Maryland Register        Issue Date: January 19, 2007        Volume 34 • Issue 2 • Pages 57—224

Subtitle 34  BOARD OF PHARMACY

10.34.19  [Parenteral/Sterile Enteral] Sterile Pharmaceutical Compounding

Authority: Health Occupations Article, §§12-205, 12-503, and 12-505,
Annotated Code of Maryland

Notice of Proposed Action

[07-028-P]

The Secretary of Health and Mental Hygiene proposes to repeal existing Regulations .01—.06 and adopt new Regulations .01—.16 under COMAR 10.34.19 Sterile Pharmaceutical Compounding. This action was considered by the Board of Pharmacy at a public meeting held September 20, 2006, notice of which was given by publication in 33:19 Md. R. 1584 (September 15, 2006) pursuant to State Government Article, §10-506(c), Annotated Code of Maryland.

Statement of Purpose

The purpose of this action is to adopt new sterile compounding regulations to be consistent with the U.S. Pharmacopeia (USP) General Chapter Pharmaceutical Compounding Sterile Preparations which is the national standard for pharmaceutical compounding.

Comparison to Federal Standards

There is no corresponding federal standard to this proposed action.

Estimate of Economic Impact

I. Summary of Economic Impact. All compounding pharmacies throughout the country must comply with the U.S. Pharmacopeia (USP) General Chapter Pharmaceutical Compounding—Sterile Preparations and U.S. Pharmacopeia (USP) General Chapter Pharmacy Compounding. These proposed regulations do not impose additional requirements. Cost for renovations to comply with Chapter 795 and Chapter 797 of USP would vary depending on the size of the compounding pharmacy. A small pharmacy might spend $10,000 to $15,000 dollars where a large hospital pharmacy may spend upwards to $100,000.

III. Assumptions. (Identified by Impact Letter and Number from Section II.)

A. There may be additional time spent by the designated inspector of pharmacies that compound.

D. and E. There may be renovation costs pursuant to compliance with USP 797 and these proposed regulations. The costs of the renovations will depend on the number of renovations that are necessary for compliance. Some pharmacies may already be compliant and therefore will need no renovations. Other pharmacies may need extensive renovations.

F. The effects on the public would be to ensure a safe compounding environment.

Economic Impact on Small Businesses

The proposed action has minimal or no economic impact on small businesses.

Impact on Individuals with Disabilities

The proposed action has no impact on individuals with disabilities.

Opportunity for Public Comment

Comments may be sent to Michele Phinney, Director, Office of Regulation and Policy Coordination, Department of Health and Mental Hygiene, 201 W. Preston Street, Room 512, Baltimore, MD 21201, or call (410) 767-6499, or fax to (410) 333-7687, or email to regs@dhmh.state.md.us. Comments will be accepted through February 20, 2007. A public hearing has not been scheduled.

.01 Scope.

This chapter applies to a licensed pharmacy in Maryland desiring to compound or mix prescription orders for sterile solutions or suspensions to be administered parenterally or by irrigation, inhalation, or intraocular routes.

.02 Incorporation by Reference.

In this chapter, the following documents are incorporated by reference:

A. U.S. Pharmacopeia (USP) General Chapter 797 Pharmaceutical Compounding— Sterile Preparations (USP 797 Standards), which has been incorporated by reference in 21 U.S.C. §351(b) (as amended).

B. U.S. Pharmacopeia (USP) General Chapter 795 Pharmacy Compounding (USP 795 Standards), which has been incorporated by reference in 21 U.S.C. §351(b) (as amended).

.03 Definitions.

A. In this chapter, the following terms have the meanings indicated.

B. Terms Defined.

(1) “Antineoplastic” means an agent that prevents the development, growth, or proliferation of malignant cells.

(2) “Anteroom” means the area, room, or rooms where personnel perform hand hygiene and garbing immediately adjacent to the designated clean room where the compounding of sterile preparations is performed.

(3) Batch.

(a) “Batch” means a preparation compounded in advance of receipt of a prescription, or a preparation compounded in a supply that will be used on more than one dispensing to a patient or patients or any preparation compounded in excess of the filling of an individual prescription.

(b) “Batch” includes a specific quantity of identical preparations compounded in a single, discrete process, by the same individuals, carried out during one limited time period.

(4) “Biological safety cabinet” means a containment unit:

(a)  Suitable for work involving agents that pose higher risk of exposure to operators during compounding; and

(b) Used when there is a need for protection of the preparation, personnel, and environment.

(5) “Clean room” means an International Standards Organization (ISO) Class 7 environment that meets current USP 797 Standards, inside which compounding occurs within an ISO Class 5 engineering control device such as a laminar airflow workstation or a biological safety cabinet.

