Lesson - 20

Parenterals-I
(Plant lay out for Parenterals)
-Dr Mona Semalty
Department of Pharmaceutical Sciences,
H.N.B Garhwal University (A Central University)
Srinagar Garhwal-246174

Learning outcome

 Basic designing and lay out of a parenteral production unit

 General guidelines required for parenteral production and their
structural specifications
 Various facilities required for production of sterile products and their
performance (EU guidelines to GMP for manufacturing of sterile
products)

Lesson Plan

 Layout of the parenteral/sterile manufacturing area: Clean-up area,

Preparation area, Aseptic area, Quarantine area, Finishing and
packaging area
 Production facilities for parenteral/sterile product manufacturing:
Principle, Personnel, Premises, Equipment
 Environmental/Air control: HEPA filters /Laminar airflow/Validation
of HEPA Filters.

Production facilities for parenterals

The manufacturing of sterile products is subjected to special

requirements in order to minimize risks of microbial contaminations. General
broad guidelines say that that the area should be kept clean (pyrogen free) and
 Module 20 Parenteral 1 (Plant lay out for Parenterals)

strict precaution is taken to prevent contamination from outside. Ceiling &

walls & floors sealed & painted or treated with aseptic solution and there
should not be any toxic effect of this treatment. High efficiency filter is used
(HEPA) which removes particles up to 0.3 micron and arefitted in laminar air
flow system, in which air is free from dust & microorganisms flows with
uniform velocity. And UV lamps are fitted to maintain sterility.

Different areas for production of sterile products

 Clean- up area

 Preparation area

 Aseptic area

 Quarantine area

 Finishing and packaging area

Clean- up area:

MOOC: Industrial Pharmacy-I by Dr Ajay Semalty (Course Coordinator), HNB Garhwal

University (A Central University) Srinagar (Garhwal) Uttarakhand, India 2
 Module 20 Parenteral 1 (Plant lay out for Parenterals)

• Non-aseptic area

• Free from dust, fibers & micro-organisms and it should withstand

moisture, steam & detergent

• washing is done in this area

Preparation area:

• The ingredients are mixed & preparation is prepared for filling

• Not essential that the area is aseptic

Aseptic area:

• Filtration & filling into final containers & sealing is done

• The entry of outside person is strictly prohibited

• To maintain sterility, special trained persons are only allowed to enter

& work

Quarantine area:

• After filling, sealing & sterilization the products or batch is kept in

this area

• The random samples are chosen and given for analysis to QC dept.

• The batch is sent to packing after issuing satisfactory reports of

analysis from QC

• If any problem is observed in above analysis the decision is to be

taken for reprocessing or others.

Principle

The preparation of sterile products is carried out in specialized designed plant

layout as to minimize risks of microbiological and other contaminations. It
depends on the facilities of plant and on the skill, training and attitudes of the
MOOC: Industrial Pharmacy-I by Dr Ajay Semalty (Course Coordinator), HNB Garhwal
University (A Central University) Srinagar (Garhwal) Uttarakhand, India 3
 Module 20 Parenteral 1 (Plant lay out for Parenterals)

personnel involved. There are various guidelines by USFDA/ISO/EU. We

will be discussing detailed guidelines provided by EU to Good Manufacturing
Practice for manufacture of sterile products.

General guidelines say that

1. The manufacturing of sterile products should be carried out in clean

areas entry to which should be through airlocks for personnel and/or
for equipment and materials. Discuss three door air lock system

2. The various operations of component preparation, product preparation

and filing should be carried out in separate areas within the clean area.

3. Manufacturing operations are divided in two categories; firstly, those

where the product is terminally sterilized, and secondly those which
are conducted aseptically at some or all stages.

3. Clean areas for the manufacturing of sterile products are classified

according to the required characteristics of the environment.

For the manufacture of sterile medicinal products 4 grades can be

distinguished.

