FAQs: <797> Pharmaceutical Compounding—Sterile Preparations

Last updated: May 31, 2019

General

Introduction and Scope

2. What is the definition of sterile compounding?

For the purposes of General Chapter <797>, sterile compounding is defined as combining, admixing, diluting, pooling, reconstituting, repackaging, or otherwise altering a drug or bulk drug substance to create a sterile medication. However, administration and preparation per approved labeling are out of the scope of the chapter as described in 1.2 Administration and 1.4 Preparation Per Approved Labeling, respectively.

3. To whom do the standards in General Chapter <797> apply?

This chapter applies to all persons who prepare CSPs and all places where CSPs 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, hospitals and other healthcare institutions, medical and surgical patient treatment sites, infusion facilities, pharmacies, and physicians’ practice sites.

Please note, compounding of sterile hazardous drugs (HDs) must additionally comply with General Chapter <800> Hazardous Drugs—Handling in Healthcare Settings.

4. Does the chapter apply to veterinary compounding?

The intent of the chapter is to establish minimum standards to help ensure quality of CSPs, whether the CSP 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 <797> with respect to veterinary compounding.

5. 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".

6. 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.

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

The revision of <797> 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.

8. Are the temperatures expressed degrees in 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).

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

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

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

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

11. Does docking and activation of a proprietary bag and vial system for immediate administration in accordance with the manufacturer’s labeling instructions have to occur under ISO 5 conditions?

No. Docking and activation of proprietary bag and vial systems in accordance with the manufacturer’s labeling for immediate administration to an individual patient is not required to meet the standards in this chapter.

12. When is docking a proprietary bag and vial system required to meet the standards of this chapter?

Docking proprietary bag and vial systems for future activation and administration is considered compounding and must be performed in accordance with this chapter.

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

Yes, repackaging of a sterile product or preparation from its original container into another container must be performed in accordance with the requirements in this chapter.

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

Yes. The intent of the chapter is to establish minimum standards for practitioners when preparing CSPs 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 CSP maintains its integrity up until the time when administration begins. Standard precautions such as the Centers for Disease Control and Prevention’s (CDC’s) safe injection practices apply to administration (see 1.2 Administration).

15. Does a conventionally manufactured sterile product prepared for administration to a single patient in accordance with manufacturer’s approved labeling outside of ISO Class 5 conditions have to be administered within 4 hours of reconstitution or mixing if it meets all the conditions in 1.4 Preparation Per Approved Labeling?

No. When all of the conditions in 1.4 Preparation Per Approved Labeling are met, the storage information in the manufacturer’s approved labeling may be followed.

16. What is the difference between compounding for immediate use and preparing a conventionally manufactured sterile product for administration?

Preparation of a single dose of a conventionally manufactured sterile product in accordance with the approved labeling that includes information about the diluent to be used, the resultant strength, storage time, and container closure system is not considered compounding. Compounding for immediate use involves mixing up to three different sterile products to make a CSP. Immediate use CSPs must be used within 4 hours following the start of preparation (see 1.3 Immediate Use CSPs).

17. Is withdrawing a dose from a container of a conventionally manufactured sterile product, without any further manipulation, for immediate administration to a patient considered compounding?

No, withdrawing a dose from a container of a conventionally manufactured sterile product without any further manipulation is considered administration and is out of the scope of <797>.

18. When compounding immediate use CSPs, can more than three individual containers of a sterile product be used?

The immediate use CSPs provision states that the preparation must not involve more than 3 different sterile products. Two or more of the same sterile product may be used as long as there are not more than three different sterile products. For example, two vials of drug are reconstituted using two vials of sterile water for injection and added to an intravenous bag may be considered immediate use as long as the criteria listed in 1.3 Immediate Use CSPs are met. As another example, when the CSP requires combining 4 vials of the same component into a single bag of diluent, only 2 different sterile products are used to prepare the CSP.

19. Can a single-dose container be used to prepare doses for more than one patient when compounding an immediate use CSP?

No. One of the conditions of the immediate use CSP provision specifies that any unused starting components from a single-dose container must be discarded after preparation for the individual patient is complete. Single-dose containers must not be used for more than 1 patient when used for preparing immediate use CSPs.

20. Why does the immediate use CSPs provision allow for administration to begin within 4 hours following the start of the preparation?

