New standards proposed by U.S. Pharmacopeia will change how drugmakers analyze and report metal impurities
Background:A 100-YEAR OLD
wet chemistry procedure based on
precipitating metal sulfide is the current standard method for testing
for "heavy metals" in pharmaceutical ingredients and products. It's a test that
nearly everyone in the industry agrees doesn't work, or at least
doesn't work well.
The wet chemistry technique described in chapter <231> of the US Pharmacopeia handbook involves precipitating metal sulfides
out of an aqueous solution, then visually comparing the colour of the
test sample with that of a standard lead solution. Unfortunately, the information value of this test with respect to detected metals is very low, since the response is varying for different metals (the colours of
the metal sulfides that arise in a test solution can be white, yellow,
orange, brown, or black) and its sensitivity and selectivity for different species is mostly unknown, according to a paper by Tiebang Wang and colleagues at Merck
Additionally, samples frequently require ignition and charring
before they can be analyzed, making the analysis far from
quantitative—especially where volatile elements such as mercury, selenium, tin and antimony are concerned. "Although still widely accepted and used in the
pharmaceutical industry, these methods based on the intensity of the
colour of sulfide precipitation are nonspecific, insensitive,
time-consuming, labor intensive, and, more often than hoped, yield low
recoveries or no recoveries at all," Wang and colleagues comment. According to the experience of analysts performing the test routinely, this test has never given any alarm during the last 20 years !
Founded in 1820, US Pharmacopeia (USP) became the country's official standard-setting
agency for pharmaceuticals through the federal Food & Drugs Act of
1906 and the Food, Drug & Cosmetic Act of 1938. A nongovernmental,
nonprofit agency, USP sets standards that are then enforced by the Food & Drug Administration.
USP publishes the book "United States Pharmacopeia-National Formulary"
(USP-NF), which sets packaging, storage, labeling, testing, and
acceptance standards for drug ingredients and products.
And so, eight years ago, US Pharmacopeia embarked on an effort to update chapter <231> describing how
drugmakers detect metal impurities in their products. "Over the last
few decades, there have been progressive advances in methodologies and
techniques that allow one to do a much better and more comprehensive
evaluation of metals in substances," says Darrell R. Abernethy, USP's chief science officer.
USP Heavy Metals Testing Methodologies Workshop
In order to consult international expertise, the Institute of Medicine (IOM) of the US National Academy of Sciences organized a workshop discussing the USP Heavy Metals Testing Methodologies that took place in Washington 26-27 August 2008.
The workshop has been organized into four primary sessions addressing
- which metals are found in various health care products and the heavy metals that engender the greatest toxicological concerns;
- risk assessment, the establishment of tolerable intakes, and specification limits;
- species considerations, bioavailability and other modifying factors in risk assessment, and
- measurement issues including sample preparation, reference materials, and performing reliable measurements.
15 invited international experts presented their viewpoints during this two day workshop which were further discussed with planning committee members, workshop presenters, and observers during panel and round table discussion sessions. EVISA director Michael Sperling
participated as an invited expert,
reporting on the State-of-the-art and current trends in speciation
There was general agreement between workshop participants that the procedure described in chapter <231> should be substituted by more state-of-the-art analytical test procedures. There was also agreement about the fact that such advanced methodology (e.g. ICP-OES, ICP-MS) is existing and already in use in most manufacturers laboratories. A point of discussion was the question how fast such techniques can be installed in a quality control laboratory arena.
There was more discussion on the question which elements should be targeted for. It was the manufacturers viewpoint that the USP should target only on those metals of known concern (e.g. "BIG FOUR"; As, Cd, Pb, and Hg). Often heard arguments were that GMP would anyhow guarantee that most "contaminants" would not make it into the final products. However such approach would not neccessarily detect counterfeit and substandard medicines, as they have been seen more often during the last years due to the global markets with products from manufacturers from Asia.
The percentage of counterfeit and substandard medicines on the market increases each year as manufacturing of active pharmaceutical ingredients (API) and finished dosage forms (FDFs) shifts from developed to lesser developed markets. Therefore, the list of target elements became longer when toxicologist presented their viewpoints based on risk assessment.
