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BIG PICTURE
Week 1-3: Unit Learning Outcomes (ULO): At the end of the unit, you are expected to:
Big Picture in Focus
ULO 1. Demonstrate knowledge of the concepts involved in pharmaceutical
quantitative analysis
Metalanguage
The most essential terms and concepts below are defined, for you to have a better
understanding of this section in the course. You are advised to frequently refer to these
definitions to help you understand the succeeding topics.
1. Quality - totality of characteristics or features of a product that bears on its capacity to
satisfy stated or implied needs
2. Quality Control - part of Good Manufacturing Practice (GMP) concerned with
sampling, specifications, testing, organization, documentation and release procedures
3. Quality Assurance - sum total of the organized arrangements made with the object
of ensuring that products will be consistently of the quality required for their intended
use
4. ISO (International Organization for Standardization) - This organization
develops the standards, and it does in order to certify businesses or organizations.
5. Quality Control Chart - a graphical representation of whether a firm's products or
processes are meeting their intended specifications
6. Accuracy - Refers to closeness of measurements to true value
7. Precision - a characteristic that refers to the agreement among repeated
measurements
8. Sampling plan - it is the process of removing appropriate # of items from a population
9. Defect - An undesirable characteristics of a product and therefore its failure to conform
to specifications
10. Volumetric Analysis - The determination of the volume of a solution of known
concentration required to react with a given amount of the substance to be analyzed
(ex. Titration)
11. Titrimetric methods- an analytical method in which the volume of a solution of known
concentration consumed during an analysis is taken as a measure of the amount of
active constituent in a sample analyzed
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ESSENTIAL KNOWLEDGE
INTRODUCTION
Several definitions of quality
• “Quality is the degree to which a specific product conforms to a design or specification.”
(Gilmore, 1974)
• “Quality is the totality of features and characteristics of a product or service that bears
on its ability to satisfy stated or implied needs.” (Johnson and Winchell, 1989)
• “Quality is fitness for use.” (Juran, 1974)
• “Quality is defined by the customer; customers want products and services that,
throughout their lives, meet customers’ needs and expectations at a cost that
represents value.” (Ford, 1991)
• “Even though quality cannot be defined, you know what it is.” (Pirsig, 1974)
• The concept of total quality control refers to the process of striving to produce a perfect
product by a series of measures requiring an organized effort by the entire company
to prevent or eliminate errors at every stage in production. Although the responsibility
of assuring product quality belongs principally to quality assurance personnel, it
involves many departments and disciplines within a company.
Quality control can be defined broadly as the day-to –day control of quality within a company,
a department staffed with scientists and technicians responsible for the acceptance or
rejection of incoming raw materials and packaging components, in-process tests and
inspections, to assure that systems are being controlled and monitored finally, for the approval
or rejection of completed dosage forms.
Quality control, therefore, includes not only the analytical testing of the finished product, but
also the assessment of all operations beginning with the receipt of raw materials and
continuing throughout the production and packaging operations, finished product testing,
documentation, surveillance and distribution.
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The potential benefits derived from a quality control system are as follows:
1. The system minimizes or eliminates the risk of marketing unsafe products
2. It guarantees conformance to regulatory requirements
3. It guarantees product efficacy
4. It reduces operating costs
5. It reduces operating losses
6. It produces higher employee morale
7. It motivates the pharmaceutical/ medical professions to sell or prescribe the product
Note :
•
•
•
in recent years, the Quality Assurance used to describe the overall organizational
body designed to assure product quality.
Quality Control is limited to that function for on line or in process testing.
