The Standard of QualityTM

USP Controls on Lead in Pharmaceuticals

Heavy Metals USP Perspective

Darrell R. Abernethy, MD, Ph.D. Chief Science Officer

Controls on Lead: USP/NF (1)

The Standard of QualityTM

Two key tests

USP <231> Heavy Metals
detects metals colored by sulfide ion (Pb, Hg, Bi, As, Sb, Sn, Cd, Ag, Cu, Mo) thioacetamide test solution color of sample compared to standard

USP <251> Lead

depends on extraction of Pb from aqueous phase into organic phase by dithizone (diphenylthiocarbazone; PhN=N(CS)NHNHPh) color produced by sample compared to standard

Controls on Lead: USP/NF (2)

The Standard of QualityTM

Main USP/NF controls are colorimetric

Arent there more accurate or more specific tests for Pb?
FDA and Albemarle both used more modern procedures to obtain their data (ICP-OES or -MS) Other alternatives exist USP has published a Stimuli Article considering replacing the methodology in <231> with instrument-based technology such as AA or ICP Firms can use alternative analytical methods provided appropriate acceptance criteria are met

Is there a need for another test?

Controls on Lead: USP/NF (3)

The Standard of QualityTM

About 4300 monographs in USP/NF

1331 for drug substances
619 have a limit on Heavy Metals (<231>) 22 have a limit for Pb (<251>)

374 for excipients (NF monographs)

203 have a limit on Heavy Metals 60 have a limit for Pb

2452 for drug products

97 have a limit on Heavy Metals 8 has a limit for Pb

Controls on Lead: USP/NF (4)

The Standard of QualityTM

Limits on heavy metals or lead exist predominantly for the components of drug products, not the drug products themselves
47% of drug substances, 54% of excipients, and 4% of drug products have a limit on heavy metals Only 2% of drug substances and 16% of excipients have a limit on lead Some have limits on heavy metals AND lead

Heavy Metal Limits in USP/NF Monographs

The Standard of QualityTM

350

Number of USP/NF Monographs with Specific Limit

300 250 200 150 100 50 0 0.2 0.3 1 2 5 10 13 15 20 25 30 40 50 60 83 100

Drug Substance Drug Product Excipient

Limit on Heavy Metals (ppm)

Lead Limits in USP/NF Monographs

The Standard of QualityTM

25

Number of USP/NF Monographs with Specific Limit

20
Drug Substance Excipient

15

10

0 2 3 5 10 15 20 25 30 40 50

Limit on Lead <251> (ppm)

IOM Meeting on Metal Impurities

The Standard of QualityTM

Currently in development, scheduled for August 26-28, 2008 Independent advisory group named by IOM Nominees from USA, nominees from Europe via EP have been solicited Advisory group has planned meeting 1.5 day meeting, 12 presentations Link known clinical toxicology with acceptable analytical methodology

Introduction
The Standard of QualityTM

Heavy metals have been monitored in APIs for many years.

Some are toxic Some are not toxic but reflect quality issues

Sources
Deliberately added (e.g., catalysts) Carried through the process (e.g., starting materials) From the process (e.g., leaching from pipes and other equipment)

Background
The Standard of QualityTM

Heavy Metals Chapter <231> has been problematic for many years Difficulties in achieving anticipated results (monitor solutions, standards, etc.) Difficulties with reagents (moved from use of H2S to other sulfide sources) With the increased use of instrumental techniques for metals analysis, some investigators began to compare instrumental methods vs. <231>

Comparisons Between Instrumental Methods and <231>

The Standard of QualityTM

It was concluded from this experiment that approximately 50% of the metals may be lost during the ash process. . . . Note that mercury, which is one of the more toxic heavy metals, was not recovered from either set of samples. . . . Because of the loss of metals during ignition, the validity of test results obtained with the current USP, JP and EP general test procedures is questionable.
(Stimuli to the Revision Process, Pharmacopeial Forum, Vol. 21, No. 6, 1995, Katherine Blake).

Comparisons Between Instrumental Methods and <231>

The Standard of QualityTM

Although still widely accepted and used in the pharmaceutical industry, these methods based on the intensity of the color of sulfide precipitation are non-specific, insensitive, time-consuming, labor intensive, and more often than hoped, yield low recoveries or no recoveries at all.
(Wang, T. et al, J. Pharm. & Biomed. Anal., Vol. 23 (2000) 867-890)

Comparisons Between Instrumental Methods and <231>

The Standard of QualityTM

A survey method that permits simultaneous qualitative to quantitative (depending on the elements and the concentration levels) detection of up to 69 elements (including all those of pharmaceutical interest) in less than 15 min would be viewed by some as a giant leap compared with the antiquated USP and EP methods. The use of such a method, which employs a very sophisticated and expensive instrument, as an alternative to a seemingly economical wet chemical test that has been in use for decades would be viewed by others as technological overkill. We take a less extreme view, and believe that since the technology is here, and present in the laboratory to address, often very challenging analytical problems, its application to more mundane uses is simply good resource management. We have found that the extensive use of ICP-MS for this metal survey analysis does not degrade its capability for even more challenging tasks.
(Wang, T. et al, J. Pharm. & Biomed. Anal., Vol. 23 (2000) 867-890)

Comparisons Between Instrumental Methods and <231> (Lewen, N. et al J. Pharm. &

Biomed. Anal. 35 (2004) 739-752)

The Standard of QualityTM

120
Averag e % Reco veries

100 80 60 40 20 0
Pb As Se Sn Sb Cd Pd Pt Ag Bi Mo Ru Elements In Hg USP Results ICP-MS Results

USP Began to Look More Closely at <231>

The Standard of QualityTM

Expert Committee on General Chapters appointed a Heavy Metals subcommittee Subcommittee disbanded and Advisory Panel Initiated Project Team Initiated

Topics Being Addressed by Advisory Panel

The Standard of QualityTM

Do we want to eliminate heavy metals as a test and adopt an inorganic impurities method, instead? What metals do we need to monitor? What concentration limits do we need to meet? Do we need a wet-bench approach? Can we use an instrumental approach? Do we provide results for individual elements? How do we reconcile results from any new procedure with results obtained previously using <231>? How does dosage form impact monitoring? How does daily dosage impact monitoring?