(6) “Compounded sterile preparation” means sterile medication preparations, such as intravenous, epidural, and intraocular medications, compounded in the pharmacy using currently accepted aseptic compounding techniques under acceptable compounding conditions.

(7) “Compounding aseptic isolator” means an enclosed positive or negative pressure environment especially designed for sterile preparation compounding that maintains a physical barrier between the workspace and the operator.

(8) “Controlled environment” means a designated area for compounding sterile preparations that consists of a clean room and an anteroom.

(9) “Cytotoxic” means drug entities that are damaging or debilitating to cells, tissues, or organs.

(10) “Laminar air flow workstation” means an ISO Class 5 (“Class 100”) laminar airflow hood inside which low, medium, and high risk compounding occurs.

(11) “Media fill verification” means a process of practical examination to verify the aseptic technique of personnel or an aseptic process by manual manipulation of microbiological growth media which simulates compounding processes and techniques used in actual compounding procedures.

(12) “Parenteral” means routes of drug administration or fluid administration other than via the gastrointestinal tract.

(13) “Pharmacist” means an individual who is licensed to practice pharmacy regardless of the location where the activities of practice are performed.

(14) “Pharmacy” means an establishment in which prescription or nonprescription drugs or devices are compounded, dispensed, or distributed.

(15) “Pyrogen testing” means an analysis of sterile preparations for the presence of cell material from microbiological organisms in sufficient quantity to elicit a febrile reaction.

(16) “Sterile” means free from living microorganisms or any other contaminants.

(17) “Total parenteral nutrition” means providing partial or total caloric needs by the parenteral or enteral route for a patient who is unable to ingest sufficient calories.

(18) “USP 795 Standards” means standards set forth in the US Pharmacopeia (USP) General Chapter Pharmacy Compounding.

(19) “USP 797 Standards” means standards set forth in the U.S. Pharmacopeia (USP) General Chapter 797 Pharmaceutical Compounding—Sterile Preparations.

.04 Pharmacy Environment.

The compounding, preparation, and dispensing of compounded sterile preparations shall be accomplished in a pharmacy environment subject to State and federal laws, regulations, and standards.

.05 General Requirements.

A. A licensed pharmacist who has appropriate practical and didactic training in compounding sterile preparations, clean room technology, laminar flow technology, quality assurance techniques, and clinical application of intravenous drug therapy shall control and supervise the pharmacy.

B. The licensed supervising pharmacist shall be responsible for the section of the pharmacy that prepares compounded sterile preparations, for, at a minimum, the following:

(1) Preparation of compounded sterile preparations within the pharmacy or pharmacy satellite;

(2) Storage of materials pertinent to the preparation of compounded sterile preparations, including drugs, chemicals, and biologicals, and the establishment of specifications for procurement of the materials;

(3) Labeling of containers of compounded sterile preparations compounded within the pharmacy;

(4) Recording of transactions of the pharmacy as may be applicable to State and federal laws and regulations, as may be necessary to maintain accurate control over, and accountability for, pharmaceutical materials; and

(5) Ensuring that licensed pharmacists meeting the requirements of §A of this regulation, or registered pharmacy technicians under direct supervision of a licensed pharmacist meeting the requirements of §A of this regulation, prepare, compound, and dispense compounded sterile preparations.

.06 Special Handling, Packaging, Labeling, and Beyond Use Dating.

A. The pharmacy shall make available special handling and packaging materials to maintain container integrity and drug stability of the prepared prescription orders, including antineoplastic or other hazardous sterile preparations, during delivery to the patient including:

(1) A reasonable effort to provide tamper-evident packaging;

(2) Delivery from the pharmacy to the patient within a reasonable time; and

(3) Proper in-transit storage consistent with preparation labeling.

B. The dispensed container for any compounded sterile preparation shall include labeling according to Maryland law and regulations, in addition to the following information that is required by federal law:

(1) The date of preparation unless otherwise readily retrievable from prescription records;

(2) Time prepared, if applicable;

(3) The pertinent requirements for proper storage;

(4) The name of the prescriber, unless in an inpatient hospital setting;

(5) The name of the patient;

(6) Directions for use;

(7) The name of the base solution for infusion preparations;

(8) The name and concentration or amount of active drugs contained in the final sterile preparation;

(9) The name or identifying initials of the pharmacist who checked or prepared the compounded sterile preparation unless otherwise readily retrievable from prescription records;

(10) The name, address, and telephone number of the pharmacy unless in an inpatient hospital facility;

(11) The beyond-use/expiration dating and time of the compounded sterile preparation, and if no time is stated, the time is presumed to be at 11:59 p.m. of the stated beyond use date;

(12) Any ancillary and cautionary instructions as needed; and

(13) A pertinent warning consistent with applicable federal and State law that cytotoxic preparations are biohazardous, when applicable.

