PHARMACEUTICAL ANALYSIS 2

BACHELOR OF SCIENCE IN PHARMACY

INTERNATIONAL COUNCIL FOR HARMONISATION

OF TECHNICAL REQUIREMENTS FOR
PHARMACEUTICALS FOR HUMAN USE

The importance of quality systems has been recognized in

the pharmaceutical industry and it is evident that quality risk
management is a valuable component of an effective quality
system.

It is commonly understood that risk is defined as the

combination of the probability of occurrence of harm and the
severity of that harm.

The manufacturing and use of a drug (medicinal) product,

including its components, necessarily entail some degree of
risk. The risk to its quality is just one component of the
overall risk. It is important to understand that product quality
is assured based on appropriate risk based
decision-making throughout the product lifecycle, such
that the attributes that are important to the quality of the drug PRINCIPLES OF QUALITY RISK MANAGEMENT
(medicinal) product are maintained and the product remains Two primary principles of quality risk management are:
safe and effective.
● The evaluations of the risk to quality should be
based on scientific knowledge and ultimately link to
the protection of the patient. (Note: Risk to quality
includes situations where product availability may
be impacted, leading to potential patient harm.)

● The level of effort, formality and documentation of

the quality risk management process should be
commensurate with the level of risk.

STABILITY TESTING OF NEW DRUG

SUBSTANCES AND PRODUCTS

The objective seeks to exemplify the core stability data

GENERAL QUALITY RISK MANAGEMENT PROCESS
Quality risk management is a systematic process for the
assessment, control, communication and review of risks to
the quality of the drug (medicinal) product across the product
lifecycle. A model for quality risk management is outlined in
the diagram (Figure 1).
package for new drug substances and products, but leaves
sufficient flexibility to encompass the variety of different
practical situations that may be encountered due to
specific scientific considerations and characteristics of the
materials being evaluated. Alternative approaches can be
used when there are scientifically justifiable reasons.
General Principles
The purpose of stability testing is to provide evidence on
how the quality of a drug substance or drug product varies
with time under the influence of a variety of environmental
factors such as temperature, humidity, and light, and to
establish a re-test period for the drug substance or a shelf
life for the drug product and recommended storage
conditions.
 PHARMACEUTICAL ANALYSIS 2
BACHELOR OF SCIENCE IN PHARMACY
The climate is different in all the countries in the world.
Stability studies of the pharmaceutical drug should be done
according to the climatic conditions of the country. According
to the ICH guidelines for stability studies, the climate of the
world is divided into five different zones.
Stability evaluation
Stress testing
● Stress testing of the drug substance can help
identify the likely degradation products, which can in
turn help establish the degradation pathways and
the intrinsic stability of the molecule and validate the
stability indicating power of the analytical
procedures used.
● The nature of the stress testing will depend on the
individual drug substance and the type of drug
product involved.
● Stress testing is likely to be carried out on a single
batch of the drug substance.
● The testing should also evaluate the susceptibility of
the drug substance to hydrolysis across a wide
range of pH values when in solution or suspension.
● Photostability testing should be an integral part of
stress testing.
Selection of Batches
Data from formal stability studies should be provided on at
least three primary batches of the drug substance. The
batches should be manufactured to a minimum of pilot scale
by the same synthetic route as, and using a method of
manufacture and procedure that simulates the final process
to be used for, production batches. The overall quality of the
batches of drug substance placed on formal stability studies
should be representative of the quality of the material to be
made on a production scale.
Container Closure System
The stability studies should be conducted on the drug
substance packaged in a container closure system that is the
same as or simulates the packaging proposed for storage
and distribution.
Specification
Stability studies should include testing of those attributes of
