The Board proposes the rule amendment to provide the standards of practice for compounded products prepared utilizing a process that includes lyophilization.

 

DEPARTMENT OF HEALTH

Board of Pharmacy

RULE NO.:RULE TITLE:

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

PURPOSE AND EFFECT: The Board proposes the rule amendment to provide the standards of practice for compounded products prepared utilizing a process that includes lyophilization.

SUMMARY: The standards of practice for compounded products prepared utilizing a process that includes lyophilization will be provided.

SUMMARY OF STATEMENT OF ESTIMATED REGULATORY COSTS AND LEGISLATIVE RATIFICATION:

The Agency has determined that this will not have an adverse impact on small business or likely increase directly or indirectly regulatory costs in excess of $200,000 in the aggregate within one year after the implementation of the rule. A SERC has not been prepared by the Agency.

The Agency has determined that the proposed rule is not expected to require legislative ratification based on the statement of estimated regulatory costs or if no SERC is required, the information expressly relied upon and described herein: During discussion of the economic impact of this rule at its Board meeting, the Board, based upon the expertise and experience of its members, determined that a Statement of Estimated Regulatory Costs (SERC) was not necessary and that the rule will not require ratification by the Legislature. No person or interested party submitted additional information regarding the economic impact at that time.

Any person who wishes to provide information regarding a statement of estimated regulatory costs, or provide a proposal for a lower cost regulatory alternative must do so in writing within 21 days of this notice.

RULEMAKING AUTHORITY: 465.005, 465.0155, 465.022 FS.

LAW IMPLEMENTED: 465.0155, 465.022 FS.

IF REQUESTED WITHIN 21 DAYS OF THE DATE OF THIS NOTICE, A HEARING WILL BE SCHEDULED AND ANNOUNCED IN THE FAR.

THE PERSON TO BE CONTACTED REGARDING THE PROPOSED RULE IS: Jennifer Wenhold, Executive Director, Board of Pharmacy, 4052 Bald Cypress Way, Bin C04, Tallahassee, Florida 32399-3254.

 

THE FULL TEXT OF THE PROPOSED RULE IS:

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

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) through (4) No change.

(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 <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 <71>.  The validation studies must be performed by an external vendor or by an internal laboratory following proper protocols.  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 <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 <797> guidelines 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 <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)(5) No change.

Rulemaking Authority 465.005, 465.0155, 465.022 FS. Law Implemented 465.0155, 465.022 FS. History–New 6-18-08, Amended 1-7-10, 10-1-14, 12-18-16,             .

 

NAME OF PERSON ORIGINATING PROPOSED RULE: Board of Pharmacy

NAME OF AGENCY HEAD WHO APPROVED THE PROPOSED RULE: Board of Pharmacy

DATE PROPOSED RULE APPROVED BY AGENCY HEAD: April 2, 2019

DATE NOTICE OF PROPOSED RULE DEVELOPMENT PUBLISHED IN FAR: August 24, 2018