C. A pharmacy compounding sterile infusion preparations shall provide a 24-hour telephone number to allow its patients or other health care providers who may be administering its prescriptions to contact its pharmacists.

D. Expiration or Beyond-Use Dating. In the absence of direct testing evidence, as detailed in USP 795 Pharmacy Compounding, the pharmacist shall use “beyond-use dating” as determined by USP 797 Standards and reference materials as cited in Regulation .16 of this chapter.

.07 Record-Keeping Requirements.

A. Patient Prescription Records.

(1) The pharmacy shall maintain records of patient prescriptions.

(2) Patient prescription records shall contain:

(a) Available medical information consistent with prevailing pharmacy standards; and

(b) The complete record of the formulations of the solutions that were compounded.

(3) The pharmacy shall keep completed patient prescription records in a retrievable manner for at least 5 years.

B. Compounded Sterile Preparations Records.

(1) For a pharmacy preparing compounded sterile preparations, the following records shall be maintained for at least 5 years:

(a) The training and competency evaluation of employees in sterile preparation procedures;

(b) Refrigerator and freezer temperatures;

(c) Certification of the sterile compounding environment, including ISO 5 workstations and the clean and anterooms;

(d) Other facility quality control logs specific to the pharmacy's policies and procedures, for example, cleaning logs for facilities and equipment;

(e) Inspection for expired or recalled pharmaceutical preparations or raw ingredients;

(f) Preparation records including compounding work sheets, and records of the registered pharmacy technicians' checking/sign-off process; and

(g) Preparation records including compounding work sheets and records of the pharmacists' checking/sign-off process.

(2) In addition to the records requirement in §B(1) of this regulation, for batch compounded sterile preparations, a pharmacy compounding sterile batch preparations for future use shall have records indicating the:

(a) Drug and ingredient names;

(b) Lot numbers;

(c) Expiration dates;

(d) Drug/diluent amounts; and

(e) Date on which the compounded sterile batch preparations were prepared.

(3) A pharmacy shall maintain records of media fill verification results for 5 years.

.08 Batch Preparation.

A. A pharmacist may prepare batched sterile preparations for future use in quantities supported by prior valid prescriptions or physician orders before receiving a valid written prescription or medication order.

B. Batch preparation of specific compounded sterile preparations is acceptable if the:

(1) Pharmacist can document a history of valid prescriptions or physician orders that have been generated solely within an established professional prescriber-patient-pharmacist relationship; and

(2) Pharmacy maintains the prescription on file for such preparations dispensed.

.09 Minimum Requirements for Space.

A. Controlled Environment.

(1) The pharmacy shall have a controlled environment.

(2) A pharmacist shall ensure that the controlled environment is:

(a) Accessible only to designated personnel; and

(b) Used only for the preparation of compounded sterile preparations, or such other tasks that require a controlled environment.

(3) The permit holder shall ensure that the controlled environment is:

(a) Structurally isolated from other areas within the pharmacy by means of restricted entry or access; and

(b) Air conditioned to maintain a temperature of 59 to 74 degrees Fahrenheit.

B. Controlled Environment—Clean Room. The permit holder shall ensure that the clean room in the controlled environment:

(1) Meets current USP 797 Standards for design and USP 797 performance criteria quality standards for clean rooms;

(2) Contains no sinks or floor drains;

(3) Contains work surfaces constructed of smooth, impervious materials, such as stainless steel or molded plastic, so that the work surfaces may be readily cleaned and sanitized;

(4) If cytotoxic agents are routinely used in compounding preparations, contains room or rooms equipped with special pressurization requirements consistent with current federal USP 797 standards and the National Institute for Occupational Safety and Health (NIOSH) standards;

(5) Has in place appropriate environmental control devices capable of maintaining current USP 797 air-quality standards during normal compounding activity; and

(6) Contains the following equipment:

(a) A laminar airflow workstation or other suitable International Standards Organization (ISO) Class 5 HEPA filtration system;

(b) Waste containers that are approved by Occupational Safety and Health Administration (OSHA) for used needles and syringes, and for chemotherapy waste; and

(c) Ancillary supplies required for proper compounding.