The immediate use CSPs provision was revised to allow up to 4 hours for beginning administration based on the lag phase of microbial growth, during which potential bacterial cells are adjusting to their environment and change very little, and they do not immediately start reproducing. On average, exponential reproduction may not start for 4 to 6 hours.1 In the event bacterial cells were inadvertently introduced into a CSP, it would not immediately start replicating, and therefore there is a window of time in which a CSP can be held prior to administration.

1For example, see:

Daquigan N et al. Early recovery of Salmonella from food using a 6-hour non-selective pre-enrichment and reformulation of tetrathionate broth. Front Microbiol. 2016;7:2103.
Jarvis, Basil. Statistical Aspects of the Microbiological Examination of Foods, Third Edition. Academic Press, 2016.
Ryan, Kenneth et al. Sherris Medical Microbiology, Sixth Edition. McGraw-Hill Education, 2014.
Wang J et al. A novel approach to predict the growth of Staphylococcus aureus on rice care. Front Microbiol. 2017;8:1140.
 

21. Is it considered compounding if the steps used to prepare a single dose of a conventionally manufactured product are different from the directions contained in the manufacturer’s approved labeling?

Yes. Any compounding (e.g., mixing, reconstituting) that is not performed according to the manufacturer’s approved labeling is considered sterile compounding and is subject to the requirements in the chapter.

22. Does the chapter address compounded radiopharmaceutical dosage forms?

No. Radiopharmaceuticals are not subject to the requirements in <797> but are subject to the requirements in General Chapter <825> Radiopharmaceuticals—Preparation, Compounding, Dispensing, and Repackaging.

Personnel Training and Evaluation

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

It is the responsibility of the facility to determine who is the designated person(s). The designated person is one or more individuals assigned by the facility to be responsible and accountable for the performance and operation of the facility and personnel for the preparation of CSPs. 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.

24. Is documentation of gloved fingertip and thumb sampling and media-fill testing only required when results exceed action levels?

No. All results of the evaluations must be documented and maintained to provide a record and long-term assessment of personnel competency. Documentation must at a minimum include the name of the person evaluated, evaluation date/time, media and components used including the manufacturer, expiration date and lot number, starting temperature for each interval of incubation, dates of incubation, the results, and the identification of the observer and the person who reads and documents the results.

25. Why are incubation conditions different for media-fill testing, gloved fingertip and thumb sampling, and environmental air and surface sampling?

Environmental air and surface samples and gloved fingertip and thumb samples are incubated at a high temperature and then a low temperature. Incubation at a lower temperature first may compromise recovery of gram-positive cocci which are often associated with humans. The incubation conditions are consistent with General Chapter <1116> Microbiological Control and Monitoring of Aseptic Processing Environments. Media-fill test samples are incubated at a low temperature and then a high temperature to detect a broad spectrum of microorganisms. The incubation time and temperatures for media-fill test samples are consistent with FDA Guidance for Sterile Drug Products Produced by Aseptic Processing ‒ Current Good Manufacturing Practices.

Personal Hygiene and Garbing

26. What is the correct order of garbing?

General Chapter <797> does not specify an order of garbing. Garb must be donned and doffed in an order that reduces the risk of contamination. The order of garbing and location where garbing occurs would depend on the type of garbing used (e.g., sterile gowns) and the placement of the sink (e.g., if the sink is located inside or outside of the ante-room). The order of garbing must be determined by the facility and documented in the facility’s SOP.

27. Can donning and doffing activities by different personnel occur in the same room at the same time?

The chapter recommends (but does not require) that donning and doffing not occur in the ante-room or the segregated compounding area (SCA) at the same time. Personnel must be aware of activity in the room to ensure that the integrity of garb is not compromised. For example, if one person is performing hand hygiene while another is donning a gown, personnel must consider the risk of contaminating the gown (e.g., from potential splashing).

28. What are examples of methods to cover jewelry that cannot be removed?

Examples of jewelry that cannot be removed are dermal piercings (also known as a microdermal piercing), which is a piercing that is held in place with a dermal anchor that is installed underneath the skin. Facilities must determine the appropriate method for covering dermal piercings to minimize the risk of contaminating the CSP and the environment. For example, depending on the location of the piercing, an adhesive bandage or head cover may be used to cover the jewelry.