Grade A: The local zone for high risk operations, e.g. filling zone, stopper
bowls, open ampoules and vials, making aspects connections. Normally grade
A follows all the specifications for environment control.

Grade B: For aseptic preparation and filling, this is the background

environment for grade A zone.

Grade C and D: Clean areas for carrying out less critical stages in the
manufacture of sterile products.

Personnel

MOOC: Industrial Pharmacy-I by Dr Ajay Semalty (Course Coordinator), HNB Garhwal

University (A Central University) Srinagar (Garhwal) Uttarakhand, India 4
 Module 20 Parenteral 1 (Plant lay out for Parenterals)

 Only the minimum number of personnel required should be present in

clean area and all persons (including those concerned with cleaning
and maintenance) employed in such areas should receive initial and
regular training in disciplines relevant to the hygiene and the basic
elements of microbiology.
 Staff who have been engaged in the processing of biologicals like
animal-tissue materials or of cultures of microorganisms should not
enter sterile-product areas unless rigorous and clearly defined
decontamination procedures have been followed.
 High standards of personal hygiene and cleanliness are essential, and
personnel involved in the manufacture of sterile preparations. should
be instructed to report any conditions that may cause the shedding of
abnormal numbers or types of contaminants; periodic health checks
for such conditions are desirable. The action to be taken in respect of
personnel who might be introducing undue microbiological hazards
should be decided by a designated competent person.
 Outdoor clothing should not be brought into clean areas, and
personnel entering changing rooms should already be clad in standard
factory protective garments. Changing and washing should follow a
written procedure designed to minimize the contamination of clean
area clothing or the carry-through of contaminants to clean areas.
 Wristwatches and jewellery should not be worn in clean areas, and
cosmetics that can shed particles should not be used.
 The clothing worn and its quality should be appropriate for the process
and the grade of the working area (workplace). It should be worn in
such a way as to protect the product from contamination. 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. Appropriate measures should be taken to avoid any
contamination from outside the clean area.
MOOC: Industrial Pharmacy-I by Dr Ajay Semalty (Course Coordinator), HNB Garhwal
University (A Central University) Srinagar (Garhwal) Uttarakhand, India 5
 Module 20 Parenteral 1 (Plant lay out for Parenterals)

 Grade C. The hair and, where relevant, beard and moustache should
be covered. A single or two-piece trouser suit, gathered at the wrists
and with a high neck, and appropriate shoes or overshoes should be
worn. The clothing should shed virtually no fibers or particulate
matter.
 Grades A/B. Headgear should totally enclose the hair and, where
relevant, beard and moustache. A single or two-piece trouser suit,
gathered at the wrists and with a high neck, should be worn. The
headgear should be tucked into the neck of the suit. A face mask
should be worn to prevent the shedding of droplets. Appropriate,
sterilized, non-powdered rubber or plastic gloves and sterilized or
disinfected footwear should be worn. Trouser bottoms should be
tucked inside the footwear and garment sleeves into the gloves. The
protective clothing should shed virtually no fibers or particulate matter
and should retain particles shed by the body.
 Outdoor clothing should not be brought into changing rooms leading
to grade B and C rooms. For every worker in a grade A/B room, clean
sterilized or adequately sanitized protective garments should be
provided at each work session, or at least once a day if monitoring
results justify this. Gloves should be regularly disinfected during
operations. Masks and gloves should be changed at least at every
working session. The use of disposable clothing may be necessary.
 Clothing used in clean areas should be laundered or cleaned in such a
way that it does not gather additional particulate contaminants that can
later be shed. Separate laundry facilities for such clothing are
desirable. If fibers are damaged by inappropriate cleaning or
sterilization, there may be an increased risk of shedding particles.
Washing and sterilization operations should follow standard operating
procedures.