The use of these titles is a matter of choice
Quality Assurance and Quality Control
• Develop and follows standard operating procedures directed toward assuring the
quality, safety, purity and effectiveness of drug products
FDA
•
has issued a primary regulation to the industry entitled current Good Manufacturing
Practice (cGMP or GMP)- AO # 220 , s. 1974
Functions and Responsibilities
Quality Assurance
• Establishes systems for ensuring the quality of the product
• Final authority for product acceptance/ release or rejection
• Report to chief executive or president
• Quality monitoring or audit functions (adequate systems, facilities and written
procedures)
Quality Control
• Responsible for the day to day control of quality w/in a company
• Staffed w/ scientists and technicians, responsible for sampling and analytical testing
for incoming raw materials and inspection of packaging components including labeling
• Conduct in- process testing
• Inspect operations for compliance
• Conduct tests on finished dosage forms
• Monitors product quality, testing product complaint samples, evaluating product quality
• Perform environmental monitoring
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In environmental monitoring:
Class 100
1.Airborne Particulate Cleanliness Classes in Cleanrooms and Clean Zones
2. are maintained in areas where parenteral products are filled into clean, sterile container
3. an area that can be controlled to contain fewer than 100 particles, 0.5 µm and larger per
cubic foot of air
Choudhary, A. (2021). An Overview of ISO 14644 Clean Room Classification. Retrieved 30
January 2021, from https://www.pharmaguideline.com/2012/07/overview-of-iso-14644-cleanroom.html
Discover ISO
ISO's name
• Because "International Organization for Standardization" would have different
acronyms in different languages ("IOS" in English, "OIN" in French for Organisation
internationale de normalisation), its founders decided to give it also a short, all-purpose
name. They chose "ISO", derived from the Greek isos, meaning "equal". Whatever
the country, whatever the language, the short form of the organization's name is always
ISO.
Why standards matter?
Standards make an enormous and positive contribution to most aspects of our lives.
Standards ensure desirable characteristics of products and services such as quality,
environmental friendliness, safety, reliability, efficiency and interchangeability - and at an
economical cost.
What standards do?
ISO standards:
• make the development, manufacturing and supply of products and services more
efficient, safer and cleaner
• facilitate trade between countries and
• provide governments with a technical base for health, safety and environmental
legislation, and conformity assessment
• share technological advances and good management practice
• disseminate innovation
• safeguard consumers, and users in general, of products and services
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Organization of Quality Control
Quality Control Manager
- Materials Inspection Section
- Analytical Laboratory
- Biological Testing Laboratory
- Specifications and Analytical development
- Quality Coordinating Office
A. Materials Inspection Section:
1. To sample and examine all raw materials received
2. Conduct physical tests on:
a. all shipments of packaging materials
b. b. all manufacturing, filling and packaging operations
3. Maintain periodic examination on the quality of inventories throughout all phases of
storage, shipping and distribution
4. Perform audit which is independent of the work done by product personnel
Note: inspection stations are placed in the area of operation, warehouse, manufacturing and
packaging areas
B. Analytical laboratory:
1. For testing and approving raw materials, work in-process and finished product
2. To perform chemical and physical analysis / tests and specifications maybe found in
several sources as USP, NF, BP and Merck Index
C. Biological Testing Laboratory:
1. Staff must be well trained and experience in both simple and complex microbiogical
procedures
2. To perform and evaluate microbiological and pharmacological assays, sterility,
pyrogen and bacteriological tests, irritation, safety or acute toxicity tests
3. Conduct environmental monitoring
• Sterile conditions should be provided for areas where biological tests are
conducted
• Noise should be precluded from areas where animals are used
D. Specifications and Analytical Development:
1. Coordinate w/ research, product development, production, sales and management
towards improvements of product
2. Establish specifications for raw and packaging materials
3. Validate existing and tentative procedures of testing
4. Establish specifications based on validation procedures
5. Develop new assay methods for in-house use
6. Develop and improve specifications for quality characteristics of the final product being
manufactured
E. Quality Coordination Office:
1. Documentation is its main responsibility
2. Maintain and store records that represent the history of the batch from start to finish.
(batch and master formula records, raw materials analytical record, printed and
packaging material inspection reports
and retention files)
3. To furnish data that will aid in analyzing product performance in the market (
documents are: stability studies and returned goods reports)
4. Investigate customer complaints
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5. Maintain and develop SOP’s
Sources
Example
1. MATERIALS
a. Variations between suppliers of same substance
b. Variations between batches of same supplier
c. Variation within a batch
2. MACHINES
a. Variation of equipment for the same process
b. Difference in adjustment of equipment
c. Aging and improper care
3. METHODS
a. Inexact and inadequate procedures
b. Negligence by chance
4. MEN
a. Inadequate training and understanding
b. Improper working conditions
c. Dishonesty and fatigue
Sources of Quality Variations
DEFECTS
• An undesirable characteristics of a product and therefore its failure to conform to
specifications
DEFECTS can be classified as:
1. According to measurability
a) Variable defect – can be measured directly by instruments (length, weight,
height, thickness, concentration, pH, etc.)
b) Attribute defect – cannot be measured directly by instruments (odor, color,
clarity, cleanliness, taste, etc.)
