GMP design of parenteral production facility

1. GMP-Design of
Parenteral Production Facility
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2. Content…
 Product characteristics,
 Personnel,
 Batch Vs continuous operation,
 Development of facility layout,
 Environmental control zones,
 Filling area design,
 Heating Ventilation Air Conditioning (HVAC),
 HEPA filter testing and rating,
 Laminar area flow systems.
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3. Background…
 Parenteral preparations are sterile, pyrogen-free liquids (solutions,
emulsions, or suspensions) or solid dosage forms containing one or more
active ingredients, packaged in either single-dose or multi-dose containers.
 They are intended for administration by injection, infusion, or
implementation into the body.
 Parenteral drugs are administrated directly into veins, muscles or under
the skin or more specialized tissues such as the spinal cord.
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4. Product characteristics
Safety (freedom from adverse toxicological concerns):
 Since parenteral drugs are directly injected into the body, they avoid the body’s
natural barriers. Therefore, all the components of the drug should be proven to
be safe at the quantity level it is injected.
 When selecting excipients to overcome drug’s solubility, stability, tonicity, and
delivery, a formulation scientist should carefully follow the safety requirements.
 Under the Drug and Cosmetic Act, pharmaceutical preparations should be tested
for safety in animals.
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5. Product characteristics
Sterility (freedom from microbial contamination)
 Many factors contribute to achieve and maintain sterility such as valid
sterile procedure for all components of manufacturing, valid procedure for
aseptic filtration, design and maintenance of clean rooms, validation of
aseptic processes, training and application of good aseptic practices, use of
antimicrobial preservatives for multi-dose products, valid testing for
sterility of the product and maintenance of container/closure integrity.
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6. Product characteristics
Nonpyrogenic (freedom from endotoxin contamination)
 Pyrogens are fever-inducing entities originating from microbial causing a
variety of complications in the human body.
 Limulus Amebocyte Lysate (LAL) test is used for the quantitative detection of
the bacterial endotoxins in all parenteral drug products.
 Various depyrogenation methods include cleaning validation, time limitations,
validated depyrogenation cycles for glassware, validation of pyrogen
/endotoxin removal from rubber closures and other items based on rinsing
techniques, validated water systems, and use of endotoxin free raw materials
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7. Product characteristics
Particle-free (freedom from visible particle contamination)
 Visible particulate matter implicates product quality and safety. Ready to use and
reconstituted solutions should be free from any visible particulate matter and must
meet compendial specifications for numbers of subvisible particles no greater or equal
to 10 or 25 micrometer.
 The factors contribute to the presence or absence of particulate matter include valid
cleaning methods of all equipment and packaging materials, valid solution filtration
procedures, adequate control of production and testing environments, adequate
training of personnel, testing and using sterile product solutions and employment of
required compendial testing procedures for detection of both visible and subvisible
particulate matter.
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8. Product characteristics
Stability (chemical, physical, and microbial)
 Parenteral drug products should be stable under predetermined manufacturing, packaging,
storage, and usage conditions. The chemical and physical stability should be maintained
throughout the shelf-life of the product.
 Complicated chemical structures and vulnerabilities to environmental conditions (temperature,
light, pH, shear, metal impurities, oxygen, etc.), therapeutic peptides and proteins offer
enormous challenges.
 Compounding, mixing, filtering, filling, stoppering, sealing, storing, shipping, and handling affect
the stability of the product.
 Many parenteral drugs are unstable in solution, which challenges their Lyophilization processes
further.
 Maintenance of sterility throughout the shelf-life and usage also affects the stability of the drug.
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9. Product characteristics
Compatibility (formulation, packaging, and other diluents)
 Many parenteral drugs are manipulated prior to injection.
 Lyophilized products should be reconstituted by sterile dilution,
and often combined with another solution or large volume infusion
fluid which may contain more than one drug already.
 This means the parenteral drug must be proven to be compatible
with other drugs may be administered together.
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10. Product characteristics
Isotonicity (isotonic with biological fluid)
 Biological cells maintain a certain concentration of ions , molecules, and other
aggregated species that give cells specific properties. Due to such properties
osmotic pressure is maintained across the semipermeable cell membrane.
 If a parenteral drug that is hypotonic to the biological solution of the cells, the
solvent from the injection can move into the cells can cause cell burst
(hemolysis of RBCs). If a parenteral drug is hypertonic, an injection could
cause cells to shrink, crenation.
 Ideally, any injection formulation should be isotonic with biological cells to
avoid any potential problems.
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11. Personnel
 The movement of personnel should be planned during the design of
individual plant areas.
 Each individual production area may have a smooth and efficient
