Quality Control

Pharmaceutical and cosmetic manufacturing is recognized as a major industry which

requires a clearly defined organization. Each segment of this organization is expected
to fine-tune its functions and responsibilities. An effective coordination is called for
among its personnel equipment building and inventory of materials. All these
activities are performed towards the production of a drug or cosmetic of the highest
standard and at the lowest cost.
!n a manufacturing firm it is common to have the following divisions under a general
manager"
#. $inance
%. Production
&. 'uality Assurance ('uality )ontrol*
+. ,ar-eting (optional in a third party contract manufacturer*
All manufacturing must be done in compliance with )urrent .ood ,anufacturing
Practice ().,P*. All production personnel should -now and understand the ).,P
applicable to their area of responsibility.
!n enforcing ).,P to achieve the desired goal of delivering a safe pure and effective
product at the lowest cost to the consumer a specific group must be organized to be
the core of the company/s quality audit program. 0hus the quality control department
is organized to maintain the quality of products to a prescribed level.
'uality is the combination of attributes or characteristics of a product which when
compared to a standard serves as a basis for measuring the uniformity of the product
and determines its degree of acceptability.
'uality control is a tool which gives the assurance that a product conforms to
standards and specifications through a system of inspection analysis and action.
'uality is everybody/s business. !t cannot be inspected into a product1 but rather it
must be built in. !t must be produced. 2ith this responsibility a quality control system
is established at the conception of a new product during production of the batch and
during distribution of the commercial pac-age. 0his system is a combination of those
administrative and technical procedures which must be used to produce and deliver a
safe pure and effective product to the end user.
0he potential benefits derived from a quality control system are as follows"
#. 0he system minimizes or eliminates the ris- of mar-eting unsafe
products.
%. !t guarantees conformance to regulatory requirements.
&. !t guarantees product efficacy.
+. !t reduces operating costs.
3. !t reduces operating losses.
4. !t produces higher employee morale.
5. !t motivates the pharmaceutical6medical profession to sell or prescribe
the product.
78.A9!:A0!79 7$ ';A<!0= )79087<
Each pharmaceutical or cosmetic company has an organizational structure which
differs somewhat from those of other companies in scope and responsibilities.
,aterials !nspection >ection
!nspectors are alert individuals who had experience and who are familiar with
the physical characteristics of the materials they sample and are well versed in
sampling techniques. 0he functions of this section are"
#. 0o sample and examine all raw materials received.
%. 0o sample and conduct physical tests on"
i. All shipments of pac-aging materials
ii. All manufacturing filling and pac-aging operations
&. 0o maintain periodic examination on the quality of inventories
throughout all phases of storage shipping and distribution.
+. 0o perform an audit which is independent of the wor- done by
production personnel.
!nspection stations are placed in the area of operation viz. warehouse
manufacturing and pac-aging areas.
Analytical <aboratory
0he analytical laboratory should be in an accessible area and protected from
noise and vibration common to manufacturing operations.
!n order to perform physical and chemical analysis the analysts should -now
the usual gravimetric and volumetric analysis. $urthermore they should be s-ilful in
handling instruments for ultraviolet and infrared spectrophotometry non-aqueous
titrimetry autoanalysis polarography x-ray diffraction x-ray fluorescence
spectrophotofluorimetry radioactive tracer techniques and chromatography viz."
column gas paper thin layer and high performance liquid chromatography.
?iological 0esting <aboratory
0he staff in a biological testing laboratory should be well trained and
experienced in both simple and complex microbiological procedures and biological
interactions. 0hey should possess a high degree of s-ill and judgment in order to
perform the job. A veterinarian is recommended to supervise the care and
maintenance of the various species of animals used in the tests. 0he functions of this
laboratory are"
#. 0o perform and evaluate microbiological and pharmacological assays
sterility pyrogen and bacteriological tests irritation safety or acute
toxicity tests.
%. 0o conduct environmental monitoring.
>terile conditions should be provided for areas where biological tests are
conducted. 9oise should be precluded from areas where animals are used. An animal
house should be maintained as a separate unit from the main laboratory if necessary.
>pecifications and Analytical @evelopment
0his sections should have firm bac-ground not only in the principles of quality
control and analytical procedures but also in manufacturing research product
development and in statistics in order to perform the following functions"
#. 0o coordinate with research product development production sales
and management towards improvement of a product.
%. 0o establish specifications for raw and pac-aging materials.
&. 0o validate existing and tentative procedures of testing.
+. 0o establish specifications based on validated procedures.
3. 0o develop new assay methods for in-house use.
4. 0o develop and improve specifications for quality characteristics of the
final product being manufactured.
'uality )oordination 7ffice
0his section should be accessible to all manufacturing and pac-aging
operations since documentation is its main responsibility. 0he functions of this section
are"
#. 0o maintain and store records that represent the history of the batch
from start to finish. 0hese records include the batch and master
formula records raw material analytical records printed and pac-aging
material inspection reports and retention files.
%. 0o be able to furnish data that will aid in analyzing product
performance in the mar-et. 0hese documents are the stability studies
and returned goods reports.
&. 0o investigate customer complaints or inquiries on product quality and
to forward the results of the investigations in the form of technical
reports to the sales organization.
+. 0o call the attention of the appropriate development group any aspect
that provides a basis for improvement of a product for consideration
and action
3. 0o provide data that give scientific and legal status i.e. data generated
from the use of recognized standard compendia. 0his is essentially a
function of the distribution section or warehouse.
4. 0o maintain and develop >7P/s
>0A9@A8@> A9@ >PE)!$!)A0!79>
'uality characteristics are interpreted by descriptive words and measurements.
)haracteristics are subject to variation. 'uality variation which is not confined within
a specific range tolerance or limit will grow to uncontrolled magnitude and will
encourage the proliferation of errors1 thus producing a defective product. Errors may
be due to chance or assignable causes such as" materials machines methods and men.
0o avoid producing a defective product standards and specifications are developed to
serve as a basis for accepting or rejecting a product. !n a product these must cover the
following points"
#. $ormula" 0his is concise and precise statement of the ingredients that
comprise the product together with the percentage and6or weight of
each.
%. 8aw material specification" 0his should enumerate the characteristics
of all the materials that go into the product and the permissible range
of purity of each ingredient. @eviation beyond this range may be
expected to cause failure of the product to function as planned or at
least result in an undesirable lac- of uniformity. >tandard compendia
li-e the ;>P 9$ ?P ?P) ,erc- !ndex etc. provide this valuable
information.
&. >tandard operating procedure" 0his is a step by step method on how to
go about a job. !t must spell out all information and instructions that
assure that variations in production from day to day and wee- to wee-
will be held to within acceptable established ranges.
+. $inished product specification" 0his should cover all characteristics
that affect the proper performance purity safety and stability of the
product. 0olerances may be minimum maximum or both depending
on the nature of the situation.
3. Pac-aging material standard" 0his should be set for everything that
goes around the product i.e. bottles cans aluminium foil cellophane
jars caps cap liners labels printed inserts cartons wrapping papers
and shipping cases. Pac-aging must be considered with the following
points in mind"
i. 0he units may have to run on a high-speed line.
ii. 0hey may involve a complicated assembly.
iii. 0he pac-age may be functional.
iv. 0he pac-age must be completely compatible with the product.
v. 0he pac-age must protect the product and assure its stability.
vi. 0he pac-age must ship well
4. 0esting ,ethods" 0hese are indispensable in assuring conformity to
standards. >ince they play such a vital role testing procedures must be
standardized so that they yield results of comparable precision and
accuracy in the hands of different operators and laboratories. 0he tests
must be validated to ensure precision and accuracy on application.
@E$E)0>
!n a broad sense a defect is an undesirable characteristic of a product. !t is defined as
a failure to conform to specifications. A unit of a product which contains one or more
defects is called a defective. @efects can be classified as follows"
#. According to measurability"
i. Aariable defect B a defect which can be measured directly by
instruments giving dimensions of length weight height
thic-ness concentration volume viscosity pC or size particles
ii. Attribute defect B a defect which cannot be measured directly
by instruments. !t shows mainly the conformance or non-
conformance of the material to specifications. 0his applies to
many things that can be judged only by odor or visual
examination li-e color clarity sheen cleanliness smoothness
taste and presence or absence of a characteristic.
%. According to seriousness or gravity"
i. )ritical defect B a defect which may endanger life or property
and may render the product non-functional. Absence of
warning in a label for a potent drug or disintegration time of
one hour for an analgesic are considered critical defects.
ii. ,ajor defect B a defect which may affect the function of the
object and therefore may render the product useless. 0he
presence of a crac- in a bottle is a major defect.
iii. ,inor defect B a defect which does not endanger life or
property nor will it affect the function but nevertheless remains
a defect since it is outside the prescribed limits. An example of
a minor defect is the slight deviation of the color of the label
from the color standards
&. According to nature"
i. 7cular defect B a defect that is visible e.g. foreign particular
contamination
ii. !nternal defect B a defect which is not seen although present
e.g. a subpotent drug product.
iii. Performance defect B a defect in function e.g. a suppository
that does not melt at body temperature.
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0he manufacture of a cosmetic or drug product frequently involves a series of simple
to complex steps. 0he ris- of errors increases as the number of materials used in the
formulation becomes larger and the manufacturing processes become more complex.
0he errors which are the sources of quality variation of a product are given below.
Sources of Variation Example
1. Materials a. Aariation between suppliers of same substance
b. Aariation between batches from same supplier
c. Aariation within a batch
2. Machines a. Aariation of equipment for the same process
b. @ifference in adjustment of equipment
c. Aging and improper care
3. Methods a. !nexact procedures
b. !nadequate procedures
c. 9egligence by chance
+. ,en a. !mproper wor-ing conditions
b. !nadequate training and understanding
c. @ishonesty fatigue and carelessness
0o minimize and eliminate the sources of variation which can cause product quality
variation approaches such as material control good manufacturing practice
pac-aging control automation and statistical sampling plans are employed.
)79087< $;9)0!79>
)ontrol functions may appear varied and never quite identical in any two
companies but basically these functions can be classified into four categories"
analysis monitor record review and release and audit function.
