Pharmacy Quality Assurance

PHRM 405
 COURSE OUTLINE

• Pharmaceutical Quality control:

• Quality Assurance:

Pharmaceutical Quality control:

Quality control of Raw materials, packaging
materials and finished pack:
Significance of qualitative and quantitative
analysis of raw materials,
primary and secondary packaging components,
intermediate process or in-process control
process control and analysis of finished
product.
• Techniques used in pharmaceutical following
monographs:
• The quality control of different components by using
techniques as guided by monographs (BP, Pheu Eur,
USP )etc by way of analysis with precision, accuracy
of representative samples with a view to obtain
persistent quality by systematic analysis compliance
and documentation.
• Monitoring of safety, health and environmental
aspects: The monitoring of safety, health aspect of
workers, machines, premises, environment and various
machineries used in the process and in process control,
cleaning and changeover process .
• Good Laboratory Practice, Good Manufacturing
practice:
• Compliance of WHO, and other Guidelines
specifications.
Quality Assurance:
Doccumentation:
• Documentation of all the activity carried out in Quality Control
with an objective of establishing persistent quality.
• Stability studies of various products.

• Validation:
Validation of reagents and chemicals used in analysis of products, validation
of methods and techniques used in Q.C. and machineries and equipments
used in process in production area, validation of methods and guidelines
adopted for primary and secondary packaging components.

• Stability:
Storage of representative samples, (finished pack, primary and
secondary components), Establishment of shelf-life dates of all
products.
 Pharmaceutical Plant Design
Assignment
Prodcution Engineering Design:
https://www.youtube.com/watch?v=09H5bUp
CpWQ
Pharmaceutical Lay Out
Pharmaceutical Lay Out
Liquid Manufacturing Lay out
Pharmaceutical Lay Out
Pharmaceutical Lay Out
Why is Quality Control and
Assurance Needed?
 Thalidomide tragedy
Thalidomide was a widely used drug in the late 1950s and early 1960s
for the treatment of nausea in pregnant women. It became apparent in
the 1960s that thalidomide treatment resulted in severe birth defects in
thousands of children.
Though the use of thalidomide was banned in most countries at that
time, thalidomide proved to be a useful treatment for leprosy and later,
multiple myeloma.
In rural areas of the world that lack extensive medical surveillance
initiatives, thalidomide treatment of pregnant women with leprosy has
continued to cause malformations. Research on thalidomide mechanisms
of action is leading to a better understanding of molecular targets. With
an improved understanding of these molecular targets, safer drugs may
be designed.
 Thalidomide tragedy

The thalidomide tragedy marked a turning point in toxicity testing, as

it prompted United States and international regulatory agencies to
develop systematic toxicity testing protocols; the use of thalidomide
as a tool in developmental biology led to important discoveries in the
biochemical pathways of limb development.
In celebration of the Society of Toxicology's 50th Anniversary, which
coincides with the 50th anniversary of the withdrawal of thalidomide
from the market, it is appropriate to revisit the lessons learned from
the thalidomide tragedy of the 1960s.
Thalidomide Tragedy
Thalidomide Tragedy
Thalidomide Tragedy
 What is Quality?
How and Why?
some assumptions or fascination
towards some of the drug
manufacturer?
(Glaxowelcome, Novartis, Beximco,
Square?)
• I like the brand!
• I trust the brand!
• I like the box!
• Another type of answers expected by
influence of other-
• My mother uses it!
• My friend uses it!
• My doctor says so!
(Doctors are prescribing according
to the brand name not by the generic
name)-it can be one reason.
• The pharmacist sells it!
 What is Quality Control
Quality Control is a process of striving to produce a
perfect pharmaceutical product (How?) by
a series of measures requiring an organized effort
(by Whom?)
by the entire company to (top to bottom)
prevent or eliminate errors (Where?)
at every stage in production.
THALIDOMIDE AND HEAVY
METAL POISONING
 When Quality will be built?
Quality must be built into a drug product
during:
• Product (drug) design
• Process (drug) design
Quality is maintained in a continuous process
Starting material
continuous process
Active ingredient Product
Inactive ingredient/Excipients

Quality control required at every step in the production

 Factors Affecting the Quality ?

It is affected by the
•Physical design of the pharmaceuticals plant:
An ideal design is required for the pharmaceutical.
•Space of the plant:
sufficient space is required for the various section of the
pharmaceutical:
•Storage area Quarantine area
•Production Quality control
•Packaging section Cleaning and Washing area
• Ventilation of the plant:
For the health of the worker as well as to avoid
the contamination between different products.

– Cleanliness
– and
– Sanitation
Product and Process (drug) design

Begins in •Preformulation of
Research the drug
and •Physical (Raw &
It includes
Development Finished)
•Chemical
•Therapeutic
consideration
•Toxicological
 QC Throughout Production Systems

Inputs Conversion Outputs

Raw Materials, Production Products and
Parts, and Processes Services
Supplies

Control Charts Control Charts

and Control Charts and
Acceptance Tests Acceptance Tests
Quality of Quality of Quality of
Inputs Partially Completed Outputs
Products
Lesson plan-2
 Quality Control
•Raw Materials Control (Starting Material)
•Packaging Materials Control
specification
•In process Control
•Product Control (Finished Product itself )

Need to be complied the specifications described in

USP, BP etc.
In process Control:
A continuous process, during manufacturing different steps
32
are checked
Product Control:
After completion of the manufacturing process or
at the terminal stage.
Raw Materials Control:
Active ingredient-
Accurate potency of the final product is dependent
on the active ingredients.
Inactive ingredient/excipient-
They are used in large quantity, if it is toxic can
33
cause mortality.
• Active pharmaceutical ingredient (API)
• Any substance or mixture of substances intended
to be used in the manufacture of a pharmaceutical
dosage form and that, when so used, becomes an
active ingredient of that pharmaceutical dosage
form. Such substances are intended to furnish
pharmacological activity or other direct effect in
the diagnosis, cure, mitigation, treatment, or
prevention of disease or to affect the structure and
function of the body.
Pharmaceutical Excipient
• A substance, other than the active pharmaceutical
ingredient (API), which has been appropriately evaluated
for safety and is included in a medicines delivery system
to:
• — aid in the processing of the medicines delivery system
during its manufacture;
• — protect, support or enhance stability, bioavailability or
patient acceptability;
• — assist in pharmaceutical product identification; or
• — enhance any other attribute of the overall safety and
effectiveness of the
• medicine during its storage or use (6, 7).
• Specification of
– Active ingredient
– Inactive ingredient/excipient

• Specification of the product itself

• Tests or experiments-
Required for the maintaining or judgment of these
specification.