29. Are wedding rings permitted to be worn under sterile gloves?

The chapter requires removing all hand jewelry that could interfere with the effectiveness of garbing or otherwise increase the risk of contamination of the CSP. Wedding rings may potentially compromise the integrity of the glove (e.g., tearing).

30. Are 3 pairs of gloves required for using a compounding aseptic isolator (CAI) or compounding aseptic containment isolator (CACI)?

If using a CAI or CACI, the chapter recommends disposable gloves to be worn inside gloves attached to the restricted-access barrier system (RABS) sleeves. However, the chapter requires sterile gloves to be worn over the gloves attached to the RABS sleeves. The use of disposable gloves inside of gloves attached to the RABS sleeve is intended to maintain the cleanliness of the gloves attached to the RABS sleeve which may collect sweat or other touch contaminants. Sterile gloves outside of the gauntlet gloves help minimize the risk of contamination to the environment and the CSP.

31. If I am compounding Category 1 CSPs in an SCA, do I have to wear the same garb as when compounding Category 2 CSPs in a cleanroom suite?

Yes. Minimum garbing requirements are not stratified based on facility design. The chapter lists the minimum garbing requirements to protect the CSP and the environment. Sterile gloves are required for preparing CSPs inside an ISO Class 5 PEC.

32. Can gowns be re-used?

Yes. Gowns may be re-used within the same shift if the gown is maintained in a classified area or inside the perimeter of an SCA. Garb must be replaced immediately if it becomes visibly soiled or if its integrity is compromised. Additionally, gowns and other garb must be stored in a manner that minimizes contamination (e.g., away from sinks to avoid splashing).

Facilities and Engineering Controls

33. Why must the HEPA filter be located in the ceiling of the buffer and ante-rooms?

Placement of HEPA filters in the ceiling eliminates the potential for post-filtration contamination of the air-stream. Air distribution systems with duct-mounted HEPA filters are susceptible to introduction of unfiltered air into the airstream after the air is filtered. HEPA filter placement in the ventilation duct is difficult to leak test and susceptible to contamination, especially in the event of water leakage or other breaches. Ceiling mounted filters help facilitate testing and servicing.

34. Why are CAIs and CACIs required to be placed in an ISO Class 7 buffer room with an ISO Class 8 ante-room for preparing Category 2 CSPs?

The PEC must be located in a controlled environment for preparing Category 2 CSPs to minimize the risk of contamination. Movement of materials in and out of the RABS (e.g., CAI or CACI) in unclassified air carries a higher risk of contamination. Placement of the RABS in a classified area mitigates the risk of inadvertent contamination of CSPs with the longer BUDs that are permitted for Category 2 CSPs.

35. Does the Integrated Vertical Laminar Flow Zone (IVLFZ) require 100% HEPA filter coverage in the ceiling? Can returns be under the work table?

The chapter requires "full coverage of HEPA filters above the work surface" but does not specify 100% coverage. HEPA filters must cover the entire area above the work tables. However, even if HEPA filters cover the entire ceiling above the table of an IVLFZ, there may be less than 100% coverage.

Returns must be positioned where they create the best "pull" of air across the work surface. Returns may be on the wall behind the table at a height where the return straddles the table. A portion of the air is drawn into the section of return above the table and a portion of the air is drawn around the front of the table to the area of the return below the table. If the returns are only located under the table, the table should be positioned in such a way to allow air to pass between the wall and the table to the return. The chapter does note that dynamic airflow smoke pattern tests have shown that it is difficult to achieve this type of design and also achieve and maintain unidirectional airflow under dynamic operating conditions.

36. Can a containment ventilated enclosure (CVE) be used for presterilization procedures (e.g., weighing, mixing nonsterile components)?

Presterilization procedures must be performed in a single-use containment glove bag, CVE, BSC, or CACI to minimize the risk of airborne contamination.

37. Are pass-throughs required to have interlocking doors?

The chapter recommends that pass-through doors be interlocking. However, if a pass-through is used, both doors must never be opened at the same time.

38. How are visual smoke studies performed in rooms where air returns are not located low on the wall?

A visual smoke study uses a visible source of smoke, which is neutrally buoyant, to verify an absence of stagnant airflow where particulates can accumulate.

