Chapter 6-Sterile Products(encrypted).pdf

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1. CHAPTER-6
Sterile products
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2. Objective

At the end of these chapter, the students will able to

+ addresses the manufacturing and packaging of sterile products (parenteral,
ophthalmic, irrigating solutions)

+ Differentiate different types of parenteral

+ Understand product development, vehicles, solutes, containers during

manufacturing of sterile products

+ Know the principle of production design facilities, steps in processing,
packaging

+ Understand aseptic room & processing, quality control and quality assurance

+ Differentiate ophthalmic and other sterile preparations

BY:-Assefa Atimo (MSc in Pharmaceutics)

3. Give example of sterile products?

@X What do you mean by sterile products?

Why parenteral products are unique among dosage forms of
drugs?

Manufacturing way for sterile product is the same as other

dosage forms?
O BY:-Assefa Atimo (MSc in Pharmaceutics)

4. OUTLINE

° Sterile Products

+ Introduction

Parenteral products

Types of parenteral

Product development, vehicles, solutes, containers

Production design facilities, steps in processing, packaging

Aseptic room & processing, quality control and quality assurance

+ Ophthalmic and other sterile preparations

BY:-Assefa Atimo (MSc in Pharmaceutics)

5. Introduction

e Sterile products are dosage forms of therapeutic agents that are free
of viable microorganisms
+ Principally, these include parenteral, ophthalmic, and irrigating
preparations
+ Of these, parenteral products are unique among dosage forms of
drugs because

e they are injected through the skin or mucous membranes into

internal body compartments.

BY:-Assefa Atimo (MSc in Pharmaceutics)

6. Introduction.....

e Thus, because they have circumvented the highly efficient first line
of body defense, i.e. the skin and mucous membranes,
+ they must be free from microbial contamination and toxic
components, as well as
+ possess an exceptionally high level of purity
+ All components and processes involved in the preparation of these
products must be selected and designed to eliminate, as much as

possible, contamination of all types,

+ whether of physical, chemical, or microbiologic origin.

BY:-Assefa Atimo (MSc in Pharmaceutics)

7. Parenteral products

e In parenteral dosage form, we breech the barrier (i.e., the skin
which is one of the tough barriers of human body) with the help of a
needle

e Parenteral preparations may be given by various routes:

e intravenous, intramuscular, subcutaneous, intradermal and

intraperitoneal

BY:-Assefa Atimo (MSc in Pharmaceutics)

8. Introduction.....

Intrayenous

BY:-Assefa Atimo (MSc in Pharmaceutics)

Subcutaneous

9. Discuss in Group

+ Discuss various routes of parenteral preparations. like ——
+ Intravenous(IV), ee po ot Nana \
+ Intramuscular(IM), wine y eos \
+ Subcutaneous(SC), son for each \
+ Intradermal(ID) and preter? enter cad \

« Intraperitoneal(IP) “eve EN wi

+ What is the difference between
+ Parenteral Solutions, Suspension & Emulsion

+ In terms of components, is parenteral liquid dosage form differ from other dosage
forms? Why?

O BY:-Assefa Atimo (MSc in Pharmaceutics)

10. Types of Parenteral products

Parenteral

Parenteral Parenteral Emulsion

Solutions Suspension

11. Types of Parenteral...

Parenteral Solutions

Most of the products are in solution form.

Drug solutions suitable for parenteral administration are

known as injections/injectables.

Injectable solutions are prepared by dissolving drug (active
ingredients) and excipients, maintaining a specific pH.
e After this solution is filtered through 0.22 um membrane

filter and finally autoclaved (if thermostable)

Assefa Atimo (MSc in Pharmaceutics)

12. Types of Parenteral...
Parenteral Suspension

e The solids content of parenteral suspensions usually ranges between
0.5 and 5%, but may go as high as 30% in some antibiotic
preparations

° The amount of solids and the nature of the vehicle determine
+ the viscosity of the product, an important factor because of syringeability,
+ the facility with which the product is passed in and out of a syringe.

e The property of thixotropy is sometimes utilized

BY:-Assefa Atimo (MSc in Pharmaceutics)

13. Types of Parenteral...
Parenteral Emulsion

e The principal problem in the formulation of parenteral emulsions is

+ the attainment and maintenance of uniform oil droplets of 1 to 5

um in size as the internal phase.
e With emulsions, separation of the phase does not occur as readily as

with suspensions because

+ the difference in density between the oil and water is relatively

small

BY:-Assefa Atimo (MSc in Pharmaceutics)

14. Types of Parenteral...

Parenteral Emulsion.....

