www.ipecamericas.org 1

ICH Q3D Metal Impurities:

Excipient Realities

David R. Schoneker

Vice Chair – Maker & Distributor Relations – IPEC

Director of Global Regulatory Affairs – Colorcon

Email: dschoneker@colorcon.com

April 25, 2011

• Approved in 2009 by ICH SC

• EWG created in Spring 2010

• Scope restricted to criteria and limits

– Methodology purview of Compendia

• Representatives

– Equal mix of Safety/Toxicologists and Quality Personnel

– US: FDA & PhRMA

– EU: EMA & EFPIA

– Japan: MHLW/PMDA & JPMA

– Interested Parties

• IPEC, WSMI, IGPA, KFDA, BIO, WHO

Q3D: the beginnings

2

• Limits to be set based on published safety

and toxicology data

• Detailed Safety & Toxicological Assessments

have been done on each of the metals of

interest

– Each will have its own report including references

to the appropriate studies

• Build upon EU Metal Catalysts guide

• Excipients within scope

ICH Q3D EWG Process

3

• Determining how we are impacted? – Since it is the finished dosage form that is required to

comply BUT….. • Testing every dosage form is not feasible • Data not yet available for all components

• Test methods are still unclear

• How do we get the data we need? – Need a layered approach to looking at dosage forms

and components

• IPEC Americas held a Q3D Workshop on April 4-5, 2012 to discuss the issues – outcome report will be sent to ICH Q3D EWG

4

Challenges

• Materials which use mined-excipients

– Since many metal impurities are naturally

present (for example Lead) in mined-

excipients and cannot be further

processed out, it is important to

understand the actual levels present

• May have finished product which

contain multiple mined excipients

Points to Consider

5

Max Concentration in Solid Dosage FormsExisting Specifications for some commonly used grades

mg

H

e

a Lead, ppm

Cadmium,

ppm Arsenic, ppm Mercury, ppm

Aluminum silicate 94

Aluminum stearate 105

Calcium carbonate 550 3 1 3 0.5

Calcium silicate 182.7

Calcium stearate 91.9

Calcium sulfate 443

Colloidal silicon dioxide 170 5

Potassium phosphate, dibasic 30

Sodium phosphate, dibasic, anhydrous 300

Sodium phosphate, dibasic, heptahydrate 500

Anhydrous Dibasic calcium phosphate 850 2 3

Dibasic calcium phosphate, dihydrate 635.5 0.3 1 3 0.1

Dihydroxyaluminum sodium carbonate 1350

Magnesium aluminum silicate hydrate 60

Magnesium carbonate 250

Magnesium hydroxide 450

Magnesium oxide 63

Magnesium stearate 256.4 5 3

Magnesium sulfate 29.8

Magnesium trisilicate 76.89

Talc 220.4

Titanium dioxide 1387 10 1 1 1

Tribasic calcium phosphate 333.3 0.3 1 3 0.1

6

IID Maximum Levels of Use in an Approved Product

Points to Consider

• Please note especially the two highlighted per dose levels – TiO2 is used in some approved drug products at very high levels

and actual typical levels of 1 to 9 ppm for lead have been seen in actual routine commercial batches .

– This may cause some issues if the lead PDE will be < 5 ug per day.

• Lead from TiO2 per dose, based on 10 ppm spec – 1387 mg x 10 ug/1000 mg = 13.87 ug

– <---- One dose could be 2 1/2 times higher than the 5 ug per day PDE.

– This only takes into consideration Pb from one excipient – other excipients in the formulation could also contribute…..

• What if there are multiple doses prescribed?

• Even if the lead level in the TiO2 was only 5 ppm which is very typical of actual commercial material, the 5 ug PDE would still be exceeded by one dose.

7

Excipient Realities!!!

