Compendia (US, Europe, and Japan)

This chapter covers a subset of a much larger but out-of-scope topic: namely, knowing, understanding, navigating, and applying information found within the three major pharmaceutical compendia to the selection and implementation of qualitative or quantitative release tests for drug substances (active pharmaceutical ingredients [APIs]), drug products, or excipients). While regulatory and consensus standard references cited and annotated herein are important, proper, real-time lookup and learning from the current or effective-in-future General Chapters (plus specific monographs) of the three major compendia are required for full understanding and knowledge. Detailed interpretation of General Chapter content is confined to only those mandatory and informational General Chapters considered to be a minimum for good manufacturing practices (GMP) literacy.

A compendium is simply a collection or compilation of distinct pieces of writing or chapters. Vis-à-vis drug substances, drug products, and excipients (collectively referred to as official articles contained within the Unites States Phar-macopeia [USP]), the term “compendium” refers to the USP, the European Pharmacopeia (PhEur), or the Japanese Pharmacopeia (JP). The USP, PhEur, and JP comprise General Notices, General Chapters, and official article-specific chapters called monographs that contain the official article’s definition, packaging, storage, and other requirements and specifications. The USP General Chapters provide frequently cited procedures common to multiple official articles. For drug substances and drug products, the USP General Chapters <1> through <999> are mandatory, whereas General Chapters <1000> through

<1999> are intended to be informational only by the USP. In reality, the United States Food and Drug Administration (FDA) considers the latter General Chapters to represent good science, which translates into FDA often enforcing informational General Chapters as extensions of current good manufacturing practices (cGMP).

Bulk pharmaceutical water serves as a pharmaceutical component (a manufacturing material that is later completely evaporated or sublimated) or a material that decontaminates, cleans, and/or sanitizes product-contact equipment. It is produced and distributed by a system that undergoes initial qualification and that must be monitored. Thus, bulk pharmaceutical water is a utility, a process material, an excipient, or all three items.

Total organic carbon (TOC) and water conductivity make up the common tests prescribed by the USP, PhEur, and JP. Water for injection (WFI) additionally requires the bacterial endotoxin test (BET) with a specification of not more than 0.25 endotoxin units/mL (international units/mL in Europe). The Japanese aseptic processing guidance (Appendix A2, “Pharmaceutical Waters”) states, “Whenever water quality is monitored and controlled by conductivity and TOC testing, it is not usually necessary to monitor individual metals or inorganic ions.” Therefore BET, TOC, and water conductivity may be considered sufficient process control and monitoring tests for maintaining a pharmaceutical water storage and delivery system in control.

For quality control (QC) monitoring tests of pharmaceutical water, neither USP nor JP require heavy metals or other specific ion testing of the pharmaceutical waters because the Environmental Protection Agency (EPA)’s National Primary Drinking Water Regulations have sufficiently tight specifications to preclude their retesting in the more purified water. Unfortunately, the PhEur is not in harmony with USP or JP by the requirement of several tests (Table 19.1).

Though not a compendial specification, the PhEur suggests a total aerobic microbial count (TAMC) action limit of 10 CFU/100 mL in its WFI monograph, which agrees with the 1993 FDA Guide to Inspections of High Purity Water Systems. The PhEur and the 1993 FDA guide give a TAMC action limit of 100 CFU/mL for purified water. The USP, in its informational General Chapter <1231> “Water for Pharmaceutical Purposes,” explains that microbial specifications would be inappropriate for a continuously produced material such as bulk pharmaceutical water and for such a validated process. The microbial incubation time lag inherently defeats the real-time production and usage of bulk pharmaceutical water.

The PhEur TAMC action limit statement, in both the purified water and WFI monographs, specifies the use of agar medium S, which is R2A media. Neither the USP nor JP specifies an agar for TAMC of bulk pharmaceutical water, permitting different process validation results to dictate the appropriate medium.

Two guides exist for the frequency and location of bulk pharmaceutical water sampling for monitoring or testing off-line. The 1993 FDA guide also created the generally accepted sampling frequency and sampling locations within a bulk pharmaceutical water distribution system, namely, daily sampling (except during shutdown) from a minimum of one point of use, with all points of use tested weekly. USP General Chapter <1231> states that “sampling frequencies should be based on system validation data and should cover critical areas including unit operation sites. . . .

samples should be collected from use points using the same delivery devices, such as hoses, and procedures, such as preliminary hose or outlet flushing, as are employed by production from those use points.”

Pure steam is manufactured such that, when condensed, it satisfies WFI specifications. Guidelines for monitoring pure steam are less well defined to nonexistent compared with those for bulk pharmaceutical waters. Providing it is manufactured within a system that already passes TOC and water conductivity, it is presumed not to deviate significantly from its source pharmaceutical water. In addition, pure steam is inherently self-sterilizing such that TAMC is highly unlikely to provide trends on the steam but only on incorrectly sampled condensate. BET results on pure steam use points or sampling points provides enough assurance against grossly contaminated (by Gram-negative bacteria) draw-off valves.

Water conductivity monitoring/testing may be performed off-line or in-line. In-line conductivity monitoring inherently prevents the progression to stage 2 or stage 3 of the USP or PhEur water conductivity test; however, the distribution system must be designed such that an out-of-specification (OOS) result (based on conductivity versus water temperature) automatically results in either diversion to drain or recirculation into the water generation system. If using the off-line pharmacopeial water conductivity test, stages 2 or 3 must be performed if the previous stage fails. No OOS investigation (per FDA out-of-specification guidance) or stoppage of the conductivity or any multistage compendial test may occur between stages. USP General Chapter <645> requires an electronic calibration of the conductivity meter by replacing the conductivity sensor with a nationally traceable resistance device, for example, Wheatstone Bridge.

The TOC compendial test for bulk pharmaceutical water is harmonized among the USP, PhEur, and JP. The apparatus for measuring TOC, like water conductivity, is either in-line or off-line. The periodic suitability testing of the apparatus is specified as employing both a standard solution of compendial sucrose and a system suitability standard solution of 1,4-Benzoquinone. The diluent/solvent is reagent water having a TOC of not more than 0.10 mg/L.

A monitoring test required for, and applicable only to, WFI and pure steam is the BET. The test, being highly dependent on the particular Limulus amebocyte lysate (LAL) and corresponding test equipment and instruments, is not a candidate for compendial test suitability verification, but must undergo complete method validation for parenteral products. For WFI and pure steam, pharmacopeial test verification of suitability may suffice. The LAL reagent used in the BET has been classified as a biologic, and is licensed by the Center for Biologics Evaluation and Research (CBER). FDA requires that a finished parenteral pharmaceutical manufacturer operating in the US or shipping to the US use an LAL reagent licensed by CBER in all validation, in- process, and end-product LAL tests.

Portions of the BET General Chapter have been harmonized among the three compendia. USP, PhEur, and JP permit and describe six methods (Figure 19.1). All three compendia contain similar wording that “in the event of doubt or dispute, the final decision is made based upon method A [Gel-clot method: limit test] unless otherwise indicated in the monograph [for a specific finished parenteral pharmaceutical].”



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