Article 74 of the Good Manufacturing Practice for Pharmaceutical Products stipulates that production equipment shall not exert any adverse impact on drug quality. The surfaces of production equipment in direct contact with the drug product shall be smooth, clean, easy to clean or disinfect, and corrosion-resistant. They shall not undergo chemical reactions with the drug product, adsorb the drug product, or release substances into the drug product [1].
After filters come into direct contact with the drug product, it is recommended to conduct compatibility studies to verify the impact of the filter on drug quality [2] [3] [4]. Compatibility studies encompass compatibility, adsorption, extractables and leachables, and safety evaluation.
Extractables:
Refer to compounds that migrate from filters and other product-contact materials into model solvents under exaggerated conditions (e.g., organic solvents, extreme high temperature, ionic strength, pH, contact time, etc.). They represent the vast majority (but not all) of potential leachables that may occur in process media. Their sources may include monomers, oligomers, degradation products, and additives (e.g., antioxidants, stabilizers, plasticizers, lubricants, and modifiers) in the filter material, as well as residual solvents from the manufacturing process.
Leachables:
Refer to chemical substances that migrate from product-contact or non-product-contact materials into the drug product or process fluid under normal manufacturing, storage, and use conditions. Leachables may be present in the final drug product, directly reflecting potential impacts on the drug product, and are typically a subset of extractables.
The testing methods for extractables and leachables are similar, with differences in test fluids and conditions: extractables testing uses model solvents with characteristics similar to those of the drug product under exaggerated conditions; leachables testing uses the actual drug product under routine process conditions or accelerated testing conditions.
Theoretically, conducting leachables studies using the actual drug product is the most direct approach. However, due to limitations in separation and detection methods, and the typically extremely low levels of leachables, direct qualitative and quantitative analysis is often difficult [5]. Conducting leachables studies based on extractables data can minimize the risk of false negatives for leachables.
The currently recognized scientific approach is to first conduct rational, worst-case extractables testing and use the extractables data to assess leachables levels for safety evaluation. If the extractables results indicate significant interference or safety risks from the process equipment, further leachables studies should be conducted based on these results; otherwise, leachables testing may be omitted. The Bio-Process Systems Alliance (BPSA) has also proposed recommendations for extractables, leachables, and safety evaluation workflows [6].
References:
[1] Good Manufacturing Practice for Pharmaceutical Products (2010 Revision).
[2] Technical Guidelines for Compatibility Studies of Chemical Drug Injections and Plastic Packaging Materials (Trial) (Announcement No. 267 of 2012 of the China Food and Drug Administration).
[3] Technical Guidelines for Compatibility Studies of Plastic Component Systems Used in the Production of Chemical Drug Injections (Trial) (Announcement No. 33 of 2020 of the Center for Drug Evaluation, National Medical Products Administration).
[4] Guiding Principles for Sterilization/Aseptic Process Validation (Draft for Comment) (Center for Drug Evaluation, National Medical Products