the drug substance that are susceptible to change during
storage and are likely to influence quality, safety, and/or
efficacy. The testing should cover, as appropriate, the
physical, chemical, biological, and microbiological attributes.
Validated stability-indicating analytical procedures should be
applied. Whether and to what extent replication should be
performed will depend on the results from validation studies.
Testing Frequency
Overall, ICH stability studies involve a drug substance tested
under storage conditions and assess its thermal stability and
sensitivity to moisture. The long-term testing should be
performed over a minimum of 12 months at 25 ° C ± 2
°C/60% RH ± 5% RH or at 30 °C ± 2 °C/65% RH ± 5% RH.
Storage Conditions
In general, a drug substance should be evaluated under
storage conditions (with appropriate tolerances) that test its
thermal stability and, if applicable, its sensitivity to moisture.
The storage conditions and the lengths of studies chosen
should be sufficient to cover storage, shipment, and
subsequent use.
The long term testing should cover a minimum of 12
months’ duration on at least three primary batches at the
time of submission and should be continued for a period
of time sufficient to cover the proposed re-test period.
● If long-term studies are conducted at 25°C ± 2°
C/60% RH ± 5% RH and “significant change”
occurs at any time during 6 months’ testing at the
accelerated storage condition, additional testing at
the intermediate storage condition should be
conducted and evaluated against significant change
criteria. Testing at the intermediate storage
condition should include all tests, unless otherwise
justified. The initial application should include a
minimum of 6 months’ data from a 12-month study
at the intermediate storage condition.
● “Significant change” for a drug substance is
defined as failure to meet its specification.
 PHARMACEUTICAL ANALYSIS 2
BACHELOR OF SCIENCE IN PHARMACY
Drug substances intended for storage in a refrigerator
Quality control requirements for
pharmaceutical dosage forms
Quality control of pharmaceutical formulations is an essential
operation in the production of drugs. It is a procedure or set
of procedures designed to ensure the output of uniform
batches of drugs conforms to the established
specifications. This requires organization and strict quality
checks at each level of production.
There are different types of dosage forms:
1. Solid dosage form,
2. Liquid dosage form,
3. Semi-solid dosage form,
4. Gas dosage form.
Compendial Requirement for Solid and
semi-solid dosage forms
Solid Dosage Form
Dosage form means a physical form by which drug
molecules are delivered into the site of action. The solid
dosage forms are the most commonly used dosage form
because of the stability and ease of mass production. The
solid dosage forms, which are solid in nature which contain
one or more drugs for therapeutic effects and excipients like
Binders, Sweeteners, coloring agents, etc.
Example of solid dosage form:
Tablets, capsules, granules, sachets, powders, dry powder
inhalers, and chewable.
Advantages of solid dosage form:
● More stable than other dosage forms.
● Easy to handle.
● More accurate of the dosage form.
● No preservation required.
Disadvantages of solid dosage form:
● Expensive Machines.
● Tough to swallow for kids and patients in sleeping
condition.
Types of solid dosage form
We can divide solid dosage form into 2 parts according to the
amount of the dose-
1. Unit Dose
● Tablets
● Capsules
● Granules
● Sachets
● Lozenges
● Pills
● Dry powder inhaler
● Chewables
2. Bulk Dose
● Powder (External and Internal)
● Tablet: Tablets are compressed solid dosage form
contain therapeutic active ingredients and
excipients.
● Capsules: Capsules are solid dosage forms where
the therapeutic active ingredient granules are
enclosed within a hard or soft soluble shell.
● Granules: Granules are solid dosage forms made
up of agglomeration of smaller particles of powders.
● Sachets: Sachets are solid dosage forms
containing therapeutic ingredients. Small size
spherical granules packed into a small bag or pouch
packet.
● Lozenges: Lozenges are the solid dosage form that
dissolves slowly into the mouth. Lozenges contain a
drug along with flavoring and sweetening agents.
● Chewables: Chewables are the solid dosage form
that
Excipients needed for solid dosage form:
Excipients are those materials which are used in every
dosage form. But it doesn't have any therapeutic effects or
