Course Objective: To provide participants with a thorough understanding of the key principles and requirements of ICH Q7 GMP for the manufacturing of Active Pharmaceutical Ingredients, ensuring compliance, quality, and patient safety.
Target Audience: Production Operators, Supervisors, Quality Control (QC) Analysts, Quality Assurance (QA) Personnel, Engineers, and Warehouse Staff.
Part 1: Foundation & Core Principles
Introduction, Objective, and Scope (Section I)
Quality Management (Section II)
Personnel (Section III)
Buildings and Facilities (Section IV)
Process Equipment (Section V)
Documentation and Records (Section VI)
Part 2: Operational Controls
7. Materials Management (Section VII)
8. Production and In-Process Controls (Section VIII)
9. Packaging and Identification Labeling (Section IX)
10. Storage and Distribution (Section X)
11. Laboratory Controls (Section XI)
Part 3: Assurance Systems
12. Validation (Section XII)
13. Change Control (Section XIII)
14. Rejection and Re-use of Materials (Section XIV)
15. Complaints and Recalls (Section XV)
Part 4: External Parties & Special Scenarios
16. Contract Manufacturers (Section XVI)
17. Agents, Brokers, Traders, etc. (Section XVII)
18. Specific Guidance for APIs by Cell Culture/Fermentation (Section XVIII)
19. APIs for Use in Clinical Trials (Section XIX)
20. Glossary (Section XX)
Module 1: Introduction, Objective, and Scope (Section I)
Objective: To ensure APIs meet the intended quality and purity characteristics.
Regulatory Status: Represents FDA’s current thinking; not legally binding but defines the standard.
Key Definition: “Manufacturing” includes all steps from material receipt to distribution. “Should” indicates a recommendation for GMP compliance.
Critical Scope Definitions:
What’s Included: APIs for human drugs, from a defined point (the “API Starting Material”).
What’s Excluded: All vaccines, whole blood/plasma, bulk-packaged drug products, medical gases, and radiopharmaceuticals.
Sterile APIs: This guide applies only up to the point before sterilization.
API Starting Material: A raw material, intermediate, or API incorporated as a significant structural fragment. The company must define and justify the point where GMP begins. The stringency of GMP increases as the process moves forward.
Module 2: Quality Management (Section II)
Principle: Quality is the responsibility of all persons involved in manufacturing.
Quality Unit(s): Must be independent of production. Its core responsibilities cannot be delegated.
Key QU Duties: Releasing/rejecting APIs, approving all specifications/procedures, reviewing batch records, investigating critical deviations, approving contractors and changes, ensuring complaints are resolved, and performing product quality reviews.
Production Responsibilities: Include following procedures, recording activities, ensuring equipment is clean and calibrated, and reporting deviations.
Internal Audits & Product Quality Review (PQR): Required for verifying ongoing compliance and process consistency. PQR is an annual review of all batches, deviations, OOS results, complaints, and changes.
Module 3: Personnel (Section III)
Qualifications: Sufficient number of qualified personnel with defined responsibilities.
Training: Regular, documented, and assessed GMP training relevant to the employee’s duties.
Hygiene: Good sanitation, clean and appropriate clothing, and restrictions on food/drink in production areas. Personnel with infectious diseases must be excluded from affecting API quality.
Consultants: Must be qualified, and their records maintained.
Module 4: Buildings and Facilities (Section IV)
Design: Must facilitate cleaning, maintenance, and orderly operations to prevent mix-ups and contamination.
Layout: Defined areas for operations (receipt, quarantine, production, packaging, storage).
Utilities: All utilities (water, HVAC, steam) that could affect product quality must be qualified and monitored.
Water: Must be suitable for its intended use. Potable water is the minimum standard.
Containment: Dedicated, self-contained facilities are required for highly sensitizing (e.g., penicillins) or highly toxic materials.
Lighting, Sanitation, and Maintenance: Adequate for operations, with written procedures for cleaning and pest control.
Module 5: Process Equipment (Section V)
Design & Construction: Must be of suitable design and size, and not alter product quality. Surfaces must be non-reactive.
Maintenance & Cleaning: Written procedures for preventive maintenance and cleaning. Cleaning procedures must be detailed and validated to prevent contamination and carryover.
Calibration: Critical equipment must be calibrated on a defined schedule using traceable standards.
Computerized Systems: Must be validated for their intended use. Key requirements include data security, audit trails, backup systems, and procedures for operation and change control.
Module 6: Documentation and Records (Section VI)
Documentation System: Controlled creation, review, approval, and distribution of all documents.
Good Documentation Practices (GDP): Entries must be made at the time of activity, in ink, legible, and errors corrected properly (single line, initial, date, reason).
Key Documents:
Master Production Instructions (Master Batch Record): The approved “recipe.”
Batch Production Records (Batch Batch Record): The real-time, step-by-step documentation of a specific batch.
Laboratory Control Records: Contain all raw data from testing.
Retention Periods: Batch records must be kept for at least 1 year after expiry or 3 years after distribution.
Module 7: Materials Management (Section VII)
General Controls: Written procedures for receipt, testing, and storage. Critical material suppliers must be evaluated and approved.
Receipt & Quarantine: Materials must be visually examined and held in quarantine until released by the quality unit.
Sampling & Testing: Must be representative and conducted to prevent contamination. A supplier’s Certificate of Analysis can be used, but the supplier must be qualified and the CoA verified periodically.
Storage & Re-evaluation: Materials must be stored to prevent degradation. Re-evaluation is needed after prolonged storage.
