parenteral manufacturing requirements, clean room, change room, environment cross contamination, cleaning and disinfection ,heating ,ventilation and air conditioning HVAC ,HEPA ,PURIFICATION

1. PARENTERAL
MANUFACTURING
FACILITY

2. Requirements
General
 Parenteral dosage forms differ from other dosage form.
 Parenteral product directly enters into systemic circulation.
 Poor conditions at a manufacturing facility can ultimately pose a life-
threatening health risk to a patient.
 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.
PARENTERAL MANUFACTURING

3.  The quality of parenteral product depend on the following
• Quality of starting materials(ingrdients),
• Design of the premises
• The design and maintenance of the equipment and
• The method of manufacture and
• The Environment
 All these factors must be taken care such as to ensure the quality and
stability of the active substance and the final product which will be
sterile and free of pyrogens and particulate matter
 All personnel should be thoroughly and specially trained in their
operations as well as Good Manufacturing Practices and Hygienic
practices

4.  Personnel should follow Good Manufacturing Practices and hygienic
practices
 According to USFDA if a product is manufactured without following
GMP it is considered to be adulterated

5. MANUFACTURING FACILITY -DESIGN CONSIDERATIONS

6. • Clean rooms are the areas where
critical operations are carried out
WHAT IS A CLEAN ROOM
• A cleanroom/area is a modular
environment in which the
following environmental factors
are kept under control;
temperature, airborne
particulates, microbes, relative
humidity, differential pressure,
and air flow.
MANUFACTURING AREAS -CLEAN ROOMS /AREAS

7. Panelled Walls ,Ceiling
and flooring
 The production of sterile preparations should be
carried out in clean areas,
 Clean areas should be maintained to an
appropriate standard of cleanliness and supplied
with air that has passed through filters of an
appropriate efficiency(HEPA, High Efficiency
Particulate Air Filter)
 The various operations of component preparation
(such as containers and closures), product
preparation, filling and sterilization should be
carried out in separate areas within a clean area.

8. • Clean areas for the production of sterile
products are classified according to the
required characteristics of the air , in grades
A, B, C and D
• Tables and other surfaces used in
manufacturing facility must be smooth,
cleanable, and impervious to moisture and
other damage.
• All connections or junctions between ceilings,
walls, and floors cannot be 90 degree angles
but coved for easy cleaning.
Clean Rooms

9. • There should be no gaps, cracks, recesses, or
other defects that can harbors for microbial
contamination.
• Air systems, lighting, and communication systems
require special design to be easily accessible
without disturbing the normal air flow.
• Doors should be self-closing and interlocked so
only one door opens at a time.

10. INTERIORS OF PARENTERAL MANUFACTURING FACILITY

15.  Changing rooms should be designed as airlocks and used to provide
physical separation of the different stages of changing and so minimize
microbial and particulate contamination of protective clothing.
 They should be flushed effectively with filtered air.
 The final stage of the changing room should, in the at-rest state, be the
same grade as the area into which it leads.
 The use of separate changing rooms for entering and leaving clean areas
is sometimes desirable.
 In general hand-washing facilities should be provided only in the first
stage of the changing rooms.
CHANGE ROOMS

23. Environment
 Environmental control is a major concern in drug manufacturing.
 In parenteral manufacturing facility control of contamination and cross
contamination plays important role in maintaining quality of the finished
product
 There is substantial evidence establishing a direct relationship between
the level of environmental control and the final quality of the product
 Hence all operations should be carried out in clean and controlled areas
under strict environmental conditions

24. What are contaminants ?
Contaminants are
1.Products or substances other than product
manufactured
1. Foreign products
2. Particulate matter
3. Micro-organisms
4. Endotoxins (degraded micro-organisms)
Contamination and Cross contamination
Fungal Contamination of drug products

25. Bacteria contamination of drug products
A small percentage of products produced between 08/01/2017 and 04/2018
have tested positive for microbial contamination. Out of an abundance of
caution, we are recalling the products
King Bio is voluntarily recalling the below products to the consumer level