The question of speciation was discussed in many presentations. While it was generally accepted that speciation matters with respect to toxicity at least for some of the target elements (e.g. mercury, arsenic, chromium), it was debated whether speciation analysis was necessary to acount for this.
Later this year, the topic has also been discusseed on the USP Annual
Scientific Meeting, that took place September 23-26 in Kansas City.
The updated approach for testing
As a result from this 8 years long discussion, USP is proposing the following changes:
- First, rather than giving pharmaceutical
manufacturers a new wet chemistry recipe, USP will allow manufacturers to
use whatever method or instrument they wish, as long as they can
demonstrate accuracy, sensitivity, and specificity.
- Second, limits will
be established for individual metals based on their toxicological profile rather
than the capability of the testing methodology.
USP describes the new testing approach in a recent Pharmacopeial Forum article
34, 1345) and suggests that plasma spectrochemistry (ICP-OES, ICP-MS) and atomic
absorption spectroscopy (GF AAS, CVG-AAS, HG-AAS) are likely to be top contenders. Whatever
method manufacturers choose, USP plans to develop reference standards
that pharmaceutical manufacturers can use to qualify their instruments
and methods. In particular, the proposed general requirement is that
procedures provide "measurement values within ±20% of the certified
concentration for each element."
Since the old visual test very seldom has given any result and does not provide any quantitative results at all , this test also was not informative for process control. The newly proposed alternative techniques are therefore very likely already part of GMP strategies anyhow in many manufacturers laboratories. Allowing drug manufacturers the ability to choose the test that best fits their processes and products would give them some desired flexibility. It should also allow them easier implementation of less expensive or more efficient technology down the road. At the same time, however, the flexibility opens up manufacturers to questions from FDA or other regulatory agencies because they could lose the protection offered by "safe harbor." Under that concept, manufacturers that follow USP-NF processes exactly will meet all FDA requirements, Abernethy says. Choosing one's own method, however, runs the risk that an auditor or regulator will disagree with the choice, even if the manufacturer has validated the method.
Metals of concern
While the list of toxicologically relevant elements is long, USP will not require manufacturers to look for every element in the
periodic table, Abernethy says. Rather, it will require them to take a
risk-based approach. For example, if a raw material comes from a plant
that is known to take up arsenic and a process uses a platinum catalyst
in a reactor made from an iron alloy, then those are the elements a
manufacturer will likely have to test for and control.
the heavy metal limits in pharmaceutical ingredients are evaluated as a
total amount of metal cations being present in the sample—the current method
cannot distinguish, for example, arsenic versus mercury, and even does not quantify their amounts at all. With the
likely instrument-based methods, however, the results can be reported
as individual element concentrations. Setting the individual limits for those metals will be a much
thornier issue, Abernethy says. Factors dictating the risk for different populations have to be considered, such as whether a
drug is taken for a short period, such as an antibiotic, or a long
period, such as insulin; whether a drug is taken orally, injected, or
inhaled; how much of the metals people are likely to consume from a
typical diet; whether to accommodate sensitive populations such as
children, pregnant women or elderly individuals; and the speciation of the metal—arsine (AsH3), for example, is highly toxic, whereas arsenocholine ([As(CH3)3CH2CH2OH]+) is considered nontoxic.
In a stimuli paper published in the jourmal Pharmacopeial Forum, the USP Ad Hoc Advisory Panel is proposing a preliminary set of limits for 31 elements. Industry is eyeing the list warily according to the director of global regulatory affairs for excipient company Colorcon and chairman of the International Pharmaceutical Excipients Council of the Americas (IPEC-Americas), Schoneker. The list
includes iron and aluminum, for example, but iron oxides and aluminum compounds are frequently used—with FDA approval—as coloring agents
in pharmaceuticals. Products that use such ingredients could exceed the
suggested amounts. Schoneker says that IPEC-Americas would like more information as to how USP came up with the limits.
