Advisory to Drug and Dietary Supplement Manufacturers, Compounding Pharmacies and Distributors of Excipients and Dietary Ingredients – FDA Detects High Levels of Peroxide in Crospovidone
[10-21-2010] The U.S. Food and Drug Administration is alerting drug and dietary supplement manufacturers, compounding pharmacies, and distributors of Povidone analogs (Povidone/Copovidone/Crospovidone), that the agency recently detected excessive levels of peroxide in one lot of Crospovidone (cross linked polyvinyl N-pyrrolidone) manufactured by China-based Tianjin Boai NKY International Ltd1. The peroxide level found by the FDA in the lot was more than four (4) times the maximum level of peroxide (400 ppm) allowed by global compendial monographs.
Other lots of Povidone analogs2 manufactured by this firm may also contain excessive levels of peroxide. An Import Alert has been issued to prevent further entry of Tianjin Boai NKY International Ltd Crospovidone into the U.S. market.
To date, the FDA is not aware of any illnesses in the United States stemming from peroxide contamination. The level of peroxide found in this particular lot does not appear, on its own, to pose a significant health risk in drugs or dietary supplements. The FDA nonetheless remains concerned that elevated levels of peroxide can cause subpotent finished products.
Crospovidone is a very common ingredient in drugs and dietary supplements. Peroxide is a potential impurity from the polymerization step involved in the manufacturing of Povidone analogs. Residual peroxide levels of <100 ppm have been reported to cause oxidative degradation.3 The FDA is concerned that drug manufacturers using excipients containing high levels of peroxides will observe a loss of drug potency and the formation of excessive impurities during the product shelf life.
It is essential that users and distributors implement robust supplier management programs to assure that peroxide levels in Povidone analogs are in control for each batch received. Manufacturers using such excipients should employ sound risk management principles in establishing appropriate scrutiny (including peroxide testing regimen) and actions to take for a given supplier, including but not limited to the following:
(a) review supplier history, including any relevant information on manufacturing reliability;
(b) assess peroxide levels obtained from testing4 of past batches of Povidone analogs;
(c) determine reliability of results reported on Certificates of Analysis;
(d) consider information obtained from ongoing communications with suppliers; and
(e) determine whether the quality of any finished product has been impacted.
Manufacturers who use ingredients that might contain elevated levels of peroxide are advised to notify the FDA if they become aware of any further findings of quality problems or potentially related adverse events.
1 May also do business as Friends Union Enterprise (Jianjin) Ltd, Boai New Kaiyuan Pharmaceutical Company, Boai NKY Pharmaceuticals Ltd or Bluetech Chemicals Limited.
2 A recently published study also found elevated levels of peroxide in multiple lots of Povidone analogs, consistent with the FDA’s findings. (Silverstein, PhD, Irwin, Pharmaceutical Technology, Vol. 33, Issue 10, pp. 84-88, October 02, 2009. “The Case for Supplier Qualification.”)
3 Hartauer, et al, Pharm. Dev. Technol. 2000;5(3):303-10. “Influence of peroxide impurities in povidone and crospovidone on the stability of raloxifene hydrochloride in tablets: identification and control of an oxidative degradation product.”
4 A peroxide test is not currently listed in the USP monographs for crospovidone and povidone. However, a non-specific USP/EP method (see Copovidone NF) can be used to readily detect peroxide present at 400 ppm in Povidone analogs. Alternatively, a validated method shown to be specific for peroxide and having at least the same sensitivity as the compendial method may be used.