39. What is the difference between a pharmaceutical isolator and a RABS (i.e., a CAI or CACI)?

Unlike RABS, pharmaceutical isolators are different in that they contain 4 major elements: controlled workspace, transfer device, access device, and a decontamination system. A pharmaceutical isolator is equipped with a generator that distributes a sporicidal agent throughout the chamber.

If the isolator is used to prepare Category 2 CSPs, it must be placed in an ISO Class 8 or better positive pressure room. In contrast, if the CAI or CACI is used to prepare Category 2 CSPs, the CAI or CACI must be placed in a cleanroom suite with an ISO Class 7 or better positive pressure buffer room with an ISO Class 8 or better positive pressure ante-room.

40. Can magnehelic gauges be used for monitoring pressure differentials?

Yes, magnehelic gauges may be used to monitor pressure. The quantitative results from the pressure monitoring device must be reviewed and documented at least daily on the days when compounding is occurring. Users should note that magnehelic gauges do not warn or alert personnel to events where there is a loss of pressure whereas there other pressure monitoring systems may have audible or visible alarms.

41. Why is the frequency of surface sampling changed to monthly?

Surface sampling was previously required "periodically" which was interpreted differently by users (e.g., monthly, quarterly, or biannually). The change to monthly surface sampling is intended to provide an additional measure of control and monitoring in between viable air monitoring and certification requirements every 6 months. Monthly surface sampling provides additional data for trending and allow for monitoring of contamination risks.

42. Why are sinks allowed to be placed outside of the ante-room? Does the sink placement in contradict the sink placement requirements in ?

In facilities with cleanroom suites, the sink used for hand hygiene may be placed either inside or outside of the ante-room. If the sink is located outside of the ante-room, it must be located in a clean space to minimize the risk of bringing in contaminants into the ante-room. Sinks are permitted outside of the ante-room to offer more flexibility to the cleanroom design and help minimize the risk of contamination from water sources to the classified areas.

In facilities preparing HDs in a cleanroom suite, General Chapter <800> requires the sink to be placed in the ante-room at least 1 meter away from the entrance of the HD buffer room to avoid contamination migration into the negative pressure HD buffer room. There are no conflicts for the sink placement in <797> and <800>. Facilities compounding sterile HDs must meet the requirements in both <797> and <800>.

43. Is an SCA required to be in an enclosed room (i.e., walls and doors)?

No. An SCA is defined as a designated, unclassified space, area, or room with a defined perimeter that contains a PEC and is suitable for preparation of Category 1 CSPs only.

44. Is certification of the compounding area required to be performed using the current Controlled Environment Testing Association (CETA) certification guide for Sterile Compounding Facilities?

No, facilities may use the CETA certification guide or an equivalent guideline. Facilities must determine the appropriate certification guide to use for certifying their compounding area.

Microbiological Air and Surface Monitoring

45. How many microbiological air and surface samples are required based on the size of classified areas?

Microbiological air and surface monitoring must be conducted in all classified areas to confirm that the required environment quality is maintained. The microbiological air and surface sampling must be facility specific and must be described in the facility’s Standard Operating Procedures (SOPs). The chapter does not specify a minimum number of samples based on the size of the room. Facilities must determine the appropriate number of locations and select the locations of sampling based on their relationship to the activities performed in the area.

46. Do microorganisms need to be identified to the genus level regardless of action level?

No, an attempt must be made to identify any microorganisms recovered to the genus level if the levels measured during sampling exceed the action levels in the chapter.

47. What is the rationale for only requiring an attempt to identify any microorganisms recovered to the genus level if the levels measured during sampling exceed the action levels in the chapter?

In some instances, microorganisms cannot be identified to the genus level because the microorganism is no longer viable or the mold may not be producing the reproductive structures necessary for identification. In these instances, the genus may not be identified, but the chapter does require than an attempt be made to identify the microorganism to the genus level.

Cleaning, Disinfecting, and Applying Sporicidal Agents in Compounding Areas

48. What is the difference between cleaning and disinfecting?

Cleaning is the process of removing residues (e.g., dirt, debris, microbes, and residual drugs or chemicals) from surfaces. Disinfecting is the process of destroying fungi, viruses, and bacteria on inanimate surfaces and objects. Applying a sporicidal agent is used to destroy bacterial and fungal spores and is expected to kill all vegetative microorganisms.