26. Cross-Contamination
What is Cross-Contamination ?
Contamination of a starting material, intermediate product, or finished
product with another starting material or product during production. (WHO)
Where does Cross-Contamination
originate?
 Poorly designed air handling systems and dust extraction systems
 Poorly operated and maintained air handling systems and dust extraction
systems
 Inadequate procedures for personnel and equipment

27.  Insufficiently cleaned equipment
Cross-contamination (in particular of unexpected contaminants) and
mix-ups (confusion) caused by,
 For example, false labels being put on containers.
 Unexpected contamination of products, causing health risk and
even death

32. Contamination and Cross-contamination can be minimized by:
• Adequate and well built premises
• Closed production systems
• Proper Cleaning and sanitation of areas and equipment, tools and
exposed surfaces
• Following proper procedures
• Following hygienic practices by personnel
• Adequate cleaning procedures
ENVIRONMENTAL CONTROL

33. CLEANING AND DISINFECTION PROCEDURES
 Ceiling, walls, and floor must be sealed, so they may
be washed and sanitized with a disinfectant, as
needed.
 Cleaning and disinfection procedures are an
important part of the environmental control
program.
 The objective is to remove debris and materials that
have been deposited or settled on surfaces and
reduce or eliminate the microorganisms present on
equipment, walls, floors and ceilings within the
aseptic environment

34.  Maintaining the clean and sanitized conditions
of clean rooms, particularly the aseptic areas
is of utmost importance
 A carefully planned cleaning schedule should
be developed, ranging from daily to monthly,
depending on the location and its relation to
the most critical areas.
 Tools used should be non-linting, designed for
clean room use, held captive to the area, and,
preferably, sterilizable.
 Liquid disinfectants (sanitizing agents) should
be selected carefully.
Sterile clean room wipes

36.  Ultraviolet (UV) light rays of 237.5 nm wavelength, as radiated by
germicidal lamps, are an effective surface disinfectant. However, it must
also be noted that they are only effective, if they contact the target
micro-organisms at a sufficient intensity for a sufficient time/
 Overnight exposure of surfaces to UV light is desirable.

37. PERSONAL HYGIENE AND HYGIENIC PRACTICES
 All personnel should be trained in the practices of
personal hygiene.
 All personnel, prior to and during employment,
should undergo health examinations.
 Personnel conducting visual inspections should also
undergo periodic eye examinations.
 All personnel should be trained in the practices of
personal hygiene.
 A high level of personal hygiene should be observed
by all those concerned with manufacturing
processes..

38.  In particular, personnel should be instructed to wash
their hands before entering production areas.
 Signs to this effect should be posted and instructions
observed
 Any person shown at any time to have an apparent
illness or open lesions that may adversely affect the
quality of products should not be allowed to handle
starting materials, packaging materials, in-process
materials or drug products

39.  Direct contact should be avoided between the operator’s hands
and starting materials, primary packaging materials and
intermediate or bulk product.
 Smoking, eating, drinking, chewing,, food, drink, smoking material
and personal medicines should not be permitted in production,
laboratory and storage area
 Personal hygiene procedures including the use of protective
clothing should apply to all persons entering production areas,
whether they are temporary or full-time employees or non-
employees,
e.g. contractors’ employees, visitors, senior managers, and
inspectors.

40.  Fumigation and fogging are two methods
commonly used in pharmaceutical companies to
control the microbial contamination in
controlled area . ...
 ULV ( Ultra low volume) fogger are generally used
for fogging. By these fogger machines solution is
sprayed in the area in form of aerosol.
Fumigation:
 Earlier this method used Formaldehyde solution
and Potassium permangnate chemical which are
kept in a dish
 The dish is kept in the center of sterile areas for
overnight .
FUMIGATION OF STERILE AREAS
Fumigator Converts
Formalin in to Aerosol
from Which is 100%

41.  The reaction is exothermic and fumes evolved used to spread the
entire area and disinfect the area
 There is a disadvantage that due to reaction the permanganate spills
on the floor and scars appear on the floor
 Hence now the Formaldehyde alone is used which is kept in the
bowl of fumigators .
 Fumigator generate the fumes and effectively kill the bacteria, fungi
and spores.
 Glutaraldehyde is also has got wide application

42.  This is very effective method for controlling the microorganisms.
 These chemicals are carcinogenic and cause irritation to the eyes,
nose and skin.
 After completion activity defumigation is required at least 6 hours.
Fogging
 Fogging is a safer technique.
 This technique used for killing of microorganisms.
 Which is directed by a blower and vaporized spray.