36
 What is Specification?
A list of detailed requirements with which the
products or materials used or obtained
during manufacture have to conform.

They serve as the basis for quality evaluation.

37
 Start
Quarantine • Intermediates
• Incoming   materials • Bulks
• Water • Finished  goods
• Returned   goods 2. Receiving • Environment   monitoring

3. Sampling
QC/QA  Status
4. Test samples
Lab  
Quarantine
Records
5. Review of batch record
Release

NO
7. Non conformance or
Reject Meet specification out of specification
investigation
YES

6. Goods release
8. Goods Reject
Release
Reject
38
End
End
 Batch (or lot)
• A defined quantity of starting material, packaging material, or
product processed in a single process or series of processes so
that it is expected to be homogeneous.
• It may sometimes be necessary to divide a batch into a number
of sub-batches, which are later brought together to form a
final homogeneous batch.
• In the case of terminal sterilization, the batch size is
determined by the capacity of the autoclave. In continuous
manufacture, the batch must correspond to a defined fraction
of the production, characterized by its intended homogeneity.
The batch size can be defined either as a fixed quantity or as
the amount produced in a fixed time interval.
 Batch number (or lot number)
A distinctive combination of numbers and/or letters which
uniquely identifies a batch on the labels, its batch records and
corresponding certificates of analysis, etc.
Batch RECORDS:
• All documents associated with the manufacture of a batch of
bulk product or finished product. They provide a history of
each batch of product and of all circumstances pertinent to the
quality of the final product.

Bulk product:
• Any product that has completed all processing stages up to,
but not including, final packaging.
Primary reference substance (or standard)
• A substance that is widely acknowledged to possess the
appropriate qualities within a specified context, and whose
assigned content is accepted without requiring comparison
with another chemical substance (8).
• Note: Pharmacopoeial chemical reference substances are
considered to be primary reference substances. In the
absence of a pharmacopoeial reference substance, a
manufacturer should establish a primary reference
substance.
Reference material
• Material sufficiently homogeneous and stable with respect
to one or more specified properties, which has been
established to be fit for its intended use in a measurement
process (4).
Reference substance (or standard)
• An authenticated, uniform material that is intended
for use in specified chemical and physical tests, in
which its properties are compared with those of the
product under examination, and which possesses a
degree of purity adequate for its intended use.
Secondary reference substance (or standard)
• A substance whose characteristics are assigned
and/or calibrated by comparison with a primary
reference substance. The extent of characterization
and testing of a secondary reference substance may
be less than for a primary reference substance.
• Analytical test report
An analytical test report usually includes a description of
the test procedure(s) employed, results of the analysis,
discussion and conclusions and/or recommendations for
one or more samples submitted for testing (see Part three,
sections 18.7–18.11).
Analytical worksheet
• A printed form, an analytical workbook or electronic
means (e-records) for recording information about the
sample, as well as reagents and solvents used, test
procedure applied, calculations made, results and any
other relevant information or comments (see Part three,
section 15).
• Reference testing:
https://www.youtube.com/watch?v=64Qa1EGqmUo
 What  are  these  colors?  

Passed in green
Rejected in red

Quarantine in orrange

Under test in pink 44

Passed in green
Rejected in red

Quarantine in orrange

Under test in pink

Quality Control Associates
https://www.youtube.com/watch?v=xU3J4HqkmsM 45
 Quality Control Raw Materials
Ref: D. H. Shah:126
• The quality of a pharmaceutical formulation is
largely governed by the quality of the raw
materials that go into it.
• Testing of the raw material is the utmost
important for the control of the material.
• Tests performed with the help of different
technical processes.
46
 Purposes of the Testing of Raw
Material (Ref: D. H. Shah:126)
• To confirm that the material is what it is
claimed to be.
• It has the quality in the dosage form produced
from it.
• To provide assurance that the shelf life of the
final product will not be affected by defects in
the material.
47
 Quarantine Program
It consists of four basic steps:
• Notification
• Record preparation
• Segregation
• Disposition
Notification is discrepancy
tracking system:
Discrepancy:
Synonym:
– Different
– inconsistency
– incongruity
– divergence
48
– disagreement
 Notification of Quarantine
There are several methods of quarantine notification:
• Management requests such as an internal memo or a
discrepancy tracking system.
• Individual or department that identifies a discrepancy
is responsible for notifying the coordinator of any
needed quarantine activities.
• Another form of notification may be as simple as a
phone call to ensure timely action, then follow-up with
official documented notification.

49
 Receipt of the Raw Material
Ref: D. H. Shah:126
• Receipt of each delivery of each raw material should be
recorded.
• Each material should be examined visually on receipt, for
proper labeling as to the contents of each container, container
damage and contamination.

Ref: D. H. Shah:126
• Damaged materials should be segregated from other
materials and dealt with in a suitable manner (e.g. returned to
the supplier or destroyed).
• Each deliver very of raw material should be given a control
reference number which can be related to the material
throughout its storage and processing.
50
 Quarantine Record Preparation
• Any documentation that supports the discrepant material (e.g., a
quarantine notification) must be attached to the quarantine
record.
• It summarizes the material, batch number, weight or quantity,
and the reason the material is quarantined.
Through this reference number one should get the full details of
the delivery.
• Name of the product
• Quantity of material received and number of containers.
• Date of receipt
• Name & address of the supplier/manufacturer
• Results of the test carried out.
• Release of material (approval or rejection of consignment/ 51
batch)
 Quality Control Raw Materials
Every Delivery---------in Quarantine area
Quarantine area must be segregated.
Label/Tag-----------Quarantine Status
Quarantined
Under test
Status of material changed
Approved (labeled)
Rejected (labeled)
The label should be near the original label. 52
 Testing of Raw material
• All the container of the raw material must
be tested.
• All type of tests (NMR, UV, IR, MASS)
for the identification must be confirmed.
• Results indicated specification must be
met.
• QC is the authority to use of the material.

