cGMP: Terminology and Regulations

Current Good Manufacturing Practice (cGMP)

• There are common terms used in cGMP for finished pharmaceuticals
• cGMP needs to be defined with its importance outlined
• Code of Federal Regulations (CFR) needs to be outlined

Common Terminology

• Drug product: Finished form containing active drug and inactive ingredients
• Component: Any ingredient used in the manufacture of a drug product
• Active Pharmaceutical Ingredient (API): Component with a pharmacologic activity or direct effect for diagnosis, cure, mitigation, treatment, or prevention of disease
• Inactive Ingredient: Any component other than the active ingredients in a drug product
• Batch: Specific quantity of a drug of uniform, specified quality produced according to a single manufacturing order during the same manufacturing cycle
• Lot: A batch or portion of a batch of uniform, specified quality with a distinctive identifying lot number

Lot Number

• A lot number, control number, or batch number is a combination of letters, numbers, or symbols
• The complete history of manufacture, processing, packaging, holding, and distribution is determined from lot numbers
• Batch number is a unique identifier that is assigned to a specific quantity of a product
• Products are produced/processed at the same time, under the same conditions, and using the same materials and are assigned with a lot number
• Batch numbers are for products that are homogeneous, like liquids, powders, or granules
• Batch numbers help track the origin, composition, and product quality to recall or dispose of defective/expired products
• Lot number is a unique identifier assigned to a specific group of products shipped/received together and used for heterogenous products
• Lot numbers track location, quantity, and status to manage inventory levels and optimize warehouse space

Master Batch Record

• Master record: Records for formulation, specifications, manufacturing procedures, quality assurance requirements, and labeling of each finished product
• Master Batch Record (MBR) contains the instructions, recipe, formula, and specific manufacturing process for a particular product
• MBRs are also known as a master production record (MPR) or master manufacturing formula (MMF)
• Most industries require a MBR with pharmaceuticals being the most notable

Master Batch Record and Batch Production Record

• Contains product name
• Contains dosage form and strength
• Contains batch size
• Lists quantity of each component in dosage unit
• Lists equipment used
• Calibration of instruments is included
• Specific instructions for each state in the manufacturing process is listed
• Contains statement of theoretical yield at each step in the manufacturing process
• Lists yield of final product
• Includes sampling and testing procedures with in-process control

Validation Process

• Establishes documented evidence providing high assurance that a process consistently produces product meeting its specifications
• Process Design (Pre-validation qualification): Relates to drug development, pilot studies, and scale-up
• Process validation: Verifies that all established limits of the critical process parameter
• Validation Maintenance Phase: Requires frequent review of all process-related documents

Validation Protocol

• A prospective experimental plan to produce documented evidence that the system has been validated.
• Includes the activities to be performed
• States who will perform the activities
• Lists when the activities should start and finish
• Lists generated documents
• States the policy on revalidation

Validation

• Documented evidence that a system does what it is supposed to do
• Major types of validation: Process, cleaning, equipment and analytical methods

Quality Audit

• Documented activity performed according to established procedures on a planned/periodic basis
• Quality audits verify compliance with procedures to ensure quality

Compliance

• Determining through inspection the extent a manufacturer is acting with prescribed regulations, standards, and practices
• Certification: Documented testimony by authorities that qualification, calibration, validation, or revalidation has been performed appropriately and the results are acceptable
• Quarantine: Marked area designated for holding incoming components prior to acceptance testing/qualification

Quality Relationship

• Quality assurance: All evidence needed for activities relating to quality being performed adequately
• Quality control: Process measuring actual quality performance and comparing it with standards
• Quality control unit: Organizational element designated by a firm to be responsible for work related to quality control

GMP Regulations

• In 1937, a public health disaster occurred where a liquid Sulfanilamide formulation contained poison, killing 107, that lead to law changes
• In 1941, 300 people were killed/injured by one company’s sulfathiazole tablets that were tainted with phenobarbital.
• The FDA drastically revised manufacturing and quality control requirements after the 1941 incident that led to GMPs
• GMP regulations are established by the FDA to ensure that minimum standards are met for drug product quality
• GMPs are rules set by the FDA that drug manufacturers need to follow to ensure a safe, effective, and high-quality product is manufactured
• cGMPs employ up-to-date technologies to comply with regulation

Importance of GMP

• GMP saves costs
• GMP minimizes risks in pharmaceutical production that cannot be eliminated through final product testing
• GMP improves the standard of drugs worldwide
• Main risks are unexpected contamination of products, incorrect labels on containers, or insufficient active ingredient

Principle of GMP

• Establish written step-by-step operating procedures and work instructions
• Follow written procedures carefully
• Promptly and accurately document work for compliance and traceability
• Validate work to ensure the system functions as designed
• Develop a good design for the facility and equipment from the beginning
• Properly maintain facilities and equipment
• Clearly define, develop, and demonstrate job competence
• Protect products against contamination by making cleanliness a habit
• Design the quality in product manufacturing, promoting effective control of quality
• The cGMP Code of Federal Regulations (CFR), includes finished pharmaceuticals, biologic products, medicated articles, and medical devices

cGMP Code of Federal Regulations (CFR) Subparts

• General Provisions
• Organization and Personnel
• Buildings and Facilities
• Equipment
• Control of Components and Drug Product
• Production and Process Controls
• Packaging and Labeling Control
• Holding and Distribution
• Laboratory Controls
• Records and Reports
• Returned and Salvaged Drug Products

Subpart B: Organization and Personnel

• Deals with responsibilities of quality control unit, employees, and consultants.
• Quality control unit has responsibility for all functions that affect product quality
• Includes accepting or rejecting product components, product specifications, finished products, packaging, and labeling
• Adequate laboratory facilities shall be provided, written procedures followed, and records maintained
• All personnel are required to have education, training, and experience
• Appropriate programs for education, training, and performance evaluations is essential for maintaining quality assurance

Subpart C: Buildings and Facilities

• Buildings and facilities must be designed with adequate size and space for operations
• There must be a good flow pattern for personnel, materials, products, and waste materials (helps to eliminate mix-ups and contamination)
• The facility must be easy to clean and sanitize (surfaces, equipment, etc..)
• Environmental controls must be in place, including lighting, ventilation, air filtration, air heating, and clean rooms
• Utilities must be validated, including water systems, plumbing, and electrical systems