49. What is a one-step disinfectant cleaner?

A one-step disinfectant cleaner is a product with an EPA-registered (or equivalent) claim that it can clean and disinfect a non-porous surface in the presence of light to moderate organic soiling without a separate cleaning step. It is important to note that sterile isopropyl alcohol (IPA) is not a one-step disinfectant cleaner.

50. Where can I find examples or sources of EPA-registered one-step disinfectant cleaners?

USP cannot endorse particular products. Users may research one-step disinfectant cleaners or contact cleaning/disinfecting agent manufacturers to get more information on available products.

51. What surfaces of the SCA does table containing the minimum frequencies of cleaning, disinfecting, and applying sporicidal agents (Table 8) apply?

The minimum frequencies in Table 8 apply to all surfaces within the perimeter of the SCA. These include the PEC(s), walls, floors, ceilings, work surfaces, equipment, and storage shelving and bins located within the perimeter of the SCA.

52. Does the equipment inside a PEC need to be cleaned?

Yes, the chapter requires equipment inside of the PEC to be cleaned, disinfected, and a sporicidal agent applied (see Table 8).

53. Are cleaning supplies required to be sterile?

No, cleaning tools are not required to be sterile. The chapter does state that all cleaning supplies (e.g., wipers, sponges, and mop heads) with the exception of tool handles and holders must be low-lint. Further, the chapter recommends that wipes, sponges, and mop heads be disposable.

54. Are cleaning agents required to be sterile?

No, cleaning agents are not required to be sterile.

55. Where can I find information about the minimum contact time for the cleaning, disinfecting, and sporicidal agents used?

Users should refer to the manufacturer’s directions or published data for the minimum contact time for the agent used. The minimum contact time may differ based on the intended purpose. For example, an agent may have a 1-minute contact time to be bactericidal and a 3-minute contact time to be sporicidal.

56. Does the chapter require a separate cleaning and disinfecting step in addition to applying a sporicidal agent?

The chapter requires cleaning and disinfecting of the compounding areas. These steps can be combined if an EPA-registered one-step disinfectant is used. One-step disinfectants have been formulated to be effective in the presence of light to moderate soiling without a separate cleaning step. Sporicidal agents must be used at least monthly. Some EPA-registered disinfectant cleaners may also have sporicidal properties. If the sporicidal agent is an EPA-registered (or equivalent) one-step disinfectant sporicidal cleaner, separate cleaning and disinfecting steps are not required.

57. Is a Biological Safety Cabinet the only PEC that has a removable work surface tray?

No. CAIs, CACIs, and some LAFWs have removable work trays.

Equipment, Supplies, and Components

58. 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.

Sterilization and Depyrogenation

59. What is the difference between aseptic processing and terminal sterilization?

Aseptic processing includes either 1) compounding with only sterile starting ingredient(s), or 2) compounding with nonsterile ingredient(s) followed by sterilization by filtration. Aseptic processing is not terminal sterilization.

Terminal sterilization includes compounding with sterile and/or nonsterile starting ingredient(s) and subsequent sterilization with a process intended to achieve a probability of a nonsterile unit (PNSU) of 10−6 (e.g., dry heat, steam, irradiation).

60. Can stoppered and crimped empty vials be sterilized using steam heat?

Sealed containers must be able to generate steam internally to be sterilized by steam heat. Stoppered and crimped empty vials must contain a small amount of sterile water to generate steam (see also <1229> Sterilization of Compendial Articles).

61. Why is a prefiltration step with a filter of a pore size of 1.2 µm required before sterilization procedures?

A prefiltration step with a filter of a pore size of 1.2 µm removes particulate matter in the solution before sterilization.

62. What is the PNSU for CSPs sterilized by filtration?

A PNSU value cannot be applied to CSPs that are sterilized by filtration because sterilization by filtration is not terminal sterilization.

63. Is a biological indicator required for each sterilization cycle using steam or dry heat?

Yes, the effectiveness of the steam and dry heat sterilization method must be verified and documented with each run or load using an appropriate biological indicator.

Release Inspections and Testing

64. What is required to be documented for the visual inspection of the CSP and the container-closure system?

All CSPs must be visually inspected to determine whether the physical appearance of the CSP is as expected. Visible quality characteristics (e.g., discoloration, visible particulates, cloudiness) may be documented. Results of visual inspection of the container-closure system (e.g. checking for leakage, cracks in the container, or improper seals) may be documented.

