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38 Pharmaceutical Technology BIOLOGICS AND STERILE DRUG MANUFACTURING 2018 P h a r mTe c h . c o m Lyophilization An advantage of the NIR method is that many samples can be analyzed non-destructively. An entire batch of processed material can be tested in their primary packaging with no sample prepara- tion or manipulation required. NIR can be used as a benchtop test where only representative samples of a batch are tested or integrated into manufactur- ing for measuring the moisture in each container within the batch. Points to consider for NIR. NIR is rapid, non-inva- sive, and non-destructive. A major disadvantage, however, is it requires calibration samples with a known residual moisture content of the lyophilized product obtained by another validated method such as Karl Fischer titration, adding time and costs to the process. More information can be found online (4). Because the NIR method is non-destructive, the samples can be tested a second time using another method (10). For example, the sample could be tested by NIR for residual moisture and then be tested by another residual moisture technique to verify the residual moisture results or for potency or assay. The ability to test the same sample by dif- ferent analytical tests is very attractive when there are a limited number of samples or when the mate- rial being testing is extremely expensive. CONCLUSION Residual moisture is considered a CQA for a ly- ophilized preparation; sufficient accuracy and precision to measuring low residual moisture levels in a lyophilized product are essential. Dif- ferent methods are available to determine the re- sidual moisture content of a lyophilized product; choosing and developing an appropriate method can be a challenging task. Once the most appro- priate method has been selected, great effort and attention must be employed to develop and vali- date a specific method with the desired accuracy and precision. The principles, advantages, and limitations of a method, as well as the quantity of water to be measured and the characteristics of the material to be tested should be considered when selecting a method. The guidance embodied within the ap- plicable compendia should be reviewed. The inf lu- encing factors need to be explored, and the suitable variables determined when developing a method. When well understood and properly developed, the method for a lyophilized product will be able to provide the residual moisture content with suitable accuracy and precision for a high level of confi- dence in the measured results. References 1. ICH, Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances (ICH, October 1999). 2. FDA, Docket No. 89D-0140, Guideline for the Determination of Residual Moisture in Dried Biological Products (Center for Biologics Evaluation and Research, January 1990). 3. USP, <1241> Water-Solid Interactions in Pharmaceutical Systems, USP40–NF35, 2017 4. A.M. Bosch and E. H. Trappler, "Residual Moisture Testing Methods for Lyophilized Drug Products," PharmTech.com, www.pharmtech.com/residual- moisture-testing-methods-lyophilized-drug-products 5. TA Instrument, Universal Analysis 2000, Version 4.5A 6. USP, <891> Thermal Analysis, USP40–NF35, 2017 7. EMD Chemicals, Inc., Aquastar, Karl Fischer Titration Basics. 8. L. Zhou, PhD, et al., American Pharmaceutical Review, 13(1):74-84, (January 2010). 9. T.P. Lin and C. C. Hsu, PDA Journal of Pharmaceutical Science and Technology, 56 (4) (July/August 2002). 10. FOSS NIRSystems, Inc. "Analysis of Residual Moisture in a Lyophilized Pharmaceutical Product by Near- Infrared Spectroscopy" PH-AN-704 08/06. 11. Metrohm USA, "Moisture Analysis in Pharma: Expanding Near-Infrared Spectroscopy with Karl Fischer Titration," Webinar, 2015, www.labroots.com/webinar/moisture- analysis-pharma-expanding-near-infrared-spectroscopy 12. FOSS "A Guide to Near-Infrared Spectroscopic Analysis of Industrial Manufacturing Processes." PT