53
Mislabeling:
There is a great chance of mislabeling, thus it is advisable to
perform an identification test on every container in a
consignment.

PASS Label:
After QC approval the raw material will go to the ware house in
a\satisfactory storage condition.
No deterioration in ware house expected.

RETENTION OF THE SAMPLE:

• Every sample need to be kept in sufficient quantity (for three tests)
for further retesting.
What is retesting???? 54
Sampling:
 Reexamination/Retest/Recheck
• A sample of each approved raw material shall be retained for
examination during shelf life it requires.
• The sample should be in adequate quantity to perform all the
required test.
• During the storage the raw material need to be checked after
a certain time period (Routine Test).
• Any complain from the market then the raw material will be
retested.
• After retesting –if it comply with the prescribed standards of
quality then the QC is the authority for its uses.
55
• If the material is not consumed up to the expiry date, it need
to be reexamined.
• Retesting can be assured by having
• “Valid up to-17-07-2009”
• Re-test on 17-07-2008”
• Rule: A retest date of no more than 12 months
• Any lot of raw material does not meet the specification must be
rejected and must carry authorized Label “REJECTED”.
Status of Identification Labels
• It must have a distinctive color scheme-for easy identification
Passed in green Rejected in red

Quarantine in orrange Under test in pink

56
 Tests for Contamination
• Contamination with dirt.
• Microbial Contamination.
• Insect infestation.
• Any other type of contamination.
All the contamination must be checked
according to the pharmaceutical monograph.

57
 Sampling
https://www.youtube.com/watch?v=AOH4lJ72BMw
– Sampling is the process of collecting a
portion of material from a larger
quantity of it.
– Samples are as representative as
possible of the lot or batch of the
material from which it is taken.
SAMPLING
Sampling instruction, including sampling
precautions and quantities of samples for
testing and for reference.
The sample taking shall be done in
accordance with written procedure that
describe:
– The method of sampling
– The sampling tools used
– The amount of samples to be taken
SAMPLING PROCESS
Sampling Plan: There should be a written
procedure describing the sampling operation.

LEACHMAN- 806
Sampling tools:
Scoop  for   solid

Dip  tube   for  liquid Spears   for  bag

Weighted   container   for  large   tank

The type and condition of the sample
container to be used (i.e. amber glass bottle)
The identification of the container sampled
Special precaution for hazardous materials
The storage condition (if any)
Instruction for cleaning and storage of
sampling equipment
Instruction for re-sealing the opened
container.
 Sampling tools:
• such as knives, pliers, saws, hammers,
wrenches, implements to remove dust
(preferably a vacuum cleaner)
• Material to re-close the packages (such as
sealing tape), as well as self-adhesive labels
to indicate that a part of the contents has
been removed from a package or container.
• Containers due to be sampled should be
cleaned prior to sampling if necessary.
• health and safety aspects of sampling.
• The container used to store a sample
should not interact with the sampled
material nor allow contamination.
• It should also protect the sample from light,
air, moisture, etc., as required by the storage
directions for the material sampled.
• Microbiology sampling tools shall be
sterilised prior to use
• Aseptic technique shall be used during
sampling
 All tests shall be performed in accordance
with the test methods as stated in the
specification
• Reduce testing rational shall be documented
• Test can be performed by in-house laboratory
or external laboratory
• Where test is performed in-house, laboratory
shall be available
RETAIN SAMPLE
• Retain sample should be representative of
the batch of materials or products from
which they are taken.
• Retain sample shall be of a size sufficient to
permit at least 2 full re-examinations
• Finished product should be kept in their final
packaging and stored under the
recommended condition (e.g. Consumer use
condition at room temperature)
• A retain sample log shall be maintained
with the sample identification, batch
number and its storage location for ease
of retrieval
• Prior to disposal of retain sample, visual
inspection should be carried out
Precautions During Sampling:
Care must be taken to ensure that
sample and material is not
contaminated (Sampling booth with
proper airflow ensures this)
• Containers (Original) must be opened
carefully and re-sealed after
sampling.
Solid Sample
• Wide mouthed, amber or colorless bottles
closed by screw caps with inert wads.
Liquid Sample
• Narrow mouthed, amber or colorless
bottles.
• Crystalline or Granular Solid- open ended
or closed ends
• Hygroscopic and volatile sample - tight
fitting polythene sheet can be used.
• Volatile liquid sample-should not be filled
to more than 70% of the capacity-to allow
for expansion.
– Other cases the sample container
completely filled up by the sample.
• Spillages-resulting from the sampling
should be cleaned, immediately and
disposed in a safe manner.
Sterile material: ( e.g. antibiotic)
• Must be sampled in a careful way-that
the bulk must not be unsterile.
• Material container is taken to a sterile
area.
• Opened under sterile condition.
• Sampling using sterile sampling kits.
Sampling Equipment and Container
• Sampling equipment (spoon, scoops,
ladles for liquid) and container,
closures
– should not affect or contaminate the
sample:
Stainless steel
Certain plastic grade
 – They must be cleaned and dried
before use.
– They must be cleaned after each use
and
– kept separately from other lab
equipment.
• For the microbial examination
• Sterilization is required before use.
First aid element need to be available.
The sample container must be labeled
– Batch number of the material
– Reference number of the consignment
– Date of sampling
– Identifying number or mark of the
material container from which the
sample is taken.
QUALITY  CONTROL  OVERVIEW