Analysis $unction
0o assure the acceptability of a product it is essential that all materials are
within specifications. 0ests are made not only on the raw materials and pac-aging
components but also on the bul- product during processing and after pac-aging prior
to its release to the mar-et. 0he analytical function continues even after distribution to
the end user when selected lots are subjected to shelf life studies to confirm the
expiration period of the finished product. Product against which a complaint is
registered may also be analyzed to determine its validity and the cause of the reported
deficiency. Appropriate steps may then be ta-en to prevent recurrence of a similar
problem.
,onitor $unction
!t is the responsibility of quality control to sample and examine materials
while they are being processed. 0his is to assure that even though production
personnel have the primary responsibility for control over their processes these
processes are maintained and that any deviation from specified requirements are
reported.
Another monitor function usually performed on a time basis rather than on a
lot or batch basis is environmental monitoring. 0his is to control the microbial and
particulate matter content of environmental air in areas where pharmaceuticals such as
parenterals are processed. 0he environmental monitoring function is also responsible
for periodically chec-ing equipment and personnel burden. 0he objective of
environmental monitoring is to assure that microbial and particulate matter levels are
within acceptable tolerances and when not to report to appropriate supervision for
corrective action.
8ecord 8eview and 8elease $unction
All records generated during the course of producing a quality controlled
product is -nown collectively as a batch record. Prior to the release of each lot of
finished product to the mar-et the record-review function is responsible for carefully
reviewing the batch record for that lot and assuring that all necessary records are
present complete and where feasible to determine accurate. A detailed chec-list is
frequently employed by the reviewer. 7nly after there is full assurance of the
completeness and accuracy may the lot of a finished pharmaceutical or cosmetic
product be released for distribution to the mar-et.
Audit $unction
0he production and quality control of quality products are governed by
standard operating procedures (>7P/s* which embrace the legal requirements set forth
by the )urrent .ood ,anufacturing Practice ().,P* regulations as well as
additional standards of operation established by the manufacturing firm. !t is the
responsibility of supervisors to train their employees to comply with the >7P/s and to
understand why and how these >7P/s are to be followed. 0he quality audit is
designed to detect areas where the established >7P/s are not being followed and to
report these findings to the supervisor for appropriate action.
Sampling and Sampling Plan
A basic quality function is that of deciding whether the product conforms to
specifications. 0his function is generally called DacceptanceE. 0o arrive at a decision
the primary step is inspection. !nspection is the comparison of certain attributes and
dimensions of a product against specifications to find out if the product is within the
prescribed limits.
Acceptance inspection is a necessary part of manufacturing and may be applied to
incoming materials to partially finished product at various intermediate stages of
manufacturing process (in-process inspection* and to the final product. Acceptance
may also be carried out by the purchaser of the manufactured product. !nspection
consists of several steps"
#. !nterpretation of the specification1
%. ,easurement of the product1
&. )omparison of the product with specification1
+. Fudgment as to conformance1
3. @isposition of the product1 and
4. 8ecording of the data obtained.
Acceptance >ampling
,uch of acceptance inspection is by sampling. >ampling may be defined as the
process of removing an appropriate number of items from a population in order to
ma-e inferences to the entire population.
Population is the totalling of all actual or conceivable items of a certain class under
consideration.
A sample is a finite number of objects selected from a population. !n other words
instead of inspecting the entire batch of &GGGGG tablets (population* one examines a
small part of the batch (sample*. A random sample is a sample chosen in such a
manner that one object has a good chance of being selected as another.
8epresentatives of materials to be sampled are"
#. 8aw materials1
%. Pac-aging and printed materials1
&. !ntermediate products1 and
+. $inal products" before during and after manufacturing and pac-aging
operations.
!t is an accepted -nowledge that no two ampules capsules or tubes will contain
exactly the same amount of ingredient. Cowever one does not have to rely on
examination performed on every unit of a batch in order to avoid sampling errors or to
ma-e a conclusion concerning the entire batch #GGH inspection often turns out to be
impracticable or clearly uneconomical. ,oreover the quality of the product accepted
may actually be better with modern statistical procedures that would be the case if the
same product were subjected to #GGH inspection. >ampling inspection has also a
psychological advantage over #GGH inspection.
>ampling inspection is therefore used in lieu of #GGH inspection for several reasons"
#. 0he cost of #GGH inspection is prohibitive.
%. #GGH inspection is tiring and the probability that the inspector will
commit errors is high.
&. 0he inspection operation may involve destructive testing.
+. A statistical sampling plan well applied may give better quality
assurance than #GGH inspection.
!t is common -nowledge that on many types of inspection even several #GGH
inspections will not eliminate all of the defective product from a stream of product a
portion of which is defective. 0he best protection is of course having the product
made right in the first place.
!nspection ,ethods
0he most common and distinct methods of inspection are the single and double
sampling methods. !n single sampling a decision is reached after only one sampling.
!n double sampling a decision is obtained after the result of the second sampling is
-nown.
>ampling Plan
!n sampling one must consider the laws of probability. 0here are certain ris-s
involved1 namely the ris- of error. A producer/s ris- is the probability of rejecting a
good batch whereas a consumer/s ris- is the probability of accepting a bad batch.
>ampling plans can be designed and applied in such a manner as to reduce these ris-s
to a minimum and over a period of time to give assurance of quality products.
A sampling plan is a definite wor-ing rule regarding size and frequency of a sample
and the basis for acceptance or rejection. !t is therefore a specification of sampling.
!t requires that three numbers be specified. 7ne is the number of items (9* in the lot
or batch from which the sample is drawn. 0he second is the number of items (n* in the
random sample drawn from the lot. 0he third is the acceptance number (c*. $or
example if 9I3G nI3 cIG1 these three numbers may be interpreted as saying" D0a-e
a random sample of 3 from a lot of 3G. !f the sample contains more than G defects
reject the lot1 otherwise accept the lot.E
0here are several sampling plans on hand. 7ne simple sampling plan is the square
root system which uses the formula" n I 9 J #. 0he acceptance number is specified
by the A'< (acceptance quality level*.
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.
A receiving tally report (reception of materials incoming cargo report receiving
report or receiving report or receiving tic-et* should be prepared for every shipment.
!nformation indicated therein are as follows"
!. Pre-printed data
#. 9ame of report
%. 9ame of drug6cosmetic company
&. Address
+. 8eceiving number
3. 9ame of the department receiving a copy
!!. !nformation to be supplied by"
a. 2arehouse
#. 9ame of the material
%. !tem code number
&. <abel clain
+. Purchase order number
3. !nvoice number
4. Aendor (supplier6distributor*
5. ;nit of measure
K. 9umber of containers received
L. 2eight6volume6pieces contained in each container
#G. @ate the report was prepared
##. @ate the shipment was received
#%. 9ame of the warehouse personnel receiving the shipment
b. 'uality )ontrol
#. !nspector/s report
a. 'uantity of sample
b. )omments if any
c. 9ame of inspector
d. @ate inspected
%. Analysis
a. Analytical reference number
b. 9ame of analyst
c. @ate of analysis
&. @isposition
a. 8eason if rejected
b. !f approved
b-#* 8eassay date
b-%* 8elease number
+. 9ame of the person responsible for receiving the report
3. @ate of the review
!f the shipment consists of more than one manufacturing lot number a separate
receiving number is assigned to each lot. 0he receiving tally report (808* should be
distributed to all groups concerned with the purchase inventory use and control of
the materials. 0hus a copy of the 808 is given to quality control warehouse
purchasing and accounting departments. ,anufacturing firms may have different
entries but the basic information is quite similar.
0he 808 is prepared in the warehouse by the warehouse personnel who is responsible
for assigning a receiving number to the material. 0he shipment is held in quarantine
pending quality control approval.
8aw materials
8aw materials are the ingredients intended for use in the manufacture of drugs and
cosmetics including those that may not appear in the final product.
0he control of raw materials at different stage is handled in the following manner"
Reception
#. 0he 808 is chec-ed by a ') inspector for accuracy.
%. Each container of raw materials is examined visually for damage or
contamination in transit including brea-age of seals when indicated.
&. Adequate number of samples are ta-en from a representative number
of containers.
i. >ampling plan is used to determine the number of raw material
container to be sample.
ii. )alculate for the total quantity of material required for a
complete test to determine the amount of sample to be ta-en
from each container.
iii. 0he composite sample should not be less than three times the
amount required for one complete test.
Quarantine
#. 0he inspector chec-s that the raw material container has a DColdE or a
quarantine stic-er pasted by the receiving warehouse personnel to
indicate that a decision to accept or reject is yet to be made by quality
control.
%. >amples are submitted to the laboratory for testing.
&. 0he sample is subjected to tests such as"
+. !f the test results indicate that the raw material meets monograph
specifications the material is approved for use1 otherwise it is
rejected. @ecision stic-ers are then issued by quality control.
3. 0he decision stic-ers are either placed on top of the quarantine stic-er
or the quarantine stic-er is first removed before the decision stic-er is
pasted. 9o two stic-ers of different dispositions must be present on the
same container. At this stage the raw material is transferred to either
the rejected or approved materials area.
Rejected
0he material so mar-ed is chec-ed that it is held at a rejected materials
area to prevent the possibility of use in any manufacturing or processing
procedure.
Approved
#. 0he material mar-ed as approved is chec-ed that it is brought to the
approved materials area.
%. Approved materials are tested when reassay date is due to assure that
they conform to appropriate specifications of identity strength and
purity at time of use.
&. Approved raw materials are audited to assure that they are rotated in
such a manner that the oldest stoc- is used first. 0his is -nown as the
$!$7 (first in first out* policy.
>tic-ers
!n order to avoid mix-ups a material warehouse is subdivided into several sections.
Accordingly the materials are segregated and properly identified by the stic-ers
attached on the individual containers cage or pallet of materials. 7n reception of the
materials a quarantine stic-er is pasted on the container of the material. 0he materials
are held in a quarantine area while waiting for its release by quality control. After
disposition is given the appropriate stic-er is pasted on top of the quarantine stic-er1
or it is more convenient the quarantine stic-er is defaced or removed prior to
attaching the approved or rejected stic-er. ;nder no circumstances should two
different stic-ers be present or prominently displayed on a material container at the
same time.