+ The dispersed phase should have droplet sizes of <1 um.
+ The emulsion must be stable to autoclaving

e Elevated temperatures tend to produce coalescence of the dispersed
phase, and excessive shaking cause acceleration of the rate of

creaming.

e Small amounts of gelatin, dextran and methylcellulose have been
found to aid in stabilizing the emulsions

BY:-Assefa Atimo (MSc in Pharmaceutics)

15. Types of Parenteral...
Parenteral Emulsion.....
+ The preparation of a parenteral emulsion is troublesome.

+ It is made more difficult by the rigid requirement for particle
size control to prevent emboli in blood vessels,

+ by the limited choice of emulsifiers and stabilizers of low toxicity,
and

+ by the preservation of the oil phase against the development of
rancidity

BY:-Assefa Atimo (MSc in Pharmaceutics)

16. Product development,
Vehicles, Solutes, Containers

BY:-Assefa Atimo (MSc in Pharmaceutics

17. Product development

e The final objective in the development of a sterile product is
+ the elicitation of a therapeutic effect in a patient
+ The formulation of a sterile product involves

+ the combination of one or more ingredients with a medicinal
agent to enhance the convenience, acceptability, or

effectiveness of the product
+ Requirements for components related to the product formula and

+ its stability are considered in the product development

BY:-Assefa Atimo (MSc in Pharmaceutics)

18. Product development....

+ Certain excipients are unique to each category of parenteral
formulations

e Depending on type of preparation, we choose the suitable excipients.
+ Selection of excipients depends upon various factors, i.e.,

+ the solubility of therapeutic agents,

+ the route through which parenteral is being administered,

+ amount of volume, and A

+ onset of action ei sas
“product canbe és

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19. Product development....
e Basic Principles of Sterile Product Formulation Development
e Active Pharmaceutical Ingredient (API) & excipients
+ Drug Product Formulation
+ Stability and Compatibility
+ Processability and Scalability
+ Admixture studies, patient in-use studies,
+ Administration device development and

+ Administration device compatibility

© BY:-Assefa Atimo (MSc in Pharmaceutics)

20. Therapeutic Agent(API)

e Atherapeutic agent is a chemical compound subject to the physical
and chemical reactions characteristic of the class of compounds to

which it belongs

e Therefore, a careful evaluation must be made of every combination
of two or more ingredients to ascertain whether or not adverse
interactions occur, and
e if they do, modify the formulation so that the reactions are

eliminated or minimized

BY:-Assefa Atimo (MSc in Pharmaceutics)

21. Therapeutic Agent(AP))....
+ Information concerning basic properties must be obtained, including

+ molecular weight, solubility, purity, colligative properties, and
chemical reactivity, before an intelligent approach to formulation

can begin.
e Improvements in formulation are a continuing process, since

+ important properties of a drug or of the total formulation may not
become evident until the product has been stored or used for a

prolonged time

e BY:-Assefa Atimo (MSc in Pharmaceutics)

22. Vehicles or Solvent System
/ Y N

« What do you mean by vehicles?

« The most frequently employed vehicle for
Discuss sterile products is water. Why?
in group «It is sometimes necessary to eliminate water

entirely or in part from the vehicle? Why?

« What do you mean by co-solvents? )

(22) BY:-Assefa Atimo (MSc in Pharmaceutics)

23. Vehicles or Solvent....

e Vehicle is a medium which provides a medium to a
system to carry a drug

+ Types of vehicles:-
+ Aqueous Systems

e Non-aqueous and Mixed Solvents

BY:-Assefa Atimo (MSc in Pharmaceutics)

24. Aqueous-Based Vehicle
+ The most frequently employed vehicle for sterile products is
water, since

e it is the vehicle for all natural body fluids

e The superior quality required for such use is described in the

monograph on Water for Injection in the USP

e Requirements may be even more stringent for some products

BY:-Assefa Atimo (MSc in Pharmaceutics)

