AQEEL

1. GOODMANUFACTURINGPROCESSESINFACTORY
ANDHOSPITALHYGIENE
BY : AQEEL IQBAL
FA21-PHM-074

2. 0UTLINES:
 INTRODUCTION
 COTROL OF MICROBIAL CONTAMINATION DURING
MANUFACTURING
 MANUFACTURE OF STERILE PRODUCT
 A GUIDE TO CURRENT GOOD PHARMACEUTICAL PRACTICE

3. INTR0DUCTION
GOOD MANUFACTURING PRACTICE (GMP):
 GMP IS A SET OF REGULATIONS THAT PHARMACEUTICAL
PRODUCTS MUST ADHERE TO.
 REGULATORY AUTHORITIES INCLUDE THE EU, MHRA, AND FDA.
 UK-MANUFACTURED PRODUCTS FOR THE US MARKET MUST
MEET FDA STANDARDS.
 GMP GUIDELINES WERE ESTABLISHED IN THE USA IN 1971 AND
LATER PUBLISHED IN THE UK.

4. Importance of GMP Compliance:
 Compliance with GMP is crucial to ensure patient safety and
avoid financial consequences.
 Failure in GMP can result in litigation, product recalls, loss of
license, and negative publicity.
 A past incident of GMP failure led to a major vaccine shortage
in the USA.
Sterile and Non-Sterile Products:
 Some products must be sterile, while others need to be free
from pathogens.
 Sterile products have more stringent quality assurance
requirements.

5. CONTROL OF MICROBIAL CONTAMINATION DURING
MANUFACTURE :
 Contamination risks during pharmaceutical
manufacturing.
 Minimizing contamination risks requires understanding
and proactive measures.
Risk Assessment:
 GMP informed by past mistakes and case studies.
 Manufacturers expected to demonstrate extensive risk
assessment.
 Methods employed: hazard analysis critical control points
(HACCP), failure mode and effects analysis (FMEA).

6. Hazard Analysis Critical Control Points
(HACCP):
Widely used in food industry and increasingly in pharmaceutical
industry.
Seven steps of HACCP:
• Conduct hazard analysis and identify preventive measures.
• Determine critical control points.
• Establish critical limits.
• Establish monitoring system.
• Establish corrective action.
• Establish verification system.
• Establish record-keeping system.
HACCP can be applied quantitatively to microbiology, pyrogens,
and particles.

7. Failure Mode and Effects Analysis (FMEA):
 Initially used in the engineering industry.
 Process breakdown into discrete steps with severity,
occurrence, and detection scales.
 Scores multiplied and compared to determine unacceptable
risk.
Environmental Cleanliness and Hygiene:
 Sources of microbial contamination during pharmaceutical
manufacturing.
 Importance of clean working areas and proper hygiene
practices.

8. Cleanliness of Working Areas:
 Importance of keeping working areas clean, dry, and tidy.
 Eliminating cracks and ensuring easy-to-clean surfaces.
 Rigorous disinfection policy and cleanliness inspection of
equipment
Prevention of Airborne Contamination:
 Prevention of contamination from dust and droplets in the
atmosphere.
 Clean air as a prerequisite during manufacturing processes.
 Closed systems for liquid preparations and creams/ointments.

9. Personal Hygiene and Training:
 Personnel as a potential source of contamination.
 High standards of personal hygiene and cleanliness.
 Adequate hand-washing, disinfecting facilities, and
protective garments.
 Training in GMP principles and basic microbiology.
Quality of Starting Materials:
 Raw materials as a significant source of microbial
contamination.
 Selection of materials with good microbiological quality.
 Acceptance of raw materials with non-pathogenic
microorganisms.
 Prevention of growth or survival through chemical or in-
process treatment.

10. Specific Considerations for Raw Materials:
 Microflora in materials of animal and plant origin.
 Statutory requirements for freedom from specific
pathogens.
 Refining processes and synthetic raw materials.
 Storage conditions and precautions for hygroscopic
substances.
Water in Pharmaceutical Manufacturing:
 Different grades of water used in manufacturing.
 Municipal water supply and treatment methods.
 Water for Injection (WFI) requirements and endotoxin
levels.
 Production methods for WFI and sterilization options.

11. Pharmaceutical Manufacturing Process Design :
 The manufacturing process must be fully defined and validated
before starting routine production operations.
 Microbiological acceptability and conformity to specifications are
essential.
 Processes and procedures should be regularly reappraised and re-
evaluated after significant changes in equipment or materials.
Quality Control and Documentation:
 Microbiological standards should be established for raw materials,
in-process samples, and the final product.
 Microbiological quality assurance includes validation of cleaning
and disinfectant solutions and monitoring of the production
environment.
 Operators' aseptic technique should be adequately trained and
monitored.
 Documentation is crucial for batch traceability and recall purposes.