0o distinguish the stic-er different color codes may be assigned such as yellow for
quarantine green for approved and red for rejected. A stic-er may have any other
color but it would be wise to use a color easily associated with what it means.
Printed and Pac-aging ,aterials
Product containers closures and other components parts of product pac-age should
not be reactive additive or absorptive so as to alter the safety identity strength
quality and purity of the product. 0hese should be tested for suitability for its intended
use. >torage and handling are audited to prevent them from contamination and
deterioration and to avoid mix-ups.
Pac-aging materials are two types namely"
#. Primary pac-aging components B pac-aging materials which come in
direct contact with the product itself1 li-e bottles tubes ampules vials
carpules caps stoppers plungers stripping materials jars fillers and
seals.
%. >econdary pac-aging components B pac-aging materials which do not
come in direct contact with the product and serve as accessory to the
primary pac-aging component. ,ost of these are labels inserts unit
cartoons brochures pac-er boxes and shippers.
Printed Materials
?y official definition labelling includes all written printed or graphic materials
accompanying a product. As such they are subjected to inspections by an experienced
proofreader for graphical errors for compliance with specifications as to type and
grade of stoc- printing quality and dimensional tolerance.
,inimum criteria for acceptance of printed materials consists of"
#. 0ext
%. )olor
&. >ize
+. 0hic-ness
3. .rain direction
4. >ealability
5. )leanliness
K. >urface finish
L. Adequate paste
#G. >hape
<abeling )ontrol
?elow is a summary of labelling requirements for drugs and cosmetics.
Labels
#. 9ame of drug or cosmetic
%. 0he strength or quantity of the substance contained per unit dosage
form
&. <ot or batch number
+. Expiration date
3. 8egistration date
4. >torage condition
5. 9ame of manufacturer pac-er or distributor
K. ?usiness address
L. 'uantity of contents of pac-age
#G. 9ames and quantities of components in the preparation
##. 8x symbol (if necessary*
#%. 2arning or precaution
#&. Adequate direction for use
Package Insert
#. Product name
%. >trength or quantity of the active substance contained per unit dosage
form
&. @escription
+. Action
3. !ndication
4. )ontraindications
5. 2arnings
K. Precautions
L. Adverse reactions
#G. @osage and Administration
##. 7verdosage
#%. Cow supplied
#&. ,anufacturer6pac-er6distributor
#+. ?usiness Address
0o prevent mix-ups of inventories of printed labelling materials of similar color and
shape bar codes placed on edge have been found useful.
)ontainers
Physical and chemical evaluation of containers li-e those made of glass plastic and
metal have been extensive.
Physical inspections generally include the following criteria"
#. >hape
%. Aolume
&. $inish
+. 7pening
3. @iameter
4. Ceight
5. >hape
K. 0hic-ness
L. )olor
#G. )larity
##. <ea-
#%. 0orque
#&. Print
#+. Peeling
#3. )leanliness
#4. <ight 0ransmission
#5. >tress crac- resistance
0he physico-chemical tests for containers include"
#. !dentification
%. !nfra-red properties
&. 0hermal analysis
+. Extractable substance
3. 9on-volatile residue
4. 2ater vapour
permeation6transmission
5. ,oisture
K. 8esistance to water
attac-
!t should be noted that plastic containers for parenteral use is tested further using
biological test procedures" e.g. implantation systemic and intracutaneous injections.
)ontainer and )losure )ontrol
0he integrity of the seal between the closure and 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.
.eometry can be controlled by the mold of the pac-aging components. A mold
number is assigned which is used as its identification number.
)losures should fit the tread of the container. !t should sit on a container
without tilting produce no lea-s should not rotate continuously be reasonably tight
and loo- elegant.
0hose familiar with bottling problems recognize the necessity for control of
cap tightness and the difficulties that can result from the failure of such control. 0he
following considerations are very important in this connection"
#. A minimum tightness is essential to avoid evaporation or lea-age of
the product.
%. Excessive torque may brea- the moulded closures.
&. )aps applied too tightly may be difficult to remove.
Experience has proven the desirability of regular testing of pac-ages from
each bottling line to ma-e sure that tightness is maintained at all times. 0o chec-
tightness a torque tester is used. 0orque is a measure of circular force required to
loosen the cap1 an application torque is the amount of force used to tighten the cap.
0he unit of force is in terms of inch pound. >ample size is #G bottles.
8eassay @ates
0he finished product can only be good as the raw materials used in its manufacture.
0o assure product excellence the monitoring of the quality of the raw materials
during storage is therefore an important step after such materials are released by
quality control. Periodic testing is done to revalidate the material. 0he date of retest is
-nown as reassay date. 0his is also given in terms of month and year determined
from the last assay date.
?ased on the stability of raw materials the reassay dates assigned are"
,onthly or prior to use B highly unstable materials
4 months B vitamins flavors
#% months B active ingredients dyes
%+ months B active ingredients excipients
9ot all tests are performed during a retest. 0he tests given below serve as a general
guide since manufacturing companies provide a listing of tests which must be
performed to satisfy the reassay requirements for the raw materials.
8etest requirements"
#. Appearance
%. !dentification
&. ,elting range
+. >pecific gravity
3. 8efractive index
4. pC
5. <oss on drying
moisture content6water
K. Al-alinity
L. Acidity
#G. Alcohol content
##. @egradation limits
#%. Assay
#&. ,icrobial tests
Manufacturing Control
2ritten procedures are extremely vital to the manufacture of drugs and cosmetics.
0hese procedures are embodied in four important documents designed to explain why
and how the products are made. 0hese are"
#. ,anufacturing monographs
%. 'uality control monographs
&. ?atch records
+. >tandard operating procedures
0he manufacturing monograph is the basic document from where the master formula
and batch production records are based. 0he quality of each and every component
used in the manufacture of the product is assured by testing these components in
accordance with the specifications and methods provided by the quality control
monographs. >tandard operating procedures are 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.
@uring processing the quality of the product at various stages of production is audited
by quality control. !n-process quality control (!P')* tests are performed to determine
if the product meets specifications throughout the entire processing period and
particularly during critical stages of manufacturing. Any out of range measurement
can thus be corrected before further processing is continued. 0he audit also fulfils the
primary objective of the !P') which is to monitor all features of a product.
,aster $ormula 8ecord
A master formula record is the original document used as -ey in the production of
products. ?eing the prototype it is -ept in a secured documentation room duplicated
or photocopied only whenever a job order is issued. !t assures identical reproduction
of the product document.
?atch 8eproduction 8ecord
A batch reproduction record is an accurate reproduction of the master formula record.
After being used as the guide to production and actual data of what has been done are
recorded therein the completed document permits reconstruction of the history of the
product formula manufacturing procedures production record (processing batch
records processing control records pac-aging records* raw material records
pac-aging materials records and product experience reports.
?atch <ot or )ontrol )odes
0he batch means a specific amount produced in a unit time or according to a single
manufacturing order during the same cycle of manufacture. 0he term lot means a
batch a portion of a batch or a combination of batches. 0he term batch number lot
number or control number mean any distinctive combination of mar-ings letters or
numbers by which the history of the manufacture and control of a batch or lot of a
product can be determined. )ontrol codes should be identified as such on the label.
@ifferences in format and content of batch production records from product to product
are to be expected. Cowever the basic information remains similar. 0hese are given
below"
Product Formula
#. 0he product name and6or unique identification such as"
a. ?atch size
b. @osage form and strength
c. $ormula code number and date
d. ?atch or lot number
%. An authorizing signature and date by a competent and responsible
individual.
&. A complete list of raw materials designated by whole names and codes
sufficiently specific to indicate any special characteristics.
+. 0he theoretical weight measure or percent of each raw material
regardless of whether it appears in the finished product or not.
3. 0he standards or specifications of each ingredient used in the product.
4. An appropriate statement concerning any calculated excess of an
ingredient reasonable variations and adjustments.
5. A statement of total weight measure or percent.
K. Appropriate statements of theoretical yield at various stages and the
termination of the product.
L. 0he actual weight measure or percent of each raw material allocated
or dispensed for the batch.
#G. 0he receiving number of the raw material dispensed.
##. 0he signature of competent individuals responsible for measuring and
dispensing the raw materials duly endorsed by another competent and
responsible individual. >ignatures should be dated.
Manufacturing Process
#. Product name and6or unique identification
%. An authorizing signature and date by a competent and responsible
individual duly endorsed by another competent and responsible
individual.
&. A step by step description of all significant aspects of the process
including where necessary"
a. ,eans of raw material measurement
b. 7rder of addition and point of addition of raw materials
c. <ist of major equipment
d. 0emperature
e. ,ixing speeds
f. ,ixing times
+. >ignature of the individual performing and endorsement of the
individual supervising each step. ?oth should be dated.
3. !ntermediate and finished product specifications test methods and
sampling instructions
4. >pecial notations and precautions including where necessary"
a. )leaning procedures
b. >torage conditions
c. $illing temperatures
d. 8emedial measures
e. >pecial safety and health measures
Product Specifications
#. 0he finished product name6or unique identification
%. Physical chemical and microbiological specifications where
necessary for the acceptance of each lot in-process samples and
finished products and a description of the sampling and test procedures
used
&. 0he result of control tests
+. >amples retained
3. Endorsement and date of the authorized individual performing the test
4. @isposition of the batch or lot endorsed by an authorized individual
)ontrol 0ests
!n order to satisfy product identity purity safety quality and strength products must
be subjected to certain specific tests. 0he specifications and test methods will not be
given. !ndividual company monographs and published compendia provide these.
,inimum attributes common to general categories of products are enumerated below.
2here necessary some of the tests are performed during processing (!P')* of the
product and repeated in the final product.
Solid Preparation
0he most common solid preparations are tablets capsules powders ca-es and stic-s.
