This document provides an overview of preformulation studies for developing drug formulations. It discusses the importance of studying the physical and chemical properties of drug substances alone and when combined with excipients. The summary is: 1) Preformulation studies investigate the physical and chemical properties of drugs and how they interact with excipients. This helps formulators develop stable, bioavailable drug products. 2) Key properties studied include solubility, particle size, solid state properties, and how the drug behaves under different conditions like temperature, light and pH. 3) The results of preformulation studies guide formulation development and ensure the final product has the desired quality, performance and safety.

1. THIS INDUSTRIAL
PHARMACY NOTES
PREPARATION BASED ON
THE TAMILNADU DR.M.G.R
MEDICAL UNIVERSITY
SYLLABUS
PREPARED BY
EKNATH BABU T.B.
DEPT. OF PHARMACEUTICS
ARUL MIGU KALASALINGAM
COLLEGE
OF
PHARMACY

2. preformulation studies
Preformulation studies is the first step in the rational development of dosage forms of a drug
substance.
 It can be defined as an investigation of physical and chemical properties of a drug substance -
alone and when combined with excipients.
 The overall objective of preformulation testing is to generate information useful to the
formulator in developing stable and bioavailable dosage forms which can be mass-produced.
 This early data collection may include such information as
- gross particle size,
- melting point,
- infrared analysis,
- thin-layer chromatographic purity,
- other characterizations of different laboratory-scale batches.
 These data are useful in guiding, and becoming part of, the main body of preformulation
work.
Steps in Preformulation Process Pharmaceutical Research
1. Stability i. Solubility
a. Solid State (1) Water and Other Solvents
(1) Temperature (2) pH-Solubility Profile
(2) Light (3) Salt Forms
(3) Humidity (4) Cosolvents
b. Solution (5) Complexation
(1) Solvent (6) Prodrug
(2) pH j. Effect of pH on UV Spectra
(3) Light k. Ionization Constant
2, Solid State Compatibility l. Volatility
a. TLC Analysis m. Optical Activity
b. IR Spectral Analysis n. Polymorphism
3. Physico-chemical Properties o. Solvate Formation
a. Molecular Structure and Weight 4. Physico-mechanical Properties
b. Color a. Bulk and Tapped Density
c. Odor b. Compressibility

3. d. Particle size, Shape, and Crystallinity
e. Melting Point 5. In Vitro Availability Properties
f. Thermal Analysis a. Dissolution of Drug Crystal
(1) DTA b. Dissolution of Pure Drug
(2) DSC
(3) TGA
g. Hygroscopicity 6. Other Studies
h. Absorbance Spectra a. Plasma Protein Binding
(1) UV b. Effect of Compatible Excipients
(2) IR on Dissolution
c. Kinetic Studies of Solution
Degradation
Preformulation scientist must consider the following:
1. The available physicochemical data (including chemical structure, different salts available)
2. The therapeutic classes of the compound and anticipated dose
3. The development schedule (i.e., the time available)
4. The availability of a stability-indicating assay
5. The nature of the information the formulator should have or would like to have.
1. ORGANOLEPTIC PROPERTIES
1.1 Color
Unappealing to the eye ==> instrumental methods variable
Undesirable ==> incorporation of a dye variable color
1.2 Odor and Taste

4. Organoleptic Properties of Pharmaceutical Powders
2. PURITY
3. Materials with impurities not necessary to be rejected
4. Another control parameter for comparison with subsequent batches
5. More direct concerns - impurity can affect:
6. - Stability: metal contamination in ppm
7. - Appearance: off-color -> recrystallized -> white
8. - Toxic: aromatic amine (p-amino phenol) -> carcinogenic
9. Often remedial action => simple recrystallization
 Techniques used for the characterizing purity:
- Thin layer chromatography (TLC)
- High-pressure liquid chromatography (HPLC)
- Gas chromatography (GC)
 Impurity index (II) defined as the ratio of all responses (peak areas) due to components other than
the main one to the total area response.

5.  Homogeneity index (HI) defined as the ratio of the response (peak area) due to the main
component to the total response.
3. PARTICLE SIZE, SHAPE, AND SURFACE AREA
Effects of particle size distribution and shape on:
- Chemical and physical properties of drug substances.
- Bioavailability of drug substances (griseofulvin).
- Flow and mixing efficiency of powders and granules in making tablets.
- Fine materials tend to require more amount of granulating liquid (cimetidine).
- Stability, fine materials relatively more open to attack from atmospheric O2, heat, light,
humidity, and interacting excipients than coarse materials.
 Very fine materials are difficult to handle, overcome by creating solid solution in a carrier
(water-soluble polymer).
 Safest - grind most new drugs with particle diameter > 100 mm (~ 140 mesh) down to ~ 10 -
40 mm (~ 325 mesh).
 Particles with diameter < 30 mm (~ 400 mesh)
 Drawbacks to grinding:
- material losses
- static charge build-up
- aggregation => increase hydrophobicity
=> lowering dissolution rate
- polymorphic or chemical transformations
3.1 General Techniques For Determining Particle Size
3.1.1 Microscopy
- Most rapid technique.
- But for quantitative size determination requires counting large number of particles.
- For size ~ 1 mm upward (magnification x400).
- Suspending material in nondissolving fluid (water or mineral oil)
3.1.2 Sieving
- Quantitative particle size distribution analysis.
- For size > 50 mm upward.
- Shape has strong influence on results.
3.1.3 Electronic methods

6. To encompass most pharmaceutical powders ranging in size 1 - 120 mm:
- Blockage of electrical conductivity path (Coulter-counter)
- Light blockage (HIAC) [adopted by USP]
- Light scattering (Royco)
- Laser scattering (Malvern)
3.1.4 Other techniques
- Centrifugation
- Air suspension
- Sedimentation (Andersen pipette)
Common Techniques for Measuring Fine Particles of Various Sizes
3.2 Determination of Surface Area
 Grinding operation:
particle size ==> surface area.
 Brunauer-Emmett-Teller (BET) theory of adsorption
Most substances will adsorb a monomolecular layer of a gas under certain conditions of
partial pressure (of the gas) and temperature.
Knowing the monolayer capacity of an adsorbent (i.e., the quantity of adsorbate that can be
accommodated as a monolayer on the surface of a solid) and the area of the adsorbate molecule, the
surface area canbe calculated.
4. SOLUBILITY
 Solubility > 1 % w/v
=> no dissolution-related absorption problem
 Highly insoluble drug administered in small doses may exhibit good absorption
 Unstable drug in highly acidic environment of stomach, high solubility and consequent rapid
dissolution could result in a decreased bioavailability

7.  The solubility of every new drug must be determined as a function of pH over the
physiological pH range of 1 – 8


8. 4.4 Solubilization
Drug not an acidic or basic, or the acidic or basic character not amendable to the
formation of a stable salt
 Use more soluble metastable polymorph
 Use of complexation (eg. Ribloflavin-xanthines complex)
 Use of high-energy coprecipitates that are mixtures of solid solutions and solid dispersions
(eg. Griseofulvin in PEG 4000, 6000, and 20,000)
 Use of suitable surfactant

9. where
D = drug molecule
C = complexing agent (ligand)
St = total solubility of free drug [D] and the
drug in the complex [DxCy]
Ligand (Complexing Agents)
- Vitamin K - Caffeine
- Menadione - Benzoic acid
- Cholesterol - PEG series
- Cholate salt - PVP
- b-cyclodextrin

10.  Intrinsic dissolution rate (mg/cm2/min) is characteristics of each solid compound in a given
solvent under fixed hydrodynamic conditions
 Intrinsic dissolution rate helps in predicting if absorption would be dissolution rate-limited
 > 1 mg/cm2/min --> not likely to present dissolution rate-limited absorption problems
 < 0.1 mg/cm2/min --> usually exhibit dissolution rate-limited absorption
 0.1 - 1.0 mg/cm2/min --> more information is needed before making any prediction
5.1.2 Method of Determination
Programmable Dissolution test apparatus:
1. Rotating Paddle method
2. Rotating Basket method
6.1 Partition Coefficient
 Like biological membrane in general, the GI membranes are largely lipoidal in character.

11.  The rate and extent of absorption decreased with the increasing polarity of molecules.
 Partition coefficient (distribution coefficient): the ratio in which a solute distributes itself
between the two phases of two immiscible liquids that are in contact with each other (mostly
n-octanol/water).
6.2 Ionization Constant
 The unionized species are more lipid-soluble and hence more readily absorbed.
 The GI absorption of weakly acidic or basic drugs is related to the fraction of unionized drug
in solution.
 Factors affecting absorption:
- pH at the site of absorption
- Ionization constant
- Lipid solubility of unionized species
“pH-partition theory”
Henderson-Hasselbalch equation
For acids:
pH = pKa + log [ionized form]/[unionized form]
For bases:
pH = pKa + log [unionized form]/[ionized form]
Determination of Ionization Constant
1. Potentiometric pH-Titration
2. pH-Spectrophotometry Method
3. pH-Solubility Analysis

12. COMPACTION AND COMPRESSION :
Compaction of powders with particular reference to distribution and measurement of forces within the
powder mass undergoing compression including- physics of tablet compression; Effect of particle size,
moisture content, lubrication etc on strength of tablets.
COMPACTION AND COMPRESSION
DEFINITIONS
COMPACTION : It is defined as ‘Compression & Consolidation’ of a two-phase (particulate solid-gas)
system due to the applied force .
COMPRESSION : A reduction in the bulk volume of the material as a result of displacement of the
gaseous phase.
CONSOLIDATION : Increase in the mechanical strength of the material resulting from particle-particle
interactions

14. FREE SURFACE ENERGY
Atoms or ions located at the surface of any solid particle are exposed to a different distribution of intra &
inter molecular bonding forces thal those within the particle. The atoms or ions have some unsatisfied
attractive molecular forces extending out some small distance beyond the solid surface.
UNSATISFIED BONDING FORCES AT THE SURFACE OF PARTICLE:
COHESION (stay together) : attraction between like particles
ADHESION (attraction process between dissimilar molecular species ): approach other type of particles or
solid surfaces.
ADSORBED LAYER OF MOISTURE
When the particle approach one another closely enough, however, these films of moisture can form liquid
bridges, which hold the particles together by surface tension effects & by negative capillary pressure.

18. BONDING OF PARTICLES:
Governed by several theories as follows:
The mechanical theory.

19.  The intermolecular theory.
 The liquid surface film theory.
THE MECHANICAL THEORY:
It occurs between irregularly shaped particles. Also increases the number of contact points between the
particles. The mechanical theory proposes that under pressure the individual particles undergo
elastic/plastic or/& brittle deformation & that the edges of the particles intermesh deforming a mechanical
bond. If only the mechanical bond exists, the total energy of compression is equal to the sum of the energy
of deformation, heat & energy absorbed for each constituent. Mechanical interlocking is not a major
mechanism of bonding in pharmaceutical tableting.
INTERMOLECULAR THEORY:
The molecules [or ions] at the surface of solids have unsatisfied forces [surface free energy] which interact
with the other particles in true contact. Under pressure the molecules in true contact between new clean
surfaces of the granules are close enough so that vanderwals forces interact to consolidate the particles.
Materials containing plenty OH groups may also create hydrogen bonds between molecules.
LIQUID SURFACE FILM THEORY:
The liquid-surface film theory attributes bonding to the presence of a thin liquid film which may be the
consequence of fusion or solution at the surface of the particle, induced by the energy of compression.
SOLID BRIDGES: The formation of solid bridges, also referred to as the diffusion theory of bonding,
occurs when two solids are mixed at their interface and accordingly to form a continuous solid phase.
HOT WELDING: Under the influence of applied pressure, an edge of the contact points between particles
undergoes a possible melting due to generation of heat in case of low melting point solids. Under
unloading of stress these melted point of contacts undergo re-solidification, forming a solid bridge
between the particles.

21. Various Forces Involved in Compaction
1. Frictional Forces
● Interparticulate
● Die-wall
2. Distribution Forces
3. Radial Forces
4. Ejection Forces
Frictional Forces
The forces which are produced due to friction are called as frictional forces.
● Interparticulate frictional forces
• The forces which arise at particle/particle contacts are of this type.
• Denoted by coefficient of Interparticulate friction µ i .
• It is more significant at low applied loads.
• Materials used to reduced this effect are referred to as glidants. e.g. colloidal silica.
● Die-wall frictional forces
• This results from material being pressed against the diewall & moved down it.
• Denoted as coefficient of die wall friction; µ w .
• It is dominant at high applied forces.
• Reduced by adding additives called as lubricants. e.g. magnesium stearate.

29. IMPORTANT QUESTION
1. Physics of tablet compression (6) Oct 2010
2. Objectives and Defects in Tablet coating (6) Oct 2011
3. Differentiate Consolidation and Compression with definitions. Write a detailed note on the
distributionand measurement of forces and physics of Tablets. (20) May 2012
4. Effect of particle size, moisture content and lubrication on strength of Tablets (6) Oct 2012, Oct
2013
5. Physics of Tablets (6) Apr 2013
6. Measurement of compressional forces within the powder mass undergoing compression (6) Apr
2014

30. PRODUCTION MANAGEMENT AND GMP CONSIDERATIONS:
An Industrial account of production management, legal control, lay out of building, finance
management, inventory management, material management, production planning and control, sales
forecasting; ISO 9000 series, GMP considerations, Quality assurance, process control and process
validation.
Good manufacturing practice
Good manufacturing practices (GMP) are the practices required in order to conform to guidelines
recommended by agencies that control authorization and licensing for manufacture and sale of food, drug
products, and active pharmaceutical products. These guidelines provide minimum requirements that a
pharmaceutical or a food product manufacturer must meet to assure that the products are of high quality
and do not pose any risk to the consumer or public.
Good manufacturing practices, along with good laboratory practices and good clinical practices, are
overseen by regulatory agencies in the United States, Canada, Europe, China, and other countries.
Good manufacturing practice guidelines provide guidance for manufacturing, testing, and quality
assurance in order to ensure that a drug product is safe for human consumption. Many countries have
legislated that pharmaceutical and medical device manufacturers follow GMP procedures and create their
own GMP guidelines that correspond with their legislation.
All guidelines follow a few basic principles:
 Hygiene: Pharmaceutical manufacturing facility must maintain a clean and hygienic manufacturing
area.
 Controlled environmental conditions in order to prevent cross contamination of drug product from
other drug or extraneous particulate matter which may render the drug product unsafe for human
consumption.
 Manufacturing processes are clearly defined and controlled. All critical processes are validated to
ensure consistency and compliance with specifications.
 Manufacturing processes are controlled, and any changes to the process are evaluated. Changes that
have an impact on the quality of the drug are validated as necessary.
 Instructions and procedures are written in clear and unambiguous language. (Good Documentation
Practices)
 Operators are trained to carry out and document procedures.
 Records are made, manually or by instruments, during manufacture that demonstrate that all the steps
required by the defined procedures and instructions were in fact taken and that the quantity and quality
of the drug was as expected. Deviations are investigated and documented.
 Records of manufacture (including distribution) that enable the complete history of a batch to be
traced are retained in a comprehensible and accessible form.
 The distribution of the drugs minimizes any risk to their quality.
 A system is available for recalling any batch of drug from sale or supply.
 Complaints about marketed drugs are examined, the causes of quality defects are investigated, and
appropriate measures are taken with respect to the defective drugs and to prevent recurrence.
Practices are recommended with the goal of safeguarding the health of patients as well as producing good
quality medicine, medical devices, or active pharmaceutical products. In the United States, a drug may be

31. deemed "adulterated" if it has passed all of the specifications tests, but is found to be manufactured in a
facility or condition which violates or does not comply with current good manufacturing guideline.
Therefore, complying with GMP is mandatory in pharmaceutical manufacturing.
GMP guidelines are not prescriptive instructions on how to manufacture products. They are a series of
general principles that must be observed during manufacturing. When a company is setting up its quality
program and manufacturing process, there may be many ways it can fulfill GMP requirements. It is the
company's responsibility to determine the most effective and efficient quality process.
The quality is built into the product and GMP is the most essential part of ensuring this product quality
QUALITY CONTROL PROCEDURE IN PHARMACEUTICAL INDUSTRY
The word ”Quality“ refers to the characteristics of a product from both qualitative and quantitative point
of view. It refers to the quality of process as well as the product itself. The word “Control“ implies a
procedure by which decisions may be made regarding whether production is proceeding according to the
plan and meeting the standards established previously. The quality of a pharmaceutical product is
standard, which is designed after a long research and development. Here quality does not concern with
active substance but the quality depends upon many other factors such as excipients and product
development procedures.
The pharmaceutical industry is responsible to design, test and produce dosage form, which provides
quality, purity, stability, safety, uniformity of contents and physiological availability to the consumer.
THE AUTHORITY OF PROCESS CONTROL
The maintenance of quality of a drug depends upon each and every person and setup in industry. To
provide Quality Assurance; Quality Function and Quality Control must be maintained. Quality Assurance:
Quality Assurance means that it can be said with confidence that Quality Function is being performed
adequately the Quality Assurance group of company provides a strict supervision in all parts of each step.
Its function is to inspect various phases of production so that the final product should be of highest quality.
The monitoring of records, procedures, systems, facilities, labeling personnel and performing tests is the
responsibility of Quality Assurance Group. The Quality Assurance may be the part of Quality Control
Department or it may work independently under its own manager.
Quality Variation:
When the quality of any drug is given by industry, then it is responsible for any variation from the
standard. Quality Variation may occur due to any mistake during the whole process i.e. from the reception
of raw material up to the final product in the packaged form.
The risk of error increases as the material increases and the method become very complicated.
The general sources causing product Quality Variation during manufacturing are as follows:
SOURCES OF VARIATIONS:
1. MATERIALS:
a. Variations among suppliers of same substances.
b. Variations among batches from same suppliers.

