N.H. Admin. Code § Ph 404.03

Current through Register No. 45, November 7, 2024

Section Ph 404.03 - Non-Sterile Pharmaceutical Compounding

(a) Compliance with USP 795 and all applicable USP chapters related to non-sterile compounding shall be followed.

(b) There are 3 general categories of non-sterile compounding described in this section that require different levels of experience, training and physical facilities. The 3 categories shall be:

(1) Simple compounding which includes reconstituting or manipulating a commercial product that might require the addition of one or more ingredients as directed by the manufacturer or preparing a product that has a USP compounding monograph or appears in a peer reviewed article that contains the quantities for all components, procedures and equipment with the exception of pre-measured compounding kits;

(2) Moderate compounding which includes making a preparation that requires complex calculation or procedures to determine quantities of components per preparation or per individualized dosage units, making a preparation for which stability data for that specific formulation is not available and mixing 2 or more manufactured creams when the stability of the mixture is unknown; and

(3) Complex compounding which includes making a preparation that requires specialized training, environment, facilities, equipment, and procedures such as transdermal dosage forms and modified-release preparations.

(c) Responsibilities of the compounder shall include:

(1) Compounding preparations of accepted strength, quality, and purity and in accordance with the prescription or medication order;

(2) Dispensing the finished preparation, with appropriate packaging and labeling, and in compliance with RSA 318:47-a, federal law, and other regulatory agencies where appropriate;

(3) Maintaining proficiency in drug or dietary supplement compounding;

(4) Ensuring the quality of compounded preparation by adhering to the general principles listed in USP 795 and all applicable compounding laws, guidelines and standards including but not limited to:

a. Training of all the personnel shall be current and documentation of such kept on site;

b. Compounding ingredients shall be purchased from reliable sources and be properly stored;

c. Bulk component containers shall be properly labeled and SDS sheets available;

d. Equipment used shall be clean, properly used and maintained;

e. Environment shall be suitable to prevent cross contamination including the use of powder containment systems if API's are used or powder is created through manipulation of solid dosage forms or emptying of powder containing vials;

f. Compounding personnel shall wear appropriate and clean clothing. Protective apparel such as lab coats gowns, gloves, shoes, or masks shall be worn as necessary to protect personnel from chemical exposure and/or contamination;

g. Only authorized personnel shall be allowed in the compounding area;

h. Compounding conditions and procedures shall be such to prevent errors;

i. There shall be assurance that processes are always carried out as intended or specified and are reproducible;

j. All aspects of compounding shall be properly documented;

k. Procedures and records exist for investigating and correcting failures or problems in compounding and testing; and

l. A valid and reproducible recall policy and procedure.

(5) The compounder shall be responsible for ensuring that each individual incidence of the compounding process meets the criteria in USP 795.

(d) The compounding area shall adhere to the general principles listed in USP 795 guidelines including but not limited to:

(1) Adequate space specifically designated for compounding and storage of equipment and materials;

(2) Be clean, orderly, and properly maintained;

(3) Easily accessible hand washing, hot and cold water, soap or detergent, and an air-drier or single-use towels must be present;

(4) Be located in a separate area from sterile compounding area;

(5) Purified water shall be used for compounding non-sterile drug preparations when formulations indicate the inclusion of water;

(6) Disposal of all hazardous drug wastes shall comply with applicable federal and state regulations; and

(7) All personnel who perform routine custodial waste removal and cleaning activities in storage and preparation areas for hazardous drugs shall be trained in appropriate procedures to protect themselves and prevent contamination including spill clean ups.

(e) All equipment and utensils used in compounding shall comply with the following:

(1) Be of appropriate design and capacity for the required task;

(2) Automatic, mechanical, electronic, or other equipment used in compounding shall be routinely inspected, calibrated, or checked according to the manufacturer's recommendations to ensure proper performance; and

(3) Equipment shall be stored to protect it from contamination. It shall be located in an area to facilitate its use, cleaning and maintenance.

(f) Component Selection, Handling and Storage shall be subject to the following requirements:

(1) A United States Pharmacopeia (USP), National Formulary (NF), or Food Chemicals Codex (FCC) substance shall be the recommended source of ingredients for compounding all preparations.