25. Aqueous-Based.....

+ In USP, there are three different types of water used in

pharmaceutical preparations, i.e.,

+ water for injection,
e sterile water for injection, €
+ bacteriostatic water for injection

e Water shall contain a minimal amount of organic compounds
e Such compounds are undesirable for two main reasons:
they may be toxic, and/or

they may serve as sources of nutrition for microorganisms

BY:-Assefa Atimo (MSc in Pharmaceutics)

26. Aqueous-Based.....
+ One of the most inclusive tests for the quality of water is the
total solids content,

+ a gravimetric evaluation of the dissociated and
undissociated organic and inorganic substances present in
water

+ However, a less time consuming test, the electrolytic
measurement of conductivity of water, is the one most

frequently used

BY:-Assefa Atimo (MSc in Pharmaceutics)

27. Aqueous-Based.....
+ Methods of producing high-purity water, such as

e distillation and reverse osmosis, can be expected to remove

undissociated substances along with those that are dissociated.

+ Undissociated substances such as pyrogens could be present in

the absence of ions and not be disclosed by the test

e Therefore, for contaminants other than ions, additional tests

should be performed

O BY:-Assefa Atimo (MSc in Pharmaceutics)

28. Non-aqueous and Mixed Solvents
+ In the formulation of sterile pharmaceutical products,

+ it is sometimes necessary to eliminate water entirely or in part

from the vehicle, primarily because of solubility factors or
hydrolytic reactions

e Anon-aqueous solvent must be selected with great care for
+ it must not be irritating, toxic, or sensitizing, and

+ it must not exert an adverse effect on the ingredients
of the formulation

BY:-Assefa Atimo (MSc in Pharmaceutics)

29. Non-aqueous and....
+ The screening of such a solvent must include
+ an evaluation of its physical properties, such as
density, viscosity, miscibility and polarity, as well as
+ its stability, solvent activity, and toxicity
e Solvents that are miscible with water, and that are usually used in
combination with water as the vehicle, include

+ dioxolanes, dimethylacetamide, butylene glycol, polyethylene glycol

400 and 600, propylene glycol, glycerin, and ethyl alcohol

O BY:-Assefa Atimo (MSc in Pharmaceutics)

30. Non-aqueous and....
e Water-immiscible solvents include
+ fixed oils, isopropyl myristate, and benzyl benzoate.

e The most frequently used non-aqueous solvents are

+ polyediylene glycol, propylene glycol, and fixed oils

BY:-Assefa Atimo (MSc in Pharmaceutics)

31. Solvent selection

+ Aparenteral therapeutic agent is given by preference as a

solution

+ If aqueous, the solution is physiologically compatible with body
tissues, and
+ the biologic response elicited should be reasonably predictable

+ Conversely, water is a poor solvent for nonpolar compounds, such as

+ alkaloidal bases, which require non-polar solvents

BY:-Assefa Atimo (MSc in Pharmaceutics)

32. Solvent selection....

e Adding to the complexity of solvent selection is
+ the requirement that solvents to be injected must be of low toxicity to
body tissues.
+ Ether is a solvent for testosterone, but
+ is highly irritating to body tissues and
cannot be used alone as a solvent for an injectable preparation.
+ The desired solubility can be achieved with mixed solvents,

+ e.g. the use of approximately 40% ethanol in water to solubilize the

digitalis glycosides

BY:-Assefa Atimo (MSc in Pharmaceutics)

33. Solvent selection....

+ Compounds that are dissolved in water are often subject to
degradative reactions, such as
+ hydrolysis, oxidation, decarboxylation, and racemization
+ Formulation must be designed to minimize the degradative
effects
+ Often, these reactions are markedly affected by the pH of the solution
+ Epinephrine in solution undergoes racemization and oxidation, but

e if the pH is maintained at 3.0 or less, little reaction occurs

BY:-Assefa Atimo (MSc in Pharmaceutics)

34. Solvent selection....

e The oxidation reaction can be further reduced by
+ displacing atmospheric oxygen with an inert head space gas and
+ adding 0.1% (w/v) sodium metabisulfite as an antioxidant.

e Atropine sulfate rapidly hydrolyzes in solution, but
e if the pH is maintained with a buffer system at about 3.5 to 4.0,

hydrolysis does not occur at a significant rate

BY:-Assefa Atimo (MSc in Pharmaceutics)

35. BY

Solutes(Properties of Drug )

The physical and chemical purity of solutes used for sterile
preparations must also be exceptional.

+ the contaminants entering a product with a solute have the same
effect as if they entered via the vehicle

Even small traces of contaminants may be detrimental to products,

+ necessitating purification of the solute.