32. c. Variations within a batch.
2. MACHINES:
a. Variation of equipment of same process.
b. Difference in adjustments of equipment.
c. Aging of machines and improper care.
3. METHODS:
a. Wrong procedure.
b. Inadequate procedure.
c. Negligence in procedure by chance.
4. MEN:
a. Improper working conditions.
b. Inadequate training and understanding.
c. Lack of interest and emotional upheavals*.
d. Dishonesty fatigue and carelessness.
QUALITY VARIATION CONTROL:
The mistakes can be controlled, minimized or eliminated by material control; packaging control and GMP
variations can be controlled when Quality Control, Quality Function, and Quality Assurance work side by
side.
* Upheavals: a violent or sudden change or disruption.
• Material control.
CONTROL PROCEDURE:
Controlling each and every step of process can control variations.
Control can be divided into:
• Manufacturing practice control.
• Packaging control.
• Distribution control.
MATERIAL CONTROL: It starts just after the reception of materials. Most of the materials that are active
substances, excipients, packaging and printed materials are received by the industry from suppliers. Thus
there should be adequate established system for the receipt, testing and storage of all these supplies. There
should be a complete record of all the procedures and tests. In the material following things are included:
• Drug substances.
• Excipients.
• Packaging and printed materials.
After the reception of material, it is kept in a definite area. Thus before laboratory testing, proper
containers, labels, lot number, expiry dates etc all are checked. The material is stored in a proper way
either they are arranged alphabetically or they are differentiated depending upon physical nature. Then
samples are taken for laboratory testing and a label (Sampled) is fixed on material.
In case of active constituents, percentage purity, adulteration, expiry date, lot number, exact packing etc is

33. checked.
In case of printing and packaging material especially the color of label, weight of label and cartons and
grammage etc is checked.
If the material is up to the mark, then a label (Passed) is pasted on it and it is placed at its proper place.
On the other hand, if it is substandard, then it is kept in “Rejected Area” and sent back to the supplier.
MANUFACTURING PRACTICES CONTROL:
Successful GMP is difficult to attain but to some extent, it can be modified and controlled. Specific
procedures can be applied to attain the best quality.
In case of manufacturing, following controls are important:
Personnel.
Equipment and building.
Control of record.
Production procedure control.
(A). PERSONNEL:
Usually properly educated and well-trained persons should be in the industry.
There should be proper selection and training in all departments i.e. production, packaging, labeling, etc,
etc.
There should be general lectures for less educated persons who work in the labeling or packaging section
in an understandable language.
They should be made aware of the fact that what is the importance of life saving.
They should be warned about all the dangers of their mistakes and errors.
There should be properly educated supervisors working above the workers.
The supervisors should always be there so that in case of any trouble or question, they must be available.
All the workers should be properly checked and all the processes at different steps should also be
monitored by highly educated and experience persons who may not only be well qualified but experienced
as well.
(B). EQUIPMENT AND BUILDING:
The equipments and building used in storage, processing, checking and packaging should be of a suitable
design, size, construction and location.
In case of equipments, these should be constructed in a proper size and proper way. The size should be
such that complete batch can be processed all at once.
The surfaces of equipments should be non-reactive, non-absorptive and non-additive.
The equipment should be constructed and fitted in such a way that it is easy to replace, easy to wash
easy to operate and easy to empty.
In case of building, there should not be any contamination i.e. the tablet and liquid section should be
separated completely and even there should be complete separation in tablet machines. It means that
machines should have separate cabinet.
(C) CONTROL OF RECORD:

34. The records such as master formula record and batch production record must be maintained.
1. MASTER FORMULA RECORD:
a. The master formula record must be prepared for each product.
b. It must be signed by a competent and responsible person.
c. The language must be so that it may not be miss-interpreted.
d. It should be checked by another competent person and must be countersigned.
e. The master formula varies from production to production and from batch to batch.
f. Master formula record include the following information:
i. Name of the product, dosage form and strength.
ii. Complete list of ingredients including excipients.
iii. Quality by weight or volume of each and every ingredient.
iv. Standards or specifications of each ingredient.
v. Any calculated excess of an ingredient.
vi. Theoretical yield and termination of process.
vii. Manufacturing and control instructions, specifications and precautions.
viii. Complete description of closures, containers, labeling, packaging and other finishing material.
2. BATCH PRODUCTION RECORD:
a. Batch production record must be prepared, maintained and controlled for each batch of a product.
b. It must be retained for about 5-years after product distribution.
c. Batch production record should have following information in addition to master formula record.
i. Batch number.
ii. Code number.
iii. Manufacturing date.
iv. Expiry date.
(D). PRODUCTION PROCEDURE CONTROL:
The processes of manufacturing are operated according to the established rules from the reception of
material up to delivery of final product.
A complete list of ingredients along with their quantities is delivered to the Production Department. It is
called Master Formula of that batch. It contains all the information of that batch i.e. procedures and
equipments to be used and precautions to be taken, etc, etc.
This master formula is taken into the store and all the materials for the batch are weighed and delivered to
Production Department. All ingredients are rechecked and tested in laboratory.
In the production procedure control, some tests are done during the process, which is called “In Process
Quality Control (IPQC)”
The IPQC is under Quality Control Department.
Both Quality Control and Production Departments are responsible for the production procedure control.
IPQC tests for different dosage forms are as under:
1. IPQC TESTS FOR TABLETS:

35. a) Drug contents determination.
b) Moisture contents of granules.
c) Assay of active ingredients.
d) Weight variation of uncoated tablets.
e) Hardness test.
f) Disintegration test.
2. IPQC TESTS FOR SYRUPS AND SUSPENSIONS:
a) Drug contents determination.
b) Assay of active ingredients.
c) pH.
d) Weight per ml.
e) particle size
3. IPQC TESTS FOR SEMI-SOLIDS:
a) Drug contents determination.
b) Assay of active ingredients.
c) Uniformity and homogeneity test.
d) Viscosity and specific gravity test.
e) Filling test.
f) Leakage test.
4. IPQC TESTS FOR INJECTABLES:
a) Drug contents determination.
b) Assay of active ingredients.
c) pH.
d) Pyrogen test.
e) Stability test.
f) Leakage test.
g) Check up of particulate matters.
PACKAGING CONTROL:
The packaging control is usually completed before manufacturing of product.
When the product come in packaging section, it should be packed in recommended containers and there
should not be any mistake in case of labeling and writing of batch number, etc, etc.
The packaging material is used according to the nature and distribution of product.
DISTRIBUTION CONTROL:
The responsibilities of Quality Control Department are not finished even after the distribution of finished
dosage form in the market.
The samples of each batch are kept in record and these samples are selected during packaging and are in
the same packs as they are marketed.
These are kept for years in order to examine or test the material for any purpose or necessary demand.

36. Process Validation
For purposes of this guidance, process validation is defined as the collection and evaluation of data, from
the process design stage through commercial production, which establishes scientific evidence that a
process is capable of consistently delivering quality product. Process validation involves a series of
activities taking place over the lifecycle of the product and process. This guidance describes process
validation activities in three stages.
• Stage 1 – Process Design: The commercial manufacturing process is defined during this stage based on
knowledge gained through development and scale-up activities.
• Stage 2 – Process Qualification: During this stage, the process design is evaluated to determine if the
process is capable of reproducible commercial manufacturing.
• Stage 3 – Continued Process Verification: Ongoing assurance is gained during routine production that
the process remains in a state of control.
This guidance describes activities typical of each stage, but in practice, some activities might occur in
multiple stages.
Before any batch from the process is commercially distributed for use by consumers, a manufacturer
should have gained a high degree of assurance in the performance of the manufacturing process such that
it will consistently produce APIs and drug products meeting those attributes relating to identity, strength,
quality, purity, and potency. The assurance should be obtained from objective information and data from
laboratory-, pilot-, and/or commercial scale studies. Information and data should demonstrate that the
commercial manufacturing process is capable of consistently producing acceptable quality products within
commercial manufacturing conditions. A successful validation program depends upon information and
knowledge from product and process development. This knowledge and understanding is the basis for
establishing an approach to control of the manufacturing process that results in products with the desired
quality attributes. Manufacturers should:
• Understand the sources of variation
• Detect the presence and degree of variation
• Understand the impact of variation on the process and ultimately on product attributes
• Control the variation in a manner commensurate with the risk it represents to the process and product
Each manufacturer should judge whether it has gained sufficient understanding to provide a high degree of
assurance in its manufacturing process to justify commercial distribution of the product. Focusing
exclusively on qualification efforts without also understanding the manufacturing process and associated
variations may not lead to adequate assurance of quality. After establishing and confirming the process,
manufacturers must maintain the process in a state of control over the life of the process, even as

37. materials, equipment, production environment, personnel, and manufacturing procedures change
Manufacturers should use ongoing programs to collect and analyze product and process data to evaluate
the state of control of the process. These programs may identify process or product problems or
opportunities for process improvements that can be evaluated and implemented through some of the
activities described in Stages 1 and 2. Manufacturers of legacy products can take advantage of the
knowledge gained from the original process development and qualification work as well as manufacturing
experience to continually improve their processes. Implementation of the recommendations in this
guidance for legacy products and processes would likely begin with the activities described in Stage 3.
ISO 9000
Quality is something every company strives for and is often times very difficult to achieve. Complications
concerning efficiency and quality present themselves everyday in business, whether an important
document cannot be found or a consumer finds a product not up to their expectations. How can a company
increase the quality of its products and services? The answer is ISO 9000.
As standards go, ISO 9000 is one of the most widely recognized in the world. ISO 9000 is a quality
management standard that presents guidelines intended to increase business efficiency and customer
satisfaction. The goal of ISO 9000 is to embed a quality management system within an organization,
increasing productivity, reducing unnecessary costs, and ensuring quality of processes and products.
ISO 9001:2008 is applicable to businesses and organizations from every sector. The process oriented
approach makes the standard applicable to service organizations as well. Its general guidelines allow for
the flexibility needed for today’s diverse business world.
ISO 9000 important
The importance of ISO 9000 is the importance of quality. Many companies offer products and services,
but it is those companies who put out the best products and services efficiently that succeed. With ISO
9000, an organization can identify the root of the problem, and therefore find a solution. By improving
efficiency, profit can be maximized.
As a broad range of companies implement the ISO 9000 standards, a supply chain with integrity is
created. Each company that participates in the process of developing, manufacturing, and marketing a
product knows that it is part of an internationally known, reliable system.
Not only do businesses recognize the importance of the ISO 9000, but also the customer realizes the
importance of quality. And because the consumer is most important to a company, ISO 9000 makes the
customer its focus.
ISO 9000 Principles
1. A Customer Focus
As stated before, the customer is the primary focus of a business. By understanding and responding to the
needs of customers, an organization can correctly targeting key demographics and therefore increase
revenue by delivering the products and services that the customer is looking for. With knowledge of
customer needs, resources can be allocated appropriately and efficiently. Most importantly, a business’s
dedication will be recognized by the customer, creating customer loyalty. And customer loyalty is return
business.
2. Good Leadership

38. A team of good leaders will establish unity and direction quickly in a business environment. Their goal is
to motivate everyone working on the project, and successful leaders will minimize miscommunication
within and between departments. Their role is intimately intertwined with the next ISO 9000 principle.
3. Involvement of people
The inclusion of everyone on a business team is critical to its success. Involvement of substance will lead
to a personal INVESTMENT in a project and in turn create motivated, committed workers. These people
will tend towards innovation and creativity, and utilize their full abilities to complete a project. If people
have a vested interest in performance, they will be eager to participate in the continual improvement that
ISO 900 facilitates.
4. Process approach to quality management
The best results are achieved when activities and resources are managed together. This process approach
to quality management can lower costs through the effective use of resources, personnel, and time. If a
process is controlled as a whole, management can focus on goals that are important to the big picture, and
prioritize objectives to maximize effectiveness.
5. Management system approach
Combining management groups may seem like a dangerous clash of titans, but if done correctly can result
in an efficient and effective management system. If leaders are dedicated to the goals of an organization,
they will aid each other to achieve improved productivity. Some results include integration and alignment
of key processes. Additionally, interested parties will recognize the consistency, effectiveness, and
efficiency that come with a management system. Both suppliers and customers will gain confidence in a
business’s abilities.
6. Continual Improvement
The importance of this principle is paramount, and should a permanent objective of every organization.
Through increased performance, a company can increase profits and gain an advantage over competitors.
If a whole business is dedicated to continual improvement, improvement activities will be aligned, leading
to faster and more efficient development.
Ready for improvement and change, businesses will have the flexibility to react quickly to new
opportunities.
7. Factual approach to decision making
Effective decisions are based on the analysis and interpretation of information and data. By making
informed decisions, an organization will be more likely to make the right decision. As companies make
this a habit, they will be able to demonstrate the effectiveness of past decisions. This will put confidence
in current and future decisions.
8. Supplier relationships
It is important to establish a mutually beneficial supplier relationship; such a relationship creates value for
both parties. A supplier that recognizes a mutually beneficial relationship will be quick to react when a
business needs to respond to customer needs or market changes. Through close contact and interaction
with a supplier, both organizations will be able to optimize resources and costs.
IMPORTANT QUESTIONS
1. Discuss about Production management in Pharma Industries. (20) (Oct 2010)
2. Production Management. (6) Oct 2011
3. Quality Assurance. (6) Oct 2011
4. Discuss in detail about GMP consideration and material management for the Pharmaceutical
Industry (20) May 2012
5. ISO 9000 series. (6) May 2012, Oct 2012, Oct 2013
6. Material management in Pharma Industry. (6) Oct 2012

39. 7. Describe about the production planning and sales forecasting. (6) Apr 2013
8. Explain production planning and control in Pharmaceutical Industry. (10) Oct 2013
9. Techniques for the study of inventory management (6) Oct 2014
10. Discuss sales forecasting techinique. (6) Apr 2015
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PATENT, INTELLECTUAL PROPERTY RIGHTS AND REGULATORY AFFAIRS:
Definitions, Pharmaceutical aspects related to GATT, TRIPS, TRIMS & WTO.
What is Intellectual Property and IPR?
• Intellectual property (IP) is a term referring to a number of distinct types of creations of the mind
for which a set of exclusive rights are recognized and the corresponding fields of law.
• Under IPR, owners are granted certain exclusive rights to a variety of intangible assets, such as
musical, literary, and artistic works; discoveries and inventions; and words, phrases, symbols, and
designs.
• Monitored by World Intellectual Property Organization (WIPO), Switzerland.
History
• The need for a system arose when foreign exhibitors refused to attend an International Exhibition
of Inventions in Vienna in 1873 because they were afraid that their ideas would be stolen and will
be emulated in other countries.
• 1883 - Paris Convention for the Protection of Industrial Property.
• 1886 - Berne Convention for the Protection of Literary and Artistic Works. It gave rights to
control, and receive payment for, the use of literary and artistic works.
• Both Conventions set up International Bureaus to carry out administrative tasks, such as
organizing meetings of the Member States.
• 1893 - United International Bureaus for the Protection of Intellectual Property - best known
by its French acronym, BIRPI.

