MATERIAL CONTROL

MATERIAL CONTROL
As each batch of incoming material
is received, it is given a receiving
number by which it will be identified in
subsequent operations. A receiving
number should have distinguishing
characteristics which will prevent
possible confusion with any number
previously placed on the container by
the supplier.
 MATERIAL CONTROL
RTR should be prepared for every shipment. If the
shipment consists of more than one number, a
separate receiving number is assigned to each lot.
RTR should be distributed to all groups concerned
with the purchase, inventory , use and control of
materials
RTR is prepared in the warehouse by the
warehouse personnel who is responsible for
assigning a receiving number to the material. The
shipment is held in pending for quality
control approval
 RAW MATERIALS
These are the ingredients
intended for use in the
manufacture of drugs and
cosmetics, including those
that may not appear in the
finished products
 RAW MATERIALS
a. 1.
b. RTR is checked by a QC inspector
c. Each container of raw materials is
examined visually for damage or
contamination in transit, including
breakage of seals when indicated
d. Adequate number of samples are
taken from a representative number
of containers
 RAW MATERIALS
C.1. Sampling plan is used to determine the
number of raw material container to be sampled

c.2 calculate for the total quantity of material

required for a complete test to determine the
amount of sample to be taken from each
container
c.3. composite sample should not be less than
three times the amount required for one
complete test
 RAW MATERIALS

2.
1. “Hold” or quarantine sticker is pasted by the
receiving warehouse personnel and are checked
by the QC inspector
2. Samples are submitted to the laboratory for
testing. Tests include:
a. Physical and organoleptic examination
b. Identification tests
c. Limits of impurities and degradation products
d. Potency or assay
e. Microbiological tests
 RAW MATERIALS
f. Decision stickers are then issued
by quality control

g. No two stickers of different

dispositions must be present on
the same container.
 RAW MATERIALS
REJECTED
The material so marked is
checked that is held at a
rejected materials area to
prevent the possibility of use
in any manufacturing or
processing procedure.
 RAW MATERIALS
APPROVED
1.The material marked as
approved is checked that it is
brought to the approved
materials area
2.Approved materials are
tested when re-assay date is
due to assure that they
 RAW MATERIALS

3. Approved raw materials

are audited to assure that
they are rotated in such a
manner that the oldest
stock is used first
 STICKERS
• A material warehouse is
subdivided into several
sections to avoid mix-ups
• Quarantine stickers are
pasted on the container of
the material on the reception
of material
 STICKERS
• Materials are held in the
quarantine area while waiting
for its release by quality
control
• After disposition is given, the
appropriate sticker is pasted
on top of the quarantine
sticker
 PRINTED AND PACKAGING
MATERIALS

Product containers, closures

and other components parts of
a product package should not
be ___,____,____so as to alter
the safety, identity, strength,
quality and purity of the
product
 PACKAGING MATERIALS

• Packaging and printed materials

should be tested for suitability for
its intended use.

• Storage and handling are audited

to prevent them from
contamination and deterioration
and to avoid mix-ups
 PRINTED MATERIALS

By official definition, labeling

includes all written, printed or
graphic materials
accompanying a product.

They are subjected to

inspections by an experienced
proofreader for graphical
 PRINTED MATERIALS

Minimum criteria for acceptance of printed

materials consists of:
• Text
• Color
• Size
• Thickness
• Grain direction
• Sealability
• Cleanliness
• Surface finish
• Adequate paste
• shape
 LABELING CONTROL

Labeling control has been

found useful in preventing
mix ups of inventories of
printed labeling materials of
similar color and shape
 LABELING CONTROL
Labeling requirements for drugs and cosmetics
Labels:
a. Name of drug or cosmetics
b. The strength or quantity of the substance contained per
unit dosage form
c. Lot or batch number
d. Expiration date
e. Registration number
f. Storage condition
g. Name of manufacturer, packer or distributor
h. Business address
i. Quantity of content of package
j. Names and quantities of components in the prepareation
 LABELING CONTROL
Package Insert
a.Product name
b.The strength or quantity of the substance contained per unit dosage form
c.Description
d.Action
e.Indication
f.Contraindication
g.Warnings
h.Precautions
i.Adverse reactions
j.Dosage and administration
k.Overdosage
l.How supplied
m.Manufacturer/ packer, distributor
n.Business adress
 CONTAINERS

