There is still room for improvement in enterprise element impurity risk assessment

U.S. and European Union regulators have seen companies perform better risk assessments as part of the implementation of the ICH Q3D Element Impurity Guide.
But regulators say there is room for improvement, with some assessments not telling the whole story, lacking narrative language to support data analysis, and leading regulators to ask unnecessary questions and slow down reviews.
made the observation at a meeting on the implementation of ICH Q3D held on November 9th by the Society for The Study of Drug Quality (PQRI).
ICH Q3D guidelines require drugmakers to report elemental impurities in medicines.
the guidelines came into effect for all new drugs in June 2016 and for all listed drugs in January 2018.
Guidelines, released in December 2014, set a maximum daily allowable exposure (PDE) limit for 24 elements and call on drugmakers to assess the risk of introducing elemental impurities such as accessories, production equipment, API and container sealing systems in finished preparations.
regulators require elemental impurity risk assessment in all new and generic applications.
, acting head of quality evaluation at the FDA's Office of Drug Quality (OPQ), noted that the industry is implementing better risk assessments, but there is still room for improvement.
, "I think the Q3D risk assessment concept is generally well accepted."
don't want to exaggerate the severity of the problem with ICH Q3D because it's not a lot, but there are still some minor problems.
, for example, the FDA continues to see confusing risk assessments.
these assessments lack a brief discussion or narrative explanation of how elemental impurity data is generated.
issues include evaluating too much emphasis on table data without providing a "large amount of context."
he also believes the assessment may lack "attention to detail" and use the wrong maximum daily dose, or that the table description and column headings are incorrect.
"These are the places that confuse us, " he says.
," says Vera, "sometimes there is a problem with the concentration unit."
Sometimes it's marked as intake, so we expect to see how many micrograms per gram, and the table shows how many micrograms per day, which can hinder the review team's progress until they figure out what's going on.
problem is the "data junk risk assessment", i.e. the assessment gives only one table of data.
Vera said the evaluation forms "control the data values within the threshold without any discussion, and then attach a large number of appendixes, including hundreds of pages of sales literature and supplier manuals, without specifying how they illustrate the overall conclusions."
risk assessment may include terms such as 'no risk found' or 'risk negligible', without a narrative analysis or explanation as to why such a conclusion was reached.
for the review team, screening all this information can be difficult and not a sustainable approach.
Sophie Bertilsson, reviewer of the Swedish Pharmaceutical Products Authority, points out that the EU does not have many problems with risk assessment.
, but after listening to Vera, "I realized that we had very similar experiences in implementation."
most risk assessments are considered acceptable, but sometimes they are very brief and do not always follow different assessment steps," she said.
mark Schweitzer, head of global analytical science and technology at Novarthics and a former Q3D guide to risk assessments, says the industry now has a better understanding of how to conduct these risk assessments as experience accumulates.
he said, "Early on we didn't really know what to do."
2020, from my experience in element analysis and submission, risk assessment of element impurities is already on a daily basis.
we still face some interesting challenges, but as experience increases, there are not many implementation challenges for both branded and generic drugs.
said Novarma has conducted more than 1,000 risk assessments of new and generic drugs, which are "mainly focused" on API and accessories.
this is the source of most elemental impurity risks.
to perform risk assessments, companies rely on data that includes information about elemental impurities generated internally, data from external databases such as Lhasa, and data from a joint FDA-International Association of Supplements.
Lhasa database was established in 2015 by the Pharmaceutical Companies Alliance to share information about elemental impurities in accessories.
the database currently covers the determination of 39,517 elemental impurities from 295 accessories.
enterprises can access the database for a fee.
so far, we have not received any challenges or questions from regulators about the evaluation of elemental impurities, " he said.
industry has made considerable progress in conducting better risk assessments.
three years ago, at a conference on the same subject, also organized by PQRI, regulators were divided over the treatment of elemental impurities risk assessments performed by the industry.
to improve the question-and-answer phase, Vera was asked what to do if suppliers did not cooperate and did not provide elemental impurity data to drugmakers for risk assessment.
Vera said drugmakers should not rely on information provided by suppliers for risk assessments.
"product quality must be the responsibility of the drugmaker, and if the supplier is unwilling to provide information, the drugmaker needs to find another way to obtain information from the supplier."
drugmakers need to fill in the blanks themselves.
" is in agreement with the recommendations made by business representatives at the Q3D implementation meeting three years ago.
asked if regulators had rejected the filings because of poor risk assessment, Mr Bertilsson said.
Vera said it was "very rare" for the FDA to reject applications because of poor risk assessment.
he said, "Early on, a full response letter was sent because there was no risk assessment in the application."
"Vera explains, "Most of the time we have no problem with Q3D risk assessment, and elemental impurities are not a major barrier to reviewing applications."
, in some cases, we ask follow-up questions.
I would like to say that some risk assessment issues may slow down the review process.
these issues include not telling stories or discussing what's behind the data.
most of the submissions are no problem, with the exception of these issues.
"Bertilsson said when asked what drugmakers can do to improve risk assessment, "the most important thing is to tell a story."
't be able to tell a complete story, so we had to ask a lot of unnecessary questions.
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