C. Controlled Environment—Anteroom. The permit holder shall ensure that the anteroom in the controlled environment:

(1) Meets current USP 797 Standards for design and USP 797 performance criteria quality standards for anterooms; and

(2) Contains the following equipment:

(a) A sink with hot and cold running water;

(b) Waste containers for personal protective equipment;

(c) An eyewash station or sink design suitable for flushing an eye injury; and

(d) A hazardous waste spill kit, if applicable.

.10 Minimum Requirements for Equipment.

A. The permit holder shall provide at least the following equipment that is maintained in working order:

(1) Adequate refrigerator and freezer space;

(2) A sink and wash area in the anteroom;

(3) Appropriate waste containers for:

(a) Used needles and syringes; and

(b) Cytotoxic waste including disposable apparel used in its preparation, if applicable;

(4) Laminar air flow workstation or compounding aseptic isolator that meets USP 797 Standards, dedicated for products other than antineoplastics;

(5) If applicable to compounded sterile preparations compounded, biological safety cabinet, or compounding aseptic isolator that meets USP 797 Standards, dedicated for use with antineoplastics or other hazardous sterile preparations;

(6) Appropriate filters and filtration equipment; and

(7) A device for light/dark field examination.

B. If used, the permit holder shall provide the following equipment that is maintained in working order, calibrated, or certified where appropriate:

(1) Autoclave;

(2) Automated compounding devices (total parenteral nutrition compounding pumps);

(3) Electronic balance;

(4) Convection oven;

(5) Thermometers or other temperature device; and

(6) Incubator.

.11 Minimum Requirements for Supplies.

A pharmacy engaging in compounding sterile preparations shall maintain adequate stock levels of the following supplies, including but not limited to:

A. Nonshedding:

(1) Gloves;

(2) Masks;

(3) Gowns;

(4) Shoe covers;

(5) Hair covers;

(6) Beard covers; and

(7) Other personal protective equipment;

B. Disposable syringes and needles in necessary sizes;

C. Disinfectant cleaning agents;

D. Disposable lint free towels;

E. Hand washing materials, including antimicrobial skin cleanser;

F. Adequate equipment and materials for antineoplastic or cytotoxic agent spills; and

G. Supplies necessary for the aseptic preparation of compounded sterile preparations.

.12 Minimum Requirements for Policies and Procedures.

A. The permit holder shall ensure that the pharmacist or the pharmacist's designee shall maintain a policy and procedure manual, reviewed annually, that sets forth in detail the permit holder's standard operating procedures with regard to compounding sterile preparations.

B. The permit holder shall insure that the policy and procedure manual that sets forth the standard operating procedures with regard to compounding sterile preparations is implemented and adhered to.

C. The policy and procedure manual shall include policies and procedures governing the following:

(1) A risk-management program including, but not limited to:

(a) Incident report procedures;

(b) An adverse drug reaction reporting system; and

(c) A preparation contamination reporting system;

(2) Security measures ensuring that the premises where sterile compounded preparations are stored and prepared are secured, to prevent access by unauthorized personnel;

(3) Equipment including, but not limited to:

(a) Procedures for use;

(b) Documentation of appropriate certifications; and

(c) Documentation of appropriate calibration and preventive maintenance if applicable;

(4) Sanitation standards and procedures including monitoring for bacterial microorganisms to demonstrate effectiveness of cleaning activities;

(5) Reference materials as set forth in Regulation .15 of this chapter;

(6) Information concerning drug:

(a) Preparation;

(b) Storage and handling;

(c) Dispensing;

(d) Labeling;

(e) Beyond-use/expiration dating;

(f) Delivery;

(g) Destruction;

(h) Recalls; and

(i) Returns;

(7) Patient record keeping as set forth in Regulation .06 of this chapter;

(8) Handling, dispensing, and documentation of investigational drugs;

(9) A quality assurance program;

(10) Verification of training and competency guidelines;

(11) Compounding process media fill verification procedures;

(12) Description of appropriate garb;

(13) Conduct guidelines for personnel in the controlled areas;

(14) Personnel responsibilities;

(15) Patient education, if appropriate;

(16) Protocol and procedures to maintain the integrity of the interior work area of the laminar air flow workstations;

(17) Written procedures as applicable for handling antineoplastic agents and other hazardous substances including:

(a) Utilizing the proper equipment and supplies;

(b) A statement that compounding shall be conducted within a properly certified biological safety cabinet or negative pressure compounding aseptic isolator;

(c) Proper use of protective attire; and

(d) Proper techniques to prevent both contamination of the preparation and chemical exposure of the individual preparing the prescription;

(18) Written procedures as applicable for the disposal of infectious materials or materials containing cytotoxic residues, or hazardous waste;

(19) Written documentation of policy and procedure changes based on data gathered from quality assurance evaluations; and

(20) Written documentation of policies and procedures assuring the sterility and stability of compounded sterile preparations;

.13 Attire.