GLASS/ PLASTIC/ METAL

CONTAINERS

PHYSICO-
PHYSICAL
CHEMICAL
INSPECTION
INSPECTION
 CONTAINERS
Physical Inspections:
Shape clarity
Volume print
Finish leak
Opening torque
Diameter cleanliness
Height peeling
Shape light transmission
Thickness stress crack resistance
Color
 CONTAINERS

Physico-chemical Inspection:

Identification
Infra-red properties
Thermal analysis
Extractable substance
Non-volatile residue
Water vapor permeation/transmission
Moisture
Resistance to water attack
 CONTAINERS

TYPES OF CONTAINERS
1.
- protects the contents from the effect
of the incident light
2.
- protect the contents from extraneous
solids and from the loss of drug under the
ordinary or customary conditions of
handling, storage and distribution
 CONTAINERS

TYPES OF CONTAINERS
3.
- protects the content from contamination
by extraneous liquids, solids, vapors from
loss of drugs and from effervescence,
deliquescence and evaporation under
ordinary conditions of handling, shipment,
storage and distribution and is capable of re-
closure
4.
- impervious to air and any other gas
 CONTAINERS

TYPES OF CONTAINERS
5.
- which is enclosed in such a manner that
none of the contents may be removed
without obvious destruction of closures and
the contents of which are intended for
promptly after it is opened for parenteral use
6.
- container that permits the withdrawal of
successive portions of the contents without
changing the strength, quality or purity of
 CONTAINERS AND CLOSURE
CONTROLS
• The integrity between the closure
and the container depends on
the geometry of the two, the
materials used in their
construction, the composition of
the cap liner and the tightness
with which the cap has been
applied.
 CONTAINERS AND CLOSURE
CONTROLS
Geometry can be controlled by the mold of
packaging components. A mold number is
assigned which is used as its identification number.
Criteria:
Closures should fit the thread of the container
Should sit without tilting
Produce no leaks
Should not rotate continuously
Reasonably tight
Must look elegant
 CONTAINERS AND CLOSURE
CONTROLS
Control of cap tightness;
Considerations:
A minimum tightness is
essential to avoid evaporation
of leakage of the product
Excessive torque may break
the moulded closure
Caps applied too tightly may
 REASSAY DATES
• Monitoring the quality of the
raw materials during storage
is an important step after
such material are released by
quality control.
• The date retest is known as
.
• This is also given in terms of
 REASSAY DATES
Re- assay dates assigned are:

6months-
-active ingredients and dyes
-active ingredients, excipients

• Monthly or prior to use- highly

unstable materials
 REASSAY DATES
Retest Requirements:
Appearance
Identification
Melting range
Specific gravity
Refractive index
pH
Loss on drying, moisture content/water
Alkalinity/ acidity
Alcohol content
Degradation limits
Assay
Microbial tests
 IV. MANUFACTURING CONTROL
• Written procedures are vital to the
manufacture of drugs and cosmetics.
• Procedures are embodied in four (4)
important documents designed to explain
why and how the products are made.
 Manufacturing monograph
 Quality control monograph
 Batch records
 Standard operating procedure
MANUFACTURING MONOGRAPH

Basic document from

where and

____________are based.
 STANDARD OPERATING
PROCEDURE

Generated to explain in detail

the reason behind a procedure
and proper sequence of steps
to be done, and how
equipment are to be operated
for maximum performance
MASTER FORMULA RECORDS

• key in the production of products

• It assures drug uniformity
• It shall be retained for a period of at
least after distribution of the
last drug batch produced using the
master formula record , or after
the expiration date of the last drug
batch
 Composition of Master
Formula Records
Name of the drug product, a description of the dosage form
The name and weight or measure of each ingredient per
dosage unit and a statement of the total weight or
measure of any dosage unit
Complete list of ingredients designated by names or codes
sufficiently specific to indicate special quality characteristic
and an accurate statement of the weight or measure of
each ingredient
Description of the containers, closures and packaging and
finishing materials
Manufacturing and control instructions, procedures,
specifications, special notations, and precautions to be
followed
 Batch Production Records

