the standard of quality tm usp controls on lead in pharmaceuticals heavy metals – usp perspective...

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)

• 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 (diphenylthio-carbazone; PhN=N(CS)NHNHPh)

• color produced by sample compared to standard



• Main USP/NF controls are colorimetric– Aren’t 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?



• 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



• 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 Limitsin USP/NF Monographs

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Lead Limitsin USP/NF Monographs

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IOM Meeting on Metal Impurities

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

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

Heavy Metals Chapter <231> has been problematic for many yearsDifficulties 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>

“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).



“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)



“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)

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USP Began to Look More Closely at <231>

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

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 Monitor—Considerations

Toxicity of potential target metalsToxicity of individual metalsToxicity of combined groups of metals

Potential target organsWhat if individual metals are not terribly

toxic, but more than one has an impact on the same target organ?

Cultural/political concernsHg, Pd


What Concentration Limits are Required?

Depends on patient population Depends on daily dosage Depends on type of dosage form Depends on whether it’s for an acute or a

chronic condition Depends on metal


Background

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

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., inductively-

coupled 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

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

Element Draft USP Oral Limit, ug/day

Aluminum 5000Antimony 2Arsenic 1.5Beryllium 10Boron 1000Cadmium 2.5Chromium 15Cobalt 100Copper 50Indium 10Iridium 1300




Iron 1500Lead 1Lithium 60Manganese 700Mercury 1.5Molybdenum 25Nickel 100Osmium 10Palladium 10Platinum 10Rhodium 10




Selenium 25Strontium 3000Thallium 0.4Tin 3000Tungsten 37.5Zinc 1500


Comments on Limits

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

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

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

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

Atomic absorption (flame, graphite furnace, cold vapor)

ICP-OES ICP-MS XRF LIBS Ion Chromatography Flame Emission Spectroscopy


Draft Sample Preparation Flow Chart

Is the compound soluble in aqueous solutions?

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

Perform Closed-Vessel Microwave Digestion

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

Perform analysis via ICP-OES or ICP-MS

Did the monitor and USP reference solution recover to within 20%?

Perform analysis using element-specific method

Yes

NoNo

Yes

Report Result

No

Yes


Methodology

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 ICP-OES will be the method of choice.

For some, particularly in difficult matrices and very low levels, ICP-MS may be necessary.


Proposed Next Steps

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 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 quality tm usp controls on lead in pharmaceuticals heavy metals – usp perspective...

Documents

standard slide

lead slide

standard usp lead

pb slide

metals colored

metals analysis

key tests usp heavy

uspnf monographs