43.  This process require fogging machine and fogging solution (Fumigant).
 By these fogger machines solution is sprayed in the area in form of aerosol.
 The small particles of disinfectant solution suspend in the air for long time
and kill all the air borne bacteria,fungus and their spores.
 This is very effective way to control the contamination.
 The recommended ULV (Ulta Low Volume)fogger used for fogging.
 Fogging purpose Hydrogen peroxide vapor or Virosil is better.
 6% Hydrogen peroxide, 10% Hydrogen peroxide and 20% Hydrogen peroxide
used for better controlling of microbes.

44.  Virosil (mixer of Hydrogen peroxide 10% and Silver Nitrate
0.01%Approximate pH 1.5).
 Fogging is safer activity.
 Defogging is not necessary
operation :
 Before stating the Fogging/ Fumigation activity Keep the area Under
Fumigation/ Fogging.
 Stop the AHU Up to Closing the Fumigation/ fogging activity.
 After completion of the activity continuously circulate the AHU (Air
Handling Unit)at least 6 hours.

45. • Air is one of the greatest potential source of contamination in clean room, a
series of treatments and monitoring systems should be in place.
• Air from the outside is passed through a prefilter (glass wool, cloth, or
shredded plastic) that removes large particles and then, it is treated with an
electrostatic precipitator that removes charged particles. The air then passes
through the HEPA filter.
• HEPA filter can remove 99.97% of particles >0.3 mm. It is made with densely
packed fiberglass.
AIR PURIFICATION

46. HEATING ,VENTILLATION AND AIR CONDITINING
(HVAC)
Heating, ventilation and air-conditioning (HVAC) play an important
role in ensuring the manufacture of quality pharmaceutical products.
A well designed HVAC system will also provide comfortable conditions
for operators
What can HVAC do?
1. Control airborne particles, dust and micro-organisms – Thru air
filtration using high efficiency particulate air (HEPA) filters.

47. 2. Maintain room pressure (delta P) – Areas that must remain “cleaner”
than surrounding areas must be kept under a “positive” pressurization,
meaning that air flow must be from the “cleaner” area towards the
adjoining space (through doors or other openings) to reduce the chance
of airborne contamination.
3.Maintain space moisture (Relative Humidity) – Humidity is controlled by
cooling air to dew point temperatures or by using desiccant
dehumidifiers. Humidity can affect the efficacy and stability of drugs.
4. Maintain space temperature - Temperature can affect production
directly or indirectly by fostering the growth of microbial contaminants on
workers.

48. TYPICAL HVAC SYSTEM

49. AIR HANDLING UNIT

51. HEPA(HIGH EFFICIENCY PARTICULATE AIR)FILTER
 HEPA filter is EU-13 or EU-14 filter of 0.3micron.
 It means that particles of more than 0.3 microns per cubic ft cannot
pass through that filter.
 This filter is highly recommended in hospitals and pharma
industries to control contamination.
 This is generally installed in the end of the AHU or you can say is
the last filter in the ahu.

