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1. Quality Assurance of
Pharmaceuticals related to Plant
Design
Presented by
Siddhartha Mukherjee
M.Pharm(Pharmaceutics), Semester-II
Dept. of Pharmaceutics, Amity Institute of Pharmacy, Amity University,
Noida

2. CONTENTS
• Introduction
• Building construction
• Personnel
• Material flow pattern
• Effluent treatment
• Aseptic and sterilization process control
• Temperature, pressure & humidity control through AHU
• Tests for air flow pattern, microbiological monitoring)
• Manufacturing facilities (equipment's, water and AHU systems and their
validation ).

3. INTRODUCTION
QUALITY- The totality of features and characteristics of a product
or service that bear on its ability to satisfy stated or implied needs
• Drugs must be marketed as safe and therapeutically active
formulations whose performance is consistent and predictable.
• Pharmaceutical quality assurance (QA)—Sum of all activities and
responsibilities required to ensure that the medicine that reaches the
patient is safe, effective, and acceptable to the patient
• Good Manufacturing Practices (GMP)— GMPs are part of the quality
assurance activities that ensure that products are consistently
produced and controlled to the quality standards appropriate to their
intended use and required by the drug regulatory authorities.

4. CURRENT GOOD MANUFACTURING
PRACTICE (CGMP)

5. • FDA ensures the quality of drug products by carefully monitoring drug
manufacturers' compliance with its Current Good Manufacturing
Practice (CGMP) regulations.
• The CGMP regulations for drugs contain minimum requirements for
the methods, facilities, and controls used in manufacturing, processing,
and packing of a drug product. The regulations make sure that a
product is safe for use, and that it has the ingredients and strength it
claims to have.
• FDA can issue a warning letter or initiate other regulatory actions
against a company that fails to comply with Current Good
Manufacturing Practice regulations. Failure to comply can also lead to
a decision by FDA not to approve an application to market a drug.

6. BUILDING CONSTRUCTION
According to c-GMP guidelines of Sec. 211.42 Design and construction
features:
• Any building or buildings used in the manufacture, processing, packing, or
holding of a drug product shall be of suitable size, construction and location to
facilitate cleaning, maintenance, and proper operations.
Schedule M of Drug and Cosmetic Act- 1940 (Rules 71, 74, 76 and 78) for
good manufacturing practices and requirements of premises, plant and equipment
for pharmaceutical products
• The building(s) used for the factory shall be designed, constructed, adapted and
maintained to suit the manufacturing operations so as to permit production of
drugs under hygienic conditions. They shall conform to the conditions laid down
in the Factories Act, 1948 (63 of 1948)

7. • Sec 211.44 Lighting
Electrical supply, lighting, should be appropriate and such that they do not adversely affect
the pharmaceutical products along with taking account of the comfort of personnel
working
• Sec 211.46 Ventilation, air filtration, air heating and cooling
Production areas should be effectively ventilated, with air-control facilities to a sufficient
level to prevent contamination and cross-contamination, as well as control of temperature
and humidity.
• Sec 211.48 Plumbing
Premises should be carefully maintained, and it should be ensured that repair and
maintenance operations do not present any hazard to the quality of products
• Sec 211.52 Washing and toilet facilities
Facilities for changing and storing clothes and for washing and toilet purposes should be
easily accessible and appropriate for the number of users. Toilets should not communicate
directly with production or storage areas.

8. • Sec. 211.56 Sanitation
Premises should be cleaned and, where applicable, disinfected according to
detailed written guidelines. Records should be maintained.
• Sec. 211.58 Maintenance.
Any building used in the manufacture, processing, packing, or holding of a
drug product shall be maintained in a good state of repair.
• Sec.211.50 Sewage and refuse
Sewage, trash, and other refuse in and from the building and immediate
premises shall be disposed of in a safe and sanitary manner.

