Manufacturing Basics
- Produce large scales of drugs and drug products for distribution and sale
- Quality Assurance (QA) & Quality Control (QC) involved
- Follow Good Manufacturing Practices (CRF Title 21)
- Inspected by FDA
Compounding Basics
- Prepare prescriptions for specific patients and in anticipation of drug orders from routine
- Can also be for teaching and research
- Follow Good Compounding Practices (USP <795> and <797>)
- Inspected by corresponding state Board of Pharmacy
Need for Quality
- shared goal by those that inspect the respective drug creators
- Need to contain labeled amount of medications and releases the drugs as designed (Batch-to-batch consistency and stability)
- Changes to approved products are strictly controlled by regulatory authorities
Regulated Changes to Approved Drug (4)
- Formulation
- Manufacturing process (drug & drug products)
- Packaging
- Labeling
Manufacturing - Facilities
- Design and construction of building
- Lighting
- Ventilation/air filtration
- Plumbing
- Sewage/sanitation
- Washing & toileting facilities
- Maintenance facilities
Compounding - Facilities
Separate areas for sterile and non-sterile compounding that are:
- Good state of repair
- Clean & sanitary
- Surfaces cleaned before and after compounding
Adequate lighting & ventilation
Adequate washing facilities (other than restroom and near the compounding room)
Manufacturing - Equipment
Design & construction:
- Materials used to make equipment
- Substances for operation of equipment
Cleaning & Maintenance
- Equipment and utensils
- Written procedures
- Verification of cleaning
Compounding - Equipment
Must be cleaned and maintained
Manufacturing - Personnel
QC/QA (QA is upper level than QC)
Defined responsibilities of QC:
- Inspect rooms/certification of balances
- Correct materials and sufficient qualities
- Authority to approve or reject batches
Personnel qualifications & responsibilities for positions:
- Properly trained and attired
- “Adequate number of qualified personnel”
Compounding - Personnel
Pharmacist:
- inspects & approves products
- Reviews records
- Responsible for maintenance
- Properly trained
- Properly attired
Manufacturing - Ingredients
- Quality ingredients - USP-NF and other specifications
- Proper storage
- Receipt of all ingredients
- Tests to verify that ingredients are what they’re supposed to be
- Approving ingredients for use
- Rejecting ingredients that do not meet specifications
- Retesting approved ingredients
Compounding - Ingredients
Quality ingredients - USP-NF
Proper storage:
- USP-NF or manufacturer instructions
- Temperature is monitored in all places drugs are stored
- Flammable and hazardous products
Manufacturing - Required Testing of Solids
After production criteria to release batch:
- Appearance
- Identification
- Potency (content testing)
- Content uniformity
- Dissolution
Compounding - Required Testing for Solids
- Identification
- Physical properties - particle size & morphology
- Potency
- Impurities
- Other: moisture content and residual solvents
Manufacturing - Procedures
- Written procedures
- Documentation of all deviations
- Charge-in of components
- Equipment identification
- Time limitations on production
- Control of microbiological contamination
- In-process sampling
- Reprocessing
Compounding - Procedures
Formulation record:
-Written procedures on file as “receipts” for all previously compounded products with sufficient details to duplicate product
Compounding record:
-Record of prescriptions compounded in the pharmacy
Manufacturing - Final Check Process
- Yield
- Physical characteristics
- Drug Release Testing
- Stability Testing
- Packaged & labeled - issuance of labels, tampering-resistant packaging of OTCs, expiration dating
Compounding - Final Check Process
- Yield
- Physical characteristics
- Labeling : contents verified with order, legal requirements, storage and administration directions
- Packaged
- Documentation
- Patient Counseling
GMP Additional Requirements (3)
- Retain samples
- Warehouse and distribution procedures
- Scale-up and Post Approval Changes (SUPAC)
Retention of Samples
- 2x quantity needed for testing
- Keep for 1 year post expiration
SUPAC
- Scale-up involves changes in equipment and processes
- Most changes require FDA approval before implementing
- “Reportable” changes - adding sieving step, change in mixing times, addition of in-process test
GCP Labeling
- Generic or chemical name of active ingredients - NOT brand name
- Strength & quantity included
- Pharmacy lot number
- BUD (beyond use date)
- Inactive ingredients
- Special storage requirements
Manufacturing - Records (8)
- Batch product records - procedures and ingredients used each time
- Equipment - cleaning, use, maintenance
- Distribution records
- Complaint records
- Returned/salvaged drug products
- Environmental monitoring for each production run
- Personnel training - GMP training
- Inventory - drugs, excipients, labels & packaging materials, etc.
Compounding - Records (4)
- Formulation record - recipes of compounded products with sufficient detail to duplicate
- Compounding record - record of scripts made and specific product compounded
- Equipment maintenance record - documents maintenance and performance checks on all equipment used
- Ingredient record - chemical inventory including certificates of purity/analysis and their MSDS
