Pharmaceutical Compounding – Sterile and Nonsterile Preparations

Jeanne Sun, PharmD

Agenda

• Legal Framework

• Overview – <795> Pharmaceutical Compounding – Nonsterile Preparations – <797> Pharmaceutical Compounding – Sterile Preparations

Legal Recognition In The US

• USP's standards for medicines, dietary supplements and foods are recognized in varying capacities in a variety of U.S. legislation. – 1938 Federal Food, Drug and Cosmetic Act (FDCA) recognized

USP & NF standards for strength, quality, purity, packaging, and labeling

• 1997 Food Drug Administration Modernization Act first recognized standards for compounding requiring USP-NF monograph standards for drug substances and ingredients and USP’s chapter on compounding

• 2013 Drug Quality and Security Act amended the FDCA reaffirmed USP’s role in compounding and granted the FDA more authority to regulate and monitor the manufacturing of compounded drugs

Regulatory Oversight

• Two Regulatory Bodies

– States • Boards of Pharmacy

– Federal Government

• Food and Drug Administration (FDA)

Compounding in the Law

There are 3 types of standards for compounding: 1. Monographs for ingredients

used in compounded preparations – Drug Substance Monographs

2. Monographs for compounded preparations – Compounded Preparation

Monographs 3. Practice standards

– General Chapters

Compounding General Chapters

• <795> Pharmaceutical Compounding – Nonsterile Preparations

• <797> Pharmaceutical Compounding – Sterile Preparations • <800> Hazardous Drugs – Handling in Healthcare Settings • <1163> Quality Assurance in Pharmaceutical Compounding • <1160> Pharmaceutical Calculations in Pharmacy Practice • <1176> Prescription Balances and Volumetric Apparatus

Used in Compounding

<795> Pharmaceutical Compounding – Nonsterile Preparations

<795> Overview

• Purpose – To provide guidance on applying good compounding practices

for nonsterile formulations for humans or animals. – To provide general information to enhance the compounder's

ability to extemporaneously compound preparations that are of acceptable strength, quality, and purity.

<795> Overview

Categories Facilities

Component Selection, Handling, & Storage

Stability & Beyond-Use Dating

Documentation Animal Patients

<795> Categories

• Criteria to determine classification

– Degree of difficulty or complexity of the compounding process

– Stability information and warnings – Packaging and storage

requirements – Dosage forms – Complexity of calculations – Local versus systemic biological

disposition – Level of risk to the compounder – Potential for risk of harm to the

patient

Complex

Moderate

Simple

<795> Facilities

• Adequate space for compounding

• Temperature and humidity monitoring for storage

• Potable Water – For hand and equipment washing – Air-dryer or single-use towels

• Purified Water

– Shall be used for compounding – Should be used for rinsing

<795> Component Selection, Handling, & Storage

• Recommended: – USP, NF, or FCC substance – Manufactured in an FDA-registered facility

• For human use

– Consult FDA list of components withdrawn or removed from the market for safety or efficacy reasons1

• For food-producing animals

– Consult FDA list of components prohibited for use2

1. See http://www.fda.gov/ohrms/dockets/98fr/100898b.txt 2. See http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?fr=530.41

<797> Stability & Beyond-Use Dating (BUD)

• The BUD is not later than the time remaining until the earliest expiration date of any API or 6 months, whichever is earlier when stored at controlled room temperature

For Nonaqueous Formulations

• The BUD is not later than 14 days when stored at controlled cold temperature

For Water-Containing Oral Formulations

• The BUD is not later than 30 days when stored at controlled room temperature

For Water-Containing Topical/Dermal and Mucosal Liquid and Semisolid Formulations

In the absence of stability information to a specific preparation, the maximum BUD recommended:

<797> Documentation

Master Formulation Record • Name, strength, and dosage form • Calculations & Verifications • Ingredients & Quantities • Compatibility & Stability Information • Equipment • Mixing instructions • Example labeling • Assigned BUD • Storage conditions • Packaging and storage requirements • Description of final preparation

Compounding Record • Name, strength, and dosage • Master Formulation Record reference • Names & quantities of all components • Source, lot no., & expiration dates of

components • Total quantity compounded • Compounder identifier and date • Assigned BUD • Duplicate label • Description of final preparation • Issues or any adverse reactions

Documentation enables a compounder to systematically trace, evaluate, and replicate the steps throughout the preparation process

<797> Animal Patients

• Nature of the animal patient shall be determined – Companion Animals – Performance Animals

• Strictly regulated by federal and state governments – Food-Producing Animals

• Accurate length of time to withhold treated animal tissues from the human food supply.

• Withdrawal time (WDT) must be included on the dispensing label • Ingredients cannot be on FDA list of prohibited components1

1. See https://www.fda.gov/animalveterinary/resourcesforyou/ucm380135.htm

<797> Pharmaceutical Compounding – Sterile Preparations

Last revised USP31-NF26 2S

Currently under revision

<797> Overview

• Purpose: – To provide quality standards for compounded sterile preparations – To describe conditions and procedures to prevent harm,

including death, to patients that could result from • microbial contamination (nonsterility) • excessive bacterial endotoxins • variability in the intended strength • unintended chemical and physical contaminants • ingredients of inappropriate quality

<797> Overview

CSP Risk Levels Facilities

Personnel Monitoring

Environmental Monitoring

Finished Preparations Monitoring

<797> CSP Risk Levels

• Assigned based on – Maintenance of sterility vs. achievement of sterility – Complexity of preparation – Stability of the components – Temperature at which stored

Low Risk Level CSPs

Low-Risk Level CSPs with 12-Hour or Less BUD

Medium-Risk Level CSPs

High-Risk Level CSPs

<797> CSP Risk Levels

Low-Risk with 12

hour

• 12 hours

• 12 hours

• N/A

Low-Risk Level CSPs

• 48 hours

• 14 days

• 45 days

Medium-Risk Level

CSPs

• 30 hours

• 9 days

• 45 days

High-Risk Level CSPs

• 24 hours

• 3 days

• 45 days

Controlled Room Temperature (20° to 25° C)

Cold Temperature (2° to 8° C)

Solid Frozen State (-25° to -10° C)

<797> Facilities

• ISO Class 5 PEC • Unclassified Space

Segregated Compounding

Area

• ISO Class 5 PEC • Buffer Room • Ante Room

Cleanroom Suite

<797> Personnel Monitoring

Gloved Fingertip Sampling • Evaluates hand hygiene and garbing competency

Aseptic Media Fill Testing • Stimulates conditions encountered during compounding

to evaluate aseptic manipulations

<797> Environmental Monitoring

Certification • Monitors primary and secondary engineering controls

Viable Air Monitoring • Monitors environmental microbial growth

Surface Sampling • Evaluates cleaning and disinfecting procedures and work

practices

<797> Finished Preparations Monitoring

Physical Inspection • Inspect for visible particles or foreign matter

Labeling and Accuracy Checks • Verify ingredients and volumes

Sterility and Endotoxin Testing • Testing for potential contamination