Premises

MOOC: Industrial Pharmacy-I by Dr Ajay Semalty (Course Coordinator), HNB Garhwal

University (A Central University) Srinagar (Garhwal) Uttarakhand, India 6
 Module 20 Parenteral 1 (Plant lay out for Parenterals)

 All premises should, as far as possible, be designed to avoid

the unnecessary entry of supervisory or control personnel.
Grade B areas should be designed so that all operations can be
observed from outside.
 In clean areas, all exposed surfaces should be smooth,
impervious and unbroken in order to minimize the shedding or
accumulation of particles or microorganisms and to permit the
repeated application of cleaning agents and disinfectants,
where used.
 To reduce the accumulation of dust and to facilitate cleaning,
there should be no uncleanable recesses and a minimum of
projecting ledges, shelves, cupboards and equipment. Doors
should be carefully designed to avoid uncleanable recesses;
sliding doors are undesirable for this reason.
 False ceilings should be sealed to prevent contamination from
the space above them.
 Pipes and ducts and other utilities should be installed so that
they do not create recesses, unsealed openings and surfaces
that are difficult to clean.
 Sinks and drains should be avoided wherever possible and
should be excluded from grade A/B areas where aseptic
operations are carried out. Where installed, they should be
designed, located and maintained so as to minimize the risks of
microbiological contamination; they should be fitted with
effective, easily cleanable traps and with air breaks to prevent
back-flow. Any floor channels should be open and easily
cleanable and be connected to drains outside the area in a
manner that prevents the ingress of microbiological
contaminants.
 Changing rooms should be designed as airlocks and used to
separate the different stages of changing, thus minimizing
MOOC: Industrial Pharmacy-I by Dr Ajay Semalty (Course Coordinator), HNB Garhwal
University (A Central University) Srinagar (Garhwal) Uttarakhand, India 7
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particulate and microbiological contamination of protective

clothing. They should be effectively flushed with filtered air.
The use of separate changing rooms for entering and leaving
clean areas is sometimes necessary. Hand-washing facilities
should be provided only in the changing rooms, not in areas
where aseptic work is done.
 Airlock doors should not be opened simultaneously. An
interlocking system and a visual and/or audible warning
system can be installed to prevent the opening of more than
one door at a time.
 A filtered air supply should be used to maintain a positive
pressure and airflow relative to surrounding areas of a lower
grade under all operational conditions; it should flush the area
effectively. Adjacent rooms of different grades should have a
pressure differential of approximately 10–15 pascals.
Particular attention should be paid to the protection of the zone
of greatest risk, i.e. the immediate environment to which the
product and the cleaned components in contact with it are
exposed. The various recommendations regarding air supplies
and pressure differentials may need to be modified where it
becomes necessary to contain certain materials, e.g.
pathogenic, highly toxic, radioactive or live viral or bacterial
materials or products. The decontamination of the facilities and
the treatment of air leaving a clean area may be necessary for
some operations.
 It should be demonstrated that airflow patterns do not present a
contamination risk; for example, care should be taken to ensure
that particles from a particle-generating person, operation or
machine are not conveyed to a zone of higher product risk.
 A warning system should be included to indicate failure in the
air supply. An indicator of pressure difference should be fitted
MOOC: Industrial Pharmacy-I by Dr Ajay Semalty (Course Coordinator), HNB Garhwal
University (A Central University) Srinagar (Garhwal) Uttarakhand, India 8
 Module 20 Parenteral 1 (Plant lay out for Parenterals)

between areas where this difference is important, and the

pressure difference should be regularly recorded.
 Consideration should be given to restricting unnecessary
access to critical filling areas, e.g. grade A filling zones, by
means of a physical barrier.

