(T1330-08-46) Compendial Strategy to Update Asbestos Testing Methods for Quality Control of USP Talc

Purpose: Talc has been widely used in industrial, pharmaceutical, personal care, and cosmetic products. In more recent years, it has been drawing attention due to concerns of asbestos in talc. The USP Talc monograph sets the compendial standard for the quality control of talc for pharmaceutical use. Due to the high public health impact, in 2010, FDA requested USP to update the asbestos testing methods in the USP Talc monograph. The USP Talc Expert Panels (EPs) #1 and #2 and Excipients Expert Committees (EXC ECs) proposed to utilize a phased approach to update the asbestos testing methods. This poster presents the USP’s strategy for asbestos testing method development and the round-robin studies for X-ray Diffraction (XRD) and Polarized Light Microscopy (PLM) tests. Consistent with this strategy, USP proposed a revision to the Talc monograph and developed two new general chapters related to the detection of asbestos in talc in Pharmacopeial Forum (PF) 48(2) [Mar-Apr 2022] and is seeking stakeholder feedback.

Methods: The current USP Talc monograph contains a test for Absence of Asbestos that includes three procedures. However, the required procedure (infrared spectroscopy (IR) or XRD) has insufficient detection limits and could lead to false-negative results. The third procedure by optical microscopy, not required unless IR or XRD is positive, could lead to false-positive or false-negative results. USP recommends omitting the IR test and including requirements to test asbestos using a revised XRD in combination with more advanced microscopic test procedures, such as PLM, transmission electron microscopy, or scanning electron microscopy. Two XRD round-robin studies were conducted by three participating labs. Talc samples were spiked with known amounts of serpentine or amphibole (tremolite or anthophyllite) respectively, to determine the detection limits of XRD. The spiked samples were analyzed using full 2θ scan and quantitative 2θ scan, respectively. The PLM round-robin study was conducted by five participating labs and represents the only recent empirical studies of asbestos (known levels) in talc for any type of microscopy. Talc samples were spiked with different forms of asbestos or non-asbestiform minerals respectively, including chrysotile, tremolite asbestos, and non-asbestos tremolite (Table 1).  There was a total of 104 samples in eight sets and 13 samples per set.

Results: The two XRD round robin studies found that: 1) Tremolite and anthophyllite were easily resolved and detected at 1%, and they had acceptable resolution and detection at 0.25%; 2) Without chlorite interference, serpentine could be easily detected at 1%, and it had acceptable detection at 0.25%; 3) With 1% -15% chlorite interference, serpentine had acceptable resolution and detection at 1%. The participating labs of PLM round-robin study reported the number of particles found, the length and width for the individual particles and the digital images of each particle (especially those of bundles or other unique features of asbestos). The observations included: 1) Wet-sieving procedure was applied prior to the PLM analysis, starting with approximately 2 g of spiked sample. A minimum of 5 mg concentrated sample is recommended for PLM analysis. 2) No false positives, as no laboratory detected asbestos in the talc-only sample and no laboratory detected tremolite asbestos in any of the samples spiked with non-asbestos tremolite with respect to morphology considerations. 3) Asbestos particles in the spiked samples showed classic asbestiform morphology attributes, including occurrence in bundles, bundles with splayed ends, and bundles showing flexibility. 4) The detection limit of 0.01% (or 100 ppm) (μg/g) was consistently achieved by the participating labs in terms of the detection of chrysotile and amphibole asbestos in the spiked samples. 5) One laboratory even detected asbestos in the 1-ppm level sample for chrysotile and two laboratories detected asbestos in the 10-ppm level sample for both chrysotile and amphibole asbestos, showing that detection at lower than 100 ppm may also be achievable.

Conclusion: Based on the round-robin study results, the USP Talc EPs and the EXC ECs proposed to revise the USP Talc monograph in conjunction with two new general chapters, Detection of Asbestos in Pharmaceutical Talc 〈901〉 and Theory and Practice of Asbestos Detection in Pharmaceutical Talc 〈1901〉 in PF 48(2) [Mar-Apr 2022]. The EXC ECs proposed to change the test title in the USP Talc monograph from “Absence of Asbestos” to "Test for Asbestos”. It was proposed to report XRD and PLM results (detected or not detected) in the certificate of analysis. In response to the FDA’s letter in 2010, a statement “Talc containing (detectable) asbestos is not pharmaceutical grade” was also proposed in the Labeling section. Due to the challenges of handling asbestos and developing physical reference standards, USP will explore the feasibility of developing digital type of reference standards to facilitate the implementation of the proposed asbestos testing methods. USP welcomes stakeholders’ comments on these proposals.

Disclaimer and Acknowledgement: The work in this poster was generated by the Talc Methods Expert Panel and the views expressed in this poster are those of the authors and do not reflect official views and policies of the USPC, USP Council of Experts, or the authors' institutions.