2. According to seriousness or gravity
a) Critical defect
• Endanger life or property and may render product nonfunctional
• Ex. Absence of warning in a label disintegration time of one hour for analgesic
b) Major defect
• Affect the function of objects and may render product useless
• Ex. Presence of a crack in a bottle
c) Minor defect
• Does not endanger life nor will it affect the function
• Ex. Deviation of the color of the label from color standards
3. According to nature
a) Ocular defect
• Visible
• Ex. Foreign particulate contamination
b) Internal defect
• Not seen but present
• Ex. Subpotent drug product
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c) Performance defect
• Defect in function
• Ex. Suppository that does not melt at body temp.
QUALITY FUNCTIONS
- Control functions may vary in companies but basically these functions can be classified into
four categories: analysis, monitor, record review and release and audit function
Analysis Functions:
• Tests are made not only on the raw materials and packaging components but also on
the bulk product during processing and after packaging prior to release to market
• Selected lots are subjected to shelf life to confirm expiration period
Monitor Functions:
• To sample and examine materials while they are being processed
• Environmental monitoring – to control the microbial and particular matter content of
environmental air
Record Review and Release Functions:
• Carefully reviewing the batch record for the lot and assuring that all necessary records
are present, complete.
Audit Function:
• The production and quality control of quality products are governed by standard
operating procedures (SOP) which embrace the legal requirements set forth by the
cGMP
Analyst in the Laboratory
Success as an analyst:
1. Manipulative skill acquired by experience
2. Ability to follow directions under supervision of skilled analyst
3. Has fundamental knowledge of theory
4. Practical ability in the application of analytical methods
5. Skill of technique, patience, neatness and accuracy
6. Must not only use common sense in the laboratory but think throughout each step of
the procedure
Accuracy and honesty
• All quantitative work be performed without even a slight loss of material or gain of
extraneous matter
• At least 2 determinations of any analytical value are required (trials and replicates)
Agreement in analytical determinations:
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Economy of Time:
1. Keep the working area clean
2. Clean all apparatus immediately after using
3. Label all solutions
4. Keep 2 or more operations going at one time
5. Utilize all time between operations in making calculations and writing up experiments
Reagents:
• Must be pure
• Conform to USP/NF requirement
• AR grade
Grades of Chemicals:
• Reagent ACS - This designates a high quality chemical for laboratory use. The
abbreviation "A.C.S.," means the chemical meets the specifications of the American
Chemical Society.
• Guaranteed Reagent (GR) - Suitable for use in analytical chemistry, products meet or
exceed American Chemical Society (ACS) requirements where applicable.
• Analytical Reagent (AR) / Reagent Grade – highly purified chemicals
• Primary Standard – use for standardization of solution to a very high degree of
accuracy
• Purified - Defines chemicals of good quality where there are no official standards. This
grade is usually limited to inorganic chemicals.
• Lab Grade - A line of solvents suitable for histology methods and general laboratory
applications.
• USP - Chemicals manufactured under current Good Manufacturing Practices and
which meet the requirements of the US Pharmacopeia.
• NF - Chemicals that meet the requirements of the National Formulary.
• Technical - A grade suitable for general industrial use; superficial purification, seldom
use in analytical work
TQM – Total Quality Management
• TQM functions on the premise that the quality of products and processes is the
responsibility of everyone who is involved with the creation or consumption of the
products or services offered by an organization.
• TQM requires the involvement of management, workforce, suppliers, and customers,
in order to meet or exceed customer expectations.
Documentation
• “if it wasn’t documented, it wasn’t done” describes the linkage between written
records of action taken and the quality operation
• Found in the product-development phase, actual manufacture and testing
• R & D reports, validation reports
• Ex. Master Production Batch Record (MPBR); Production Batch Record (PBR)
Contemporary Issues:
• The pace of change in pharmaceutical industry continues unabated
• Increase emphasis on analytical chemistry as it relates to entire drug discovery
• Computer modeling of drug compounds
• Sophisticated instrumental method of analysis
• Replacement of rabbit pyrogen test w/ bacterial endotoxin (LAL) method
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SAMPLING AND SAMPLING PLAN
A basic quality function is that of deciding whether the product conforms to specifications
This function is called “acceptance”
To arrive at decision, the primary step is inspection (comparing product against
specifications)
Advantages of sampling:
The three main advantages of sampling are that the cost is lower, data collection is
faster, and since the data set is smaller it is possible to ensure homogeneity and to
improve the accuracy and quality of the data.