65. Why should CSPs administered epidurally have the same endotoxin limit as that of intrathecally administered CSPs?

CSPs delivered by implanted pumps may be administered over a long period of time and may be compounded from nonsterile components. Bacterial endotoxin testing helps ensure that CSP do not contain excessive bacterial endotoxins. Although <797> refers to General Chapter <85> Bacterial Endotoxins Test for calculating endotoxin limits for the appropriate route of administration, <85> does not address products administered epidurally or administered directly into the central nervous system. Compounders should be aware that endotoxin testing is also important for CSPs administered epidurally.

Establishing Beyond-Use Dates

66. What is the difference between the beyond-use date (BUD) and “hang time” (e.g., administration time)?

The BUD is the date or the hour and date after which the CSP must not be used. BUDs applies to CSPs and are not intended to limit the time during which a CSP is administered (e.g., infused). "Hang time" is often used to refer to the amount of time during which a CSP or conventionally manufactured product (e.g. pre-mix, large volume parenteral solution) may be infused before which either the tubing or the medication must be changed. General Chapter <797> does not address administration time (e.g., hang time).

67. How does the storage conditions affect the BUD of a CSP?

Generally, longer BUDs are permitted for CSPs stored in colder conditions than for CSPs stored at controlled room temperature as colder temperatures have been shown to slow the growth of most microorganisms.

68. Are BUDs cumulative?

No, BUDs must not be additive. The storage time of a CSP must not exceed the original BUD placed on the CSP for its labeled storage condition. For example, a CSP that is assigned a BUD based on storage at room temperature cannot subsequently be refrigerated or frozen in order to extend the original BUD assigned. Likewise, the BUD of a frozen CSP must not be extended based on storage at room temperature when it is thawed.

69. Can the BUD of Category 2 CSPs be extended beyond those in Table 11. BUDs for Category 2 CSPs?

The chapter states that BUDs for Category 2 CSPs must be established in accordance with Table 11. However, if there is a compounded preparation monograph for a particular CSP formulation, that BUD may be assigned if the CSP is prepared according to the monograph and all monograph requirements are met (e.g., Specific Tests). General Notices 3.10 states that where the requirements of a monograph differ from the requirements in an applicable general chapter, the monograph requirements apply and supersede the general chapter. In the absence of a compounded preparation monograph, the chapter does not allow for extension of BUDs beyond those in Table 11. BUDs must be assigned conservatively and must take into account factors such as validated stability-indicating assays and testing for sterility, endotoxins, container-closure integrity, and particulate matter.

70. Why is the BUD for aseptically prepared Category 2 CSPs using only sterile ingredients 4 days when stored at controlled room temperature?

The previous version of <797> specified a storage time of 48 hours and 30 hours at controlled room temperature for low- and medium-risk level CSPs, respectively. The longer BUD in the revised chapter is based on a risk based approach to balance the need for quality CSPs and to facilitate patient access. Further, the revised chapter contains additional requirements (e.g., facility and engineering controls and surface sampling) to help mitigate risks of inadvertent contamination.

Use of Conventionally Manufactured Products as Components

71. Is a conventionally manufactured single-dose container required to be stored in an ISO Class 5 PEC in order for it to be allowed to be used for up to 12 hours?

No, opened or punctured conventionally manufactured single-dose containers may be stored outside of an ISO Class 5 PEC. However, the chapter does require that the conventionally manufactured single-dose container be entered or punctured inside of an ISO Class 5 PEC. These containers may be used up to 12 hours after initial entry or puncture provided that the storage requirements (e.g., controlled room temperature, cold temperature) are maintained. Opened single-dose ampules must not be stored for any period of time.

72. Are conventionally manufactured sterile topical ophthalmic products considered multiple-dose containers?

No, <659> Packaging and Storage Requirements defines multiple-dose containers as a container–closure system that holds a sterile medication for parenteral administration (injection or infusion) that has met antimicrobial effectiveness testing requirements, or is excluded from such testing requirements by FDA regulation. Therefore, the requirement that multiple-dose containers not be used for more than 28 days unless otherwise specified on the labeling does not apply to conventionally manufactured sterile topical products.