(2) If ingredients are from a non-FDA registered facility the professional judgment of the compounder shall be used in selecting an acceptable and reliable source and shall establish purity and safety including obtaining a certificate of analysis from the manufacturer or qualified third party;

(3) Components for compounding shall be properly labeled with lot numbers and expiration dates. If a component is transferred from the original container to a new container, the new container shall be labeled with the component name, original supplier, lot or control number, transfer date, and expiration date and shall provide integrity that it is equal to or better than the original container;

(4) For components that do not have expiration dates assigned by the manufacturer or supplier the compounder shall label the container with the date of receipt and assign a conservative expiration date not to exceed 3 years after receipt;

(5) Written control procedures shall be established to monitor the output and to validate the performance of those compounding processes that might be responsible for causing variability in the final drug product, including but not limited to, the following:

a. Capsule weight variation;

b. Adequacy of mixing to insure uniformity and homogeneity;

c. Clarity, completeness, or pH of solutions; and

d. Observation of instability;

(6) When compounding with manufactured drug products, the compounder shall consider all ingredients, including excipients, present in the drug product relative to the intended use of the compounded preparation and the effect of manipulating the drug product on the therapeutic appropriateness and stability of the components;

(7) All components used in compounding shall be stored as directed by the manufacturer, or according to USP or NF requirements, in a clean, dry area under appropriate temperature conditions. All components shall be stored off the floor, handled and stored to prevent contamination, and rotated so that the oldest stock is used first. All containers shall be properly labeled; and

(8) Use of pre-measured compounding kits shall adhere to all USP 795 standards, including the level of non-sterile compounding and utilizing a master formulation record and a compounding record.

(g) The following provisions of USP 795 shall be followed when determining stability and beyond use dating:

(1) Compounders shall consult and apply drug-specific and general stability information and literature when available;

(2) Compounders shall consider the following when determining BUDs:

a. Nature of the drug and degradation mechanism;

b. Dosage form and its components;

c. Potential for microbial proliferation in the preparation;

d. Container when it is packaged;

e. Intended duration of therapy; and

f. Expected storage conditions;

(3) When using manufactured solid dosage forms to prepare a solution or aqueous suspension, the compounder shall also consider factors such as hydrolysis, oxidation, and the freeze - thaw property of the final preparation;

(4) When a manufactured product is used as the source of the active pharmaceutical ingredient for a non-sterile compounded preparation, the product expiration date shall not be used to assign a BUD for the compounded preparation. Instead the compounder shall refer to the manufacturer for stability information and to the literature for applicable information on stability, compatibility, and degradation of ingredients. All data shall be carefully interpreted in relation to the actual compounded formulation;

(5) Susceptible preparations should contain suitable antimicrobial agents to protect against bacteria, yeast, and mold contamination inadvertently introduced during or after the compounding process. When antimicrobials are contraindicated, storage of the preparation at controlled cold temperature shall be necessary to retard microbial growth. Appropriate patient or caregiver instruction regarding storage and handling shall be essential;

(6) In the absence of reliable stability information or published date the following general guidelines for maximum BUD shall be:

a. A maximum of 6 months for non-aqueous formulations;

b. A maximum of 14 days under refrigeration for water-containing oral formulations; and

c. A maximum of 30 days for water containing topical, dermal and mucosal liquid and semisolid formulations.

(7) The BUD shall not exceed the expiration date of the API or any other component.

(h) The compounder shall ensure that the containers and closures used in packaging compounded preparations meet the following USP requirements:

(1) The containers and closures shall be made of clean material in order not to alter the quality, strength, or purity of the compounded preparation;

(2) Container-drug interaction shall be considered for substances that have sorptive or leaching properties; and

(3) Containers and closures shall be handled and stored in such a way as to prevent contamination.

(i) Compounders shall comply with the following requirements regarding compound documentation;

(1) Documentation, written or electronic, shall be kept for 4 years;

(2) Documentation shall comply with state and federal laws;

(3) Documentation shall not be required when preparing a compounded preparation according to the manufacturer's labeled instructions;

(4) The record may be a copy of the prescription in written or machine-readable form and shall include a master formula record and a compound record;

(5) Information contained in the master formulation record shall include the following:

a. Official or assigned name, strength, and dosage form of the preparation;

b. Calculations needed to determine and verify quantities of components and doses of active pharmaceutical ingredients;

c. Description of all ingredients and their quantities;

d. Compatibility and stability information, including references when available;

e. Equipment needed;

f. Mixing instructions;

g. Order of mixing;

h. Mixing temperature or other controls;

i. Duration of mixing;

j. Any other pertinent instruction;

k. Labeling information in addition to legally required information found in RSA 318:47-a including:

1. Name and quantity or concentration of each active ingredient;

2. Assigned BUD;

3. Storage conditions; and

4. Prescription number;

l. Container used in dispensing;

m. Packaging and storage requirements;

n. Description of final preparation; and

o. Quality control procedures and expected results; and

(6) The compound record shall contain at least the following:

a. Official or assigned name, strength, and dosage of the preparation;

b. Master formulation record reference for the preparation;

c. Names and quantities of all components;

d. Sources, lot numbers, and expiration dates of components;

e. Total quantity compounded;

f. Name of the person who prepared the compound, who performed the quality control procedures, and approved the preparation;

g. Date of the preparation;

h. Assigned controlled or prescription number;

i. Assigned BUD;

j. Description of final preparation;

k. Results of quality control procedures such as weight range of filled capsules, pH record; and

l. Documentation of any QC issues and any ADRs reported by patient or caregiver;

(j) All significant procedures performed in the compounding area shall be covered by written standard operating procedures (SOPs) including:

(1) Facility maintenance, workflow, and cleaning;

(2) Equipment use and maintenance;

(3) Personnel;

(4) Training;

(5) Preparation;

(6) Packaging;

(7) Storage of compounded preparations;

(8) Quality assurance;

(9) Safety;

(10) Uniformity;

(11) Continuous quality improvement; and

(12) Maintain updated SDS library.