A copy of the master formula showing

the complete manufacturing history
of each batch of drug.
It indicates that it has been
manufactured , tested and analyzed
in accordance with the manufacturing
procedures and written instructions
as per the master formula
 Batch Production
Records
Shall be retained for at least 2 years
after batch distribution is complete, or
1 year after the batch expiration date
Records relating to
production( packaging, labeling, and
control of each batch and copies of
the labeling bearing the lot) shall be
available during the retention period
Composition of the Batch
Production Records
a. History of the production formula
b. Manufacturing procedures
c. Production records ( processing
batch record, processing control
records, packaging records)
d. Raw material records
e. Packaging material records
f. Product experience reports
 Production Formula
1. Product name and or unique identification such as:
.Batch size
.Dosage form and strength
.Formula code number and date
.Batch or lot number
2. Statement on any calculated excess of an
ingredient, reasonable variation and adjustments
3. A specific to indicate any special characteristics
4. Theoretical weight, measure or percent of each
raw material regardless of whether it appears on the
finish product or not
 Production
Formula
Product Formula:
5. The standard or specifications of each
ingredient used in the product
6. The actual weight, measure or percent of
each raw material allocated or dispensed for a
batch
7. Statement of theoretical yield at various
stages and the termination of the product
8. The receiving number of raw material
dispensed.
 Manufacturing Process
1. Product name/ or unique Identification
2. Authorizing signature with dates by a competent
individual endorsed by another responsible individual
3. A step by step description of all significant aspects of
the process including:
•. Means of raw material measurement
•. List of major equipment
•. Temperature
•. Order of addition and point of addition RM
•. Mixing speeds
•. Mixing times
 Manufacturing
Process:
4. Signature of the individual performing and the
individual supervising each step
5. Intermediate and finished product specifications,
test methods and sampling instructions
6. Special notes and precautions:
• Cleaning procedure
• Storage conditions
• Filling temperatures
• Remedial measures
• Special safety and health measures
 Product
Specifications
1. Finished product name or unique specification
2. Physical, chemical and microbiological
specifications, for the acceptance of each lot
and the description of the sampling and test
procedures used
3. Result of control test
4. Samples retained
5. Endorsement and date of the authorized
individual performing the test
6. Disposition of the lot or batch
 MANUFACTURING CONTROL
Control Tests
This is done to satisfy product
identity, purity safety quality and
strength
Tests are performed during in-
process (IPQC) and repeated in
the final product
 MANUFACTURING CONTROL
Control Tests
A. SOLID PREPARATIONS
.Assay for the active ingredient
.Assay for the degradation of the product
.Disintegration
.Dissolution/ bioavailability
.Content uniformity
.Weight variation
.ID tests for the active ingredients and possible
contaminants
.Visual appearance
.odor
 MANUFACTURING CONTROL
Control Tests
SOLID PREPARATIONS
Taste
Texture
Hardness
Friability
Powder fitness
Moisture content
Humidity effect
Color stability
Storage condition
Microbiological burden
thickness
 MANUFACTURING CONTROL
Special Test
LIQUID PREPARATION
Assay of the active ingredient
Assay of degradation
ID tests and contamination test
Visual appearance
Color
Odor
Taste
Redipersibility
Pourability
Viscosity
Particle size agglomeration and particle distribution
 MANUFACTURING CONTROL
Special Test
LIQUID PREPARATION
 Clarity
 Crystallization and precipitation
 Gas evolution
 Specific gravity
 pH
 Refractive Index
 Surface tension
 Pyrogenic testing
 Sterility
 Toxicity testing
 Storage condition
 Fill volume
 Leak test
 Raw material
Quality Control
CHEMICAL METHOD
A. Identification Tests
1. Ammonium- yellowish brown precipitates
2. Bismuth- orange or copper-coloured precipitate
3. Calcium- reddish brown precipitates, which
dissolves in chloroform to give a red solution
4. Chlorides- blue coloration of moistened starch
or iodide paper
5. Ferrous Salts- intense red color which is
discharged by the addition of Ceric Sulfate TS
6. Iodides- brown solution which
becomes colorless
7. nitrates- intense violet color in
the upper phase
8. potassium- white precipitates
9. salicylates- separation of w
white crystalline precipitates
10 sodium- yellow crystalline
precipitates
B. Limit Tests
- Quantitative test assayed to
identify amount of impurities that
is likely present in the substance
Sources- incomplete reactions,
solvent used degradation product
while storing Raw material
Types of Impurities:
1.Gross impurities
2.Chemical Impurities
3.Biological Impurities
Limit Test
Substance Test reagent Limit
Arsenic diethyldithiocarbamate not >
1ug/g
Chlorides silver nitrate 250 ug
Heavy metals lead nitrate 1ug/g
Iron ammonium thiocyanate 40ug
Lead ammonium cyanide solution 1ug
Sulfates barium chloride 480ug
C. Oxygen Flask Method
- Used for the determination of halogens
and sulfur in organic compounds consists
of a combustion procedure followed by
appropriate titrimetric determination.
- Combustion of the organic material in
oxygen yields water- soluble inorganic
products, which are determined as
directed for the individual element
Oxygen Flask Method
Titrimetry
Determination of Chlorine and Bromine
Titrants – sodium hydroxide TS(0.1 mol/L)
mercuric nitrate TS(.01 mol/L)
Indicators- bromophenol blue/ethanol TS
diphenylcarbazone/ethanol
Endpoint- solution turns light violet
*Each mL of mercuric nitrate VS is
equivalent to 1.598mg of Br or 0.709 mg
of Cl
Determination of Fluorine
Titrant – thorium nitrate TS
( 0.005mol/L)
End point- yellow color changes to
pinkish yellow color