73. If the approved labeling of a pharmacy bulk package describes a long storage time (e.g., 14 days), can the pharmacy bulk package be stored and used for that period of time?

Users should carefully review the manufacturer’s approved labeling for pharmacy bulk packages. Some approved labeling may provide a storage time based on stability (e.g., 14 days) as well as a shorter time (e.g., 4 hours) based on the risk of microbial contamination. Users must use the shorter storage time specified in the manufacturer’s approved labeling. The pharmacy bulk package must be used according to the manufacturer’s approved labeling.

Use of CSPs as Components

74. Do compounded pH solutions affect the BUD assigned to the final CSP?

The BUD of a CSP prepared from one or more compounded components may not exceed the shortest BUD of any of the individual starting components. If a nonsterile pH solution is compounded and used within 6 hours for a single CSP or a single batch, the pH solution would not be assigned a BUD, and therefore would not affect the BUD assigned to the final CSP. The nonsterile pH solution is considered to be part of the compounding process. However, if a pH solution is prepared and stored, it must be sterilized within 6 hours and must be treated as a compounded stock solution. Sterilized and stored pH solutions must be assigned a BUD and the BUD must be taken into account when assigning a BUD to the final CSP.

75. What is an example of assigning a BUD to compounded stock solutions and their subsequent CSPs?

A compounder wants to reconstitute a conventionally manufactured sterile product and further dilute it to prepare a subsequent CSP (see 16.2 Use of Compounded Single-Dose CSPs and CSP Stock Solutions).

  • Day 1: a 2 gram single-dose conventionally manufactured container of powder for solution is reconstituted with 8 mL of a conventionally manufactured diluent, yielding 10 mL of 200 mg/mL of drug (CSP-A, original CSP). CSP-A is assigned a BUD of 10 days because it is aseptically processed, has not passed sterility testing, was prepared from only sterile starting components, and will be stored in a refrigerator (see Table 11).
  • Day 3: CSP-A is entered or punctured in ISO Class 5 PEC, where 10 mL of CSP-A solution is further diluted with 40 mL of diluent, yielding 50 mL solution of 40 mg/mL of drug (CSP-B, a finished CSP). CSP-B is aseptically processed, has not passed sterility testing, was prepared from only sterile starting components, and will be stored in a refrigerator. The BUD of a CSP prepared from one or more compounded components may not exceed the shortest BUD of any of the individual starting components. Therefore, the assigned BUD for CSP-B will be 7 days (10 days minus the 3 lapsed days of CSP-A), because that is the shortest BUD of all of its individual components.
    • Additionally, CSP-A must be used within 12 hours of initial entry/puncture or its originally assigned BUD, whichever is shorter, and the remainder must be discarded.

Compounding Allergenic Extracts

76. What are allergenic extracts?

Allergenic extracts are biological substances used for the diagnosis and/or treatment of allergic diseases such as allergic rhinitis, allergic sinusitis, allergic conjunctivitis, bee venom allergy, and food allergy. Allergenic extract prescription sets are combinations of licensed allergenic extracts which would be mixed and diluted to provide subcutaneous immunotherapy to an individual patient, even though these allergenic extract combinations are not specified in the approved Biological License Application (BLA) for the licensed biological products.

77. Does 21. Compounding Allergenic Extracts apply to physician and pharmacy settings?

Yes, the provisions in 21. Compounding Allergenic Extracts apply regardless of where the allergenic extract is compounded when:

  1. The compounding process involves transfer via sterile needles and syringes of conventionally manufactured sterile allergen products and appropriate conventionally manufactured sterile added substances, and
  2. Manipulations are limited to penetrating stoppers on vials with sterile needles and syringes, and transferring sterile liquids in sterile syringes to sterile vials.
78. Why are the BUDs for compounded allergenic extracts longer than those required for Category 1 and Category 2 CSPs?

Because of certain characteristics of allergenic extracts and allergy practice (e.g., preservative systems and risk of anaphylaxis), preparation of allergenic extract prescription sets is not subject to the requirements in this chapter that are applicable to other sterile CSPs. Further, FDA provides additional guidance for preparation of allergenic extracts in the FDA Guidance for Mixing, Diluting, or Repackaging Biological Products Outside of the Scope of an Approved Biologics License Application.