In addition, solutes should be free from microbial and pyrogenic
contamination

Assefa Atimo (MSc in Pharmaceutics)

36. Added Substances

BY

Substances added to a product to enhance its stability are essential for

almost every product.

Such substances include

+ solubilizer, antioxidants, chelating agents, buffers, tonicity
contributors, antibacterial agents, antifungal agents, hydrolysis
inhibitors, antifoaming agents, and numerous other substances for
specialized purposes.

At the same time, these agents must be prevented from adversely

affecting the product

Assefa Atimo (MSc in Pharmaceutics)

37. Added Substances ,,.....

+ In general, added substances must be nontoxic in the quantity
administered to the patient.

+ They should not interfere with the therapeutic efficacy or with
the assay of the API

+ They must also be present and active when needed throughout
the useful life of the product.
+ Therefore, these agents must be selected with great care, and must

be evaluated as to their effect upon the entire formulation

BY:-Assefa Atimo (MSc in Pharmaceutics)

38. BY

Containers

Containers are in intimate contact with the product

No container presently available is totally non-reactive,

particularly with aqueous solutions

Both the chemical and physical characteristics affect the

stability of the product, but

+ the physical characteristics are given primary consideration

in the selection of a protective container

Assefa Atimo (MSc in Pharmaceutics)

39. Containers....

e Glass containers traditionally have been used for sterile products,
many of which are closed with rubber stoppers

e Interest in plastic containers for parenteral is increasing, and such
containers are

+ being used for commercial ophthalmic preparations and IV
solutions

40. Containers....

Plastic Containers

+ The principal ingredient of the various plastic materials used for
containers is the thermoplastic polymer (which melt at elevated

temperatures)
e Added ingredients for special purposes
+ are not usually chemically bound in the formulation and, therefore,

may migrate out of the plastic and into the product under the

conditions of production and storage

BY:-Assefa Atimo (MSc in Pharmaceutics)

41. Containers...

+ Plastic containers are used mainly because
+ they are light in weight, are non-breakable, and, when low in

additives, have low toxicity and low reactivity with products

O BY:-Assefa Atimo (MSd

42. Containers....

Glass Containers
e Preferred material for containers for injectable products
+ Composed principally of the silicon dioxide tetrahedron,
+ modified physicochemically by such oxides as
those of sodium, potassium, calcium, magnesium, aluminum,
boron, and iron
+ The two general types of glass are soda-lime and

borosilicate

BY:-Assefa Atimo (MSc in Pharmaceutics)

43. Containers...
+ The glass that is most resistant chemically is composed almost
entirely of silicon dioxide, but

e it is relatively brittle and can only be melted and molded at high

temperatures
+ Boric oxide somewhat modifies the above characteristics as
+ it enters the structural configuration

BY:-Assefa Atimo (MSc in Pharmaceutics)

44. Containers...

Chemical Resistance

+ The USP provides the Powdered Glass and the Water Attack tests for
evaluating chemical resistance of glass
+ The test results are measures of the amount of alkaline constituents

leached from the glass by
purified water under controlled elevated temperature conditions;
+ The Powdered Glass test is performed on ground, sized glass
particles, and

e the Water Attack test is performed on whole containers.

B

Assefa Atimo (MSc in Pharmaceutics)

45. Containers....

e USP glass types, test limits and selection guide

Type General description Typeof test

I Highly-resistant
borosilicate glass

II Treated soda-lime
glass
Ill Soda-lime glass

NP General-purpose
soda-lime glass

Powdered glass

Water attack

Powdered
glass
Powdered
glass

BY:-Assefa Atimo (MSc in Pharmaceutics)

Test limits

Size mlof002N
(ml) H,SO,
All 10

100 or less 0.7
over 100 0.2

All 85

All 15.0

General use

Buffered and unbuffered
aqueous solutions. All
other uses

Buffered aqueous solu-
tions with pH below 7.0.
Dry powders, oleaginous
solutions

Dry powders, oleaginous
solutions

Not for parenterals. For
tablets, oral solutions and
suspensions, ointments,
and external liquids

46. Containers...

Physical Characteristics

+ The protection of light-sensitive products from the

degradative effect of ultraviolet rays
e Ultraviolet rays can be completely filtered out by the use of
amber glass; however,

+ the colour of amber glass is produced largely by the presence of
iron oxide, traces of which may subsequently be leached into the

product.