personnel flow pattern, a discontinuous or crowded pattern may
develop when several individual production area plants are
combined.
 The flow of material and personnel through corridors are inefficient
and unsafe paths for moving materials, particularly if heavy forklifts
are required.
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12. Personnel
 Only the minimum number of personnel required should be present in clean
areas; this is particularly important during aseptic processes.
 All personnel (including those concerned with cleaning and maintenance)
employed in such areas should receive initial and regular training in
disciplines relevant to the correct manufacture of sterile products, including
hygiene and the basic elements of microbiology.
 Staff who have been engaged in the processing of animal-tissue materials or of
cultures of microorganisms may be restricted to enter in sterile area.
 Wrist-watches, cosmetics and jewelry should not be worn in clean areas.
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13. Personnel
 High standards of personal hygiene and cleanliness are essential and personnel
involved in the manufacture of sterile preparations.
 Changing and washing should follow a written procedure designed to minimize the
contamination.
 The clothing and its quality should be appropriate for the process and the grade of
the working area.
 It should be worn in such a way as to protect the product from contamination.
 Outdoor clothing should not be brought into changing rooms leading to Grade B and
C rooms.
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14. Personnel
 The clothing required for each grade is as follows:
 Grade D: The hair and, where relevant, beard and moustache should be covered.
Protective clothing and appropriate shoes or overshoes should be worn.
 Grade C: The hair and, where relevant, beard and moustache should be covered. The
clothing should shed virtually no fibres or particulate matter.
 Grades A and B: Entry of personnel into Grade A areas should be minimized. Sterilized,
non-powdered gloves of appropriate material and sterilized or disinfected footwear
should be worn.
 Clothing used in clean areas should be laundered or cleaned in such a way that it
does not gather additional particulate contaminants.
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15. Batch Vs continuous operation
 Batch Operation:
 Traditional pharmaceutical batch processing sees the different components of
a drug assembled through a step-by-step process.
 The current batch must be done before a new batch can be produced since
the materials go from phase to phase.
 In the process, there could be about six or seven phases that are performed
within six or seven pieces of equipment before a component is final.
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16. Batch Vs continuous operation
 Continuous Operation:
 Continuous pharmaceutical manufacture involves a drug being transported from its
base ingredients to the finished product, without having to pause during processing.
 This ensures that there is no need to shut down machines and no interruption when it
produces the commodity.
 Essentially, batch processing must pause during the production, step by step, while the
continuous process produces a product that has no need to pause until the product is
complete.
 Both technologies provide the producer with both benefits and drawbacks and each
one is a completely sound means of making a fantastic finished product, depending on
the needs.
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17. Advantages of Batch Production
 Probably the most significant benefit of batch processing is that originally, the
set-up costs are less.
 Each batch is more easily tailored to be unique.
 There are certain products and materials that require batch manufacturing due
to their composition or formula.
 Using batch processing, drug makers may manufacture fixed quantities of a
single commodity, and then adapt their manufacturing goals to the evolving
consumer demands.
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18. Advantages of Continuous Manufacturing
 Continuous manufacturing can be a potential to the problems associated
with batch manufacturing.
 Continuous pharmaceutical production is more time-efficient, decreases
energy costs, helps increase efficiency and lowers the gross loss.
 The probability of human error is minimized, as continuous manufacturing
ensures less people involved from start to finish in the production process.
 Many have asked about problems that could occur in the event of a recall
using the continuous production process, but with the use of lot numbers,
questions may be easily set away.
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19. Overview of manufacturing process of parenterals
Planning & scheduling
Manufacturing
requirement
Manufacturing
Bulk analysis
Sterilization
Aseptic filling
Q.C. TestingVisual inspection
Material management -
Raw material & API -
Packaging material
Warehousing
Equipment & facility
Documentation
Personal
Labelling & packing
Finishing
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20. Flow of materials
Ingredients
Vehicle
Solute
Compounding
of product
Processing
equipment
Container
component
Cleaning
Cleaning
Filtration of
solutes
Sterilization
Sterilization
Filling
Sealing
Packaging
Product storage
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21. Qualitative layout of parenteral manufacturing
Function
Area
Square meter Percentage
Production 11250 45
Warehouse 7750 31
Utility 1000 4
Quality control 1750 7
Administration 1000 4
Maintenance 1000 4
Employee services 1000 4
Security 250 1
Total 25000 100
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22. Environmental control zones
 Zones as per Gazzete of India
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 White zone: Final step (filling of parenteral),
 Grey zone: Weighing, dissolution & filtration,
 Black zone: Storage, worst area from
contamination view point.
Black
Gray
White