40. • BIRPI was the predecessor of what is today known as the World Intellectual Property
Organization or WIPO. Source: http://www.wto.org/
Treaties:
• There are 21 international treaties in the field of intellectual property, which are administered by
WIPO.
• The treaties fall into three groups namely
• treaties, which establish international protection
• treaties, which facilitate international protection and
• treaties, which establish classification systems.
• 1994 Uruguay round - Agreement on Trade-Related Aspects of Intellectual Property Rights
(TRIPs) and Agreement on Trade Related Investment Measures (TRIMs) by WTO (then
GATT).
• 1996 - An Agreement between WIPO and the WTO provides for cooperation concerning the
implementation of the TRIPS Agreement, such as notification of laws and regulations, and
legislative assistance to member countries.
Types of IPR:
Intellectual property is divided into two categories
Industrial property which includes
• patents for inventions,
• trademarks,
• industrial designs and
• geographical indications
Copyright and related rights which cover
• literary and artistic expressions (e.g. books, films, music, architecture, art),
• rights of performing artists in their performances, producers of phonograms in their recordings,
and broadcasters in their radio and television broadcasts which are also referred to as neighbouring
rights.
Common types of IPR

41. • Copyrights - a legal concept giving the creator of an original work exclusive rights to it, usually
for a limited time.
• Trademarks - a distinctive sign or indicator used by an individual, business organization, or
other legal entity to identify those products or services to consumers
• Patents - a set of exclusive rights granted by a sovereign state to an inventor for a limited period of
time in exchange for the public disclosure of an invention.
• Industrial design rights - protects the visual design of objects that are not purely utilitarian.
• Geographical Indication - place names (in some countries also words associated with a place)
used to identify the origin and quality, reputation or other characteristics of products
• Trade Secrets
Why do we need IPR?
• Incentive to produce
• Protects the Creator
 Protects innovators from theft.
 Individuals have all elements of control.
 Easy to sort out disputes between individuals.
• Document Creations
 Creators document their innovations.
 Provide creators the freedom to converse about their innovation.
TRIPS
• Negotiated in the 1986-94 Uruguay Round
• Trade Related Aspects of Intellectual Property Rights (TRIPS) is a World Trade Organization
(WTO) agreement designed by developed countries to enforce a global minimum standard of
Intellectual Property Rights.
• Only one actually enforceable under GATT Arts. XXI & XXII & the WTO dispute settlement
understanding.
• Since TRIPS is part of the WTO agreements, developing countries that want access to the global
market through the WTO must accept the TRIPS agreement, and integrate its IPR standards into
their national legislation.
Broad Issues dealt in the Agreement
• How basic principles of the trading system and other international intellectual property agreements
should be applied
• How to give adequate protection to intellectual property rights
• How countries should enforce those rights adequately in their own territories
• How to settle disputes on intellectual property between members of the WTO
• Special transitional arrangements during the period when the new system is being introduced.
TRIPS:Standards for IIP

42. Patent
• Patents shall be granted for any inventions, whether products or processes, provided they are new,
involve an inventive step, & are capable of industrial application.
• Patents shall be granted in all fields of technology.
Trademark
• Defines what types of signs must be eligible for protection as trademarks.
• Service marks protected the same way.
Copyright
• Protection of computer programs as literary works & of compilations of data.
• The agreement says performers must also have the right to prevent unauthorized recording,
reproduction and broadcast of live performances (bootlegging) for no less than 50 years.
Industrial Designs
• Protection should be conferred on designs which are new or original.
• Exclusive rights can be exercised against acts for commercial purposes, including importation.
• The minimum term of protection is 10 years
Trade Secrets
• Undisclosed commercial information is to be protected against unfair commercial practices
• Secret data submitted for the approval of new chemical entities for pharmaceutical &
agrochemical products should be protected against unfair commercial use & disclosure by
governments.
Access to essential medicines
The most visible conflict has been over AIDS drugs in Africa. Despite the role that patents have played in
maintaining higher drug costs for public health programs across Africa, this controversy has not led to a
revision of TRIPs. Instead, an interpretive statement, the Doha Declaration, was issued in November 2001,
which indicated that TRIPs should not prevent states from dealing with public health crises. After
Doha, PhRMA, the United States and to a lesser extent other developed nations began working to
minimize the effect of the declaration.[7]
A 2003 agreement loosened the domestic market requirement, and allows developing countries to export
to other countries where there is a national health problem as long as drugs exported are not part of a
commercial or industrial policy.[8]
Drugs exported under such a regime may be packaged or colored
differently in order to prevent them from prejudicing markets in the developed world.
In 2003, the Bush administration also changed its position, concluding that generic treatments might in
fact be a component of an effective strategy to combat HIV. Bush created the PEPFAR program, which
received $15 billion from 2003–2007, and was reauthorized in 2008 for $48 billion over the next five
years. Despite wavering on the issue ofcompulsory licensing, PEPFAR began to distribute generic drugs
in 2004-5.
IMPLEMENTATION & IMPACT

43. • Transition period
 Developing countries (2005)
 Least developed countries to implement TRIPS was extended to 2013, and until 1 January
2016 for pharmaceutical patents.
• Impacta of TRIPs on Pharmaceutical industry in developed and developing countries
• Relaxation
 Doha Declaration(2001)- circumvents patent rights for access to essential medicines
through compulsory licenses.
Diff b/w TRIPS and Indian Patent Act
TRIMS
• Agreement on Trade Related Investment Measures (Uruguay round )
• TRIMs are rules that apply to the domestic regulations a country applies to foreign investors
• Restrictions:
1. Include local content requirements
2. Manufacturing requirements
3. Trade balancing requirements
4. Domestic sales requirements
5. Technology transfer requirements
6. Export performance requirements
7. Local equity restrictions
8. Foreign exchange restrictions
9. Remittance restrictions
10. Licensing requirements
11. Employment restrictions

44. Legal Framework
• The TRIMs agreement does not provide any new language
• It focusses on two Articles that were identified in a previous case under the GATT
– Article III (National Treatment)
• National treatment of imported product, unless specified in other agreements
• Subjects the purchase or use by an enterprise of imported products to less favorable
conditions than the purchase or use of domestic products
– Article XI (Quantitative Restrictions)
• Prohibition of quantitative restrictions on imports and exports
• Part of the general trend in textiles and agriculture to phase out the use of
quantitative restrictions
Aims of the Agreement
• Desiring
 to promote the expansion and progressive liberalisaiton of world trade and to facilitate
investment, while ensuring competition
• Take into account
 trade, development and financial needs of developing countries, particularly least
developed countries
• Recognising
 certain investment measures can cause trade-restrictive and distorting effects
Notification
• Governments of WTO members, or countries entitled to be members within 2 years after 1
January, 1995 should make notifications within 90 days after the date of their acceptance of the
WTO agreement.
India’s notified TRIMs
• TRIMs Agreement India had notified three trade related investment measures as inconsistent with
the provisions of the Agreement:
1. Local content (mixing) requirements in the production of News Print,
2. Local content requirement in the production of Rifampicin and Penicillin – G, and
3. Dividend balancing requirement in the case of investment in 22 categories consumer goods.
Transition periods
• Members are obliged to eliminate TRIMs which have been notified. Such elimination is to take
place within
– two years for developed countries
– five years for developing countries

45. – seven years for LDC
Implementation Difficulties
• Difficulties in identifying TRIMs that violate the agreement
• Difficulties in identifying alternative policies to achieve the same objective
• Difficulties in accounting for non-contingent outcomes such as the financial crisis in Asia and
Latin America
• Difficulties in meeting the transition period deadlines
• LDCs lack the capacity to identify measures that are inconsistent with the TRIMs agreement and
hence are unable to meet the notification deadline.
Patent filings rebound in 2010
• Patent filings worldwide grew by 7.2% in 2010.
• China and the US, which accounted for four-fifths of worldwide growth.
• Japan and the US the main contributors for patent grants worldwide
• Japan and the US the main contributors for patent grants worldwide
Limitations
• Monopoly On Creation
 Creator holds a monopoly over his creation.
 Power in the hands of one person or company.
 Companies can charge any amount they desire.
• Benefit Large Businesses
 benefit large corporations and businesses not individuals
 New innovations, are costly.
 Outdated patents to generate income rather then creating new, efficient innovations.
World Trade Organization (WTO):
1. World trade organization (WTO) is the only international organization dealing with the global rules of
trade between nations.
2. Its main function is to ensure that trade flows as smoothly, predictable and free as possible
3. World Trade Organization (WTO) deals with the rules of trade between nations at a global or near-
global level.
FUNCTIONS:
• Administering WTO trade agreements
• Forum for trade negotiations
• Handling trade disputes
• Monitoring national trade policies

46. • Technical assistance and training for developing countries
• Cooperation with other international organizations
Principles of the trading system of WTO
The WTO agreements are lengthy and complex because they are legal texts covering a wide range of
activities. They deal with: agriculture, textiles and clothing, banking, telecommunications, government
purchases, industrial standards and product safety, food sanitation regulations, intellectual property, and
much more But a number of simple, fundamental principles run throughout all of these documents. These
principles are the foundation of the multilateral trading system.
How can you ensure that trade is as fair as possible, and as free as is practical? :
The WTO’s rules–the agreements–are the result of negotiations between the members. GATT is now the
WTO’s principal rule-book for trade in goods. The Uruguay Round also created new rules for dealing with
trade in services, relevant aspects of intellectual property, dispute settlement, and trade policy reviews.
The complete set runs to some 30,000 pages consisting of about 60 agreements and separate commitments
(called schedules) made by individual members in specific areas such as lower customs duty rates and
services market-opening.
Through these agreements, WTO members operate a non-discriminatory trading system that spells out
their rights and their obligations. Each country receives guarantees that its exports will be treated fairly
and consistently in other countries’ markets. Each promises to do the same for imports into its own
market. The system also gives developing countries some flexibility in implementing their commitments.
1. GOODS
2. SERVICES
3. INTELLECTUAL PROPERTY
GOODS
It all began with trade in goods. From 1947 to 1994, GATT was the forum for negotiating lower customs
duty rates and other trade barriers; the text of the General Agreement spelt out important rules, particularly
non-discrimination. Since 1995, the updated GATT has become the WTO’s umbrella agreement for trade
in goods. It has annexes dealing with specific sectors such as agriculture and textiles, and with specific
issues such as state trading, product standards, subsidies and actions taken against dumping
SERVICES
Banks, insurance firms, telecommunications companies, tour operators, hotel chains and transport
companies looking to do business abroad can now enjoy the same principles of freer and fairer trade that
originally only applied to trade in goods. These principles appear in the new General Agreement on Trade
in Services (GATS). WTO members have also made individual commitments under GATS stating which
of their services sectors they are willing to open to foreign competition, and how open those markets are.
INTELLECTUAL PROPERTY
The WTO’s intellectual property agreement amounts to rules for trade and investment in ideas and
creativity. The rules state how copyrights, patents, trademarks, geographical names used to identify
products, industrial designs, integrated circuit layout-designs and undisclosed information such as trade
secrets–“intellectual property”–should be protected when trade is involved. The WTO’s Agreement on
Trade-Related Aspects of Intellectual Property Rights (TRIPS), negotiated in the 1986–94 Uruguay
Round, introduced intellectual property rules into the multilateral trading system for the first time.
THE 10 BENEFITS OF WTO
1. The system helps promote peace
2. Disputes are handled constructively

47. 3. Rules make life easier for all
4. Freer trade cuts the costs of living
5. It provides more choice of products and qualities
6. Trade raises incomes
7. Trade stimulates economic growth
8. The basic principles make life more efficient
9. Governments are shielded from lobbying
10. The system encourages good government
GATT- general agreement on tariff and trade
The international conference of 1944 which recommended the establishment of IMF(International
Monetary Fund) and World Bank and also recommended the establishment of ITO(International Trade
Organisation) but did not materialize, but in the year 1948 GATT was established.
International trading system, since 1948 was at least in principles, guided by the rules and procedures
agreed to the signatories to the GATT which was an agreement sign by the member nations, which where
admitted on the basis of there willingness to accept the GATT disciplines.
The primary objectives of GATT was to expand international trade by liberalizing so as to bring about
all round economic prosperity, the important objective are as follows as:-
1) Raising standards of living.
2) Ensuring full employment and large and steady growing volume of real income and effective demand.
3) Developing full use of resources of the world.
4) Expansion of production and international trade.
GATT has certain conventions and general principles governing international trade among countries that
follows the GATT agreement:-
1) Any proposed change in the tariff or any type of commercial policy of a member country should
not be undertaken without the consultation with the other parties to the agreement.
2) The countries that adhear to get work towards the reduction of tariff and other barriers to the
international trade should be negotiated within the frame work of GATT.
BARRIERS
a) TARIFF b) NON TARIFF
(Change in monetary value) (Quality & Quantity of product and services)
The general agreement on trade and service which extends multi-lateral rules and disciplines to
services is regarded as the land mark achievement of uruguay round . The GATS defines, services as the
supply of service from:-
# The territory of one member into the territory of other member. (Transport)
# In the territory of one member, to the service consumer of any other member.(Franchisee)
# By a service supplier of one member through the commercial presence in the territory of any other
member. (Tourism)

48. # By a service supplier of one member through the presence of natural persons of a member, in the
territory of any other member. (Foreign Consultant)
Among the most important obligation, is a most favored nation obligation that essentially
prevents countries from discriminating among foreign suppliers of services
Another obligation is a transparency requirement according to which each member country
will publish all its relevant laws and regulations, pertaining to services.
# For the realization of the objective GATT adopted the following:-
1) NON DISCRIMINATION- The principle of non-discrimination requires that no member country
shall discriminate between in the conduct of international trade, to ensure non-discrimination the members
of GATT to apply the principle of MFN (most favored nation) status to all import and export duties. The
GATT also permits to member to adopt step to counter dumping and export subsidies.
2) PROHIBITION OF QUANTITATIVE RESTRICTIONS- GATT seek to prohibit quantitative
restrictions as far as possible and limit restrictions on trade to the less rigid tariffs, however certain
exceptions to this prohibition are granted to countries, confronted with balance of payment difficulties and
to the developing countries.
3) CONSULTATION - By providing a forum for continuing consultation, GATT has provided to
resolve disagreements through consultation.
IMPORTANT QUESTIONS
1. TRIPS and WTO (6)Oct 2010, Oct 2011
2. Pharmaceutical aspects related to GATT and TRIPS. (6) May 2011,Apr 2015
3. World Trade Organization (6) May 2012
4. Intellectual Property Rights (6) Oct 2012
5. P a t e n t L a w s ( 6 ) A p r 2 0 1 3
6. Intellectual Property Rights (6) Oct 2013
7. GATT and TRIPS (6) Oct 2014
BY
T.B.E.K.B (ARMOURZ)

49. OPTIMIZATION TECHNIQUES IN PHARMACEUTICAL FORMULATION AND
PROCESSING:
Concept of optimization, Optimization parameters, Classical optimization, Statistical design, and
Optimization methods.

65. Concept of optimization

67. IMPORTANT QUESTION
1.What is Optimization? Discuss the various optimization techniques in formulation and processing. (20)
Oct 2010, Oct 2011
2. Describe briefly on search methods used in optimization (6), Oct 2012
3. Optimization methods (6) May 2012, Oct 2013, Apr 2014
4. Define Optimization and explain about Lagrangian method (6) Apr 2013, Oct2014
5. Discuss optimization parameters (6) Apr 2015
BY
T.B.EKNATH BABU (T.B.E.K.B)
ARMOURZS

68. STERILIZATION PROCESS.
Sterilization of various injectables, implantable devices, blood products, and biotechnological products
Pharmaceutical technical procedures:
5.8 Methods of sterilization
Sterilization is necessary for the complete destruction or removal of all microorganisms (including spore-
forming and non-spore-forming bacteria, viruses, fungi, and protozoa) that could contaminate
pharmaceuticals or other materials and thereby constitute a health hazard. Since the achievement of the
absolute state of sterility cannot be demonstrated, the sterility of a pharmaceutical preparation can be
defined only in terms of probability. The efficacy of any sterilization process will depend on the nature of
the product, the extent and type of any contamination, and the conditions under which the final product
has been prepared. The requirements for Good Manufacturing Practice should be observed throughout all
stages of manufacture and sterilization.
Classical sterilization techniques using saturated steam under pressure or hot air are the most reliable and
should be used whenever possible. Other sterilization methods include filtration, ionizing radiation
(gamma and electron-beam radiation), and gas (ethylene oxide, formaldehyde).
For products that cannot be sterilized in the final containers, aseptic processing is necessary. Materials and
products that have been sterilized by one of the above processes are transferred to presterilized containers
and sealed, both operations being carried out under controlled aseptic conditions.
Whatever method of sterilization is chosen, the procedure must be validated for each type of product or
material, both with respect to the assurance of sterility and to ensure that no adverse change has taken
place within the product. Failure to follow precisely a defined, validated process could result in a non-
sterile or deteriorated product. A typical validation programme for steam or dry-heat sterilization requires
the correlation of temperature measurements, made with sensory devices to demonstrate heat penetration
and heat distribution, with the destruction of biological indicators, i.e. preparations of specific
microorganisms known to have high resistance to the particular sterilization process. Biological indicators
are also used to validate other sterilization methods (see specific methods), and sometimes for routine
control of individual cycles. Periodic revalidation is recommended.
Pharmaceutical Importance of Sterilization
Moist heat sterilization
Moist heat sterilization is the most efficient biocidal agent. In the pharmaceutical industry it is used for:
Surgical dressings, Sheets, Surgical and diagnostic equipment, Containers, Closures, Aqueous injections,
Ophthalmic preparations etc . ..
Dry heat sterilization
Dry heat sterilization can only be used for thermo stable, moisture sensitive or moisture impermeable
pharmaceutical and medicinal . These include products like; Dry powdered drugs, Suspensions of drug in
non aqueous solvents, Oils, fats waxes, soft hard paraffin silicone, Oily injections, implants, ophthalmic
ointments and ointment bases etc .