9. Regulatory Education for Industry (REdI): Focus on CGMPs & FDA Inspections

10. PERSONNEL
• Personnel engaged in the manufacture, processing, packing, or holding of a
drug product shall wear clean clothing appropriate for the duties they
perform. Protective apparel, such as head, face, hand, and arm coverings,
shall be worn as necessary to protect drug products from contamination.
• Personnel shall practice good sanitation and health habits.
• Only personnel authorized by supervisory personnel shall enter those areas
of the buildings and facilities designated as limited-access areas.
• Any person shown at any time (either by medical examination or
supervisory observation) to have an apparent illness or open lesions that
may adversely affect the safety or quality of drug products shall be excluded
from direct contact with components, drug product containers, closures, in-
process materials, and drug products until the condition is corrected or
determined by competent medical personnel not to jeopardize the safety or
quality of drug products.

11. MATERIAL FLOW PATTERN
• The overall facility as well as the individual process areas should always
take into consideration the most simplistic route of material flow and the
control of cross contamination.
• The 3 typical layouts for pharmaceutical manufacturing are as follows-
• CIRCULAR FLOW
• PARALLEL FLOW
• CROSSOVER TRAFFIC

12. CIRCULAR FLOW

13. PARALLEL FLOW

14. CROSSOVER TRAFFIC

15. EFFULENT TREATMENT
what is effluent?
liquid waste flowing out of a factory, farm, commercial establishment,
or a household into a water body such as a river, lake, or lagoon, or a sewer
system or reservoir.
• Sec.211.50 Sewage and refuse
Sewage, trash, and other refuse in and from the building and immediate
premises shall be disposed of in a safe and sanitary manner.
• Effluent can be treated in a number of different ways depending on the level
of treatment required. These levels are known as preliminary, primary,
secondary and tertiary (or advanced)
• The mechanisms for treatment can be divided into three broad categories:
physical, chemical and biological, which all include a number of different
processes
• Many of these processes will be used together in a single treatment plant

16. Treatment Level Description Process
Preliminary Removal of large solids such as rags,
sticks, grit and grease that may
damage equipment or result in
operational problems
Physical
Primary Removal of floating and settleable
materials such as suspended solids
and organic matter
Physical and chemical
Secondary Removal of biodegradable organic
matter and suspended solids
Biological and
chemical
Tertiary/advanced Removal of residual suspended
solids / dissolved solids
Physical, chemical and
biological

17. STERLIZATION PROCESS CONTROL
• The microbiological contamination of starting materials should be minimal,
and their bioburden should be monitored and whenever possible, products
intended to be sterile should preferably be sterilized by heat in their final
container.
• Before any sterilization process is adopted it must be validated, its
suitability for the product and its efficacy in achieving the desired sterilizing
conditions in all parts of each type of load to be processed should be
demonstrated by physical measurements and by biological indicators, where
appropriate.
• Sterilization can be achieved by the use of
moist heat
dry heat
Radiation
Gaseous

18. ASEPTIC PROCESS CONTROL
• The objective of aseptic processing is to maintain the sterility of a product
that is assembled from components, each of which has been sterilized by
one of the above methods.
• In order to maintain the sterility of the components and the product during
aseptic processing, careful attention needs to be given to:
The environment
The personnel
The container/closure sterilization and transfer procedures
The maximum holding period of the product before filling into the final
container
The sterilizing filter
• Certain solutions and liquids that cannot be sterilized in the final container
can be filtered through a sterile filter of nominal pore size 0.22 mm (or less)

19. AIR HANDLING UNIT
• AHU is a device used to condition and circulate air as part of a heating
ventilating and air-conditioning (HVAC) system.
• It is a large metal box containing a blower, heating or cooling elements,
filter racks or chambers, humidity & temperature control loops.

