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

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

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

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.

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

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

The solubility of every new drug must be determined as a function of pH over the

physiological pH range of 1 – 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

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

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.

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

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

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.

BONDING OF PARTICLES:

Governed by several theories as follows:

The mechanical theory.

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.

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.

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

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

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.

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

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:

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:

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.

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

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

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

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.

• 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

• 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

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

• 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

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

– 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

• 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

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)

# 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)

OPTIMIZATION TECHNIQUES IN PHARMACEUTICAL FORMULATION AND

PROCESSING:

Concept of optimization, Optimization parameters, Classical optimization, Statistical design, and

Optimization methods.

Concept of optimization

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

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 .

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)

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.

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.

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 60Co (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.

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

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

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 Action\Duration 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

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

containing specific antibodies obtained from blood of humans who have had the disease or have been

immunized against it with a specific biologic product.

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

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.

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)

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.

• 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

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

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

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

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

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

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.

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

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.

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.

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.

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

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.

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

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

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 121oC 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

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.

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

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

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.

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:

(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

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%.

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

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.

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.

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

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

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

» Toxicological

Various ways of chemical degradation includes:

• hydrolysis

• dehydration

• isomerization & racemization

• decarboxylation & elimination

• oxidation

• photo degradation

• drug – excipients & drug – drug interactions

HYDROLYSIS

REMEDIES:

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.

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

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:

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.

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.

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)