Many times the metal content of

certain excipients is inherent from

their sources and cannot be “easily”

purified

Excipient Sources

• Mineral-based Excipients – Conversion of Ores from Mines

– Conversion of Waste Materials

• Plant-derived Excipients – Grown in Soil

– Grown in the Ocean

• Synthetic Excipients – Derived from Oil through synthetic

processes – may use metal catalysts

Kaolin mine near Kaznejov,

Czech Republic

Known – at least

12 to 55 ppm Lead

from periodic testing

Talc extraction in Trimouns Talc Mine,

Midi-Pyrenees, France

Known – Current USP

Spec <10 ppm – only

tested once per year

Typical Open Pit Mining

Operation

Raw Material for Iron Oxide

Manufacturing

Iron Oxides – from scrap

metal to oxidation tanks

Known – Current USP

Spec <10 ppm – only

tested periodically

Cellulose Sources – for MCC,

Cellulose derivatives, etc.

What’s in that Soil the

Tree is growing in?

Brown Seaweed – used to

manufacture Sodium Alginate

What has been

absorbed from

the ocean?

Unknown Unknowns

Most Excipients have not been routinely tested for the metals covered by ICH Q3D – therefore current levels

are Unknown!!

CAN WE PREDICT WHAT TO EXPECT?

Knowns - Metal Impurities from Supplier

COAs – Mineral Based Excipients

Item Description Supplier/Manufacturer Arsenic

ppm

Cadmium

ppm

Total Lead

ppm

Inorganic

Mercury

ppm

Chromium

ppm

Copper

ppm

Nickel

ppm

TITANIUM DIOXIDE,

USP/FCC/EP/JP Supplier A 1.0 max 0.2 max 10.0 max 1.0 max 1.9 max 0.5 max N/A

TITANIUM DIOXIDE USP/EP/JP Supplier B 3.0 max 1.0 max 10.0 max 1.0 max N/A N/A N/A

CALCIUM CARBONATE EP Supplier C 3 max 1 max 10 max N/A N/A N/A N/A

CALCIUM CARBONATE USP - PRECIPITATED Supplier D N/A N/A 3 max 0.5 max N/A N/A N/A

TALC USP/FCC/EP/JP - Supplier E 3 max N/A 10 max N/A N/A N/A N/A

TALC MICRONIZED USP/EP Supplier F 4 max N/A 10 max N/A N/A N/A N/A

TALC USP/EP Supplier G 3 max N/A 5 max N/A N/A N/A N/A

Unknowns: The following additional Metal Impurities did not have Specifications or Results on the Suppliers COA & Specification: Manganese, Molybdenum, Palladium, Platinum, Vanadium, Osmium, Rhodium, Ruthenium, and Iridium.

Titanium Dioxide (TiO2) Global Supply

Ore sources used to manufacture TiO2 are common to all producers

Lead content in TiO2 is determined by the Ore used as starting material

TiO2 used in Pharmaceuticals is generally High Purity Anatase made using Sulphate process

There are limited number of HP SP Anatase producers

TiO2 supply is constrained and price is under pressure as demand exceeds supply

TiO2 Purified Anatase

Sulphate Process

Ilmenite Ore

from Mine

USP Current

Spec for Pb

<10 ppm

Hmmm…I wonder what the

lead level is like Here

And Here And Here

And Here

Illmenite Ore Sources

High purity Anatase SP Plants

World's largest opencast ilmenite

mine - in Sokndal, Norway

Ilmenite from Kragero,

Norway.

Ilmenite from the

Normanville, South Australia.

Ilmenite from St-Urbain,

Quebec, Canada.

Purified Anatase (PA) Supply

The Global TiO2 Shortage has put pressure on the availability of PA.

As demand for Technical grades has increased so has pricing for technical grades.

Technical grade pricing now exceeds that of PA.

This gives producers incentive to switch to Technical grade production.

