Chapter 6-Sterile Products(encrypted).pdf

CHAPTER-6
BY:-AssefaAtimo (MSc in Pharmaceutics)
1
Sterile products

Objective
2
 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

3
What do you mean by sterile products?
Give example of sterile products?
Why parenteral products are unique among dosage forms of
drugs?
Manufacturing way for sterile product is the same as other
dosage forms?

4
 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

Introduction
5
 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
 they are injected through the skin or mucous membranes into
internal body compartments.

Introduction…..
6
 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.

Parenteral products
7
 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
 Parenteral preparations may be given by various routes:
 intravenous, intramuscular, subcutaneous, intradermal and
intraperitoneal

Introduction…..
8

Discuss in Group
9
 Discuss various routes of parenteral preparations, like
 Intravenous(IV),
 Intramuscular(IM),
 Subcutaneous(SC),
 Intradermal(ID) and
 Intraperitoneal(IP)
 What is the difference between
 Parenteral Solutions, Suspension & Emulsion
 In terms of components, is parenteral liquid dosage form differ from other dosage
forms? Why?

Types of Parenteral products
10
Types of Parenteral
Parenteral
Solutions
Parenteral
Suspension
Parenteral
Emulsion

Types of Parenteral…
11
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.
 After this solution is filtered through 0.22 μm membrane
filter and finally autoclaved (if thermostable)

12
Parenteral Suspension
 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.
 The property of thixotropy is sometimes utilized

13
Parenteral Emulsion
 The principal problem in the formulation of parenteral emulsions is
 the attainment and maintenance of uniform oil droplets of 1 to 5
μm in size as the internal phase.
 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

14
Parenteral Emulsion…..
 The dispersed phase should have droplet sizes of <1 μm.
 The emulsion must be stable to autoclaving
 Elevated temperatures tend to produce coalescence of the dispersed
phase, and excessive shaking cause acceleration of the rate of
creaming.
 Small amounts of gelatin, dextran and methylcellulose have been
found to aid in stabilizing the emulsions

15
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

16
Product development,
Vehicles, Solutes, Containers

Product development
17
 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

Product development….
18
 Certain excipients are unique to each category of parenteral
formulations
 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
 onset of action

Product development….
19
 Basic Principles of Sterile Product Formulation Development
 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

Therapeutic Agent(API)
20
 A therapeutic agent is a chemical compound subject to the physical
and chemical reactions characteristic of the class of compounds to
which it belongs
 Therefore, a careful evaluation must be made of every combination
of two or more ingredients to ascertain whether or not adverse
interactions occur, and
 if they do, modify the formulation so that the reactions are
eliminated or minimized

Therapeutic Agent(API)….
21
 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.
 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

Vehicles or Solvent System
22
• What do you mean by vehicles?
• The most frequently employed vehicle for
sterile products is water. Why?
• It is sometimes necessary to eliminate water
entirely or in part from the vehicle? Why?
• What do you mean by co-solvents?
Discuss
in group

Vehicles or Solvent….
23
 Vehicle is a medium which provides a medium to a
system to carry a drug
 Types of vehicles:-
 Aqueous Systems
 Non-aqueous and Mixed Solvents

Aqueous-Based Vehicle
24
 The most frequently employed vehicle for sterile products is
water, since
 it is the vehicle for all natural body fluids
 The superior quality required for such use is described in the
monograph on Water for Injection in the USP
 Requirements may be even more stringent for some products

Aqueous-Based…..
25
 In USP, there are three different types of water used in
pharmaceutical preparations, i.e.,
 water for injection,
 sterile water for injection, &
 bacteriostatic water for injection
 Water shall contain a minimal amount of organic compounds
 Such compounds are undesirable for two main reasons:
 they may be toxic, and/or
 they may serve as sources of nutrition for microorganisms

Aqueous-Based…..
26
 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

Aqueous-Based…..
27
 Methods of producing high-purity water, such as
 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
 Therefore, for contaminants other than ions, additional tests
should be performed

Non-aqueous and Mixed Solvents
28
 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
 A non-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

Non-aqueous and….
29
 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
 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

Non-aqueous and….
30
 Water-immiscible solvents include
 fixed oils, isopropyl myristate, and benzyl benzoate.
 The most frequently used non-aqueous solvents are
 polyediylene glycol, propylene glycol, and fixed oils

Solvent selection
31
• A parenteral 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

Solvent selection….
32
 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

33
 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
 if the pH is maintained at 3.0 or less, little reaction occurs

34
 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.
 Atropine sulfate rapidly hydrolyzes in solution, but
 if the pH is maintained with a buffer system at about 3.5 to 4.0,
 hydrolysis does not occur at a significant rate

Solutes(Properties of Drug )
35
 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

Added Substances
36
 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

Added Substances ,,…..
37
 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

Containers
38
 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

Containers….
39
 Glass containers traditionally have been used for sterile products,
many of which are closed with rubber stoppers
 Interest in plastic containers for parenteral is increasing, and such
containers are
 being used for commercial ophthalmic preparations and IV
solutions

Containers….
40
Plastic Containers
 The principal ingredient of the various plastic materials used for
containers is the thermoplastic polymer (which melt at elevated
temperatures)
 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

Containers….
41
 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

Containers….
42
Glass Containers
 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

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

Containers….
44
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
 the Water Attack test is performed on whole containers.

