lead control in products - bp specs

8/12/2019 Lead control in products - BP Specs

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The Standard of QualityTM

USP Controls on Lead inPharmaceuticals

Heavy MetalsUSP Perspective

Darrell R. Abernethy, MD, Ph.D.

Chief Science Officer


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Controls on Lead: USP/NF (1)

Two key tests USP 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 Lead

depends on extraction of Pb from aqueous phaseinto organic phase by dithizone (diphenylthio-

carbazone; PhN=N(CS)NHNHPh)

color produced by sample compared to standard


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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) Otheralternatives exist

USP has published a Stimuli Article consideringreplacing the methodology in with

instrument-based technology such as AA or ICP Firms can use alternative analytical methods

provided appropriate acceptance criteria are met

Is there a needfor another test?


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About 4300 monographs in USP/NF 1331 for drug substances

619 have a limit on Heavy Metals ()

22 have a limit for Pb () 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


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Limits on heavy metals or lead existpredominantly 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


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Heavy Metal Limitsin USP/NF Monographs

0

50

100

150

200

250

300

350

0.2 0.3 1 2 5 10 13 15 20 25 30 40 50 60 83 100

Limit on Heavy Metals (ppm)

Number

ofUSP/NFMono

graphswith

SpecificLimit

Drug Substance

Drug Product

Excipient


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Lead Limitsin USP/NF Monographs

0

5

10

15

20

25

2 3 5 10 15 20 25 30 40 50

Limit on Lead (ppm)

NumberofUSP/NFMonog

raphswith

SpecificLimit

Drug Substance

Excipient


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IOM Meeting on Metal Impurities

Currently in development, scheduled forAugust 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 withacceptable analytical methodology


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Introduction

Heavy metals have been monitored in APIsfor 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 pipesand other equipment)


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Background

Heavy Metals Chapter has beenproblematic for many years

Difficulties in achieving anticipated results(monitor solutions, standards, etc.)

Difficulties with reagents (moved fromuse of H2S to other sulfide sources)

With the increased use of instrumentaltechniques for metals analysis, someinvestigators began to compare instrumental

methods vs.


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Comparisons Between Instrumental Methods and

It was concluded from this experiment thatapproximately 50% of the metals may belost during the ash process. . . . Notethat mercury, which is one of the moretoxic heavy metals, was not recovered

from either set of samples.. . . Because of the loss of metals duringignition, the validity of test resultsobtained with the current USP, JP and EPgeneral test procedures is questionable.

(Stimuli to the Revision Process, Pharmacopeial Forum, Vol.21, No. 6, 1995, Katherine Blake).


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Although still widely accepted and used in thepharmaceutical industry, these methodsbased on the intensity of the color of sulfideprecipitation are non-specific, insensitive,

time-consuming, labor intensive, and moreoften than hoped, yield low recoveries or norecoveries at all.

(Wang, T. et al, J. Pharm. & Biomed. Anal., Vol. 23 (2000) 867-890)


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A survey method that permits simultaneous

qualitative to quantitative (depending on the elementsand the concentration levels) detection of up to 69elements (including all those of pharmaceutical interest)in less than 15 min would be viewed by some as a giantleap compared with the antiquated USP and EP methods.The use of such a method, which employs a verysophisticated and expensive instrument, as analternative to a seemingly economical wet chemical testthat has been in use for decades would be viewed byothers as technological overkill.

We take a less extreme view, and believe that sincethe technology is here, and present in the laboratory toaddress, often very challenging analytical problems, its

application to more mundane uses is simply goodresource management. We have found that theextensive use of ICP-MS for this metal survey analysisdoes not degrade its capability for even morechallenging tasks.

(Wang, T. et al, J. Pharm. & Biomed. Anal., Vol. 23 (2000) 867-890)


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

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

0

20

40

6080

100

120

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

Elements

Average%Reco

veries

USP Results

ICP-MS Results


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USP Began to Look More Closely at

Expert Committee on General Chaptersappointed a Heavy Metals subcommittee

Subcommittee disbanded and Advisory PanelInitiated

Project Team Initiated


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Topics Being Addressed by Advisory Panel

Do we want to eliminate heavy metals as atest and adopt an inorganic impuritiesmethod, 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 previouslyusing ?

How does dosage form impact monitoring?

How does daily dosage impact monitoring?


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What Metals to MonitorConsiderations

Toxicity of potential target metalsToxicity of individual metals

Toxicity of combined groups of metals

Potential target organs

What if individual metals are not terriblytoxic, but more than one has an impacton the same target organ?

Cultural/political concerns

Hg, Pd


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What Concentration Limits are Required?

Depends on patient population Depends on daily dosage

Depends on type of dosage form

Depends on whether its for an acute or achronic condition

Depends on metal


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Background

The current chapter relies on testswhich 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


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Proposed Way Forward

EMEA draft guidance - specific to residuesof metal catalysts

USP is proposing a broader-reaching chapter

on inorganic impurities that reflectsModern instrumentation (e.g., inductively-

coupled plasma or atomic absorptionspectroscopy)

Realistic toxicological limits for individualmetals

The requirement to control the levels ofmetals in foods and dietary supplements.


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Current Status

USP has commissioned an Advisory Panel oftoxicologists to consider appropriate levels.

The initial values are shown on the next few

slides.


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Proposed Limits Initial Discussions

Element Draft USP Oral Limit, ug/dayAluminum 5000

Antimony 2

Arsenic 1.5

Beryllium 10Boron 1000

Cadmium 2.5

Chromium 15

Cobalt 100

Copper 50

Indium 10

Iridium 1300


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Element Draft USP Oral Limit, ug/dayIron 1500

Lead 1

Lithium 60

Manganese 700Mercury 1.5

Molybdenum 25

Nickel 100

Osmium 10

Palladium 10

Platinum 10

Rhodium 10


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Element Draft USP Oral Limit, ug/daySelenium 25

Strontium 3000

Thallium 0.4

Tin 3000

Tungsten 37.5

Zinc 1500


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Comments on Limits

Limits are still tentative and under activediscussion.

Oral PDE for Dosage Forms are 10X higher.

USP Parenteral Limits are proposed 10Xlower.

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


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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)


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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 SafetyFactor


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Conclusions on Levels

A General Chapter can only provide levelsbased on the best available toxicology dataand a set of use instructions.

Risk can be dependent on dose form, route

of administration, age, gender, and length ofexposure.

Covering the range from ActivePharmaceutical Ingredients to foods and

dietary supplements will necessitateincluding many elements in the chapter.


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Advisory Panel Discussed Potential Detection Techniques

Atomic absorption (flame, graphite furnace,cold vapor)

ICP-OES

ICP-MS

XRF

LIBS

Ion Chromatography

Flame Emission Spectroscopy


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Draft Sample Preparation Flow Chart

Is the compound

soluble in aqueoussolutions?

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 No

No

Yes

Report Result

NoYes


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Methodology

Methodology will depend on the number ofelements that need to be monitored on aroutine basis, and the levels to bemeasured.

For the routine monitoring of a few specificelements 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 benecessary.


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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 toreach consensus on levels and scope ofchapter.

Begin formal chapter revision process.


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Proposed Next Steps

The Heavy Metals Chapter impactapproximately 1000 monographs.

USP realizes that eliminating or replacing thetest for existing compounds and compounds

late in development is unrealistic. It is believed that many manufacturers are

already testing beyond the use of 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 ascientific and timing perspective.


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