FAQs: <795> Pharmaceutical Compounding—Nonsterile Preparations

Last updated: May 31, 2019

General

Introduction and Scope

2. What is the definition of nonsterile compounding?

For purposes of General Chapter <795>, nonsterile compounding is defined as combining, admixing, diluting, pooling, reconstituting other than as provided in the manufacturer’s labeling, or otherwise altering a drug or bulk drug substance to create a nonsterile medication.

3. To whom do the standards in General Chapter apply?

The chapter applies to all persons who prepare CNSPs and all places where CNSPs are prepared for human patients. This includes but is not limited to pharmacists, technicians, nurses, physicians, dentists, naturopaths, and chiropractors, in all places including but not limited to pharmacies, hospitals and other healthcare institutions, patient treatment sites, and physicians’ practice sites. Personnel engaged in the compounding of CNSPs must additionally comply with laws and regulations of the applicable regulatory jurisdiction. Compounding of nonsterile hazardous drugs (HDs) must additionally comply with General Chapter <800> Hazardous Drugs—Handling in Healthcare Settings.

4. How do I know what are requirements versus recommendations in the chapter?

Generally, requirements in a General Chapter are conveyed by use of the terms “must” or “shall”. Recommendations are conveyed by use of the terms “should” and “may”.

5. What does “official date” mean?

The USP “official date” indicates the date by which affected users are expected to meet the requirements of a particular standard. Ensuring compliance with the requirements of these standards is the responsibility of regulators such as the FDA, states, and other government authorities. USP has no role in enforcement.

All text in the United States Pharmacopeia (USP) or National Formulary (NF) that has reached its official date is “official text.” Although all text of the USP–NF that has reached its official date is “official text,” not all official text states requirements with which compendial users must comply. Some official text is intended to assist or guide compendial users or to serve informational purposes.

6. When do the revisions to General Chapter become official?

The revision of <795> published on June 1, 2019 will become “official” on December 1, 2019. The “official date” indicates the date by which affected users are expected to meet the requirements of a particular standard. However, ensuring compliance with the requirements of these standards is the responsibility of regulators such as the FDA, states, and other government authorities. Regulatory bodies such as state boards of pharmacy may have a different official date. USP has no role in enforcement.

7. Is splitting tablets required to meet the standards in the chapter?

No, breaking or cutting a tablet into smaller portions is not required to meet the standards in this chapter.

8. Is reconstitution of conventionally manufactured products required to meet the standards in the chapter?

Reconstitution of a conventionally manufactured nonsterile product in accordance with the directions contained in the manufacturer approved labeling is not required to meet the standards in this chapter. Reconstitution that is not performed according to manufacturer approved labeling is considered nonsterile compounding and is subject to the requirements in the chapter.

9. Is administration out of the scope of the chapter?

Yes. The intent of the chapter is to establish minimum standards for practitioners when preparing compounded nonsterile preparations in order to minimize harm, including death, to human and animal patients. The scope of the chapter is intended to be limited to compounding and the standards are designed to help ensure a CNSP maintains its integrity up until the time when administration begins. Additionally, the preparation of a single dose for a single patient when administration will begin within 4 hours of beginning the preparation is not required to meet the requirements in the chapter.

10. Does the chapter address compounded radiopharmaceutical dosage forms?

No. Radiopharmaceuticals are not subject to the requirements in <795> but are subject to the requirements in General Chapter <825> Radiopharmaceuticals—Preparation, Compounding, Dispensing, and Repackaging.

11. Are the temperatures in the chapter expressed in degrees Fahrenheit or Celsius?

Unless otherwise specified, all temperatures in the USP-NF are expressed in degrees centigrade (Celsius) (see also General Notices 8.180 Temperatures).

12. Are products manufactured by 503B facilities or conventionally manufactured products considered active pharmaceutical ingredients (APIs)?

No. The term "API" refers to a bulk drug substance (pure chemical substances), usually in powder or liquid form, which is intended to be used in compounding. API is distinguished from finished dosage forms.

13. Why were the categories of compounding (simple, moderate, and complex) in the previous chapter eliminated in the new revision?

The categories of compounding were originally adapted from <1075> Good Compounding Practices in 2011. The categories often led to confusion among users on how to apply the criteria and the chapter did not provide standards on how to use these categories in applying the compounding standards.

14. Who can be the designated person(s)?

The designated person is one or more individuals assigned to be responsible and accountable for the performance and operation of the facility and personnel for the preparation of compounded nonsterile preparations (CNSPs). Facilities must determine whether they have one or more designated person, select the designated person, and determine how to allocate responsibility if there is more than one designated person.

