Module 15 | Slide 1 of 23 January 2006

Basic Principles of GMP

Active Pharmaceutical Ingredients

Part Three, 18

Module 15 | Slide 2 of 23 January 2006

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, 18.1–18.59

Module 15 | Slide 3 of 23 January 2006

Active Pharmaceutical Ingredients

Areas to be Covered

General considerationsPersonnelPremisesEquipmentSanitationDocumentationRetention of records and samplesProduction Part Three, 18.1–18.59

Module 15 | Slide 4 of 23 January 2006

Active Pharmaceutical Ingredients

General ConsiderationsOverall controlConsistent uniform batchesCompliance with GMP

production quality control

General guidelinesCooperation in productionHuman and veterinary preparations

Part Three, 18.1–18.6

Module 15 | Slide 5 of 23 January 2006

Active Pharmaceutical Ingredients

Personnel

Qualified and competent production and quality control sufficient number education, knowledge, experience

Organizational chart with responsibilitiesWritten job description or instructionsTrainedHealth

diseases open lesions

Part Three, 18.7–18.10

Module 15 | Slide 6 of 23 January 2006

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

Part Three, 18.11–18.13

Module 15 | Slide 7 of 23 January 2006

Active Pharmaceutical Ingredients

Premises (continued)

Hygiene clothes, washing, toilets eating, drinking, smoking

Part Three, 18.11–18.13

Module 15 | Slide 8 of 23 January 2006

Active Pharmaceutical Ingredients

EquipmentDesign, construction, location and maintenance

intended use, cleaning, contamination validated operation

Cleaning sterilized, used, maintained: SOPs, records and checks

Part Three, 18.14–18.18

Module 15 | Slide 9 of 23 January 2006

Active Pharmaceutical Ingredients

Equipment (continued)

Process monitoring and control calibrated, checked records

Defective equipment removed or labelled repaired, documented

Part Three, 18.14–18.18

Module 15 | Slide 10 of 23 January 2006

Active Pharmaceutical Ingredients

SanitationWritten programmes

validated for premises and equipment quality standard for water hygiene, health and clothing practices waste disposal

Implementation and trainingPractices not permitted:

eating, smoking unhygienic practices

Part Three, 18.19–18.22

Module 15 | Slide 11 of 23 January 2006

Active Pharmaceutical Ingredients

DocumentationMaster formulae

written instructions master formula contents authorization outdated documents amendments

Batch documentation batch manufacturing record contents contract production data recording Part Three, 18.23–18.30

Module 15 | Slide 12 of 23 January 2006

Active Pharmaceutical Ingredients

Record and reference sample retention

Activities are traceable production and quality control

Retention of records and samples retention period

Part Three, 18.31–18.32

Module 15 | Slide 13 of 23 January 2006

Active Pharmaceutical Ingredients

ProductionProcessing procedures

master formula critical steps defined and validated supervision labelling

– vessels, containers, equipment daily activities - information

Part Three, 18.33–18.37

Module 15 | Slide 14 of 23 January 2006

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 Part Three, 18.38–18.40

Module 15 | Slide 15 of 23 January 2006

Active Pharmaceutical Ingredients

Production (continued)

Active pharmaceutical ingredients meet specifications limits for residue and reactants sterile APIs

Part Three, 18.41–18.42

Module 15 | Slide 16 of 23 January 2006

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– Storage conditions– Names of manufacturers and suppliers

Part Three, 18.43–18.45

Module 15 | Slide 17 of 23 January 2006

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 Part Three, 18.46–18.51

Module 15 | Slide 18 of 23 January 2006

Active Pharmaceutical Ingredients

Stability Studies Written programme

stability indicating methods

Samples containers storage conditions

Expiry or retest date

Part Three, 18.46–18.51

Module 15 | Slide 19 of 23 January 2006

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 Part Three, 18.52–18.55

Module 15 | Slide 20 of 23 January 2006

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, 18.56–18.59

Module 15 | Slide 21 of 23 January 2006

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?

Module 15 | Slide 22 of 23 January 2006

Active Pharmaceutical Ingredients

Possible Issues

Manufacturers supplying various types of industries

Imports through brokers

Hazardous processes

Commercial secrecy

Unsatisfactory final facilities

Module 15 | Slide 23 of 23 January 2006

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