Regulatory Class - Oct 3 Flashcards
Drug Substance
the active pharmaceutical ingredient (API); provides the pharmacologic or biologic effect
Drug Product
the dosage form that the patients takes, contains inactive ingredients (excipients) and the API
Placebo
dosage form that does not contain an API
Label of investigational drugs
“Caution: New drug limited by Federal (or US) law to investigational use
CMC Info Required for IND
Sufficient info to assure identity, quality, purity, and strength
Final specifications are not expected
Stability data are required at all IND phases to demonstrate that the drug substance and product are within acceptable chemical and physical limites for the duration of the trial
CMC Info Required for Clinical Trial Phases
Phase I: identification and control of raw materials and the new drug substance
Phase II: need synthesis procedures, controls, reference standards, specifications, stability data on all Phase I lots
Phase III: need drug substance fully characterized, full manufacturing and controls; need drug product full manufacturing and controls information
Stability data
need to make sure that the drug substance or product will last in storage throughout a clinical trial period; especially important if only one batch of the drug is made
CMC Changes during Clinical Trials
CMC updates go into IND information amendments
Changes due to scale up manufacturing; improve cost, time efficiency of manufacturing
Validation
Documented process verifying that something operates within acceptable and expected limits
Demonstrates that a facility, system, equipment, software, method or process used in the manufacture of a drug operates in a repeatable and reliable manner within predefined parameters of operation
Assay Validation
Evaluate accuracy, precision, range, sensitivity, specificity, ruggedness
Need to demonstrate that assay produces reliable results
Manufacturing process validation
Assess effect of temperature, time, mixing rate (check variation in)
Need to demonstrate that process produces reproducible material
Need validated assays to do process validation
Facility and equipment validation
Evaluate ability to maintain temperature, produce water meeting specifications
Need to demonstrate that facility and equipment function reliably as specified
Cleaning validation
Evaluate ability of cleaning procedure and materials to remove residuals from equipment
Need to demonstrate that subsequent batches will not be contaminated by prior batches’ residue
Computer validation
Evaluate reliability of computer data storage, data calculations/transformation, collection
Need to demonstrate that computers and associated activities function reliably as specified
NDA: CMC: Drug substance
Full description (physical/chemical characteristics and stability)
Name and address of manufacturer
Method of synthesis or isolation and purification
Process controls used during manufacture and packaging
Specifications and analytical methods as necessary to assure identity, strength, quality, purity and bioavailability
Specification relating to stability, sterility, particle size, and crystalline form
NDA: CMC: Drug product
List all components used in manufacture
Composition
Specification and analytical methods for each component
Name and address of manufacture(s)
Description of manufacturing and packaging procedures and in-process controls
Specification and analytical methods necessary to assure its identity, strength, quality, purity and bioavailability including specification relating to sterility, dissolution rate, containers and closure systems
Real-time stability data with proposed expiration dating
NDA: CMC: Additional manufacturing information
Proposed or actual master batch production record
Specifications and test procedures for each component and the drug product
Names and addresses of sources of drug substance, noncompendial inactive components
Identification of operations performed by each contract facility
Results of any test performed on components used in the manufacture of drug product
Environmental Impact
Categorical Exclusion: make such a small amount that it won’t affect the environment
Environmental assessment: toxins used or plants or animals needed, or large amounts of toxins produced
CMC Issues for Biologics
Usually development genetics and expression system and need to validate virus removal
Specific Issues: Equivalent Methods and Processes Potency General Safety Sterility Purity Identity Constituent Materials Cultures
Current Good Manufacturing Practices (cGMPs)
apply to the preparation of drug products for administration to humans or animals (includes biologics)
GLP do not apply to the drug product
Quality Control Unit (QCU)
Person or organization responsible for the quality control duties
Completely independent of manufacturing organization
Need their own lab space for the testing and approval/rejection of all materials
Responsibilities and procedures must be in writing and they must be followed
QA responsibilities included in QCU
QCU Responsibilities
Approve or reject all: raw materials, drug product containers & closures, in-process materials, packaging materials, labels and labeling, drug products, procedures/specifications
Responsible for components contracted from other manufacturers (each manufacturer also has their own QCU)
cGMPs: Personnel Qualifications
People involved in manufacture, processing, packaging, or holding of a drug product must have education/training/experience, or any combination to enable that person to perform the assigned functions.
Qualified individuals must provide cGMP training at appropriate frequency
Adequate personnel required
cGMPs: Personnel Responsibilities
Wear clean clothing, and protective apparel as necessary to protect drug product from contamination
Use good sanitation/health habits
Enter limited-access areas only if authorized
Those with an illness that may affect drug product are excluded from product contact
Need SOPs to cover these topics
cGMPs: Building and Facilities
Buildings must be of suitable size, construction and location to facilitate cleaning, maintenance and proper operations
Have adequate space to organize materials and prevent mix-ups
Design flow of materials within facility to prevent contamination
Have a separate or defined areas for various activities
cGMPs: Equipment
Equipment must be of appropriate design, adequate size and suitably located to facilitate operations for its intended use and for its cleaning and maintenance
Equipment must be constructed, cleaned and maintained appropriately
Equipment must be validated/qualified (need written protocols)
Equipment Validation
Installation Qualification
Operational Qualification
Performance Qualification
cGMPs: Production and Process Controls
Written procedures required for production/processing of drug products (approved by QCU)
Deviations from written procedures recorded and justified
In-process sampling and testing
Time limits on production
Control microbiological contamination
Reprocessing of batches that don’t conform to standards or specifications
cGMPs: Specifications
acceptable limits for what the test results may be
Established for drug product, in-process materials, components, labeling and packaging materials, drug product containers and closures
Include description of sampling and testing procedures used, may reference test procedure
Describe what constitutes conformance to specifications
Describe frequency of retesting
cGMPs: Release Testing
Test each lot of drug product prior to release for distribution
Testing plans must be in writing (include method of sampling, number of samples to test)
Test (analytical) methods must be validated
Write SOPs for testing and sampling
If lot does not meet specifications, it must be rejected
Rejected lots may be reprocessed and retested
cGMPs: Stability Testing
Written stability testing program required and must include:
Sample size and test intervals
Storage conditions
Test methods
Use same container/closure system in which drug product is marketed
Test stability of reconstituted products both before and after reconstitution
Need real time stability data to set expiration date
General properties of drug substance
appearance, melting/boiling points, optical rotation, solubility, pH, and biological activities
Conformance to specifications
the drug substance, when tested accordingly, will meet the listed acceptance criteria
Acceptance Criteria
the associated numerical limits, ranges, or other criteria for the tests described
Batch analysis
collation of analytical data for all the tests included in the specifications
Overage
a fixed amount of the drug substance in the dosage form that is added in excess of the label claim
Compatibility
compatibility of drug product with any dilutents or dosage devices specified in labeling; compatibility with coadministered drug products
Adulterated Drug
if the methods used in or the facilities or controls used for, its manufacture, processing, packaging, or holding do not conform to or are not operated or administered in conformity with cGMPs to assure that such drug meets the requirements of this Act as to safety and has the identity and strength, and meets the quality and purity characteristics, which it purports or is represented to possess
cGMPs: Process understanding
requires the identification of critical sources of variability, the ability to manage variability, and the knowledge that the management of variability will result in a quality product
FDA Quality Systems Approach to cGMPs
Senior management support
Sufficient resources
Manufacturing operations partnership
Continual self-evaluation
Complete List of cGMPs
Personnel Components (materials) Procedures Equipment Facilities
Quality Agreements
define quality roles and responsibilities between the contracted company and sponsor
Provides oversight through written agreements
