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ICH Q3D Metal Impurities:

Excipient Maker’s Perspective

David R. Schoneker

Vice Chair – Maker & Distributor Relations – IPEC

Director of Global Regulatory Affairs – Colorcon

Email: dschoneker@colorcon.com

April 4, 2011

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!!!

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!!!

•

USP – ICH Efforts

• USP now states in their FAQs the following:

• Frequently Asked Questions: USP's Proposed Standards for Elemental Impurities

• Q. What is the timing of the new standard?

• A. USP's standards–revision process involves international collaboration among USP experts, industry, regulators, and the general public. When there is no specific medical emergency, as is the case with elemental impurities, it is beneficial to allow careful deliberation and scientific dialog to reach conclusions that are supported by a maximum number of interested stakeholders. In addition, where the new standards represent a significant change from existing standards, as is also the case with elemental impurities, it is important to provide sufficient time for manufacturers to incorporate the changes in their processes necessary to implement the new standards. The new elemental impurities standards, which are intended to replace the existing methods in General Chapter <231> Heavy Metals, are expected to be finalized sometime in 2010 and become official at a later date which has not yet been determined.

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

Q3D – Step 2 Publication

• Publication of the ICH Q3D guideline (possibly in June 2012)

will then drive many suppliers of excipients and food additives

to begin compiling more information on the levels of

elemental impurities than currently exists

• Q3D & USP Requirements will NOT be on the excipients, just

the dosage form. However many users may want to set

specifications on the excipients which the supplier will not

agree to. Excipients do not have to “comply” to Q3D!!

• Most suppliers will not invest heavily into this testing until the

ICH limits are published. Therefore they don’t know the

actual levels present or variability at this point

• Doubtful that many suppliers will implement routine testing

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

• After the ICH Q3D Step 2 guideline is published, 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

Bring your questions to

the Breakout sessions