A. When compounding sterile preparations, individuals shall comply with the following standards:

(1) Sequencing of garbing that complies with federal standards;

(2) Thorough hand-washing before gowning;

(3) Wearing clean room garb inside the designated area at all times, which consists of:

(a) A low-shedding coverall;

(b) Head and facial hair covers;

(c) A face mask; and

(d) Shoe covers;

(4) Clean room garb shall be donned and removed outside the designated clean room area;

(5) Hand, finger, and wrist jewelry shall be eliminated, unless it cannot be removed, and then it shall be thoroughly cleaned and covered with a sterile glove;

(6) Gloves made of low-shedding materials are required; and

(7) Make-up may not be worn in the clean room.

B. The requirements of this regulation may not be applicable if a compounding aseptic isolator is used to compound sterile preparations in accordance with federal standards and isolator vendor/manufacturer specifications.

.14 Training of Staff, Patient, and Caregiver.

A. The pharmacist shall make counseling available to the patient or primary caregiver, or both, concerning proper use of compounded sterile preparations and related supplies furnished by the pharmacy.

B. The permit holder shall ensure that pharmacy personnel engaging in compounding sterile preparations are trained and demonstrate competence in the safe handling and compounding of compounded sterile preparations and parenteral solutions, including cytotoxic agents if applicable.

C. The permit holder shall maintain records of training and demonstrated competence for individual employees for 5 years.

D. The permit holder shall ensure the continuing competence of pharmacy personnel engaged in compounding sterile preparations.

E. A pharmacy that compounds sterile preparations shall comply with the following training requirements:

(1) The pharmacy shall establish and follow a written program of training and performance evaluation designed to ensure that individuals working in the designated area have the knowledge and skills necessary to perform the assigned tasks properly and include at least the following:

(a) Aseptic technique with media fill verification procedure:

(i) 12 months for low and medium risk; and

(ii) 6 months for high risk;

(b) Pharmaceutical calculations and terminology;

(c) Compounding sterile preparation documentation process;

(d) Quality assurance procedures;

(e) Aseptic preparation procedures;

(f) Proper cleansing gowning and gloving technique;

(g) General conduct in the controlled area;

(h) Cleaning, sanitizing, and maintaining equipment used in the controlled area;

(i) Sterilization techniques for high risk preparations; and

(j) Container, equipment, and closure system selection.

(2) Individuals assigned to the controlled area shall successfully complete practical skills training in aseptic technique and aseptic area practices.

(3) Evaluations shall include:

(a) Written testing;

(b) Observation for adherence to aseptic technique and aseptic area policies and procedures; and

(c) Media fill verification as set forth in §E(1)(a) of this regulation.

.15 Quality Assurance.

The permit holder shall ensure that the compounded sterile preparation retains its potency and sterility throughout the assigned “beyond use” dating period through a written quality assurance program that includes:

A. A reasonable effort by the pharmacist to assure that compounded sterile preparations shall be kept under appropriate controlled conditions before dispensing, during transport, and at the location of use by providing adequate labeling and verbal or written instructions regarding proper storage and administration, as set forth by the product manufacturer and established standards and literature, with each compounded sterile preparation dispensed;

B. The phases of compounded sterile preparation, distribution, storage, administration, and directions for use for each type of preparation dispensed;

C. Environmental sampling for microbial organisms in laminar air flow workstations and clean rooms is performed according to methods and schedules specified by USP 797 Standards any time microbial contamination is suspected, for example, positive media fill verification results;

D. Laminar air flow workstations, biological safety cabinets, and compounding aseptic isolators certified by an independent certification company;

E. Clean room and anteroom certified by an independent certification company that meets the standards of the USP 797 Standards;

F. The proper disposal in accordance with accepted professional standards and applicable State and federal laws of unused drugs and materials used in the preparation of compounded sterile preparations, including antineoplastic agents and hazardous materials;

G. A formal written review process to report and evaluate compliance with this chapter; and

H. A process that complies with applicable USP 797 Standards for performing sterility checks or pyrogen testing, or both, for applicable compounded sterile preparations.

.16 Reference Library.

Minimum reference materials in a pharmacy shall include:

A. Current U.S. Pharmaceutical, General Chapter 797, Pharmaceutical Compounding— Sterile Preparations and other applicable reference materials in order to perform sterile compounding;

B. Reference materials containing drug stability and compatibility data; and

C. Reference materials concerning drug interactions and incompatibility.

S. ANTHONY McCANN
Secretary of Health and Mental Hygiene