BY:-Assefa Atimo (MSc in Pharmaceutics)

47. Containers...

+ If the product contains ingredients subject to iron catalyzed chemical

reactions, amber glass cannot be used.
e The product must then be protected from ultraviolet rays by

+ means of an opaque carton surrounding a flint (colourless) glass container.
+ In addition to other physical characteristics, glass containers should have

+ sufficient physical strength to withstand the high pressure differentials

+ a low coefficient of thermal expansion to withstand the thermal shocks

+ transparency to facilitate inspection of the contents

BY:-Assefa Atimo (MSc in Pharmaceutics)

48. Containers...

Rubber Closures
e Are used to seal the openings of cartridges, vials, and bottles,

e Providing a material soft and elastic enough to permit entry and
withdrawal of a hypodermic needle

+ without loss of the integrity of the sealed container

BY:-Assefa Atimo (MSc in Pharmaceutics)

49. Devices
e Devices are the various items of equipment used to convey the
product from its container into the body of the patient or from one
container to another
e Devices associated with sterile products include the following:

Administration sets for large volume barenterals (LVPs)
Plastic LVPs containers

Filter needles

Hypodermic needles Plastic ophthalmic dropping bottles
Hypodermic syringes Transfer needles

In-line filters Transfer sets

Plastic irrigating solution bottles

O BY:-Assefa Atimo (MSc in Pharmaceutics)

51. Devices....

ara

Measured Volume Set with Blood Transfusion Set IV Set With Y-Site
Fluid

IV Set With Tube Latex IV Set With Bulb Latex Measuring Volume Set for
Blood Transfusion

O BY:-Assefa Atimo (MSc in Pharmaceutics)

52. 4
Devices...
e The materials used for devices are mostly the same as those used for

containers

+ For example, nylon and silicone rubber are used for i.v. catheters,
and stainless steel is used for hypodermic needles.

+ Parts of a device that do not come into contact with the product,

such as

+ the clamp on an i.v. administration set, need not pass product

stability evaluation

BY:-Assefa Atimo (MSc in Pharmaceutics)

53. Production design
facilities,

O Steps in processing,

® Packaging

BY:-Assefa Atimo (MSc in Pharmaceutics)

54. PRODUCTION

+ The production process includes

+ all of the steps from the accumulation and combining of the
ingredients of the formula to the enclosing of the product in

the individual container for distribution
+ Intimately associated with these processes are

+ the personnel who carry them out and the facilities in which

they are performed

BY:-Assefa Atimo (MSc in Pharmaceutics)

55. Production....

+ To enhance the assurance of successful manufacturing operations,
+ all process steps must be carefully reduced to writing after being

shown to be effective

+ These written process steps are often called standard operating

procedures (SOPs)

+ Extensive records must be kept to give assurance at the end of
the production process that all steps have been performed as

prescribed

BY:-Assefa Atimo (MSc in Pharmaceutics)

56. | Production Desian Facilities

e Manufacturing of sterile pharmaceuticals and medical devices requires
e clean room, which is a controlled environment where the limit
for the number of specified size is properly maintained
° The construction of the rooms for sterile manufacturing needs

+ a proper design which minimizes generation, introduction, and

retention of the particles

© BY:-Assefa Atimo (MSc in Pharmaceutics)

57. Production Design....

+ Other key parameters which include
e temperature, humidity, air flow filtration/velocity, and pressure are

the trigger factors to be controlled for ensuring production of the

aseptic products
e For parenteral drug manufacturing, environmental control is the major
challenge to be addressed, because

+ quality of the final products is directly influenced by the processing
environment

BY:-Assefa Atimo (MSc in Pharmaceutics)

58. Production Design....

e The objective of environmental control in a sterile facility is
+ to minimize the presence of all contaminants (both viable and
non-viable)
e Microorganisms and dust particles suspended in the air are most
likely to gain access to the product; therefore,

+ an adequate environmental control program is needed

BY:-Assefa Atimo (MSc in Pharmaceutics)

59. Production Design....

e The following are the most imperative facilities that are required for

ensuring and controlling the aseptic environment for the sterile

products:

4.