,inimum test requirements are as follows"
#. Assay for the active ingredient(s*
%. Assay for degradation product(s*
&. @isintegration
+. @issolution6bioavailability
3. )ontent uniformity
4. 2eight variation
5. !dentification tests for the active ingredient(s* and possible
contaminants
K. Aisual appearance
L. 7dor
#G. 0aste
##. 0exture
#%. Cardness
#&. $riability
#+. Powder fineness
#3. ,oisture content
#4. Cumidity effect
#5. )olor stability
#K. >torage condition
#L. ,icrobiological burden
%G. 0hic-ness
Liquid Preparation
#. Assay for the active ingredient(s*
%. Assay for degradation product(s*
&. !dentification tests for the active ingredient(s* and possible
contaminants
+. Aisual appearance
3. )olor
4. 7dor
5. 0aste
K. 8edispersibility
L. >uspendability
#G. Pourability
##. Aiscosity
#%. !sotonicity
#&. Particle size agglomeration and particle distribution
#+. )larity
#3. )rystallization and precipitation
#4. .as evolution
#5. >pecific gravity
#K. pC
#L. 8efractive index
%G. >urface tension
%#. Pyrogen testing
%%. >terility testing
%&. 0oxicity testing
%+. >torage condition
%3. $ill volume
%4. <ea- test
Semisolid Preparations
0he following tests are applicable to ointments creams jellies and suppositories"
#. Assay for the active ingredient(s*
%. Assay for degradation product(s*
&. !dentification tests for the active ingredient(s* and possible
contaminants
+. Aisual appearance
3. )olor
4. 7dor
5. Aiscosity
K. >oftening range
L. <oss of water
#G. )onsistency
##. Comogeneity
#%. Particle size distribution
#&. pC
#+. 8elease rate of active ingredient from dosage form
#3. >terility testing
#4. >torage condition
L!op"ili#ed Preparations and Products for Reconstitution $efore %se
#. Assay for the active ingredient(s*
%. Assay for degradation product(s*
&. !dentification tests for the active ingredient(s* and possible
contaminants
+. Aisual appearance (original and reconstituted*
3. )olor of ca-e
4. 7dor of ca-e
5. 7dor of solution
K. )olor of solution
L. pC (original and reconstituted*
#G. ,oisture content of ca-e
##. )larity of solution
#%. 8ate of solution (lyophilized*
#&. )ontainer pressure
#+. >torage condition
Aerosols
#. Assay for active ingredient(s*
%. Assay for degradation product(s*
&. !dentification tests for the active ingredient(s* and possible
contaminants
+. 9et content
3. >pray test
4. <ea- test
5. Pressure measurement
K. ,oisture determination
L. Propellant
#G. Aalve delivery accuracy
##. Particle size distribution
#%. >torage condition
Pacaging Control
0he burden of auditing the quality of the product during the pac-aging and labelling
operations falls on the inspector. 0hese operations are controlled for the following
reasons"
#. 0o assure that only those products that have met the standards and
specifications established in the master formula records shall be
distributed to the mar-et.
%. 0o prevent mix-ups and errors.
&. 0o assure that correct labels and labelling materials are employed for
the product
+. 0o assure that the finished product is properly indentified with a
control code that permits construction of the history of the product.
At this stage the inspector should see to it that mix-ups and errors are prevented by
the following measures"
#. Prior to use facilities are cleared out of pac-aged finished products
and pac-aging materials of the previous run.
%. Products which are similar in appearance containers or labelling are
not processed simultaneously on adjacent or nearby lines unless these
operations are separated by a physical barrier.
&. Proper reconciliation is done after the pac-aging operation is
completed. @iscrepancies between the theoretical yield and the actual
yield should be adequately explained before final release of the
product.
At regular intervals the inspector chec-s the pac-aging operation with the aid of a
chec-list. 0he important points considered are"
Products
#. Product mixed with another product
%. 2rong product or strength
&. Comogeneity
+. Appearance6color6odor
3. )ontamination with foreign matter
4. $ill6weight6volume
5. Ceat mar-s on product
K. $reedom from capping chips crac-s
&ontainers
#. $reedom from crac-s chips
%. $reedom from dents distortions
&. )ontamination with foreign matter
+. <ea-age
3. $ill6weight6volume
Strips'Pouc"es
#. Product name6strength
%. )ontrol code
&. Expiration date
+. 8x symbol
3. <ea-ers in vacuum test
4. 2ea- seal
5. Empty of wrong count
K. 0orn strip of pouch
L. $reedom from dust or smears
#G. )orrect cutting
##. Powder in pouches and seals
#%. Perforations of tear notches non-functional
#&. $ill6weight6volume
&losures
#. >ealing tightness
%. $reedom from dust6smears
&. )rimping
+. )orrect design6color
Labels
#. Product name6strength
%. )ontrol code
&. Expiration date
+. 8x symbol
3. 8egistration number
4. !ncorrect
5. .lueing
K. Alignment
L. 0orn6soiled
#G. $reedom from dust6smears
##. ,issing
Package insert
#. !ncorrect
%. ,issing
&. $reedom from dirt6smears
+. 0orn6soiled
3. Poorly folded or inserted
Printing( &ontrol &ode' )*piration +ate
#. !ncorrect
%. ,issing
&. !llegible
+. >meared by legible
3. ,islocation
4. Printing s-ips
5. ,isaligned
Accessories
#. ,issing
%. ,islocated
&. $reedom from dust and smears
+. @efective
Product %nit
#. !ncorrect pac-aging
%. Empty pac-age
&. !ncomplete pac-age content
+. !ncorrect count per unit
3. !ncorrect count per display unit
4. )ontamination with foreign material
5. 2rong size
K. !mproper assembly of printed materials
L. !mproper position of liquid containers
#G. 0orn pac-aging component
##. >oiled pac-aging component
#%. !ncorrect count per pac-er6shipper
#&. 8agged cuts
!istri"ution Control
$inished products pending disposition should be separately stored from finished
goods which have been approved by quality control for distribution.
)ertificate antibiotics and insulin are withheld from distribution until batch
certification certificate from the $ood and @rug Administration ($@A* is actually
received.
$inished goods warehouse control and distribution records should include an adequate
perpetual inventory control system or other suitable system so that distribution of each
lot of product identified by its control code can be readily determined to facilitate
recall if necessary from all consignees of the manufacturer or repac-er.
A stoc- card indicates a beginning and an ending inventory within a certain period. !f
the stoc- goes from the manufacturer to a single distributor the stoc- card need not
indicate the name of the recipient. Cowever it is good inventory practice to write the
name of the distributor if there are several involved. A stoc- transfer number or its
equivalent is posted on the card. 7ther details such as receiving report number of
stoc- by the distributor actual date of receipt by the distributor etc. are included in
the card depending on the actual warehouse practice of the manufacturing company.
?elow is an example of a simple stoc- card.

>toc- )ard 9o.MMMMMMM
Product MMMMMMMMMMMMMMMMMMMMMMMMMMMM Pac- size MMMMMMMMMMMMMMMMMMM
<ot 9o. MMMMMMMMMMMMMMMMMMMMMMMMMMMM Expiration @ate MMMMMMMMMMMMMM
@ate received MMMMMMMMMMMMMMMMMMMMMMM 'uantity received MMMMMMMMMMMM
@ate !nvoice 9o. 'uantity !ssued ?alance !ssued by
At the distribution level it is necessary to indicate the name of the customer. 0his
information is of great value in recalls. ?elow is an example of a typical distribution
card.

>toc- )ard 9o.MMMMMMM
Product MMMMMMMMMMMMMMMMMM Pac- size MMMMMMMMMMMMMMM <ot 9o.MMMMMMMMMMMMMM
'uantity received MMMMMMMMMM @ate receivedMMMMMMMMMMMM Expiry @ate MMMMMMMMMM
@ate !nvoice 9o. )ustomer6Address 'uantity !ssued !ssued by
2hen the stoc- is not handled by a professional distributor the stoc- card and the
distribution card can be made into only one document.
!n both cases separate cards are prepared per lot and arranged in such a way wherein
the card bearing the nearest expiration date is filled up. 0his will ensure that the oldest
approved stoc- is distributed first whenever possible.
Statistical Quality Control
0he quality of a manufactured product is defined as its conformity to given standards
or specifications. 2hen measured quality is always subject to a certain amount of
variation as a result of chance which is inevitable. Cowever as soon as the variation
is due to assignable factors the product departs from conformity to standard and
quality is no longer in control.
0o maintain quality at optimum level with a minimum of non-uniformity quality
control is faced with the problem of evaluating the magnitude of chance variation and
detecting the existence of assignable causes of variation which can be corrected.
>tatistical methodology which is now an integral part of many quality control
systems has been shown to be applicable in solving this problem.
>tatistical quality control is monitoring the quality by the application of statistical
methods in all stages of production. !t consists of proper sampling determining
quality variation of the sample and ma-ing inferences to the entire batch under
investigation. !t ma-es use of control charts a tool which may influence decisions
related to the functions of specification production or inspection.
'uality )ontrol )harts
0here are two basic quality control charts which are based on the measurability of the
quality characteristics namely"
#. Attribute chart B this is a chart which ma-es use of discrete data classifying
the number of items conforming and the number of items failing to conform to
any specified requirements. An example of an attribute chart is the control
chart for fraction defective -nown as P chart.
%. Aariable chart B this is a chart using actual records of numerical measurement
on a full continuous scale such as meter grams liter.
A control chart consists of a solid and two horizontally parallel lines on either side of
the solid line. 0he control solid line is the target value of the historical process
average and6or range. 0he two dotted parallel lines indicate the limits within which
practically all observed results should fall as long as the process is under normal
variation (statistically controlled*. 0he upper dotted line is the upper control limit
(;)<* which is normally three standard deviations above the center line. <i-ewise
the lower line is the lower control limit (<)<* and is also three standard deviations
below the center line.
!f the process is in control the six standard deviations spread between the upper and
lower control limits will encompass LL.5 percent of the values in a normal distribution
with its mean at the center line.
0he control limits on the chart are so placed as to disclose the presence or absence of
assignable causes. Although their actual elimination is usually an engineering job the
control chart tells when and in some instances suggests where to loo-.
>tatistical )ontrol of 'uality )haracteristics
0he principle of the control chart technique is that quality measurements obtained
from samples from production will vary due to chance causes or assignable causes.
