64B16-27.797. The Standards of Practice for Compounding Sterile Products  

Effective on Monday, August 19, 2019
  • 1The purpose of this section is to assure positive patient outcomes through the provision of standards for 1) pharmaceutical care; 2) the preparation, labeling, and distribution of sterile pharmaceuticals by pharmacies, pursuant to or in anticipation of a prescription drug order; and 3) product quality and characteristics. These standards are intended to apply to all sterile pharmaceuticals, notwithstanding the location of the patient (e.g., home, hospital, nursing home, hospice, doctor’s office, or ambulatory infusion center).

    76(1) 77Adoption of the United States Pharmacopeia: Beginning on October 1, 2014, all sterile compounding shall be performed in accordance with the minimum practice and quality standards of the following chapters of the United States Pharmacopeia (USP):

    113(a) Chapter 797, Pharmaceutical Compounding-Sterile Preparations;

    119(b) 120Chapter 71, Sterility Tests;

    124(c) 125Chapter 85, Bacterial Endotoxins Test;

    130(d) 131Chapter 731, Loss on Drying.

    136All referenced chapters of the USP, in subsection (1), are specifically referring to the United States Pharmacopeia, 36th revision, Second Supplement, which is hereby incorporated and adopted by reference with the effective chapter dates of December 1, 2013. A subscription to all relevant chapters is available for purchase at 185www.uspnf.com186. 187The Board has determined that posting the incorporated material on the Internet would constitute a violation of federal copyright law. At the time of adoption, the copyrighted incorporated material will be available for public inspection and examination, but may not be copied, at the Department of Health, 4052 Bald Cypress Way, Tallahassee, Florida 32399-3254, and at the Department of State, Administrative Code and Register Section, Room 701, The Capitol, Tallahassee, Florida 32399-0250.

    259(2) 260Minimum Standards: The minimum practice and quality standards of the USP are adopted as the minimum standards to be followed when sterile products are compounded. However, nothing in this rule shall be construed to prevent the compounding of sterile products in accordance with standards that exceed the USP.

    308(3) Current Good Manufacturing Practices: The Board deems that this rule is complied with for any sterile products that are compounded in strict accordance with Current Good Manufacturing Practices per 33821 U.S.C. §351 341(2012), adopted and incorporated herein by reference, available at 350https://www.flrules.org/Gateway/reference.asp?No=Ref-04436 352and 35321 C.F.R. Parts 210 357and 211 (2013), adopted and incorporated herein by reference, available at 368http://www.flrules.org/Gateway/reference.asp?No=Ref-04437370.

    371(4) Registered Outsourcing facilities: For any pharmacy registered as an outsourcing facility, the minimum standards of practice for sterile compounding shall be the current good manufacturing practices as adopted in subsection (3).

    403(5) The board finds that the production of sterile compounded products prepared with a process that includes the lyophilization of the sterile product may not be adequately regulated under the provisions of subsection (1). Sterile compounded products prepared using a process that includes lyophilization shall, in addition to all applicable provisions of USP Chapter 797, be subject to the following additional requirements:

    465(a) Compounded sterile products prepared for lyophilization shall be maintained in ISO 5 unidirectional laminar flow air throughout sterilization, filling, and transport from the Primary Engineering Control (“PEC”) into the lyophilizer. Smoke studies shall be conducted to demonstrate that transport from the PEC to the lyophilizer can be accomplished while maintaining ISO 5 laminar flow air at all times. The smoke study shall be recorded and available for inspection.

    534(b) The pharmacy shall establish, maintain, and follow policies and procedures for the high-level disinfection of the chamber, piping, and all other areas of the lyophilizer which pose a potential risk of contamination to the product.

    570(c) The pharmacy shall, initially and after any change to the cleaning process or agents, validate a high-level disinfection process for the lyophilizer.  593For the purposes of this rule, validation means that the high-level disinfection process shall be proven with validation studies performed with the 5 aerobic bacterial and fungal ATCC organisms referenced in USP Chapter 71. 627The validation studies must be performed by an external vendor or by an internal laboratory. A pharmacy with an internal laboratory shall be separated from the compounding area and the work area to prevent contamination in the pharmacy. Documentation of validation shall be readily available for inspection.

    674(d) A policy and procedure for cleaning the lyophilizer prior to high level disinfection to include cleaning agents and schedules shall be established. Documentation of cleaning shall be maintained and readily available for inspection.

    708(e) The pharmacy shall establish policies and procedures as well as a schedule for the maintenance of the lyophilizer, which shall be, at a minimum, based on the manufacturer’s recommendations. As leakage into the vacuum chamber poses a risk of contamination to the product, the maintenance schedule shall include provisions for periodically testing for leaks along with all recommended procedures described by the equipment manufacturer.  Documentation of routine maintenance shall be available for inspection.

    782(f) The pharmacy shall develop standard operating procedures (SOPs) and a quality assurance program to include validation of the filling process, container closure integrity, the frequent monitoring of fill volumes, training and assessment of personnel involved in all aspects of compounding sterile products for lyophilization, identification of overfills and underfills, equipment qualification, formula verification, and evaluation of the finished product for conformance to specifications.

    846(g) The pharmacy shall establish provisions for sterilizing the inert gas or air used for backfilling during the vacuum release phase. Filters shall be used to sterilize the gas or air and shall undergo manufacturer’s recommended integrity testing.