69. STERILIZATION STERILITY: Absence of life or absolute freedom from biological contamination.
STERILIZATION: Inactivation or elimination of all viable organism and their spores.
STERILIZATION DISINFECTANT: Substance used on non-living objects to render them non-infectious;
kills vegetative bacteria, fungi, viruses but Not Spores. e.g. Formaldehyde
STERILIZATION BACTERICIDE (GERMICIDE): Substance that kills vegetative bacteria and some
spores BACTERIOSTAT: Substance which stops growth and multiplication of bacteria but does not
necessarily kill them. Growth usually resumes when bacteriostat is removed.
STERILIZATION ANTISEPTIC: Substance used to prevent multiplication of microorganism when
applied to living systems. An antiseptic is bacteriostatic in action but not necessarily bacteriocidal.
STERILIZATION VEGETATIVE CELL: Bacterial cell capable of multiplication (as oppose to spore
form which cannot multiply). Less resistant than the spore form. SPORE: Body which some species of
bacteria form within their cells which is considerably more resistant than the vegetative cell.
STERILIZATION Methods:
1. Steam Sterilization
2. Dry heat sterilization
3. Filtration
4. Gas sterilization
5. Irradiation
NOTE: End products must pass sterility tests.
Heating in an autoclave (steam sterilization)

70. Exposure of microorganisms to saturated steam under pressure in an autoclave achieves their destruction
by the irreversible denaturation of enzymes and structural proteins. The temperature at which denaturation
occurs varies inversely with the amount of water present. Sterilization in saturated steam thus requires
precise control of time, temperature, and pressure. As displacement of the air by steam is unlikely to be
readily achieved, the air should be evacuated from the autoclave before admission of steam. This method
should be used whenever possible for aqueous preparations and for surgical dressings and medical
devices.
The recommendations for sterilization in an autoclave are 15 minutes at 121-124 °C (200 kPa).1
The
temperature should be used to control and monitor the process; the pressure is mainly used to obtain the
required steam temperature. Alternative conditions, with different combinations of time and temperature,
are given below.
1
1 atm = 101 325 Pa
Temperature
(°C)
Approximate
corresponding pressure
(kPa)
Minimum sterilization time
(min)
126-129 250 (~2.5 atm) 10
134-138 300 (~3.0 atm) 5
Minimum sterilization time should be measured from the moment when all the materials to be sterilized
have reached the required temperature throughout. Monitoring the physical conditions within the
autoclave during sterilization is essential. To provide the required information, temperature-monitoring
probes should be inserted into representative containers, with additional probes placed in the load at the
potentially coolest parts of the loaded chamber (as established in the course of the validation programme).
The conditions should be within ±2 °C and ±10 kPa (±0.1 atm) of the required values. Each cycle should
be recorded on a time-temperature chart or by other suitable means.
Aqueous solutions in glass containers usually reach thermal equilibrium within 10 minutes for volumes
up to 100 mL and 20 minutes for volumes up to 1000 mL.
Porous loads, such as surgical dressings and related products, should be processed in an apparatus that
ensures steam penetration. Most dressings are adequately sterilized by maintaining them at a temperature
of 134 - 138 °C for 5 minutes.
In certain cases, glass, porcelain, or metal articles are sterilized at 121 - 124 °C for 20 minutes.
Fats and oils may be sterilized at 121 °C for 2 hours but, whenever possible, should be sterilized by dry
heat.
In certain cases (e.g. thermolabile substances), sterilization may be carried out at temperatures below 121
°C, provided that the chosen combination of time and temperature has been validated. Lower temperatures
offer a different level of sterilization; if this is evaluated in combination with the known microbial burden
of the material before sterilization, the lower temperatures may be satisfactory. Specific conditions of
temperature and time for certain preparations are stated in individual monographs.
The bioindicator strain proposed for validation of this sterilization process is: spores of Bacillus
stearothermophilus (e.g. ATCC 7953 or CIP 52.81) for which the D-value (i.e. 90% reduction of the
microbial population) is 1.5-2 minutes at 121 °C, using about 106
spores per indicator.

71. Dry-heat sterilization
In dry-heat processes, the primary lethal process is considered to be oxidation of cell constituents. Dry-
heat sterilization requires a higher temperature than moist heat and a longer exposure time. The method is,
therefore, more convenient for heat-stable, non-aqueous materials that cannot be sterilized by steam
because of its deleterious effects or failure to penetrate. Such materials include glassware, powders, oils,
and some oil-based injectables.
Preparations to be sterilized by dry heat are filled in units that are either sealed or temporarily closed for
sterilization. The entire content of each container is maintained in the oven for the time and at the
temperature given in the table below. Other conditions may be necessary for different preparations to
ensure the effective elimination of all undesirable microorganisms.
Temperature
(°C)
Minimum sterilization time
(min)
160 180
170 60
180 30
Specific conditions of temperature and time for certain preparations are stated in individual monographs.
The oven should normally be equipped with a forced air system to ensure even distribution of heat
throughout all the materials processed. This should be controlled by monitoring the temperature.
Containers that have been temporarily closed during the sterilization procedure are sealed after
sterilization using aseptic techniques to prevent microbial recontamination.
The bioindicator strain proposed for validation of the sterilization process is: spores of Bacillus
subtilis (e.g. var. niger ATCC 9372 or CIP 77.18) for which the D-value is 5-10 minutes at 160 °C using
about 106
spores per indicator.
Filtration
Sterilization by filtration is employed mainly for thermolabile solutions. These may be sterilized by
passage through sterile bacteria-retaining filters, e.g. membrane filters (cellulose derivatives, etc.), plastic,
porous ceramic, or suitable sintered glass filters, or combinations of these. Asbestos-containing filters
should not be used.
Appropriate measures should be taken to avoid loss of solute by adsorption onto the filter and to prevent
the release of contaminants from the filter. Suitable filters will prevent the passage of microorganisms, but
the filtration must be followed by an aseptic transfer of the sterilized solution to the final containers which
are then immediately sealed with great care to exclude any recontamination.
Usually, membranes of not greater than 0.22 μm nominal pore size should be used. The effectiveness of
the filtration method must be validated if larger pore sizes are employed.
To confirm the integrity of filters, both before and after filtration, a bubble point or similar test should be
used, in accordance with the filter manufacturer's instructions. This test employs a prescribed pressure to
force air bubbles through the intact membrane previously wetted with the product, with water, or with a
hydrocarbon liquid.

72. All filters, tubes, and equipment used "downstream" must be sterile. Filters capable of withstanding heat
may be sterilized in the assembly before use by autoclaving at 121 °C for 15 - 45 minutes depending on
the size of the filter assembly. The effectiveness of this sterilization should be validated. For filtration of a
liquid in which microbial growth is possible, the same filter should not be used for procedures lasting
longer than one working day.
Exposure to ionizing radiation
Sterilization of certain active ingredients, drug products, and medical devices in their final container or
package may be achieved by exposure to ionizing radiation in the form of gamma radiation from a suitable
radioisotopic source such as 60
Co (cobalt 60) or of electrons energized by a suitable electron accelerator.
Laws and regulations for protection against radiation must be respected.
Gamma radiation and electron beams are used to effect ionization of the molecules in organisms.
Mutations are thus formed in the DNA and these reactions alter replication. These processes are very
dangerous and only well-trained and experienced staff should decide upon the desirability of their use and
should ensure monitoring of the processes. Specially designed and purpose-built installations and
equipment must be used.
It is usual to select an absorbed radiation level of 25 kGy1
(2.5 Mrad)2
, although other levels may be
employed provided that they have been validated.
1
kilogray
2
megarad
Radiation doses should be monitored with specific dosimeters during the entire process. Dosimeters
should be calibrated against a standard source on receipt from the supplier and at appropriate intervals
thereafter. The radiation system should be reviewed and validated whenever the source material is
changed and, in any case, at least once a year.
The bioindicator strains proposed for validation of this sterilization process are: spores of Bacillus
pumilus (e.g. ATCC 27142 or CIP 77.25) with 25 kGy (2.5 Mrad) for which the D-value is about 3 kGy
(0.3 Mrad) using 107
-108
spores per indicator; for higher doses, spores of Bacillus cereus (e.g. SSI C 1/1)
or Bacillus sphaericus (e.g. SSl C1A) are used.
Gas sterilization
The active agent of the gas sterilization process can be ethylene oxide or another highly volatile substance.
The highly flammable and potentially explosive nature of such agents is a disadvantage unless they are
mixed with suitable inert gases to reduce their highly toxic properties and the possibility of toxic residues
remaining in treated materials. The whole process is difficult to control and should only be considered if
no other sterilization procedure can be used. It must only be carried out under the supervision of highly
skilled staff.
The sterilizing efficiency of ethylene oxide depends on the concentration of the gas, the humidity, the time
of exposure, the temperature, and the nature of the load. In particular, it is necessary to ensure that the
nature of the packaging is such that the gas exchange can take place. It is also important to maintain
sufficient humidity during sterilization. Records of gas concentration and of temperature and humidity
should be made for each cycle. Appropriate sterilization conditions must be determined experimentally for
each type of load.

73. After sterilization, time should be allowed for the elimination of residual sterilizing agents and other
volatile residues, which should be confirmed by specific tests.
Because of the difficulty of controlling the process, efficiency must be monitored each time using the
proposed bioindicator strains: spores of Bacillus subtilis (e.g. var. niger ATCC 9372 or CIP 77.18) or
of Bacillus stearothermophilus, (e.g. ATCC 7953 or CIP 52.81). The same quantity of spores should be
used as for "Heating in an autoclave" and "Dry-heat sterilization".
Ethylene oxide (ETO) has been widely used as a low-temperature sterilant. It is liquid at
temperatures below 10.8oC
ETO is an effective sterilizing agent for heat- and moisture sensitive materials in hospitals, industry,
and laboratories. Bacterial spore show little resistance to destruction by this agent. It is effective at
relatively low temperatures and does not damage materials exposed to it.
It has high penetrating power and passes through and sterilizes large packages of materials, bundles
of cloth, and even certain plastics.
STERILIZATION STERILITY TESTS (A) Microorganisms: USPXXll recommends the use of biological
indicators.
1. For liquid preparations-add directly to the preparations.
2. For solid preparations or equipments- add the culture to strips of filter paper.
Different organisms for different methods of sterilization. The organisms that are resistant to a particular
sterilization method should be chosen as the marker organism
Sterilization Method Marker organisms Steam sterilization Bacillus stearothermophyilus Dry-heat
sterilization Bacillus subtilis Ethylene oxide Bacillus subtilis sterilization Ionizing radiation Bacillus
pumilus sterilization
(B) Pyrogen and Pyrogen Testing
Pyrogens are fever producing organic substances arising from microbial contamination. The causative
material is thought to be a Lipopolysaccharide from the outer cell wall of the bacteria. This is
Thermostable

74. STERILIZATION TESTS: 1. RABBIT TESTS a) Render the syringes, needles and glassware free from
Pyrogens by heating at 250 deg. C for not less than 30 minutes. b) Warm the product to be tested to 37
deg. ± 2 deg. C. c) Take three healthy rabbits
d) Inject into an ear vein of each of three rabbits 10 ml of the product per kg body weight. e) Record the
temperature at 1,2,and 3 Hrs.
STERILIZATION CASE I Results: (i) No rabbit shows an individual rise in temperature at 0.6 deg. C or
more above its respective control temp. (ii) Sum of the three individual maximum temp. rises does not
exceed 1.4 deg. C. Conclusion: The material meets the USP requirements for the absence of Pyrogen.
STERILIZATION CASE II Results: (i) If any rabbits show a temp. rise of 0.6 deg.C or more or (ii) If sum
of the temp. rises exceeds 1.4 deg. C Conclusion: Repeat the tests using five other rabbits.
STERILIZATION Results: (i) If not more than three of the eight rabbits show individual rises in temp. of
0.6 deg. C or more (ii) If the sum of the eight temp. rises does not exceed 3.7 deg.C Conclusion: The
material meets the USP requirements for the absence of Pyrogens.
2) LAL TESTS: Limulus Amebocyte Lysate (LAL) Tests Extract from the blood cells of the Horse Shoe
Crab (Limulus Polyphemus) contains an enzyme and protein that coagulates in the presence of low levels
of Lipopolysaccharides.
PARENTERALS Injections:
These are sterile, Pyrogen free preparations intended to be administered parenterally (outside alimentary
tract). Parental Routes Of Administration
Most Common:
1. Subcutaneous (SC;SQ;Sub Q)
2. Intramuscular (IM)
3. Intravenous (IV)
Others:
4. Intracisternal
5. Intradermal (ID)
6. Intraspinal
7. Intraarterial (IA)
PARENTERAL ROUTE IS USED FOR:
1) Rapid action
2) Oral route can not be used
3) Not effective except as injection
PARENTERALS Official Types of Injections:
1. Solutions of Medicinal Example: Codeine Phosphate Injection Insulin Injection
2. Dry solids or liquid concentrate does not contain diluents etc. Example: Sterile Ampicillin Sodium
3. If diluents present, referred to as.....for injection Example: Methicillin Sodium for injection
4. Suspensions "Sterile....Suspension" Example: Sterile Dexamethasone Acetate Suspension
5. Dry solids, which upon the addition of suitable vehicles yield preparations containing in all respects to
the requirements for sterile suspensions. Title: Sterile....for Suspension Example: Sterile Ampicillin for
Suspension

75. The form into which a given drug is prepared for parenteral use by the manufacturer depends on the nature
of the drug. 1. physicochemical characteristics 2. therapeutic consideration
PARENTERALS Onset of ActionDuration 1. Chemical form of the drug 2. Physical state of the injection
(a) Solution (b) Suspension 3. Vehicle used
Most rapid onset of action: Drugs that are very soluble in body fluids. Drugs in aqueous solutions > Drugs
in oleaginous solution. Drugs in aqueous suspension > Drugs in oleaginous suspension. "Repository" or
"Depot" Type injections - Long acting
PARENTERALS Requirements: Solvents or vehicles used must meet special purity and other standards.
Restrictions on buffers, stabilizers, antimicrobial preservative. Do not use coloring agents. Sterile and
Pyrogen - Free.
Must meet compendial standards for particular matter. Must be prepared under aseptic conditions. Specific
and high quality packaging.
PARENTERALS Vehicles: Aqueous: Sterile water for injection. Nonaqueous: Fixed oils Glycerin PEG
Alcohol
Restrictions on Fixed Oils: Remain clear when cooled to 10 deg. C. Not contain Paraffin or Mineral oil.
Must meet the requirement of iodine number and Saponification number.
Iodine Number (Value): It represents the number of g of iodine absorbed, under the prescribed conditions,
by 100g of the substance. Saponification Value (Number): It represents the number of mg of Potassium
Hydroxide required to neutralize the free acids and saponify the esters contained in 1.0g of the substance.
Must specify the oil used e.g. corn oil, cottonseed oil, peanut oil, sesame oil. Must be free from rancidity.
Solvents used must be: Non-irritating Non-toxic Non-sensitizing No pharmacological activity of its own
Not affect activity of medicinal
PARENTERALS Added Substances -preservatives -buffers -antioxidants -solubilizers -thickeners -
materials to adjust tonicity
Do Not Use Color Preservatives: Multidose containers must have preservatives unless prohibited by
monograph.
PARENTERALS ASEPTIC TECHNIQUE: An aseptic technique is one which is designed to prevent
contamination of materials, instruments, utensils, containers, during handling.
PARENTERALS Sources of Contamination -The Air -The Breath -The Skin -The Hair -Clothing -
Working surfaces
PARENTERALS Methods of minimization of contamination: apply common sense Airborne
contamination--use laminar airflow Horizontal Vertical

76. PARENTERALS HEPA filter (High efficiency particulate air filter) Contamination from the breath--use
masks Contamination from the skin: Nails should be scrubbed Hands and forearms should be washed
thoroughly with detergent solutions
Hair and Clothing: Always wear sterile gown over normal clothing Long hair should be tied back Wear a
cotton cap Working surfaces: Clean the working surface with a bactericidal solution or ethyl alcohol
PARENTERALS PACKAGING: 1) Single dose: Hermetic container holding a quantity of sterile drug
intended for parenteral administration as a single dose. Example: ampuls sealed by fusion 2) Multiple
dose: Hermetic container permits withdrawal of successive portions of the contents without changing the
strength, quality, or purity of the remaining portion.
PARENTERALS LABELING: Name of product % of drug or amount of drug in specified volume of
amount of drug and volume of liquid to be added Manufacturer/Distributor Lot number Name and
quantity of all added substances
PARENTERALS Expiration date Veterinary product should be so labeled Must check each individual
monogram for: Type of container Type of glass Package size Special storage instructions
PARENTERALS LARGE VOLUME PARENTHERALS (LVP'S): Generally administered by
intravenous infusion to replenish body fluids, electrolytes, or to provide nutrition--100ml-1L These
solutions should not contain: *Bacteriostatic agents *Other pharmaceutical additives
PARENTERALS BIOLOGICALS: -vaccines -toxins -toxoids -antitoxins -immune serums -blood
derivatives -diagnostic aids
PARENTERALS Storage: Refrigerator at 2 deg C to 8 deg C, avoid freezing These preparation should
meet the std. of the bureau of biologies of the FDA.
PARENTERALS IMMUNITY: Power of the body to resist and overcome infection. NATURAL OR
NATIVE IMMUNITY: Individuals resistance to a particular toxic agent because of race, endocrine
balance, etc. ACQUIRED IMMUNITY: Specific immunity that may be acquired (Active or Passive)
PARENTERALS ACTIVE IMMUNITY: *Naturally acquired active immunity--occurs in response to an
infection *Artificially acquired active immunity-- response to a specific vaccine or toxoid PASSIVE
IMMUNITY: Introduce already formed antibodies into body to combat a specific antigen
PARENTERALS :
PARENTERALS VACCINES: Administered primarily for prophylactic action for the development of
active acquired immunity. TOXOIDS: Toxins modified and detoxified by moderate heat and chemical
treatment Example: Diphtheria, Tetanus
PARENTERALS :
PARENTERALS ANTITOXINS: Prepared from blood of animal immunized by repeated injections of
bacterial toxins
PARENTERALS :
PARENTERALS ANTISERUMS: Prepared in same manner as antitoxins except that viruses or bacteria
injected to produce antibodies. Produce passive immunity human immune serums and globulins. Serums

77. containing specific antibodies obtained from blood of humans who have had the disease or have been
immunized against it with a specific biologic product.