Heating, Ventilation, and Air Conditioning (HVAC) system
Personnel contamination control systems
Cleaning and disinfection of the area

Environmental monitoring systems

BY:-Assefa Atimo (MSc in Pharmaceutics)

60. HVAC System

+ HVAC systems are considered the most imperative component
of the environmental control systems design.

+ The main objective of HVAC system is to ensure
+ the required standard environmental conditions for

manufacturing of the pharmaceutical products

BY:-Assefa Atimo (MSc in Pharmaceutics)

61. HVAC System....

BY

e Several components of an HVAC system can be segregated as
follows:

+ Blowers and fans for air generation

+ Cooling, heating, humidifying, and dehumidifying system for
air conditioning

+ Metal ducts for air distribution networks

e Air filtration equipment's, depending upon the type of manufacturing

For sterile manufacturing, HEPA filters are installed

Assefa Atimo (MSc in Pharmaceutics)

62. HVAC System....

+ For designing an effective HVAC system,

+ Some of the operational parameters need to be defined, since these

parameters are considered critical for aseptic processing
Temperature and Humidity Control
Pressure Differential Control

Airborne Contamination Control

Personnel Contamination Control Systems
Cleaning and Disinfection of the Area

Environmental Monitoring Systems

BY:-Assefa Atimo (MSc in Pharmaceutics)

63. Air Handling Unit

a a |

Cooling Tower to KE

Heat

Fan Exchanger:
Water/Air
Cool Water Hot Water
—
Condensor
Expansion
Valve Electric Chiller
— Evaporator

Chilled Water

BY:-Assefa Atimo (MSc in Pharmaceutics)

64. Steps in processina

Identification and confirmation of raw materials

Materials and Equipments

BY:-Assefa Ati

Fig. Process Flow Chart of Parenteral Manufacture

65. Steps in processing...

Equipment and Facility

Rsepiic fing >)

Labeling and Packing

BY: Assefa Aumo (| Figure, Overview of Manufacturing Process of Parenteral

66. ae, _, Compoundig_, ieaion = =
sola of product of solution cs q

=>?

Processing

. — Cleaning
equipment

— Siezaton — Filing — Seaing packaging — PM

storage
/
Container i si
— Cleanin — Sterilization
component 9

BY:-Assefa Atimo (MSc in Pharmaceutics)

Figure. Material Flow in Parenteral Unit

67. Packaaina

BY

It must be particularly dignified, neat, and attractive in appearance
e if it is to convey to the user the quality, purity, and reliability
The package also must accurately and completely provide the user
with the information necessary for its use

The labeling should be legible and the identity and strength of the
drug clearly distinguishable

+ This is particularly difficult with the small containers used for

many sterile products

Assefa Atimo (MSc in Pharmaceutics)

68. Packaging.....
e Packaging requirements for injections are given by the USP
+ The volume of an injection in single-dose containers should provide the

amount specified for administration at one time and in no case is more than
one liter

+ Preparations intended for intraspinal, intracisternal, or peridural
administration should be packaged only in single-dose containers

+ No multiple-dose container shall contain a volume of injection more than is

sufficient to permit the withdrawal of 30 ml

The operation of the packaging department for sterile products is

essentially the same as for other pharmaceutical packaging departments.

BY:-Assefa Atimo (MSc in Pharmaceutics)

69. Aseptic room & processing

What is aseptic room?

+ The aseptic area is a specially designed area & constructed
with the intention of preventing the microbial contamination
of pharmaceutical products

e Along with the construction of the aseptic area,

it is also mandatory to train the aseptic area workers about

all the precautions of the aseptic area

© BY:-Assefa Atimo (MSc in Pharmaceutics)

70. Aseptic room &.....

e Aseptic processing is the processing of commercially sterile
products being
e filled into commercially sterile containers under aseptic

conditions

+ What is a clean room for aseptic processing?
+ Acleanroom should be a controlled area with minimal

contamination of surface and air

BY:-Assefa Atimo (MSc in Pharmaceutics)

71. Classification of....

+ Aseptically prepared products:

+ These are the products which are prepared within aseptic
environment and are packed by closed system of aseptic
transfer

+ It does not undergo sterilization step after packing. Why?

+ Terminally sterilized products:
+ These are the products which are sterilized in the final

container

BY:-Assefa Atimo (MSc in Pharmaceutics)

72. Classification of...

a b
{PRODUCT | [CONTAINER | PRODUCT | [CONTAINER]

à À
FILL/CLOSE }< {DEPYROGENATE|

STERILE FILTER/
FILL/CLOSE

STERILIZE/
DEPYROGENATE

A comparison of (a)
terminal sterilization and (b) aseptic
processing in sterile manufacturing.

