TOPIC 6 - Production & Process Control

General Production Requirement

• Written procedures for production and process control are needed to ensure product identity, strength, quality, and purity

• Follow procedures during execution and document real-time performance

• Deviations must be recorded, explained, and critical deviations investigated and documented (both the investigation and conclusion)

• In-process controls and testing are required to ensure batch uniformity and integrity

• Equipment must be cleaned, maintained and sanitised regularly to prevent contamination or malfunction

• A formal change control system must assess changes affecting production or control of drug products

Controls

• Purpose: To ensure drug products are produced with the required quality attributes (ie. identity, purity, potency, safety, etc)

  • GDP and SOPs must be followed at every production step

OVERVIEW

• Before starting production – Area & Line Clearance

• During Production – GDP/SOPs

• After Production – Batch Record Review

• Cleaning, Maintenance & Calibration

• Deviation Management & CAPA

• Change Control

Before Starting Production (Area & Line Clearance)

• Check that:

  • SOPs and documents are correct and of the latest revision (ie. remove old batch documents)

  • Raw materials, intermediates and packaging correctly identified and within expiry

  • Correct, clean, calibrated and functional equipment and appropriate lines are selected and changeover done if needed

  • All previous deviations resolved

After Production (Production Record Review)

• Quality Assurance must review and approve all records (ie. production, control) before a batch is released

  • Ensures batch was made according to intended process and consistent in quality

• Must comply with GMP and GDP

• All deviations/non-conformance, including related batches, to be investigated in accordance to company procedures

Equipment Cleaning & Maintenance

• Equipment and utensils must be regularly cleaned, maintained and sanitized to prevent contamination and malfunction

• Cleaning:

  • Removes product residue to prevent cross-contamination

  • Removes food source for microorganisms

  • Uses cleaning detergents and soaps with high purity water; hot water alone used when possible

• Sanitising (NOT Sterilisation):

  • Reduces microbial counts on equipment surfaces 

  • Uses thermal or chemical sanitising agents

  • Water utility systems primarily follow sanitization practices

• Degree of cleaning and maintenance depends on if the next batch is of the same or different product

  • Product changeover is more stringent

• SOPs (for equipment cleaning and maintenance) must have:

  • Personnel responsibility

  • Schedule, frequency and status expiry

  • Methods for cleaning/maintenance (including equipment and materials used), disassembly  and reassembly  

  • Protection of clean equipment before use

  • Inspection of equipment for cleanliness before use

  • Maintenance of cleaning/maintenance records

Clean In Place (CIP)

• Cleaning is done without disassembling equipment (eg. vessels, tanks, associated pipings)

• Cleaning chemicals and rinse water (PW and/or WFI) are sent through pipes in a circulating or once-through manner

• Removes media, culture, and product residues to a consistent, acceptable level and cleaning agents by final WFI rinse

• CIP Cycle:

  • Pre-rinse with PW/WFI

  • Caustic wash with KOH (dissolve and remove organic residues and kill microorganisms)

  • Rinse with PW/WFI

  • Acid wash with H₃PO₃ (removes inorganic deposits and neutralises metal surfaces → prevents corrosion)

  • Rinse with PW/WFI

  • Final Rinse with HOT PW/WFI (removes all remaining cleaning agents)

  • Air blow (blows out residual water and dry equipment → prevents stagnation and reduces moisture)

Clean Out of Place (COP)

• Used to clean parts or systems that must be removed, disassembled or brought out of place 

  • eg. flexible hoses, sanitary clamps, end caps etc.

• Can be manual and automated

• Care must be taken to prevent contamination from environmental exposure or personnel interference

• COP washer is an automated COP system

  • Cleans disassembled and brought out of place parts/fittings

  • Same stages as CIP cycle

  • Uses jet sprays inside wash chamber to create turbulent flow and mixing (for effective cleaning)

CIP vs COP

• Advantages of CIP:

  • Eliminates environment and personnel exposure to the containment

  • Improves cleaning process consistency and reproducibility

  • No need to shut down or disassemble equipment so does not impact manufacturing efficiency

Equipment Maintenance

• To ensure equipment reliability and prevent reactive failures through scheduled programs

• SOPs must outline:

  • Responsibility

  • List of critical instrument

  • Maintenance schedules

  • Description of methods, equipment and materials used in maintenance operations

  • Management of Out-of-Tolerance (OOT) observations

  • Records

• 2 types of maintenance – ① Preventive ② Predictive

Preventive	Predictive
Time-interval maintenance	Condition-based maintenance
Based on calendar time or equipment running hours	Based on equipment conditions
Intervals are based on average deterioration rate	Uses trend data from condition monitoring to predict failure
Increases reliability of assets and reduces reactivity to failure

Preventive Maintenance

• All production-related equipment must be certified by accredited bodies to ensure accuracy at all times

• Preventive maintenance program:

  • Ensures all equipment are in optimal condition

  • Documents all maintenance activities, dates and personnels involved

Calibration (Standards)

• All relevant data-recording equipment must be calibrated to ensure accuracy

• New or repaired instruments require calibration before use

• All equipment to be reviewed on calibration requirements upon receipt

• Maintain clear inclusion/exclusion lists with reasons, location and final approval by Quality

• Calibration standards must be traceable to national or international standards (eg. SPRING Singapore, NIST)

Calibration Guidelines

• Classification of equipment depends on severity of accuracy of equipment on the product

  • Critical (affects product quality) – Calibrated minimally every 6 months

  • Non-critical (no direct impact) – Calibrated minimally every 12 months

• Accuracy requirements should be set in consent with Quality and Calibration departments

• Non-conforming equipment must NOT be used

Calibration Records

• Must include:

  • Equipment identification

  • Calibration dates

  • Individual performing each calibration

  • Next calibration date

• Records must be displayed on/near the equipment or be readily available