<1664> ASSESSMENT OF DRUG PRODUCT LEACHABLES ASSOCIATED WITH PHARMACEUTICAL PACKAGING/DELIVERY SYSTEMS 

BACKGROUND

Management of leachables is important to pharmaceutical and biotechnology/biologic product manufacturers and regulatory authorities because certain leachables above specific concentrations can present safety concerns for patients and/or compatibility issues for drug product formulations. 

During the 1980s, the U.S. Food and Drug Administration (FDA) began to formally and comprehensively address leachables in drug products after findings of patient sensitivity induced by leachables and other potential safety concerns related to leachables (2–4). Since then, management of both extractables and leachables for packaging systems and final drug products has become an important part of pharmaceutical development and regulatory submissions for many dosage form types, particularly for those deemed of relatively high risk for dosage form interaction with the packaging system, along with a relatively high safety risk relative to the route of administration (see Table 1). 

Note that Table 1 is a version of the original concept that appears in the FDA guidance Container Closure Systems for Packaging Human Drugs and Biologics (1), in which certain dosage forms in the above guidance have been downgraded to having lower potential for interaction with packaging components. 

Remaining relatively high-risk dosage forms include: inhalation aerosols and solutions, injectables and injectable suspensions, ophthalmics, and transdermal ointments and patches. It is important to note, however, that even low-risk dosage forms present some risk and that appropriately rigorous leachables assessments can be important to particular drug products in lower risk dosage form categories (e.g., topicals and oral dosage forms, etc.).

Table 1. Modified FDA/CDER/CBER Risk-Based Approach to Consideration of Leachables^a (1)

Examples of Packaging Concerns for Common Classes of Drug Products

^a While this table provides a convenient overview of the general level of regulatory concern with various dosage forms regarding leachables, it should not be inferred that “low-risk” dosage forms (e.g., oral tablets) by that definition carry no risk for leachables issues.

This chapter will describe scientific principles and best practices for the assessment of drug product leachables, and will cover various important concepts, including: 

1) the requirement for leachables studies; 

2) fundamental concepts for leachables studies; 

3) the basis of thresholds for leachables and general guidance about application of these thresholds; 

4) design and implementation of leachables studies; 

5) leachables method development and validation; 

6) correlation of results from extractables assessments and routine extractables testing with leachables studies; and 

7) establishment of leachables specifications including acceptance criteria.

These scientific principles and best practices apply to all organizations and individuals involved in the manufacture, marketing, and qualification of drug products and in their stability studies, including but not limited to:

• Manufacturers of drug products for human and veterinary use where manufacturing may involve operations at the applicant holder's facilities (i.e., facilities that belong to the holder of an approved New Drug Application or Abbreviated New Drug Application) or at those of a contractor for the applicant holder

• Manufacturers of combination drug products

• Packaging operations by the manufacturer or a designated contractor for the applicant holder

• Repackaging operations in which the drug product may be owned by an organization other than the primary manufacturer.

Although it is ultimately the drug product applicant's responsibility to ensure that appropriate leachables assessments are completed, manufacturers and fabricators of pharmaceutical packaging/delivery systems, packaging components, and materials of construction should also apply these scientific principles and best practices as appropriate, and applicants are encouraged to work with component manufacturers and fabricators to this end.