Question: In the USP General Notices, there is a statement that USP monograph content supersedes a General Chapter content. Can you shed some light on this?

Answer:
As you can see in the detailed discussion below, the General Chapters were intended as the interpretation and application of the standards, tests, assays, and other specifications of the USP and to eliminate the need to repeat throughout the book those requirements that are pertinent in numerous instances. Let’s look at it in more detail in the following.

Interpretations and Application of [Beyond-use Date] BUDs in USP Pharmaceutical Compounding Standards and the USP General Notices

The issue has come up concerning a statement in the General Notices involving individual monographs superseding items in the General Chapters. This is true, and, if there is no issue as discussed below, this is an approach that can be implemented to use the BUDs listed in the individual USP compounding monographs where the General Chapters have placed limits as long as compliance with the entire monograph are met. Let’s hope it is true but there are some issues that must be considered, as follows:

1. The General Chapters were put in place to support drug substance and drug monograph standards, tests, assays, and other specifications so that there was no need to repeat all the information within each drug substance or drug product monograph, but could be referred to, and save space in the compendium.
   
   
2. The USP General Chapters numbered less than 1000, the General Tests and Assays, are divided into the following sections:
   • General Requirements for Tests and Assays
   • Apparatus for Tests and Assays
   • Microbiological Tests
   • Biological Tests and Assays
   • Chemical Tests and Assays
   • Physical Tests and Determinations

When specific tests are referred to in the individual drug substance or drug product monograph, the General Chapters provide detailed information on the performance of the:

• microbiological,
• biological,
• chemical, and
• physical tests.

When the USP professional practice chapters on nonsterile and sterile compounding were first written, there was essentially no designated place within the USP for these chapters. It was decided to place them in the section of “Physical Tests and Determinations� as follows:

In reality, the pharmacy compounding chapters have nothing to do with the actual performance of either microbiological, biological, chemical, or physical tests (in laboratories); they are professional practice chapters.

The question has arisen of whether or not the references to a BUD in the individual compounding monograph supersedes the BUD in the nonsterile and sterile compounding General Chapters, since the practice chapters are not the same as the other chapters in the General Tests and Assays Division and were just inserted there for convenience.

Let’s look at a brief history of the development of the General Chapters to determine their original intent.

General Chapters first appeared in USP 19 (1975) and were not numbered at that time. The General Notices start out by stating the following:

“The General Notices and Requirements (hereinafter referred to as the “General Notices�) provide in summary form the basic guidelines for the interpretation and application of the standards, tests, assays, and other specifications of the United States Pharmacopeia and obviate the need to repeat throughout the book those requirements that are pertinent in numerous instances.

Where, occasionally, exceptions to the General Notices are necessary, the wording in the individual monograph or general test chapter takes precedence and specifically indicates the directions or the intent. To emphasize that such exceptions do exist, the General Notices employ where indicated a qualifying expression such as “unless otherwise specified.� Thus, it is understood that the specific wording of standards, tests, assays, and other specifications is binding wherever deviations from the General Notices exist. By the same token, where no language is given specifically to the contrary, the General Notices apply.�

“Where exceptions to the General Notices are made, the wording in the individual monograph or general test chapter takes precedence and specifically indicates the directions or the intent.�

(The remainder of the paragraph is the same.)

USP 23 (1995) —The revised statement stays the same.
USP 24 (2000) —The statement is changed as follows:

“The General Notices and Requirements (hereinafter referred to as the General Notices) and general requirements appearing in General Chapters provide in summary form the basic guidelines for the interpretation and application of the standards, tests, assays, and other specifications of the United States Pharmacopeia and eliminate the need to repeat throughout the book those requirements that are pertinent in numerous instances. Where no specific language is given to the contrary, the requirements under the General Notices and General Chapters apply.

