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