FDA Urges Firms To Control Metal Impurities From Equipment And Containers
Executive Summary
Drug makers working to comply with new ICH Q3D metal impurity standards should pay special attention to the possibility of metals leaching from manufacturing equipment and container closures, an FDA official says at agency workshop.
Drug manufacturers should pay attention to manufacturing equipment and container closures to make sure they don't exceed threshold limits specified in the International Council on Harmonization’s Q3D guideline, and to consult US Pharmacopeia guidelines on these topics, advised an FDA official at a recent public meeting on ICH Q3D implementation at FDA’s Silver Spring, Md., headquarters.
Meanwhile, an industry official raised concerns at the meeting about discrepancies between the ICH guideline and one of the USP chapters that could pose implementation challenges.
Health regulators worldwide are issuing harmonized regulatory guidance for implementing the ICH Q3D guideline, effective June 1 for new drug products and January 2018 for legacy products. (Also see "ICH Q3D Metal Impurities Guidance Issued By FDA, EMA, Health Canada" - Pink Sheet, 15 Aug, 2016.) The ICH Q3D Step 4 guideline published Dec. 18 sets permitted daily exposure (PDE) limits for 24 individual elements. It replaces a non-specific 19th century wet chemical ‘heavy metals’ test.
FDA officials said that there are five sources of elemental impurities that can potentially contaminate drug products: manufacturing equipment, the drug substance, excipients, the container closure system, and water.
Edwin Jao, acting branch chief for the Office of Process Facilities in the FDA Center for Drug Evaluation and Research's Office of Pharmaceutical Quality, focused his remarks at the Aug. 23 event on how manufacturers can control impurities that can enter the drug product from manufacturing equipment and from container closure systems.
Jao said that manufacturers should refer to two USP chapters that are currently in effect that address container closures systems: USP Chapter <661.1> and USP Chapter <1663>.
USP <661.1> became official on May 1, 2016. The chapter provides test methods and specifications for plastic materials of construction used in packaging systems. It contains tests, methods and specifications for some of the following materials: cyclic olefins, polyethylene and polypropylene.
USP Chapter <1663> became official on Aug. 1, 2015. It outlines a method for assessing extractables associated with pharmaceutical packaging and delivery systems. It states that for inorganic extractables, use of a simulating solvent having similar metal-chelating properties as the drug product vehicle should also be appropriate and justifiable. It says that the principles and recommendations should be applied to equipment as well.
Jao said that manufacturers should also be aware of two more USP chapters on plastic packaging systems that are currently under development: USP Chapter <665> and USP Chapter <1665>. Another chapter in the works, USP Chapter <662>, addresses metal packaging systems.
Jao also said that manufacturers should consult the American Society for Testing and Materials (ASTM) 316/316/L standard on controlling contaminants that could leach from manufacturing equipment into the final drug product. The standard sets elemental impurity limits for stainless steel and addresses elemental impurities from petroleum raw materials, catalysts, reagents used during polymerization and fabrication.
Jao said that the sources of elemental impurities introduced from the equipment include wear and tear such as chipping and grinding and friction and extractable metals leaching from stainless steel and polymeric equipment, and from processing solvents such as water.
Lack Of Alignment Noted
Yet one challenge is the disparate elemental impurity limits set by USP’s Chapter <661> on container closure testing and those set by ICH Q3D. These discrepancies could pose some difficulties for manufacturers who want to comply with both guidelines.
Tim Shelbourn of Eli Lilly pointed out some of these discrepancies at the FDA public meeting.
For example, he said that there are seven metals that are listed in USP Chapter <661.1> that are not included in ICH Q3D: aluminum, titanium, zinc, zirconium, germanium, manganese, and calcium.
Yet on the other hand, ICH Q3D’s table on safety limits has two elements, copper and lithium, that are not included in USP Chapter <661.1>.
Shelbourn said the copper and lithium "should be included for parenteral products in my view. If you look in the verbiage of <661> it speaks to patient safety. The reason these elements are included is because of patient safety.”
From the editors of Gold Sheet