3  Lectures  
merged
• National pharmaceutical quality control laboratories The government,
normally through the national medicines regulatory authority (NMRA),
may establish and maintain a pharmaceutical quality control laboratory to
carry out the required tests and assays to verify that APIs, excipients and
pharmaceutical products meet the prescribed specifications.
• Large countries may require several pharmaceutical quality control
laboratories which conform to national legislation, and appropriate
arrangements should, therefore, be in place to monitor their compliance
with a quality management system.
• Throughout the process of marketing authorization and postmarketing
surveillance, the laboratory or laboratories work closely with the NMRA.
A national pharmaceutical quality control laboratory provides effective
support for an NMRA acting together with its inspection services.
• The analytical results obtained should accurately describe the properties
of the samples assessed, permitting correct conclusions to be drawn
about the quality of the samples of medicines analysed, and also serving
as an adequate basis for any subsequent administrative regulations and
legal action
• National pharmaceutical quality control laboratories usually
encompass essentially two types of activity:
• —compliance testing of APIs, pharmaceutical excipients and
pharmaceutical products employing “official” methods
including pharmacopoeial methods, validated analytical
procedures provided by the manufacturer and approved by the
relevant government authority for marketing authorization or
validated analytical procedures developed by the laboratory; and
• — investigative testing of suspicious, illegal, counterfeit
substances or products, submitted for examination by medicine
inspectors, customs or police.
• To ensure patient safety, the role of the national pharmaceutical
quality control laboratory should be defined in the general
pharmaceutical legislation of the country in such a way that the
results provided by it can, if necessary, lead to enforcement of
the law and legal action.
 QUALITY  CONTROL  OVERVIEW
Assurance
Objective Product with consistent quality for its intended use

Established Quality System Requirements

How Product contain the correct materials of specified quality & quantity
Manufactured under proper conditions accordingly to SOPs

Sampling
Inspection & testing of: Starting Material, Bulk, Intermediate, Finished product
Key Environment monitoring program Batch record review/documentation
Focus
Area Sample retention program Stability study Calibration Reagent Handling
Release/Reject: Control for materials & product disposition

Reprocessing Specification Control Return

 Basic Requirements of QC Department
Quality Control department should have :
resources:
Ø adequate facilities
Ø qualified personnel
Ø approved written procedures
Ftasks :
Ø sampling, inspecting, testing,
Ø releasing or rejecting
Ø monitoring
Øobjects:
Ø Starting materials, intermediates, bulk, and
finished products
Ø Returned products
Ø Environmental conditions
 Responsibilities of QC
• To provide adequate facilities such as:
Trained personnel
Sampling procedures
Process Inspection
Testing
• Necessary and relevant test to be carried out to evaluate the
quality.
• Reliable analytical procedure is required
• Test methods must be specified and validated.
• The test result must compliance with the specification.

EXAMPLE: NF-21, Monographs: Page-3181

Glucosamine Tablet
NF-21, Monographs: Page-3181
Procedures:

• Weigh and finely powder not fewer than 20 tablets.

• Transfer the accurately weighed portion of the powder
equivalent to about 25 mg of glucosamine to a 25 ml of
volumetric flask, and dilute with diluents to volume.
• Mix on a vortex mixer to suspend the powder in solution.
• Sonicate at a 65oC on water bath for 20 minutes.
• Remove from the bath, stir for 5 minute with the aid of a
magnetic stirrer, and centrifuge.
Calibration
• The set of operations that establish, under
specified conditions, the relationship between
values indicated by an instrument or system for
measuring (especially weighing), recording and
controlling, or the values represented by a
material measure, and the corresponding known
values of a reference standard. Limits for
acceptance of the results of measuring should be
established.
• Any deviations in the test procedures must be recorded and
investigated.
• Sufficient samples of starting materials and finished products must
be retained (for 2-3 experiments) to permit future examination, if
necessary.
• Materials are not released for sale or supply until their quality has
been judged to be satisfactory
• QC is not confined only to the laboratory but also involves all
decisions concerning the quality of the product.
• The ingredients of the finished products must comply qualitatively
and quantitatively with master formula, of the required purity, in
their proper packing, and correctly labeled.
• No product should go to the market without certification of
QC.
• All the steps followed must be documented.
Accuracy
• The degree of agreement of test results with the true value or the
closeness of the results obtained by the procedure to the true value
(1).
• Note: It is normally established on samples of the material to be
examined that have been prepared to quantitative accuracy.
Accuracy should be established across the specified range of the
analytical procedure. It is generally acceptable to use a “spiked”
placebo which contains a known quantity or concentration of a
reference substance.
Sensitivity: The change in measured value per change in analyte
or experiment.
Precision
• The degree of agreement among individual results when the
procedure is applied repeatedly to multiple samplings of a
homogeneous sample. Precision, usually expressed as
relative standard deviation, may be considered at three
levels: repeatability (precision under the same operating
conditions over a short period of time), intermediate
precision (within laboratory variations — different days,
different analysts or different equipment) and
reproducibility (precision between laboratories).
Example:
Accepted Deviation by different
experiment:
Inhibitor of acetyl cholinesterase enzyme:
1. IC50=23 µM
2. IC50=70 µM
How much deviation ±5% is allowed but
too much deviation is imprecision or
measurement caused by random error.
 Methods of Preformulation
•Candidate selection
• Form selection and Formulation design
• Process development and optimization
• Process control
• Scale-up and tech transfer
• Process validation
• Process monitoring and continuous improvement
•Demonstrate reduced risk to regulatory agencies
• Obtain regulatory relief
• Demonstrate value to company management
Definition:

Preformulation may be described as a phase of the research and

development process where the preformulation scientist
characterizes the physical, chemical and mechanical properties of
a new drug substance, in order to develop stable, safe and effective
dosage form.