Producers are on allocation

New Pharma customers mean they have to shed volumes in other markets

Example – TiO2

• Supplier A

– Manufactures TiO2 with Ore from Ore Mine A

– Supplier A routinely tests for a number of Metal Impurities including Lead and

Leachable Lead

– Experiences unplanned Excursions from

typical historical levels that can be

prolonged

Batch to Batch Variability of some Metal

Impurities in TiO2 from Supplier A

TITANIUM DIOXIDE, USP/FCC/EP/JP COA Results

Lot Number Arsenic Cadmium Total Lead Leachable

Lead

Inorganic

Mercury Chromium Copper Nickel

1 < 0.2 ppm < 0.2 ppm 5.1 ppm 2.4 ppm < 0.1 ppm 1.9 ppm < 0.5 ppm N/A 2 < 0.2 ppm < 0.2 ppm 5 ppm 2.5 ppm < 0.1 ppm 1.7 ppm < 0.5 ppm N/A 3 < 0.2 ppm < 0.2 ppm 5 ppm 2.6 ppm < 0.1 ppm 1.9 ppm < 0.5 ppm N/A 4 < 0.2 ppm < 0.2 ppm 5 ppm 2.8 ppm < 0.1 ppm 2.1 ppm < 0.5 ppm N/A 5 < 0.2 ppm < 0.2 ppm 7 ppm 3.7 ppm < 0.1 ppm 2 ppm < 0.5 ppm N/A 6 < 0.2 ppm < 0.2 ppm 5 ppm 2.7 ppm < 0.1 ppm 2 ppm < 0.5 ppm N/A 7 < 0.2 ppm < 0.2 ppm 4 ppm 1.6 ppm < 0.1 ppm 2 ppm < 0.6 ppm N/A 8 < 0.2 ppm < 0.2 ppm 5 ppm 2.7 ppm < 0.1 ppm 2 ppm < 0.5 ppm N/A 9 < 0.2 ppm < 0.2 ppm 3 ppm 1.8 ppm < 0.1 ppm 2 ppm < 0.5 ppm N/A

10 < 0.2 ppm < 0.2 ppm 4 ppm 2.0 ppm < 0.1 ppm 1.8 ppm < 0.5 ppm N/A 11 < 0.2 ppm < 0.2 ppm 4 ppm 1.6 ppm < 0.1 ppm 2 ppm < 0.6 ppm N/A 12 < 0.2 ppm < 0.2 ppm 3 ppm 1.9 ppm < 0.1 ppm 2 ppm < 0.5 ppm N/A 13 < 0.2 ppm < 0.2 ppm 2 ppm 0.8 ppm < 0.1 ppm 2 ppm < 0.5 ppm N/A 14 < 0.2 ppm < 0.2 ppm 2 ppm 0.8 ppm < 0.1 ppm 2 ppm < 0.5 ppm N/A 15 < 0.2 ppm < 0.2 ppm 2 ppm 1.1 ppm < 0.1 ppm 2 ppm < 0.5 ppm N/A

0

1

2

3

4

5

6

7

8

9

10

Total

Leachable

0 – 4 ppm

5 – 9 ppm

0 – 4 ppm

3 – 7 ppm

2008 2009 2011

Lead Content Variability in Titanium Dioxide from Supplier A – Ore Mine A

Lead Content, ppm

2008 - 2011

2010

What Metal Impurities are

Bioavailable? • ICH Q3D says they are setting “safety-based” limits,

however, they are focusing just on Total metal content which makes no sense!!!

• Ex; Only Leachable Lead is bioavailable from TiO2

• Leachable Lead level is typically much lower than the Total Lead content

• Sample prep and test methodology is very important to utilize data for decision making!!

• Using Total Lead content in Q3D PDE requirements is NOT “safety-based” and should be re-evaluated!!!

CALCIUM CARBONATE

PhEur

Lot Number Arsenic Cadmium Lead Inorganic

Mercury Chromium Copper Nickel

1 0.29 ppm 0.73 ppm 2 ppm N/A N/A N/A N/A 2 0.29 ppm 0.73 ppm 2 ppm N/A N/A N/A N/A 3 < 3 ppm 0.19 ppm 2.2 ppm N/A N/A N/A N/A 4 < 3 ppm 0.17 ppm 2.4 ppm N/A N/A N/A N/A 5 0.42 ppm 0.21 ppm 2.3 ppm N/A N/A N/A N/A 6 0.26 ppm 0.5 ppm 2 ppm N/A N/A N/A N/A 7 0.21 ppm 0.3 ppm 1.1 ppm N/A N/A N/A N/A 8 0.29 ppm 0.5 ppm 4.7 ppm N/A N/A N/A N/A 9 0.14 ppm 0.6 ppm 2.5 ppm N/A N/A N/A N/A

