Application of United States Pharmacopeia Monographs to Manufacturing and Compounding
In this issue, let's look at why some United States Pharmacopeia (USP) General Chapters are for Good Manufacturing Practices (GMPs), some are for Good Compounding Practices (GCPs), and some are for both. It is inappropriate to try to apply many USP General Chapters to compounding and finding "They just don't fit." Many were never intended for compounding in the first place, but were intended for the pharmaceutical industry and manufacturing, and, some for both.
Manufacturing vs Compounding
The emphasis of the USP started with compounding in 1820, then changed to manufacturing midway in the 20th century and then to a combination of manufacturing and compounding in the latter part of the 20th century; this is the situation we are in today. Basically, the chapters related to manufacturing tend to take on the GMP approach, and those related to compounding take on the GCP approach…and there are differences.
As an example, sterility testing that is required for GMP sterile products and either required or recommended for GCP sterile preparations presents the following issues. The requirements to meet USP Chapter <71> Sterility Tests do not work unless larger quantities of preparation are compounded. For example, Chapter <71> states:
<71> STERILITY TESTS
TEST FOR STERILITY OF THE PRODUCT TO BE EXAMINED
Number of Articles to be Tested
"Unless otherwise specified elsewhere in this chapter or in the individual monograph, test the number of articles specified in Table 3."
Table 3 for Parenteral Preparations includes the following:
|Not more than 100 containers||Test 10% or 4 containers, whichever is the greater.|
In USP <71>, it appears that the minimum number required for testing is four containers, unless the volume in each is insufficient for the tests; in those cases, the number will be increased to eight. If one is compounding less than four vials, it does not meet the requirements of this chapter. It is impractical in many cases to prepare additional vials to bring the number up to the minimum required for this chapter. For example, it is not feasible to prepare five vials so one can be dispensed and four can be used for sterility testing. One must remember that most of the chapters in the USP General Chapters were designed, developed, and written for the pharmaceutical industry where large volumes are prepared, not for compounding where only a few may be prepared. In addition, many of these compounded sterile preparations are quite expensive, and this prohibits compounding extra units. Also, as mentioned above, I don't know of any hospitals that would compound five intravenous admixtures so they could send four for sterility testing and one for the patient. We are in an awkward time when compounding has rapidly grown, but many try to inadvertently apply to compounding pharmacy USP chapters that have been written over the past 30 to 40 years for the pharmaceutical industry.
Development of the United States Pharmacopeia General Chapters
Up until USP XVIII (1970), the USP did not have "General Chapters"; it had a section on "General Tests, Processes, and Apparatus." Also, in the PREFACE, it stated, "However, procedures by which good manufacturing practice is implemented are decidedly related to drug standards, and consequently much of the revision embodied herein serves to necessitate and/or demonstrate compliance with what are regarded as the best practices." The USP also discusses the relationship and impact of the 1962 Amendments to the Food, Drug, and Cosmetic Act, the Food and Drug Administration, and United States Pharmacopeia.
The USP introduced the General Chapters in USP XIX (1975), but they were un-numbered. It is apparent that these chapters were targeted at both pharmacist practitioners and manufacturers. In some cases, both practitioners and manufacturers are referred to within the same chapter. There were about 80 General Chapters, and 16 sections of the General Information, Processes, Techniques and Apparatus remained.
The USP began "numbering" General Chapters (i.e., <1>) in USP XX. There were 100 enforceable General Chapters and 19 General Information chapters. Information contained in the General Information, Processes, Techniques and Apparatus sections was incorporated into the General Chapters.
In the last 32 years, additional General Chapters have been written. In USP 35, there are 145 General Chapters numbered <1000 (Enforceable), 94 General Chapters numbered in the 1000s (Informational), and 7 Dietary Supplement General Chapters numbered in the 2000s.
It is evident that the vast majority of these chapters are directed to GMPs and manufacturers; and some are pharmacy practice specific. However, some also apply to both, and it is in this area that we have difficulties.
Even though it is felt by some regulators that some action is necessary in light of recent events, it is the patient that is placed at risk when their medications are no longer available because standards are forced where they are not intended. There is a "middle ground" to accommodate patients with quality compounded pharmaceuticals and that is what we should strive for!
United States Pharmacopeia General Chapter <1163>
The purpose of USP General Chapter <1163> Quality Assurance in Pharmaceutical Compounding is to provide information on developing a quality-assurance system that is guided by written procedures that define responsibilities and practices that ensure compounded preparations are produced with quality attributes appropriate to meet the needs of patients and healthcare professionals.
USP Chapters referred to in <1163> Quality Assurance in Pharmaceutical Compounding include those in the accompanying Table. Those chapters listed in the Table that were written specifically for compounding include <1160> and <1176>; the remainder were written originally for the pharmaceutical industry. However, parts of those chapters are appropriate for assistance in establishing a quality-assurance program in compounding. There are other chapters mentioned in <1163>, however, that are written for compounding pharmacy.
It is impossible to apply many of the chapters to compounding pharmacy when they were written primarily for manufacturers because "they just don't fit"! However, there are some portions of some of the chapters that can be used, but not in their entirety. This is a vitally important project for the USP Expert Committee on Compounding to undertake and clearly delineate what chapters and what parts of some chapters are intended for compounding practitioners.
Loyd V. Allen, Jr., PhD, RPh
International Journal of Pharmaceutical Compounding
Remington: The Science and Practice of Pharmacy
Table. United States Pharmacopeia Chapters for Selected Quality Testing Methods and Procedures.
|Boiling point||Distilling Range|| <721>|
|Density||Density of Solids||<699>|
|Ion selective potentiometry||-||-|
|Loss on drying||Loss on Drying||<731>|
|Pharmaceutical calculations in prescription compounding||Pharmaceutical calculations in Prescription Compounding||<1160>|
|Melting point||Melting Range or Temperature||<741>|
|Osmolality and osmolarity||Pharmaceutical Calculations in Prescription Compounding||<1160>|
|Osmolality and osmolarity||Osmolality and Osmolarity||<785>|
|Particle size||Powder Fineness||<811>|
|Particulate matter in injections||Particulate Matter in Injections||<788>|
|Refractive index||Refractive Index||<831>|
|Volumetric||Prescription Balances and Volumetric Apparatus||<1176>|
|Weight||Prescription Balances and Volumetric Apparatus||<1176>|
|Flame emission and atomic absorption spectroscopy||Spectrophotometry and Light-Scattering||<851>|
|Fluorescence/phosphorescence spectroscopy||Spectrophotometry and Light-Scattering||<851>|
|Infrared spectroscopy||Spectrophotometry and Light-Scattering||<851>|
|Ultraviolet/visible spectroscopy||Spectrophotometry and Light-Scattering||<851>|
|Column chromatography (CC)||Chromatography||<621>|
|Gas chromatography (GC)||Chromatography||<621>|
|High-performance liquid chromatography (HPLC)||Chromatography||<621>|
|Paper chromatography (PC)||Chromatography||<621>|
|Thin-layer chromatography (TLC)||Chromatography||<621>|
|Endotoxin testing||Bacterial Endotoxins Test||<85>|
|Microbial limit testing||Microbiological Examination of Nonsterile Products: Microbial Enumeration Tests||<61>|
|Microbiological Examination of Nonsterile Products: Tests for Specified Microorganisms||<62>|
|Preservative effectiveness testing||Antimicrobial Effectiveness Testing||<51>|