O BY:-Assefa Atimo (MSc in Pharmaceutics)

73. Classification of Clean Room

BY

Sterile manufacturing involves different sections, such as
¢ compounding, filling, and packaging section

Each section requires different standards for environmental

cleanliness

Clean rooms are classified on the basis of cleanliness level in

terms of viable particle and non-viable particles

Assefa Atimo (MSc in Pharmaceutics)

74. Classification of....

+ The most universally applied classification was based on ISO 14644-1
e Based on the required standard of cleanliness,

e clean room may be divided into critical area and supporting area
e Critical area is the area for sterile manufacturing, where

+ manufacturing containers, formulation ingredients, primary

packaging material, and closures are exposed to environment

BY:-Assefa Atimo (MSc in Pharmaceutics)

75. Classification of....

e Critical area must be designed in such a way that it ensures sterility

of the final products, while
+ the supporting area is the area adjacent to the critical area.
e For aseptically produced products,

e it is very imperative to control environmental cleanliness to the

highest standard

+ However, terminally sterilized products require less stringent

control compared to aseptic manufacturing

BY:-Assefa Atimo (MSc in Pharmaceutics)

76. Classification of....
e Clean areas for the manufacture of sterile products are

e classified according to the required characteristics of the

environment

according to the quantity and size of particles per cubic

meters of air

° The cleanrooms classification is given on two different conditions:

1. “At-Rest” and ae \

2. “In-Operation” — prtter anat \

O BY:-Assefa Atimo (MSc in Pharmaceutl

77. Classification of....

e The greatest threat to cleanrooms is airborne particles that cause

contamination
e Common contaminants are
e skin particles, fibers, dust, grease, bacteria, viruses, metals,
fungi, ions and film
e Cleanroom classifications are established by

+ measurement of the number of particles 0.5 micron and larger

that are contained in 1 ft3 of sampled air

BY:-Assefa Atimo (MSc in Pharmaceutics)

78. Classification of....
+ Classification should be clearly differentiated from operational
process environmental monitoring

e Air Classification—Grades A, B, C and D:

The air system shall be provided
with the appropriate filters such

as HEPA for grades A, B and C

O BY:-Assefa Atimo (MSc in Pharmaceutics)

79. Classification of....

Q The maximum number of particles permitted “at rest”

condition shall approximately be as follows:

|. Grade A corresponds with class 100, M 3.5, or ISO class 5

ll. Grade B corresponds with class 1000, M 4.5, or ISO class 6
Il. Grade C corresponds with class 10,000, M 5.5, or ISO class 7

IV. Grade D corresponds with class 100,000, M 6.5, or ISO class 8

+ Generally, class 100 to 100,000 rooms are used in the pharmaceutical industry

O BY:-Assefa Atimo (MSc in Pharmaceutics)

80. Classification of....

+ The maximum permitted airborne particle concentration for each grade is given:-

ISO 14644-1 Cleanroom Standards

FED STD 209E
equivalent

Maximum Particles/m*

>=0.1pm >-02um >=03pm >=0.5yum >=1 um >=5 um
10 2
100 24
1,000 237

4
35

10
102

Class 1

10,000 2,370 1,020 352 83 Class 10
100,000 23,700 10,200 3,520 832 29 Class 100
1,000,000 237,000 102,000 35,200 8,320 293 Class 1,000

352,000 83,200 2930 Class 10,000
3,520,000 832,000 29,300 Class 100,000

z
8

35,200,000 8,320,000 293,000 Room Air

+ NB:-class 100 is the area where the particle count must not exceed a total of

© 3,520 particles per ms of a size 0.5 microns and larger.

81. Classification of...

e The requirement and limit for the area shall depend on the

nature of the operation carried out.

