Revised US Approach For Parenteral Drug Leachables Could Prevent Regulatory Missteps
Executive Summary
Broad agreement across US FDA on modified PQRI recommendations could reduce approval delays over risk of chemicals leaching into parenteral drugs.
In a development that could prevent some US Food and Drug Administration approval delays, a group of industry, regulatory and academic experts recently won agreement across agency review divisions on a consistent, streamlined approach to determining whether unsafe levels of chemicals might leach into parenteral drugs from their containers.
The Product Quality Research Institute is a collaboration of the FDA, industry and academia that since 1996 has worked to put chemistry, manufacturing and controls regulatory filings on a firmer scientific footing.
One of PQRI’s major successes was its 2006 report on extractables and leachables for orally inhaled and nasal drug products. It established a threshold-based evaluation process that was embraced by the main division in the FDA’s Center for Drug Evaluation and Research that evaluates applications for such products, now called the Division of Pulmonology, Allergy and Critical Care. (Also see "ORALLY INHALED AND NASAL DRUG PRODUCT" - Pink Sheet, 15 Feb, 2007.)
PQRI formed a working group in 2008 to build on that success by applying its framework to parenteral drugs, which are assessed by a wide array of review divisions, culminating in a recent set of recommendations, updated in October, that PQRI plans to publish in the PDA Journal.
The development process reflects buy-in from the FDA across therapeutic areas. The working group’s core team includes participants from the FDA’s centers for drugs and biologics and Health Canada. Input on the evolving recommendations included perspectives from experts from divisions for assessing anesthesiology, addiction medicine, pain medicine, cardiology, nephrology, hepatology and nutrition, diabetes, lipid disorders and obesity, nonprescription drug products, pulmonology, allergy and critical care products, rheumatology and transplant medicine, generic drugs, new drugs, and product quality. There also was a representative from the UK Medicines and Healthcare Regulatory products Agency.
Key Points
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An approach PQRI developed for assessing extractables and leachables safety risks associated with parenteral drugs has won US FDA support.
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However, some aspects of the assessment process changed in response to feedback from the agency.
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PQRI is moving ahead with a 1.5 micrograms/day safety concern threshold for parenterals.
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However, a 50 micrograms/day systemic threshold is on hold until PQRI gets more data.
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Additionally, assessment of extractables and leachables for ophthalmics dosage forms was set aside for later consideration.
Fewer Regulatory Missteps Expected
Consensus around the PQRI approach could reduce regulatory missteps that have delayed and even derailed drug applications over the years.
Under the case-by-case approach still in use today, it is difficult for manufacturers to tell whether they are doing too much or too little to make sure they will protect patients from toxic leachables.
Doing too much could delay filings, complicate designs and increase manufacturing costs.
Doing too little could lead to complete response letters and delays of a year or more while firms conduct new in silico, in vitro or animal studies.
The FDA has cited poor extractables/leachables studies in many complete response letters, one agency review official told the Pink Sheet. In fact, problems with these studies are the norm rather than the exception, according to another FDA reviewer.
A Potpourri Of Complete Responses
Pharmaceutical companies have been filing applications that approach leachables risks in a wide variety of inappropriate ways, according to Dan Mellon, a pharmacology toxicology supervisor in the FDA’s Office of New Drugs.
Some are silent on the issue, Mellon explained in a recent workshop presentation. Others justify components based on their use in other approved products, or on in vitro biocompatibility data. Still others assess risk based on compounds extracted in studies that may not necessarily leach into drug product.
Mellon noted some of the typical problems cited in complete response letters including failure to identify compounds that exceeded thresholds, lack of the test method sensitivity required to detect them, use of the wrong thresholds like the ones in International Council on Harmonization Q3A and Q3B guidelines for impurities and degradation products, and poor explanations of how extractables data were used in designing leachables assessments.
When the FDA takes exception to a firm’s extractables/leachables studies, the results can be damaging to the firm. An official with one pharmaceutical company recalled getting a complete response letter over questions about possible leachables from cardboard packaging for what could have been a first-to-file generic drug product. It took the firm more than a year to conduct the necessary studies, and during that time competitors claimed most of the market share – and profit.
Extractables Versus Leachables
For parenterals, leachables are organic or inorganic substances that can leach from the container/closure system into the drug product. They also include substances that can leach from container/closure system components that don’t directly contact the drug product such as labels, inks and adhesives.
Generally, leachables correlate with extractables, which are compounds extracted by solvents from packaging systems or their components in tests.
PQRI notes that guidance the FDA, the European Medicines Agency and Health Canada have issued over the years generally calls for a four-step process of showing materials meet industry standards, conducting extractables studies, then leachables studies, and then performing a toxicological assessment. There also can be a fifth step that involves reconciling or correlating information to help with planning for worst-case scenarios.
