<2251> Adulteration of Dietary Supplements with Drugs and Drug Analogs (superseded title) <2251> Screening for Undeclared Drugs and Drug Analogues (new title) Type of Posting Revision Bulletin Posting Date 27–May–2016 Official Date 01–Aug–2016 Expert Committee Non-Botanical Dietary Supplements Reason for Revision Compliance In accordance with the Rules and Procedures of the 2015-2020 Council of Experts, the Non-Botanical Dietary Supplement Expert Committee has revised the General Chapter <2251> Adulteration of Dietary Supplements with Drugs and Drug Analogs. The purpose of the revision is to: • Align the General Chapter terminology with that currently in use by the FDA • Update of the General Chapter title to better reflect its content. The revised title is “Screening for Undeclared Drugs and Drug Analogues” • Update the Chemical Abstracts (CAS) numbers for compounds in Tables 4 and 5 The Adulteration of Dietary Supplements with Drugs and Drug Analogs Revision Bulletin supersedes the Adulteration of Dietary Supplements with Drugs and Drug Analogs General Chapter published in the First Supplement to USP 39–NF 34, and will become official on August 1, 2016. The Revision Bulletin will be incorporated in the USP 40–NF 35. Should you have any questions, please contact Anton Bzhelyansky, Scientific Liaison, at (301) 203–6303 or [email protected]. C173956_160319-M8206-NBDS2015, Rev. 0 20160527 Revision Bulletin Official August 1, 2016 〈2251〉 Screening for Undeclared Drugs and Drug Analogues 1 functionally coherent group of adulterants, including sev- Add the following: eral approved drugs, their numerous approved and unap- ·. proved analogues, and synthetic intermediates. · (RB 1-Aug- 2016) Their functionality is manifested by inhibition of phosphodiesterase type 5 enzyme (PDE5), which hydro- Change to read: lyzes cyclic guanosine 3′,5′-monophosphate (cGMP); this ·. group of compounds· (RB 1-Aug-2016) is frequently identified as PDE5 inhibitors. Screening methods for ·.products (RB . · 1-Aug-2016) adulterated with ED ·.compounds (RB 1-Aug-2016) are I · .〈2251〉 ·.SCREENING FOR UNDECLARED presented in Appendix A. · Weight Loss (WL): This category comprises a function- DRUGS AND DRUG ANALOGUES (RB 1-Aug- · ally and chemically diverse collection of compounds that 2016) include stimulants, laxatives, diuretics, anorexiants, and INTRODUCTION psychoactive drugs. Although stimulants constitute an important segment of WL adulterants, the oral anorexiant sibutramine dominates this category, frequently in com- Change to read: bination with phenolphthalein, a laxative. Methods for ·. ·. analysis of products· (RB 1-Aug-2016) adulterated with WL The illegal addition of undeclared synthetic compounds to compounds· (RB 1-Aug-2016) will be addressed in Appendix B 1 products marketed as dietary supplements . (DS) is ·.an issue (to come). of universal concern.· (RB 1-Aug-2016) This fraud is practiced to · Sports Performance Enhancement (SPE): These com- impart therapeutic effects that cannot be achieved by the ·. pounds constitute the third major category of adultera- dietary ingredients· (RB 1-Aug-2016) alone. Increasingly, synthetic tion. Professional and amateur athletes are targeted with intermediates and structural analogues of the pharmaceuti- designer anabolic steroids and stimulants, which are sys- cals and drugs that have been discontinued or withdrawn tematically banned by the World Anti-Doping Agency. ·. from the market · (RB 1-Aug-2016) are being used as adulterants. Functional and structural diversity, synthetic proclivity of Multiple adulterating compounds may be added to a single the adulterators, and the generally small amounts of the ·. product,· (RB 1-Aug-2016) frequently in erratic amounts. infringing substances required to elicit a therapeutic ef- ·. The proposed test methodologies facilitate screening · (RB 1-Aug- fect make this category especially challenging to address. 2016) for synthetic adulterants. No individual technique is ca- These supplements are customarily formulated in protein- pable of addressing all potential analytes; thus, a combina- and fat-rich matrices, thereby further complicating detec- n tion of orthogonal approaches adds certainty to the analyti- tion. For these reasons, GC- and LC-MS . techniques con- cal outcome. Mass spectrometric techniques provide strong stitute primary analytical methodologies within this cate- ·. substantiation of the analytical findings. In some cases, e.g., gory. Analysis of products· (RB 1-Aug-2016) adulterated with ·. with hormonal drugs, the amounts of physiologically rele- SPE compounds· (RB 1-Aug-2016) will be addressed in Appen- vant adulterants may be so low that GC-MS or LC-MS may dix C (to come). be the only fitting analytical options. The express purpose of