78. Blood products are sterilized on filtration sterilization. Biotechnological products are used also filtration
sterilization. Implantable devices are ETO process.
IMPORTANT QUESTIONS
1. Discuss in detail the formulation and evaluation of Parenteral products (10) Oct 2010
2. Define Sterilization and briefly explain types of sterilization (6) Oct 2011, May 2011, May 2012
3. Sterilization of various Injectables (6) Oct 2012, Oct 2013
4. Differentiate moist heat and dry heat sterilization (6) Apr 2012, Oct 2014
5. Sterilization of blood products (6) Apr 2014
6. Discuss sterilization equipment (6) Apr 2015

79. INTRODUCTION
Pilot plant technique is defined as a part of the pharmaceutical industry where a lab scale process is
transformed into a viable product by the Development of liable practical procedure for manufacture of
dosage forms. The Scale-up is the art of designing of prototype using the data obtained from the pilot plant
model.
The Objective of Scale up Technique
To develop and formulate physically and chemically stable therapeutic dosage forms by optimizing
various parameters. To create a guidelines for production and process control. Raw materials handling
and its specifications requirements To identify the critical steps involved in the process. To develop a
master manufacturing formula. Pilot plant studies may be developed to establish the identical
examination of the formula to withstand batch scale. Infrastructure the related to scale up efforts in the
pilot plant: Production and process controls are evaluated, validated and finalized. Any Process
modification can be allowed To Evaluate and validate the developed product. To update the processing
equipment. Physical and mechanical Compatibility of the equipment with the formulation. Time and
cost factor. Need for current market strategies. To overcome the difficulties in small scale and create
large scale production.
Significance of Pilot Plant [3]
Standardization of formulae. Review of range of relevant processing equipments. Optimization and
control of production rate. Information on infrastructure of equipments during the scale up batches
physical space required. Identification of critical features to maintain quality of a product. Appropriate
records and reports to support GMP.
Pilot Plant Design for Tablets:
The primary responsibility of the pilot plant staff is to ensure that the newly formulated tablets developed
by product development personnel will prove to be efficiently, economically, and consistently
reproducible on a production scale. The design and construction of the pharmaceutical pilot plant for
tablet development should incorporate features necessary to facilitate maintenance and cleanliness. If
possible, it should be located on the ground floor to expedite the delivery and shipment of supplies. Each
stage considered carefully from experimental lab batch size to intermediate and large scale production.
Same process, same equipment but different performance when amount of material increased
significantly. May involve a major process change that utilizes techniques and equipment that were
either unavailable or unsuitable on a lab scale.
Stages of Production of Tablets
Material handling Dry blending Granulation Drying Reduction of particle size Blending Direct
compression Slugging (dry granulation)
Material Handling System
In the laboratory, materials are simply scooped or poured by hand, but in intermediate- or large-scale
operations, handling of this materials often become necessary. If a system is used to transfer materials for
more than one product steps must be taken to prevent cross contamination. Any material handling system
must deliver the accurate amount of the ingredient to the formulation. The More sophisticated methods of
handling materials arevacuum loading systems, metering pumps, screw feed system. The types of the
system selected depend on the nature of the materials, e.g., density and static change.

80. Dry Blending
Inadequate blending at this stage could result in discrete portion of the batch being either high or low in
potency. Steps should be taken to ensure that all the ingredients are free from lumps and agglomerates. For
these reasons, screening and/or milling of the ingredients usually makes the process more reliable and
reproducible. There are various equipment used in blending process they are V- blender, double cone
blender, Ribbon blender, Slant cone blender Bin blender, Orbiting screw blenders vertical and horizontal
high intensity mixers. The blending will be optimized by following parameters.
1. Time of blending.
2. Blender loading.
3. Size of blender
Granulation
Sigma blade mixer, Heavy-duty planetary mixer. More recently, the use of multifunctional “processors”
that are capable of performing all functions required to prepare a finished granulation, such as dry
blending, wet granulation, drying, sizing and lubrication in a continuous process in a single equipment.
Drying
The most common conventional method of drying a granulation continues to be the circulating hot air
oven, which is heated by either steam or electricity. The important factor is to consider as part of scale-up
of an oven drying operation are airflow, air temperature, and the depth of the granulation on the trays. If
the granulation bed is too deep or too dense, the drying process will be inefficient, and if soluble dyes are
involved, migration of the dye to the surface of the granules. Drying times at specified temperatures and
airflow rates must be established for each product, and for each particular oven load. Fluidized bed dryers
are an attractive alternative to the circulating hot air ovens. The important factor considered as part of
scale up fluidized bed dryer are optimum loads, rate of airflow, inlet air temperature and humidity.
Reduction of Particle Size
First step in this process is to determine the particle size distribution of granulation using a series of
“stacked” sieves of decreasing mesh openings. Particle size reduction of the dried granulation of
production size batches can be carried out by passing all the material through an oscillating granulator, a
hammer mill, a mechanical sieving device, or in some cases, a screening device. As part of the scale-up of
a milling or sieving operation, the lubricants and glidants, in the laboratory are usually added directly to
the final blend. This is done because some of these additives, especially magnesium stearate, tend to
agglomerate when added in large quantities to the granulation in a blender.
Blending
Type of blending equipment often differs from that using in laboratory scale. In any blending operation,
both segregation and mixing occur simultaneously are a function of particle size, shape, hardness, and
density, and of the dynamics of the mixing action. Particle abrasion is more likely to occur when high-
shear mixers with spiral screws or blades are used. When a low dose active ingredient is to be blended it
may be sandwiched between two portions of directly compressible excipients to avoid loss to the surface
of the blender.
Slugging (Dry Granulation)

81. This is done on a tablet press designed for slugging, which operates at pressures of about 15 tons,
compared with a normal tablet press, which operates at pressure of 4 tons or less. Slugs range in diameter
from 1 inch, for the more easily slugged material, to ¾ inch in diameter for materials that are more
difficult to compress and require more pressure per unit area to yield satisfactory compacts. If an
excessive amount of fine powder is generated during the milling operation the material must be screened
& fines recycled through the slugging operation.
Dry Compaction
Granulation by dry compaction can also be achieved by passing powders between two rollers that compact
the material at pressure of up to 10 tons per linear inch. Materials of very low density require roller
compaction to achieve a bulk density sufficient to allow encapsulation or compression. One of the best
examples of this process is the densification of aluminum hydroxide. Pilot plant personnel should
determine whether the final drug blend or the active ingredient could be more efficiently processed in this
manner than by conventional processing in order to produce a granulation with the required tabletting or
encapsulation properties.
Compression
The ultimate test of a tablet formulation and granulation process is whether the granulation can be
compressed on a high-speed tablet press. When evaluating the compression characteristics of a particular
formulation, prolonged trial runs at press speeds equal to that to be used in normal production should be
tried, only then are potential problems such as sticking to the punch surface, tablet hardness, capping,
and weight variation detected. Highspeed tablet compression depends on the ability of the press to
interact with granulation. The following parameters are optimized during pilot plant techniques of
Granulation feed rate, Delivery system should not change the particle size distribution., System should
not cause segregation of coarse and fine particles, nor it should induce static charges. The die feed
system must be able to fill the die cavities adequately in the short period of time that the die is passing
under the feed frame. The smaller the tablet, the more difficult it is to get a uniform fill a high press
speeds. For high-speed machines, induced die feed systems is necessary. These are available with a
variety of feed paddles and with variable speed capabilities. So that optimum feed for every granulation
can be obtained. Compression of the granulation usually occurs as a single event as the heads of the
punches pass over the lower and under the upper pressure rollers. This cause the punches to the
penetrate the die to a preset depth, compacting the granulation to the thickness of the gap set between
the punches. During compression, the granulation is compacted to form tablet, bonds within
compressible material must be formed which results in sticking. High level of lubricant or over blending
can result in a soft tablet, decrease in wet ability of the powder and an extension of the dissolution time.
Binding to die walls can also be overcome by designing the die to be 0.001 to 0.005 inch wider at the
upper portion than at the center in order to relieve pressure during ejection. The machine used are high
speed rotary machine, multi rotary machine, double rotary machine, upper punch and lower punch
machine ,and single rotary machined.
Scale-up for parenterals
Injectables
• The majority of the parenteral solutions are solutions requiring a variety of tankage, piping and
ancillary equipment for liquid mixing, filteration, transfer and related activities.
• The majority of the equipments are composed of 300 series austenitic stainless steel, with tantalum
or glass lined vessels employed for preparation of formulations sensitive to iron and other metal
ions.

82. • The vessels can be equipped with external jackets for heating and/or cooling and various types of
agitators, depending upon the mixing requirements of the individual formulation.
Working area of a parenteral pilot plant
• Incoming goods are stored in special areas for Quarantine, Released and Rejected status.
• A cold room is available for storage of temperature-sensitive products. Entrance into the
warehouse and production areas is restricted to authorized personnel.
• Sampling and weighing of the raw material is performed in a dedicated sampling area and a
central weighing suite, respectively.
• The route for final products is separated from the incoming goods; storage of final products is
done in designated areas in the warehouse while they are awaiting shipment.
• Several clothing and cleaning procedures in the controlled transport zone and production
area ensure full quality compliance.
• In addition, a technical area is located in between the production zone and the area for formulation
development.
• Here, the water for injection equipment is located, as well as the technical installation of
the lyophilizer.
Facility Design
To provide the control of microbial, pyrogen and particles controls over the production
environment are essential.
Warehousing:
All samples should be aseptically taken, which mandates unidirectional airflow and full operator
gowning.
These measures reduce the potential for contamination ingress into materials that are yet to receive any
processing at any site.
Preparation Area:
The materials utilized for the production of the sterile products move toward the
preparation area through a series of progressively cleaner environments.
Compounding area:
The manufacture of parenterals is carried out in class 10,000 (Grade C) controlled environments in
which class 100 unidirectional flow hoods are utilized to provide greater environmental control
during material addition.
These areas are designed to minimize the microbial, pyrogen, and particulate contamination to the
formulation prior to sterilization.
Aseptic filling rooms:
The filling of the formulations is performed in a Class 100 environment.
• Capping and Crimp sealing areas:
The air supply in the capping line should be of Class 100
• Corridors:
They serve to interconnect the various rooms. Fill rooms, air locks and gowning rooms are
assessed from the corridor.
• Aseptic storage rooms.
• Air-locks and pass-throughs:
Air locks serve as a transition points between one environment and another.
They are fitted with the UltraViolet lights, spray systems, or other devices that may be effectively
utilized for decontamination of materials.
Formulation aspects
Solvent:
The most widely used solvent used for parenteral production is water for injection. WFI is prepared
by by distillation or reverse osmosis. Sterile water for injection is used as a vehicle for reconstitution

83. of sterile solid products before administration and is terminally sterilized by autoclaving
Solubilizers:
They are used to enhance and maintain the aqueous solubility of poorly water-soluble drugs.
Solubilizing agents used in sterile products include:
1. co-solvents: glycerine, ethanol, sorbitol, etc.
2. Surface active agents: polysorbate 80, polysorbate 20, lecithin.
3. Complexing agents: cyclodextrins etc
They act by reducing the dielectric constant properties of the solvent system, thereby
reducing the electrical, conductance capabilities of the solvent and thus increase the solubility.
Antimicrobial preservative agents:
Buffers:
They are used to maintain the pH level of a solution in the range that provides either maximum
stability of the drug against hydrolytic degradation or maximum or optimal solubility of the drug in
solution.
Antioxidants:
Antioxidants function by reacting prefentially with molecular oxygen and minimizing or
terminating the free the free radical auto-oxidation reaction. Examples phenol
(0.065-0.5%), m-cresol (0.16-0.3%) etc.
Scale up for Liquid orals
• The physical form of a drug product that is pourable displays Newtonian or pseudoplastic flow
behaviour and conforms to it’s container at room temperature.
• Liquid dosage forms may be dispersed systems or solutions.
• In dispersed systems there are two or more phases, where one phase is distributed in another.
• A solution refers two or more substances mixed homogeneously.
Steps of liquid manufacturing process
1. Planning of material requirements:
2. Liquid preparation:
3. Filling and Packing:
4. Quality assurance:
Critical aspects of liquid manufacturing
Physical Plant:
2. Heating, ventilation and air controlling system
The effect of long processing times at suboptimal temperatures should be considered in terms of
consequences on the physical or chemical stability of ingredients as well as product.
SOLUTION :
Parameters to be considered are –-
1. Tank size ( diameter )
2. Impeller type
3. Impeller diameter
4. Rotational speed of the impeller

84. 5. Number of impellers
6. Number of baffles
7. Mixing capability of impeller
8. Clearance between Impeller Blades and wall of the mixing tank
9. Height of the filled volume in the tank
10. Filteration equipment (should not remove active or adjuvant ingredients)
11. Transfer system
12. Passivation of SS (prereacting the SS with acetic acid or nitric acid solution to remove the surface
alkalinity of the SS)
SUSPENSION :
Parameters to be considered are –-
1. Addition and dispersion of suspending agents (Lab scale – sprinkling method & Production scale –
vibrating feed system)
2. Hydration/Wetting of suspending agent
3. Time and temperature required for hydration of suspending agent
4. Mixing speeds (High speed leads to air entrapment)
5. Selection of the equipment according to batch size
6. Versator (to avoid air entrapment)
7. Mesh size (the one which is chosen must be capable of removing the
unwanted foreign particulates but should not filter out any of the active
ingredients . Such a sieve can only be selected based on production batch size trials.)
EMULSION :
Parameters to be considered are –-
1. Temperature
2.Mixing equipment
3. Homogenizing equipment
4. Inprocess or final product filters
5. Screens , pumps and filling equipment
6. Phase volumes
7. Phase viscosities
8. Phase densities
9. Formulation aspects of oral liquids
10. Solutions:
Protecting the API Buffers, antioxidants, preservatives
Maintaining the Colorings, stabilizers, co-solvents, antimicrobial preservatives
appearance
Taste/smell masking Sweetners, flavorings.
Suspensions:
Purpose
Agent
Facilitating the connection between API and -wetting agents

85. vehicle Salt formation ingredients
Protecting the API
- Buffering-systems, polymers, antioxidants
Maintaining the suspension appearance
Colorings, suspending agent, flocculating
agent.
Masking the unpleasant taste/smell
Sweeteners, flavorings
Emulsions:
Purpose Agent
Particle Size Solid particles, Droplet particles
Protecting the API Buffering-systems, antioxidants, polymers
Maintaining the appearance Colorings, Emulsifying agents, Penetration
enhancers, gelling agents
Taste/smell masking Sweetners, flavorings
SCALE UP FOR SEMISOLID PRODUCTS
The following parameters are to be considered during the scale up of semisolid products :
1. Mixing equipment (should effectively move semisolid mass from outside walls
to the center and from bottom to top of the kettle)
2. Motors (used to drive mixing system and must be sized to handle the product
at its most viscous stage.)
3. Mixing speed
4. Component homogenization
5. Heating and cooling process
6. Addition of active ingredients
7. Product transfer
8. Working temperature range (critical to the quality of the final product)
9. Shear during handling and transfer from manufacturing to holding tank to
filling lines
10. Transfer pumps (must be able to move viscous material without applying excessive shear and
without incorporating air)
11. While choosing the size and type of pump ,
a. Product viscosity
b. Pumping rate
c. Product compactibility with the pump surface
Pumping pressure required should be considered
IMPORTANT QUESTION
1. Explain in detail the filling of Hard gelatin capsules. Add a note on evaluation of
capsules. (20) Oct 2010
2.Explain in detail about the significance of Pilot plant scale up study and large scale manufacturing
techniques of Injections and Liquid orals (20) Oct 2011, Apr 2013, Apr 2014
3. Pilot plant scale up preparation for liquid orals (6) May 2012
4. Significance of Pilot plant scale up study (6) Oct 2012, Oct 2013
5. Large scale manufacturing of parenterals (20) Oct 2015

