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Istanbul, TurkeyJanuary 17, 2013

Elemental Impurities: Recent Changes

<231> Heavy Metals - Background

Introduced in USP VIII (1905)Consists of three procedures, all involving

–Sulfide precipitation of metals –Visual comparison to lead standards

Methods in the EP and JP are similar to the USP methods

<231> Heavy Metals - Issues

Difficulties in reproducibility–Monitor solutions/standards change with time, recovery issues

Difficulties with reagents – safety issues–All procedures generate H2S (USP via thioacetamide reaction

with base). H2S more toxic than cyanide

–Thioacetamide not allowed in California and several European countries (EP uses Na2S)

Nondiscriminatory screening test–Not element specific

–Sensitivity varies by element

–Only a few elements respond at required sensitivities

Visual comparison test –Limits based on visual acuity, not toxicology

Heavy Metals Background

0

20

40

60

80

100

120

Pb As Se Sn Sb Cd Pd Pt Ag Bi Mo Ru In Hg

Elements

Aver

age

% R

ecov

erie

s

USP Results

ICP-MS Results

Comparisons Between Instrumental Methods and <231> (Lewen, N. et al J. Pharm. & Biomed. Anal. 35 (2004) 739-752)

USP is proposing an approach to elemental impurity control that is both health based and risk based

Control metals that are toxic

At limits that are toxicologically relevant

At all times during a drug product’s shelf life

With a risk-based approach as to what and when to test

Toxicology

<232>: Elements

Elements in the environment – critical contaminant are Lead, Arsenic, Mercury and Cadmium (the “Big Four”)

EMEA Guideline on the Specification Limits for Residues of Metal Catalysts (CPMP/SWP/4446/00) lists 14 catalysts used in pharmaceutical synthesis

– Exclude zinc and iron, which are not toxic at levels relevant in pharmaceuticals

Need to control in drug products if presence is possible

– Deliberately added (catalyst)

– Possible supply-chain contaminant or adulterant

– Process issue (equipment)

<232> : Basics

Applies to: – Drug products, but levels in excipients and API’s must be known

and reported

– Veterinary products, levels must be adjusted based on species, dosage, and toxicology

Does not apply to dietary supplements

Speciation is not addressed in this Chapter

Procedures are specified in Elemental Impurities – Procedures <233>

9

Elemental Impurities <232>

Element Oral Daily Dose PDE (µg/day)

Parenteral

Daily Dose PDE (µg/day)

Inhalational Daily Dose PDE (µg/day)

LVP Component Limit (µg/g)

Inorganic Arsenic

1.5 1.5 1.5 0.15

Cadmium 25 2.5 1.5 0.25

Lead 5 5 5 0.5

Inorganic

Mercury

15 1.5 1.5 0.15

10

Elemental Impurities <232>

Element Oral Daily Dose PDE (µg/day)

Parenteral

Daily Dose PDE (µg/day)

Inhalational Daily Dose PDE (µg/day)

LVP Component Limit (µg/g)

Chromium * * 25 *

Copper 1000 100 70 25

Molybdenum 100 10 10 1.0

Nickel 500 50 1.5 5.0

Palladium 100 10 1.5 1.0

Platinum 100 10 1.5 1.0

Vanadium 100 10 30 1.0

Osmium 100 10 1.5 1.0

Rhodium 100 10 1.5 1.0

Ruthenium 100 10 1.5 1.0

Iridium 100 10 1.5 1.0

Drug Product Analysis Option –Sample and measure dosage form–Scale results to daily dose

Summation Option –Sample and measure all components–Validate process will add no additional impurities–Sum each metal and scale to daily dose

Individual Component Approach for LVP

Options to Determine Content

<2232> : Basics

Applies to Dietary Supplements –Dietary Ingredients–Excipients

Does not apply to drug productsProcedures in Elemental Impurities – Procedures <233> are specified

Speciation is critical for Dietary Supplements–Arsenic and Mercury procedures addressed in this

ChapterOnly “the big four” Elemental Impurities considered

Elemental Impurities - Procedures <233>

Elemental Impurities - Procedures <233> Definitions Compendial Procedures

• Procedure 1: ICP-OES• Procedure 2: ICP-MS

Validation• Limit Procedures• Quantitative Procedures

Calculations and Reporting Comment on Method Verification per <1226>

Key Issues Page on www.usp.org

Implementation and Postponement

• Chapters <232> and <233> appear in Second Supplement to USP35 (official Dec 1, 2012), but…– The official dates of these chapters have been postponed via

Revision Bulletin

• The postponement will allow the Executive Committee of the Council of Experts adequate time to rule on three appeals related to the chapters.

• A planned General Notices proposal will appear in PF 39(1) in January 2013, which if approved, will make the two chapters applicable to all monographed articles as of May 1, 2014.

• All references to USP general chapter Heavy Metals <231> will be removed from the monographs in USP37, but requirements still apply via General Notices.

Errata from October 1, 2012 for <232>

• Limits in Table 1 (Elemental Impurities for Drug Products) for Molybdenum: Inhalation Daily Dose = 10 µg/day (not 250)

• Limits in Table 2 (Default Concentration Limits for Drug Substances and Excipients):– Ruthenium and Vanadium limits for oral, parenteral and

inhalational products were incorrectly increased by factor of 10– Molybdenum inhalation limit incorrectly increased by a factor of

25

• Last line under Analytical Testing: “when testing is done…minimally include As, Cd, Pb (not Pd) and Hg in the Target Element evaluation.”– Same errata for <233> in the Target Elements Definition

Contact Information

General Chapters <231>, <232> and <233>

Kahkashan Zaidi, Ph.D., Senior Scientist kxz@usp.org