of amines that can form nitrosamines.
- Contamination in vendor sourced raw materials.
- Recovered solvents, catalysts and reagents as sources of contamination.
- Use of a quenching step performed directly in the main reaction mixture.
- Lack of process development and control.
General Recommendations for Industry to Implement
- Manufacturers should prioritize evaluation of API and drug products based on factors such as maximum daily does, duration of treatment, therapeutic indication and number of patients treated.
- The guidance lists the recommended acceptable intake limits for the 5 nitrosamine impurities that have been detected to be present by FDA in API and drug products. The limits are applicable only if a drug product contains a single nitrosamine impurity. If more than 1 of the nitrosamine impurities are detected, then additional guidance is given.
- Sensitive methods with limits of quantitation in the parts-per-billion (ppb) range are needed and methods with limits of detection (LOD) at or below 0.3 parts-per-million (ppm).
- API and drug product manufacturers should take the following steps to mitigate nitrosamine impurities (these steps very closely resemble the process that was laid out by the EMA but differs about how the risk assessments are handled):
- Assess the risk of nitrosamines in API, marketed products, and products under development and in pending applications. The risk assessments should be conducted promptly (see the last section on recommended timeline) based on the prioritization of the drugs. This section of the guidance states that the risk assessments do not need to be submitted to FDA but kept available for inspection or if requested by the agency.
- Conduct confirmatory testing when there is any risk for the presence of nitrosamine impurities.
- Report changes implemented to prevent or reduce the impurities in API and drug products for DMF, approved and pending applications.
Specific Recommendations for API Manufacturers
There is a general sequence of 4 steps that FDA recommends each API manufacturer follow: (1) review API processes and perform a risk assessment; (2) if a risk of a nitrosamine impurity has been identified, conduct confirmatory testing; (3) if the risk assessment determines there is no potential for nitrosamine impurities, no further action is needed; (4) if a nitrosamine impurity is detected, then investigate the root cause and implement changes in the process to mitigate or reduce the impurity.
FDA recommends that API manufacturers take these steps to mitigate and control the presence of nitrosamine impurities:
- Develop and optimize the design of manufacturing processes to minimize or prevent the formation of nitrosamine impurities.
- Consider removing quenching steps from the main reaction mixture to reduce the risk of nitrosamine formation.
- Audit supply chains and monitor them for any at-risk raw materials, starting materials, and intermediates. Consider establishing controls and additional specifications for at-risk materials.
- To avoid cross-contamination, recovered materials should only be used in the same or earlier process step (if there was sufficient purification) of the same process from which it was collected. Recovered materials should meet appropriate standards. If the recovery operations are outsourced, the manufacturer should audit the contractor’s cleaning procedures.
- Manufacturers should analyze nitrite and nitrosamine levels in potable water used in manufacturing and use water that has been purified to remove unacceptable impurities.
- Batches may be reprocessed or reworked to control the level of nitrosamine impurities.
- Develop an appropriate controls strategy, including specification limits, to ensure that the nitrosamine levels remain consistently below the allowable intake limit.
- For API with an impurity detected above the LOQ or at-risk API, testing each batch on release should be conducted.
- Any API batch with levels of nitrosamines above the recommended allowable intake limit should not be released unless the FDA agrees that the API is needed to mitigate a drug shortage.
Specific Recommendations for Drug Product Manufacturers
Similar to the recommendations for API manufacturers, there is a general sequence of 4 steps that FDA recommends each drug product manufacturer follow: (1) conduct risk assessments to determine the potential for nitrosamine impurities – the risk assessment should involve the API manufacturer and examine formulation process conditions and degradation pathways on stability; (2) if the risk assessment determines there is no potential for nitrosamine impurities, no further action is needed; (3) if a risk of a nitrosamine impurity has been identified, conduct confirmatory testing;; (4) if a nitrosamine impurity is detected, then investigate the root cause and implement changes in the process to mitigate or reduce the impurity.
FDA recommends that drug product manufacturers take these steps to mitigate and control the presence of nitrosamine impurities:
- Test representative samples of all incoming API prior to use and continue testing until they have verified that the API supplier can consistently manufacture API without unacceptable levels of nitrosamine impurities.
- Evaluate whether nitrites could be present during manufacturing processes where at-risk API is used and also evaluate whether nitrosamines could form in a finished drug product over its shelf-life.
- If a nitrosamine impurity is detected above the LOQ, develop a control strategy to ensure that the limit remains within the allowable intake limit – including specification limits.
- A control strategy is also recommended in situations where the introduction of a nitrosamine is inherent due to the API structure, route of synthesis or the manufacturing process of the API or drug product.
- Testing of each batch on release should be conducted.
- If drug product batches with unacceptable levels of nitrosamine impurities are in distribution, the manufacturer should contact the FDA.
- Any drug product batch found to contain levels of nitrosamine impurities at or above the recommended allowable intake limits should not be released for distribution.
Recommended Timelines for Risk Assessments, Confirmatory Testing and Reporting of Changes
- For approved or marketed products:
- Conclude risk assessments within 6 months of date of publication of the guidance.
- Confirmatory testing should start as soon as the risk of a nitrosamine impurity is identified from the risk assessments (however, the guidance is silent on time needed to develop and validate the necessary analytical tests for in-process, release and stability).
- Confirmatory testing should begin immediately for products considered high risk (again, the guidance is silent on time needed to develop and validate the necessary analytical tests for in-process, release and stability).
- Confirmatory testing of drug products and submission of required changes in drug application should be concluded within 3 years of the date of publication of this guidance.
- For pre-submission products:
- Conduct risk assessment for API and drug product and perform confirmatory testing as needed prior to submission of the original application.
- The risk assessment and confirmatory testing, if needed, and changes to a DMF or application may be submitted in an amendment if they are not available at the time of the original application submission (this appears to conflict with the earlier statement in the guidance that risk assessments do not need to be submitted to the FDA but only available for inspection or on request).
- For pending applications:
- Conduct risk assessment for API and drug product expeditiously and inform FDA if confirmatory testing finds nitrosamine levels above the recommended allowable intake limit.
- If the nitrosamine impurity is detected above the LOQ but is within the allowable intake limit, the applicant should amend the application.
Parexel are here to help
Our 1000+ consulting group includes over 80 former regulators that can help clients rapidly navigate the process of re-tooling supply chains, ensuring compliance with applicable cGMP, preparing regulatory applications and responding to agencies to drive solutions that work to protect public health.