2hen all observations are found within the limits the process is in control. !f an
observation is found outside the limit lines this variation is due to an assignable
cause.
.eneral ,ethod"
#. >elect the sample of size n at random from production.
%. )ompute an average for each set of sample measurements.
&. )ompute the appropriate standard deviation of the average used.
+. Prepare a graphic control chart (see $igure below by drawing a solid
horizontal line extending from the vertical quality scale at the average value. A
pair of dotted lines or bro-en lines (control limits* are drawn on either side of
this central line at a distance x times the standard deviation.
3. Plot the averages obtained from the sample average values. !f any of the
plotted points fall outside of the established control limits the process is out of
control.
Sta"ility
>tability of a drug or cosmetic can be defined as the ability of a particular formulation
in a specific container to remain within its physical chemical therapeutic and
toxicological specifications.
Assurances that the product in its container will be suitably stable for an anticipated
shelf life must come from an accumulation of data on the pac-age preparation. 0hese
stability data involve several parameters which when ta-en together form the
stability profile.
0he period of stability of a preparation is the time from the date of manufacture of the
formulation until its chemical or biological activity is not less than LGH of the
labelled potency. 0his in a sense is the shelf life of the product1 the duration of time
during which a preparation will remain physically chemically and biologically stable.
A good quality assurance program provides for a comprehensive stability testing plan.
!n accordance with .,P stability studies should be conducted on products in its
intended pac-aging container and determined by reliable meaningful and specific test
methods. ,onograph assays may be used if they are stability-indicating i.e. if they
accurately differentiate between intact drug molecules and their degradation products.
0hese tests are performed at certain intervals of time for the pac-ages stored at
specific temperature humidity air and light exposure and other storage conditions.
>tability considerations should include not only the specific compendial requirements
but also changes in physical appearance of the product that should warn users of the
product that its continued integrity is questionable. !mportant parameters for drug
products are loss of activity or potency of the active ingredient and amount of
degradation product. $or cosmetics retention of the physical qualities of a freshly
manufactured product is of prime importance. !nstability is gauged by its loss of
elegance.
Accelerated stability testing is used to predict product stability. $actors that accelerate
instability are"
#. 0emperature
%. <ight
&. ,oisture
+. .ravity
3. Agitation
4. !nversion
5. ,ethod of ,anufacture
Accelerating stress conditions are often used to intensify the degradation loss with
time. 0his enables the researcher to predict the shelf life of a product within a short
period of time. A suggestion that has been made by the ;> $@A that shows wide
acceptance of this method is as follows"
#. 0hree months acceptable data at &5-+G degrees )653H 8.C. can be
extrapolated to a two-year expiry date.
%. !f two-year controlled room temperature (8.0.* samples are available up to
two more years could be added to the expiry daye (i.e. four years total* by
storing the two-year 8.0. samples at &5 degrees )653H 8.C. for three months.
Assessment of product stability by using accelerated stress conditions can prove
beneficial provided careful consideration is given to the interpretation of results. !n all
cases accelerated stress conditions should be validated with regard to the correctness
of their predictions at normal storage conditions.
>helf life is calculated by using the Arrhenius equation if applicable or by the
regression line analysis by the method of least squares.
0he expiration date is a direct application and interpretation of the -nowledge gained
from stability testing. !t limits the period during which a preparation may be expected
to have its labelled potency provided it has been stored as directed in the labelling.
0he storage requirements must be observed throughout the distribution of the product
i.e. beyond the time it leaves the manufacturer up to and including the time it is
handled by the consumer. Although proper storage conditions are indicated in the
labelling it is recognized that control beyond the dispenser or seller is difficult. 2hen
the expiration date appears on the product labelling as month and year it is
understood that if refers to the last day of the indicated month.
Physical and )hemical >tability
Product stability evaluations have been separated into a study of the physical and
chemical stability of a formulation.
Physical stability is of importance to formulators for three primary reasons"
#. Appearance B a pharmaceutical product most specially a cosmetic is expected
to loo- fresh elegant and professional no matter how long it stands on the
shelf. A product that undergoes physical deterioration can easily cause a loss
of confidence in the formulation.
%. ;niformity B since most products are sold in multiple dose containers the
manufacturer must insure that the patient will receive the proper amount of the
ingredient in each dose. A cloudy solution or a bro-en emulsion can lead to a
non-uniform dosage pattern.
&. Availability B the active ingredient must be available to the patient throughout
the expected shelf life of the preparation. A brea-down in the physical system
can lead to non-availability of the medicament to the patient.
0he chemical causes of product deterioration have been classified into incompatibility
oxidation reduction hydrolysis racemisation and others. !n the latter category
decarboxylation deterioration of hydrogen peroxide and hypochlorites and the
formation of precipitates have been included.
7verages
0he problem of declining potency in an unstable preparation can be ameliorated by
the addition of an excess or overage of the active ingredient. 0his can be calculated
mathematically or by drawing a line parallel to the slope of loss of potency.
0he use of overages to extend shelf life is a particularly tempting solution except
perhaps in the case of extremely expensive substances. 2ith some drugs overage can
mean overdosage since there is no guarantee that administration will occur at the
appropriate period of declining potency. Cowever there is a need for the use of
overage in some pharmaceutical preparations under some conditions.
0he .eneral Assembly of the !nternational Pharmaceutical $ederation ($!P* at their
>eptember #L4+ meeting in Amsterdam defined overage as Dthe voluntary
introduction of a specific excess during the manufacture of pharmaceutical forms of
medicaments that are unstable by nature and difficult to stability in order to maintain
during their period of use an active content within the limits compatible with
therapeutic requirementsE.
!t was noted that overages are justifiable when"
#. 0he labile (unstable* active ingredients cannot possibly be standardized.
%. 0he overage allows an even equilibrium of the content of the active ingredient
within the acceptable limits.
&. 0he overage would not present a possibility of a therapeutic overdosage if the
preparation were used during the early part of the product/s shelf life.
+. 0he clinical studies show that overage is safe therapeutically.
3. 0he lower limit proposed for the decrease in strength applies only at the end of
the period of validity of unstable preparations.
0he proposed rules on overages for vitamins are"
#. A loss of not more than #GH of the labelled potency potency is considered
normal at the end of the term of validity of the product.
%. @ifferent galenical dosage forms is considered separately with a distinction
made between simple and complex preparations including a separate study of
preparations containing higher doses.
&. 0he added overage is limited to no more than &GH of the labelled potency of
the particular ingredient.
A #3H decrease in potency of antibiotic products is considered admissible for
unstable antibiotics but the following overages normally should not be exceeded" dry
dosage forms #3H1 fluids %GH1 ointment suppositories aerosols creams and foams
%3H.
7verage added to a preparation to compensate loss during manufacturing of the
preparation is called a manufacturing overage. A stability overage is the excess added
to a preparation to extend its shelf life.
3. #egulatory $spects of !rug and Cosmetics Quality Control
0o ensure the safety and purity of drugs and cosmetics made available to the public
the $ood @rug and )osmetic Act otherwise -nown as 8epublic Act 9o. &5%G was
finally passed by the )ongress in #L4&. 0his act declared that it is the policy of the
state to ensure safe and good quality supply of food drug and cosmetics and to
regulate the production sale and traffic of the same to protect the health of the people.
0o carry out the provisions of this act 0he $ood and @rug Administration in the
@epartment of Cealth was created.
>everal terms are defined under this act. 0hey are"
+rugs
#. Articles recognized in the ;nited >tates Pharmacopeia official
Comeopathic Pharmacopeia of the ;nited >tates of official 9ational
$ormulary or any supplement to any of them.
%. Articles intended for use in the diagnosis cure mitigation treatment
or prevention of disease in man or animals.
&. Articles (other than food* intended to affect the structure or any
function of the body of man or animals.
+. Articles intended for use of component of any articles specified in
clause (#* (%* and (&* but does not include devices or their
components parts or accessories.
+evices
!nstrument apparatus or contrivances including their components parts and
accessories intended"
#. $or use in the diagnosis cure mitigation treatment or prevention of
disease in man or animals or1
%. 0o affect the structure or any function of the body of man or animals.
&osmetics
#. Articles intended to be rubbed poured sprin-led or sprayed on
introduced into or otherwise applied to the human body or any part
thereof for cleansing beautifying promoting attractiveness or altering
the appearance.
%. Articles intended for use as a component of any such articles.
0o enforce the $ood @rug and )osmetics Act the ?$A@ upon presenting appropriate
credentials to the owner operator or agent in-charge is authorized"
#. 0o enter at reasonable hours any factory warehouse or establishment
in which drugs or cosmetics are manufactured processed pac-ed or
held before and after introduction into the mar-et1 or to enter any
vehicle being used transport or hold any drug or cosmetic for
commercial use.
%. 0o inspect in a reasonable manner such factory warehouse
establishment or vehicle and all pertinent equipment finished or
unfinished materials containers and labelling therein.
)urrent .ood ,anufacturing Practice
Among the regulatory guidelines promulgated by the $@A Administrative 7rder 9o.
%%G s. #L5+ on current good manufacturing practice ().,P* made the strongest
impact on the drug and cosmetic industry. 0his administrative order was patterned
after the guidelines developed in #L4& by the ;> $@A with the participation of the
drug companies. As the word implies current means dynamic changing as the
occasion arises viz. the need for technical improvement and for the greater
protection of the consumer.
!t should be emphasized at this point that good manufacturing practices is not the sole
responsibility of quality control but also of the production group. 0he quality control
function is to audit or inspect periodically the procedures equipment and facilities
employed by the various disciplines within the firm engaged in research
development production control purchasing distribution and sale of the product to
detect non-compliance to ).,P and to correct the said deviations.
).,P also permits the use of precision automatic mechanical or electronic
equipment in the production and control of drugs when adequate inspection and
chec-ing procedures are used to assure proper performance.
)ontamination
9on-compliance to ).,P could result in quality variation and worse in
contamination mix-ups and errors. !n extreme cases where the product is already in
the mar-et a recall is made.
A recall can involve millions of units of one product. Every hospital pharmacists or
doctor who has received a shipment may have to be notified since every unit must be
sent bac- to the plant. 8ecalls have the following disadvantages"
#. !t causes a lot of money lost.