10 0.35 ppm 0.63 ppm 4.5 ppm N/A N/A N/A N/A 11 0.57 ppm 0.44 ppm 2.6 ppm N/A N/A N/A N/A 12 0.36 ppm 0.38 ppm 7.1 ppm N/A N/A N/A N/A 13 0.16 ppm 0.6 ppm 3 ppm N/A N/A N/A N/A 14 0.43 ppm < 0.1 ppm 1.4 ppm N/A N/A N/A N/A

Excursion

Common Excipients Existing Elemental Impurity Data

Item Description Lead Limit Listed on

COA Typical Lead Limit Test Method Frequency of Testing

TITANIUM DIOXIDE, USP/FCC/EP/JP

Max 10 ppm 1 to 9 ppm based on 2

year history, 2 to 5 ppm typically

ICP Every Batch

HPMC 3 cP - USP/EP/JP NMT 20 ppm (Heavy

Metals) 0.2 to 2 ppm ICP-MS Once per year

HPMC 6 cP - USP/EP/JP NMT 20 ppm (Heavy

Metals) 0.2 to 2 ppm ICP-MS Once per year

PEG 400 NF/EP/JP < 5 ppm (Heavy

Metals) NMT 1 mg/kg * *

SODIUM CITRATE - DIHYD. USP/EP/JP/FCC/JSFA

< 2 mg/kg < 1 mg/kg ICP Weekly

POLYSORBATE 80 (VEG.) NF/EP/JP < 10 ppm (Heavy

Metals) Max 1 ppm

Atomic Absorption Electro-thermal

Atomization (Furnace Atomization) according to

“Combined Compendium of Food

Additives Specifications”, FAO JECFA Monographs,

vol 4 (2005).

Statistic Basis

POLYVINYL ALCOHOL, USP/FCC/EP/JPE

NMT 2 ppm * AA Analysis Once per year

PEG 3350 NF/EP/JP < 5 ppm (Heavy

Metals) * * *

Testing of Aluminum Lakes Test Results

Target Maximum Limits (ppm)

Product Batch No Aluminum Arsenic Barium Cadmium Iron Lead Zinc Mercury

Expected Target Maximums >100000 1 500 1 500 1 500 1

Method Reference EPA 6010B EPA 7471B

Method Detection Limit 389 0.486 0.245 0.0225 2.08 0.191 0.132 0.0309

Reporting / Quantitation Limit 10 1 1 0.4 5 2 1 0.1

FD&C RED #40/ALLURA RED AC ALUMINUM LAKES

low dye% 1 226000 0.724 8.60 1.00 57.1 <0.191 <0.132 <0.0309

2 235000 0.492 16.6 1.08 74.2 <0.191 <0.132 <0.0309

low dye%

1 214000 <0.486 10.3 1.04 59.7 <0.191 <0.132 <0.0309

2 225000 1.70 14.2 1.03 66.3 <0.191 <0.132 <0.0309

3 233000 0.740 8.44 1.14 65.8 <0.191 <0.132 <0.0309

medium dye%

1 161000 <0.486 8.85 0.703 49.4 <0.191 <0.132 0.0550

2 155000 0.978 5.71 0.674 58.8 <0.191 <0.132 <0.0309

3 154000 0.731 6.07 0.677 63.7 <0.191 <0.132 <0.0309

medium dye% 1 169000 0.755 8.00 0.761 57.4 <0.191 <0.132 <0.0309

high dye% 1 153000 <0.486 5.59 0.681 18.0 <0.191 <0.132 <0.0309

2 158000 <0.486 5.31 0.699 18.0 <0.191 <0.132 <0.0309

80 Samples

7 Metals

Cost > $20,000

USP – ICH Efforts

• USP plans to implement General Chapter requirements once ICH

publishes their limits which will include the lCH PDE limits and

some information about the use of appropriate test methods

based on the matrix issues that may exist

• FDA appears to understand the need for a slow implementation

to gain an understanding first of the impact

• USP had indicated last year they would like to implement these

General Chapters in 2013 – IPEC FELT THIS WOULD HAVE BEEN A

BIG MISTAKE!!!

• This date has now been taken off the USP website. USP Plans to

be publishing their current position and a new date in the near

future

USP – ICH Efforts

• No implementation date should be identified at this point since most excipient manufacturers will not have a good

understanding of their true variability for some time.