Sampling is the process of removing appropriate # of items from a population
Sample is a finite # of objects selected from a population
Representatives of materials to be sampled are:
1. Raw materials
2. Packaging / printed materials
3. Intermediate products
4. Final products
• Sampling inspection is used in lieu of 100% inspection for ff. reasons:
1. The cost of 100% inspection is prohibitive
2. Tiring
3. A statistical sampling plan gives better quality assurance than 100% inspection
Inspection Methods:
• Single sampling – a decision is reached after only one sampling
• Double sampling –the result obtained after second sampling
• Triple sampling
• Multiple
• n = sample size
• c = acceptance # or maximum # of defectives allowed
• batch = specific amount produced in a unit time
• lot = a batch or any portion of a batch
Ex. of Lot/Batch Numbering System:
Year Code (Digit 1) is coded to the following sequence:
• T is used for 2005
• U is used for 2006
• V is used for 2007
• W is used for 2008
• X is used for 2009
• Y is used for 2010
Month Code (Digit 2) is coded to the following sequence:
• A = January
• B = February
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•
•
•
•
•
•
•
•
•
•
C = March
D = April
E = May
F = June
G = July
H = August
I = September
J = October
K = November
L = December
Day of Month (Digits 3 and 4) are coded from 01-31
Dow Geographic Location (Digits 5 and 6) are coded by:
• 01 = Dow Chemical USA
• 02 = Dow Chemical Canada
• Facility Location (Digits 7 and 8)
• XX = North American Facility Location
• Specific Tank Code Number (Digits 9 and 10)
• YY = Specific Tank Code Number
Example A: UJ1901XXYY (2006, October 19: Dow Chemical USA)
•
•
•
•
•
•
U = 2006
J = October
19 = 19th Day
01 = Dow Chemical USA
XX = North American Facility Location
YY = Specific Tank Code Number
Sampling Plan:
• In sampling, one must consider the laws of probability
• Risk involved: risk of error
producer’s risk (∞) – probability of rejecting good batch
consumers ‘s risk (β) – probability of accepting
bad batch
• A sampling plan is a definite working rule regarding size and frequency of sample
and the basis for acceptance or rejection
• It requires that 3 numbers be specified:
N = # of items in the batch/lot
n = # of items drawn from the batch/lot
c = acceptance number
Ex:
N = 50
n=5
c=0
“ take a random sample of 5 from a lot of 50. if the sample contains more than 0 defect,
reject the lot: otherwise, accept the lot”
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Types of Sampling Plan:
A. Square Root System - n = √N + 1
B. Government Sampling Plan - Consists of master table first developed in 1942 by
engineers, then developed and adopted by US Department of Defense thus they are
now known as MILITARY STANDARDS
AQL – acceptable quality level is the maximum % defective or the maximum # of
defects per hundred units.
Sample Size Code Letter
MIL-STD-105D (ABC Standard)
Sample size code letters – determine the sample size
Unless otherwise specified, Inspection Level II should be used
Problems:
1. Twenty eight drums of muriatic acid were received in the warehouse
a. If the shipment has the same batch # in all drums, how many drums should be
sampled using:
square root and military standards
b. If the shipment consists of 5 drums w/ one batch number and 23 drums w/ another batch
number, give the sample sizes using square root and military standards
MATERIAL CONTROL
As each batch of incoming material is received, it is given a receiving number or the
receiving tally report (RTR)
A.Raw Materials – ingredients intended for use in the manufacture are handled in the
following manner:
1. Reception - RTR
- examined visually for any damage
- adequate # of samples are taken (sampling plan)
2. Quarantine
• “HOLD” sticker until QC accepts or rejects
• Sample submitted to lab (ID test, potency, etc)
• If results meet the specs, decision stickers are pasted
• The decision stickers are placed on top of quarantine sticker or the quarantine sticker
is first removed before decision sticker is pasted
• No 2 stickers of different disposition must be present in the container
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3. Rejected – placed in rejected materials area
4. Approved – brought to approved materials area
B. Stickers
• To avoid mix-ups
• Different colors must be assigned
yellow for quarantine
green for approved
red for rejected
C. Printed and Packaging Materials
2 types:
1. Primary packaging components – direct contact w/ the product (ex. Capsules,
bottles, caps, seals)
