KEY POINTS

Elemental impurities may not be as risky as assumed, at least for some exposure routes and dosage forms, due to poor bioaccessibility, industry says.
Topicals shouldn’t be treated like parenterals in terms of risk, industry says.
There should be more clarity and consistency in the calculation of permitted daily exposures, industry says.
ICH and USP remain somewhat at odds in toxicological analysis of elemental impurities.
The timeline for extending ICH Q3D standards to currently marketed drug products remains unknown.

As international limits on elemental impurities in pharmaceuticals near final approval, industry is arguing for relaxing the standards for certain exposure routes and dosage forms on the basis of bioaccessibility.

An expert working group is resolving questions manufacturers have raised as it refines the Q3D elemental impurities guideline for new drugs, which U.S., European and Japanese authorities aim to adopt in June at an International Conference on Harmonization meeting in Minneapolis, Minn.

Meanwhile, the same issues are in play at the U.S. Pharmacopeia, which is working on compendial standards for elemental impurities that would be substantially harmonized with the ICH guideline and that would also apply to existing drug products marketed in the U.S.

FDA and industry have done some initial analysis of supply chains and ingredients, enough to know that limits on elemental impurities will not be a problem for most drug products. The worry is that in cases where there is a potential issue such as lead in a mined excipient, it may be difficult or impossible to resolve Also see "As ICH Q3D Metal Impurity Limits Near, Industry Worries What New Tests May Find" - Pink Sheet, 26 April, 2012..

A cost but no benefit?

Industry’s main argument is that a June 2013 draft of the ICH Q3D guideline would require it to identify and control elemental impurities that the human body could not absorb. There would be a cost, perhaps a substantial cost, but no benefit.

A better approach would be to focus on the bioaccessible fraction of metals that can be leached from oral drug products by acids that mimic the work of digestive fluids, industry is saying. Such an approach would also approximate the risk of metals leaching from topical drug products better than ICH’s proposed approach of assuming the 100% bioavailability that comes with parenteral use, industry is saying. For oral drug products, bioaccessibility is a key factor in bioavailability, or the fraction that gets into the blood.

Leading the charge for industry is an ad hoc group called the Coalition for the Rational Implementation of the Elemental Impurities Requirements.

Chaired by Colorcon’s Dave Schoneker, the group echoes an earlier lobbying effort Schoneker spearheaded on the issue of residual solvents Also see "FDA Offers More Flexibility on Residual Solvents in Generic Drug Applications" - Pink Sheet, 1 November, 2008.. Schoneker told “The Gold Sheet” he believes elemental impurities requirements will prove even more challenging to implement. “This is going to make residual solvents look like it was a cakewalk.”

The coalition includes broad representation from manufacturers of pharmaceutical excipients, active pharmaceutical ingredients and generic and over-the-counter drug products through the International Pharmaceutical Excipients Council of the Americas, the Society of Chemical Manufacturers and Affiliates’ Bulk Pharmaceuticals Task Force, the Generic Pharmaceutical Association and the Consumer Healthcare Products Association.

A focus on topicals

One key concern is that the “Step 2b” draft guideline appears to require manufacturers to set limits on topical drug products as if they were oral or parenteral products, an approach the coalition believes “would be scientifically unjustifiable and would substantially overestimate the risk.”

CHPA also filed comments of its own that underscored the association’s concerns about over-the-counter topicals, particularly those that don’t have defined daily dosages.

The coalition also wants ICH to assert that testing should focus on bioaccessible impurities rather than total impurities. This the coalition says would support the use of methods that are more representative of actual risks when manufacturers evaluate compliance with permitted daily exposure limits set under the guidance.

The coalition raised other concerns as well, urging the ICH expert working group to agree that the guideline:

should say it doesn’t address any elements beyond those it mentions;
should be like ICH’s M7 guideline on mutagenic impurities in that it doesn’t apply to cancer treatments in development;
shouldn’t default to lifetime limits; and
should allow that risk assessments can obviate the need for routine testing, even for Class 1 metals.

A question of exposure routes

The issue of assessing topicals as parenterals is part of a broader request by the coalition for a more consistent, transparent approach to deriving permitted daily exposure (PDE) limits.

