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Consortium Grows As Drugmakers Share Excipient Metal Impurities Data To Ease ICH Q3D Testing Burden

Executive Summary

More manufacturers are contributing their analytical data to an excipient database to pool knowledge on the risk posed by excipients that may cause drugs to exceed acceptable PDE levels under ICH Q3D.

More manufacturers are agreeing to pool their knowledge on excipient elemental impurity risks and contribute to a centralized database to help ease risk assessments called for by the International Council on Harmonization’s Q3D guideline.

Laurence Harris, director of global GMP analytics for Pfizer Inc. gave an update, and touted the benefits, of the excipient database on 10 November at a workshop on ICH Q3D implementation sponsored by the Product Quality Research Institute. Due to the pandemic, the workshop was held virtually.

The ICH Q3D guideline sets permitted daily exposure (PDE) limits for 24 elements and calls on manufacturers to assess the impurity risks posed by excipients, manufacturing equipment, active pharmaceutical ingredients and container closure systems in the final drug product.

The guideline went into effect in January 2018 for legacy products and June 2016 for new products.

According to ICH Q3D, the information and the data used in the risk assessments can be derived from numerous sources including prior knowledge, published literature, data derived from similar processes, supplier information, testing the components of the drug product and testing of the drug product.

Why Do Duplicate Testing For Mannitol?

The database can help aid in risk assessments by identifying excipients and their elemental impurities levels which have already been used in marketing applications.

Harris said that the database eliminates the need for manufacturers to do their own testing of excipients and their use in formulations. “If six or seven companies have tested 15 different sources of mannitol for the levels of lead, then why would I need to do that?”

New Companies Joining

Each member company of the consortium donates the results of their in-house analytical studies of  elemental impurity levels in excipients in exchange for being able to access the database.

There are now 13 members of the consortium: AbbVie Inc., Ache Laboratorios Farmaceuticos S.A., AstraZeneca PLC, Braun Corp., Bristol Myers Squibb CompanyCelgene Corporation, GlaxoSmithKline Pharmaceuticals Ltd.,
Novartis AG, Pfizer, Polpharma SA Sanofi Pasteur, Takeda Pharmaceutical Co. Ltd. and UCB Biopharma LTDA.

The Lhasa database was established in 2015 and launched in 2016 with contributions from eight members to help reduce the burden of testing excipients that have already been tested. (Also see "Excipient Database Should Help Take Mystery Out Of ICH Q3D Risk Assessments" - Pink Sheet, 8 Sep, 2016.)  

With the expansion in membership since then, the database has grown from 800 analytical studies and 26,723 elemental impurities on 200 excipients when first launched to 2,962 analytical studies and 40,574 elemental determinations on 299 excipients.

The data, besides being accessible to members of the consortium, is also available to regulators to make it clear why certain excipients are regarded as a lower relative risk than others in a particular formulation for a given daily intake. It includes multiple excipient samples from a range of suppliers.

Harris said that the database enables assessments to be done quickly, “in less than 10 minutes,” to make an elemental impurity determination for a particular excipient. He said that Lhasa, the non-profit group that collects the data and manages the database, provides training on how to use the database.

Very Little Data In 2014

Harris said that when the ICH Q3D guideline was first published in 2014, there was “very little data” available on elemental  impurity risks, yet excipients “were considered to be a significant risk.” Mined excipients such as talc were considered the highest risk and those excipients synthesized without a metal catalyst thought to pose the lowest risk.

A study published in 2015 disproved these assumptions.

The study, conducted by the US Food and Drug Administration and the International Pharmaceutical Excipients Council, assessed the risk of 24 elemental impurities in 205 samples for a total of 4,900 determinations and found excipients posed a lower risk than originally perceived.

More Data Driven Tools Needed

After this study was published, there was industry consensus on the need for a more “scientifically driven” way to assess the risk of excipients. There was also recognition of the need to “save time and reduce the amount of testing” for ICH Q3D risk assessments.

Harris said that “the intention for the initiative was that we would be able to build something that would allow us to be data driven and hopefully generate a resource which would reduce any ongoing need to test excipients that we felt it would be unnecessary.”

The integrity of the data is important, so the names of the suppliers are blinded, and only the names of the excipients are listed. The database is updated every year.

Harris said that the database is meant to supplement the data that is in the published literature on excipients. It is also currently the “largest known collection” of this type of data, he said.

At Pfizer, the database was used to conduct a product risk assessment to ensure that palladium would remain under PDE threshold levels. Palladium was used in an API and a catalyst being formulated by the company.

Database Is Relevant For Drug Development

The database, he said is also “relevant” in that it reflects that 42 of the 49 novel drugs approved in 2018 were formulated with excipients listed in the database.

Harris said that “we had a warm feeling from this that the data in our database is relevant to the new drugs being approved by FDA.”

The 49 novel drugs approved in 2018 included 30 oral drugs, 17 parenteral drugs, one topical drug and one inhaled formulation.

Harris said that the consortium welcomes new members. “We are open to new members joining the consortium. We want to continue to grow this database.”


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