Objectives:

The preformulation investigations confirm that there are no

significant barriers to the compound’s development as a marketed
drug. The formulation scientist uses these informations to develop
dosage forms.
Preformulation is a multidisciplinary development of
a drug candidate. See TABLE-1
 Principal  areas  of  Preformulation
1. Bulk  characterization
(i) Crystallinity  and  polymorphism
(ii) Hygroscopicity
(iii) Fine  particle  characterization
(iv) Powder  flow

2. Solubility  analysis

(i) Ionization  constant  – pKa

(ii)  pH  solubility  profile
(iii) Common  ion  effect  – KSP.
(iv) Thermal  effects
(v) Solubilization
(vi) Partition  coefficient
(vii) Dissolution
3. Stability  Analysis
(i) Stability  in  toxicology  formulation
(ii) Solution  stability
– pH  stability  profile
(iii) Solid  state  stability
– Bulk  stability
– Compatibility
 Objectives of Preformulations
List reasons drugs are incorporated into various dosage
forms.
1.Compare and contrast the advantages/disadvantages of
various drug dosage forms.
2. Describe the information needed in preformulation
studies to characterize a drug substance for possible
inclusion into a dosage form.
3. Describe the mechanisms of drug degradation and
provide examples of each.
4. Describe the five types of drug instability of concern to
the practicing pharmacist.
5. Summarize approaches employed to stabilize drugs in
pharmaceutical dosage forms.
6. Calculate rate reactions for various liquid dosage forms.
7. Categorize various pharmaceutical ingredients and
excipients.
 Compatibility Studies
• Compatibility studies are usually aimed at
identifying the most common or previously
• encountered incompatibilities.
Example: an incompatibility:
• Change in color/appearance (e.g., tablet
hardness)
• Loss in mechanical properties
• Physical form conversion
• Loss through sublimation
• Decrease in potency,
• Increase in degradation products
• Unintended physicochemical interaction of an
excipient with a drug substance
• in a dosage form can result in the complexation
or binding of the drug, resulting
• in slow and/or incomplete drug release in a
dissolution medium.
 Background  Information  and  Literature  Review

Binary,  ternary  mixtures  OR

Study  Design Mini  formulations  or  n-­1  design

Physical  mixtures
Compaction
Sample  Preparation
Effect  of  water
Temperature • Addition in sealed container
• Incubation in RH chambers
Humidity Incubation  at  stress  condition  
UV  for  
photostability Physical  (color)  changes
Analysis  and  data  Interpretation     Thermal  changes  by  DSC
Oxidizing   Drug degradation by HPLC
agents Form  change  by  PXRD
 Dosage Form Design:
Pharmaceutical and Formulation
Considerations
General Considerations in Dosage
Form Design
• Preformulation Studies
– Physical Description
– Microscopic Examination
– Heat of Vaporization
– Melting Point Depression
– The Phase Rule
– Particle Size
– Polymorphism
General Considerations in Dosage
Form Design (cont’d)
• Preformulation Studies (cont’d)
– Solubility
– Solubility and Particle Size
– Solubility and pH
– Dissolution
– Membrane Permeability
– Partition Coefficient
– pKa/Dissociation Constants
General Considerations in Dosage
Form Design (cont’d)
• Drug and Drug Product Stability
– Drug Stability: Mechanisms of
Degradation
– Drug and Drug Product Stability:
Kinetics and Shelf Life
– Rate Reactions
– Q10 Method of Shelf Life Estimation
– Enhancing Stability of Drug Products
– Stability Testing
 Pharmaceutical Ingredients and
Excipients
• Definitions and Types
• Handbook of Pharmaceutical Excipients
• Harmonization of Standards
• Appearance and Palatability
– Flavoring Pharmaceuticals
– Sweetening Pharmaceuticals
– Coloring Pharmaceuticals
 Pharmaceutical Ingredients and
Excipients (cont’d)
• Preservatives
– Sterilization and Preservation
– Preservative Selection
– General Preservative Considerations
– Mode of Action
– Preservative Utilization
 The Need for Dosage Forms
• Mechanism for safe and convenient delivery
of accurate dosage
• Protection of drug from atmosphere
• Protection of drug from gastric acid (EC)
• Conceal bitter, salty, or offensive taste or
odor
• Provide liquid preparations of insoluble drugs
 The Need for Dosage Forms
(cont’d)
• Provide clear liquid dosage forms
(solutions)
• Provide rate-controlled drug action
• Provide topical drug action (ointments,
creams, patches, ophthalmic, otic, nasal)
• Provide for insertion into body cavity
• Provide for placement into bloodstream
• Provide for inhalation therapy
General Considerations in
Dosage Form Design
 Physiological States Altering
Response to Drugs
• Age (infants) • Body weight
• Age (elderly) • Time of
administration
• Diurnal variation
• Tolerance
• Pregnancy
• Temperature
• Sex
• Physiological
• Menopause
reserve
• Race
• Milieu
Factors Affecting Drug Presentation
to the Body
• Portal of drug entry into the body
• Physical form of the drug product
• Design and formulation of the product
• Method of manufacture of the product
• Physicochemical properties of the drug
and excipients
 Design of Drug Products
• Effectiveness
• Safety
• Reliability
• Stability
– Physical
– Chemical
– Microbiological
 Why proper Packing is necessary?

