MEGGLE’s new low nitrite lactose grades

Wasserburg, Germany: – Pharmaceutical excipient industry leader MEGGLE is about to launch three new premium low nitrite lactose grades to address the increasingly urgent pharma industry concern over nitrosamine impurities.

These new Low Nitrite grades of GranuLac®, Tablettose®, and FlowLac® will be measured and validated as having nitrite parameters not higher than one tenth of a part per million.

MEGGLE low nitrite response

Due to the nitrosamine issue, the risk management and review of nitrite content in excipients have become essential. Pharmaceutical manufacturers must take appropriate measures, especially for critical products.

While nitrite testing is not a pharmacopoeial requirement, MEGGLE has developed a superior measurement method using ion chromatography to accurately detect nitrite levels down to a limit of quantification (LOQ) of 0.03 ppm. Values below this limit will be reported as < 0.03 ppm. Through additional validation, MEGGLE has demonstrated that it can safely specify a nitrite limit of ≤ 0.10 ppm, as discussed as a reasonable target for excipients e.g. in the USP Nitrosamine Exchange Forum.

MEGGLE Low Nitrite grades

MEGGLE’s initial three new premium lactose grades launched are GranuLac® 200 Low Nitrite, Tablettose® 100 Low Nitrite, and FlowLac® 100 Low Nitrite, with further low nitrite grades in development.

All Low Nitrite variants will have their nitrite parameters measured for each batch, with nitrite value now part of the Product Specification and the corresponding CoA Certificate of Analysis. This not only simplifies mandatory nitrosamine risk assessment for manufacturers but also demonstrates compliance with the defined nitrite limits for critical products.

MEGGLE can provide further information and samples upon request.

MEGGLEs pharma-grade lactose excipients already have extremely low nitrite content, making them safer choices for manufacturers concerned to minimize risks of nitrosamine contamination of drug products.

About Nitrosamine Contamination

Nitrosamine contamination has been an issue of increasing concern for the pharma industry since June 2018, when the FDA was notified of the presence of N-nitrosodimethylamine (NDMA), an impurity found in valsartan, an angiotensin II receptor blocker. In July EMA issued a press-release regarding the recall of some Valsartan medicines following the detection of an impurity. Later, several other medications, including Ranitidine, Nizatidine, and Metformin, were also found to contain unacceptable amounts of Nitrosamines.

Nitrosamines are a class of compounds having the chemical structure of a nitroso group bonded to an amine (R1N(-R2)-N=O). The compounds can be formed by a nitrosation reaction between amines and nitrous acid (nitrite salts under acidic conditions). Some Nitrosamines, such as NDMA and N-Nitrosodiethylamine (NDEA), have been classified as probable or possible human carcinogens by the International Agency for Research on Cancer (IARC). They are referred to as “cohort of concern compounds” in the ICH guidance for industry M7(R1) Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk. The guidance recommends that any known mutagenic carcinogen, such as nitroso compounds, should be controlled at or below levels such that there is a negligible human cancer risk associated with exposure to potentially mutagenic impurities.

Nitrosamines can be introduced into APIs or excipients due to raw material or process contamination, use of amines in synthesis, acidic reaction with nitrite impurities, use of Dimethylformamide (DMF) or Dimethylamine (DMA) solvents, or contamination from packaging materials containing nitrogen-based stabilizers during long-term storage.

A wide range of commonly used excipients, including lactose, MCC Microcrystalline Cellulose, SLS Sodium Lauryl Sulfate surfactant, PEG Polyethylene Glycols, Polysorbates, PVP Povidone & Crospovidone, starch & modified starches have all been identified as being at risk, due to their chemical composition and manufacturing processes.

However, excipients are not created equal when it comes to nitrite levels. Lactose typically has a very low nitrite content with a recent study (Boetzel et al., 2022) finding nitrite content in Lactose from eight suppliers ranging from 0.07 to 1.7 ppm, with a mean of 0.54 ppm¹. This compares with mean levels for corn starch of 0.15 ppm at the low end, up to 0.8 ppm or higher for Hypromellose and Povidone.

Regulatory advice

Leading regulatory agencies, including the FDA, EMA, ICH, and WHO, have all now issued guidance for controlling nitrosamines in excipients. The latest guidelines emphasize risk assessment, risk-based testing, and stricter limits.

In February 2023, the IPEC Federation provided an updated Questionnaire for Excipient Nitrosamines Risk Evaluation that reflects guidance from the EMA, including its “Questions and answers for marketing authorization holders and the FDA Guidance for Industry Control of Nitrosamine Impurities in Human Drugs”². The questionnaire includes a matrix to consider the structure and the origin of the excipient as a first indication of risk, as well as measured values for nitrite and Nitrosamines. The use of a standard format facilitates the collection of data from excipient suppliers and assists pharmaceutical manufacturers in their Nitrosamine risk assessment.

However, it should be noted that it is impossible for excipient suppliers to carry out this risk assessment, as risk of nitrosamine contamination depends on actual drug formulation and the properties of the active substance.

Specific measures recommended also include supplier & raw material controls and analytical testing & monitoring using advanced analytical methods, such as LC-MS/MS Liquid Chromatography-Mass Spectrometry, GC-MS Gas Chromatography-Mass Spectrometry, HR-MS High-Resolution Mass Spectrometry, etc., along with use of low-nitrite packaging materials and controlled temperature storage. Also the manufacturing process plays an important role for critical products. The conversion rate in direct compression is significantly lower than for example in wet granulation process.

MEGGLE offers a wide variety of excipients enabling direct compression.

References

1. Boetzel, R., Schlingemann, J., Hickert, S., Korn, C., Kocks, G., Luck, B., Blom, G., Harrison, M., François, M., Allain, L. R., Wu, Y. & Bousraf, Y. (2022). A Nitrite Excipient Database: A useful Tool to Support N-Nitrosamine Risk Assessments for Drug Products. Journal of Pharmaceutical Sciences. https://doi.org/10.1016/j.xphs.2022.04.016
2. IPEC Questionnaire for Excipient Nitrosamines Risk Evaluation, Feb 2023. https://www.ipec-europe.org/articles/questionnaire-for-excipient-nitrosamines-risk-evaluation.html

About MEGGLE

Bavarian-based company MEGGLE is one of the world’s experts in co-processing and powder technology. From its roots as a dairy operation in the late 1880’s, MEGGLE has become one of the world’s leading manufacturers of pharmaceutical grade lactose, supplying the pharmaceutical industry with a broad-based and unique lactose product portfolio.

MEGGLE’s Business Unit Excipients has harnessed outstanding product quality and intelligent innovation to become a global leader in the manufacture of lactose-based excipients, focusing on products for direct tableting and dry powder inhalation.

A multidisciplinary team of committed and highly qualified people allows MEGGLE clients to benefit from pioneering experience and innovation in industrial milk and whey processing. The company constantly strives to develop high-technological, functional products for solid dosage forms and DPI applications, where they can deliver maximum performance.

The company has introduced several revolutionary products, notably Tablettose®, the world’s first agglomerated pharmaceutical lactose grade for direct tableting, Cellactose® 80, a pioneering co-processed excipient based on powdered cellulose and lactose for outstanding compression and flow properties and RetaLac®, the first direct compressible co-processed excipient using Hypromellose and lactose for sustained release formulations.

To learn more, visit: https://www.meggle-pharma.com/en/home.html

Resources

Click on Risk Mitigation of Nitrosamines formation in Drug Products: Role of Excipients to access MEGGLE White Paper.