* Ech mL of thorium nitrate TS is

equivalent to 0.380 mg of Fluorine
Determination of Iodine
Titrant- Sodium Thiosulfate(0.005mol/L)
Indicator – starch TS
* Each mL of Sodium thiosulfate is equivalent to 1.06mg
of iodine

Determination of Sulfur
Titrant- Barium nitrate TS (0.01mol/L)
Indicators- thorin and methylthionin chloride
Endpoint- yellow color changes to pink color
* Each mL of barium Nitrate is equivalent to 0.321mg of
sulfur
Physicochemical Methods
A.Solubility Test
•. Review the number of Solvents required to for 1 g of
solid

B. Refractive Index (n)

•. Ratio of the velocity of light in air to its velocity in the
substance
•. Used to establish the identity and purity of liquid
substances.
•. Abbe refractometers are used to give the refractive
index in terms of the sodium light of wavelenght
589.3nm at 20+/- 0.5c
C. Boiling Point- boiling point
of a liquid is the corrected
temperature at which the
liquid boils under normal
atmospheric pressure

D. Melting point- the

temperature at which the
 Dissolution
USP APPARATUS TYPE:
Apparatus I- Basket Assembly
Apparatus II- Paddle Assembly
Apparatus III-?
Apparatus IV-?
Apparatus V-?
Apparatus VI-?
Apparatus VII-?
 Apparatus I
• Most widely used apparatus for dissolution
testing of solid dosage forms together with
Apparatus II
• The dosage form is placed in a basket
affixed to the end of the spindle
• Agitation is achieved by rotating the
basket, with a speed of 100rpm (most
common)
• Appropriately used for dosage form that
floats
 Apparatus II
• The dosage form is directly drop
into the vessel
• A paddle is used to induce
agitation with typical rotation of
50-75rpm
• Tablet or capsule, may be placed
in a sinker designed to enclosed
the dosage form
Medium:
• Simulated gastric juice TS
• Simulated intestinal juice TS

Temperature:
• 37°c +/- 0.5°c

Assay:
• UV-VIS
 Acceptance Criteria
Stages Number of samples Acceptance criteria

