Journal of Literature Pharmacy Sciences

Farmasötik Ürünler ve Ham Maddelerde N-Nitrozaminlerin Oluşum Mekanizması ve Toksisitesi: Sistematik Derleme
Formation Mechanism and Toxicity of N-Nitrosamines in Pharmaceutical Products and Raw Materials: Systematic Review
Güler Yağmur AKYÜZa , Ela KADIOĞLUa
aGazi Üniversitesi Eczacılık Fakültesi, Farmasötik Toksikoloji ABD, Ankara, Türkiye
J Lit Pharm Sci. 2023;12(2):171-82
doi: 10.5336/pharmsci.2022-94271
Article Language: TR
Full Text
ÖZET
 Geçtiğimiz yıllarda beşerî ilaçlardaki N-nitrozamin safsızlıklarının tespiti küresel düzenleyici kurumların odak noktası hâline gelmiştir. Bunun başlıca nedeni, N-nitrozaminlerin güçlü mutajenik kanserojenler olarak bilinen bir bileşik sınıfı olmasıdır. Düzenleyici kurumlar bu safsızlıkların hastalar üzerindeki etkileri ve olası risklerin tespit edilmesi üzerine bir seri önlem almıştır. Alınan önlemler çoğu ilaç ürününün piyasadan geri çağrılmasıyla sonuçlanmıştır. İlaç ürünlerinde kanserojen safsızlıkların varlığı ürün geri çağırmanın en endişe verici nedenleri arasında yer almaktadır. İlk olarak 2018 yılında bir aktif farmasötik bileşen üreticisinden alınan valsartanda N-nitrozodimetilamin safsızlığının tespitiyle düzenleyici kurumlar ilaçlarda N-nitrozaminlerin varlığından haberdar olmuşlardır. Yapılan çalışmalar sonucunda, düzenleyici kurumlar incelemeyi sadece valsartan ilaçlarını değil diğer anjiyotensin reseptör blokerlerini (sartanlar) kapsayacak şekilde genişletmiştir. Daha sonra başka ilaç ürünleri ranitidin ve metforminde de eşik limitin üzerinde N-nitrozamin safsızlığı tespit edilmiştir. N-nitrozamin safsızlığı içeren ilaçların yalnızca valsartan ve tetrazol içeren anjiyotensin reseptör blokerleri ile sınırlı kalmayıp aynı zamanda ranitidin ve metformin ilaç ürünlerinin de bu duruma dâhil olması piyasadaki diğer ilaçların kullanıma yönelik güvenlik endişelerini artırmıştır. Geçtiğimiz yıllarda meydana gelen bu olaylar serisinin sonucunda ham madde ve ilaç ürünü üreticilerinin yetersiz ve eksik denetlenmesinin nihai ilaç ürünü kalitesi, güvenilirliği ve muhtemelen etkinliğinde nasıl bir olumsuz etkiye neden olduğu ortaya çıkmıştır. Bu derleme, N-nitrozaminlerin kimyasal ve toksikolojik özelliklerini, ilaçlarda N-nitrozamin safsızlıklarının oluşum mekanizmasını ve düzenleyici kurumlarının ilaç ve ham madde üreticilerine uyguladığı yaptırımlar ve oluşturulan yönergelerin ilaç ve ham madde üretim prosedürlerini nasıl etkilediğini anlatmayı amaçlamaktadır.

Anahtar Kelimeler: Nitrozaminler; ilaç kontaminasyonu; toksisite
ABSTRACT
 In recent years, the determination of N-nitrosamine impurities in human pharmaceuticals have been the focal point of global regulatory agencies. This is mainly because N-nitrosamines are a class of compounds known as potent mutagenic carcinogens. A series of precautions have been taken to identify the effects on patients and potential risks of these impurities by regulatory agencies. These precautions ended up with recalling of most of the pharmaceutical products from the markets. The presence of carcinogenic impurities in pharmaceutical products is amongst the most worrying reasons for product recalls. Regulatory authorities had become aware of the presence of N-nitrosamines in drugs with the determination of N-nitrosodimethylamine impurity in valsartan, which is purchased from an active pharmaceutical ingredient manufacturer in 2018. Regulatory agencies expanded the investigation to cover other angiotensin receptor blockers (sartans) not only valsartan. Afterwards, N-nitrosamine contamination was also determined above the threshold limit in other drug products such as ranitidine and metformin. The fact that determination of N-nitrosamine impurities in drugs are not only limited to angiotensin receptor blockers containing valsartan and tetrazole ring , but also includes ranitidine and metformin drug products , increased the safety concerns for the use of other drugs on the market. As a result of this series of events in the past years, it has been revealed that inadequate and incomplete inspection of raw material and pharmaceutical product manufacturers has had a negative impact on the quality, safety and possibly efficacy of the final drug product. This review aims to explain the chemical and toxicological properties of N-nitrosamines, the mechanism of formation of N-nitrosamine impurities in drugs, and how the sanctions and regulations imposed by regulatory agencies on drug and raw material manufacturers affect drug and raw material production procedures.

Keywords: Nitrosamines; drug contamination; toxicity
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