54. AIR CLASSIFICATION SYSTEM FOR MANUFACTURE OF STERILE
PRODUCTS
 Clean areas for the manufacture of sterile products are classified
according to the required characteristics of the environment.
 Each manufacturing operation requires an appropriate level of
environmental cleanliness in the operational state to minimize the
risks of particulate or microbial contamination of the product or
materials being handled.
Air classification of sterile production area:
 Warehouse (Unclassified)  Preparation/Washing of equipment
/components (Class 100,000)  Compounding of the product (Class
10,000) Class 1000 Filling Room  LAF Filling and rubber cap closing
area (Class 100)  Capping (Class 100,000 Sampling Class 10000 
Sterilization (Class 100000) Finishing/Packing (Unclassified)

55.  Clean room classifications are established by measurement of the number of
particles 0.3 micron and larger that are contained in a cubic feet of sampled
air.
 Generally class 100,1000,10000 and 100,000 rooms are used in the
pharmaceutical industry.
 Cleanrooms classifications differ for sterile and non-sterile areas
Critical Areas
 Critical areas of processing, wherein the product or product contact surfaces
may be exposed to the environment, even for a brief period of time, must
meet Class 100 clean room standards

56. U. S standards define “Critical Areas”, as the areas where Sterilized
operations are carried out. These shall have aseptic clean rooms.
Requirement - Air in “critical areas” is generally of acceptable particulate
quality if it has a per cubic foot particle count of not more than 100 in
size range of 0.3 micron and larger (Class 100) when measured in the
vicinity of the exposed articles during periods of activity.
 With regard to microbial quality, an incidence of no more than 0.1
colony forming units per cubic foot is acceptable.
In order to maintain air quality in sterile areas… laminar airflow at
velocity of 90 feet per minute ± 20 and, in general, a pressure differential
of at least 0.05 inch of water gauge (with all doors closed) is
recommended. No specific air change rate is specified

57.  To avoid cross contamination independent air handling systems should
be provided for various discrete operations like manufacturing,
coating, tabletting, inspection and packing.
 Dehumidifiers are used to control relative humidity (RH) to lower levels.
RH of 50±5%
Controlled Areas
 U.S standards define the “controlled area” as the areas where Non-
sterilized products are prepared.
 This includes areas where compounds are compounded and where
components, in-process materials, drug products and contact surfaces of
equipment, containers and closures, are exposed to the plant
environment

58. Requirement - Air in “controlled areas” is generally of acceptable
particulate quality if it has a per cubic foot particle count of not more
than 10000 and 100000(class 10000 and calss 100000) in size range
of 0.3 micron and larger when measured in the vicinity of the
exposed articles during periods of activity.

59. AIR CLASSIFICATION FOR STERILE MANUFACTURING FACILITY
AS PER SCHEDULE M
Grade
Maximum permitted number of particles/m3 equal or above
at rest in operation
0.3µm 5.0µm 0.3µm 5.0µm
A 3,520 29 3,500 29
B 35,200 293 3,52,000 2,930
C 3,52,000 2,930 35,20,000 29,300
D 35,20,000 29,300 not defined not defined
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

60.  For the manufacture of sterile pharmaceutical preparations, four
grades of clean areas are distinguished as follows:
• Grade A: The local zone for high-risk operations, e.g. filling and making
aseptic operations.
• Grade B:
In aseptic preparation and filling area , this is the background
environment for the Grade A zone.
• Grades C and D:
 Clean areas for carrying out less critical stages in the manufacture of
sterile products or carrying out activities during which the product is
not directly exposed (i.e. aseptic connection with aseptic connectors
and operations in a closed system).
 A unidirectional airflow and lower velocities may be used in closed
isolators and glove boxes.

64. COMPOUNDING AREA( STERILE PREPARATION
/MANUFACTURING )
 Although it is not essential that this area be
aseptic, control of micro-organisms and
particulates should be more stringent
than in the materials support area.
For example, provisions to control dust
generated from weighing and compounding
operations.
 Cabinets and counters should, preferably, be
constructed of stainless steel.

65.  The ceiling, walls, and floor should be similar to
those for the materials support area
ASEPTIC AREA
 Aseptic area requires construction features
designed for maximum microbial and particulate
control.
 All light fixtures, utility service lines, and
ventilation fixtures should be recessed in the
walls or ceiling to eliminate ledges, joints, and
other locations for the accumulation of dust and
dirt.

