ELEMENTAL, NITROSAMINES  OTHER IMPURITY TESTING

Kymos provides Elemental and N-Nitrosamine impurities testing of drug products, substances and other sources in compliance with ICH Q3D guidelines, EMA and FDA LoQs and recommendations. This service targets clients interested in routine testing of finished dosage forms in drug products or identifying potential sources of impurities in drug substances, excipients, manufacturing equipment and reagents. We have significant analytical capacity with two ICP/MS and an AAS for elemental impurities plus HS-GC-MS and LC-MS/MS instruments for nitrosamines. The full service includes risk assessments with our strategic partner Azierta. We propose a three-step approach compliant with regulatory requirements:

  • Risk assessment according to regulatory guidelines
  • Limit test/semi-quantitative screening at default limits or upon client request
  • Quantitative method validation for impurities exceeding established limits

Our impurity services are grouped in two main chapters:

Elemental impurities

The European Pharmacopoeia and USP General Chapters are <232>, <233> and <2232> for drug substances, excipients and drug products, requires most drugs, including those for veterinary use, to be tested for the potential presence of the 24 elements listed in the ICH Q3D guideline. The chart below comprises all of them plus others required case by case:

Class 1Co, V, Ni Class 2A Class 2B Class 3 Others
Cd, Pb, As, Hg Co, V, Ni Tl, Au, Pd, Ir, Os, Rh, Ru, Se, Ag, Pt Li, Sb, Ba, Mo, Cu, Sn, Cr Al, B, Ca, Fe, K, Mg, Mn, Na, W, Zn…

Kymos has an experienced team dedicated solely to elemental impurities and equipped with two Ion Coupled Plasma Mass Spectrometers Agilent (7700, 7800) with high capacity autosamplers and Atomic Absorption (Varian 240 FS with graphite furnace and hydride generator) as well as two Ultrawave digestion systems from Milestone. Moreover, our team continues to develop assays to comply with new regulatory requirements:

• ICH Q3D-compliant pharmacopoeia compendial method for purified water (04/2018:0008)
• In-house validation of ICP-MS determination methods to replace colorimetric compendial methods such as Arsenic monograph (04/2018:20402)
• Bioanalysis of metals in biological samples from preclinical and clinical studies of IMPs
• Bioequivalence studies of metallic and organometallic compounds containing Sr, Li, Pt, Fe

 

N-nitrosamine impurities

N-nitrosamine impurity analysis includes all main impurities identified by the health authorities. Default screening limits originally established at 0.03ppm have been gradually improved, with our current sensitivity levels having reached 0.1ppb. The list below shows currently available nitrosamines, but new ones can be added upon client request:

Analytical Serviceprovider
  • NDMA: N-Nitrosodimethylamine
  • NDEA: N-Nitrosodiethylamine
  • NDIPA: N-Nitrosodiisopropylamine
  • NEIPA: N-Nitrosoethylisopropylamine
  • NDBA: N-Nitroso-di-n-butylamine
  • NMEA: N-nitrosomethylethylamine
  • NDPA: N-nitroso-di-n-propylamine
  • NMBA: N-Nitroso-N-methyl-4-aminobutyric acid
  • NPYR: N-Nitrosopyrrolidine
  • NPIP: N-Nitrosopyperidine
  • NMOR: N-Nitrosomorpholine
  • NDELA: N-Nitrosodiethanolamine
  • MNPZ: mono-N-Nitrosopiperazine
  • DNPZ: di-N-Nitrosopiperazine
  • NDPhA: N-nitroso-di-phenylamine
  • NMPA: N-nitrosomethyl-phenylamine

Kymos offers a competitive service owing to its dedicated team, significant sample analysis capabilities and two back-up methods available: Liquid chromatography-mass spectrometry (LC-MS/MS) Agilent 6490 Triple Quadrupole plus a Headspace Gas Chromatography (HS-GC-MS) Agilent 7890 with a 5977 Single Quadrupole limits. Our team continuously adapts our service to comply with new request of the Regulatory Agencies:

  • Lower LoQs: Initial 0.03ppm default limits were lowered to our current sensitivity of 0.1ppb
  • New LoQs based on acceptable intake (AI) and API maximum daily dose (MDD) depending on quantification type: ≤ 30% if the quantitative testing is performed to justify skip testing or ≤ 10% if performed to justify omission of specification.
  • Acceptable intake limits (AI): FDA recommends the following limits for nitrosamines listed below:
HPLC Agilent
Nitrosamine AI Limit (ng/day)
NDMA 96.0
NDEA 26.5
NMBA 96.0
NMPA 26.5
NDIPA 26.5
EIPNA 26.5
MeNP 26.5 
NDBA 26.5
NMOR 127.0
NN 37.0

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