(k) The compounder shall perform the following to ensure quality control;

(1) Review calculation, ingredients, measurements and procedures; and

(2) Observe the finished preparation to ensure that it appears as expected and investigate any discrepancies and take appropriate corrective action before the prescription is dispensed to the patient.

(l) The compounder shall ensure the following compounding controls are followed:

(1) There are written procedures for the compounding of drug preparations to ensure that the finished preparations have the identity, strength, quality, and purity that they purport to have. These procedures shall be available in either written form or electronically stored;

(2) The written procedures shall be followed in execution of the compounding process;

(3) Check and document each weight and measurement;

(4) Document the identity of the person(s) actually performing the compounding;

(5) Document the name of compounder;

(6) Establish written procedures that will describe quality assurance tests or examinations to be conducted on the compounded preparation to ensure uniformity and integrity;

(7) To monitor the output and to validate the performance of those compounding processes and equipment that could be responsible for causing variability in the final compounded preparation; and

(8) Records shall be maintained with compounding records for 10 years.

(m) At the time of dispensing, the patient or the patient's agent shall be counseled about proper use, storage, handling, and disposal of the compounded preparation. The patient or the patient's agent shall also be instructed to observe and report to the compounder any changes in the physical characteristics of the compounded preparation. Counseling may be in written, oral, electronic, or other formats. The compounding pharmacist shall investigate any reported problem with a compounded preparation and take corrective action.

(n) It shall be the responsibility of the compounder to ensure that a training program has been implemented and that it is ongoing. Compounding personnel shall be trained initially and the training shall be documented.

(o) Steps in the training procedure shall include the following:

(1) All employees involved in pharmaceutical compounding shall read and become familiar with USP Chapter 795. They shall also be familiar with other relevant publications including how to read and interpret SDSs;

(2) All employees shall read and become familiar with each of the procedures related to compounding including those involving the facility, equipment, personnel, actual compounding, evaluation, packaging, storage and dispensing;

(3) All personnel who compound hazardous drugs shall be fully trained in the storage, handling and disposal of these drugs. This training shall occur before preparing or handling hazardous drugs;

(4) All training activities shall be documented. The compounder shall meet with employees to review their work and answer any questions the employee may have concerning compounding procedures;

(5) The compounder shall demonstrate the procedures for the employee and shall observe and guide the employee throughout the training process. The employee shall then repeat the procedure without any assistance from, but under the supervision of the compounder;

(6) When the employee has demonstrated to the compounder a verbal and functional knowledge of the procedure, then and only then shall the employee be permitted to perform the procedure without direct supervision. However the compounder shall be physically present and shall approve all ingredients and their quantities and the final preparation;

(7) When the compounder is satisfied with the employee's knowledge and proficiency, the compounder shall sign the documentation records to show that the employee was appropriately trained;

(8) The compounder shall continually monitor the work of the employee and ensure that the employee's calculations and work are accurate and adequately performed; and

(9) The compounder shall be solely responsible for the finished preparation.

(p) The following requirements shall be met when compounding for animal patients:

(1) Intended use on any animal patient, such as companion, performance or food, shall be determined before compounding for that patient. Because humans can consume animals as food, care shall be taken to prevent drug residue from entering the human food chain;

(2) Compounders who compound for animals shall possess knowledge of drug regulation, uses, dosing and disposition in animal patients to properly determine appropriateness of therapy; and

(3) The compounding pharmacist shall be knowledgeable about the individual species limitations in physiology and metabolic capacity that can result in toxicity when certain drugs or excipients are used in compounded preparations. For this reason, pharmacists compounding for animals shall use when possible, formulations developed specifically for animal patients. If such formulations are not available, the compounding pharmacist shall conduct a literature review to determine whether a specific component of the formula is toxic to the target species. Compounded preparations shall not to be dispensed or sold to veterinary offices for resale.

N.H. Admin. Code § Ph 404.03

#6181-B, eff 2-5-96, EXPIRED: 2-5-04

New. #8316, eff 3-26-05

Amended by Volume XXXV Number 18, Filed May 7, 2015 , Proposed by #10812, Effective 4/18/2015, Expires 4/18/2025.