FDA Good Manufacturing Practice (21 CFR 210/211)

Overview

The FDA Current Good Manufacturing Practice (CGMP) regulations are the foundation of pharmaceutical quality in the United States. These regulations ensure that drug products are consistently produced and controlled according to quality standards appropriate for their intended use.

Key Points:

• Regulatory Authority: 21 CFR Parts 210 and 211


• Statutory Authority: Federal Food, Drug, and Cosmetic Act (FD&C Act)


• Enforcement: FDA Center for Drug Evaluation and Research (CDER), Office of Regulatory Affairs (ORA)


• Scope: All finished pharmaceutical manufacturers (human and veterinary drugs)


• Massachusetts Context: 500+ life sciences companies in MA biotech corridor (Cambridge, Boston, Worcester)


• Penalties: Warning Letters, Consent Decrees, injunctions, product seizure, criminal prosecution

Regulatory Framework

21 CFR Part 210: Current Good Manufacturing Practice in Manufacturing, Processing, Packing, or Holding of Drugs; General

Establishes the current good manufacturing practice regulations applicable to finished pharmaceuticals.

Source: 21 CFR Part 210

21 CFR Part 211: Current Good Manufacturing Practice for Finished Pharmaceuticals

Comprehensive regulations covering all aspects of pharmaceutical manufacturing:

Subpart A - General Provisions (Sec. 211.1-211.3):

• Scope of CGMP regulations


• Definitions

Subpart B - Organization and Personnel (Sec. 211.22-211.34):

• Qualified personnel


• Personnel qualifications


• Training requirements

Subpart C - Buildings and Facilities (Sec. 211.42-211.58):

• Design and construction features


• Lighting, ventilation, sanitation


• Maintenance

Subpart D - Equipment (Sec. 211.63-211.72):

• Design, construction, installation


• Maintenance, cleaning, and sanitization


• Automatic, mechanical, and electronic equipment


• Filters

Subpart E - Control of Components and Drug Product Containers and Closures (Sec. 211.80-211.94):

• Receipt and storage


• Testing and approval


• Rejected components, containers, closures

Subpart F - Production and Process Controls (Sec. 211.100-211.115):

• Written procedures, deviations


• Charge-in of components


• Yield calculations


• Equipment identification, cleaning verification


• Time limitations on production

Subpart G - Packaging and Labeling Control (Sec. 211.122-211.137):

• Materials examination and usage criteria


• Labeling issuance, control, operations


• Packaging and labeling operations


• Drug product inspection, expiration dating

Subpart H - Holding and Distribution (Sec. 211.142-211.150):

• Warehousing procedures


• Distribution procedures

Subpart I - Laboratory Controls (Sec. 211.160-211.176):

• General laboratory controls


• Testing and release for distribution


• Stability testing


• Special testing requirements


• Reserve samples


• Laboratory animals


• Penicillin contamination

Subpart J - Records and Reports (Sec. 211.180-211.198):

• General requirements


• Equipment cleaning and use log


• Component, drug product container, closure, and labeling records


• Master production and control records


• Batch production and control records


• Production record review


• Laboratory records


• Distribution records


• Complaint files

Subpart K - Returned and Salvaged Drug Products (Sec. 211.204-211.208):

• Returned drug products


• Drug product salvaging

Source: 21 CFR Part 211

Key CGMP Requirements

1. Organization and Personnel (Sec. 211.22-211.34)

Qualified Personnel:

• Adequate number of qualified personnel to perform and supervise manufacture


• Each person engaged in manufacture, processing, packing, or holding must have education, training, and experience (or combination) to enable performance of assigned functions

Responsibilities:

• Quality control unit with authority to approve or reject all components, containers, closures, in-process materials, packaging materials, labeling, and drug products


• Quality control unit responsibilities independent from production


• Written procedures, investigations, and quality assurance

Personnel Qualifications (Sec. 211.25):

• Training in operations performed and CGMP


• Job descriptions


• Training documentation

Personnel Hygiene (Sec. 211.28):

