Parenteral,Sterile, Aseptic condition Air classification, Quantitative layout of parental manufacturing, Equipment as per schedule-M Environmental control zone presented by: Eknath Vasant Unde Rajarambapu college of pharmacy kasegaon sangali

1. Presented by : Mr. Eknath V. Unde
M.pharm (PharmaceuticalQuality assurance)
Guided By: Mrs. Archana Dhole
(AssistantProfessor)

2. Content
MANUFACTURING
LAYOUT
EQUIPMENTS

3. Introduction
 Sterile-Absolute terms the state of freedom from all
viable organism
 Type of sterile preparations
 OPTHALMIC
 PARENTERAL
 IRRIGATING PREPARATION
 DIAGNOSTIC AGENTS
 ALLERGIC EXTRACTS
 SURGICALS
 RADIO PHARMACEUTICALS

4. Parenteral:
 Definition:
 The dosage form for conveying a drug by means of injection
through the skin or mucous membranes.
Parenteral drugs are administered directly into the veins,
muscles or under the skin, or more specialized tissues such as
the spinal cord.
Circumvented the highly efficient first line body defense that is
skin and mucus membrane.
Thus they should be free from microbial contamination and
should have high purity.

5. TERMINOLOGY
 Aseptic-“without sepsis” Used to designate a practical level of sterility.
 Parenteral
 Sterile
 Alert level-An established microbial or airborne particle level giving early warning of
potential drift from normal operating conditions.
 Action Level-An established microbial or airborne particle level that, when exceeded,
should trigger appropriate investigation and corrective action based on the investigation.
 HVAC-Heating, ventilation, and air conditioning.
 Laminar flow of air-Airflow moves in a single direction and in parallel layers at constant
velocity.

6. Conti…
ULPA filter : Ultra-low penetration air filter with minimum
0.3 μm particle retaining efficiency of 99.999 percent.
LVP : A liquid intended for infusion and hermetically sealed
in a container of greater than 100 ml volume.
SVP : A parenteral preparation hermetically sealed in a
container of 100 ml or less volume.
Pyrogen : The fever producing lipid associated with
polysaccharide or polypeptide of microbial origin.
Sterilization : A process designed to completely eliminate or
destroy all living microorganism.

7. IMPORTANT PARENTERAL PREPARATON
 A.IV Admixtures consist of one or more sterile drug products added to an IV
fluid.
 Used for
 •Drugs intended for continuous infusion
 •For drugs that may cause irritation or toxicity when given by direct IV
injection.
 B.IV fluids
 These fluids have multiple uses,
 •Vehicles in IV admixtures
 •Provide means for reconstituting sterile powders
 •Serve as the basis for correcting body fluids and electrolyte disturbances
 •For administering parenteral nutrition
 STES

8.  Dextrose: Generally, a solution of 5% dextrose in water
 •pH of 5% dextrose ranges from 3.5-6.5. Instability may result if
it is combined with an acid sensitive drug.
 •In higher conc. (e.g. 10% solution in water), dextrose provides a
source of carbohydrate in parenteral nutrition solutions.
 •Should used cautiously in patients with diabetes mellitus.
 Sodium chloride :usually given as 0.9% solution called as normal
saline solution.
 Sterile sodium chloride for injection:
 •Used as vehicle in IV admixtures and fluid for electrolyte
replacement.
 Bacteriostatic sodium chloride for injection:
 •It contains an agent that inhibits bacterial growth (e.g. Benzyl
alcohol, Propylparaben. Methyl paraben), allowing its use in
multiple dose preparation.

9. Water
•Used for reconstitution and for dilution of IV
solutions such as dextrose and sodium chloride.
•Water suitable for parenteral preparations include
sterile water for injection and bacteriostatic water for
injection.
Ringer solutions
•Used for fluid and electrolyte replacement.
•Commonly administered to post surgical patients.
•It contains sodium lactate, sodium chloride,
potassium chloride, and calcium chloride.