2. Secondary – does not come in contact w/ the product; accessory to primary ( ex.
Labels, inserts, cartoons)
D. Labeling Control
E. Containers
F. Reassay Dates
• The monitoring of the quality of raw materials during storage is important
• Periodic testing is done to revalidate the mat’l
• The date of retest is known as reassay date
• Based on the stability of raw mat’l, the reassay dates assigned are:
monthly or prior to use – for highly unstable mat’l
6 months – vitamins, flavors
12 months – active ingredient, dyes
24 months – active ingr., excipients
Some of retest requirements:
1. Appearance
2. pH
3. ID
4. Moisture
5. Assay
6. RI
7. Melting range
8. Microbial test
9. Etc.
STATISTICAL QUALITY CONTROL
Is the monitoring quality by the application of statistical methods in all stages of
production
Consists of proper sampling, determining quality variation of the sample
Make use of CONTROL CHARTS, a tool w/c may influence decisions related to the
functions of specifications, production or inspection
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Statistical process control involves establishing and monitoring standards, making
measurements, and taking corrective action as a product or service is being
produced
Samples of process output are examined
If they fall outside certain specific ranges, the process is stopped and the assignable
cause is located and removed
A control chart is a graphical presentation of data over time and shows upper and
lower limits of the process we want to control
A.QC Charts
2 types:
1. attribute chart – makes use of discreet data classifying the # of items failing (ex. P chart)
2. variable chart – use actual records of numerical measurement on a full continuous scale
such as meter, grams,
liter (ex. Ẋ , R chart)
P-CHART
is the most versatile and popular control chart. To use P-CHART, quality inspectors
classify sample items into two groups: good or bad. This can mean defective or
nondefective, conforming or nonconforming to specifications, acceptable or
unacceptable, or other definitions in which there are only two categories of results.
To construct a control chart for fraction defective (p):
1. Record the number inspected (n) and the number of defectives found (d)
p=d
n
Control Charts consist of:
1. Control solid line – target value of the historical process average
2. 2 horizontally parallel lines on either side of the solid line – indicates the limit
a. upper line – is the upper control limit (UCL) w/c is normally 3 standard deviations
above the center line
b. lower line – is the lower control limit (LCL) w/c is 3 standard deviation below the
center line
B. Statistical control of Quality Characteristics
General Method:
1. Select the sample of size n at random from production
2. Compute an average for each set of sample measurements
3. Compute standard deviation
4. Prepare graphic control chart
5. Plot the average obtained from sample average values. If any of the plotted points
fall outside of the established control limits, the process is out of control
Calculating the mean, average deviation, standard deviation and range:
Mean
It is the average of a series of results. The mean of a finite number of measurements,
xl, x2, x3, x4,........, xn, is commonly represented as x. It may be calculated by taking
the average of individual results as
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Average deviation or mean deviation
It is the average of the differences between the individual results and the mean. It is
regarded as a measure of variability.
In the case of a small number of observations the average deviation is found to be
not quite significant statistically.
Standard Deviation
It shows how much variation or "dispersion" there is from the average (mean, or
expected value).
A low standard deviation indicates that the data points tend to be very close to the
mean,
whereas high standard deviation indicates that the data points are spread out over a
large range of values.
Relative standard deviation or coefficient of variation = dividing the standard deviation by
mean and multiply by 100
Range (R) = difference between largest and smallest results
Ex. Normality of NaOH
0.2140
0.2142
0.2152
0.2146
Get the mean, average deviation, relative average deviation, standard deviation (SD),
relative standard deviation (RSD)
OUTLIER
In statistics, an outlier is an observation that is numerically distant from the rest of the
data.
An outlying observation, or outlier, is one that appears to deviate markedly from other
members of the sample in which it occurs.
VALIDATION
Verification, by data and analysis, that the design objectives of a given facility,
system, system, apparatus or procedures are reliably fulfilled in routine operation
A. Process Validation
• Gathering and documenting of sufficient evidence to give reasonable assurance that
the process under review does what is expected to do.