• Personnel with apparent illness or open lesions that may adversely affect drug product quality or safety shall be excluded from direct contact


• Clean clothing appropriate for duties


• No eating, drinking, chewing gum, or tobacco use in manufacturing or laboratory areas

Source: 21 CFR 211 Subpart B

2. Buildings and Facilities (Sec. 211.42-211.58)

Design and Construction (Sec. 211.42):

• Suitable size, construction, and location to facilitate cleaning, maintenance, and proper operations


• Adequate space for orderly placement of equipment and materials to prevent mix-ups

Lighting (Sec. 211.44):

• Adequate lighting in all areas

Ventilation, Air Filtration, Air Heating and Cooling (Sec. 211.46):

• Adequate ventilation


• Equipment for adequate control of air pressure, microorganisms, dust, humidity, and temperature when appropriate


• Air filtration systems including prefilters and particulate matter air filters

Plumbing (Sec. 211.48):

• Adequate size, properly installed and maintained


• Sewage, trash, and other refuse disposed of in safe manner

Sewage and Refuse (Sec. 211.50):

• Sanitary manner, timely disposal

Washing and Toilet Facilities (Sec. 211.52):

• Adequate number, conveniently located, sanitary

Sanitation (Sec. 211.56):

• Written procedures for cleaning and sanitizing


• Pesticide, rodenticide, fungicide use that does not contaminate equipment, components, or drug products

Maintenance (Sec. 211.58):

• Routine maintenance programs


• Cleaning and maintenance operations do not contaminate drug products

Source: 21 CFR 211 Subpart C

3. Equipment (Sec. 211.63-211.72)

Design, Size, and Location (Sec. 211.63):

• Appropriate design, adequate size, suitably located


• Facilitate operations, cleaning, maintenance


• Prevent contamination, adulteration, mix-ups

Construction (Sec. 211.65):

• Surfaces that contact components, in-process materials, or drug products shall not be reactive, additive, or absorptive


• Easily cleanable

Cleaning and Maintenance (Sec. 211.67):

• Written procedures for use, cleaning, maintenance


• Logs for cleaning, maintenance, sanitization


• Non-dedicated equipment cleaned to prevent contamination

Automatic, Mechanical, and Electronic Equipment (Sec. 211.68):

• Routinely calibrated, inspected, or checked according to written program


• Appropriate controls to assure proper performance


• Written records

Filters (Sec. 211.72):

• Not release fibers into components or drug products


• Asbestos-containing filters not used

Source: 21 CFR 211 Subpart D

4. Production and Process Controls (Sec. 211.100-211.115)

Written Procedures; Deviations (Sec. 211.100):

• Written procedures for production and process control designed to assure drug products have identity, strength, quality, and purity they purport or represent to possess


• Deviations documented and justified

Charge-in of Components (Sec. 211.101):

• Weight and measure of components verified and documented


• Each component added to production verified by QC

Calculation of Yield (Sec. 211.103):

• Actual yields compared with theoretical yields


• Significant discrepancies investigated

Equipment Identification (Sec. 211.105):

• Identify contents and, when necessary, phase of processing

Sampling and Testing of In-Process Materials and Drug Products (Sec. 211.110):

• Appropriate in-process specifications, tests, or examinations


• Acceptance criteria as necessary to assure finished products meet specifications

Time Limitations on Production (Sec. 211.111):

• Time limits specified to ensure quality not adversely affected

Control of Microbiological Contamination (Sec. 211.113):

• Written procedures for manufacture, processing, packing, or holding of drug products purporting to be sterile or requiring low microbiological counts


• Validation of sterilization processes and procedures

Reprocessing (Sec. 211.115):

• Written procedures for reprocessing


• Reprocessing does not adversely affect quality of finished drug product

Source: 21 CFR 211 Subpart F

5. Laboratory Controls (Sec. 211.160-211.176)

General Requirements (Sec. 211.160):

• Establishment of scientifically sound and appropriate specifications, standards, sampling plans, and test procedures