Containers….
45
 USP glass types, test limits and selection guide

Containers….
46
Physical Characteristics
 The protection of light-sensitive products from the
degradative effect of ultraviolet rays
 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.

Containers….
47
 If the product contains ingredients subject to iron catalyzed chemical
reactions, amber glass cannot be used.
 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

Containers….
48
Rubber Closures
 Are used to seal the openings of cartridges, vials, and bottles,
 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

Devices
49
 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
 Devices associated with sterile products include the following:

Devices….
50

Devices….
51

Devices….
52
 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,
Steps in processing,
Packaging

PRODUCTION
54
 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

Production….
55
 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

Production Design Facilities
56
 Manufacturing of sterile pharmaceuticals and medical devices requires
 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

Production Design….
57
 Other key parameters which include
 temperature, humidity, air flow filtration/velocity, and pressure are
 the trigger factors to be controlled for ensuring production of the
aseptic products
 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

58
 The objective of environmental control in a sterile facility is
 to minimize the presence of all contaminants (both viable and
non-viable)
 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

59
 The following are the most imperative facilities that are required for
ensuring and controlling the aseptic environment for the sterile
products:
1. Heating, Ventilation, and Air Conditioning (HVAC) system
2. Personnel contamination control systems
3. Cleaning and disinfection of the area
4. Environmental monitoring systems

HVAC System
60
 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

HVAC System….
61
 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
 Air filtration equipment's, depending upon the type of manufacturing
 For sterile manufacturing, HEPA filters are installed

HVAC System….
62
 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

63

Steps in processing
64
Fig. Process Flow Chart of Parenteral Manufacture

Steps in processing….
65 Figure. Overview of Manufacturing Process of Parenteral

66
Figure. Material Flow in Parenteral Unit

Packaging
67
 It must be particularly dignified, neat, and attractive in appearance
 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

Packaging…..
68
 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.

Aseptic room & processing
69
What is aseptic room?
 The aseptic area is a specially designed area & constructed
with the intention of preventing the microbial contamination
of pharmaceutical products
 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

Aseptic room &…..
70
 Aseptic processing is the processing of commercially sterile
products being
 filled into commercially sterile containers under aseptic
conditions
 What is a clean room for aseptic processing?
 A cleanroom should be a controlled area with minimal
contamination of surface and air

Classification of….
71
 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

72

Classification of Clean Room
73
 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

74
 The most universally applied classification was based on ISO 14644-1
 Based on the required standard of cleanliness,
 clean room may be divided into critical area and supporting area
 Critical area is the area for sterile manufacturing, where
 manufacturing containers, formulation ingredients, primary
packaging material, and closures are exposed to environment

75
 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.
 For aseptically produced products,
 it is very imperative to control environmental cleanliness to the
highest standard
 However, terminally sterilized products require less stringent
control compared to aseptic manufacturing

76
 Clean areas for the manufacture of sterile products are
 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
2. ‘In-Operation”

77
 The greatest threat to cleanrooms is airborne particles that cause
contamination
 Common contaminants are
 skin particles, fibers, dust, grease, bacteria, viruses, metals,
fungi, ions and film
 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

78
 Classification should be clearly differentiated from operational
process environmental monitoring
 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

79
 The maximum number of particles permitted “at rest”
condition shall approximately be as follows:
I. Grade A corresponds with class 100, M 3.5, or ISO class 5
II. Grade B corresponds with class 1000, M 4.5, or ISO class 6
III. 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

80
 The maximum permitted airborne particle concentration for each grade is given:-
 NB:-Class 100 is the area where the particle count must not exceed a total of
3,520 particles per m3 of a size 0.5 microns and larger.

81
 The requirement and limit for the area shall depend on the
nature of the operation carried out.
 Types of Operations to be Carried Out in the Various Grades for Aseptic
Preparations

82
 Clean room requirement for aseptically prepared products and
terminally sterilized products

Quality Control and Quality Assurance
83
 The quality assurance function is usually one of pre-planning
those factors that bear upon the quality of a product and
 is thus a preventative development process
 Quality control
 it more likely concentrates on those operations and tests
that
 have been designed to evaluate the quality actually
achieved in a product

Quality control and….
84
 The three general areas of quality control are
 incoming stock, manufacturing (processing), and the finished
product
 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

85
 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

86
 The production control includes
 all of the final assays and tests to which the product is
subjected.
 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

Ophthalmic and other sterile preparations
87
 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
 intracameral) injection in the form of solution, suspension, or
ointment

Ophthalmic and other …..
88
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?!!!!

89
 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

90
Classes of Topical Ophthalmic Product
 The common classes of topical ophthalmic products are
 eye drops,
 eye ointment,
 gels, and
 gel-forming solutions
Eye drops can be in the form of
solutions,
suspensions, or
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.

91
 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.

92

Chapter 6-Sterile Products(encrypted).pdf

More Related Content

Similar to Chapter 6-Sterile Products(encrypted).pdf

More from interaman123

Recently uploaded

Chapter 6-Sterile Products(encrypted).pdf