Equipment

 A conveyor belt should not pass through a partition between a

grade A or B clean area and a processing area of lower air
cleanliness, unless the belt itself is continuously sterilized (e.g.
in a sterilizing tunnel).
 Whenever possible, equipment used for processing sterile
products should be chosen so that it can be effectively
sterilized by steam or dry heat or other methods.
 As far as possible, equipment fittings and services should be
designed and installed so that operations, maintenance and
repairs can be carried out outside the clean area. Equipment
that has to be taken apart for maintenance should be re-
sterilized after completing reassembly, wherever possible.
 When equipment maintenance is carried out within a clean
area, clean instruments and tools should be used, and the area
should be cleaned and disinfected again, where appropriate,
before processing recommences if the required standards of
cleanliness and/or asepsis have not been maintained during the
maintenance work.
 All equipment, including sterilizers, air-filtration systems, and
water treatment systems, including stills, should be subject to
planned maintenance, validation and monitoring; its approved
use following maintenance work should be documented.
 Water-treatment plants and distribution systems should be
designed, constructed and maintained to ensure a reliable
MOOC: Industrial Pharmacy-I by Dr Ajay Semalty (Course Coordinator), HNB Garhwal
University (A Central University) Srinagar (Garhwal) Uttarakhand, India 9
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source of water of an appropriate quality. They should not be

operated beyond their designed capacity.
 Consideration should be given to include a testing programme
in the maintenance of a water system. Water for injection
should be produced, stored and distributed in a manner which
prevents the growth of microorganisms, e.g. by constant
circulation at a temperature above 70 °C or not more than 4 °C.

Environment control/Air control

As we know that preparation of sterile product requires strict control over

protection against microbial contaminations. Surrounding environment and air
can be greatest source of contamination. It can be mi- nimised by using
special bacterial and particulate filters. Air for aseptic area is then passed
through high efficiency particulate air (HEPA) filters. HEPA filters are highly
efficient it can remove 99.7% of all particles 0.3 μm or larger. A positive
pressure is maintained relative to corridors, to prevent outside air from
entering aseptic areas.

A Laminar air flow system is used. It provides an effective means for

environment control of an aseptic area. Laminar air flow system contains
three basic elements-a blower, a high efficiency air filter, and a plenum. The
flow is called laminar because the turbulent air upstream is changed by the
filter into a straight-line flow off the downstream face of the filter. Many
blowers, many filters, and very large plenums but all have the same basics.
The necessity of laminar air flow is to remove most of the particulate matter,
as a matter of fact 99.99% of everything air-borne down to 0.3 microns
should be screened out to have an environment whose air supply is free of
bacteria, fungi, pollen, and practically all air-borne dirt.

Horizontal Flow
(Laminar Flow Hood)
MOOC: Industrial Pharmacy-I by Dr Ajay Semalty (Course Coordinator), HNB Garhwal
University (A Central University) Srinagar (Garhwal) Uttarakhand, India 10
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Air blows towards worker

Used for non-chemotherapy preparations

Vertical Flow
(Biological Safety Cabinet or Chemotherapy Hood)
Air blows from top down to maintain sterility and protect the worker

The HEPA filters validated by DOP-dioctylphthalate-method.

When manufactured, DOP liquid plasticiser, heated to the point of

vaporization and reconstituted into 0.3-micron particles to form a
monodisperse aerosol. These single size particles are diluted with air until a
conc. of 100 μg per litre is reached and aerosol mixture allow to be passed
through the filter. The amount of penetration is measured on the downstream
side with a forward light scattering photometer, giving the familiar reading of
0.03% or better studies were made of the effect of different size leaks on
typical types of work such as photoresist, microweld, sterile transfers, and the
like where it was shown that a leak of 0.01% was the border at which reject
rates began to increase and excessive contamination was detected for in-situ
DOP test this also represents the linear mass photometer threshold accuracy.

MOOC: Industrial Pharmacy-I by Dr Ajay Semalty (Course Coordinator), HNB Garhwal

University (A Central University) Srinagar (Garhwal) Uttarakhand, India 11
 Module 20 Parenteral 1 (Plant lay out for Parenterals)

Air Classification system monitors the numbers of particle accepted and

permitted in the manufacturing area. (It is defined as the number of particles
per cubic foot of air that are larger than 0.5 μm in diameter. e.g. Class 100,
Class 1000, Class 10000).