• Ex. Dissolution
blending time
temperature
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B. Assay Validation
• Appropriate specification, standards and test procedures to assure that components,
finish product conform to standards of identity, strength, quality and purity
• Provides an estimate of assay accuracy and precision
Precision or reproducibility
• Is a characteristic that refers to the agreement among repeated measurements
• Reproducibility of data
• Precise results are not necessarily accurate
Accuracy
Refers to closeness of measurements to true value
the difference between the mean and the true value is known as the ABSOLUTE
ERROR
the RELATIVE ERROR is found by dividing the absolute error by the true value and
multiplied by 100
A sample known to contain 60.52% chlorine as chloride was assayed the following
results were obtained:
57.63, 57.68, 57.66 and 57.63 percentages.
Calculate the relative and absolute error committed in the assay.
A sample known to be 98.50% pure yielded results on analysis in duplicate of
98.30% and 98.12% respectively. What is the error in ppt of each determination.
In the course of analysis, duplicate values are obtained and should agree closely. The best
estimate is the average value.
A batch of paracetamol tablets are stated to contain 500 mg of paracetamol per tablet,
presumed that 100% of the stated content is the correct answer. Make a diagrammatic
representation of accuracy and precision of the following percentages of stated content:
Factors Giving Rise To Imprecision and Inaccuracy in the Assay:
Incorrect weighing and transfer of analytes and standards
Inefficient extraction of the analyte from a matrix
Incorrect use of pipet, buret or vol. flask
Improperly calibrated instrument
Failure to use analytical blank
Selection of assay conditions that cause degradation of the analyte
Failure to allow for or to remove interference by excipients in the measurement of the
analyte
C. Validation of Equipment – calibration to maintain efficiency
Ex. balance, thermometer
D. Validation of Existing Products
Ex. Potency, content uniformity
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E. Cleaning Validation
•
contamination is a critical factors leading to product failure
• Cleaning procedure must be adequate and effective
F. Post Validation
• Required whenever there is a change in formulation, processing conditions,
analytical methods, cleaning procedures or materials
CALCULATION OF RESULTS AND ERRORS
Duplicate results that are close are not an assurance of accuracy
Generally, results that agree closely when obtained by 2 different methods of
analysis are a good indication of the reliability of methods
2 types of ERRORS:
1. Indeterminate errors
• Manifest themselves by slight variations in a series of observations made by same
observer under identical conditions
• Causes are difficult to detect
• Intangible errors over which the operator has little control
• Elimination is impossible
• Also called random errors
• Ex. Fluctuations in temp, slight variation in the functioning of instrument
2. Determinate errors
Also called Systematic error
• Recur in constant manner
• Causes such as personal error by analyst
• Faulty procedures, incorrect sampling, contamination, improper selection of
indicators
• Are detectable
• May be eliminated
• Instrumental error: Apparatus not calibrated, incorrect mass
• Personal error : inability to judge color
• Methodic error: incorrect use of method
Suggest how the following might give rise to errors in an analytical procedure;
1. Analysis of sucrose-based elixir using a pipet to measure aliquot for analysis
2. Use of analytical standard that absorbs moisture form atmosphere
3. Incomplete of powdering of coated tablets prior to extraction
4. Extraction of ointment with a solvent in which it is poorly soluble
5. Use of buret that has not been rinsed free of traces of grease
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SIGNIFICANT FIGURES
1 -9 are significant
A zero is significant when it is:
1. Between non-zero digits
205 – 3
2.05 – 3
61.09 – 4
2. At the end of a number that includes a decimal point
0.500 – 3
25.160 – 5
3.00 – 3
A zero is non-significant when it is:
1. Before the first non- zero digit. These zeros are used to locate a decimal point:
0.0025 - 2
0.108 – 3
2. At the end of a number without a decimal point
1000 – 1
590 - 2
ANALYSIS OF MEDICINALS
Pharmacists have made important contributions in the field of medicinal chemistry
both in discovery and isolation
Today, such activity is rarely a function of the practicing pharmacist in the
prescription lab or industrial pharmacist rather analytical chemists perform this
function
The use of analytical method is justified only after it has been found to be valid (has
been validated)
Both FDA and USP are vitally interested in assay method validation to be certain that
methods are as they purport to be
Validation of Analytical Methods
The use of analytical method is justified only after it has been found to be valid (has
been validated)
Both FDA and USP are vitally interested in assay method validation to be certain that
methods are as they purport to be
Selectivity (ability to measure analyte in presence of impurities or other compounds
contained in the sample
Linearity - the concentration range over which the concentration and response are