To ensure the closure system to assure the

products against the factors such as:
• Moisture Oxygen
• Light
• Volatility (loose cap volatile substance –
cosmetic eg. Perfumes will be lost)
• After marketing the empty bottle??
 Provide Functional Protection
of the Product against:
• Moisture-may help to grow microbial
contamination
• Oxygen-may start the free radical reaction
• Light-sometime helps to decompose the
materials.
• Volatility-volatile material can be evolved.
• Drug /package interaction
 Factors Affecting Drug
Presentation to the Body (cont’d)

• Physicochemical properties of the drug

product
• Control and maintenance of location of drug
at the absorption site
• Control of the release rate of the drug from
the drug product
Design of Drug Products (cont’d)
• Pharmaceutical elegance
– Appearance
– Organoleptic properties
• Convenience
– Ease of use
– Dosing frequency
– Consumer acceptance
 General Considerations in
Dosage Form Design
• Preformulation Studies
• Drug and Drug Product Stability
 Preformulation Studies

• Chemical characterization
• Physical characterization
 Physical Description
• Solids, liquids, gases
• Chemical Properties
– Structure, form, reactivity
• Physical Properties
– Description, particle size, crystalline structure, melting
point, solubility
• Biological Properties
– Ability to get to site of action and elicit a response
 Microscopic Examination
• Particle size
• Particle size range
• Crystal structure
• Particle shape
 Dissolution
• Dissolution may be rate-limiting step in the
absorption of poorly soluble drugs.
• Can affect onset, intensity, and duration of
response and control overall bioavailability
of the drug from the dosage form
 Responsibility of the Pharmacist
• Dispense oldest stock first and observe expiration dates.
• Store products under conditions stated in USP
monographs and/or labeling.
• Observe products for evidence of instability.
• Properly treat/label products that are repackaged,
diluted, or mixed with other products.
Responsibility of the Pharmacist
(cont’d)
• Dispensing in proper container with proper
closure
• Informing/educating patients concerning
proper storage and use of products,
including the disposition of outdated or
excessively aged prescriptions
 Why Do We Need Shelf Life
Estimates?
• Expiration date given at room temperature:
– What is the expiration extension if refrigerated?
• Expiration date for refrig temperature given:
– How long if left at room temperature?
• Expiration date for room temperature given
and it is desired to heat (autoclave):
– What is the % decomposition?
 Why Do We Need Shelf Life
Estimates? (cont’d)
• Expiration date for refrigerated
temperature given; product stored at
room temperature and then returned
to refrigerator:
– What is the new expiration date?
 Stability: USP
• The extent to which a product retains,
within specified limits, and throughout its
period of storage and use (i.e., its shelf life),
the same properties and characteristics that
it possessed at the time of manufacture
 Definitions
• Accelerated Testing
– Studies designed to increase the rate of
chemical or physical degradation by using
exaggerated storage conditions
• Bulk Drug Substance
– Active drug before formulation
• Drug Product
– Finished dosage form
 Definitions (cont’d)
• Expiration Date
– The date placed on the immediate container
label of a drug product that designates the date
through which the product is expected to
remain within specifications
• Expiration Dating Period
– The interval that a drug product is expected to
remain within the approved specifications after
manufacture
 Definitions (cont’d)
• Primary Stability Data
– Data on the drug product stored in the proposed
container-closure for marketing under storage
conditions that support the proposed expiration
date
 Definitions (cont’d)
• Stability-Indicating Methodology
– Quantitative analytical methods based on the
characteristic structural, chemical, or biological
properties of each active ingredient of a drug
product, and that will distinguish each active
ingredient from its degradation products so that
the active ingredient content can be accurately
measured
 Definitions (cont’d)
• Stability
– The capacity of a drug product to remain within
specifications established to ensure its identity,
strength, quality, and purity
• Strength
– A quantitative measure of active ingredient, as well
as other ingredients requiring quantitation
• Supportive Stability Data
– Data other than primary stability data
 Physical Paths of Instability
• 1. Polymorphs
– Cocoa butter, Cortisone Acetate
• 2. Crystallization
– Solutions, suspensions
• 3. Vaporization
– Flavoring agents, cosolvents, nitroglycerin
• 4. Particle sedimentation
– Suspensions
 Observing Products for
Evidence of Instability

• Solid Dosage Forms

– Hard/soft gelatin capsules
– Uncoated tablets
– Coated tablets
– Dry powders and granules
– Powders/granules for solution/suspension
– Effervescent tablets/granules/powders
 Observing Products for Evidence of
Instability (cont’d)

• Liquid Dosage Forms

– Solutions/elixirs/syrups
– Emulsions
– Suspensions
– Tinctures/fluid extracts
– Sterile liquids
• Semisolids
– Creams
– Ointments
– Suppositories
 Energy of Activation and
Reaction Types

• 2-3 kcal/mole---------- • Diffusion or photolysis

• Fast reactions stability problems

• <10 kcal/mole--------- in development
• Solvolytic process; most drug
degradation
• 10-30 kcal/mole-------
• Pyrolytic reactions

• 50-70 kcal/mole-------
 Shelf Life Estimates
• Q10 = [K(T+10)]/KT

• =e[-(Ea/R) ({1/T+10} - {1/T}]

• Q10 =2 Lower limit

• Q10 = 3 Average, best estimate
• Q10 = 4 Upper limit
 t90 Equation for Shelf Life
Estimates
• t90(T2) = t90(T1)/Q10(Delta T/10)

• Note: A “+” Delta T decreases shelf life and

a “-” Delta T increases shelf life
Pharmaceutical Ingredients and
Excipients
 Definitions and Types
• Active pharmaceutical ingredients
• Pharmaceutical ingredients added to prepare
a dosage form
 Components of Drug Delivery
Systems
• Drug
• Route of administration
• Suitable physical dosage form
• Use of chemical derivatives of the drug
• Control of certain physicochemical and/or
biochemical processes that alter the rate and
extent of response
 Excipients