Q Types of Operations to be Carried Out in the Various Grades for Aseptic
Preparations

Grade Types of Operations for Aseptic Preparations

Aseptic preparation and filling

B Background room conditions for activities requiring grade A
C Preparation of solution to be filtered
D Handling of components after washing

BY:-Assefa Atimo (MSc in Pharmaceutics)

82. Classification of....

° Clean room requirement for aseptically prepared products and
terminally sterilized products

Sterile manufacturing Clean room requirement Pressure differential
Terminally sterilized
Solution preparation Class D +15 pa next to outside
Component preparation Class D +15 pa next to outside
Filling (usually) Class B*/C* +15 pa adjacent area
Filling (risk of contamination) | Class AYC® +15 pa adjacent area
Aseptically prepared
Solution preparation (needs Class C +15 pa next to outside
filtration)
Product preparation Class A‘/B° +15 pa adjacent arca
Filling Class A°/B° +15 pa adjacent area
“Critical area

*Surrounding area
BY:-Assefa Atimo (MSc in Pharmaceutics)

83. Quality Control and Quality Assurance

e The quality assurance function is usually one of pre-planning
those factors that bear upon the quality of a product and
e is thus a preventative development process

e Quality control

e it more likely concentrates on those operations and tests
that

e have been designed to evaluate the quality actually
achieved in a product

BY:-Assefa Atimo (MSc in Pharmaceutics)

84. Quality control and....
e The three general areas of quality control are
+ incoming stock, manufacturing (processing), and the finished
product
e For sterile products, incoming stock control encompasses routine
tests on all ingredients as well as
special evaluations such as
- pyrogen tests on WFI,
+ glass tests on containers, and

» identity tests on rubber closures

© BY:-Assefa Atimo (MSc in Pharmaceutics)

85. Quality control and....

e Process control in the manufacture of sterile products involves
+ all of the innumerable tests, readings, and observations including
conductivity measurements during the distillation of WFI,
confirmation of volume of fill in product containers,

recording of cycle time and temperature for thermal

sterilization of the product, and
confirming the count and identity of labels for the product

BY:-Assefa Atimo (MSc in Pharmaceutics)

86. Quality control and...
+ The production control includes

+. all of the final assays and tests to which the product is
subjected.

e In addition to the usual chemical and biologic tests, a sterile
product is subjected to
+ a leak test (when applicable),

+ a Clarity test,

+ a pyrogen test (when applicable), and
+ a sterility test

+ Drug Content

BY:-Assefa Atimo (MSc in Pharmaceutics)

87. Ophthalmic and other sterile preparations

+ Ophthalmic preparations are sterile products that may contain
© one or more pharmaceutical ingredient (s) administered

+ topically, or by subconjunctival or intraocular (e.g. intravitreal

and

e intracameral) injection in the form of solution, suspension, or

ointment

BY:-Assefa Atimo (MSc in Pharmaceutics)

88. Ophthalmic and other .....
Formulation Considerations
+ The bioavailability from topical products is affected by
+ continued turnover of tears, nasolacrimal drainage, etc.
° The absorption from corneal surface can be increased by:
+ Increasing the residence time of drug on the corneal surface

+ Enhancing the permission of the drug through membrane

» How it achieved?!!!!

BY:-Assefa Atimo (MSc in Pharmaceutics)

89. Ophthalmic and other .....

+ The residence time of drug in the eye can be prolonged
+ by increasing the viscosity

+ Drug permeation through ocular barrier can be increased
+ by using lipophilic prodrug

+ Permeability can also be increased
+ by the use of penetration enhancers

+ The osmolarity of the product is also a critical parameter to be
maintained. The optimum pH value for ophthalmic products is 6-8

BY:-Assefa Atimo (MSc in Pharmaceutics)

90. Ophthalmic and other .....

Classes of Topical Ophthalmic Product
+ The common classes of topical ophthalmic products are

+ eye drops
y . PS; Eye drops can be in the form of
e eye ointment, .
solutions,
+ gels, and .
. . suspensions, or
+ gel-forming solutions j
emulsions

Preparations for the eye are placed in contact with tissues that are very sensitive
to contamination.

Therefore, similar standards are required for ophthalmic preparations.

BY:-Assefa Atimo (MSc in Pharmaceutics)

91. Ophthalmic and other ..

e Irrigating solutions are also required to meet the same standards as
parenteral solutions because during an irrigation procedure,

+ substantial amounts of these solutions can enter the bloodstream
directly through open blood vessels of wounds or abraded
mucous membranes.

+ Therefore, the characteristics and standards for the production of
large-volume parenteral solutions apply equally to irrigating
solutions.

B

2

Assefa Atimo (MSc in Pharmaceutics)

92. @ _sBY:-Assefa Atimo (MSc in Pharmaceutics)