86. PACKAGING OF PHARMACEUTICALS:
Desirable features and a detailed study of different types of Pharmaceutical containers and closures (Glass,
Plastics and Rubber), including their merits and demerits; selection and evaluation of Pharmaceutical
packaging materials
PACKAGING OF PHARMACEUTICALS
The packaging can be defined as an economical means of providing presentation, protection, identification
information, containment, convenience and compliance for a product during storage, carriage, display and
until the product is consumed. Packaging must provide protection against climatic conditions biological,
physical and chemical hazards and must be economical. The package must ensure adequate stability of the
product throughout the shelf life. The primary packaging consist of those packaging components which
have a direct contact with the product (i.e. bottle, cap, cap liner, etc). The main functions of the primary
package are to contain and to restrict any chemical, climatic or biological or occasionally mechanical
hazards. The packaging external to the primary package is known as the secondary packaging. The
secondary packaging mainly provides the additional physical protection necessary to endure the safe
warehousing and for refill packaging.
Ideal packaging requirement
a) They must protect the preparation from environmental conditions.
b) They must not be reactive with the product.
c) They must not impart to the product tastes or odors.
d) They must be nontoxic.
e) They must be FDA approved.
f) They must meet applicable tamper-resistance requirements.
Table 1: Primary and Secondary packaging material
Material Type Example of use
Plastic Primary
Ampoule, vial, infusion fluid container,
dropper bottle
Glass Primary Metric medical bottle, ampoule, vial
Paper Secondary Labels, patient information leaflet
Cardboar
d Secondary Box to contain primary pack
Hazards encountered by package
Hazards encountered by the package can be divided into three main groups

87. a. Mechanical hazards
b. Climatic or environmental hazards
c. Biological hazards
The only exception is theft, which can be a serious risk with drugs and may demand special protection in
certain cases.
a. Mechanical hazards
1- Shock or impact damage
Damage due to shock is usually caused by rsough handling, during transport etc. Cushioning can be
provided and a warning label may be useful. Restriction of movement and more careful handling should
be made.
2-Compression
Fragile items may be broken, or collapsible articles crushed by compression, the usual procedure then
being to protect with a rigid outer package. Top pressure or loading can distort inside. The crushing of a
carton can make a product un- sealable even though no damage has occurred to the contents. This is more
likely to occur during stocking in the ware house or during transport where vibration adds a further
hazard. Compression can also occur in other situations like capping on a production line, when being
carried home by the user etc.
3- Vibration
Vibration consists of two variables-frequency and amplitude. Considerable vibration may occur during
transport, especially with exported items. Sometimes screw caps may be loosen or labels or decorations may
abrade etc.
4- Abrasion
Although abrasion results from both regular and irregular forms of vibration , it is listed separately as the
visual appearance of the product or package can be affected. eg: rectangular bottle in a carton will move up
and down and from side to side. A round bottle in the same circumstances will suffer from an additional
possibility of rotation.
b. Climatic or environmental hazards

88. Environmental conditions encountered by the package are likely to vary considerably, especially in articles
for export to the tropical areas. In general, it is extremes of conditions that give rise to problems, and this is
especially true of fluctuating conditions.
1- Temperature
Extreme conditions may cause deterioration, low temperatures leading to aqueous solutions freezing and,
hence, to fracture of containers. High temperatures increase diffusion coefficients, accelerating the entry of
water vapor into hygroscopic products and the loss of volatile components. In addition, high, temperatures
increase reaction rates and product breakdowns either by hydrolysis or oxidation. High temperature coupled
with a high relative humidity will produce a slower effect if the temperature is lowered sufficiently to reach
dew point. Contamination from liquid moisture can encourage mould and bacterial growth.
2-Moisture
Moisture as liquid or water vapor may cause physical changes (e.g. color fading, softening, hardening etc)
or chemical changes (hydrolysis, oxidation, effervescence etc). Although liquid moisture may cause obvious
damage, water vapour may penetrate into a package, leading to hydrolysis, without visual changes. It is
essential to check the water vapour permeability of materials to be used for packaging moisture-sensitive
products; for example, plastics show considerable variation in this property. It may also act as a carrier for
other contaminants like moulds and fungi.
3-Pressure
Decrease in pressure, as in mountainous regions or during flight in non-pressurized transport aircraft, may
cause thin containers to burst or strip packs to inflate.
4- Atmospheric Gases
Gases from the atmosphere may diffuse into the package, leading to deterioration. Thus, oxygen will
encourage oxidation, while carbon dioxide can cause a pH
shift (un buffered solution in plastic bottle
particularly Low Density Poly Ethylene (LDPE), which is relatively permeable to carbon dioxide) or lead to
precipitation of some products (barbiturates from solutions of their sodium salts). Permeation of the
common gases through plastic is typically in the ratio of 1:4:20 for nitrogen, Oxygen and Carbon dioxide
respectively, nitrogen being more permeable. Odorous gases or volatile ingredients associated with
perfumes, flavors and product formulation may also pass into or out of a package. If a volatile ingredient is
lost from a flavor, an unpleasant odor or taste may result.

89. 5-Light
Light consist of wavelengths from the UV zones through the visible to infrared. A number of deteriorations
are due to photochemical reactions particularly affected by the ultra-violet band of the spectrum. Such
changes may not always be visible. Printed or deteriorated packaging materials may also suffer from
discoloration ( white may go yellow, deeper colors may fade) and this may be seen as implying a change in
the product efficacy or strength. Although light can be excluded by using selected material, tin plate, soil etc
opacity and/or color may reduce penetration or filter out selected wavelength. The additional use of UV
absorbers in plastics may also restrict light rays entering the packed it should also be noted that many
products are protected by a carton, outer etc. Alternatively, an opaque outer packaging may be used, with a
warming that the advantage that the latter may be transparent, permitting the contents to be inspect
5-Solid airborne contamination( particulars)
Particulars matters present in the atmosphere will make the containers dirty during transport or storage.
This can be prevented by outer wrappers or by anti-static agents.
c. Biological hazards
Microbiological
The packaging materials must be reasonably clean initially and when put together to form a finished
package and restrict any further contamination as much as possible. In the case of sterile products the
package and its closure must maintain a 100% effective seal against microbiological contaminants like
bacteria, moulds and yeasts. Growth of yeasts is critical with sugar based products as fermentation may
occur. Moulds will also grow on cellulose based materials like paper if these are kept under humid
conditions. Care should be taken in order to avoid fluctuation in temperature.
Chemical Hazards
The main risk of chemical hazard is due to interaction or in compatibility between the product and
package. Compatibility investigations must basically cover any exchange that can occur between the
product and the package and vice versa. These may be associated with interaction or contamination,
covering migration, absorption, adsorption, extraction, corrosion, etc. where by ingredients may either
be lost or gained. Such exchange may be identifiable as organoleptic changes, increase in
toxicity/irritancy degradation, loss or gain of microbial effectiveness, precipitation, turbidity, color
change, PH
shift etc. These external influences may catalyze, induce or even nullify chemical changes.
Function of packaging

90. The various functions of packaging are
1. Protective function
2.Storage function
3.Loading & Transport functions
4.Identification
1. Protective function
Protective function of packaging essentially involves protecting the contents from the environment and
vice versa. The inward protective function is intended to ensure full retention of the utility value of the
packaged goods. The packaging is thus intended to protect the goods from loss, damage and theft.In
addition packaging must essentially be able to withstand the many different static and dynamic forces
to which it is subjected during transport, handling and storage operations. The goods frequently also
require protection from climatic conditions, such as temperature, humidity etc. The precipitation and
solar radiation may require additional packaging measures in the interior portion of the container.The
exterior protection provided by the packaging must prevent any environmental degradation by the
goods. This requirement is of particular significance in the transport of hazardous materials, with
protection of humans being of primary importance. The packaging must furthermore as far as possible
prevent any contamination, damage or other negative impact upon the environment and other goods.
The interior and exterior protective function primarily places demands upon the strength, resistance and
leak proof properties of transport packaging.
2. Storage function
The materials used for packaging should be stored properly so as to preserve the quality of the material
both before packaging and once the package contents have been used.
3. Loading and transport functions
Packaging has a crucial impact on the efficiency of transport, handling and storage of goods. Packaging
should therefore be deigned to be easily handled and to permit space-saving storage and stowage. The
shape and strength of packages should be such that they may not only be stowed side by side leaving
virtually no voids but may also stowed safely one above the other. The most efficient method of
handling general cargo is to make up cargo units. Packaging should thus always facilitate the formation
of cargo units; package dimensions and the masses to be accommodated should be possibly tailored to
the dimensions and load- carrying capacity of standard pallets and containers.

91. 4. Identification
The packaging should give clear identification of the product at all stages. The life of the patient may
depend upon rapid and correct identification in emergencies. Packaging also serves as a mean to
identify the manufacturer of the product. The manufacturer must consider the packaging requirement
for the usage of product in different localitie
Selection of the Packaging Materials
Selection is based
1. On the facilities available, for example, pressurized dispenser requires special filling
equipment.
2. On the ultimate use of product. The product may be used by skilled person in hospital
or may need to be suitable for use in the home by a patient.
3. On the physical form of the product. For example, solid, semi-solid, liquids or
gaseous dosage form.
4. On the route of administration. For example, oral, parenteral, external, etc.
5. On the stability of the material. For example, moisture, oxygen, carbon dioxide, light,
trace metals, temperature or pressure or fluctuation of these may have a deleterious
effect on the product.
6. On the contents. The product may react with the package such as the release of alkali
from the glass or the corrosion of the metals and in turn the product is affected
7. On the cost of the product. Expensive products usually justify expensive packaging
Glass –containers
Manufacture of Glass
Four basic processes are used in the production of glass:-
Blowing
Drawin
g
Pressing
Casting.

92. Blowing uses compressed air to form the molten glass in the cavity of a metal mold. Most commercial
bottles and jars are produced on automatic equipment by this method. In drawing, molten glass is pulled
through dies or rollers that shape the soft glass. Rods, tubes, sheet glass, and other items of uniform
diameter are usually produced commercially by drawing. Ampoules, cartridges, and vials drawm from
tubing have a thinner, more uniform wall thickness, with less distortion than blow-molded containers. In
pressing, mechanical force is used to press the molten glass against the side of a mold. Casting uses gravity
or centrifugal force to initiate the formation of molten glass in the cavity.

93. Type 1 —Borosilicate Glass
Borosilicate Glass is a highly resistant glass. In this type of glass a substantial part of the alkali and earth
cations are replaced by boron and/or aluminum and zinc. It is more chemically inert than the soda-lime
glass, which contains either none or an insignificant amount of these cations. Although glass is considered
to be a virtually inert material and is used to contain strong acids and alkalies as well as all types of solvents,
it has a definite and measurable chemical reaction with some substances, notably water. The sodium is
loosely combined with the silicon and is leached from the surface of the glass by water. Distilled water
stored for one year in flint type III glass (to be described) picks up 10 to 15 parts per million (ppm) of
sodium hydroxide along with traces of other ingredients of the glass.
Type 2 —Treated Soda-Lime Glass
Type II containers are made of commercial soda-lime glass that has been de-alkalized, or treated to remove
surface alkali. The de-alkalizing process is known as "sulfur treatment" and virtually prevents "weathering"
of empty bottles. The treatment offered by several glass manufacturers exposes the glass to an atmosphere
containing water vapor and acidic gases, particularly sulfur dioxide at an elevated temperature. This results
in a reaction between the gases and some of the surface alkali, rendering the surface fairly resistant, for a
period of time, to attack by water. The alkali removed from the glass appears on the surface as a sulfate
bloom, which is removed when the containers are washed before filling. When glassware is stored for
several months, especially in a damp atmosphere or with extreme temperature variations, the wetting of the
surface by condensed moisture (condensation) results in salts being dissolved out of the glass. This is called
"blooming" or "weathering," and in its early stages, it gives the appearance of fine crystals on the glass. At
this stage, these salts can be washed off with water or acid.
Type 3—Regular Soda-Lime Glass
Containers are untreated and made of commercial soda-lime glass of average or better-than-aver-age
chemical resistance.
General-Purpose Soda-Lime Glass

94. Containers made of soda-lime glass are supplied for nonparenteral products, those intended for oral or
topical use.
1.1.Composition of Glass
The only anion of consequence is oxygen. Many useful properties of glass are affected by the kind of
elements it contains. Reduction in the proportion of sodium ions makes glass chemically resistant; however,
without sodium or other alkalies, glass is difficult to melt and is expensive. Boron oxide is incorporated
mainly to aid in the melting process through reduction of the temperature required.Lead in small traces
gives clarity and brilliance, but produces a relatively soft grade of glass. Alumina (aluminum oxide),
however, is often used to increase the hardness and durability and to increase resistance to chemical
actionGlass is composed principally of silica with varying amount of metal oxides, soda-ash, limestone, and
cullet. The sand is almost pure silica, the soda-ash is sodium carbonate, and the limestone, calcium
carbonate. Cullet is broken glass that is mixed with the batch and acts as a fusion agent for the entire
mixture. The composition of glass varies and is usually adjusted for specific purposes. The most common
cations found in pharmaceutical glassware are silicon, aluminum, boron, sodium, potassium, calcium,
magnesium, zinc, and barium.
Colored Glass—Light Protection
The USP specifications for light-resistant containers require the glass to provide protection against 2900 to
4500 Angstroms of light. Amber glass meets these specifications, but the iron oxide added to produce this
color could leach into the product. Therefore, if the product contains ingredients subject to iron-catalyzed
chemical reactions, amber glass should not be used. Manganese oxide can also be used for amber glasses
Glass containers for drugs are generally available in clear flint or amber color. For decorative purposes,
special colors such as blue, emerald green, and opal may be obtained from the glass manufacturer. Only
amber glass and red glass are effective in protecting the contents of a bottle from the effects of sunlight by
screening out harmful ultraviolet rays.
Glass for Drugs
The powdered glass test is performed on crushed glass of a specific size, and the water attack test is
conducted on whole containers. The water attack test is used only with type II glass that has been exposed
to sulfur dioxide fumes under controlled conditions. The USP and NF describe the various types of glass
and provide the powdered glass and water attack tests for evaluating the chemical resistance of glass. The
test results are measures of the amount of alkalinity leached from the glass by purified water under
controlled elevated temperature conditions.