12. Packaging, Storage, and Transport :
 Packaging serves the functions of containment, preventing
contaminants' entry, and facilitating identification.
 Primary packaging contains the product, while secondary
packaging is used for storage and transport.
 Considerations include packaging fabric, cleaning, and
compatibility with sterilization processes.
 Packaging material should not be a source of
contamination.
 Different types of containers (e.g., glass, plastic) require
specific treatments for sterilization or disinfection.

13. Packaging Materials and Microbial Contamination:
 Glass containers may contain mold spores and bacteria from cardboard
packaging but can be treated to remove contaminants.
 Plastic bottles usually have a low microbial count but may be
contaminated during transport in unsanitary packaging.
 Packaging materials with smooth, impervious surfaces have a lower
microbial count.
 Closure liners of pulpboard or cork can introduce moulds contamination.
 Closure sterilization can be done with formaldehyde or ethylene oxide gas.
Aseptic Manufacturing and Sterilization:
 Injectable and ophthalmic preparations manufactured
aseptically require sterilized packaging.
 Dry heat, moist heat, chemicals, or irradiation can be used for
sterilizing containers and closures.
 Validation of the sterilization process and establishment of
critical control points or risk assessment parameters are
necessary.

14. STERILE PRODUCT MANUFACTURING
Sterile Product Manufacturing:
 Terminal sterilization involves sealing the product in its
container and sterilizing it, usually by heat, ionizing radiation, or
ethylene oxide.
 Aseptic preparation involves using previously sterilized
materials or sterile filtration, with aseptic filling as a post-
sterilization step.
 Separate premises are needed for the filling of live or attenuated
vaccines and other products derived from live organisms.

15. Clean and Aseptic Areas: General Requirements:
 Sterile production should take place in a purpose-built unit
separated from other manufacturing areas.
 Internal surfaces, fittings, and floors must be smooth,
impervious, and easily cleaned to prevent particulate and
microbial contamination.
 Preferred materials for surfaces include plastic, epoxy-coated
plaster, plastic fiberglass, and glass-reinforced polyester.
 Well-sealed glass panels and flush doors and windows
promote visibility and supervision.
 Equipment must be designed for easy cleaning, sterilization,
or disinfection.

16. Services in Clean and Aseptic Areas:
 Adequate illumination with lights housed in translucent
panels is required.
 Electrical switches and sockets should be flush with the
wall or placed outside.
 Pipes and ducts entering the clean area must be sealed,
boxed in, or located above false ceilings to prevent dust
accumulation.
 Sinks should be stainless steel, without overflow, and
connected to effective, cleanable traps and drains.
 Air supply is critical, with filtered air at positive pressure
throughout the clean or aseptic area. Different levels of air
cleanliness are required for specific manufacturing
activities.

17. Air Supply and Monitoring:
 Filtered air is used to achieve required cleanliness
standards.
 The air should be maintained at positive pressure, with the
highest pressure in the most critical rooms (aseptic or
clean filling rooms) and a progressive reduction in
pressure through preparation and changing rooms.
 Air quality should be monitored for bacteria, fungi, and
particles.
 Airborne particle counters and slit samplers can measure
particles, while bacterial and fungal contamination can be
assessed through microbiological monitoring.

18. Operations in Sterile Manufacture:
 Minimize the number of personnel involved to reduce turbulence and
shedding of particles and organisms.
 Undertake all operations in a controlled and methodical manner to
avoid excessive activity that can increase turbulence and particle
shedding.
 Containers made from fibrous materials (e.g., paper, cardboard,
sacking) are heavily contaminated and should not be taken into clean
areas.
 Ingredients for clean areas should be transferred to suitable metal or
plastic containers.
Cleaning and Preparation of Containers Content:
 Containers and closures for terminally sterilized products should be
thoroughly cleaned before use.
 They should undergo a final washing and rinsing process using
pyrogenic distilled water, passed through a bacteria-proof membrane
filter, immediately prior to filling.
 Containers and closures for aseptic manufacture must be sterilized
after washing and rinsing, in preparation for aseptic filling.

19. GUIDE TO GOOD PHARMACEUTICAL MANUFACTURING
PRACTICE (GMP)
 The Guide to Good Pharmaceutical Manufacturing Practice, also
known as the "Orange Guide," covered essential GMP features in
the UK between 1971 and 1983.
 The guide was prepared by the UK Medicines Inspectorate in
consultation with various stakeholders.
 The principles of the Orange Guide were incorporated into the
EC Guide to Good Manufacturing Practice for Medicinal Products
in 1989.
 Currently, the Rules and Guidance for Pharmaceutical
Manufacturers and Distributors (2007) by the MHRA serves as
the publication for GMP guidelines.
 The FDA has its own publication called FDA Requirements for
cGMP Compliance (2007).
 Compliance with GMP is a crucial factor considered by the
licensing authorities when reviewing applications for
manufacturing licenses under the Medicines Act (1968).