21. PRESSURE CONTROL
• Air infiltration of unfiltered air into a pharmaceutical plant can be the source of
contamination. Manufacturing facilities should be maintained at a positive pressure
relative to the outside, to limit the ingress of contaminants. Where facilities are to be
maintained at negative pressures relative to the ambient pressure to prevent the escape of
harmful products to the outside (such as penicillin and hormones), special precautions
should be taken.
• The pressure cascade regime and the direction of airflow should be appropriate to the
product and processing method used should be individually assessed according to the
product handled and level of protection required.
• pressure cascade system can assist in preventing cross contamination by application of the
displacement concept (low pressure differential, high airflow), or the pressure differential
concept (high pressure differential, low airflow).
• Building structure should be given special attention to accommodate the pressure cascade
design with airtight ceilings and walls, close fitting doors and sealed light fittings in place

23. DISPLACEMENT CONCEPT (LOW
PRESSURE DIFFERENTIAL, HIGH
AIRFLOW)
• This concept should ideally be applied in production processes where large
amounts of dust are generated.
• Under this concept the air should be supplied to the corridor, flow through
the doorway, and be extracted from the back of the cubicle.
• Normally the cubicle door should be closed and the air should enter the
cubicle through a door grille, although the concept can be applied to an
opening without a door.
• This displacement airflow should be calculated as the product of the door
area and the velocity, which generally results in fairly large air quantities.

24. PRESSURE DIFFERENTIAL CONCEPT (HIGH
PRESSURE DIFFERENTIAL, LOW AIRFLOW)
• The pressure differential concept may normally be used in zones
where little or no dust is being generated.
• The pressure differential should be of sufficient magnitude to ensure
containment not be so high as to create turbulence problems.

25. RELATIVE HUMIDITY
• Relative humidity should be controlled, monitored and recorded, where
relevant, to ensure compliance with requirements pertinent to the materials
and products, and to provide a comfortable environment for the operator
where necessary.
• Cubicles, or suites, in which products requiring low humidity are processed,
should have well-sealed walls and ceilings and should also be separated
from adjacent areas with higher humidity by means of suitable airlocks.
• Dehumidification (moisture removal) may be achieved by means of either
refrigerated dehumidifiers or chemical dehumidifiers.
• Humidifiers should be avoided if possible as they may become a source of
contamination (e.g. microbiological growth). Where humidification is
required, this should be achieved by appropriate means such as the injection
of steam into the air stream.

26. Mechanical/Refrigerative
Dehumidification
• Most Common
• Draws moist air over refrigerated coil using a small fan
• Saturation Vapor Pressure decreases with the decreasing temperature
• Moisture in air condenses and drips into collection bucket
• Air is then reheated by warmer part of refrigeration coil
• Most effective in high ambient and RH>45%

27. Desiccative Dehumidification
• Employs a desiccant material to produce a dehumidification effect
• Desiccant- a substance with the ability to attract moisture from the environment to
induce dryness
• Ex: Silica Gel
• More effective in low temps with low humidity
• Process
• Expose desiccant to high humidity air stream and allow it to absorb moisture
• Then expose to low humidity (reactivation) air stream to draw out retained
moisture
• Heat the reactivation air stream to remove moisture or have it exit the system

28. TEMPERATURE
• Systems that operate and are maintained at elevated temperatures, in the range of
70–80°C, are generally less susceptible to microbiological contamination than
systems that are maintained at lower temperatures.
• When lower temperatures are required due to the water treatment processes
employed or the temperature requirements for the water in use, then special
precautions should be taken to prevent the ingress and proliferation of
microbiological contaminants.
• Control of temperature in the system by pipeline heat exchange or plant room
cooling to reduce the risk of microbial growth (guidance value <25°C).

29. • In this type of airflow pattern, there will be substantial amount of turbulence
and it can be used in rooms where major contamination is expected from
external source i.e. compose air. This turbulence enhances the mixing of
trapped low and high particulate concentrations, producing a homogenous
particle concentration acceptable to the process.
• In this type of airflow pattern is a single pass, single direction air flow of
parallel streams. It is also called 'laminar‘ airflow since the parallel streams
are maintained within some angular deviation. Unidirectional cleanrooms
are used where low airborne contaminant levels are required, and where
internal contaminants are the main concern.