What Metals to MonitorConsiderations

The Standard of QualityTM

Toxicity of potential target metals Toxicity of individual metals Toxicity of combined groups of metals Potential target organs What if individual metals are not terribly toxic, but more than one has an impact on the same target organ? Cultural/political concerns Hg, Pd

What Concentration Limits are Required?

The Standard of QualityTM

Depends on patient population Depends on daily dosage Depends on type of dosage form Depends on whether its for an acute or a chronic condition Depends on metal

Background
The Standard of QualityTM

The current chapter <231> relies on tests which are limited in the metals detected. The test limit reflects all metals detected and is not toxicologically based. The tests can be
Unreliable Difficult to perform correctly Difficult to perform safely

Proposed Way Forward

The Standard of QualityTM

EMEA draft guidance - specific to residues of metal catalysts USP is proposing a broader-reaching chapter on inorganic impurities that reflects
Modern instrumentation (e.g., inductivelycoupled plasma or atomic absorption spectroscopy) Realistic toxicological limits for individual metals The requirement to control the levels of metals in foods and dietary supplements.

Current Status
The Standard of QualityTM

USP has commissioned an Advisory Panel of toxicologists to consider appropriate levels. The initial values are shown on the next few slides.

Proposed Limits Initial Discussions

The Standard of QualityTM

Element Aluminum Antimony Arsenic Beryllium Boron Cadmium Chromium Cobalt Copper Indium Iridium

Draft USP Oral Limit, ug/day 5000 2 1.5 10 1000 2.5 15 100 50 10 1300

Proposed Limits Initial Discussions

The Standard of QualityTM

Element Iron Lead Lithium Manganese Mercury Molybdenum Nickel Osmium Palladium Platinum Rhodium

Draft USP Oral Limit, ug/day 1500 1 60 700 1.5 25 100 10 10 10 10

Proposed Limits Initial Discussions

The Standard of QualityTM

Element Selenium Strontium Thallium Tin Tungsten Zinc

Draft USP Oral Limit, ug/day 25 3000 0.4 3000 37.5 1500

Comments on Limits
The Standard of QualityTM

Limits are still tentative and under active discussion. Oral PDE for Dosage Forms are 10X higher.

USP Parenteral Limits are proposed 10X lower.

PDE limit for lead from FDA bottled water limit of 5 ug/L assuming 2L/day.

EU Approach
The Standard of QualityTM

EMEA classifies impurities by risk level

Class 1 Metals Significant safety concern (e.g., Pt, Pd) Class 2 Metals Metals with low safety concern (e.g., Cu, Mn) Class 3 Metals Metals with minimal safety concern (e.g., Fe, Zn)

EMEA Approach Other Issues to Consider

The Standard of QualityTM

Route of Administration
Oral Parenteral Inhalation

Duration of exposure Age at Exposure

Genotoxicity or Carcinogenicity Potential

Extrapolation of Toxicological Data Safety Factor

Conclusions on Levels
The Standard of QualityTM

A General Chapter can only provide levels based on the best available toxicology data and a set of use instructions. Risk can be dependent on dose form, route of administration, age, gender, and length of exposure. Covering the range from Active Pharmaceutical Ingredients to foods and dietary supplements will necessitate including many elements in the chapter.

Advisory Panel Discussed Potential Detection Techniques

The Standard of QualityTM

Atomic absorption (flame, graphite furnace, cold vapor) ICP-OES ICP-MS XRF LIBS Ion Chromatography Flame Emission Spectroscopy

Draft Sample Preparation Flow Chart

The Standard of QualityTM
Is the compound soluble in aqueous solutions? No

Is the compound soluble in other (including organic) solvent?

No

Perform Closed-Vessel Microwave Digestion

Yes

Prepare sample, monitor solution and USP reference solution according to sample prep. procedure

Perform analysis via ICP-OES or ICP-MS

Yes
Did the monitor and USP reference solution recover to within 20%? No Perform analysis using elementspecific method

Yes
Report Result

Methodology
The Standard of QualityTM

Methodology will depend on the number of elements that need to be monitored on a routine basis, and the levels to be measured. For the routine monitoring of a few specific elements in an API made without catalysts, atomic absorption may be acceptable. For most elements, it is anticipated that ICPOES will be the method of choice. For some, particularly in difficult matrices and very low levels, ICP-MS may be necessary.

Proposed Next Steps

The Standard of QualityTM

Stimuli article prepared by advisory panel. Conference in June/July to gain consensus on

Levels Sample preparation techniques Measuring tools

Work with other pharmacopeias in an effort to reach consensus on levels and scope of chapter. Begin formal chapter revision process.

Proposed Next Steps

The Standard of QualityTM

The Heavy Metals Chapter <231> impact approximately 1000 monographs. USP realizes that eliminating or replacing the test for existing compounds and compounds late in development is unrealistic. It is believed that many manufacturers are already testing beyond the use of <231> and going forward the introduction of new methodology will not be overly burdensome. USP will work closely with its stakeholders to determine the best way forward from both a scientific and timing perspective.

The Standard of QualityTM

The Standard of QualityTM