23. Environmental control zone grouping:
Zones as per the c GMP
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Zone 7: Filling Line
Zone 6: Filling Area
Zone 5: Weighing, mixing & transfer area
Zone 4: Clean area
Zone 3: General production
Zone 2: Warehouse
Zone 1: Exterior

24. Environmental control zone
 The walls of the filling area are the last physical barrier to the ingress of
contamination, but within the filling area a technique of contamination control
known as laminar flow may be considered as the barrier to contamination.
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For aseptic filling
process
Provision must be
made for
Sterilization and
Depyrogenation of containers
before filling, normally hot air
oven or autoclave.
Filling requires
An aseptic environment with the
attendant support rooms
Inspection and
packaging
Zone 7: Filling line

25. Environmental control zone
 Zone 6: Filling area
 Zone 6 is a distinct zone of the controlled environment area for an aseptic
filling process but may not be distinct zone for non-aseptic filling process.
 Zone 5: Weighing, mixing, and transfer area
 Zone 5 encompasses activities of “weighing, mixing, filling or transfer
operations” addressed by cGMP section 212.81 which are not handled as zone
6 but which require a controlled environment.
 Zone 4: Clean area
 Activities in this may include washing and preparations of equipment or
accumulation and sampling of filled product. 25

26. Environmental control zone
 Zone 3: General production and administration area
 The third zone of environmental controls is formed by the periphery of the
general production area. Only essential materials-handling equipment and
personnel.
 Zone 2: Warehouse
 It is a base point from which to work in determining the requirements for the
various control barriers.
 Zone 1: Plant exterior
 Control might include the maintenance of sterile areas around the facility.
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27. Filling area
 The product & sterilized components are exposed to room environment.
 Therefore these areas are specially constructed, filtered, and maintained to prevent
environmental contamination.
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28. Heating Ventilating and Air-Conditioning

29. HVAC System
 HVAC: Heating Ventilating and Air-Conditioning
 Heating: Heating is provided by heaters. Heaters are appliances whose purpose is to generate heat
for the building. This can be done via central heating or by direct heating system.
 Ventilation: Ventilating or ventilation (the V in HVAC) is the process of exchanging or replacing air in
any space to provide high indoor air quality which involves temperature control, oxygen
replenishment, and removal of moisture, odors, smoke, heat, dust, airborne bacteria, carbon dioxide,
and other gases. Ventilation removes unpleasant smells and excessive moisture, introduces outside
air, keeps interior building air circulating, and prevents stagnation of the interior air.
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30. HVAC System
 Air-Conditioning: An air conditioning system provides cooling and humidity control for all or part of
a building.
 Air conditioned buildings often have sealed windows, because open windows would work against the
system intended to maintain constant indoor air conditions.
 Dehumidification (air drying) in an air conditioning system is provided by the evaporator. Since the
evaporator operates at a temperature below the dew point, moisture in the air condenses on the
evaporator coil tubes.
 This moisture is collected at the bottom of the evaporator in a pan and removed by piping to a central
drain or onto the ground outside.
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31. Working of HVAC
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32. Functions of HVAC
 To control temperature.
 To control humidity.
 To develop differential pressure.
 To prevent cross contamination.
 To maintain proper air movement.
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33. Types of HVAC
 There are two types of Air-Conditioning system:
 Ducted,
 Non Ducted.
 Ducted includes:
 Chilled Water System &
 Dx System (Direct Expansion),
 Non Ducted includes:
 Window System &
 Split system.
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34. Components of HVAC
 Air Handling Unit (AHU):
 AHU are the lungs of any HVAC system.
 An air handling unit is a device used to regulate and circulate air as part of
the heating, ventilation and air conditioning system.
 The AHU takes in outside air, reconditions (filtered and either heated or
cooled) it and supplies it as fresh air to the air conditioned room.
 Air handler that conditions 100% outside air, and no recirculated air, is
known as a makeup air unit.
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35. Components of HVAC
 Filters in AHU: Filters are typically placed first in the AHU in order to keep all the
downstream components clean.
 Classification: Following types of filters are used.
 Standard Filters: Coarse Filters, Medium Filters, Fine filter
 Aerosol Filters:
 Efficient Particulate Air Filters (EPA) E10,E11,E12
 High Efficient Particulate Air Filters (HEPA) H13,H14
 Ultra Low Particulate Air Filters (ULPA) U15,U16,U17
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36. Components of HVAC
 Ducting System: Ducts are passages used in heating, ventilation, and air
conditioning (HVAC) to deliver and remove air.
 The needed airflows include, for example, supply air, return air, and exhaust air.
 Types of ducts:
 SAD: Supply Air Duct- It supplies air from AHU to the required area to be conditioned. This
air is treated air & contains all the desired qualities as provided by the air conditioning
system.
 RAD: Return Air Duct- It supplies air from conditioned area back to the AHU for
retreatment and recirculation or fully exhaust in the air.
 FAD: Fresh Air Duct- It supplies ambient/fresh air to the AHU from the outside atmosphere.
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37. Components of HVAC
 Grille: A fixed opening through which air passes. Typically used for return air applications. A
grill is used on the return side to protect the system from objects entering the intake. As a grill is
often used on the return side, it must be free of a damper to ensure the unrestricted flow of air
back to the central system.
 Register: A grille equipped with a damper which supplies conditioned air. Typically used for
supply air applications.
 Diffuser: An air flow device designed to discharge conditioned air in a specific direction, path,
or pattern. Used for supply air applications.
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38. 38
High Efficiency Particulate Air