15. Is the repackaging of a conventionally manufactured product required to meet the standards in the chapter?

No, repackaging of conventionally manufactured drug products is not required to meet the standards in this chapter (see also <1178> Good Repackaging Practices).

16. Since the section on Compounding for Animal Patients in the previous chapter was removed, does the chapter still apply to veterinary compounding?

The intent of the chapter is to establish minimum standards to help ensure quality of CNSPs, whether the CNSP is for human or animal patients. USP has no role in the enforcement of compounding chapters. Pursuant to General Notices, 2.30 Legal Recognition, ensuring compliance with USP standards is the responsibility of regulatory bodies. Regulators may choose to enforce the requirements of <795> with respect to veterinary compounding.

Personal Hygiene and Garbing

17. What garb is required for nonsterile compounding?

Gloves must be worn for all compounding activities. All other garb (e.g., shoe covers, head and facial hair covers, face masks, gowns) should be worn as required by the facility’s Standard Operating Procedures (SOPs). Garb is recommended for the protection of personnel and to minimize the risk of CNSP contamination. The garb must be appropriate for the type of compounding performed. The garbing requirements and frequency of changing the garb must be determined by the facility and documented in the facility’s SOPs.

18. Are gloves required to be wiped or changed before beginning to compound a CNSP with different components?

The chapter recommends wiping or replacing gloves before beginning to compound a CNSP with different components to minimize the risk of cross-contaminating other CNSPs and contaminating other objects. General Chapter <795> does not describe the use of specific wipes or agents to use for wiping gloves. Facilities must determine whether gloves should be changed or replaced and the appropriate wipe/agent to use if they are wiped.

19. Can gowns be reused for multiple days if not soiled?

If gowns are worn, they may be re-used if not soiled. If gowns are visibly soiled or have tears or punctures, they must be changed immediately. Facilities must determine the frequency for changing gowns.

Buildings and Facilities

20. Is a compounding space required to be in an enclosed room (i.e., with walls and doors)?

No. While a room may be used as the compounding space, the chapter does not require a separate room. The chapter requires a space that is specifically designated for nonsterile compounding. A visible perimeter should establish the boundaries of the nonsterile compounding area.

21. What is considered an appropriate temperature range to store CNSPs or components?

The storage area must be maintained at a temperature that is appropriate for the CNSPs and components. The storage conditions for the CNSP would be dependent on the assigned beyond-use date (BUD) and CNSP-specific properties (see <795>, 10.2 Parameters to Consider in Establishing a BUD). The storage conditions for components may be provided by the manufacturer or vendor on the labeling and/or specified in the USP monograph for that component (see also <659>).

22. Since reconstitution and repackaging are not considered compounding and are out of scope of the chapter, can they still be performed in the designated compounding space?

Yes, other activities may be performed in the compounding space when compounding is not occurring. The chapter requires that a compounding space be designated for nonsterile compounding, however, the space is not required to be dedicated for sole use in compounding. Other activities may occur in the compounding space but they must not be occurring in the space at the same time as compounding.

Cleaning and Sanitizing

23. Can non-compounding personnel clean and sanitize the compounding space?

Facilities must determine the appropriate personnel for cleaning and sanitizing the compounding space. The chapter does not specify who may perform the cleaning and sanitization procedures.

24. What is the difference between cleaning and sanitizing?

Cleaning is the process of removing soil (e.g., organic and inorganic material) from objects and surfaces, normally accomplished by manually or mechanically using water with detergents or enzymatic products. Sanitizing is the process of reducing, on inanimate surfaces, the number of all forms of microbial life including fungi, viruses, and bacteria.

Equipment and Components

25. Are containment ventilated enclosures (CVEs) required for nonsterile compounding?

No. The chapter requires facilities to assess particle-generating activities (e.g., weighing, measuring, or other manipulation of components) to determine whether a closed system processing device is needed. The chapter does not require a closed system processing device but does require facilities to perform a process evaluation to determine whether a device is needed. A closed system processing device reduces the potential exposure to personnel and contamination to the facility from airborne particles that weighing, measuring, or otherwise manipulating components could generate. A CVE is one example of a closed system processing device; other examples include BSCs and single-use containment glove bags.

26. Why are APIs required to be obtained from an FDA-registered facility and components other than APIs only recommended to be obtained from an FDA-registered facility?

