USP Draft Chapter for E&Ls in Parenteral Drug Products

The USP is expanding the Extractables and Leachables (E&Ls) Chapter Series <1664>. The draft chapter <1664.2> Parenteral Drug Products (Intramuscular, Intravenous, and Subcutaneous), has just been officially published in Pharmacopeial Forum (PF) 51(3) and is now open for public comment until 31 July 2025.

Scope and Key Terms

USP chapter <1664> and its subsections address leachables derived from a drug product’s packaging and/or delivery systems. However, drug products can also 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 (PDPs), the proposed chapter also discusses leachables derived from manufacturing equipment and its components. A more detailed discussion of E&Ls associated with manufacturing components can be found in USP chapter <665> Plastic Components and Systems used to Manufacture Pharmaceutical Drug Products and Biopharmaceutical Drug Substances and Products. Users of medical devices and combination products regulated as medical devices (e.g. delivery devices), as well as packaging considered a device constituent part, should refer to additional device-specific FDA guidance for industry.

The proposed new chapter addresses specific considerations for (organic) leachables in parenteral drug products (PDPs). It focuses on drug products (injections) administered by intramuscular, intravenous, and subcutaneous routes. Parenteral drug products that use alternative routes such as intradermal, intra-arterial, intracardiac, intraspinal, intra-articular, epidural, and perineural may present unique leachable concerns relating to their specific route of administration .

PDPs are generally categorised as high-risk dosage forms due to safety concerns relating to the route of administration. The packaging systems used for these drug products usually consist of various types of components (e.g. elastomers, glass, and plastics). Polymeric materials (plastics or elastomers) may have complex chemical compositions and therefore a variety of potential leachables. Thus PDPs typically require the following:

• Extractables studies for the packaging system (or components),
• Extractables studies for the manufacturing system (or components),
• A leachables stability study for drug product registration that supports the intended storage and use conditions throughout the proposed shelf-life, 
• Sensitive, selective, and fully qualified leachables analytical methods for both targeted and nontargeted analysis,
• Leachables assessments based on a justified toxicological threshold,
• Rigorous leachables–extractables correlations.

Leachables specifications, including acceptance criteria, may occasionally be necessary where control of leachables cannot be exercised through incoming control of packaging components (e.g. extractables). However, the development and application of extractables and leachables specifications with appropriate acceptance criteria is a regulatory issue and must therefore be carried out on a case-by-case basis, with input from the relevant regulatory authority.

More information is available online in the Pharmacopeial Forum (PF).