39. High Efficiency Particulate Air
 HEPA is an acronym for “High Efficiency Particulate Air”.
 Synonyms:
 High-efficiency Particulate Absorbing and
 High-efficiency Particulate Arrestance
 This type of air filter can remove at least 99.97% of dust, pollen,
mold, bacteria and any airborne particles with a size of 0.3 μm.
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40. Types of HEPA
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Types Application Performance
A Industrial, Noncritical 99.97 % @ 0.3 µm
B Nuclear Containment 99.97 % @ 0.3 µm (certified by DOE)
C Laminar Flow 99.99 % @ 0.3 µm
D Ultra-Low Penetration
Air (ULPA)
99.9995 % @ 0.12 µm
E Stopping Toxic,
Nuclear, Chemical and
Biological Threats
99.999 % efficiency

41. Construction of HEPA
 HEPA filter is constructed of borosilicate microfibers in the form of pleated (folded) sheet.
 Sheet is pleated to increase the overall filtration surface area.
 The pleats are separated by serrated aluminum baffles or stitched fabric ribbons, which
direct airflow through the filter.
 This combination of pleated sheets and baffles acts as filtration medium.
 It is installed into an outer frame made of fire-rated particle board, aluminum, or stainless
steel.
 The frame-media junctions are permanently glued or ‘‘pot-sealed’’ to ensure a leak proof.
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42. HEPA FILTER
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43. Filtration Mechanisms
 Inertial Impaction: Particle inertia causes it to leave the
flow streamlines and impact on the fiber.
 Diffusion: The particles traverse the flow stream, they
collide with the fiber and are collected.
 Interception: These mid-sized particles follow the flow
stream as it bends through the fiber spaces. Particles
are intercepted or captured when they touch a fiber.
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44. HEPA in Laminar air flow systems
 Laminar air flow systems are used for cleaning air in
aseptic rooms.
 In laminar air flow systems, clean air is obtained through
HEPA filters
 This air flows at a speed of 100 ft/min & sweeps dust
particles making entire room free of particulate matter
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45. HEPA Filters
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46. Classification of clean rooms
 Six classes have been established to designate cleanroom cleanliness .
 Class 1
 Class 10
 Class 100
 Class 1,000
 Class 10,000
 Class 100,000
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47. Types of Laminar air flow systems
 Laminar air flow systems are of 3 types
 Downward flow systems
 Horizontal flow systems
 Wall to floor flow systems
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48. Downward flow systems
 This system consists of false floor & ceiling.
 3 filters are placed in false ceiling: pre-filters,
electrostatic filters and HEPA filters in sequence.
 From the false floor, a small portion of filtered air is
recirculated in to false ceiling through a recirculation
duct.
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49. Horizontal flow systems
 The air is filtered through prefilters, HEPA filters
which are placed in lateral walls.
 Air is recirculated through punched plate wall or
recirculation duct.
 Achievement of complete sterile conditions is not
possible because the airflow is not focused on working
area.
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50. Wall to floor flow systems
 The filtered air enters from lateral wall with an inclined flow towards
the floor.
 In this system working area is offered with high aseptic conditions.
 This system is more expensive.
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51. Damage of HEPA Filters
 Moisture: 95-100% relative humidity
 Hot air: greater than 275 °F
 Fire: direct fire or high concentrations of particulate matter produced by fire
 High pressure: 8 in. of water, gauge (in. wg) internal or differential across filter media.
 Corrosive : dilute moist or moderately dry concentrations of acids and caustics
 Any acid and some caustics will attack uncoated aluminum separators
 Hydrofluoric acid will attack the media
 Nitric acid
 Shock pressures. 51

52. Shipment, Storage, Handling
 The HEPA filter is extremely fragile and should be shipped,
stored, and handled in the same manner as delicate
instrumentation.
 Personnel responsible for receiving and handling HEPA filters
should receive training in proper handling technique.
 All incoming HEPA filters should be visually inspected for
apparent.
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