66.  Personnel entering the aseptic area should
enter only through an airlock.
 They should be attired in sterile coveralls
with sterile hats, masks, goggles, foot covers,
and double gloves.
 Movement within the room should be
minimal, and in-and-out movement rigidly
restricted during a filling procedure.

67. WATER PURIFICATION
• Water is widely used as a raw material,
inactive ingredient, medicinal vehicle, and
solvent in the processing, formulation, and
manufacture of pharmaceutical products
(dosage forms), active pharmaceutical
ingredients (apis), api intermediates,
compendial articles, and analytical reagents
as well as in cleaning applications.

68. WHY PURIFICATION?
Although tap water is reasonably pure, it is always variable due to
seasonal variations, regional variation in quality.
One must remove impurities and control microbes to avoid
contamination of products.
Pretreatment depends on quality of feed water.
Water contains,
Organic and inorganic impurities
Microbial contamination
Endotoxin
Particulate contamination

69. Low quality of water can lead to
product degradation
product contamination
loss of product and profit
Most organizations classify water purity levels as Type I, Type II,
and Type III, with Type I being the most pure
Water quality Applications Water purification
system
Type I General and non-critical
application
For general washing in
Pharma industry and
drinking
Chlorination Sand filter
,carbon filter , softener
,reverse osmosis ,UV
purification either alone
or in combination

70. Type II Standard application
For washing of equipment in
Pharma manufacturing facility
and glassware in lab and
manufacturing of oral dosage
and external dosage forms
Sand filter, carbon filter, De -
ionization (Anion and cation
exchanger and mixed bed
resins),reverse osmosis ,UV
purification
Type III Critical application
Sterile products
manufacturing
and testing in lab
Sand filter, carbon filter, De -
ionization (Anion and cation
exchanger and mixed bed
resins),reverse osmosis ,UV
purification and multiple
distillation ,distribution loop

71. • United States Pharmacopeia (USP) and other compendial specifications
for the water used in pharmaceutical manufacturing, Water for
Injection (WFI) limits the amount of endotoxins (0.25 EU/ml).
• WFI can be prepared by distillation or Reverse Osmosis (RO) or Ultrafiltration
(UF).
• The European Pharmacopeia (EP) permits distillation as the only process
for producing WFI, but the USP and Japanese Pharmacopeia (JP) allow
other technologies as well.
• Potential impurities in feed water (city water) include bacteria,
endotoxins, particles, electrolytes, organics, colloids, and disinfectants
such as chlorine.
• Water purification methods include:

72.  Distillation – a process of converting water from a liquid to its gaseous
form. Since steam is pure and other contaminants are removed.
Water purification methods include:
 Reverse Osmosis (RO) – pressure, 200-400 psig is applied to force pure
water to permeate through a semipermeable membrane that filters
contaminants.

73. • WFI is either collected in a holding tank or recirculated through facility
piping systems. The holding tank with several thousand gallon capacity
is normally kept at a constant 80 degree in Celsius to prevent microbial
growth (the requirement by the USP). If stored at room temperature,
any unused WFI should be discarded after 24 hours.
• USP and EP provide the official standards of purity for WFI.
 Inorganic content – water conductivity at 25 oC, <1.3 mS/cm
 Organic content – total organic carbon, <0.5 mg/L
 Pyrogen content – LAL test, <0.25 EU/ml
 Microbial content – total bacterial count, <10 CFU/100ml

74. PARENTERAL
MANUFACTURING
FACILITY
LAYOUT

75. Class 1000
Class
1000
Cooling
zone
for
Unloaded
sterilized
materials
Class 10000
Class 100000
Sterilisation
Dry Heat
Steriliser
Class 10000
Containers and closures
washing
Equipments
Washing
tools
Class
100
Class
10000
Class 1,00,000
Class 1,00,000

76. Sterilisers loading side –Materials to
be steriliused will be loaded from
this side
Unloading side -Sterilised material
will be unloaded into cool zone of
sterile areas
Dry
Heat
Steri
liser
Moist
Heat
Sterili
ser