1. INTRODUCTION
This chapter addresses specific considerations for leachables in parenteral drug products (PDPs) as defined in Injections and Implanted Drug Products 〈1〉 and Pharmaceutical Dosage Forms 〈1151〉. It focuses on drug products (injections) administered by intramuscular, intravenous, and subcutaneous routes. Parenteral drug products that use other routes such as intradermal, intra-arterial, intracardiac, intraspinal, intra-articular, epidural, and perineural may have unique leachables concerns specific to their administration route.
Secondly, it is noted that the following discussion is primarily devoted to organic leachables. For consideration of leachables reported as elements, see Assessment of Drug Product Leachables Associated with Pharmaceutical Packaging/Delivery Systems 〈1664〉.
Lastly, it is noted that in general, 〈1664〉 and its subsections address leachables derived from a drug product’s packaging and/or delivery systems. However, drug products can contain leachables derived from their manufacturing equipment. Given the prevalent use of plastic and/or polymeric components in manufacturing equipment used to produce biological parenteral drug products, this chapter discusses leachables derived from manufacturing equipment and its components. A more detailed discussion of extractables and leachables associated with manufacturing components is contained in Plastic Components and Systems used to Manufacture Pharmaceutical Drug Products and Biopharmaceutical Drug Substances and Products 〈665〉. For medical devices and combination products regulated as medical devices (e.g., delivery devices), and for packaging that is considered a device-constituent part, users should refer to additional device-specific FDA guidance for industry (1).
2. KEY TERMS
In addition to the key terms listed in 〈1664〉, some key terms more specific to PDPs are the following:
Analytical response factors of organic compounds in chromatographic screening methods applied to leachables study vary, often significantly, from compound to compound, confounding accurate quantitation and application of the analytical evaluation threshold (AET). The uncertainty factor (UF) reflects the variation of response factors.
Single use and multiple use systems (SUS and MUS) used in the manufacture of primarily biological drug products (bDPs) can be composed of disposable polymer-based components, including connectors, filters, gaskets, process containers (bags), tubing, and valves, etc., see 〈665〉. As many SUS components are polymeric, they are potential sources of primarily organic leachables.
By FDA definition (2), a drug product is a “finished dosage form that contains a drug substance, generally, but not necessarily in association with other active or inactive ingredients”. Additionally, “a dosage form is the physical form in which a drug is produced and dispensed, such as a tablet, a capsule, or an injectable”. Consistent with these definitions, drug products can be classified by their physical form (their dosage form) and/or their route of administration. Of specific interest to this chapter are parenteral drug products, which are injected through the skin to allow the direct administration of the active drug substance(s) into blood vessels, organs, tissues, or lesions. These routes of parenteral administration include, but are not limited to:
Epidural injections
Intra-arterial injections
Intra-articular injections
Intracardiac injections
Intracranial applications
Intradermal injections
Intramuscular injections
Intravenous injections and infusions
Intraspinal injections
Perineural injections
Subcutaneous injections
Parenteral dosage forms include emulsions, solutions, suspensions for solutions, and suspensions (including liposomes). These dosage forms can be classified based on the nature of their packaging and the drug product’s volume per package unit:
Type of packaging:
Multiple dose units: multiple dose vials, multiple dose cartridges
Single dose units: ampules, bags, bottles, cartridges, prefilled disposable syringes, and vials
Drug product volume per package unit:
Large volume parenteral (LVP), volume >100 mL
Small volume parenteral (SVP), volume ≤100 mL
Packaging for parenteral dosage forms may be constructed from elastomers, glass, and polymers.