Timeline of implementation
The current timeline for the new protocols calls
for USP to have the new draft USP-NF chapter published in the summer of
2009, with the final version out by June 2010. Actual implementation
will probably take several years beyond that. Drug manufacturers will have to
evaluate their suppliers and processes; purchase testing equipment; train
laboratory personnel; develop, validate, and implement new analytical methods in
quality-control labs; and document everything for regulatory agencies.
And if a drug ingredient has an unacceptably high level of a metal, the
manufacturer will have to figure out a way to prevent it or remove it.
USP wants to allow manufacturers the time to accomplish all of this
without threatening the drug supply, Abernethy says.
R. Ciciarelli, D. Jakel, E. Konig, R. Mullerkafer, M. Rock, M. Thevenin, H.
Ludwig, Determination of metal traces - a critical review of the Pharmacopeial
heavy-metal test, Pharmacopeial forum, 21/6 (1995) 1638-1640.
T.B. Wang, J. Wu, R. Hartman, X.J. Jia, R.S. Egan, A multi-element ICP-MS survey method as an alternative to the heavy metals limit test for pharmaceutical materials, J. Pharm. Biomed. Anal., 23/5 (2000) 867-890. doi:10.1016/S0731-7085(00)00361-7
A. Lásztity, A. Kelkó-Lévai, I. Varga, K. Zih-Perényi, É. Bertalan, Development of atomic spectrometric methods for trace metal analysis of pharmaceuticals, Microchem. J., 73/1-2 (2002) 59-63. doi:10.1016/S0026-265X(02)00052-8
Nancy Lewen, Shyla Mathew, Martha Schenkenberger, Thomas Raglione, A rapid ICP-MS screen for heavy metals in pharmaceutical compounds, J. Pharm. Biomed. Anal., 35/4 (2004) 739-752. doi:10.1016/j.jpba.2004.02.023
María R. Gomez, Soledad Cerutti, Roberto A. Olsina, María F. Silva, Luis D.
Martínez, Metal content monitoring in Hypericum perforatum pharmaceutical derivatives by atomic absorption and emission spectrometry, J. Pharm. Biomed. Anal., 34/3 (2004) 569-576. doi:10.1016/S0731-7085(03)00643-5
USP Ad Hoc Advisory Panel on Inorganic Impurities and Heavy Metals and USP Staff, Stimuli to the revision process: General chapter on inorganic impurities: Heavy Metals, Pharmacopeial forum, 34/5 (2008) 1345.
Sergio Lira, Peter Brush, Laurence Senak, Chi-san Wu, Edward Malawer, The Use of Inductively Coupled Plasma-Optical Emission Spectroscopy in the Determination of Heavy Metals in Crospovidone and Povidone as a Replacement for the Concomitant Visual Comparison Test, Pharmacopeial forum, 34/6 (2008) 1613
Web site of US Pharmacopeia
Institute of Medicine of the US National Academy of Sciences , Agenda of the 26-27 August 2008 USP Heavy Metals Testing Methodologies Workshop.
Institute of Medicine of the US National Academy of Sciences , verbatim transcripts of the 26-27 August 2008 USP Heavy Metals Testing Methodologies Workshop
USP Annual Scientific Meeting Agenda: Quality of Manufactured Medicines, Quality of Food Ingredients and Dietary Supplements, September 23–26, 2008, Westin Crown Center • Kansas City, Missouri
Darrell R. Abernethy, USP Chief Science Officer: The Public Health Framework: Report of IOM Meeting on Heavy Metals
Nancy L. Lewen, Bristol-Myer Squibb, Co., Member, USP General Chapters Expert Committee: Revision Approaches to the Heavy Minerals General Chapter
Frances Byrne, M.S., Member, USP Heavy Metals Project Team, Heavy Metals Industry Perspective
EMEA Guideline on the Specification Limits for Residues of Metal Catalysts
Related EVISA Resources
Journals Database: Journals related to Pharmacology and Pharmacy
Companies Database: US Pharmacopeia and their products
Summary Information: Speciation and Toxicity
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last time modified: December 12, 2008