MOOC: Industrial Pharmacy-I by Dr Ajay Semalty (Course Coordinator), HNB Garhwal

University (A Central University) Srinagar (Garhwal) Uttarakhand, India 12
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Table 1: Clean Room Classification

Table 2: Air Borne Particulate Classification

Table 3: LAF Specifications

MOOC: Industrial Pharmacy-I by Dr Ajay Semalty (Course Coordinator), HNB Garhwal

University (A Central University) Srinagar (Garhwal) Uttarakhand, India 13
 Module 20 Parenteral 1 (Plant lay out for Parenterals)

Summary

In this module we have discussed about layout of the parenteral/sterile

manufacturing area. These areas may be classified as Clean-up area,
Preparation area, Aseptic area, Quarantine area, Finishing and Packaging
area. Production facilities for parenteral/sterile product manufacturing:
Principle, Personnel, Premises and Equipment are also discussed in details
.Environmental/Air control includes (HEPA filters /Laminar
airflow/Validation of HEPA Filters).

Further Readings

 https://www.terrauniversal.com/uploads/tech_resources/verticalvshori
zontallaminarflow150121_052815154749.pdf
 Federal standard 209 E: Clean room and workstation requirements:
Controlled Environment

References

 Semalty et al., Essentials of Pharmaceutical Technology, II Edn, 2018,

Pharma Med press, Hyderabad, India, ISBN 9789386819994.
 Good manufacturing practices for sterile pharmaceutical products. In:
WHO Expert Committee on Specifications for Pharmaceutical
MOOC: Industrial Pharmacy-I by Dr Ajay Semalty (Course Coordinator), HNB Garhwal
University (A Central University) Srinagar (Garhwal) Uttarakhand, India 14
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Preparations. Thirty-sixth report. Geneva, World Health Organization,

2002 (WHO Technical Report Series, No. 902), Annex 6; and in
Quality assurance of pharmaceuticals. A compendium of guidelines
and related materials. Vol. 2. 2nd updated ed. Good manufacturing
practices and inspection. Geneva, World Health Organization, 2007;
and in Quality Assurance of Pharmaceuticals. A compendium of
guidelines and related materials. Geneva, World Health Organization,
2010 (CD-ROM).
 Federal standard 209 E: Clean room and workstation requirements:
Controlled Environment
 ISO 14644-1. Clean rooms and associated controlled environments.
Part 1: Classification of airborne particles. Geneva, International
Organization for Standardization.
 ISO 14644-3. Clean rooms and associated controlled environments.
Part 3: Test methods. Geneva, International Organization for
Standardization.
 ISO 1822-4. High efficiency air filters (HEPA and ULPA).
Determining leakage of filter elements (scan method).
 ISO 14644-4. Clean rooms and associated controlled environments.
Part 4: Design, construction and start-up. Geneva, International
Organization for Standardization.
 ISO 14644-2. Clean rooms and associated controlled environments.
Part 2: Monitoring for continued compliance with ISO 14644-1.
Geneva, International Organization for Standardization.
 ISO 14644-5 Clean rooms and associated controlled environments.
Part 5: Cleanroom operations. Geneva, International Organization for
Standardization.
 Remington: The Science and Practice of Pharmacy, Lippincott
Williams & Wilkins, New York, Vol.–1, 21st. edn, 2006.

MOOC: Industrial Pharmacy-I by Dr Ajay Semalty (Course Coordinator), HNB Garhwal

University (A Central University) Srinagar (Garhwal) Uttarakhand, India 15
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 Boylan JC, Nail SL, In; Banker GS, Rhodes CT (Eds). Modern
Pharmaceutics. 2005 (Vol. 121) Marcel Dekker, Inc. New York,
Basel, US, pp 381-414.

MOOC: Industrial Pharmacy-I by Dr Ajay Semalty (Course Coordinator), HNB Garhwal

University (A Central University) Srinagar (Garhwal) Uttarakhand, India 16