• Laboratory facilities adequate to perform testing and control


• Scientifically trained personnel

Testing and Release for Distribution (Sec. 211.165):

• Each batch tested for conformity to specifications


• Batch records reviewed for compliance before release


• Approved or rejected by quality control unit

Stability Testing (Sec. 211.166):

• Written testing program for appropriate drug product intervals


• Establish expiration dates supported by stability data


• Reserve samples stored under labeled conditions

Special Testing Requirements (Sec. 211.167):

• Sterility testing for sterile products


• Pyrogen testing for products labeled as such


• Contamination testing for ophthalmic ointments

Reserve Samples (Sec. 211.170):

• Appropriate quantity from each lot


• Stored under same conditions as marketed product


• Retained for 1 year after expiration date or 3 years after distribution, whichever is longer

Source: 21 CFR 211 Subpart I

6. Records and Reports (Sec. 211.180-211.198)

General Requirements (Sec. 211.180):

• Records retained in original form or true copies (paper or electronic)


• Readily available for inspection


• Retained at establishment where activity occurred or readily available from central location

Equipment Cleaning and Use Log (Sec. 211.182):

• Product name, lot number for each batch processed


• Cleaning and maintenance

Master Production and Control Records (Sec. 211.186):

• Prepared for each drug product, signed and dated by independent quality control unit


• Contains: Name and strength, dosage form, all ingredients, statement of theoretical weight or measure, manufacturing and control procedures, special notations, labeling

Batch Production and Control Records (Sec. 211.188):

• For each batch manufactured


• Accurate reproduction of appropriate master records


• Complete information relating to production and control of each batch


• Documentation of each step in manufacture, packaging, labeling


• Signatures of persons performing each step

Production Record Review (Sec. 211.192):

• All drug product production and control records reviewed and approved by quality control unit before batch release

Laboratory Records (Sec. 211.194):

• Complete data from all tests (including failed) for compliance with established specifications


• Instrument printouts, charts, graphs

Distribution Records (Sec. 211.196):

• Name and strength, lot number, quantity shipped


• Name and address of consignee, date of shipment

Complaint Files (Sec. 211.198):

• Written procedures for complaint handling


• Review by quality control unit


• Investigation for products that may be defective


• Review for trends

Source: 21 CFR 211 Subpart J

Massachusetts-Specific Requirements

Massachusetts Department of Public Health (DPH) Oversight

Drug Manufacturing Facilities:

• MA DPH oversight of pharmaceutical manufacturing facilities in Massachusetts


• Coordination with FDA for inspections and enforcement

Massachusetts Board of Registration in Pharmacy

Pharmacy Manufacturing:

• Compounding pharmacies subject to both CGMP (503B outsourcing facilities) and USP standards (503A traditional compounding)


• MA Board of Registration in Pharmacy licensing and oversight


• Registration requirements for sterile compounding (105 CMR 700.000)

Source: MA Board of Registration in Pharmacy

Massachusetts Biotech Industry

Cambridge/Boston Biotech Corridor:

• Over 500 life sciences companies in Massachusetts


• Major pharmaceutical manufacturers: Takeda, Sanofi, Pfizer, Moderna, Biogen


• Contract manufacturing organizations (CMOs)


• All subject to FDA CGMP regulations

Source: MassBio

Enforcement and Penalties

FDA Inspections

Types:

• Pre-approval inspections (PAI) before new drug approval


• Routine surveillance inspections (every 2 years for drug manufacturers)


• For-cause inspections (complaints, recalls, adverse events)


• Foreign inspections

Inspection Outcomes:

• NAI (No Action Indicated): No objectionable conditions or practices


• VAI (Voluntary Action Indicated): Objectionable conditions, but no regulatory action


• OAI (Official Action Indicated): Objectionable conditions warrant regulatory action

Warning Letters

Issued For:

• Significant CGMP violations


• Product quality issues


• Data integrity problems


• Falsification of records

Example Violations:

• Failure to establish adequate written procedures


• Inadequate investigation of failures and discrepancies


• Lack of validation of computer systems


• Insufficient testing of components and finished products


• Inadequate cleaning procedures

Source: FDA Warning Letters

Consent Decrees

Definition: Court-ordered agreements requiring corrective action

Requirements:

• Hire independent expert to audit operations


• Cease manufacturing until compliant


• Implement comprehensive quality system


• FDA re-inspection before resumption

Recent Examples: Multiple pharmaceutical companies under consent decree for CGMP violations

Import Alerts

Effect: Detention without physical examination (DWPE) of drug products from non-compliant facilities

Import Alert 66-40: CGMP non-compliance - drugs manufactured in non-compliant facilities detained at entry

Source: FDA Import Alerts

Criminal Prosecution

Violations:

• Knowing manufacture of adulterated drugs (21 USC 331)


• Falsification of records


• Distribution of substandard products

Penalties:

• Individuals: Up to $250,000 fine, up to 10 years imprisonment


• Companies: Up to $1 million fine


• Enhanced penalties for repeat offenses or causing serious bodily injury

Source: FD&C Act Sec. 303

Compliance Program Elements

Quality Management System

Core Elements:

1. Quality Policy: Senior management commitment to quality


2. Quality Objectives: Measurable quality goals


3. Quality Risk Management: ICH Q9 - systematic assessment of risks to quality


4. Change Control: Management of changes to facilities, equipment, processes


5. Management Review: Periodic review of quality metrics, trends

Process Validation

Three Stages (FDA Guidance):

1. Stage 1 - Process Design: Lab and pilot-scale studies, commercial scale design


2. Stage 2 - Process Qualification: Facility and equipment qualification, process performance qualification


3. Stage 3 - Continued Process Verification: Ongoing monitoring and control

Source: FDA Process Validation Guidance

Data Integrity

ALCOA+ Principles:

• Attributable: Who performed action and when


• Legible: Readable and permanent


• Contemporaneous: Recorded at time performed


• Original: First recording or certified true copy


• Accurate: Correct and truthful


• Complete: All data included


• Consistent: Sequence of events logical


• Enduring: Throughout record retention period


• Available: Available for review

Source: FDA Data Integrity Guidance

Deviation and CAPA Systems

Deviations:

• Prompt investigation of unexpected events


• Root cause analysis


• Impact assessment


• Corrective and preventive actions

CAPA (Corrective Action/Preventive Action):

• Systematic investigation of causes


• Corrective actions to address immediate issue


• Preventive actions to prevent recurrence


• Effectiveness checks

Supplier Quality Management

Requirements:

• Qualification of suppliers and contract manufacturers


• Audits of suppliers


• Quality agreements defining responsibilities


• Testing of incoming components


• Approved supplier lists

Training and Personnel Qualification

Training Program:

• Initial qualification training for new hires


• Ongoing GMP training (annual minimum)


• Job-specific training


• Training documentation and records


• Assessment of training effectiveness

Key Takeaways

1. CGMP is Foundation: All pharmaceutical manufacturing must comply with 21 CFR 210/211


2. Quality Systems: Establish robust quality management system with QC unit independence


3. Documentation: Extensive documentation and record-keeping required at every step


4. Validation: Process validation required to ensure consistent product quality


5. Data Integrity: ALCOA+ principles essential for electronic and paper records


6. Massachusetts Context: 500+ life sciences companies subject to CGMP in MA biotech corridor


7. Severe Consequences: Non-compliance results in Warning Letters, Consent Decrees, injunctions, criminal prosecution


8. Continuous Improvement: CAPA, change control, management review ensure ongoing compliance

Additional Resources

FDA Resources:

• FDA CGMP Regulations


• FDA Guidance Documents


• FDA Warning Letters


• FDA Inspection Classifications

Federal Regulations:

• 21 CFR Part 210


• 21 CFR Part 211

Massachusetts Resources:

• MA Department of Public Health


• MA Board of Registration in Pharmacy


• MassBio