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www.biopharminternational.com October 2020 BioPharm International eBook 21 (e.g., the mandatory Ultraviolet- Visible Spectroscopy <857> has a companion informational gen- eral chapter <1857> Ultraviolet- Visible Spectroscopy–Theory and Practice). There is an exception to this r u l e , w i t h U S P < 1 2 2 5 > ( I C H [ I n t e r n a t i o n a l C o u n c i l f o r H a r m o n i z a t i o n ] Q 2 ( R 1)) o n Analytical Procedure Validation (12, 13) that is considered man- datory by regulators. Analysis requirements in monographs When pharmacopoeias were first w id e ly p ubl i she d i n t he 19 t h century, the aim was that phar- macists would conduct analysis in their premises. Therefore, tests were relatively simple, but as the p h a r m a c e ut i c a l i n d u s t r y a n d a na ly t ic a l sc ie nce have deve l- oped, both molec ules and ana- ly tical procedures have become more comple x. Moder n mono - g r a p h s f o r s i mp l e s u b s t a n c e s have b ecome hybr id i n nat u re and may be a mixture of classi- cal and non-classical analytical techniques. T he pha r macop o eia s a ssu me t h at t he i nd iv idu a l s c onduc t- i n g t he a n a ly t ic a l pro c e du r e s are competent analysts and that they are trained in the GMP reg- u lat ions a nd good doc u menta- t ion prac t ice as i nter preted by the organization for which they work . I n add it ion, t he re is a n unwritten assumption regarding the ethical and cultural behavior expected from those involved in all aspects of analysis and testing i nc lud i ng rev iew. I n add it ion, they are required to interpret the minimalist requirements in the monog raph and translate them into a working method. L ack of t ra ining a nd exper i- ence is at the heart of many data integrity failures. USP <1029> on Good Documentation Guidelines (14) has a number of requirements for review and approval of docu- ments, including second person review of analytical testing that is consistent with FDA GMP in 21 Code of Federal Regulations (CFR) 211.194(a)(8) (15). H o w e v e r, g i v e n t h e i m p o r- t a n c e o f t h e s e c o n d p e r s o n review in ensuring complete and accurate results and data integ- rity, this requirement should be i n t he G e ne r a l Not ic e s r at he r t ha n a n i n for mat iona l genera l chapter, as demonstrated in the following example. METHENAMINE MANDELATE USP MONOGRAPH T he USP monog raph for met h- enamine mandelate illustrates the problem of ensuring data integ- rity in pharmacopeial testing. The monog raph specif ies a number of tests, and their interrelation- ships with General Chapters and the General Notices are shown in Figure 2. Note that the LOD test for methenamine mandelate is to dry over silica gel for 18 hours. However, as this is not a common test for LOD, we have selected the most frequently used LOD method (oven dr y ing) described in USP <731> (16) for illustrative purposes using the betamethasone valer- ate monograph later in this arti- cle. It will become apparent that inter pretation of a compendial monograph is not a simple and straightforward task. For the interpreted analytical procedure for the identification test by infrared spectroscopy (IR), for example, there are two manda- tory and two informational general chapters that should be taken into consideration as follows: • U S P < 19 7 > S p e c t r o s c o p i c Identification Tests • U S P < 8 5 4 > M id I n f r a - R e d Spectroscopy • USP <18 54 > M id I n f ra - Re d S p e c t r o s c o p y –T h e o r y a n d Practice • U S P < 1 0 5 8 > A n a l y t i c a l Instrument Qualification. In addition, there are the fol- low ing sec tions of the General Notices that must be considered when all tests in the methenam- i ne ma nde late monog raph a re implemented (11): • 4.10.10. Applicability of Test Procedures • 4.10.20. Acceptance Criteria • 7. 1 0 . I n t e r p r e t a t i o n o f Requirements • 7.20. Rounding Rules • 8.70. Desiccator • 8.180. Temperatures • 8.190. Time. Before it can be applied, the a n a l y t i c a l p r o c e d u r e f o r t h e monograph still needs to be inter- preted, developed, documented, and verified in accordance with USP <1226> (17), which states, "Users should have the appropri- ate experience, k nowledge, and t ra ining to understa nd a nd be able to perform the compendial procedures as written. Verification should be conducted by the user such that the results will provide confidence that the compendial procedure will perform suitably as intended." It also states, "The Regulatory Sourcebook Data Integrity Analysts are required to interpret the minimalist requirements in the monograph and translate them into a working method.