1 6 All units should be at least Q + 5%

2 +6 Average of 12 units nlt Q, no units outside Q-15%

3 +12 Average of 24 units nlt Q, nmt 2 units outside Q-15,

no units outside Q-25%

What is Q?
 How to get the %Q?
•  
%Q = X 100
Label claim
 Packaging Control
• Auditing the packaging and labeling
operations falls under the inspector
Reasons of the operation:
1. To assure that only those that have
met the standards and
specifications against the MFR shall
be distributed in the market
2. To prevent mix-ups and errors
3. Assuring that the correct labels and
labeling materials are employed to
Prevention of mix-ups and errors
1. Prior to use, facilities are cleared
out of package finished products
and packaging material of the
previous run
2. Products which are similar in
appearance, containers or
labeling should not be
simultaneously on adjacent
nearby lines unless, these
operations are separated by a
 Operational Checklist
(Product itself)
• Product mixed with another product
• Wrong product or strength
• Homogeneity
• Appearance/ color/ odor
• Contamination with foreign matter
• Fill/ weight/ volume
• Heat marks on the product
• Freedom from capping, chips or
cracks
 Operational Checklist
(containers)
• Freedom from cracks or chips
• Freedom from dents or
distortions
• Contamination with foreign
matter
• Leakage (leaker’s test)
• Fill/ weight/ volume
 OPERATIONAL CHECKLIST
(STRIPS/ POUCHES)
• Product name or strength torn strip of
pouch
• Control code freedom from dust
• Expiration date correct cutting
• Rx symbol powder in pouches
• Leakers in vacuum test empty or
wrong count
• Weak seal fill/weight/volume
 Operational checklist
Labels: Package Insert:
Product name incorrect
Control code missing
Expiration date freedom from dirt
Rx symbol` torn/ soiled
Registration number poorly folded
Glueing
Allignment
Torn/ soiled
Freedom from dust
Missing
 Operational checklist
Accessories: Product unit:
Missing incorrect packaging
Mislocated empty package
Freedom from dust incomplete package content
Defective incorrect count per unit
incorrect count per unit display
wrong size
improper assembly of printed matl
improper position of liquid container
torn packaging component
soiled packaging component
incorrect count per packer or shipper
ragged cuts
 Distribution Control
 Pending finished product should be
separated from approved finished products
for distribution
 Certificate antibiotics and insulin are
withheld from distribution until batch
certification certificate from FDA is
received
 Finished-good warehouse control and
distribution records shall include an
adequate perpetual inventory control
system or other suitable system for
warehoused finished goods so that the
 RECALL
DRUG RECALL- involves a
government ordered removal from
the market. Typically, a recalled
product must present a significant
threat to consumers due to a
product defect, or violate a
minimum federal or state safety
standard.-us fda
 Reasons for Recall
• significant contamination of foreign material
• Significant deviation from the required potency
• IND( investigational New Drug) Termination
• Revocation of Antibiotic Certificate
• No New Drug application
• Withdrawal of the New Drug Application
• Non-sterility
• Misbranding
• Faulty disintegration and substandard quality
against the monograph
• Label mixed-ups
 Reasons for Recall
accdg. to Degree of Consumer Hazard
Class I- the use or exposure to a volatile product
will cause serious adverse health consequences or
death

Class II- causes temporary or medically reversible

adverse health consequences or where the
probability of serious adverse health
consequences is remote

Class III- these are not likely to cause adverse

health consequences
 Market withdrawal
Occurs when a product
has minor violation
that would not be
subject to FDA legal
action
Medical Device Safety Alert
Issued in situations where a
medical device may present
an unreasonable risk of
substantial harm. In some
cases, these would mean a
recall
Who initiates recall?
 Procedure: as soon as known
1. Evaluation of the depth of the problem
a. Necessary depth of the recall
b. Based on evaluation of the problem, make
decision on means of communication for
drug:
2. Indicate the procedure for recall
-. Reasons for recall
- Provide the lot/batch number to be recalled
Provide proper direction where to bring the
drug to be recalled
 Statistical Quality Control
• Quality is defined as its conformity to
given standards or specifications
• It is measured and subject to certain
amount of variation
• 2 Causes of variation:
a. Result of chance- inevitable
b. Assignable factors- quality is not in
control
Statistical methodology- used to address
the evaluation of the magnitude of chance
variation and detecting the existence of
assignable causes of variation which can be
corrected

Statistical quality control- it is the

monitoring quality by the application of
statistical methods in all stages of
production
Statistical quality control
- Consists of proper sampling
- Determines quality variation of the
sample
- Making inferences to the entire batch
- Uses control charts
 Quality Control Charts
1. Attribute chart- makes use of discrete
data classifying the number of items
conforming and the number of items failing
to conform to any specified requirements
Ex.
2. Variable chart- this is a chart using actual
records of numerical measurement on a full
continuous scale such as meter, grams, liter
Ex.
General method:
• Select the sample of size n at random from
production
• Compute an average for each set of sample
measurements
• Compute the appropriate standard deviation of the
average used
• Prepare a graphical control chart. A pair of dotted
lines are drawn on either side of the central line at a
distance x times the standard deviation
• Plot the averages obtained from the sample average
values. If any of the plotted points fall outside of the
established control limits, the process is out of control
 Sample Problem
•  
1. Twenty sets of ten tablets were weighed during compression
at thirty minutes interval, calculate the upper control limit and
lower control limit
Using the formula:
σ

UCL= xx  + 3 σ

LCL= xx  - 3 σ

• using the table below, compute for the standard deviation.

