Pharmaceutical Leachables Part 2: USP <1664> Case Studies

A Refresher on USP <1664>

Pharmaceutical leachables are chemical entities from packaging or delivery systems which migrate into a drug product under normal storage conditions, potentially impacting the safety or efficacy of the drug.

The primary United States Pharmacopoeia (USP) chapter directing leachable testing is USP <1664> “Assessment of Drug Product Leachables Associated with Pharmaceutical Packaging/Delivery Systems“. This chapter discusses practical and technical aspects for assessing leachable risk and designing appropriate experiments to monitor leachables. Last month, EKG Labs published a thorough review of USP <1664>.

EKG Labs has performed pharmaceutical leachable studies on a wide variety of products. Four case study snapshots are presented below.

Case Study: Oral Drug Product Bottles

EKG received a PET bottle used for storing an oral pharmaceutical product.  After performing an extractable study per USP <1663>, we performed a leachable study using the drug product matrix. Following analysis by LCMS, GCMS, and ICPMS, one key leachable was identified; oxidized Irgafos 168 was observed at significant levels by LCMS.  Since the client was able to justify the presence of this chemical through a toxicological study, we did not move into a phase of validating a leachable method for continuous detection of the Irgafos-related compound over time and across lots.

Case Study: Ointment and Cream Bottles

A client approached EKG Labs with bottles of their pharmaceutical product in both an ointment and cream form. EKG Labs had previously provided extractables testing on the client’s plastic bottles, but now the client was concerned about new label options for these bottles, particularly in light of growing regulatory concern about potential leachables from adhesives and inks. The client provided samples of these labels as well as filled bottles with and without the labels applied.

EKG developed a sample extraction method for the complex ointment and cream matrices and demonstrated consistent ability to quantify down to 5 µg of impurities per gram of sample.  While leachables were observed from the bottles, no label-specific leachables were observed, and the client was satisfied.

Further detail (including chromatograms!) is available here: extractables and leachables study on packaging.

Case Study: Inhalers

USP <1664.1> is a more recent chapter that addresses specific considerations for leachables in orally inhaled and nasal drug products (OINDP). These products are considered high-risk due to the degree of concern associated with the route of administration and because of the increased likelihood that the drug product will interact with packaging components (often polymeric).

EKG Labs has performed leachable studies on inhalation devices.  In one such study, we evaluated a set of inhalation devices by: 6 polymeric components that the liquid drug product was exposed to prior to final delivery, 2 types of metal device chambers containing the pressurized formulation, and 3 different atomizers. After a simulated leachable extraction, the samples and control extracts were analyzed by LCMS, GCMS, and ICPMS.

Very few semi-volatile or non-volatile leachables were observed by LCMS. Most notably, the presence of butylated hydroxytoluene (BHT), an antioxidant, at ~4.5 mg/device was observed in an atomizer extraction.

The extractions were analyzed for volatile and semi-volatile compounds using GCMS. In one of the chambers analyzed, a total of ~52 mg/chamber of cyclic polydimethyl siloxanes were observed. Hydrocarbons and stearic acid were observed in the polymeric components.  The atomizers contained 2-ethylhexanol, BHT, cyclohexyl isocyanate, and a variety of hydrocarbons.

Of perhaps greatest concern, from the ICPMS elemental impurities analysis, 30-100 µg of lead was extracted per device in all three of the atomizers tested.

Further detail (including chromatograms!) is available here: inhalation drug device case study.

Case Study: IV Bags

Another client approached EKG with an IV solution for the treatment of neurological disease in polymeric bags.  After initial screening extractables studies, EKG validated leachable methods for LCMS, GCMS, and ICPMS using selected targeted compounds selected by the client’s toxicologist from the list of compounds observed in the initial studies.  IV solutions often pose a significant challenge in leachable studies, as the dosages are high and toxicological thresholds are quite low.  EKG has developed methods for evaluating leachables and elemental impurities even in complex saline and drug matrices.

Leachable Testing at EKG Labs

EKG Labs provides leachable testing services for pharmaceutical packaging or delivery systems. We have experience developing and validating a risk-based, product-specific method in order to monitor one or more targeted compounds in even the most challenging matrices.

EKG Labs is an analytical service provider for the pharmaceutical and medical device industries. Our wide variety of analytical services support product development, regulatory filings, and analytical chemistry investigations. EKG Labs is now a part of the Infinity Laboratories group, a powerful network of state-of-the-art testing facilities that are FDA registered, ISO 17025 accredited, and DEA licensed. With an enhanced focus in the areas of chemical and microbiological sciences, we support pharmaceutical and medical device manufacturers. Our goal is to go Beyond Testing and become a partner in the success of our customers.

To find out more about USP <1664> testing, please contact us at or at 810-354-5229.