3. LEACHABLES ASSESSMENT RATIONALE FOR INTRAMUSCULAR, INTRAVENOUS, AND SUBCUTANEOUS PARENTERAL DRUG PRODUCTS
PDPs are generally categorized as high-risk dosage forms (as injections) due to the highest risk related to safety considerations related to the route of administration and a moderate probability of packaging component interaction with the formulation (see 〈1664〉, Table 1). The packaging systems used in these drug products consist of components of various types, some of which are constructed from polymeric (plastic or elastomeric) materials with complex chemical compositions and therefore a variety of potential leachables. Chemical entities can migrate (i.e., leach) into the drug product when there is direct contact with the primary packaging and indirect contact with secondary packaging.
PDPs typically require:
Extractables studies for either the commercial packaging system or components thereof, performed as described in Assessment of Extractables Associated with Pharmaceutical Packaging/Delivery Systems 〈1663〉.
Extractables studies for the manufacturing system or its components, as necessary and appropriate, performed as described in 〈665〉.
A leachables stability study for drug product registration that supports intended storage and use conditions throughout the proposed shelf-life, ideally on drug product stability batches manufactured with the same lots of packaging and manufacturing components used in extraction studies (to facilitate a leachables–extractables correlation). Such studies are described in 〈1664〉.
Sensitive, selective, and fully qualified leachables analytical methods for both targeted and nontargeted analysis.
Leachables assessments based on justified toxicological threshold (for the analytical evaluation threshold, AET [e.g., safety concern threshold (SCT)].
Rigorous leachables–extractables correlations.
Leachables specifications, including acceptance criteria, may be necessary in infrequent circumstances where leachables control cannot be exercised by incoming control of packaging components (e.g., extractables). Note that the development and application of extractables and leachables specifications with appropriate acceptance criteria is a regulatory issue and therefore must be accomplished on a case-by-case basis with input from the regulatory authority.
4. CALCULATION OF THE AET FOR PARENTERAL DRUG PRODUCTS
A critical aspect of a leachables study is establishing the proper value for the AET, the threshold at or above which leachables should be reported for toxicological safety risk assessment. Some parenteral drug products may present a particular challenge with respect to the AET as they are used in chronic therapy (meaning a lower toxicological threshold is applicable) and have relatively large daily dose volumes (e.g., 100 mL or larger). Given the inverse relationship between dose volume and the AET, parenteral drug products with large daily dose volumes may require AETs so low that they cannot be achieved with even state of the art analytical technologies operated by qualified experts.
Once calculated, the AET can be expressed in units of:
μg per product unit (e.g., µg/syringe) to represent the leachables based on the commercial drug product
μg per container volume (e.g., µg/mL) to represent the leachable’s concentration in the PDP
μg/component in the packaging system (e.g., µg/component) to allow for an assessment of the leachables’ source(s)
µg/day to reflect actual daily patient exposure to the leachables
Examples of how to calculate the AET are provided for the following systems to illustrate the range of AETs that can be encountered:
Prefilled syringe (PFS) consisting of a 1-mL Luer lock cyclic olefin barrel, 6.4-mm diameter elastomeric plunger stopper and tip cap
Injection pen consisting of a 2-mL glass cartridge, 6.4-mm diameter elastomeric plunger stopper and seal
Multidose vial consisting of a 10-mL glass vial and 20-mm diameter elastomeric stopper
Single dose vial and multiple doses consisting of a 2-mL glass vial and 13-mm diameter elastomeric stopper
Single dose vial and single dose/day consisting of a 2-mL glass vial and 13-mm diameter elastomeric stopper
Single dose flexible container (bag) consisting of a 120-mL plastic bag and elastomeric injection site
Intravanous (IV) bag/single dose/day consisting of a 1000-mL plastic bag and elastomeric injection site
IV bag and multiple bags/day consisting of a 1000-mL polymer bag and elastomeric injection site
In all cases, the AET is calculated with a toxicological threshold of 1.5 µg/day, the relevant SCT for a chronically administered drug product considering carcinogenic and noncarcinogenic toxic effects. As other quantities can be used as the toxicological threshold in the AET calculation (for example, an acutely administered drug product), it is suggested that the quantity used as the toxicological threshold be discussed and confirmed with the relevant regulatory authority.
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