%. ?ad publicity damages the good reputation of the company.
&. Carmful publicity can hurt sales.
+. 8ecalls have an adverse effect on the employees.
0he main objective of ).,P is to produce a product that is safe pure and effective.
0o understand the objective better the following terms are defined"
Safe( unable to cause damage free from danger
Pure( free from contamination
)ffective( producing the desired effect
0here are three types of contamination" Particulate cross and microbial
contamination. 0he sources and prevention of each type of contamination is tabulated
below.
)ontamination >ources Prevention
Particulate ;nclean clothing Always wear clean clothing
and uniform
)lothing that sheds lint or
particles
Avoid wearing clothes that
shed lint or particles
2ear head coverings gloves
mas-s facial hair covering
and protective gear
7bjects falling out of one/s
poc-et
@o not use breast poc-et
9ot following >7P/s $ollows >7P/s that relate to
proper cleaning of equipment
)ross-contamination Airborne particles within the
storage area and through the
ventilation system
Neep containers tightly closed
and in separate rooms
Pac-aging machines not
cleared out prior to a new
pac-aging run
$ollow specific >7P/s on
cleaning equipments and
proper labelling and pac-aging
procedures
!mproper dispensing of
components
$ollow >7P/s on correct
dispensing of components
!naccuracies and mix-ups in
record -eeping
$ollow >7P/s on record
-eeping
,icrobial People .ood personal hygiene
8eport all injuries and
illnesses
>7P/s not being followed $ollow >7P/s on handling
storage cleaning and
sterilization
)onduct quality control tests
Environment ,onitor microbial level of
environment
!t is clear that contamination mix-ups and error come from people and environment.
).,P provides specific guidelines to ensure production of quality products.
!t should be noted that firms manufacturing both penicillin (including certifiable
antibiotics* and non-penicillin products on the same premises or use the same
equipment create a condition or environment conducive to cross-contamination. 9on-
penicillin products are therefore tested for cross-contamination. >uch products should
not be mar-eted for human consumption if found to contain an amount of penicillin
equivalent to G.G3 unit or more of penicillin . per maximum single dose
recommended in the labelling of a drug intended for parenteral and oral use.
Personnel
0he qualified personnel are those with the proper education training and experience
to execute technological assignments.
Personnel having direct contact with drugs and cosmetics should have periodic health
chec-s and should be free from communicable disease and open lesions on the
exposed surface of the body. 0hey should have an awareness of the importance of
good personal hygiene wear clean outer garments and maintain a high degree of
personal cleanliness and conform to hygienic practices.
9o personnel should store personal belongings eat food drin- beverages or use
tobacco in any but prescribed areas.
$uildings
?uildings must be planned for easy cleaning maintenance and freedom from
congestion and traffic. ?uildings should provide for"
#. Adequate space for proper operation of manufacturing processing
pac-aging control and storage of products and their components.
%. Adequate lighting ventilation and when necessary for the intended
production and control purposes facilities for adequate air-pressure
microbiological dust screening filtering humidity and temperature
controls to minimize contamination of products and dissemination of
microorganisms from one area to another.
&. Adequate loc-er facilities and hot and cold washing facilities
including soap or detergent air drier or single serve towels and clean
toilet facilities near wor-ing areas.
+. Adequate supply of potable water under continuous positive pressure
in a plumbing system free of defects that could cause or contribute to
contamination. @rains should be of adequate size and where
connected directly to a sewer should be equipped with traps to prevent
bac-siphonage.
3. >uitable housing and space for the care of all laboratory animals.
4. >afe and sanitary disposal of sewage trash and other refuse within and
from the buildings and immediate premises.
)quipment
Equipment used for the manufacture processing pac-aging holding testing or
control of drugs and cosmetics should be maintained in a clean and an orderly
manner. 0hey should be of suitable design size construction and location in relation
to surroundings to facilitate maintenance and operation for its intended purposes. 0he
equipment should have the following properties"
#. !ts surface should not be reactive additive or absorptive so as to alter
the properties of the drug or cosmetic.
%. !t should prevent any substance required for its operation such as
lubricants or coolants to come in contact with the product.
&. !t should facilitate adjustment disassembly cleaning and maintenance
as necessary to assure the reliability of control procedures uniformity
of production and exclusion of the product from contaminants from
previous and current operations.
+. !t should be of suitable type size and accuracy for any intended
testing measuring mixing weighing or other processing or storage
operations.
Each piece of equipment should have its own logboo- and identification number.
Entries in the equipment logboo- must cover"
#. @ate when equipment was used
%. 9ame of product where equipment was used
&. @ate when it was cleaned
+. Person responsible for cleaning it
3. @ate when equipment was validated
4. 8esult of validation
)omplain 8ecords
!t is the consumer who performs the final test on the product. A dissatisfied consumer
may write or phone his complain and such complaint must be received by the
company. A decision is made whether or not an investigation is necessary. )omplaint
records must contain the following.
#. 9ame and address of the person complaining
%. Product name strength and control number
&. 9ature of the complaint
+. 8eply to the person complaining
3. 8esult of the investigation and follow-up action that was required
4. !f no investigation too- place the record must indicate"
i. 2hy it was considered unnecessary
ii. 0he name of the person responsible for that decision
Preservation" >amples and 8ecords
A reserve sample of components and finished products consisting of at least twice the
quantity necessary for all required test of identity quality purity and strength is set
aside for preservation. )omplete records related to the control use production
distribution and complaint are maintained to permit reconstruction of the history of
the product. !n general records and samples are retained for a period of five years.
Cowever local ?$A@ recommends the following retention periods"
&omponents
#. At least two years after the distribution of the last lot of product
incorporating the component has been completed or
%. 7ne year after the expiration date of this last lot incorporating the
components
Finis"ed Products
#. At least two years after lot distribution is completed or
%. 7ne year after the expiration date of the product
Records
#. @rugs" as above
%. )osmetics" at least three years after manufacture is completed.
Spectrometry
>pectrometry may be defined as methods of analysis which deals with the
measurement of spectra. !n pharmaceutical analysis the more common measurements
which are made of spectra and which are aspects of spectrometry are measurements of
the position (wavelength* in the electromagnetic spectrum where radiant energy has
interacted with a chemical species and measurement of transmitted fluorescent
reflected or emitted energy.
>pectrophotometry is a branch of spectrometry which embraces the measurement of
the absorption by chemical species of radiant energy of definite and narrow
wavelength approximating monochromatic radiation. ,onochromatic radiation is
radiation of a single wavelength. !n actual practice monochromatic radiation is
obtained by using prism or diffraction grating and consists of more than a single
wavelength. 0he length of a complete wave or cycle from pea- of the wave to the
pea- of the next is called wavelength. 0he units of wavelength measurement generally
used are the micrometer (um* which is equal to #G
-+
cm the nanometer (nm* which is
equal to #G
-5
cm and less frequently is the angstrom (A* which is equal to #G
-K
cm. 0he
ranges of the wavelength of radiant energy of importance in the practice of
spectrophotometry are" ;A (%%G-&KGnm* Aisible (&KG-5KGnm* near !8 (5KG-
&GGGnm* medium !8 (&.G-#3um* and far !8 (#3-&GGum*.
>pectrophotometer is a term used to designate the instruments which have a radiant
energy dispersing device such as prism or grating and the associated electronics which
permit the measurement of wavelength and radiant power. 0hese instruments may
either by manually operated or automatic recording instruments. ?oth type of
instruments have (#* a radiant power source (%* a radiant energy dispersing device
(&* a sample compartment and (+* the associated electronics which permit the
measurement of radiant power transmitted by the sample. ,anually operated
instruments are either direct reading or null-balance instruments. An example of null-
balance manually operated instrument is the ?ec-man @;-% spectrophotometer. 0his
instrument which covers the ;A visible and near !8 regions has continuous range
from #LG-#GGGnm isolating spectra region from G.3-#.3nm. An example of a direct-
reading manully operated spectrophotometer is the ?ausch and <omb >pectronic %G.
0his instrument has an operating range of %+G-L3Gnm.
$undamental <aws of >pectrophotometry
?eer/s <aw states that the power of a transmitted radiant beam decreases
exponentially as the concentration of the solution containing the absorbing chemical
species increases arithmetically. <ambert/s or ?ouguer/s <aw states that the power of
a transmitted radiant beam decreases exponentially as the thic-ness of the solution
containing the absorbing chemical species increases arithmetically.
?eer-<amber or ?eer-?ouguer/s <aw is a combination of the above law and relates
the power of the incident and the transmitted radiant beam to the thic-ness and
concentration of the solution containing the absorbing chemical species.
7fficial !dentification 0ests using >pectrometric Absorption ,ethods
>pectrometric absorption methods are frequently used as identification tests for
pharmaceutical substances. Although all three regions of the electromagnetic
spectrum are used the ;A and !8 regions are used most frequently. 7f the three
regions the medium region (&-#3um* is most often applied for identification purposes.
0he region from &-K um is referred to as the group frequency region because the
absorption pea-s which appear in this region are due to functional groups (carbonyl
amine hydroxyl etc.* formed in the organic compound. 0he K-#3 um region is -nown
as the fingerprint region because this region gives a spectrum of the molecule as a
whole.
#. $lame >pectroscopy
$lame >pectroscopy or $lame photometry is used in the assay of lithium carbonate.
0his technique is also used for the assay of other elements or metals such as
potassium sodium and calcium in blood and other biological samples. 0he flame
spectroscopic methods most frequently used for analysis are flame emission
spectrophotometry and atomic absorption spectrophotometry. 0his method deals with
the emission of energy of a particular wavelength when a diluted solution of a
metallic ion is sprayed into a colorless flame. 0he intensity of the emitted radiation is
determined by a suitable spectrophotometer and compared to a standard.
%. $luorometry
!n $luorometric Analysis the test solution absorbs some of the incident light photons
and observations is made of light emerging from the test solution at right angles to the
beam of incident light. >ome of the energy of the incident light photons absorbed by
the test solution is re-emitted as light photons of a longer wavelength. A substance
capable of performing this function is called a fluorescent substance and may be
quantitatively determined by the fluorometric method.