The Federal Food, Drug, and Cosmetic Act requires compounded preparations to be prepared from bulk drug substances that are obtained from FDA-registered facilities. The Expert Committee recognizes that there may be some components other than APIs that cannot be obtained from an FDA-registered facility, thus, it is a recommendation that these components be obtained from an FDA-registered facility.

Labeling of CNSPs

27. Are all CNSPs required to be labeled, regardless of whether they are dispensed?

Yes. CNSPs must be labeled with the information specified in 9. Labeling regardless of whether or not they are dispensed.

Establishing Beyond-Use Dates

28. What is water activity (Aw)?

Aw is the measure of free water in a pharmaceutical dosage form. Aw is used in accessing the susceptibility of CNSPs to microbial contamination and the potential for API degradation due to hydrolysis. A lower Aw is associated with a lower risk of microbial contamination. Thus, dosage forms such as suppositories, ointments, fixed oils, or waxes which have an Aw ≤ 0.6 have a BUD of 90 days. Dosage forms that have an Aw > 0.6 such as emulsions, gels, creams, solutions, sprays, and suspensions have a BUD of 14 or 35 days depending on whether it is non-preserved or preserved, respectively.

29. Are compounders expected to measure the Aw of CNSPs to determine the BUD?

No, the chapter does not require compounders to measure Aw for CNSPs. Aw is intended to be used as a guide for assigning BUD. General Chapter <795> provides examples of dosage forms that have an Aw ≤ 0.6 and those that have an Aw > 0.6. Additionally, General Chapter <1112> Application of Water Activity Determination to Nonsterile Pharmaceutical Products provides a list of products and corresponding Aw in Table 2.

30. Why is the BUD for nonaqueous dosage forms with an Aw ≤ 0.6 (e.g., suppositories, ointments, fixed oils, or waxes) limited to 90 days?

Although many nonaqueous formulations, including anhydrous oil formulations, may be stable for a long period of time, this is not consistently demonstrated for all nonaqueous formulations. For example, a stability-indicating assay of doxycycline compounded in oil exhibited degradation before 90 days. Additionally, there are other ingredients that may oxidize or otherwise react with the fatty acids in the oil. The chapter provides a conservative approach due to numerous examples where preparations in oil are not stable for 180 days. Further, the chapter allows the BUD of CNSPs to be extended up to 180 days if there is a stability study using a stability-indicating assay (see <795>, 10.5 Extending BUDs for CNSPs).

31. If a stability study shows that a CNSP is stable for longer than 180 days, can that BUD be assigned?

No. General Chapter <795> specifies that the BUD for CNSPs may be extended up to a maximum of 180 days if there is a stability study (published or unpublished) using a stability-indicating assay for the API(s), CNSP, and type of container–closure that will be used. If the CNSP is aqueous, the chapter additionally recommends testing for antimicrobial effectiveness for extending BUDs beyond those contained in Table 3 (see 10.5 Extending BUDs for CNSPs).

However, if there is a USP–NF compounded preparation monograph for the CNSP, the BUD must not exceed the BUD specified in the monograph. As stated in General Notices 3.10, monograph requirements supersede the requirements of General Chapters.

32. If I extend the BUD beyond those described in Table 3. Maximum BUD by Type of Preparation in the Absence of a USP-NF Compounded Preparation Monograph or CNSP Specific Stability Information, why does the CNSP have to be tested for antimicrobial effectiveness?

The chapter allows an extension of BUD if there is stability data supported by a stability-indicating study. Although the CNSP may be stable, the CNSP may be susceptible to microbial proliferation especially from prolonged and repeated use. Antimicrobial effectiveness testing is recommended and only needs to be performed once for a particular CNSP. If a range of concentration is used in the same CNSP formulation and stored under the same conditions, the antimicrobial effectiveness test can be conducted for the highest and lowest concentrations. The results can be extrapolated for the concentrations within the range studied (e.g., bracketed study design).

33. Is there a difference between testing stability with a strength (potency) or a stability-indicating method?

Yes, a strength (potency) over time test determines the amount of active ingredient in a preparation, however, it may not be able to separate the active ingredient from its degradation products and impurities for quantitation depending on the analytical methods used for the test. A stability-indicating method will be able to quantitate the active ingredient and its degradation products or related impurities in the preparation by separating the active ingredient from its degradation products and impurities, and to show a change in the concentration of the active ingredient with increasing storage time. A stability-indicating method is used to determine stability of a drug and used to establish the Beyond-Use Date. (See article, “Strength and Stability Testing for Compounded Preparations.”)