• Refer for the divisor
σ=
Sample sine (N) Divisor (D)
2 1.1
3 1.7
4 2.1
5 2.3
6 2.7
8 2.8
9 3.0
10 3.1
15 3.5
20 3.7
30 4.0
50 4.5
100 5.0
500 6.0
2. The volume of 5 vials was determined
during the filling of an injectable. Determine
the UCL and LCL using the formulas below:
3. A batch of ointment was filled into
tubes during ten working days. 500
tubes were filled each day. The
inspector withdrew a random sample
based on the master table and noted
the number of leaking tubes
To construct a control chart for fraction defective
the following steps are performed:
1. Record the number inspected (n) and the
number of defectives found (d)
2. Compute for the fraction defective (p) which is
the ratio of the number of defectives found to
the total number of units actually inspected in
the batch
3. Compute for the average fraction defective( p )
obtained by dividing the total number of
defectives found by the total number of the units
inspected in a series of batches.
4. Calculate the UCL and LCL through the following
5. Plot the p’s on the control chart with
p on the center line
6. When all the points fall within the
control limits, the product is said to be
in statistical control
* Percent defective, a more convenient
value may be used in constructing the
P chart
 Formulas for P charts
•UCL
 

UCL
Day Number of leaking n p
tubes
1 4
2 6
3 7
4 5
5 3
6 1
7 6
8 3
9 2
10 0
Total: ∑d ∑n
 Stability
• The capacity of the drug to remain
within specifications established to
assure its identity, strength, quality
and purity
• The _________ of a preparation is the
time from the date of the manufacture
of the formulation until its chemical or
biological activity is not less than 90%
of the labeled potency
 Factors that Accelerates drug
Instability
• Light/ radiation
• Temperature
• Moisture/ relative humidity
• Agitation
• Inversion
• Method of manufacture
• Gravity
 Significance of Stability
Testing
Used to predict shelf-life and
product stability
Uses to establish expiration
date
Determine the appropriate
storage condition of a
formulation/ pack
 Methods on Stability
Testing
1. Accelerated or Stress Testing
.Product is stored at accelerated
temperature (40±2 °c at 75±5% RH)
for a period of 6 months
.Drug products intended for storage
in a refrigerator (25°C ± 2°C/60% RH
± 5% RH ,
6 months)
 Methods on Stability
Testing
2. Real time stability testing
 Product is stored at room
temperature
 Methods on Stability
Testing
3. Long term stability studies
 Product is stored at a proposed container
closure system in a controlled room
temperature condition and carried out in
25±2 °c at 40±5% RH until its expiration
date
 Minimum of __________time period to cover
long term stability studies
 For pharmaceutical article that requires refrigeration,
usually 5±3°c
STABILITY TEST SCHEDULES
Within the first year of Study:

Within the second year of the study:

 Physical Stability
Its significance on:
A. - a pharmaceutical
product is expected to look
fresh, elegant and professional
no matter how long it stands
on the shelves
 Physical Stability
Its significance on:
B. - patient must receive
the proper amount of the
ingredient in each dose
 Physical Stability
Its significance on:
C. - active ingredient must be
available to the patient throughout
its expected shelf life
 Overages
• It is the voluntary introduction of a
specific excess during the
manufacture of pharmaceutical
forms of medicaments that are
unstable by nature and are difficult
to stabilize
 Expiration date
It is the direct application and or
interpretation of the knowledge gained
through stability testing

Also limits the period during which a

pharmaceutical preparation may be
expected to have its labeled potency,
provided it has been stored as directed
on its labeling
 SHELF LIFE
 Shelf life (also referred to as
expiration dating period)
 The time period during which a drug
product is expected to remain within
the approved shelf life specification,
provided that it is stored under the
conditions defined on the container
label.
 Overages
Overages are justifiable when:
 The labile active ingredient cannot be
possibly standardized
 The overage allows an even equilibrium of
the content of the actives within acceptable
limits
 Clinical studies show that the overage is
therapeutically safe
 The overage would not present a possibility
of a therapeutic over dosage if the
preparation were used during the early part
of the product’s shelf life.
 The lower limit proposed for the decrease in
Overage Limits
 KINDS OF OVERAGES
1. Manufacturing overages