10. C. Electrolyte preparation
•Ions present in both intracellular and extracellular fluid.
•Surgical and medical patients who can not take food by
mouth or who need nutritional supplementation require
the addition of electrolytes in hydrating solutions or
parenteral nutrition solutions.
D. Dialysate
•Used in patients with disorder as renal failure, poisoning,
and electrolyte disturbances.
•In peritoneal dialysis, a hypertonic dialysis is infused
directly into peritoneal cavity via a surgically implanted
catheter. It contains Dextrose and electrolyte, which
removes the harmful substances by osmosis and diffusion.

11. E. Irrigating solutions
Not intended for infusion into the venous system.
Topical administration
Used in irrigating wounds, moistening dressings, and
cleaning surgical instruments.
Infusion of irrigating solutions
Surgeons performing urological procedure often use
irrigating solution to perfuse tissues in order to
maintain the integrity of surgical field, remove blood,
and provide a clear field of view.

12. PARENTERAL PREPARATION
 Intravenous, Intraspinal, Intramuscular, Subcutaneous, and Intradermal.
No absorption
 Intravascular is necessary complete drug availability occurs
route immediately
 For all other routes, at least a blood vessel wall, and usually one or more tissue cell walls,
must be permeated before the drug can enter the circulation.
 Most often this occurs by passive diffusion and is most favourable when the drug has
both lipophilic and hydrophilic properties, with the former being predominant.
 So with nonvascular injection, absorption is also affected by such factors
 Size and number of blood vessels supplying the tissue,
 Physical & chemical properties of drug
 Characteristic of the dosage form as whether it is a solution, suspension or emulsion
 Nature of vehicle & its pH

14. Flow of the material:

15. TYPES OF PROCESSING:
 Terminal sterilization:
The product in its final container is subjected to a
sterilization process such as heat or irradiation.
In most cases, the product, container, and closure have low
bio-burden, but they are not sterile.
 Aseptic process:
The drug product, container, and closure are first subjected
to sterilization methods separately, as appropriate, and
then brought together.
Because there is no process to sterilize the product in its
final container, it is critical that containers be filled and
sealed in an extremely high-quality environment.

16. Types of Operationsfor TerminallySterilized Products:
GRADE Types of Operations for Terminally Sterilized Products
A. Filling of products, when unusually at risk
B. Placement of filling and sealing machines, preparation of solutions,
when unusually at risk.
C. Moulding, blowing (pre-forming) operations of plastic containers,
Preparation of solutions and components for subsequent filling
Note
Grade A and B correspond to with class 100, M 3.5, ISO 5
Grade C correspond to with class 10000, M 5.5, ISO 7
Grade D correspond to with class 100000, M 6.5, ISO 8

18. Parameters to be taken into consideration in the Design of a Parenteral
Production Facility:
 Environmental factors such as site selection, area planning,
space planning, design and construction features, traffic
flow of personnel and supplies, and service features.
1.Site selection
Criteria for site selection
Basic Factors
land availability, land cost, construction cost, taxes,
utility costs, labor availability,labor cost and so on
Pharmaceutical Important factor
Requires special consideration because of
unique pharmaceutical needs.

19. 2.Area planning
Area planning
Type of
production
Container size
Environmental
control plan
Product
Characteristics
Environmental
control zone
Space
Requirements

20. A. Type of Production:
Type of Production
Batch Operation Continuous Operation
Batch Operation :
It is suited to very high volume production requirements
•It requires more space and more complex equipments.
Advantages:
•Minimizes shortcoming of batch operations; labor, production time, and
environmental exposure of the product.
•Since the intermediate material handling steps are eliminated, the potential for product
contamination during those steps is no longer exists.

21.  Disadvantages:
I. Product quality assurance is difficult.
II. It is very difficult to document the ingredients or
process cycle for a product produced in a continuous
process.
B. Container size:
 SVPs and LVPs obviously requires different space
considerations.
 All the production equipment has container size
limitations-large container requires large equipments
and more space.

