Basic Principles of GMP

Active Pharmaceutical

Ingredients

Part Three, 18
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Active Pharmaceutical Ingredients

Objectives

To discuss the GMP guidelines for the manufacture of Active Pharmaceutical Ingredients (APIs) To examine key problems experienced during inspections of the manufacturers of APIs and to seek possible solutions

Part Three, 18.118.59

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Active Pharmaceutical Ingredients

Areas to be Covered
General considerations Personnel

Premises
Equipment Sanitation Documentation Retention of records and samples

Production

Part Three, 18.118.59

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Active Pharmaceutical Ingredients

General Considerations
Overall control Consistent uniform batches

Compliance with GMP

production quality control

General guidelines
Cooperation in production Human and veterinary preparations
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Part Three, 18.118.6

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Active Pharmaceutical Ingredients

Personnel
Qualified and competent production and quality control sufficient number education, knowledge, experience Organizational chart with responsibilities Written job description or instructions Trained Health diseases open lesions
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Part Three, 18.718.10

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Active Pharmaceutical Ingredients

Premises
General suitable construction and environment adequately adapted and sufficient size mix-ups or contamination logical work flow

Special purposes antibiotics, hormones, cytostatic substances separate, specifically-designed, enclosed areas separate air-handling systems
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Part Three, 18.1118.13

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Active Pharmaceutical Ingredients

Premises (continued)

Hygiene clothes, washing, toilets eating, drinking, smoking

Part Three, 18.1118.13

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Active Pharmaceutical Ingredients

Equipment
Design, construction, location and maintenance intended use, cleaning, contamination validated operation
Cleaning sterilized, used, maintained: SOPs, records and checks

Part Three, 18.1418.18

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Active Pharmaceutical Ingredients

Equipment (continued)
Process monitoring and control calibrated, checked records Defective equipment removed or labelled repaired, documented

Part Three, 18.1418.18

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Active Pharmaceutical Ingredients

Sanitation
Written programmes validated for premises and equipment quality standard for water hygiene, health and clothing practices waste disposal
Implementation and training

Practices not permitted: eating, smoking unhygienic practices

Part Three, 18.1918.22
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Active Pharmaceutical Ingredients

Documentation
Master formulae written instructions master formula contents authorization outdated documents amendments Batch documentation batch manufacturing record contents contract production data recording
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Part Three, 18.2318.30

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Active Pharmaceutical Ingredients

Record and reference sample retention
Activities are traceable production and quality control

Retention of records and samples retention period

Part Three, 18.3118.32

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Active Pharmaceutical Ingredients

Production
Processing procedures master formula critical steps defined and validated supervision labelling vessels, containers, equipment daily activities - information
Part Three, 18.3318.37

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Active Pharmaceutical Ingredients

Production (continued)
Starting materials receiving, quarantine, sampling testing release, reject, storage, labelling dispensing SOP exceptions for hazardous materials

Intermediates testing labelling storage

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Part Three, 18.3818.40

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Active Pharmaceutical Ingredients

Production (continued)
Active pharmaceutical ingredients meet specifications limits for residue and reactants sterile APIs

Part Three, 18.4118.42

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Active Pharmaceutical Ingredients

Production (continued)
Packaging packaging material selection procedures to prevent error labelling, including: Product name Quality Batch number Expiry or retest date Warnings, if required Part Three, 18.4318.45 Storage conditions Names of manufacturers and suppliers

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Active Pharmaceutical Ingredients

Quality Control
Independent unit Duties: approve, reject or release specifications and methods sampling, sanitation and hygiene reprocessing stability complaints Laboratory access and requirements Contract laboratories
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Part Three, 18.4618.51

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Active Pharmaceutical Ingredients

Stability Studies
Written programme stability indicating methods

Samples containers storage conditions

Expiry or retest date
Part Three, 18.4618.51

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Active Pharmaceutical Ingredients

Self-Inspection and Quality Audits
Regular independent inspection expert or team of experts production and quality control Records

Storage
Suitable conditions based on stability studies

Distribution records for each batch written SOP facilitate recalls

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Part Three, 18.5218.55

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Active Pharmaceutical Ingredients

Complaints and Defects
Written instructions Prompt action and investigation record facts Product review system

Reject materials
Written procedures starting materials, intermediates, packaging materials identified storage pending fate

Part Three, 18.5618.59

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Active Pharmaceutical Ingredients

Group Session
Identify major deficiencies experienced in GMP in active pharmaceutical ingredients manufacture.
Are there any deficiencies that should prevent material being released? Within what timescale should these deficiencies be corrected? What are the implications for bulk active supply to your country?

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Active Pharmaceutical Ingredients

Possible Issues
Manufacturers supplying various types of industries

Imports through brokers

Hazardous processes Commercial secrecy Unsatisfactory final facilities

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Active Pharmaceutical Ingredients

Possible Issues (continued)
The interpretation of the meanings of expiry dates and retest dates

The use of APIs close to their expiry date

Blending of rejected APIs Reprocessing, recovery and/or reworking of APIs Recycling and treatment of solvents Addition of impurities to batches of APIs Traceability, repacking and relabelling
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