Where exceptions to the General Notices or General Chapters are made, the wording in the individual monograph takes precedence and specifically indicates the directions or the intent. To emphasize that such exceptions do exist, the General Notices or General Chapters in some places employ where indicated a qualifying expression such as “unless otherwise specified.� In the individual monographs, it is understood that the specific wording of standards, tests, assays, and other specifications is binding wherever deviations from the General Notices or General Chapters exist whether or not a statement of exception is made.�

USP 25 (2002) —The statement is the same.
USP 26 (2003) —The statement is the same.
USP 27 (2004) —The statement is the same.
USP 28 (2005) —The statement is the same.
USP 29 (2006) —The statement is the same.
USP 30 (2007) —The statement is the same.
USP 31 (2008) —The statement is the same
USP 32 (2009) —The statement is changed, as follows:

“The General Notices and Requirements section (the General Notices) presents the basic assumptions, definitions, and default conditions for the interpretation and application of the United States Pharmacopeia (USP) and the National Formulary (NF).

Requirements stated in these General Notices apply to all articles recognized in the USP and NF (the ‘compendia’) and to all general chapters unless specifically stated otherwise. Where the requirements of an individual monograph differ from the General Notices or a general chapter, the monograph requirements apply and supersede the requirements of the General Notices or the general chapter, whether or not the monograph explicitly states the difference.�

USP 34 (2011) —The statement is the same.
USP 35 (2012) —The statement is the same.
USP 36 (2013) —The statement is the same.
USP 37 (2014) —The statement is the same.
USP 38 (2015) —The statement is the same.
USP 41 (2018) —The statement is changed:

“The General Notices and Requirements section (the General Notices) presents the basic assumptions, definitions, and default conditions for the interpretation and application of the United States Pharmacopeia (USP) and the National Formulary (NF).

Requirements stated in these General Notices apply to all articles recognized in the USP and NF (the ‘compendia’) and to all general chapters unless specifically stated otherwise.�

Under the section: 3. Conformance to Standards;

The following section has also been added.

Thoughts, Conclusions, and Recommendations

Starting in 1975 and over the years, the above statements in the USP General Notices refer to standards, tests, assays, and other specifications in General Chapters and in the Monographs. It is clear that the purpose of the General Chapters and General Notices was to

“eliminate the need to repeat throughout the book those requirements that are pertinent in numerous instances�

It is clear that a monograph specification supersedes a General Chapter in the list of standards, tests, assays, and other specifications. It is not clear that this now extends to the implementation of pharmacy practice standards.

If the statement does apply to compounded monographs and the Pharmacy Compounding Practice Standards, then the BUDs in the monographs will apply as long as all the monograph specifications are met.

Two recommendations follow:

1. It is very important that a separate statement to the fact that the BUDs for USP Compounded Preparation Monographs supersede those standards established in the compounding standards General Chapters be added to the General Notices, as this does not appear to be specifically covered in the descriptions above.
   
   
2. A simple statement should be added in USP General Chapters <795> Pharmaceutical Compounding—Nonsterile Preparations and in <797> Pharmaceutical Compounding—Sterile Preparations in the sections on Beyond-use Dates stating that individual USP Compounding Monographs supersede those in this (these) chapters provided all the specifications are met.

If the interpretation that the USP General Notices also incorporate pharmacy practice standards and that the USP compounding monographs supersede the USP General Chapters, then the USP extended BUD dates presented in the monographs can be utilized, provided all the other specifications are met. As an example, Morphine Sulfate Compounded Injection requires the following:

• Assay,
• pH (791),
• Sterility test (71),
• Bacterial Endotoxins test (85),
• Particulate Matter in Injections test (788), and
• proper packaging and storage and labeling.

It also brings up the issue that since the official compounding monographs were developed utilizing the same or equivalent analytical standards as those in the peer-review published literature, why those published or individually tested and developed BUDs do not also apply in place of the arbitrary limits in both USP <795> and USP <797>? This is also appropriate as many laboratories are involved in the work setting official BUDs as well as in publishing results in the peer-reviewed literature and for individual companies; both utilizing stability-indicating analytical methods for establishing BUDs.

Loyd V. Allen, Jr., PhD, RPh
Editor-in-Chief
International Journal of Pharmaceutical Compounding
Remington: The Science and Practice of Pharmacy Twenty-second edition

Did You Know ...

...that “Common Sense� is also a pamphlet written by Thomas Paine published (anonymously) on January 10, 1776, advocating independence from Great Britain? The writing was clear and persuasive as Paine marshaled moral and political arguments to encourage common people in the Colonies to fight for equalitarianism, where all human persons are equal in fundamental worth or moral status.

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