95. Ampoules
Ampoules are thin-walled glass containers, which after filling, are sealed by either tip sealing or pull
sealing. The contents are withdrawn after rupture of the glass, or a single occasion only. These are great
packaging for a variety of drugs. The filed – in product is in contact with glass only and the packaging is
100% tamper proof. The break system OPC (one –point cut) or the color break ring offer consistent
breaking force. There are wide variety of ampoule types from 0.5 to 50ml. Up to 3 color rings can be placed
the stem or body for identification purpose. Printed ampoules with heavy metal free colors are available.
Some of them are:
• Type B straight –stem
• Type C funnel –tip
• Type D closed
Bottles, vials and syringes
These are more or less thick walled containers with closures of glass or of material other than glass such as
plastic materials or elastomers. The contents may be removed in several proportions on one of or more
occasions.
Test for glass containers
Test for surface hydrolytic resistance
Surface hydrolytic resistance test is conducted on unused glass containers. The number of containers to be
examined and the volume of the test humid necessary for final determination are indicated in the following
table.
Table 1:
Nominal capacity of
container Number of
Volume of
test
containers
to b e
solution to
be
used
used for
titration
ml
3 or less At least 10 25.0
3 to 30 At least 5 50.0
More than 30 At least3 100.0
Initially each container is rinsed three times carefully with carbon dioxide free water. Then the container is
allowed to drain and it is filled with the carbon dioxide free water to the required volume. If vials and
bottle are used they are covered with neutral glass dishes or aluminum foil which is previously rinsed with
carbon dioxide free water. If ampoules are used, they are sealed by heat fusion. The containers are then
placed on the tray of the autoclave a containing a quantity of water in such a way that the tray remains clear

96. and temperature is maintained between 100oC to 120o C over 20minutes. Then the temperature is adjusted
between 120o-1220C for 60 minutes and finally the temperature is lowered from 120oC for 40 minutes.
Remove the containers from the autoclave once the pressure reaches the atmospheric pressure and cool
under running tap water Combine the liquids obtained from the containers being examined. The following
titration should be carried out within 1 hour after removing the container from the autoclave. Introduce the
prescribed volume of liquid in to a conical flask. Add 0.05ml of methyl red solution for each 20ml liquid.
Titrate with 0.01M hydrochloric acid taking as the end point the color obtained by repeating the operation
using the same volumes of carbon dioxide free water. The result is not greater than the volume state in
table
Table 2:
Capacity of container
Volume of 0.01M hydrochloric acid VS per 100 ml of
test solution
Type 1 or II glass ml Type III glass ml
Not more than 1 3.0 20.0
More than 1 but not more than 2 1.8 17.6
More than 2 but not more than 5 1.3 13.2
More than 5 but not more than 10 1.0 10.2
More than 10 but not more than
20 0.80 8.1
More than 20 but not more than
50 0.60 6.1
More than 50 but not more than
100 0.50 4.8
More than 100 but not more than
200 0.40 3.8
More than 200 but not more than
500 0.30 2.9
More than 500 0.20 2.2
Test for hydrolytic resistance of powdered glass
The Containers to be tested are initially rinsed with water and dried in hot air oven. At least three
containers are taken and broken with a hammer to get coarse fragments of about 100g size of the largest
fragment should not be greater than 25mm. Transfer a part of the sample to a mortar and insert the pestle
and strike heavily once with the hammer. Transfer the contents of the mortar to the coarsest sieve. Repeat
the operation sufficient number of times until all the fragment have been transferred to the sieve. The glass

97. is sifted and the portion retained by the 710{mu)m and 423 {mu)m sieve are taken and are further
fractured. The operation is respected until 20g of glass is retained by the 710{mu)m sieve. Rejected this
portion and the portion that passes through 250{mu)m sieve. Shake the nest of sieve manually or
mechanically for 5 minutes. Glass grains that passes through 425{mu)m sieve is taken metal particles are
removed by suspending the glass grains in acetone the supernatant liquid is decanted the operation is
repeated five times glass grains are speeded on an evaporating dish and allow the acetone to evaporating by
drying in an oven at 110oC for 20minutes and allow to cool.
20g of the glass grains to treated is introduced into a 250ml conical flask add 100ml of carbon dioxide free
water and weigh In the second flask 100ml carbon dioxide free water serve as blank and weigh. Close the
two flasks with neutral glass dish or aluminum foil rinsed with carbon dioxide free water. The flask is then
placed in on auto clave and maintain the temperature at 121o
C for 30minutes and carry out the operations
similar to those described in Test A for surface hydrolytic resistance. After cooling remove the closure, wipe
the flask and adjust the original weight by adding carbon dioxide free water. Transfer 50ml (corresponding
to 10g of glass grains) of the clear supernatant liquid into a conical flask. 50ml of water is taken in other
flask which is used as blank 0.1ml methyl red solution is added as indicator and titrated with 0.001M
hydrochloric acid until the color of the liquid is same as that obtained with blank. Subs tract the value of the
blank and express the result in millilitres of hydrochloric acid consumed per 10g of glass. Type I glass
containers require not more than 2.0ml, Type II or III requires not more than 17.0ml and Type IV glass
containers requires not more than 30.0ml of 0.001M hydrochloric acid.
Glass is commonly used in pharmaceutical packaging because it possesses superior protective qualities.
Advantages
a. Economical
b. Readily available container of variety of sizes and shapes
c. Impermeability
d. Strength and rigidity
e. Has FDA clearance
f. Does not deteriorate with age
g. Easy to clean
h. Effective closure and resolves are applicable.
i. Colored glass, especially amber, can give protection against light when it is required.
Disadvantages
a. Fragility
b. Heavy weight
Plastic container

98. Thermoplastic type
On heating, they are soften to viscous fluid which hardens again on cooling. e.g. polyethylene ,PVC
,Polystyrene ,polypropylene ,Polyamide ,Polycarbonate.
Thermosetting type
When heated, they may become flexible but they do not become liquid. Phenol formaldehyde , urea
formaldehyde, melamine formaldehyde
Plastics in packaging have proved useful for a number of reasons, including the ease with which they can
be formed, their high quality, and the freedom of design to which they lend themselves. Plastic containers
are extremely resistant to breakage and thus offer safety to consumers along with reduction of breakage
losses at all levels of distribution and use. Plastic containers for pharmaceutical products are primarily
made from the following polymers: polyethylene, polypropylene, polyvinyl chloride, polystyrene, and to a
lesser extent, polymethyl methacrylate, polyethylene terephthalate, polytrifluoroethylene, the amino
formaldehydes, and polyamides.Plastic containers consist of one or more polymers together with certain
additives. Those manufactured for pharmaceutical purposes must be free of substances that can be
extracted in significant quantities by the product contained. Thus, the hazards of toxicity or physical and
chemical instability are avoided.
Advantages of Plastic Containers
Plastic containers have a number of inherent practical advantages over other containers or dispenses. They
are
Low in cost
Pleasant to touch
Flexible facilitating product dispensing
Odorless and inert to most chemicals
Unbreakable
Leak proof
Able to retain their shape throughout their use.

99. They have a unique 'suck-back' feature, which prevents product doze.
Disadvantages
Plastics appear to have certain disadvantage like interaction, adsorption, absorption lightness and hence
poor physical stability. All are permeable to some degree to moisture, oxygen, carbon dioxide etc and most
exhibit electrostatic attraction, allow penetration of light rays unless pigmented, black etc. Other negative
features include
• Stress cracking
A phenomenon related to low density polythene and certain stress cracking agents such as wetting agents,
detergents and some volatile oils.
• Paneling or cavitation
Where by a container shows in ward distortion or partial collapse owing to absorption causing swelling of
the plastic or dimpling following a steam autoclaving operation.
• Crazing
A surface reticulation which can occur particularly with polystyrene and chemical substances (e.g.
isopropyl myristate which first cause crazing and ultimately reaches of total embitterment and
disintegration).
• Poor key of print
Certain plastics, such as the poly olefins need pre-treating before ink will key. Additives that migrate to the
surface of the plastic may also cause printing problem.
• Poor impact resistance
Both polystyrene and PVC have poor resistance. This can be improved by the inclusion of impact
modifiers such as rubber in case of polystyrene and methyl methacrylate butadiene styrene for PVC.
MATERIALS
Polyethylene

100. High-density polyethylene is the material most widely used for containers by the pharmaceutical industry
and will probably continue to be for the next several years. Polyethylene is a good barrier against moisture,
but a relatively poor one against oxygen and other gases. Most solvents do not attack polyethylene, and it is
unaffected by strong acids and alkalies.Polyethylene has certain disadvantages that it lack clarity and a
relatively high rate of permeation of essential odors, flavors, and oxygen. Despite these problems,
polyethylene in all its variations offers the best all-around protection to the greatest number of products at
the lowest cost. The density of polyethylene, which ranges from 0.91 to 0.96, directly determines the four
basic physical characteristics of the blow-molded container
(1)Stiffness
(2)Moisture-vapor transmission
(3)Stress cracking
(4)Clarity or translucency
As the density increases, the material becomes stiffer, has a higher distortion and melting temperature,
becomes less permeable to gases and vapors, and becomes less resistant to stress cracking. The molecular
structure of high-density material is essentially the, same as that of low-density material, the main difference
being fewer side branches.
Polypropylene
Polypropylene has recently became popular because it has many good features of polyethylene, with one
major disadvantage either eliminated or minimized. Polypropylene does not stress-crack under any
conditions. Except for hot aromatic or halogenated solvents, which soften it, this polymer has good
resistance to almost all types of chemicals, including strong acids, alkalies, and most organic materials. Its
high melting point makes it suitable for boilable packages and for sterilizable products.
Lack of clarity is still a drawback, but improvement is possible with the construction of thinner
walls.Polypropylene is an excellent gas and vapor barrier. Its resistance to permeation is equivalent to or
slightly better than that of high-density or linear polyethylene, and it is superior to low-density or branched
polyethylene. One of the biggest disadvantages of polypropylene is its brittleness at low temperatures. In its
purest form, it is quite fragile at 0°F and must be blended with polyethylene or other material to give it the
impact resistance required for packaging.
Polyvinyl Chloride (PVC)
PVC can be softened with plasticizers. Various stabilizers, antioxidants, lubricants, or colorants may be
incorporated. Polyvinyl chloride is seldom used in its purest form. PVC is an inexpensive, tough, clear

101. material that is relatively easy to manufacture. PVC must not be overheated because it starts to degrade at
280°F, and the degradation products are extremely corrosive. Polyvinyl chloride yellows when exposed to
heat or ultraviolet light, unless a stabilizer is included by the resin supplier. From the standpoint of clarity,
the best stabilizers are the tin compounds, but the majority cannot be used for food or drug products
Polyvinyl chloride is not affected by acids or alkalis except for some oxidizing acids. Its impact resistance is
poor, especially at low temperatures.
Polystyrene
Polystyrene is attacked by many chemicals, which cause it to craze and crack, and so it is generally used for
packaging dry products only. To improve impact strength and brittleness, general-purpose polystyrene may
be combined with various concentrations of rubber and acrylic compounds. Certain desired properties like
clarity and hardness diminish with impact polystyrene. The shock resistance or toughness of impact
polystyrene may be varied by increasing the content of rubber in the material, and often these materials are
further classified as intermediate-impact, high-impact, and super-impact polystyrene.
General-purpose polystyrene is a rigid, crystal clear plastic. Polystyrene has been used by dispensing
pharmacists for years for containers for solid dosage forms because it is relatively low in cost. At present,
polystyrene is not useful for liquid products. The plastic has a high water vapor transmission (in comparison
to high-density polyethylene) as well as high oxygen permeability. Depending on the methods of
manufacture and other factors, polystyrene containers are easily scratched and often crack when dropped.
Polystyrene will build up static charge. Polystyrene has a low melting point (190°F) and therefore cannot be
used for hot items or other high-temperature applications. Polystyrene is resistant to acids, except strong
oxidizing acids, and to alkalies.
Nylon (Polyamide)
As a barrier material, nylon is highly impermeable to oxygen. It is not a good barrier to water vapor, but
when this characteristic is required, nylon film can be laminated to polyethylene or to various other
materials.Its relative high-water transmission rate and the possibility of drug-plastic interaction have reduced
the potential of nylon for long-term storage of drugs. Some of the nylon approved by FDA are Nylon 6,
Nylon 6/6, Nylon 6/10, Nylon 11, and certain copolymers. sNylon is made from a dibasic acid combined
with a di-amine. Variety of nylons can be made with different dibasic acids and amines. The type of acid and
amine that is used is characteristic and denotes the type of acid and amine used.e.g. nylon 6/10 has six carbon
atoms in the diamine and ten in the acid. Nylon and similar polyamide materials can be fabricated into thin-
wall containers. Nylon
can be autoclaved and is extremely strong and quite difficult to destroy by mechanical means. Important to
the widespread acceptance of nylon is its resistance to a wide range of organic and inorganic chemicals.

102. Polycarbonate
The plastic is known for its dimensional stability, high impact strength, resistance to strain, low water
absorption, transparency, and resistance to heat and flame. Polycarbonate is resistant to dilute acids,
oxidizing or reducing agents, salts, oils (fixed and volatile), greases, and aliphatic hydrocarbons. It is
attacked by alkalies, amines, ketones, esters, aromatic hydrocarbons, and some alcohols. Polycarbonate
resins are expensive and consequently are used in specialty containers. Since the impact strength of
polycarbonate is almost five times greater than other common packaging plastics, components can be
designed with thinner walls to help reduce cost. Polycarbonate can be made into a clear transparent
container. Polycarbonate is expensive and offers some advantage that it can be sterilized repeatedly. The
containers are rigid, as is glass, and thus has been considered a possible replacement for glass vials and
syringes. It is FDA-approved, although its drug-plastic problems have not been investigated adequately. It
is only moderately chemically resistant and only a fair moisture barrier.
Acrylic Multipolymers (Nitrile Polymers)
The present safety standard is less than 11 ppm residual acrylonitrile monomer, with allowable migration at
less than 0.3 ppm for all food products. These polymers represent the acrylonitrile or methacrylonitrile
monomer. Their unique properties of high gas barrier, good chemical resistance, excellent strength
properties, and safe disposability by incineration make them effective containers for products that are
difficult to package in other plastic containers. Their oil and grease resistance and minimal taste transfer
effects are particularly advantageous in food packaging. These type of polymers produce clear container and
are less costly. The use of nitrile polymers for food and pharmaceutical packaging is regulated to standards
set by the Food and Drug Administration.
Polyethylene terephthalate (PET)
Polyethylene terephthalate is used in food packaging and offers favorable environmental impact system.
Polyethylene terephthalate, generally called PET, is a condensation polymer typically formed by the
reaction of terephthalic acid or dimethyl terephthalate with ethylene glycol in the presence of a catalyst.
Although used as a packaging film since the late 1950s, its growth has recently escalated with its use in the
fabrication of plastic bottles for the carbonated beverage industry.
Product-Plastic interactions
Product-Plastic interactions have been divided into five separate categories:

103. (1)Permeation
(2)Leaching
(3)Sorption
(4)Chemical reaction
(5)Alteration in the physical properties of plastics or products
1) Permeation
Transmission of gases, vapors, or liquids through plastic packaging materials can have an adverse effect on
the shelf-life of a drug. Permeation of water vapor and oxygen through the plastic wall into the drug can
present a problem if the dosage form is sensitive to hydrolysis and oxidation. Temperature and humidity are
important factors influencing the permeability of oxygen and water through plastic. An increase in
temperature reflects an increase in the permeability of the gas. Great differences in permeability are
possible, depending on the gas and the plastic used. Molecules do not permeate through crystalline zones;
thus, an increase in crystallinity of the material should decrease permeability. Two polyethylene materials
may therefore give different permeability values at various temperatures. Materials such as nylon, which are
hydrophillic in nature, are poor barriers to water vapor, while such hydrophobic materials as polyethylene
provide much better barriers. Studies have also revealed that formulations containing volatile ingredients
might change when stored in plastic containers because one or more of the ingredients are passing through
the walls of the containers. Often, the aroma of cosmetic products becomes objectionable, owing to
transmission of one of the ingredients, and the taste of medicinal products changes for the same reason.
2) Leaching
Problems may arise with plastics when coloring agents in relatively small quantities are added to the
formula. Particular dyes may migrate into a parenteral solution and cause a toxic effect. Release of a
constituent from the plastic container to the drug product may lead to drug contamination and necessitate
removal of the product
from the market. Plastic containers have one or more ingredients added in small quantities to stabilize or
impart a specific property to the plastic and the prospect of leaching, or migration from the container to
the drug product is present.
3)Sorption
It is the process involves the removal of drug content from the product by the packaging material.
Sorption may lead to serious consequences active ingredients are in solution. Since drug substances of
high potency are administered in small doses, losses due to sorption may significantly affect the

104. therapeutic efficacy of the preparation. Sorption is seen mainly with preservatives. These agents exert
their activity at low concentration, and their loss through sorption may be great enough to leave a product
unprotected against microbial growth. Factors that influence characteristics of sorption from product are
chemical structure, pH, solvent system, concentration of active ingredients, temperature, length of contact,
and area of contact.
4) Chemical Reactivity
Certain ingredients that are used in plastic formulations may react chemically with one or more
components of a drug product. At times, ingredients in the formulation may react with the plastic. Even
micro-quantities of chemically incompatible substances can alter the appearance of the plastic or the drug
product.
5) Modification
Polyvinyl chloride is an excellent barrier for petroleum solvents, but the plasticizer in polyvinyl chloride is
extracted by solvents. This action usually leaves the plastic hard and stiff. Sometimes, this effect is not
immediately perceptible because the solvent either softens the plastic or replaces the plasticizer; later,
when the solvent evaporates, the full stiffening effect becomes apparent. The changes in physical and
chemical properties of the packaging material by the pharmaceutical product are called modification. Such
phenomena as permeation, sorption, and leaching play a role in altering the properties of the plastic and
may also lead to its degradation. Deformation in polyethylene containers is often caused by permeation of
gases and vapors from the environment or by loss of content through the container walls. Some solvent
systems have been found to be responsible for considerable changes in the mechanical properties of
plastics.
Oils, for example, have a softening effect on polyethylene; fluorinated hydrocarbons attack polyethylene
and polyvinyl chloride. In some cases, the content may extract the plasticizer, antioxidant, or stabilizer,
thus changing the flexibility of the package.
TESTS FOR PLASTIC CONTAINERS
LEAKAGE TEST
The plastic containers (non injectables and injectables 1996 IP): fill 10 plastic containers with water and
fit the closure keep them inverted at room temperature for 24 hrs no sign of leakage should be there from
any container
WATER PERMEABILITY TEST
Fill 5 containers with nominal volume of water and sealed weigh each container allows to stand for 14
days at relative humidity of 60% at 20-250C reweigh the container loss of weight in each container should
not be more than 0.2%.