• Coloring agents • Thickening agents

• Sweetening agents • Suspending agents
• Flavoring agents • Binding agents
• Surfactants • Solvents
• Solubilizing agents • Lubricants
• Antioxidants • Perfumes
• Preservatives • Fats and oils
 Handbook of Pharmaceutical
Excipients
• Monographs on more than 250 excipients
used in dosage form preparation
• Additional excipients listed in Food
Chemicals Codex and National Formulary
 Harmonization of Standards
• International harmonization of excipients
• Pharmaceutical industry is multinational
• Uniform standards needed
 Appearance and Palatability
• Compliance issues
• Odor, color, and taste
• Important for all age groups, especially
pediatrics and geriatrics
 Flavoring Pharmaceuticals
• Complex area
• Important for compliance
• Color and taste should generally match
 Flavor
• Taste
• Touch
• Smell
• Sight
• Sound
 Four Primary Tastes
• Sweet
• Bitter
• Sour
• Salty
 Four Primary Tastes (cont’d)
• TASTE SLIGHT MOD STRG
• Sweet/Sucrose 5% 10% 15%
• Sour/Citric Acid 0.05 0.10 0.20
• Salty/NaCl 0.4 0.7 1.0
• Bitter/Caffeine 0.05 0.10 0.20
 Causative Factors for Taste
• Hot Mild, counterirritant
• Astringent Tannins, acids
• Coarseness/Grittiness Texture
• Coolness Neg heat of solution
• Greater sensitivity to odors than to tastes
• Females have greater sensitivity to odors than males
Flavor/Odor Correlations with
Chemical Structure
• Sour taste H+
• Saltiness Anions & cations
• Bitter High-MW salts
• Sweet Polyhydroxyl cmpds,
polyhalogenated cmpds,
alpha amino acids
• Sharp, biting Unsaturation
• Camphoraceous odor Tertiary “C” atom
Flavor/Odor Correlations with
Chemical Structure (cont’d)

• Pleasant odor Ketones

• Methylparaben Floral,
gauze-pad
• Propyl/butyl paraben
Numbing mouthfeel
 Flavor Selection
• Immediate flavor identity
• Rapid full flavor development
• Acceptable mouthfeel
• Short aftertaste
• No undesirable sensations
 Flavoring Techniques
• Blending
– Fruit===========èSour
– Salty/Sweet/Sour===èBitter
– Salty===========èDecreases sourness
– Salty===========èIncreases sweetness
• Overshadowing
– Methylsalicylate====èGlycyrrhiza
 Flavoring Techniques (cont’d)
• Physical
– Formation of insoluble compounds
– Emulsification of oils
– Effervescence
– High-viscosity fluids
– Coating tablets
 Flavoring Techniques (cont’d)
• Chemical
– Adsorption-silica gel
– Complexation
• Physiological
– Anesthetic effect====èMenthol (mint)
Raspberry Concentrate Imitation
• Vanillin 0.180 g
• Indol 0.004 g
• Aldehyde C16 0.240 mL
• Diacetyl 0.060 mL
• Phenylethyl alcohol 240 mL
• Aldehyde C14 0.015 mL
• Aldehyde C18 0.015 mL
• Aldehyde C20 0.400 mL
Raspberry Concentrate Imitation
(cont’d)
• Orange flower oil 0.005 mL
• Ethyl butyrate 0.120 mL
• Benzyl acetate 0.075 mL
• Alpha novoviol 0.400 mL
• Beta novoviol 0.200 mL
• Lemon oil 0.060 mL
• Propylene glycol qs 100 mL
 Flavor Selection Guide
• Salty Butterscotch/Maple
• Bitter Wild Cherry/Licorice
Chocolate Mint
• Acrid/Sour Raspberry/Fruit
Berry/Acacia Syrup
 Flavor Selection Guide (cont’d)
• Oily Peppermint/Anise
Wintergreen
• Sweet Fruit/Berry/Vanilla
• Acid Citrus
 Sweetening Pharmaceuticals
• Complex area
• Natural vs. synthetic
• Heat stability
 Sweetening Agents
• Dextrose
• Mannitol
• Saccharin
• Sorbitol
• Sucrose
 Coloring Pharmaceuticals
• Lighter shades preferred
 Coloring Agents
• Dyes: FD&C, D&C, Ext D&C
• Lakes: Calcium and aluminum salts
• Liquids: 0.001% to 0.0005%
• Powders: 0.1%
• Caramel
• Ferric oxide: Red/yellow
 Coloring Agents (cont’d)
• Red No. 1, Ponceau 3R, Cherry Red
– 9.8/5
• Blue No. 1, Brilliant Blue, Blue-Green
– 20/20
• Yellow No. 5, Tartrazine, Lemon Yellow
– 20/18
 Preservatives
• Sterilization and Preservation
• Preservative Selection
• General Preservative Considerations
• Mode of Action
• Preservative Utilization
 Sterilization and Preservation
• Some products must be sterile
– Injectables
– Ophthalmics
• Sterilization
– Autoclave
– Filtration
– Dry heat
– Irradiation
 Preservative Selection
• Dosage form
• Route of administration
• Compatibility with excipients
• Container and closure compatibility
 General Preservative
Considerations
• Range of activity
• Concentration required
• pH requirements
• Compatibility
 Mode of Action
• Modification of cell membrane permeability
• Lysis and cytoplasmic leakage
• Irreversible coagulation of cytoplasmic
constituents
• Inhibition of cellular metabolism
• Oxidation of cellular constituents
• Hydrolysis
 Preservative Utilization
• Benzoic acid/sodium benzoate
• Alcohol
• Phenylmercuric nitrate/acetate
• Phenol
• Cresol
• Chlorobutanol
• Benzalkonium chloride
• Methylparaben/propylparaben
• Others
 Active pharmaceutical ingredient
(API)
Any substance or mixture of substances intended to be used in the
manufacture of a pharmaceutical dosage form and that, when so
used, becomes an active ingredient of that pharmaceutical dosage
form. Such substances are intended to furnish pharmacological
activity or other direct effect in the diagnosis, cure, mitigation,
treatment, or prevention of disease or to affect the structure and
function of the body.
 Airlock
• An enclosed space with two or more doors,
which is interposed between two or more rooms,
e.g. of differing classes of cleanliness, for the
purpose of controlling the airflow between those
rooms when they need to be entered. An airlock
is designed for use either by people or for goods
and/or equipment.
 Authorized person
• The person recognized by the national regulatory
authority as having the responsibility for ensuring
that each batch of finished product has been
manufactured, tested and approved for release in
compliance with the laws and regulations in force in
that country.
 Batch (or lot)
• A defined quantity of starting material, packaging material, or
product processed in a single process or series of processes so
that it is expected to be homogeneous. It may sometimes be
necessary to divide a batch into a number of sub-batches,
which are later brought together to form a final homogeneous
batch. In the case of terminal sterilization, the batch size is
determined by the capacity of the autoclave. In continuous
manufacture, the batch must correspond to a defined fraction
of the production, characterized by its intended homogeneity.
The batch size can be defined either as a fixed quantity or as
the amount produced in a fixed time interval.
 Batch number (or lot number)
• A distinctive combination of numbers and/or letters which
uniquely identifies a batch on the labels, its batch records
and corresponding certificates of analysis, etc.
Batch RECORDS:
• All documents associated with the manufacture of a batch of
bulk product or finished product. They provide a history of
each batch of product and of all circumstances pertinent to
the quality of the final product.
 Bulk product
Any product that has completed all
processing stages up to, but not including,
final packaging.
Calibration