“Text should be added to clarify how PDE derivation data were prioritized for each metal and each route of exposure,” the coalition said, calling attention to the case of cadmium salts. The default is for PDEs to be 10 times stricter for parenterals than for oral products, but for cadmium salts they are almost identical. Similarly, the default for inhalables is 100 times stricter than for orals, but in this case, a relaxed standard derived from an occupational exposure limit was proposed.

A PDE calculator

The coalition in October had presented its arguments on bioaccessibility to USP, which is revising its compendial approach to heavy metals testing in line with the ICH Q3D process.

The coalition shared with ICH its USP comments, which note that the pharmacopeia already has set precedents for use of more biorelevant analyses such as dilute acid leach methods for measuring and controlling lead and arsenic in food and pharmaceutical ingredients such as talc and kaolin.

The group’s USP comments concluded with the assertion that most industries assess elemental impurity risks “based on biorelevant extraction techniques rather than total digestion techniques,” and the pharmaceutical industry should too.

The coalition included with its comments an elemental impurity PDE calculator, along with instructions for using it.

USP/ICH Convergence

USP has been revising its compendia on a parallel track with Q3D. The pharmacopoeia is revising its general chapters 232 and 233 to supplant the general chapter 231 heavy metals test with a collection of more-specific tests that focus on metals of concern, particularly the big four: arsenic, cadmium, lead and mercury.

There has been some anxiety in industry as USP and ICH diverged on proposed limits and implementation timing, but the two organizations now appear to be on a path toward convergence, more or less.

In its Dec. 20 comments, USP confirmed that it had backed away from plans to revise its elemental impurities general chapters this May. Now it won’t happen until August 2015. And yet more time will pass before USP applies the revised chapters to drug product monographs.

USP also agreed that it should propose the same list of elements with the same limits as ICH, and promised that it “will make every effort to achieve this goal.” That said, the pharmacopoeia hinted that if necessary, it could go final with its standards even if they differ from ICH’s “with the understanding that further accommodations can be made over time via revisions to the USP-NF.”

The bulk of USP’s comments laid out its differences with ICH on metal-specific toxicological risk analysis, including:

Why USP supports a PDE of 15 mcg/day for mercury instead of ICH’s 40 mcg/day;
Why USP supports reducing the parenteral PDE for molybdenum from the ICH-proposed 180 mcg/day to 90 mcg/day;
Why USP would use a greater uncertainty factor for cadmium data quality due to uncertainties with the subcutaneous route of administration;
Why USP believes PDEs for platinum-group metals osmium, iridium, ruthenium and rhodium should match that of palladium, which is 100 times lower than platinum’s PDE for the oral route;

USP disagrees with ICH’s proposal to set parenteral PDEs without regard to dose volume, saying it could lead to such low component limits for large-volume parenterals that it would be extremely difficult or impossible to test for them.

USP, like industry, disagreed with ICH’s plan to set limits for topical and mucosal products based on parenteral limits. USP prefers using U.S. Environmental Protection Agency oral reference doses instead.

Timeline for existing products

Another worry for industry is how soon regional authorities will apply the new elemental impurities limits to existing drug products.

Although ICH only produces harmonized guidelines for regulating the approval of new drugs, its guidelines have implications for drug products that are already on the market.

The draft Q3D guideline says merely that “the application of this guideline to existing marketed drug products will be addressed by regional regulatory processes.”

In its Q3D comments, the Consumer Healthcare Products Association shared some thoughts on implementation timing.

CHPA requested that FDA publish guidance on implementation expectations of the ICH Q3D guideline well before enforcing it. CHPA wants FDA to wait at least another year for new drugs and two years for existing drugs before enforcing the guideline.

Restraint Advised in Testing

Given the uncertainty about what standards authorities will adopt, how thoroughly the standards will be harmonized and when they will take effect, it can be difficult to chart a path forward on elemental impurities.

Experts who spoke at a recent American Association of Pharmaceutical Scientists workshop shared their thoughts on priorities and key considerations for manufacturers who will need to comply with new elemental impurities requirements.

One key point: Don’t go overboard on testing. To get their advice – and a chart showing currently proposed limits for 27 metal impurities – see the story, ([A#08140430002]).

ICH Urged to Allow for Bioaccessibility in Metal Impurities Standards

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