105. Metal-container
Tin
Tin containers are preferred for foods, pharmaceuticals, or any product for which purity is an important
consideration. Tin is chemically inert of all collapsible tube metals. It offers a good appearance and
compatibility with a wide range of products.
Aluminum
Aluminum tubes offer significant savings in product shipping costs because of their light weight. They
provide good appearance.
Lead
Lead has the lowest cost of all tube metals and is widely used for nonfood products such as adhesives, inks,
paints, and lubricants. Lead should never be used alone for anything taken internally because of the risk of
lead poisoning. The inner surface of the lead tubes are coated and are used for products like fluoride
toothpaste.
Linings
If the product is not compatible with bare metal, the interior can be flushed with wax-type formulations or
with resin solutions, although the resins or lacquers are usually sprayed on. A tube with an epoxy lining
costs about 25% more than the same tube uncoated. Wax linings are most often used with water-base
products in tin tubes, and phenolics, epoxides, and vinyls are used with aluminum tubes, giving better
protection than wax, but at a higher cost.
RUBBER

106. Rubber
It is used mainly for the construction of closure meant for vials, transfusion fluid bottles, dropping bottles
and as washers in many other types of product.
BUTYL RUBBER
Advantages
Permeability to water vapor . Water absorption is very low. They are relatively cheaper compared to other
synthetic rubbers.
Disadvantages
Slow decomposition takes place above 130 0 C. Oil and solvent resistance is not very good.
NITRILE RUBBER
Advantages
Oil resistant due to polar nitrile group. Heat resistant.
Disadvantages
Absorption of bactericide and leaching of extractives are considerable.
CHLOROPRENE RUBBERS
Advantages
Oil resistant. Heat stability is good.
SILICON RUBBERS
Advantages
Heat resistance. Extremely low absorption and permeability of water.
Excellent aging characteristic.
Disadvantages
They are very expensive.

107. TESTS FORRUBBER CLOSURES
FRAGMENTATION TEST
Place a volume of water corresponding to nominal volume-4ml in each of 12 clean vials close vial with
closure and secure caps for 16hrs pierce the closure with number 21 hypodermic needle(bevel angle of 10
to 140c)and inject 1ml water and remove 1ml air repeat the above operation 4 times for each closure count
the number of fragments visible to naked eye Total number of fragments should not be more than 10.
SELF SEALABILITY TEST FOR RUBBER CLOSURES APPLICABLE TO MULTI DOSE
CONTAINERS ONLY
Fill 10 vials with water to nominal volume and close the vials with closures pierce the cap and closures 10
times at different places with no 21 syringe needle immerse the vials in 0.1 %W/v solution of methylene
blue under reduced pressure restore the nominal pressure and keep the container for 30 min and wash the
vials none of the vial should contain traces of colored solution.
Blister packaging technology
Blister packaging is a type of pre-formed plastic packaging used for small consumer goods. The two
primary components of a blister pack are the cavity made from either plastic or aluminum - and the
lidding, made from paperboard, paper, plastic or aluminum. The cavity contains the product and the
lidding seals the product in the package.
Blister packaging helps retain product integrity because drugs that are pre- packaged in blisters are
shielded from adverse conditions. Furthermore, opportunities for product contamination are minimal, and
each dose is identified by product name, lot number, and expiration date. Therefore, blister packaging
ensures product integrity from the producer directly through distribution to the consumer.
Material used in blister packaging 1.
PVC
The most basic material for the forming web is polyvinyl chloride (PVC). The principal advantages of
PVC are the low cost and the ease of thermoforming.
2. PCTFE
Polychlorotrifluoro ethylene or PCTFE can be laminated to PVC to obtain very high moisture
barrier. 3. COC
Cyclic olefin copolymers (COC) or polymers (COP) can provide moisture barrier to blister packs.

108. Advantages
1. Product integrity.
2. Product protection.
3. Tamper evidence.
4. Reduced possibility of accidental misuse.
5. Patient compliance.
Tamper-evident packaging
(TEP) means packaging that has an indicator or barrier to entry which, if breached or missing, can
reasonably be expected to provide visible or audible evidence to consumers that tampering may have
occurred.
Tamper-Evidence
The degree to which tampering is apparent to the observer.
Tamper-Resistance: The degree to which it is difficult to tamper (and repair) without leaving evidence. A
tamper-resistant package has an indicator or barrier to entry which, if breached or missing, can
(reasonably) be expected to provide visible evidence to consumers that tampering has occurred.
Tamper- Evident Features
The packaging features listed below are considered to be acceptable forms of TEP provided they are
validated in accordance with Clause
Whilst these forms of TEP are acceptable, they should not be seen to be exclusive of other forms of TEP or
to preclude technological innovation. Tamper-evident packaging must not be regarded as replacing or
obviating the need for child- resistant packaging wherever the law requires such packaging. In selecting or
developing tamper-evident packaging, consideration should be given to the special.
Film Wrappers
Transparent A transparent film with distinctive design is wrapped securely around the entire product
container ensuring the product is completely sealed and a secure tight fit is achieved.
Blister or Strip Packs

109. Individual doses (for example, capsules or tablets) are sealed in plastic and/or foil. Blister or strip pack
seals around individual compartments and the strip as a whole must be intact and complete.
Bubble Packs
The product and container are sealed in a plastic bubble and mounted in or on a display card.
Heat Shrink Bands or Wrappers
Bands or wrappers with a distinctive design are shrunk by heat to tightly seal the union of the cap and
container.
Pouches, Sachets and Form Fill Seal Packs
The product is enclosed in an individual pouch or sachet that must be ripped, peeled open or broken to gain
access to the product.
Container Mouth Inner Seals
Paper, thermal plastic, polystyrene foam, plastic film, foil, or combinations thereof, with a distinctive
design is sealed to the mouth of a container under the cap.
Design
During design of TEP, the following aspects must be considered.
a. Suitability of the packaging for its intended purpose.
b. Compatibility of the packaging components.
c. Compatibility of the packaging components with the packaging process.
d. Presence of the required TEP statements on the final pack. The tamper-evident packaging features
must be designed to remain intact, when handled in a reasonable manner, during manufacture,
distribution and retail display.
Specifications
In recognition of the variability of packaging components, the sponsor must ensure that clear and concise
specifications are developed and agreed between the packaging material supplier and the product
manufacturer.
IMPORTANT QUESTIONS
1.Describe Plastic containers used in packing of Pharmaceutical preparations. Add a note on evaluation of
plastic containers. (20) Oct 2010, Oct 2012. Oct 2013
2. Evaluation of plastic containers used in packaging of pharmaceutical preparation. (6) Oct 2011, Apr2015
3. T h e r m o s e t t i n g s . ( 6 ) M a y 2 0 1 2
4 . Define Pharmaceutical Packing? What are the salientfeatures of packing
material? Discuss about the packing of glass container and Plastic containers. (20) Apr 2013
5.Selection and evaluation of packaging materials. (6) Apr 2014

111. What does stability mean for drugs and pharmaceuticals ?
 The stability of the product is its ability to resist deterioration. It is always expressed in terms of
shelf life.
 Stability: is the capacity of a drug product to remain within specifications established to ensure its
identity, strength quality and purity. (USP-NF)
As per USP there are five types of stability studies :
» Chemical
» Physical
» Microbiological
» Processing factors

112. » Toxicological
 Various ways of chemical degradation includes:
• hydrolysis
• dehydration
• isomerization & racemization
• decarboxylation & elimination
• oxidation
• photo degradation
• drug – excipients & drug – drug interactions
 HYDROLYSIS
 REMEDIES:

113.  DEHYDRATION
 There are two types of dehydration process:
1) Covalent dehydration
2) Physical dehydration
 Sugars such as glucose and lactose are known to undergo dehydration to form 5-
(hydroxymethyl)furural.
 Erythromycin is susceptible to acidcatalyzed dehydration
 Batanopride undergoes an intramolecular ring-closure reaction in the acidic pH range due to
dehydration
 ISOMERIZATION & RACEMIZATION
 Isomerization
Conversion of active drug into less active or inactive drug.
• EX-Vit-A susceptible to isomerization in presence of light.
 Racemization
 Conversion of optically active drug into its enantiomer.
 The best known racemerization reaction of drugs are epinapherine,pilocarpine,ergotamine &
tetracycline.
 DECARBOXYLATION
 Drug substances having a carboxylic acid group are sometimes susceptible to decarboxylation. 4-
Aminosalicylic acid is a good example.
 Foscarnet also undergoes decarboxylation under strongly acidic conditions,whereas etodolac is
susceptible to decarboxylation by acid catalysis.
 REMEDIES
 This action is minimised by passing CO2 into the solution for one minute & sealing the container so
as to make it gas-tight prior to autoclaving.
 Ionic Strength (Primary Salt Effects)
 For drug degradation involving reactions with or between ionic species, the rate is affected by the
presence of other ionic species such as salts like sodium chloride.
 Ionic strength affects the observed degradation rate constant, k, by its effect on the activityn
coefficients, ƒ. Ionic strength, µ, is described by
 where Ci is the concentration of ionic species i and Zi is its electric charge.
 OXIDATION
 Drugs can be affected by the availability of oxygen.
 Some photo degradation reactions involve photo oxidative mechanisms that are dependent on conc.
of oxygen.
 Oxygen participates as reactant and also alters the degradation rate.
 Oxygen exists in various states such ground state triplate oxygen, etc.
 The following excipients may have low level residues from manufacture that can lead to oxidative
degradation in susceptible compounds.

114.  REMEDIES:
1) Minimum oxygen level used which may be achieved by boiling the water & allowing to cool in an
atmosphere free from oxygen.
2) Hydrogenation of product.
3) Incorporation of inert gas in containers.
4) Use of anti-oxidant.
5)Buffering the solution at favourable pH, Use of metal free solvents.
 PHOTOLYSIS
 Reactions such as oxidation-reduction, ring alteration and polymerisation can be catalysed or
accelerated by exposure to sun or artificial light.
 Photolytic degradation can be very complex, the products of such degradation being numerous and
difficult to identify.
 Exposure to light can cause discolouration of both drugs and excipients even when degradation is
modest and not even detectable analytically. This can lead to “off colour” product, perceived by the
patient as a quality deficiency.
 CATALYSIS
 In parentrals, great care is taken to exclude metals, because only slight decomposition caused by
trace metals may cause sufficient discoloration to the product unsatisfactory.
 Ex of metal catalysed oxidation in pharmaceutical system are cynocobalamine & erythromycin.
2) Physical factors
o TEMPERATURE
o pH AND pH RATE PROFILES
o BUFFER
o LIGHT
o CRYSTALLINE STATE & POLYMORPHISM IN SOLID DRUGS
o MOISTURE AND HUMIDITY
o EXCIPIENTS
o MISCELLANEOUS FACTORS
 TEMPERATURE
 It is one of the primary factors affecting drug stability.
 The rate constant/temperature relationship has traditionally been described by the Arhenius
equation,
k = A exp(-Ea/RT)
 where Ea = activation energy
A = frequency factor
.
 REMEDIES:-
 Pharmaceutical product should be stored within the temperature range in which they are stable.
 They should not be exposed to extremes of temperature.
 Usually they should be stored at low temperature if they lack sufficient stability at room

115. temperature.
 There are few drugs on which freezing has an adverse effect, so freezing should be avoided unless
until it is stable at such temperatures.
 pH AND pH RATE PROFILES
 Second most important parameter.
 The effect of pH on degradation rate can be explained by the catalytic effects that hydronium or
hydroxide ions can have on various chemical reactions.
 If critical path in a reaction involves a proton transfer or abstraction step, other acids and bases
present in solution can affect the rate of reaction.
 A reaction in which hydronium ion, hydroxide ion, and water catalysis are observed can be
described by
Kobs = kH+ aH+ + KH2O + KoH- aOH-
 Where Kobs = sum of specific rate constants
aH+ = activities of hydronium ion
aOH- =activities of hydroxide ion
 BUFFER
 These buffer species, like H+ and OH-, participates in formation of break down of activated
complexes of various reaction and determine their reaction rate.
 These catalytic species are referred to as general acid-base catalysts.
 Studies with phosphate buffer indicates that it enhance the degradation of various drug substances
such as carbenicillin etc.
 LIGHT
 The number and wavelength of incident photons affect the photo degradation rate of drugs.
 It is not easy to study the effect of light quantitatively as the wavelength dependence of degradation
varies among drug substances and because light sources have different spectral distributions.
 Photo degradation for drug strongly dependence on the spectral properties of the drug substances
and the spectral distribution of the light source.
 CRYSTALLINE STATE & POLYMORPHISM IN SOLID DRUGS
 The stability of drugs in their amorphous form is generally lower than that of drugs In their
crystalline form due to higher free energy level of amorphous form decreased chemical stability of
solid drugs brought about by mechanical stresses such as grinding is said to be due to change in
crystalline state.
 ex: grinding of aspirin increased degradation rate in suspension form.
 MOISTURE AND HUMIDITY
 Drug degradation in heterogeneous system such as solid and semisolid states is affected by
moisture.
 Moisture plays important role in catalyzing chemical degradation:
1) Water participates in the drug degradation process itself as a reactant, leading to hydrolysis;
hydration etc. Here degradation rate is directly affected by the concentration of water, hydronium
ion, hydroxide ion.
2) Water absorbs onto the drug surface and forms a moisture-sorbed layer in which the drug is
dissolved and degraded.
3) Ex-Sodium ampicillin , potassium propicillin
 REMEDIES:

116.  Maintenance of controlled humidity condition
 Moisture proof packaging.
 EFFECT OF SOLUBILITY:-
 Applicable to drugs in solution form.
Ex:-
Penicillins are very unstable in aqueous solution because of hydrolysis of β-lactam ring.
 REMEDIES:
 Stabilised by using insoluble salts of API.
 Formulate the drug in suspension dosage form.
 EXCIPIENTS
 The role that excipients play in drug stability has been extensively reported-e.g.: accelerating the
effect of talc on hydrolysis of thiamine hydrochloride, the accelerating effect of magnesium stearate
on tablet containing amines and lactose etc.
 Additional informations include reports on compatibility and incompatibility of drugs.
 Excipients can affect drug stability via various mechanisms.
 VAPORIZATION
 Some drugs & pharmaceutical adjuvants possess sufficiently high vapor pressures at R.T. that their
volatization constitutes a major route of drug loss.
 Flavors may be lost from the formulation in this manner.
 Ex-Nitroglycerine= 0.00026mm at 20˚c
= 0.31mm at 93˚c
 AGING:
 This is a process through which changes in the disintegration &/or dissolution characteristics of the
dosage form are caused by alteration in the physico chemical properties of the inert ingredient or the
active drug in the dosage form.
 Ex-melting point of aminophylline suppository increased from about 20 mins to over an hour after
24 weeks of storage at 22 c
 RADIATION
 Radiation generally used during gaseous sterilization of thermolabile drugs.
 The exposure also produce deterious changes in the product since the procedures also cause
ionization in the irradiated material.
 Irradiation of a drug in aq. solution produces greater changes than the irradiation of the pure
material because irradiation of water produces H2O2,free oxidative action in drug.
 Drugs affected by radiation are:
1) Alkaloids
2) Atropine
3) Steroids
4) Sulphonamides
5) Biological products-Insulin,Heparin.ss
 All the above ex. are irradiated at low level of 2.5 µ rad.

117. Preparation Preservative Concentration
% w.v
Creams Parabens
Chlorocresol
0.1-0.2
0.1
Tablets Methylparaben 0.1
Biological Factors:
Microbial degradation Effects of Microbial Instability:
Contamination of a product may sometimes cause a lot of damage and sometimes may not be
anything at all. Thus it is dependent on the type of microbe and its level of toxicity it may produce.
If parenterals or opthalmic formulations are contaminated, it may cause serious harm.
But contamination in other nonsterile products is usually not so damaging.It results in general
spoilage such as discoloration, breakdown of emulsions and the production of gas and other
odours.In some cases active drugs may be destroyed without any outward signs. Thus, salicylates,
phenacetin, paracetamol, atropine, chloramphenicol and hydrocortisone can be degraded to a variety
of therapeutically inactive products. Preservatives, especially those that are aromatic in structure can
themselves act as a ready source of nutrition to microbes.
Pyrogens which are the metabolic products of bacterial growth are usually lipo-polysaccharides and
they represent a particularly hazardous product released by gram negative bacteria. If administered
inadvertently to a patient they may cause chills and fever.

136. IMPORTANT QUESTIONS:
1. Industrial hazards and preventive measures due to fire accident (6) Oct 2010, Oct 2011, Oct 2014
2. Describe about the preventive measures due to electrical hazards (6) May 2012
3. Hazards and safety measures due to mechanical and electrical equipments used in Pharma Industry
(6) Oct 2012, Oct 2013, Apr 2015
4. Chemical Hazards and their preventive measures (6) Apr 2013
NOTES PREPARED BY
EKNATH BABU T.B.
I.M.PHARMACY
DEPT.OF
PHARMACEUTICS
(T.B.E.K.B)