Module 3 - Strategic case studies in practice

Due to lack of general N- nitrosamine determination methods for any kind of API or FP, the workup procedures for specific API, e.g. ‘sartans’ or ranitidine, or drug formulations have to be re-evaluated when additional compounds get into the focus of analysis. To overcome time-consuming efforts for routine screenings on NDMA or NDEA, novel high throughput MS applications were already tested to analyse great numbers of samples (e.g. RapidFire-MS). Unfortunately, the desired LOD and LOQ levels have not yet been reached so far. It is important to note that results, LODs and LOQs for a certain finished product should always be reported in relation to the declared amount of API in this finished product since the declared amount of API is used for estimation of exposure to N- nitrosamines. The actual weight of a dosage unit is usually unknown to either the patient or the physician. Thus, results or LOQs reported in relation to the weight of the dosage unit are meaningless for estimation of exposure.

2.3.8. Discussion on analytical aspects

The CHM considers that analytical procedures for N- nitrosamines should be carefully chosen taking into account:

• potential presence of precursors (secondary amines; nitrite) in the sample

• workup procedures must be validated for any potential interferences

• hydrophilicity / lipophilicity as well as volatility / non-volatility of the target analyte

• use of an adequate internal standard with high purity grades to overcome any loss during sample preparation and to assure accurate quantitation • LOQ provides the minimum level at which an analyte can be quantified with acceptable accuracy and precision and is thus preferred over LoD for impurity testing and decision-making • LOQ should be minimum at or sufficiently below the toxicologically required limit, taking into account the purpose of testing (e.g. routine testing, justifying skip testing, justifying omission of specification) Since different matrices and target analytes are possible, a universally applicable sample preparation method and the use of either HPLC or GC cannot be recommended in general. However, the sample preparation performed by the Swiss OMCL using suspension of the sample in sodium hydroxide solution followed by liquid-liquid extraction with dichloromethane may be applicable to various APIs and finished products. Nevertheless, specific validation is necessary in each case.

2.4. Considerations for calculating risk for exposed patients in case of detection of N-nitrosamines in medicinal product(s)

2.4.1. Background exposure to N- nitrosamines

2.4.1.1. Exposure to exogenous N-nitrosamines

N- nitrosamines are considered as a serious health risk in all products with consumer/patient exposure and remaining levels in these are limited by the ALARA/ALARP principles. As concluded in the Sartan referral, the intake of NDMA and NDEA should be seen in relation to the overall intake of genotoxic carcinogens, e.g. as benzo[a]pyrene and other PAHs and also other nitrosamines that are present in common food sources such as grilled meat. As it is beyond the scope

EMA/369136/2020

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