related linearly; based on processes where the method produces a response that is
linear and which increases or decreases linearly with analyte concentration
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Selectivity (ability to measure analyte in presence of impurities or other compounds
contained in the sample
Linearity - the concentration range over which the concentration and response are
related linearly; based on processes where the method produces a response that is
linear and which increases or decreases linearly with analyte concentration
Limit of detection or LOD - concentration that gives the smallest perceptible
response; smallest amount of analyte which can be detected by a particular method
Limit of quantitation/quantification or LOQ - lowest concentration measurable with
good precision and accuracy; quantitative results can be reported with a high degree
of confidence; smallest amount of analyte which can be quantified reliably
Intralaboratory reproducibility (different instruments, chemists w/in lab)
Robustness - the capacity of method to remain unaffected by small variations in
method parameters; how resistant the precision and accuracy of an assay is to a
small variation in the method ex. Stability of analytical solutions, length of extraction
time, effect of variation of pH, the effect of temperature
Instrument Qualification
An installation qualification (IQ)- provides verification that equipment
installation adhere to standards
An operation qualification (OQ) – equipment performs as intended
Performance qualification (PQ)
Calibration, Maintenance and Use
schedules must be established
Ex. Analytical balance that is calibrated quarterly is checked on weekly basis by
weighing a NIST- traceable weight
Calibration are recoded into a logbook
Detailed instrument records – help investigations of out of specification or out of
trend results
ASSAY OF RAW MATERIALS AND DRUGS
•
•
•
•
•
•
•
Volumetric method
Terms: analyte, titrant, titration, indicator, endpoint
Standard solutions
Normality
Molarity
Standardization – primary, secondary
Types of titration – direct, residual
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Quality control tests for products:
1. Physical and Chemical Tests
appearance
identity
content uniformity
hardness
moisture
contaminants
2. Biologic and Microbiologic Tests
potency
sterility
safety
antiseptic activity
CHEMICAL TESTS
Quantitative analysis deals with the methods of determining the amounts of various
substances in a sample.
Objectives of the Student in Quantitative Analysis:
1. To become familiar with the analytical methods and understand the theoretical
principles on which they are based
2. To appreciate the limitations of each method and the magnitude of possible errors
involved
3. To acquire manipulative ability and to acquire speed in performance of analytical
operations without sacrifice of accuracy
4. To acquire the habit of recording all data in notebook in clear, systematic form
5. To be able to locate in the chemical literature that may be referred in the discussion
of analytical procedure
6. To make calculations from analytical data with speed and accuracy and precision
METHODS USED IN OFFICIAL PHARMACEUTICAL ANALYSIS
1. Volumetric method (titrimetric) – determination of volume of a solution of known conc.
required to react with a given amount of substance to be analyzed.
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2. Gravimetric method – separation by extraction, precipitation or other means, of the
constituent to be determined and the weighing of the resulting product.
3. Special method – require distinct type of technique such as analysis of crude drugs, assay
of fats and fixed oils, assay of volatile oil and alkaloids
4. Physico-Chemical methods- based on some physical and chemical properties of
substance. Commonly employed instrumental tests: spectrometric, chromatographic,
electrometric and polarographic.
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PRINCIPLES OF TITRIMETRIC (VOLUMETRIC) ANALYSIS
Volumetric Analysis
The determination of the volume of a solution of known concentration required to
react with a given amount of the substance to be analyzed (ex. Titration)
Titrimetric methods
as an analytical method in which the volume of a solution of known concentration
consumed during an analysis is taken as a measure of the amount of active
constituent in a sample analyzed
Analyte – or the active constituent in the sample
Titrant – standard solution; solution of known concentration
Titration – process by which a standard soln. is brought into reaction until the desired
reaction is accomplished
Indicator – chemical which changes color at a point equivalent quantities of analyte and
titrant have reacted
Stoichiometric point or Equivalence point – the theoretical point at which equivalent amounts
of each have reacted
Endpoint – practical; a sudden change apparent by use of indicators
Acids :
# of replaceable Hydrogen
Ex: HCl
= 1
H2 SO4
= 2
CH3 COOH
= 1
Bases:
# of replaceable OH
Ex: NaOH
=1
Mg(OH)2
=2
Al(OH)3
=3
Salts:
total positive or negative charges/ cation or anion
Ex: NaCl
=1
MgO
=2
Ca3 (PO4) = 6
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STANDARD SOLUTION:
• is a solution of known normality or molarity
NORMALITY
• One gram equivalent wt. of solute in liter of soln. or one gram milliequivalent weight
in an mL of soln.