0his method has found most applications in the analysis of vitamins in particular in
the analysis of thiamine and riboflavin.
&. 0urbidimetry and +. 9ephelometry
0urbidimetry and 9ephelometry may be considered as branches of >pectrometry in
which transmitted or reflected light respectively is measured after radiant energy
passes through a turbid solution or suspension. >ince light transmittance is used as a
measure of turbidity instruments such as colorimetric and spectrophotometric may be
employed in turbidimetric measurements. 9ephelometry is based on the measurement
of the brightness of light reflected by a cloud of finely divided particles suspended in
a liquid. )olorimeters may also be used. 0urbidimetric methods are used in the
official assay of the majority of antibiotics calcium panthothenate vitamin ?#% and
other medicinal agents. !n these methods the activity of the biological agent is
determined by measuring the turbidity produced in a series of antibiotics dilutions
containing microbiological culture. 0he greater the turbidity (due to microbial
growth* the less is the activity of the antibiotic. 0urbidimetric tests are also applied to
certain official chemicals to ensure the absence of excessive amounts of chloride and
sulfate.
3. 9uclear ,agnetic 8esonance
!n 9uclear ,agnetic 8esonance (9,8* transitions between energy levels may be
generated by radiant energy if the molecules are first placed in a magnetic field.
9uclear transitions of the protons/ C for example can be made to occur in the
radiofrequency region when an organic compound is placed in a magnetic field of
about #+GGG grams. ;nder these conditions protons absorb radiant energy and pea-s
characteristic of the organic groups associated with the protons are observed. 0he
spectral data obtained provide useful information in qualitative and quantitative
studies of medicinal agents and other organic compounds. 0he basic instrumentation
needed to measure 9,8 spectra includes (#* a magnet with strong stable
homogenous field (%* a stable radiofrequency transmitter (&* a radio receiver and
detector (+* a coil of wire surrounding the sample which serves as a sensor (3* a cell
containing the sample (4* a method of sweeping through the spectrum and (5* a
recorder to display absorption pea-s.
Chromatography
)hromatography is a process in which a solution of a mixture containing inert
materials drug principles and impurities is separated into its components while
moving through a bed of fixed porous solid having different and reversible affinities
for the substance being separated. 0he separation of substances comes about because
each component of the mixture possesses a different mobility by reason of differences
in adsorption partition solubility vapor pressure molecular size or ionic charge. 0he
drug principles so separated on a porous solid may be removed from the solid by
means of a flowing solvent (elution* or by simple solvent extraction and assayed by
any suitable analytical method appropriate for the specific drug.
)hromatography is particularly useful as a means of separating and purifying
complex and closely related chemical substances which are difficult if not impossible
to separate by chemical methods based on differences in solubility and volatility.
)hromatographic techniques are more applicable in instances where small quantities
are involved in the assay or identification test.
0he principal objectives obtainable through the use of chromatography are"
#. 8esolution of mixtures into constituent parts
%. @etermination of homogeneity
&. )omparison of substances suspected to be identical
+. Purification
3. )oncentration of substance from dilute solutions
4. !dentification and control of technical products
5. 'uantitative separation from complex mixtures
K. !ndication of molecular structure
0he basic principles upon which chromatographic separation depends on" (#*
adsorption (%* partition (&* ion-exchange and (+* molecular exclusion. ?ased on the
techniques employed in holding the porous solid the procedure is called column
chromatography paper chromatography and thin layer chromatography.
)olumn )hromatography
0he simplest type of chromatographic column consists of a suction flas- and a
cylindrical glass tube constricted to one end. 0he material placed in the column to
absorb the drug is referred to as the adsorbent. Purified siliceous earth activated
alumina silica gel and calcium carbonate are examples of adsorbents commonly used.
0he adsorbent is uniformly and firmly pac-ed into the tube so that the solvents called
mobile phase will pass through it. 0he column adsorbent is treated with fresh portions
of components as each drug progresses down the column at a characteristic rate
resulting in a chromatogram. 2hen the separated column are colored or fluorescent
under ;A light the adsorbent column is forced intact from the tube and the fractions
are easily divided into segments with a -nife. 0he segments are then extracted with a
suitable solvent to obtain the pure compounds which may be analyzed by any
appropriate method applicable to the drug in question. 2hen the compounds are
colorless they may be visualized by spraying the column with a color-forming agent
and proceed as described above.
Another procedure commonly used to develop chromatograms is -nown as elution
chromatography. 0he column is washed with suitable solvents referred to as eluants
until each compound is successively obtained in the effluent liquid -nown as the
eluate. 0he separated drug in different fractions of the eluate may then be determined
by any appropriate method selected.
Adsorption )hromatography
Adsorption )hromatography brings about the separation of a mixture through a
competitive process in which the molecules of the mobile phase compete with the
analyte molecules for polar adsorption site on the adsorbent. 0he chromatographic
process is -nown as liquid-solid chromatography (<>)*. 0he mobile phase is a liquid.
Partition )hromatography
Partition )hromatography in which the molecule and stationary phases are liquids
referred to as liquid-liquid chromatography (<<)*.
Paper-Partition )hromatography
0he basic principle of separation in the partition chromatography is that of difference
in partition coefficients of substances between two immiscible liquids. 7ne of which
is a stationary phase supported on a solid adsorbent with the other mobile liquid phase
flowing through it. !f the solid adsorbent is filter paper (cellulose* the process is
referred to as paper-partition chromatography. !n this process the mobile phase an
organic solvent moves slowly over the stationary phase usually water is held in place
by the fibers of the filter paper. @ifferent substances move over the paper at different
rates depending upon the relative solubilities in the immiscible solvents resulting in a
separation by partition. 0he ratio of the distance travelled over the paper sheets by a
given compound to the distance travelled by the front of the mobile phase from the
point of application of the test substance is designated as the 8f value of the
compound.
8etention factor (8f* I distance solute moves6distance solvent moves
0he ratio between the distance travelled by a given compound and reference
substance constitutes the 8r value.
0here are three main methods for the preparation of paper-partition chromatograms.
0hese are" (#* descending chromatography which is accomplished by allowing the
mobile phase to flow downward on the paper strip (%* ascending chromatography in
which the mobile phase is allowed to rise upward on the paper by capillary attraction
and (&* radial chromatography in which the mobile phase moves out in concentric
circles from the center of a circular piece of paper.
8eversed-Phased )hromatography
8eversed-Phase )hromatography is based on partition phenomenon but the non-polar
solvent is fixed to the paper or solid column materials and acts as the stationary phase
and a polar solvent is used as a mobile phase. 0his method is especially useful in the
separation of water-insoluble substances such as steroids.
!on-Exchange )hromatography
,aterials used to pac- column for use in ion-exchange chromatography are either cat-
ionic or an-ionic exchange resins. 0hese substances are insoluble in water and
exchange cations or anions in solutions in the mobile phase which comes in contact
with the active sites of exchange resins.
,olecular Exclusion )hromatography
0his is also -nown as gel filtration or gel permeation chromatography and maybe
defined as a separation procedure in which differential migration of solute molecules
is based on molecular size.
0hin-<ayer )hromatography
0hin-layer )hromatography (0<)* involves the spotting of a sample of a mixture of
components at one end of an adsorbent-coated glass plate or other suitable support
followed by passage of solvent through the adsorbent for the purpose of separating
components of the sample. !t offers the advantages over column and paper
chromatography of (#* achieving separations in a relatively short time of about &G
minutes or less (%* accomplishing a complete analysis with as little as %G mg of
material (&* providing a complete separation of components in complex mixtures.
0he method is rapid sensitive and provides a high degree of resolution. >ilica gel .
and alumina are the best widely used adsorbents. $or colored components such as
dyes it is not necessary to spray a special color producing reagent in order to detect
the location of the spot. 7ne general reagent used when components are colorless for
the purpose of detecting organic is concentrated sulfuric acid. 0he organic
components char after chromatogram has been sprayed with sulfuric acid and heated.
Another method is the placing of the chromatogram in a close container holding a few
iodine crystals. 0he organic component reacts with iodine and form brown spots. A
third method is the use of ;A radiation for organic compounds the fluorescence. 8f
and 8r values are determined as in that of paper chromatography. $or quantitative
analysis spots may be scraped from the 0<) plate into a suitable solvent and
arranged by an appropriate method.
.as )hromatography
.as )hromatography (.)* uses as mobile phases an inert gas commonly -nown as
carrier gas. 0he stationary phase referred to as the liquid substrate consists of a high
boiling liquid which is used to coat granular particles made of siliceous earth or fire
tric-. 0he coated particles are placed in a tube made up of copper glass or stainless
steel. 0he tube containing the coated particles is called a column. 0his is mounted in a
constant temperature heating chamber of .) apparatus. 0he temperature of the
column is elevated to a constant value with the carrier gas passing through the column
at a constant rate. A small quantity of the liquid sample is injected into a heated
injection port using a needle and syringe. 0he components of the sample will
volatilize and are carried to the column by the carrier gas. 0he substances then
partition between the liquid substrate and gas phase and are transported at different
rates down the column. 2hen a component of the sample finally reaches the end of
the column it passes through a differential detector connected to a strip chart recoder.
A pea- is then recorded on the chart paper and the position of the pea- on the
chromatogram is characteristic of the component and is measured in terms of its
retention on the column. 8etention time is defined as the time required by an average
molecule of component to pass from the injection point through the column to the
detector. !t may be determined from the chromatogram by measuring the distance
from the point of injection A to pea- maximum ) and multiplying this value by the
reciprocal (minutes6millimetres* of the recorded speed. 8etention volume is defined
as the volume of carrier gas necessary to carry an average molecule of the component
from the point of injection to the detector. !t is found by multiplying the retention time
by the gas flow rate of the carrier gas. $or identification purposes the distance
measured in centimeters from the point of injection to the pea- maximum furnishes
sufficient retention data. 0he essential parts of the .) apparatus consist of inert gas
detector injection port column exit port and recorder.
Cigh Pressure <iquid )hromatography
>eparations using high-pressure liquid chromatography (CP<)* depend upon the
same basic processes of adsorption partition ion-exchange and molecular exclusion.