Module 8: Production and In-Process Controls (Section VIII)
Production Operations:
Weighing and dispensing must be accurate and controlled.
Materials and equipment must be verified before use.
Yields must be calculated and investigated if outside expected ranges.
All deviations must be documented; critical deviations must be investigated.
In-Process Controls (IPC): Defined checks during production to monitor and control the process. Performed by production, but critical IPC limits are approved by the quality unit.
Blending: Combining conforming batches is acceptable. It must be documented, validated for homogeneity if critical (e.g., for solid dosage forms), and the retest date is based on the oldest batch in the blend.
Module 9: Packaging and Identification Labeling (Section IX) & Module 10: Storage and Distribution (Section X)
Packaging & Labeling: Procedures to ensure correct materials are used. Labels must be reconciled (issued vs. used vs. returned). Access to labels must be controlled.
Label Information: Must include name, batch number, storage conditions, and for external transfer, manufacturer’s name and retest/expiry date.
Storage: Conditions (e.g., temperature) must be maintained and recorded if critical. Separate areas for quarantined, rejected, and released materials.
Distribution: APIs can only be distributed after release by the QU. A system must be in place for full traceability and recall.
Module 11: Laboratory Controls (Section XI)
General Controls: All specifications and test methods must be scientifically sound and approved by the QU.
Testing of APIs: Includes testing for conformance and establishing an impurity profile.
Stability Monitoring: An ongoing program is required to support retest/expiry dates.
Out-of-Specification (OOS): Any OOS result must be investigated according to a defined procedure.
Reference Standards: Must be qualified and stored properly.
Certificates of Analysis (CoA): Must be authentic and contain specific, truthful information.
Module 12: Validation (Section XII)
Policy: A documented approach to validation (process, cleaning, analytical methods).
Process Validation: Documented evidence that the process consistently produces material meeting its spec.
Approaches: Prospective (preferred), Concurrent, Retrospective (for well-established processes).
Qualification (DQ, IQ, OQ, PQ): The foundation for process validation.
Cleaning Validation: Required to prevent cross-contamination. Includes defining scientifically justified residue limits and using validated sampling and analytical methods.
Module 13: Change Control (Section XIII)
Formal System: A formal system is required to evaluate all changes that could affect quality.
Process: Proposal -> Evaluation of Impact -> Approval (by QU!) -> Implementation -> Evaluation of first batches under the change.
Module 14: Rejection and Re-use of Materials (Section XIV)
Rejection: Non-conforming materials must be identified and quarantined.
Reprocessing: Repeating a step from the established process is acceptable.
Reworking: Using a process step not part of the established process requires investigation, evaluation, and validation to show equivalent quality.
Returns: Must be handled carefully; can only be re-released after a full quality evaluation confirms they still meet spec.
Module 15: Complaints and Recalls (Section XV)
All quality-related complaints must be recorded and investigated.
A written recall procedure must be in place, defining roles and responsibilities.
Module 16: Contract Manufacturers & Module 17: Agents, Brokers, etc.
Contractors must comply with GMP. A formal agreement must define responsibilities, and the contract giver has the right to audit.
Agents, brokers, etc., must also comply, maintain full traceability, and have a quality management system. They must transfer all quality information between the manufacturer and customer.
The vast majority of Sections I-XVII apply directly to chemical API manufacturing.
Starting Point: GMP applies from the introduction of the defined API Starting Material (see Table 1 in guidance, e.g., “Introduction of the API starting material into process” for chemical synthesis).
Key Focus Areas:
Process Validation: Especially for the chemical synthesis and purification steps.
Impurity Profile: Monitoring and controlling organic impurities, residual solvents, and catalysts.
Contamination Control: Preventing cross-contamination, especially when using multi-product equipment.
Physical Attributes: For APIs for solid oral dosage forms, particle size distribution, polymorphism, etc., may be critical and require control.
This section adds additional controls to the general GMP principles for biological processes.
Types:
Biotechnological Processes (Biotech): Use recombinant cells. Typically for high molecular weight substances (proteins). Requires a higher degree of control.
Classical Fermentation: Uses naturally occurring/mutated microbes. Typically for low molecular weight substances (antibiotics). Control level is similar to chemical but with biological considerations.
Key Additional Requirements:
Cell Bank System: A defined system (Master and Working Cell Banks) must be established and maintained. Access and storage conditions are critically controlled.
Contamination Control: The risk is higher. Use of closed systems, sterile media, and aseptic techniques are emphasized. Procedures for detecting and handling microbial contamination are required.
Viral Safety: For biotech processes, viral removal/inactivation steps are critical and must be validated. Specific facility controls (separate areas, dedicated air handlers) are often needed.
Process Controls: Monitoring of critical parameters (temp, pH, dissolved oxygen) and critical performance indicators (cell growth, viability, productivity).
Purification: Processes must adequately remove/control host cell proteins, media components, and other process-related impurities.
GMP principles are applied, but with flexibility appropriate to the stage of development.
Key Differences from Commercial GMP:
Quality Unit: Must be independent and approve/reject batches, but some testing functions can be performed by other units.
Documentation: Can be in lab notebooks or less formal batch records, but must capture all critical information.
Process Validation: Not normally required for early-phase clinical trials. Quality is ensured through controls, calibration, and equipment qualification.
Analytical Methods: Do not need to be fully validated but must be “scientifically sound.”
Specifications & Changes: Are expected to evolve and must be well-documented.
Stability Data: Retest/expiry dates for early phases may not be as comprehensive as for commercial products.
Principle: The level of control should be consistent with the stage of product development, increasing in formality as the product moves toward commercial application.