22. C. Environment control needs:
For aseptic filling
process Provision
For Sterilization and
Depyrogenation of
containers before filling,
normally hot air oven or
autoclave.
Provision must be
made for
Sterilization
An aseptic
environment with
the attendant
support rooms
Filling requires
Inspection and
Packaging

23.  Non aseptic filling, followed by terminal sterilization,
normally requires less rigid environmental control
Terminal sterilization
Eliminates
Eliminates the
sterilization prior to
filling
Following to
filling and sealing
An accumulation and segregation
area is required to accumulate the
product for transfer to the next
process step

24. D. Product characteristics:
 Liquid are probably the easiest product to handle.
 Emulsion may require compounding areas close to filling
lines to ease transfer problems. Pumping systems will be
very critical.
 Suspension will require a means of maintaining a
homogenous mixture prior to filling.
 To minimize the time the suspension resides in piping,
reservoir, and pump system, filling rate should be kept high
and the distance from compounding to filling should be
minimized.

25. E. Environmental control zone groupings:
Zones as per cGMPs
Zone7:-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:-ExteriorZones

26.  Zone as per Gazette of India:
 White zone:-Final step ( filling of parenteral )
 Grey zone:-weighing, Dissolution & filtration .
 Black zone:-Storage, Worst area from contamination view point.
Black
Grey
White

27. F. Space requirements:
Function Area Area
Square meter Percentage
Production 110094 45.1
Warehouse 7606 30.9
Administration 1018 4.1
Utility 1716 4.1
Quality control 1716 7.0
Maintenance 1014 4.5
Employes services 1014 4.1
Security 39 0.9

28.  Personnel flow :
Wrong flow Right flow
2
1
5
3
4
1
5
4 3
2

29. Change room:

30. Filling area
 The product & sterilized components are exposed to room
environment.
 Therefore these areas are specially constructed, filtered,
and maintained to prevent environmental contamination

31. Environmental control:
Sources Control
People Total body covering in critical are and partial covering in
noncritical area.
Adequate personal flow and restricted access to aseptic and
critical environment.
Barrier Adequate sterilization procedure
Protective laminar flow equipment
Barrier and separation between high risk and low risk
operation.
Material Adequate material control and selection.
Adequate sterilization and filtration procedure
Air Adequate air filtration system
Adequate monitoring of air cleanliness level.
Adequate air system validation procedure.

32. PERSONNEL & GOWNING:
No. of workers should kept to a minimum.
Training of personal
Personal hygiene:-All employees should be in good
health, Subjected to Physical examination,
Understood their responsibilities to report own illness
like cold, a sore throat, or other infection.
Clothing:
Uniform is made up of Dacron and Span polyethylene.
Hats & masks are sometimes made of special
parchment paper.
Foot wears plastic and rubber material.

33. Air Classification as per Schedule M:
Grade
Grade Maximum permitted number of particles/m3 equal or above
At rest In operation
0.5μm 0.5μm 0.5μm 0.5μm
A 3520 29 3500 29
B 35200 293 352000 293
C 352000 2930 3520000 2930
D 3520000 29300 Not defined Not defined

34. Air Classifications by USFDAguideline on Sterile DrugProducts:
Clean Area
Classification
<0.5 μm
Particles/ft3
<0.5 μm
Particles/mt3
Microbiolo gical limit
cfu/ft3 cfu/m3
100 100 3500 <1 <3
1000 1000 35000 <2 <7
10000 10000 350000 <3 <18
100000 100000 3500000 <25 <88

35. As per ISO:
Grade ISO Class Particle/cum Class/SI
A 5 100 3.5 M 3.5(filling)
B 6 1000 35 M 4.5
C 7 10000 350 M5.5(preparat
ion)
D 8 100000 3500 M 6.5

36. As per BritishPharmacopoeial Codex:
Class Maximum microorganism
1(A)HEPA filter every where <1
1(B)only at station 5
2 100
3 500

37. QUALITATIVE LAYOUT OF PARENTERAL MANUFACTURING
(parallel flow):

38. Layout for Aseptic Production:

39.  EQUIPMENTS

40. Thefollowingequipments asperSchedule-Marerecommended:
 Manufacturing area
 1.Storage equipment for ampoules, vials bottles and closures.
 2.Washing and drying equipment.
 3.Dust proof storage cabinet
 4.Water still.
 5.Mixing and preparation tanks or other containers.
 •The tanks or containers shall be made of either glass
or such materials as will not react with the liquid.
 6.Mixing equipment where necessary.
 7.Filtering equipment.
 8.Hot air sterilizer

41.  b)Aseptic filling and sealing rooms
 9.Benches for filling and sealing.
 10.Bacteriological filters.
 11.Filling and sealing unit under laminar flow work station.
 c)General Room
 12.Inspection table.
 13.Leak testing table.
 14.Labeling and packing benches.
 15.Storage of equipment including cold storage and refrigerators if necessary.