The main problem with this approach is some extractables won’t leach into drug product or will leach at such low levels that they would pose a negligible risk to patients.
The Safety Concern Threshold
The PQRI parenterals working group explained its evolving approach to regulatory thresholds for leachables in a 2013 report in the PDA Journal, during an April 2018 workshop, in a series of conference presentations over the years and inthe recommendations recently posted on PQRI's website.
The key concept, adapted from the OINDP workgroup, is what PQRI calls the safety concern threshold or SCT. It is the total daily intake below which a leachable would present negligible safety concerns from either mutagenic or non-mutagenic toxic effects.
The benefit of the SCT is that it frees companies from the compulsion to identify and risk-assess every chromatographic peak presented by their increasingly sensitive analytical equipment, no matter how inconsequential.
Why SCT Was Relaxed For Parenterals
PQRI set the safety concern threshold at 0.15 micrograms/day for OINDPs but raised it to 1.5 micrograms/day for parenterals.
The OINDP threshold was set conservatively – based on a one-in-a-million lifetime cancer risk – because metered-dose-inhaler formulations contain powerful solvents likely to react with typical extractable and leachable chemicals, which the MDIs would deliver directly to diseased organs of a sensitive patient population, leading participants in the PQRI PODP (Parenteral and Ophthalmic Drug Product) Working Group explained in a review article in the September/October 2013 issue of the PDA Journal.
The less-restrictive level set for parenterals made sense to PQRI, given their primarily aqueous nature and the type of packaging systems involved.
A key factor in justifying the higher threshold for parenterals: the working group’s risk evaluation of more than 600 likely extractables and leachables.
Analytical Evaluation And Qualification Thresholds
For parenterals, the analytical evaluation threshold or AET is adjusted from the SCT for use in triggering toxicological assessments based on doses per container, container volume, doses per day and an analytical uncertainty factor.
Companies must identify substances only if their chromatography peaks exceed the AET. They must also report those substances to a toxicologist for toxicological safety qualification.
The toxicologist must qualify identified compounds that are potentially mutagenic or genotoxic based on the International Council on Harmonization’s M7 guideline for limiting daily intake of mutagenic impurities. Even though M7 does not apply to leachables, its safety risk assessment principles can be used for them, the PODP update report says.
The M7 approach includes an adjustment to a safety control limit for identified mutagens, called the threshold of toxicological concern, to allow higher levels when treatment duration is shorter. However, there is no such adjustment allowed for the PQRI’s SCT, which is a benchmark for identification rather than a safety control limit.
The toxicologist must qualify non-mutagenic leachables that could cause irritation or sensitization if they exceed a 5 micrograms/day threshold, which applies both to OINDPs and parenteral drugs. “If it’s above five, that doesn’t mean you can’t use it, but you have to prove that it would be safe above five,” Diane Paskiet, director of scientific affairs at West Pharmaceutical Services and chair of the working group, told the Pink Sheet.
For non-mutagens that pose no sensitization or irritation concerns, there still could be a risk of systemic toxicity. The PQRI PODP group had proposed a qualification threshold of 50 micrograms/day below which compounds would not have to be examined for possible systemic toxicity. However, this proposal did not survive the broader vetting process across multiple FDA review divisions.
It is possible the systemic toxicity threshold could resurface, Paskiet said, noting that it was removed “because there was not enough data to verify, not because they didn’t agree with it.”
A Pass On Ophthalmics, For Now
The PODP working group set aside efforts to apply the risk-based threshold concepts to ophthalmics because the FDA prefers to continue assessing leachables on a case-by-case basis for such products. Also, the working group requires more data on relevant toxicity endpoints before it can recommend specific safety thresholds.
In addition, the working group decided some parenteral routes of administration are out of scope: intrathecal, intracerebroventricular, intra-articular, epidural and perineural.
Simulation Studies Might Be Needed In Cases
One issue the working group recognizes is that analytical evaluation thresholds may be so low for large-volume parenterals that it will not be feasible to discover and identify unknown leachables in them. There could be similar issues for small-volume parenterals if given to patients many times a day.
In these and other cases, sponsors may want to conduct simulation studies to supplement and guide their drug product leachables studies.
Additional Considerations And Next Steps
The working group provided additional considerations on how to go about assessing extractables for parenteral packaging systems and noted several unique considerations for assessing leachables risks for biologics.
Next steps for PQRI on leachables and extractables: ophthalmics, transdermals and drug/device combination products. Eventually there could be something on single-use systems, which involve product contact with plastic bioreactor bags.