Impurity Profiling of Oligonucleotide Medicines by Two-Dimensional LC-MS/MS

Analytical techniques using high-sensitivity and high-resolution instruments are essential for the profiling of oligonucleotide medicines, because their impurities have structures similar to those of the parent compounds.
A two-dimensional LC-MS/MS system that combines anion-exchange chromatography (AEX) with ion-pair reversed-phase chromatography (IP-RP) is an efficient technique in order for identifying the structures of impurities.

• We conduct our studies based on ICH guidelines.
• We conform to the Japan’s Reliability Criteria*1, and the GMP (Japan, the USA, and the Europe).
• We comply with the Japanese and global laws, guidance, and guidelines and we ensure data integrity*2.

• We have abundant experience in FDA inspections, PMDA inspections, QP audits, and audits by clients worldwide including Japan.

Quality Assurance System（Pharmaceutical Business）

• We provide structural information, even when the mobile phase used in the first dimension of LC contains non-volatile salts, by on-line desalting in the second dimension, which enables sample introduction into the MS.
• Nucleic acids have a tendency to adsorb easily to metals. Bio-inert HPLC*3 reduces the contamination risk and carryover to the next run.
• We identify the structures of impurities using our mass spectrometer*4 equipped with high resolution, high scan speed, and multi-stage MS.
• In addition to the combination of AEX and IP-RP, we develop other separation methods according to the characteristics of the analytes based on our extensive experience.

• Lyophilized nucleic acids are sensitive to humidity in the testing environment. We handle the samples in a humidity-controlled laminar flow cabinet.
• Powder containment facilities (EC2) enable our handling of highly potent compounds up to OEL Category 5.
• BSL-2 laboratories enable our handling of biohazard samples.

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  1: Article 43 of Regulation for Enforcement of the Act on Securing Quality, Efficacy and Safety of Products Including Pharmaceuticals and Medical Devices
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  2: FDA 21 CFR Part11
  Notification by the Director General of the Pharmaceutical and Food Safety Bureau, MHLW Regarding Use of Electromagnetic Records and Electronic Signatures in Applications for Drug Approval or Licensing, etc. (PFSB Notification No. 0401022)
  Annex11 to the EU Guide to GMP Computerized Systems
  Notification " Guideline on Management of Computerized Systems for Marketing Authorization Holders and Manufacturers of Drugs and Quasi-drugs" (Pharmaceutical and Food Safety Bureau, Pharmaceutical and Food Safety Bureau, MHLW, PFSB Notification No. 1021-11)
  A risk-based Approach to Compliant GxP Computerized Systems (GAMP 5), ISPE/GAMP COP (2008.2)
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  3: 1290 Infinity II Bio LC Systems manufactured by Agilent Technologies
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  4: Orbitrap Eclipse Tribrid mass spectrometer manufactured by Thermo Fisher Scientific