2. Stability overages
 VALIDATION
The verification by data and analysis,
that the design and objectives of a
given facility, system, apparatus, or
procedures are reliably fulfilled in
routine operation
 Process Validation
Gathering and documenting of
sufficient evidence to give reasonable
assurance that the process under
review does what it purports and
expected to do
 Process Validation
1. Blending operations
2. wet granulation
3. evaluation of mixed granulation
4. evaluation of the drying step and
dried granulation
5. evaluation of milling granulation
6. Tablet compression
7. Tablet coating
 Analytical /Assay Method Validation
 The establishment of scientifically
sound and appropriate specifications,
standards and test procedures to
assure the components, drug
preparations in the course of
processing, and finished products
conform to appropriate standards of
identity, strength, quality and purity
 Objectives
To introduce the concept of:

• Protocol development
• Instrument qualification
• Analytical procedure
• Extent of validation
Validation of analytical procedures
requires:
 Qualified and calibrated instruments
 Documented methods
 Reliable reference standards
 Qualified analysts
 Sample integrity
Validation protocol for analytical method

 Statement of purpose and scope

 Responsibilities
 Documented test method
 List of materials and equipment
 Procedure for the experiments for each
parameter
 Statistical analysis
 Acceptance criteria for each performance
parameter before the experimental phase
of work commences
Qualification of the instrument
 Maker’s manual
 Modifications(if any)
 Installation and operational qualification
 Calibration programs
 Maintenance schedules
HPLC QUALIFICATION
Module: Pump
Performance attributes: flow rate
accuracy
General expectations: +/- 2% of the
flow rate & no leakage
Frequency: 6 months
Three Validation Principles

Installation Operational
qualification qualification

Performance
qualification
 Class B

Analytical
Performance Limit
Characteristics Class A Quantitative Tests Class C Class D
Accuracy Yes Yes * * No
Precision Yes Yes No Yes No
Specificity Yes Yes Yes * Yes
Detection Limit No No Yes No
*

Quantitation No Yes No *
No
Limit

Linearity Yes Yes No *

No
Range Yes Yes * * No
*  May be required, depending on the nature of the specific test.
 Analytical Validation
Parameters
• Class A: Tests designed to establish identity, whether of bulk drug
substances or of a particular ingredient in a finished dosage form.

• Class B: Methods designed to detect and quantitate impurities in a bulk

drug substance or finished dosage form. The detection of impurities,
without quantitation, is referred to as a limit test.

• Class C: Methods used to determine quantitatively the concentration of

a bulk drug substance or of a major ingredient in a finished dosage
form; referred to as assay.

• Class D: Methods used to assess the characteristics of finished dosage

forms, such as dissolution profiles and content uniformity.
 Characteristic of Analytical
Procedures/Methods
Accuracy- The accuracy of the procedure is
the closeness of the results obtained by the
procedure to the true value.
Precision- The precision of the procedure is
the degree of agreement among individual
test results.
three levels of Precision:

Repeatability
This is the precision of the procedure when
repeated by the same analyst under the same set
of condition and within a short interval of
time.
Intermediate precision
expresses within-laboratories variations: different
days, different analysts, different equipment, etc.
Reproducibility
expresses the precision between laboratories
(collaborative studies, usually applied to
standardization of methodology)
 
Characteristics of analytical procedures (cont…)
• Linearity-The linearity of an analytical
procedure is its ability to produce results that
are directly proportional to the concentration
of analyte in the samples
• Specificity- The specificity or selectivity of a
procedure is its ability to measure the
analyte in a manner that is free from
interference from other components in the
sample being examined
• Sensitivity
• Limit of detection
• Limit of quantitation
 Analytical Validation Scope
• Balances
• Chromatography
– HPLC, HPTLC, GC, TLC
• Dissolution or disintegration apparatus
• Karl Fischer moisture determination
• Melting, softening or freezing point apparatus
• Ovens, refrigerators, incubators
• pH meter
• Polarimeter - optical rotation
• Refractometer
• Spectrophotometer UV/Vis, IR, FTIR, Raman,
AA
• Timers
 Validation of existing Products
1. Data that are directly related to the
efficiency of the product such as
a. Potency
b. Content Uniformity
c. Dissolution (bioavailabilty)
2. Data concerned in the processing
characteristic
a. Moisture content
b. Weight content
 Cleaning Validation
Three Phases of Validation:
1. Pre-validation
- to evaluate the cleaning, sampling and
analytical testing procedures
2. Validation
- to establish that the cleaning results are
repeatedly acceptable
3. Re-Validation
- to ensure continuing validity of the cleaning
procedures