assembling the procedures recom- Change to read: ·. mended herein is their suitability for· (RB 1-Aug-2016) screening. The level of evidence achievable by application of one or ·. several of the recommended procedures is ultimately dic- BULK INGREDIENTS· (RB 1-Aug-2016) AND DOSAGE FORMS ·. tated by the specific requirements of the end-user. It should Adulteration may occur either at the level of bulk ingredi- ·. be noted that structure elucidation and quantitative assess- ents· (RB 1-Aug-2016) or at any subsequent· (RB 1-Aug-2016) stage of the finished product manufacturing. Analysts should be ment ·. (RB 1-Aug-2016) are beyond the scope of this chapter. · mindful of the ·.possibility of (RB 1-Aug-2016) adulterants ·. ·. This chapter is meant to be updated regularly, as· (RB 1-Aug-2016) · new concealment methodologies for the adulterants are in- physically associated with· (RB 1-Aug-2016) the finished dosage ·. troduced, or improvements to the methods of analysis are · (RB 1-Aug-2016) matrix or excipients, as well as components. In the latter, synthetic compounds ·.have been found (RB 1- realized. · Aug-2016) embedded into the capsule shell body. This under- scores the need for deliberate adjustment to the laboratory Change to read: procedures that typically focus on the capsule contents alone. Appropriate sampling practices for powders and fin- ·. ished dosage forms should be exercised, particularly when · (RB 1-Aug-2016) ADULTERATION CATEGORIES ·. only a limited amount of sample is available. The following major categories of adulterated products· (RB 1- Aug-2016) are recognized: · Sexual Enhancement: This category is also referred to as Change to read: the Erectile Dysfunction (ED) category. It encompasses a 1 .In the United States, dietary supplements are defined as substances that are RECOMMENDED ANALYTICAL METHODOLOGIES ·. ingested, in agreement with 21 U.S. Code §321(ff)(2)(A)(i). Definitions of Adulteration analysis· (RB 1-Aug-2016) may be broadly catego- dietary supplements, nutritional supplements, functional foods, and bioactive rized into targeted and nontargeted methods. The distinc- food additives may vary extensively, depending on local or national legisla- tion between these types may be subtle, and a minor ad- tion. In the marketplace, there is a trend toward expanding the mode of justment to the methodology will transform a nontargeted delivery of the adulterating compounds to routes not covered by the regula- method into a targeted method. tory definition for dietary supplements, i.e., topical oils, creams, lotions, e- Targeted cigarettes, chewing gums, sprays, and others. Such novel delivery systems These techniques are warranted when the analytes are present unique challenges, particularly from the standpoint of sample prepa- known. An example of a targeted approach would be ration, and are not considered for the purposes of this chapter to be dietary monitoring a chromatographic run at a particular wave- supplements. However, recognizing the emerging threat, USP chooses to length (or mass), and quantifying the analyte that ap- highlight the existence of these products. In no way should mention of pears within a predefined retention time window. these products be interpreted as a comment on their legal status or be Targeted analysis is conceptually straightforward, because perceived as an expansion of the definition of DS. it relies on pre-existing knowledge of the analyte and al- 2016 The United States Pharmacopeial Convention All Rights Reserved. C173956_160319-M8206-NBDS2015, Rev. 0 20160527 Revision Bulletin 2 〈2251〉 Screening for Undeclared Drugs and Drug Analogues Official August 1, 2016 lows optimization of test methodology for its reliable de- Table 1 (Continued) ·. tection. The targeted approach also is a rarity in the Time Solution A Solution B adulterated products analysis,· (RB 1-Aug-2016) where the (min) (%) (%) nature of the analyte may be anticipated only tentatively, and variable amounts of multiple adulterants belonging 24 95 5 to several functional categories are commonplace. 31 95 5 Nontargeted These methods are better suited to a broad-spectrum de- Diluent: Acetonitrile and water (50:50) Standard solution: 100 µg/mL each of USP Sildenafil Cit- tection requirement presented by adulterated ·.products. rate RS, USP Tadalafil RS, ·.and (RB 1-Aug-2016) USP · (RB 1-Aug-2016) Nontargeted screening trades precise knowl- · edge of the analyte identity, along with specificity and Vardenafil Hydrochloride RS in Diluent accuracy, for a wider detection scope. Examples of Sample solution: Combine one-fifth of the dosage unit, nontargeted chromatographic screening include acquisi- 10±20 mg of bulk material, or a small fragment of the tion of photodiode array data and full mass-spectral scan-