side effects. Here we are discussing those excipients which
are important for solid dosage form formulation.
 PHARMACEUTICAL ANALYSIS 2
BACHELOR OF SCIENCE IN PHARMACY
1. Binding Agents: The role of binders or binding agent is to
make the plasticity in the tablet formulation. So it helps to
maintain the inter-particle bonding strength and to achieve
mechanical strength and sometimes for the drug release
properties.
● Natural polymers: Starch, gelatin, acacia,
tragacanth.
● Synthetic polymer: Hydroxypropyl methylcellulose
(HPMC), Methyl cellulose, Ethylcellulose,
Polyethylene glycol (PEG).
● Sugar: Glucose, Sucrose, Sorbitol
2. Coating Agents: This is used in tablet preparation. The
role of the coating agent is protecting the drug from
environmental moisture, light, or the acidic environment of
the stomach and it also masks the bitter taste of many drugs.
● Suger Coating
● Film Coating
● Enteric coating
3. Preservatives: Preservatives are basically used to protect
the formulation from the attack of microorganisms. Such as
bacterial growth, fungus growth, etc.
Examples of preservative: Phenol, parabens, aryl and alkyl
acids, etc.
4. Coloring Agents: Coloring agents are used to giving an
attractive outlook for the patients.
Example of natural colors: Turmeric, Titanium Dioxide, etc.
Examples of Synthetic colors: Erythrosine, Tartrazine, etc.
5. Sweetening Agents: Sweetening agents are used in
basically chewable tablets. To cover up the unpleasant taste
of the tablet or any pharmaceutical formulation.
Example of sweetening agents: Sucrose, fructose, etc.
Semi-solid Dosage Form
Semisolids constitute a significant proportion of
pharmaceutical dosage forms. They serve as carriers for
drugs that are topically delivered by way of the skin, cornea,
rectal tissue, nasal mucosa, vagina, buccal tissue, urethral
membrane, and external ear lining.
Topical semisolid dosage forms are normally presented in
the form of creams, gels, ointments, or pastes. They
contain one or more active ingredients dissolved or uniformly
dispersed in a suitable base and any suitable excipients such
as emulsifiers, viscosity increasing agents, anti microbial
agents, antioxidants’, or stabilizing agents.
Semisolid dosage forms contain very limited quantities of a
liquid or aqueous phase. The surface pH of semisolids
should be tested during manufacturing for monitoring
batch-to-batch uniformity and quality control of dosage
forms. Surface pH can be measured by using a simple pH
meter or by using a probe-type pH meter. If the formulation is
thick, the pH can be measured by diluting it with distilled
water. Because the skin has a neutral pH, the formulation
should also have nearly the same pH; otherwise, it may
cause local irritation and can affect drug release.
Semisolid dosage forms are plastic in behavior hence they
retain their shape on application of outside force.
A wide range of raw materials is available for the preparation
of a semisolid dosage form. Apart from the usual
pharmaceutical ingredients such as preservatives,
antioxidants, and solubilizers, the basic constituents of a
semisolid dosage form are unique to its composition.
In general, semisolid dosage forms are complex formulations
having complex structural elements.
Often they are composed of two phases (oil and water), one
of which is a continuous (external e.g. suppositories and
pessaries) phase, and the other of which is a dispersed
(internal e.g. cream, ointment, paste) phase. The active
ingredient is often dissolved in one phase, although
occasionally the drug is not fully soluble in the system and is
dispersed in one or both phases, thus creating a three-phase
system.
The physical properties of the dosage form depend upon
various factors, including the size of the dispersed
particles, the interfacial tension between the phases, the
partition coefficient of the active ingredient between the
phases, and the product rheology. These factors combine to
determine the release characteristics of the drug, as well as
other characteristics, such as viscosity.
Advantage of semi-solid dosage form:
● It is used externally
● Probability of side effect can be reduce
● Local action
● First pass gut and hepatic metabolism is avoided.
● Patient compliance is increased, the drug
termination is problematic cases is facilitated as
compared with other routes of drug
● Administration.
 PHARMACEUTICAL ANALYSIS 2
BACHELOR OF SCIENCE IN PHARMACY
Disadvantages of semi-solid dosage form:
● There is no dosage accuracy in this type of dosage
form
● The base which is used in the semi-solid dosage
form can be easily oxidized.
● If we go out after using semi-solid dosage form
problems can occur.
Ointments
- are homogenous, semi-solid preparations intended
for external application to the skin or mucous
membrane. They are used as emollients or for the
application of active ingredients to the skin for
protective, therapeutic, or prophylactic purpose and
where a degree of occlusion is desired.
- are semisolid preparations for external application
to skin or mucous membranes. Their composition
softens but does not melt upon application to the
skin. Therapeutically, ointments function as skin
protectives and emollients, but they are used
primarily as vehicles for the topical application of
drug substances.
Different type of semi-solid:
Hydrophobic ointments:
Hydrophobic (lipophilic) ointments are usually anhydrous and
can absorb only small amounts of water. Typical bases used
for their formulation are water-insoluble hydrocarbons such
as hard, soft and liquid paraffin, vegetable oil, animal fats,
waxes, synthetic glycerides and polyalkyl siloxanes.
Water-emulsifying ointments:
Water-emulsifying ointments can absorb large amounts of
water. They typically consist of a hydrophobic fatty base in
which a w/o agent, such as wool fat, wool alcohols, sorbitan
esters, mono glycerides, or fatty alcohols can be
incorporated to render them hydrophilic. They may also be
w/o emulsions that allow additional quantities of aqueous
solutions to be incorporated. Such ointments are used
especially when formulating aqueous liquids or solutions.
Hydrophilic ointments:
Hydrophilic ointment bases are miscible with water. The
bases are usually mixture of liquid and solid polyethylene
glycols (macrogols).
Creams
- are homogeneous, semi-solid preparations
consisting of opaque emulsion systems. Their
consistency and rheological properties depend on
the type of emulsion, either water-in-oil (w/o) or
oil-in –water (o/w), and on the nature of the solids in
the internal phase. Creams are intended for the
application to the skin or certain mucous
membranes for protective, therapeutic, or
prophylactic purposes, especially where an
occlusive effect is not necessary.
- are semisolid dosage forms that contain one or
more drug substances dissolved or dispersed in a
suitable base, usually oil in- water emulsion or
aqueous microcrystalline dispersion of long-chain
fatty acids or alcohols that are water washable and
are cosmetically and aesthetically acceptable.
Gels
- Gels are usually homogeneous, clear, semi-solid
preparation consisting of a liquid phase within a
three-dimensional polymeric matrix with physical or
sometimes chemical cross linkage by means of
suitable gelling agents.
- are semisolid systems that consist of either
suspensions of small inorganic particles or large
organic molecules interpenetrated by a liquid.
Hydrophobic gels:
Hydrophobic gel (oleogel) bases usually consist of liquid
paraffin with polyethylene or fatty oils gelled with colloidal
silica or aluminium or zinc soaps.
Hydrophilic gels:
Hydrophilic gels (hydrogel) bases usually consist of water,
glycerol, or propylene glycol gelled with suitable agents such
as tragacanth, starch, cellulose derivatives, carboxyvinyl
polymers, and magnesium aluminium silicates.
Pastes
- Pastes are homogeneous, semi-solid preparations
containing high concentrations of insoluble
powdered substances (usually not less than 20%)
dispersed in a suitable base. The pastes are usually
less greasy, more absorptive, and stiffer in
consistency than ointments because of the large
quantity of powdered ingredients present. Some
pastes consist of a single phase, such as hydrated
pectin, and others consist of a thick, rigid material
that does not flow at body temperature. The pastes
should adhere well to the skin. In many cases they
form a protective film that controls the evaporation
of water.
- are semisolid dosage forms that contain one or
more drug substances incorporated in a base with
large proportions of finely dispersed solids.
Poultices
is an ancient form of topical medication also known as a
cataplasma. It is a soft mass of vegetable constituents or
clay, usually heated before application. Kaolin poultice BP is
prepared by mixing and heating dried, heavy kaolin and boric
acid with glycerine. After cooling, the aromatic substances
are incorporated with stirring. The product is spread on
adressing and applied hot to the skin.