42. Sterile Garment cabinet
Stainless steel
Ensure a clean storage space by
making use of UV disinfectant and
heating through IR lamps.
These cabinets may be designed
in horizontal air flow system and
clean air through HEPA filters

43. Cooler or Cold Storage:

44. HEPA Filter:
 HEPA filters can remove at least 99.97% of airborne particles 0.3μm in diameter.
 HEPA filters are composed of a mat of randomly arranged fibres (poly-vinylidene
fluoride -PVDF)
 Key metrics affecting function are fibre density and diameter, and filter thickness.
 The air space between HEPA filter fibres is much greater than 0.3 μm. The common
assumption that a HEPA filter acts like a sievewhere particles smaller than the largest
opening can pass through is incorrect.
 Smaller pollutants and particles are mainly trapped (they stick to a fibre) by one of the
following three mechanisms
 1.Interception
 2.Impaction
 3.Diffusion

46. Laminar flow hoods:
 Clean air work benches are specially designed to ensure the aseptic preparation of
sterile products.
 •Air flow rates
 •0.3 m/s (vertical)
 •0.45 m/s (horizontal)
 •Introduction of personnel, equipment, and material into the work area provides
sources of particulate matter which may contaminate the product.
 •Very small particles are not heavy enough to settle due only to the force of gravity,
but instead are carried and directed by air currents. and if there is turbulent air,
particles may be driven into product.
 •Laminar air flow velocity satisfactorily sweeps the area yet does not create
unacceptable turbulence

47. Laminar flow hoods:

48. Rubber Stopper Washing Machine:

49. •Syringe Filling Machine
Characteristics
 Barrier isolators
 In-process check weighing
 Filling: rotary piston pumps.
 0.2 to 29 ml.
Filling :
 All types of syringe including glass, plastic can be
filled.
 300 to 600 syringes in a minute.

50. Syringe Filling Machine

51. Ampoule Washing Machine
 PROCESS
 Water is sprayed onto the ampoules.
 Turned to an angle of 180 degree with their mouth
downward to remove water.
 Finally the ampoules are filled with compressed air to
remove residual water.
 Certain machines have a high temperature zone meant
for killing any bacteria.

52. Ampoule Washing Machine

53. Vial Washing And Sterilizing Machine

54. •Vial Filling Machine
 Fill vials and bottles .
 liquids, viscous material and suspensions and
powders.
 PROCESS:
 The machine comprises of an intake section which
loads the vials.
 Transferred through an intermittent transport section.
 liquid filling section which fill the vials with
predetermined quantity.
 Finally the filled and rubber stopper vials are released
and discharged.

55. Vial Filling Machine

56. Fully automated inspection systems

57. Vial Labeling Machine

58. •Ampoule Filling Machine
 Filling range of these machines is normally between 1ml to
20 ml.Features of Ampoule Filling Machines
 Accommodate a variety of ampoules in terms of shapes and
size.
 'no ampoule no fill' capability
 Check weight mechanism of the machine helps to maintain
consistency in each batch.
 Sealing is done either by laser sealing system or
conventional gas flame. Application of Ampoule Filling
Machine
 •Pharmaceutical
 •Neutraceutical

59. Ampoule Filling Machine

60. Sip system
 For in-line sterilization of various processing
equipments.
 Handling various biological solutions and mixtures
requires cleaning and sterilizing these equipments
from time to time as they are susceptible to
contamination.
 Proper SIP integration with pharmaceutical
equipment is very important for the overall success of
the operation.

61. Sip system