Current through Reg. 50, No. 187; September 24, 2024
The 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).
(1) Adoption 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):
(a) Chapter 797, Pharmaceutical
Compounding-Sterile Preparations;
(b) Chapter 71, Sterility Tests;
(c) Chapter 85, Bacterial Endotoxins
Test;
(d) Chapter 731, Loss on
Drying.
All 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 www.uspnf.com. The 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.
(2)
Minimum Standards: Notwithstanding subsection (1) above, beginning on November
16, 2023 all sterile compounding shall be performed in full compliance with the
minimum practice and quality standards of state and federal law. Section
465.016(1)(e),
F.S., mandates that those licensed pursuant to Chapter 465, F.S., must comply
with ss. 21 U.S.C.
301-392, known as the Federal Food,
Drug, and Cosmetic Act (FD&C Act). Section 503A of the FD&C Act,
codified at 21 U.S.C.
353a, requires compliance with minimum
practice and quality standards for compounding sterile drug products pursuant
to a valid prescription for an identified patient When compounding pursuant to
this provision of the Act, the Act requires that sterile compounding must be
done in compliance with all Chapters related to compounding found in the
current United States Pharmacopeia. The Board, until November 2025, shall not
take disciplinary action for failing to compound pursuant to the minimum
practice and quality standards of this subsection as long as the compounding
was done in compliance with the minimum practice and quality standards
subsection (1).
(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 21 U.S.C.
353(b).
(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 mandated by Section
465.016(1)(e),
F.S. and Section 503B of the FD&C Act, codified at
21 U.S.C.
353(b).
(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) or (2). 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:
(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.
(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.
(c) The pharmacy shall, initially and after
any change to the cleaning process or agents, validate a high-level
disinfection process for the lyophilizer. For 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. The 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.
(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.
(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.
(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.
(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.
(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.
(i) Personnel preparing sterile compounds for
lyophilization shall wear sterile Personal Protective Equipment (PPE) that
allows all exposed skin to be covered.
(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.
(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.
(l) Laboratory testing.
1. 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.)
2. 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 standards shall, in lieu of sterility testing, conduct
viable air, surface, and personnel (gloves and sleeves) sampling for each
batch.
3. Endotoxin limits shall be
established for every lyophilized product.
4. 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.
5. 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.
6.
Initial potency testing shall be established based on worst case
scenario.
(6)
Clarifications, Variances, or Exceptions to the United States Pharmacopeia: The
provisions of this subsection shall only apply when the compounding is being
performed pursuant to the minimum practice and quality standards of subsection
(1).
(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.
(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.
(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.
(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:
1. 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.
2. 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.
3. 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.
Rulemaking Authority 465.005, 465.0155, 465.022 FS. Law
Implemented 465.0155, 465.022 FS.
New 6-18-08, Amended 1-7-10, 10-1-14, 12-18-16, 8-19-19,
11-16-23.
