USP 232 and USP 233 – Over 100 Years in the Making

The United States Food and Drug Administration (USFDA) expects companies to be USP 232 and USP 233 compliant by 2013. The United States Pharmacopeia (USP) and the National Formulary (NF) contain the standard specifications for medical devices, dietary supplements, medicines, dosage types, excipients, and other therapeutics. These standards are enforceable by the USFDA for any medicines being sold or manufactured within the U.S. Many other countries have also adopted these same regulations.

The old standards

USP was founded in 1820 in an effort to provide standards for food and medicine in an effort to protect the welfare of the public. USP 231 defines qualitative testing for metals through the use of a colorimetric process based on insoluble metal sulfide precipitation. Introduced over 100 years ago, USP 231 is outdated in limits as well as procedures. Colorimetric testing focuses on the visibility of the precipitate and not on the toxicology data. It does not detect some modern contaminants, such as chromium and nickel that can potentially arise from the use of stainless steel equipment. The process is not elemental specific or equally reactive with each element. Additionally, the second method utilized in USP 231 has been shown to have inconsistent recoveries.


The new standards of USP 232

Heavy criticism of the old standards surrounding elemental impurities started about 15 years ago, and the USP began developing the new standards with the advice of experts on metal toxicology while addressing public concerns. USP 232 specifies the permitted daily exposure (PDE) limits of additional analytes that were not previously tested.

Analytes with Permitted Daily Exposure (PDE) limits

  • Arsenic (As)
  • Vanadium (V)
  • Manganese (Mn)
  • Ruthenium (Ru)
  • Cadmium (Cd)
  • Chromium (Cr)
  • Copper (Cu)
  • Rhodium (Rh)
  • Mercury (Hg)
  • Nickel (Ni)
  • Platinum (Pt)
  • Osmium (Os)
  • Lead (Pb)
  • Molybdenum (Mo)
  • Palladium (Pd)
  • Iridium (Ir)

The new procedures of USP 233

USP chapter 233 identifies the methods that are acceptable for detecting elemental impurities. The new instrumentation can vary according the needs of the company, such as the use of Inductively Coupled Plasma-Optical Emission Spectrometry (ICP-OES) and Inductively Coupled Plasma-Mass Spectroscopy (ICP-MS). Although USP 233 does not specify which method has to be used, there are certain attributes these specific analytical techniques produce. The technique used is expected to have selective measuring with specific sensitivity of the elemental impurities being tested, and they must be accurate and maintain appropriate recoveries. From the industry's perspective, these same methods have needed to be simple, clear and not time-consuming.

Who does this affect?

Americans will spend over $300 billion this year just on prescription drugs. Companies that manufacture and distribute pharmaceuticals will have to implement these procedures over the next year to comply with USFDA standards in accordance to USP 232 and USP 233 in conjunction with USP 2332 – the new standard for elemental impurities in dietary supplements. New equipment will have to be purchased and the need for experts capable of understanding the new processes will have to be trained. In essence, these new limits and procedures effect the entire industry on nearly every level.

Why is this update important?

Elemental impurities can have a direct effect on the shelf-life of pharmaceuticals from manufacturing to the packaging that is used to store it. Excipients, such as colors, binders, and coatings, catalysts, and active pharmaceutical ingredients can all be adversely affected by elemental impurities. The “Big Four” analytes (As, Cd, Hg, Pb) are known to be toxic even at very low levels. Of course, toxicology is one of the biggest concerns of the USFDA.

With recent allegations against compounding drug companies, it has become increasingly important for the USFDA to focus on providing more guidelines that are appropriate for today's technology, advances, and public awareness. Even the pharmaceutical industry has been demanding changes to the outdated USP Chapter 231.The mandates provide in USP Chapter 232 and USP Chapter 233 are instrumental for the industry to adequately protect the public from toxicology while still being able to extend the shelf-life, flavor and other consumer-oriented benefits. Ultimately, USP 232 and USP 233 provide the solution for the demand of regulatory organizations, the needs of manufacturers and distributors, and the safety of the consumer.

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