0he advantages of using CP<) as compared to other classical chromatographic
methods are (#* greater speed (%* precision accuracy and (&* ease of operation. 0he
column materials used in CP<) are unique structure and provides the basic for
separations. )olumn materials may be divided into two categories" porous and
superficially porous. 0he second category is the most widely used.
A wide variety of aqueous and non-aqueous solvents may be used as the mobile
phase. 0he mobile phase is generally pumped through the column under pressure.
;A absorbance and refractive index detectors are frequently used CP<). 0his type of
detector monitors the column effluent continuously as it passes through the microcell.
Potentiometry
Potentiometry may be defined as a branch of electrochemisty which deals with the
study and measurement of electrode potentials.
,easurement of electrode potentials find wide application in pharmaceutical sciences
especially in potentiometric titrations and related measurements.
0his branch of electrochemisty finds application in potentiometric titrations. $or
many years analysts have depended on their ability to perceive indicator color
changes as the endpoint in titrimetric procedures. >everal factors influence the
accuracy of such indicator titrations including (#* lightning conditions (%* color or
turbidity of the solution (&* color blindness (+* fatigue of the operator. $or many
assay a suitable indicator is not available so other end-point technique li-e
potentiometric method must be used.
Potentiometric )onsideration of pC
2hen hydrogen ion concentration is determined with a laboratory device as
potentiometer of pC meter equipped with electrodes one actually measures the
activity of the hydrogen ion rather than the concentration.
0he glass electrode is the most popular of all indicator electrodes for pC
determination because of the high resistance of the glass. 0he quinhydrone electrode
is the most least expensive of the hydrogen ion sensitive electrodes.
$or the purpose of measuring pC of pharmaceutical solutions and products a properly
standardized pC meter equipped with glass and calomel electrodes may be used.
Validation
Aalidation has stimulated a good deal of interest and discussion during the recent
years. !t is not a new concept in science and technology for it has been around for a
long time B perhaps called by different names. 2ith the advent of good manufacturing
practices the pharmaceutical and cosmetic industries were made aware that
parameters processes test methods and products must be challenged in a more
organized manner. 2ith this new insight the exercise became more meaningful for
now the consuming public can be assured with full confidence that the final product
has met its design criteria uniformly and consistently.
Aalidation is defined as the verification by data and analysis that the design
objectives of a given facility system apparatus or procedures are reliably fulfilled in
routine operation.
A validated product is one that has been shown by appropriate scientific means to be
uniform within a lot consistent between lots and meeting design criteria within
defined limits.
Aalidated involves the following important steps"
#. )hoosing the desired attributes of the products.
%. @etermining specifications for those attributes.
&. >electing appropriate processes and equipment.
+. ,onitoring and testing processes equipment and personnel while in operation.
3. Examining test procedures themselves to ensure their accuracy and reliability.
?y examining the preceeding steps one can visualize the scope of validation wor- to
embrace"
#. Process validation
%. Assay validation
&. 'ualification of manufacturing equipments
+. Aalidation of existing products by statistical evaluation
3. )leaning validation
Process Aalidation
According to ).,P/s control procedures should be established to monitor output
and to validate performance of the manufacturing processes that may be responsible
for causing variability in the characteristics of in-process material and the drug
product. 0he importance of process validation was emphasized as problems with
certain products (often involving sterility* developed. !t is evident that an examination
of finished samples was not enough.
Process validation is the gathering and documenting of sufficient evidence to give
reasonable assurance that the process under review does what is purports and is
expected to do.
$or instance in tablet manufacturing the processes selected and evaluated are"
#. ?lending operations
a. 7ptimal blending time
b. 7bjective of blending B addition of lubricant or active ingredient
c. 0ime when mixing does occur
d. Physical characteristics of powder blend
e. Effect of load on blending
f. !nfluence of process on dissolution
%. 2et granulation
a. Evaluation of binder
b. )oncentration required versus solubility in granulating solution
&. Evaluation of mixed granulation
a. 7ptimal density for powder flow
b. Cow much granulating solution is required to effect a good granulation
c. )ompactibility of wet granulation
d. 7ptimal mixing time
e. Effects of granulation on dissolution or other physical6chemical
properties
+. Evaluation of the drying step and dried granulation
a. 7ptimal moisture content
b. Particle size distribution
c. Any requirement for millingO
d. 2hat conditions are required for optimal dryingO
3. Evaluation of milling the granulation
a. ,oisture pic--up vs. H8C
b. )ompression qualities (without lubricant*
c. .ranule disintegration characteristics
4. 0ablet )ompression
a. )ompression force required
b. Ejection characteristics
c. @issolution
d. Powder flow from hopper
e. Powder behavior (separation etc.*
f. Powder moisture
5. 0ablet coating
a. Purpose of coating (appearance mas- odor etc.*
b. >olubility of core/s ingredients in coating solution
c. Effect of sealing on tablet core
d. !ntegrity of seal coat
e. @rying conditions
f. Effect of coating on dissolution or disintegration
0he essential tools that will generate necessary information not only of the final
product but also about the process are three-fold"
#. Aalid sampling
%. Accurate and precise test methodologies
&. >tatistical interpretation of data
Assay Aalidation
Assay validation is a requirement in ).,P. >ection ## of Administrative 7rder 9o.
%GG s. #L5+ states that Dlaboratory controls shall include the establishment of
scientifically sound and appropriate specifications standards and test procedures to
assure that components drug preparations in the course of processing and finished
products conform to appropriate standards of identity strength quality and purityE.
Assay validation is important for the following reasons"
#. !t can lead the way to a scientifically sound test procedure and is therefore
fundamental to the quality control release function.
%. !t is important in the evaluation of stability and for the establishment of
expiration dates. 0he stability profile generated should reflect the true picture
of product degradation under different -inds of stress such as light heat and
humidity. 0he factors which contribute to the degradation of the product must
be measured by precise and accurate methods. 0he use of validated assay
procedures can give us the assurance that the shelf life so obtained is correct.
&. 0he need for validated control procedures for monitoring output and process
variability cannot be over emphasized. 7bviously process validation loses its
value when results are obtained by employing doubtful assay methods.
+. 7nce the validity of assay methods is proven the validated assay procedures
can be used for routine monitoring of laboratory accuracy and
training6evaluation of new analysts. !n fact each new analyst should be
validated for each procedure he performs.
Assay validation is a method that provides an estimate of assay accuracy and
precision. Precision or reproducibility is a characteristic that refers to the agreement
among repeated measurements. !t is a measure of reproducibility of data within a
series of results. Accuracy is a characteristic that refers to the closeness of such
measurements to the DtrueE magnitude concerned.
!n other words accuracy shows how closely a method measures what it is supposed to
measure while precision shows only how closely many measurements agree. An
accurate method of measurement is both precise and unbiased. !t should be noted that
a validated assay procedure should measure only what it intends to measure
otherwise bias enters into the picture.
!n the figure below the diagram illustrates bias precision and accuracy. 0he shots on
targets (#* and (%* are biased" in both cases the shots cluster away from the bull/s eye.
0he clusters on targets (&* and (+* are both unbiased" the center of each cluster is on
the bull1s eye. 0he shots on targets (#* and (&* are precise" both set are bunched
together. 0he shots on target (%* and (+* are widely scattered hence imprecise. 7nly
the shots on target (&* are accurate i.e. precise and unbiased.
MMMMMMMMMMMMMMMMMMMMMMMM$!.;8E
!n the course of an analysis duplicate values are obtained and should agree closely.
0he best estimate is the average value.
0o challenge the assay procedure the following steps are done"
#. Preparation of samples
%. Analysis of samples
&. )alculation of percent relative deviation
+. )alculation of percent relative error
3. @isposition
4. @ocumentation
Preparation of >amples
Prepare a total of 4 validation samples (or & pairs for duplicate determination* as
follows"
#. Prepare two samples to contain the nominal product formula quantity of the
substance to be assayed.
%. Prepare two samples to contain an amount equal to the nominal product
formula minus #.3 times the difference between the nominal formula quantity
and the lower assay specification limit.
&. Prepare two samples to contain an amount equal to the nominal product
formula plus #.3 times the difference between the nominal formula quantity
and the upper assay specification limit.
0he percent of formula quantity of active drug corresponding to specification is
shown on table below.
MMMMMMMMMMMMMMMMMMMMMMMMM0A?<E
!f the monograph limits are LG and #%GH the validation samples should contain the
active drug at K3H #GGH and #&GH of label claim. 0hese assay values need not be
precisely K3H #GGH and #&GH but they must be accurately -nown.
0he validation samples apart from the active ingredient to be assayed are composed
of the other formula components in the prescribed formula composition. 0hese
preparations should be made by an experienced analyst and analyzed by another
experienced analyst on a coded DblindE basis.
$or the best results a placebo of suitable quantity is prepared by blending the active
ingredient(s* into the inactive base to give an amount suitable for several assays. !f the
active ingredient is of a very small amount it is first mixed well with a small portion
of the placebo before final blending. $or liquid preparations a spi-ing solution is
usually prepared. 0his is measured accurately by pipet. 0he placebo is used for
diluting the sample to volume.
Analysis
0wo different analysts should carry out a single determination on each of the
three drug levels by the assay method prescribed for the product. 0he analysts should
carry out the assay validation analysis on different days. 8esults of the analyses
should be reported as percent of formula quantity.
)alculation
0he upper half of the table in attachment A >7P 9o. #.GG Assay Aalidation
gives the symbols used for the data presented in the lower half of the table. !n the
example given three levels of samples have been prepared. >ince the assay
specification is LGH to ##GH the active ingredients incorporated into the sample were
K3H #GGH and ##3H of the claim.
0he symbol : stands for the average of the two determinations per drug level.
Attachment ? shows the formula for the computations required. 0he percentage
relative deviation (@* is a measure of the precision of the method. !n using the
formula ignore the negative sign from subtraction. 0he percentage relative error (E*
is a measure of the accuracy of the method. Cere any negative sign is ta-en into
account during the calculation.
)riteria for Assay >uitability
4. !issolution