• eq/L or meq/ml
MOLARITY
• A mole of solute in a liter of soln.
• moles/L or mmoles/mL
MOLALITY
• moles/1000 g of solvent
• A mole in one thousandth part of a mole
TITER
• The strength in mg of analyte/mL of titrant
Equivalent weight = molecular weight in grams/n
Milliequivalent weight = equivalent weight/ 1000
n = number of reacting entities
Tenth normal =
N
10
=
0.1 N
Twentieth molar =
M
20
= 0.05 M
N = wt.
V x meq. wt.
=______g_________
mL x g/mole
meq/mole
What is the normality of the following:
0.1381 M NaOH
0.0521 M H3PO4
What is the molarity of the following:
0.3181 N HCL
0.1115 N Sr(OH)2
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STANDARDS
Standardization – determination of the exact concentration of the solution
Standardize using 2 types of standards:
1. Primary standard – pure solid subst. used for direct standardization of a soln.
2. Secondary standard – standard solution of known concentration, these are
volumetric solutions.(VS)
Requirements for Primary Standard:
1. High purity = 99.9%
2. Definite and known composition
3. Not affected by drying
4. Soluble in water
Ex.
Stdzn. Of NaOH
4 primary stds:
1. Potassium acid phthalate (KHP)/ C6H4COOK . COOH
2. Sulfamic acid (HSO3)
3. Benzoic acid
4. Potassium acid iodate
Example: standardization of HCL
• Standardize titrimetrically using sodium carbonate of known purity as a primary
standard or
• using standard NaOH as a secondary standard
Standardization using Primary Standard
Std. solutions
Primary std
Indicator
NaOH
KHP/sulfamic acid
phpt
HCl
Na2CO3
phpt
AgNO3
NaCl
K2CrO4
EDTA
EDTA
hydroxynaphthol
KMnO4
Na2C2O4
Iodine
As2O3
starch
Sodium Methoxide
Benzoic acid
Thymol blue
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Ceric sulfate
As2O3
Karl Fischer reagent
Sodium tartrate
Na2S2O3
K2Cr2O7
orthophenanthroline
starch
Standardization using Secondary Standard
o A solution of known concentration used to standardize another solution
Secondary Standard
Indicator
HCl
NaOH
phpt
NH4SCN
AgNO3
Ferric alum
Na2S2O3
Iodine
Starch
Volumetric Apparatus
2 types:
a) to deliver: burets, pipets
b) to contain: volumetric flask, graduated cylinders
Burets
Graduated glass tubes of uniform bore throughout the whole length
Closed at the bottom by glass or stopcock
Volumes read at lower meniscus except highly colored liquid
BURETS
Calibration by means of:
1. Ostwald pipet
2. Kiehl buret
Types:
Mohr – economical, w/ rubber tubing at the tip, for bases
Geissler – more expensive, for acids and bases
Volumetric flasks
a. Should be calibrated to contain the indicated volume when filled to the mark
b. Used to make up standard solutions
Graduated cylinders
a. Used in making approximate measures of volume
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Pipets
a. Should be graduated
b. Class A and B
Sources of error in the use of volumetric apparatus:
1. Rinse water adhering to walls of apparatus
2. Grease films and dirty apparatus
3. Parallax
4. Variations in temperature
5. Air bubbles trapped beneath liquid surface
6. Hot solutions that cause calibrated volumetric apparatus to suffer change in volumes
CLEANING SOLUTIONS
1. Sodium dichromate in sulfuric acid - best
2. Chromic acid
3. Solution of trisodium phosphate
4. Synthetic detergent
- END Great Job!
Self-Help: You can also refer to the sources below to help you further
understand the lesson
KNEVEL, A., & DiGANGI, F. (1977). Jenkins Quantitative Pharmaceutical Chemistry (7th ed., pp.
56-84). United States of America: McGraw-HIll.
Choudhary, A. (2021). An Overview of ISO 14644 Clean Room Classification. Retrieved 30
January 2021, from https://www.pharmaguideline.com/2012/07/overview-of-iso-14644-cleanroom.html