APIC Guidance on the Risk Assessment for Presence of N-Nitrosamines in APIs

The EMA and other Health authorities have published requirements (EMA/189634/2019) and Health Canada Letter for the API industry and the MAH for drug products to expand the scope of potential sources of nitrosamines beyond that of ICH M7.

This requirement is based on the fact that, as the Industry and the authorities are gathering more information about the potential ingress / formation of such impurities in APIs, there is need to expand the evaluation of risk assessments that are needed to ensure APIs are fit for their intended use and do not pose a patient safety risk for such impurities.

Risk Assessment Guidance

The request from health authorities is to perform the assessment to all market products. Due to the large numbers of products involved, EMA document suggests the use of a risk-based approach to prioritize the evaluations and later the confirmatory testing (if the risk evaluation would indicate that testing would be required). The factors suggested are daily dose taken, duration of treatment, therapeutic indication and number of patients treated. However, this data is not always available at the API manufacturers side, who might use other criteria such as the ones suggested below to perform the requested risk evaluations.

Prioritization of the Rrisk Assessment

The following criteria might be used for prioritization (“>” meaning “higher priority than”) Mdepending on the information available:

Higher daily dose taken
Long duration of treatment
Therapeutic indication
Higher number of patients treated
Commercial APIs > APIs used for clinical trials
API manufactured in multipurpose equipment > dedicated equipment
API manufactured in multipurpose equipment exposed to nitrosating agents
API > Intermediate > RSM (for companies manufacturing the three categories)
APIs still manufactured > APIs no longer manufactured but still on the market
APIs sold to markets where risk assessment have already been requested by authorities > APIs sold to other markets
Knowledge of the likelihood of a risk based on the chemistry of the process (presence of amine, nitro functionalities, nitrosating agents)

Management of Raw Materials in the Risk Assessment

The need and type of information to be obtained from suppliers depends on the type of material and on its use in the manufacturing process. Following factors are helpful to assess the impact of the raw materials on the risk to have nitrosamines in the API.

Regulatory status of the raw material in the associated regulatory file (RSM, processing
aid etc.)

Chemistry of the raw material such as:

complex process
use of nitrosating agents and amines
type of solvents used (e.g. recovered in house or by 3rd party)

Number and type of chemical steps between introduction of raw material and final API stages. The evaluation should take in consideration:

if the raw material is used in early or late steps of the API synthesis
If the next step(s) can purge the impurities or not, and if yes at which level the impurity can be purged
type of chemical process(es) is involved and process conditions
if the next step(s) can purge the impurities or not and if yes at which level
if the raw material is used in later stages of the API synthesis and no further crystallization is performed

The information from raw material suppliers can be also obtained through questionnaires, which cover chemical process and risk of contamination at the raw material supplier’s facility.

The scope of the questionnaire can be very narrow and composed by just the 2 questions below to perform an efficient screening, or more complex covering all applicable potential sources of nitrosamines as described in EMA.

Do you manufacture nitrosamines, amines or sources of amines in the same equipment as those used to manufacture the raw material?

Do you use or is there a potential presence of nitrosating agents and/or amines (secondary or tertiary amines) in your manufacturing process?

Examples of nitrosating agents can be found in EFPIA decision-tree for N-nitrosamine risk
assessment or IPEC questionnaire.

Risk Assessment

EFPIA decision tree is a helpful tool to undertake the risk assessment. The risk assessment should consider the following possible sources:

Raw materials
Manufacturing process and reaction conditions
Structural study and potential subsequent degradation of the structural fragments
Water
Cross contamination and cleaning of equipment
Steam, cleaning agents other than solvents, and consumables
Nitrogen
Primary packaging

Boundaries of the Risk Assessment

As the risk assessment has to address routine and accidental presence of nitrosamines in APIs, the definition of the boundaries of the risk assessment should be justified. A difference should be made between “possibility” to have nitrosamine and “likelihood” to have nitrosamines.

Some potential helpful criteria are listed below:

Number of synthesis steps where critical components are used (e.g. sodium nitrite and secondary amines) by calculating the theoretical value, assuming that all nitrites and amines a converted in nitrosamines.
Number of synthesis steps after potential nitrosamine formation and if they are able to purge the potential impurities formed.

Methodology and Outcome of the Risk Assessment

The risk assessment can be performed:

Through a FMEA-type tool with different scores assigned to various risk levels
Through a yes/no questionnaire which has the benefit of better orienting the result. An example of such a questionnaire can be found in the IPEC questionnaire.

The outcome of the risk assessment can be:

A high/medium/low risk to further establish planning and priority of next steps (in particular analytical testing), so that the API producer can prioritize further mitigation measures
A negligible/potentially present outcome for external use to provide a clear position to the MAH.

Lifecycle of the Risk Assessment

The risk assessment is a living document which will be updated whenever additional knowledge is obtained on the API or process change is conducted (when risk assessment may need repeated). Mitigation actions should be defined if a risk is identified.

Analytical Testing

The outcome of the risk assessment performed for the API manufacturing process will determine the need for analytical testing to confirm the presence and content of any potential Nitrosamine impurity(ies). The confirmatory testing is defined as Step 2 on the EMA document.

During the confirmatory testing – step 2 on the EMA, priority should be provided to the APIs with a theoretical value classified as “potentially present” and “at risk” as per the following table:

At least 3 consecutives commercial batches of API should be tested to confirm the level of nitrosamines in the API. Whenever values above 30% of the interim limit are confirmed, Marketing Authorization Holder should be informed. API Manufacturer should clearly identify the sources of the concerned impurities, to define actions to reduce the values determined and to update the control strategy document accordingly.