    884(h) Media fills shall be conducted using maximum batch sizes. The media fills shall demonstrate the filling, transportation to the lyophilizer, loading, and stoppering operations. Media shall not be frozen as part of the media fill as freezing of the media could reduce the ability of the media to support growth.

    935(i) Personnel preparing sterile compounds for lyophilization shall wear sterile Personal Protective Equipment (PPE) that allows all exposed skin to be covered.

    957(j) Personnel shall perform Glove Fingertip Sampling with each batch after the fill and transport of the vials. This sampling shall be documented and incorporated into the batch record.

    986(k) In-process acceptance criteria for each lyophilized product shall be established and may include criteria such as color, moisture limits and visual appearance. A one hundred percent (100%) visual examination of the finished product shall be conducted to determine that the product conforms to the established visual criteria. This examination shall be documented and incorporated in the batch record.

    1045(l) Laboratory testing.

    10481. Finished product testing shall be conducted on all batches. Procedures for selecting samples from the batch for testing shall be written and followed.  Procedures may include location of vials in the lyophilizer (e.g. select from each corner and the middle of each shelf) and position in the fill line (e.g. beginning, middle, and end of fill.)

    11052. Finished product testing for all batches shall include sterility testing with methods described in USP Chapter 71 unless an alternative method has been validated and shown to be equivalent or better. Diluents for reconstituting the vials for testing shall be preservative free. Lyophilized products released with beyond use dates within USP Chapter 797 guidelines shall, in lieu of sterility testing, conduct viable air, surface, and personnel (gloves and sleeves) sampling for each batch.

    11793. Endotoxin limits shall be established for every lyophilized product.

    11894. Endotoxin testing for all lyophilized batches shall be performed in accordance with USP Chapter 85 and confirmed to fall within the set limits.  This shall be documented on the batch record.

    12215. Potency, radiochemical purity or applicable test to assure label claim shall be conducted on every batch and documented in the batch record. In lieu of potency testing, weight-based verification may occur based on formula verification. Weight based verification will be based on ninety to one hundred ten percent (90% – 110%) theoretical yield. Potency testing shall be based on USP monograph if one is available; if not, it shall be based on ninety to one hundred ten percent (90% – 110%) theoretical yield.

    13056. Initial potency testing shall be established based on worst case scenario.

    1317(6) Clarifications, Variances, or Exceptions to the United States Pharmacopeia:

    1327(a) Although the USP requires the donning of gloves prior to entry into the clean-room, all required donning of gloves can be performed after entry into the clean-room to avoid contamination of the gloves from the door handle or access device leading into the clean-room.

    1372(b) USP Chapter 797 requires that: “When closed-system vial-transfer devices (CSTDs) (i.e., vial-transfer systems that allow no venting or exposure of hazardous substance to the environment) are used, they shall be used within an ISO Class 5 (see Table 1) environment of a BSC or CACI. The use of the CSTD is preferred because of their inherent closed system process. In facilities that prepare a low volume of hazardous drugs, the use of two tiers of containment (e.g., CSTD within a BSC or CACI that is located in a non-negative pressure room) is acceptable.” For purpose of said provision, a “low volume of hazardous drugs” is defined as less than 40 doses per month.

    1486(c) USP Chapter 797 provides as follows in the “Facility Design and Environmental Controls” section: “An ISO Class 7 (see Table 1) buffer area and ante-area supplied with HEPA-filtered air shall receive an ACPH of not less than 30. The PEC is a good augmentation to generating air changes in the air supply of an area but cannot be the sole source of HEPA-filtered air. If the area has an ISO Class 5 (see Table 1) recirculating devise, a minimum of 15 ACPHs through the area supply HEPA filters is adequate, providing the combined ACPH is not less than 30. More air changes may be required, depending on the number of personnel and processes. HEPA-filtered supply air shall be introduced at the ceiling, and returns should be mounted low on the wall, creating a general top-down dilution of area air with HEPA-filtered make-up air. Ceiling-mounted returns are not recommended.” Notwithstanding the quoted provision, pharmacies that meet the standards set forth in the section quotes as of the effective date of this rule are not required to change the location of supply air or return filters or ducts so long as the ISO standards are maintained.

    1681(d) USP Chapter 797 provides in part that the compounding facility’s ceiling tiles located in the ante-area, buffer area, and clean room that consist of inlaid panels “shall be impregnated with a polymer to render them impervious and hydrophobic, and they shall be caulked around each perimeter to seal them to the support frame.” A pharmacy shall not be required to caulk the inlaid ceiling tiles to the perimeter of the support frame if the following are met:

    17591. The ceiling tiles are specifically manufactured to be utilized in a facility that must meet and maintain an airborne particulate cleanliness of ISO Class 7 or better.

    17872. The core of the ceiling tiles are sealed on the front, back, and all edges to render them impervious and hydrophobic, so they can be properly maintained and cleaned as required by this rule.

    18223. The ceiling tiles are inlaid or installed using a gasket grid sealing system, which is manufactured for use in facilities that must meet and maintain an airborne particulate cleanliness of ISO Class 7 or better. The sealing system must create and maintain a positive seal between the ceiling tiles and the support frame and the seal between the ceiling tiles and support frame shall be secured with retention clips.

    1892Rulemaking Authority 1894465.005, 1895465.0155, 1896465.022 FS. 1898Law Implemented 1900465.0155, 1901465.022 FS. 1903History–New 6-18-08, Amended 1-7-10, 10-1-14, 12-18-16, 8-19-19.