4 questions on QC of nitrogen-containing compounds in pharma

A total of 84% of the 1035 small molecule drugs approved by the FDA have at least one nitrogen atom in them. How is quality control performed on these nitrogen-containing compounds?

Kjeldahl analysis is a primary reference method for nitrogen determination in quality testing of pharmaceutical manufacturing.

1.??????What types of samples can you analyze with Kjeldahl?

• Raw materials
• Biomaterials
• Nutraceuticals
• Active Pharmaceutical Ingredients (APIs)
• Toxins
• Ointments
• Vaccines
• Pharmaceutical excipients
• Blood plasma products

2.??????What are the benefits of the Kjeldahl method?

The Kjeldahl method is particularly advantageous for quality control of nitrogen-containing pharmaceutical compounds, because it is a precise primary method. Furthermore, its limit of detection (LOD) is only 0.008 mg of nitrogen and its limit of quantification (LOQ) lies at 0.02 mg of nitrogen. The method achieves more than 98% accuracy. Especially useful are Kjeldahl systems with available IQ/OQ services, automated quantification via titration and a time-efficient workflow thanks to automation. Some systems are also compliant with 21 CFR Part 11.

3.??????How does the Kjeldahl method work?

In the Kjeldahl process, a sample is digested with concentrated sulfuric acid, together with potassium sulfate to raise the boiling point. A catalyst is used to speed up the digestion. At this step, the nitrogen in the sample is converted to nonvolatile ammonium sulfate. The ammonium sulfate is converted to ammonia gas by heating with sodium hydroxide. The ammonia is steam-distilled into an excess of boric acid solution, where it is captured by forming ammonium borate. The amount of borate that has formed is determined by using titration, whose endpoint is indicated either by a color indicator or potentiometrically. The percentage of protein present is calculated from the nitrogen content using a sample-specific factor.

4.??????How does the Kjeldahl method fit in a time-efficient and compliant SOP?

There are several factors that are important in achieving compliance with 21 CFR Part 11:

• IQ/OQ and training
• Electronic signature
• Data traceability
• Data records management
• Security
• User administration

A proper Kjeldahl system with the appropriate service contract makes it easy for you to satisfy all the above requirements. More automation upgrades (such as an Autosampler) help to save time, while working compliantly.