• Therefore, all they can do is commit to the existing USP-NF specifications if they exist – this results in higher levels than

might be typical

– Many Q3D metals do not have specifications in USP-NF

– Suppliers may not agree to any spec on these metals

• ICH Q3D EWG targeting to publish a Step 2 document in

June 2012 at Tokyo meeting

Supplier Information concerning

Metal Impurities • As the ICH Q3D Guideline and the USP Chapters are being

finalized, many suppliers are waiting to assess their products so that they are using the appropriate test methods and detection limits which will be necessary once the limits are established

• Therefore, many suppliers currently have very limited information related to the actual levels of metal impurities in their excipients and food additives

• Routine testing for these Metal Impurities is not typically done at this time and actual levels below the current specifications are not known

• The IPEC Federation has published a position paper on the web which explains why users should NOT request detailed metal impurity information from their suppliers at this time

Supplier Realities

• Many suppliers who don’t routinely test for metal impurities

may NOT be willing or able to agree to specifications that

are lower than what they are required to meet to comply

with USP-NF monograph, 21 CFR or other regulatory

requirements for the component

• In some cases, they may be willing to agree to levels based

on their best understanding of typical values but it is

expected that this will be the exception not the rule

• Remember, for many excipient companies, the pharma

business is a very minor part of their sales and they will not

implement a lot of additional controls without getting

premium prices if they are even willing to do it at all.

User Realities

• What does this all mean

to Pharma Companies? Option #1

?

Option #2a or 2b

?

Option #3 ?

Confusion

?

Realities for Implementation

• Many Excipients do sometimes contain Metal Impurities at the 1 to 10 ppm level. Typical levels Unknown at this time. – Forget using Option 1 limits – not realistic for many excipients

• Suppliers typically will not be willing to agree to tighter specifications than the historical compendial requirements for Option 2 calculations

• Most Suppliers may not do significant testing to determine typical levels until after the ICH Q3D requirements are published – excursions may make it impossible to define typical levels

• Some suppliers may choose not to participate in supplying the pharmaceutical industry if too much pressure is put on them to do routine testing and agree to lower limits

Realities for Implementation

• Pharmaceutical companies will probably need to do significant testing themselves on their excipients or drug products to determine actual levels and if they comply with PDEs – Think Option 3!!!

• Some drug products will probably need to be reformulated to meet PDE requirements – Lead from TiO2 per dose, based on 10 ppm spec

– IID Max. of 1387 mg x 10 ug/1000 mg = 13.87 ug

– One dose could be 2 1/2 times higher than the 5 ug per day PDE.

• All these efforts are going to take quite a bit of time to do properly (probably several years min.)

• ICH and Compendias MUST work closely with industry to only make these requirements official once the unknowns are much better understood!!

IPEC Proposals

• IPEC plans to develop a standardized mechanism for how makers and users should best share information on metal impurities

• Standard format will be provided that meets the key needs at this time

• Request will NOT allude to setting tighter specifications – just information gathering

• Mechanism will be shared throughout the Coalition associations and with Rx-360 for broad usage

• Q3D Workshop – many recommendations to the EWG and points to consider

Q3D Workshop

Recommendations to EWG • Categories should be added to the guideline – with metals

segregated according to whether they are likely to be present from the environment or may be due to use as catalysts (etc)

• Clarification is needed on risk assessments and testing – specifically to indicate that process knowledge, understanding of your materials and so forth could be used to justify not checking for all 27 metals

• If the limits are to truly be safety based, the guideline limits should be focused on the amount of metal that is absorbed by the body (as opposed to total metals)

• Target to meet total metals (PDEs) as a first step for simplicity, however if that is not achievable

• Then consider what portion of the metal(s) is absorbed by the body (bioavailable)

Q3D Workshop

Recommendations to EWG • An adequate implementation timeframe (minimally 2 years) is

required for new drugs and an additional 5 years after that

would probably be needed for existing drugs.

• The ICH Q3D EWG postpone the publication of the Step 2 guideline until the November meeting so that additional data

concerning actual metal impurity content and potential for

bioavailability can be developed and considered by the EWG

• Many other points were made concerning excipient realities

for consideration by EWG during the meetings in Japan in

June

Questions?