The set of operations that establish, under specified conditions, the

relationship between values indicated by an instrument or system for
measuring (especially weighing), recording, and controlling, or the
values represented by a material measure, and the corresponding
known values of a reference standard. Limits for acceptance of the
results of measuring should be established.
 Clean area
An area with defined environmental control of particulate and
microbial contamination, constructed and used in such a way as
to reduce the introduction, generation, and retention of
contaminants within the area.

consignment (or delivery)

• The quantity of a pharmaceutical(s), made by one manufacturer and
supplied at one time in response to a particular request or order. A
consignment may comprise one or more packages or containers and may
include material belonging to more than one batch.
 Contamination
The undesired introduction of impurities of a chemical or
microbiological nature, or of foreign matter, into or on to a starting
material or intermediate during production, sampling, packaging or
repackaging, storage or transport.
critical operation
An operation in the manufacturing process that may cause variation in the
quality of the pharmaceutical product.
 Cross-contamination
Contamination of a starting material, intermediate product or finished
product with another starting material or product during production.

Finished product
A finished dosage form that has undergone all stages of manufacture,
including packaging in its final container and labelling.

in-process control
Checks performed during production in order to monitor and, if necessary, to adjust
the process to ensure that the product conforms to its specifications. The control of
the environment or equipment may also be regarded as a part of inprocess control.
 Intermediate product
Partly processed product that must undergo further manufacturing steps before it becomes a
bulk product.

large-volume parenterals
Sterile solutions intended for parenteral application with a volume of
100 ml or more in one container of the finished dosage form.

manufacture
All operations of purchase of materials and products, production,
quality control, release, storage and distribution of
pharmaceutical products, and the related controls.
 manufacturer
A company that carries out operations such as production,
packaging, repackaging, labelling and relabelling of
pharmaceuticals.
marketing authorization (product licence, registration
certificate
A legal document issued by the competent drug regulatory authority that
establishes the detailed composition and formulation of the product and
the pharmacopoeial or other recognized specifications of its ingredients
and of the final product itself, and includes details of packaging,
labelling and shelf-life.
 master formula
A document or set of documents specifying the starting materials with
their quantities and the packaging materials, together with a
description of the procedures and precautions required to produce a
specified quantity of a finished product as well as the processing
instructions, including the in-process controls.

master record
A document or set of documents that serve as a basis for the batch documentation
(blank batch record).
 Production
All operations involved in the preparation of a pharmaceutical product, from
receipt of materials, through processing, packaging and repackaging, labelling
and relabelling, to completion of the finished product.

Qualification
Action of proving that any premises, systems and items of
equipment work correctly and actually lead to the expected
results. The meaning of the word “validation” is sometimes
extended to incorporate the concept of qualification.
Packaging
All operations, including filling and labelling, that a bulk product has to undergo in
order to become a finished product. Filling of a sterile product under aseptic
conditions or a product intended to be terminally sterilized, would not normally be
regarded as part of packaging.

packaging material
Any material, including printed material, employed in the packaging of a
pharmaceutical, but excluding any outer packaging used for transportation or
shipment. Packaging materials are referred to as primary or secondary according
to whether or not they are intended to be in direct contact with the product.
 Quarantine
The status of starting or packaging materials, intermediates, or
bulk or finished products isolated physically or by other effective
means while a decision is awaited on their release, rejection or
reprocessing.

Reconciliation
A comparison between the theoretical quantity and the actual
quantity.
 Recovery
The introduction of all or part of previous batches (or of
redistilled solvents and similar products) of the required quality
into another batch at a defined stage of manufacture. It includes
the removal of impurities from waste to obtain a pure substance or
the recovery of used materials for a separate use.
Reprocessing
Subjecting all or part of a batch or lot of an in-process drug, bulk
process intermediate (final biological bulk intermediate) or bulk
product of a single batch/ lot to a previous step in the validated
manufacturing process due to failure to meet predetermined
specifications. Reprocessing procedures are foreseen as
occasionally necessary for biological drugs and, in suc

h cases, are validated and pre-approved as part of the marketing

authorization.
 Reworking

• Subjecting an in-process or bulk process intermediate (final

biological bulk intermediate) or final product of a single batch to
an alternate manufacturing process due to a failure to meet
predetermined specifications. Reworking is an unexpected

occurrence and is not pre-approved as part of the marketing

authorization.
 self-contained area
Premises which provide complete and total
separation of all aspects of an operation, including
personnel and equipment movement, with well
established procedures, controls and monitoring.
This includes physical barriers as well as separate
air-handling systems, but does not necessarily
imply two distinct and separate buildings.
 Specification
A list of detailed requirements with which the products or
materials used or obtained during manufacture have to conform.
They serve as a basis for quality evaluation.

starting material

Any substance of a defined quality used in the production of a

pharmaceutical product, but excluding packaging materials.
standard operating procedure (SOP)
• An authorized written procedure giving instructions
for performing operations
• not necessarily specific to a given product or material
(e.g. equipment operation,
• maintenance and cleaning; validation; cleaning of
premises and environmental
• control; sampling and inspection). Certain SOPs may
be used to
• supplement product-specific master and batch
production documentation.
 Validation
Action of proving, in accordance with the principles of GMP,
that any procedure, process, equipment, material, activity or
system actually leads to the expected results (see also
qualification).