Quality Management in The Drug Industry Quality Control

Asst. Prof. Rhona P. Ramos, MSc. PHA 6122

November 11, 2020 Lecture

QUALITY MANAGEMENT QUALITY

The aspect of management function that determines and • suitability of either a drug substance or drug product for its
implements the “quality policy” as formally expressed, determined intended use
and authorized by top management. • combination of attributes or characteristics (i.e., identity, strength,
and purity) of a product which, when compared to a standard,
QUALITY POLICY serves as a basis for measuring the uniformity of the product and
The overall intention and direction of an organization as to how they determines its degree of acceptability
want to implement quality within their company. • must always be compared to a standard, you cannot test for
quality when there is no standard. The standard serves as the
BASIC ELEMENTS uniformity of the product and determines its degree of
1. An appropriate infrastructure or “quality system”, acceptability; accepted or not accepted.
encompassing the organizational structure, procedures, • defined based on several measurable criteria:
processes, and resources of the company to implement the 1. Conformance
quality. o within prescribed limits
2. Systematic actions necessary to ensure adequate confidence o example: assays where product is within the criteria for it to
that a product (or service) will satisfy given requirements for/of conform in the prescribed limit
good quality – “quality assurance” 2. Fitness for use
o functionality of the product; determined for products with
QUALITY ASSURANCE function
o example:
• overall organizational body designed to assure product quality
§ Drug delivery systems e.g. patches, puffs suppositories.
• wide-ranging concept covering all matters that individually or
These are drug products or devices that has functions. If
collectively influence the quality of a product
it delivers the product well at an appropriate strength and
performs that function, your device is fit for use. That is
§ GOOD MANUFACTURING PRACTICE (GMP) quality.
That part of quality assurance which ensures that products are 3. Reliability
consistently produced and controlled to the quality standards o function in the specified environment for a prescribed length
appropriate to their intended use and as required by the marketing of time.
authorization o Prescribed length of time (expiry date) is to be determined
and if it performs its function within the expiry date, then the
• QUALITY CONTROL product is reliable until that particular date.
- sum of all procedures undertaken to ensure the identity and 4. Yield
purity of a particular pharmaceutical/drug product o high degree of acceptable units produced
- tool which gives the assurance that a product conforms to o For procedures, equipment that produces acceptable units
standards and specifications through a system of inspection, o example:
analysis, and action § quality of a tableting machine measure quality through its
o 3 main steps of quality control: inspection, analysis, and high yield of acceptable units, then that machine is of good
action quality. The same is true of a procedure if it produces a
- It is just the testing of the quality of the product, it will not add high yield/degree of acceptable units.
but only determine the quality 5.Customer satisfaction
- can have no effect on the quality of the product o requires the product to be safe, pure, and effective.
o If costumer is satisfied with your product with no complaints
QUALITY MANAGEMENT then product is of quality.
Overall policy of the organization towards quality
REPORTING RESPONSIBILITIES IN A MANUFACTURING FIRM

QUALITY ASSURANCE
The unit that ensures the policy is achieved

GMP
Deals with risks that cannot be tested and builds
quality into the product

QUALITY CONTROL
Focused on testing of the environment and
facilities, the materials, components and product
in accordance with the standard or specifications

§ Explanation of the diagram QC is not under manufacturing because if ever an unfavorable result
- This is a representation of what was previously discussed. would come from the manufacturing department then it would not
Quality Management is the overall policy that is determined by hinder the quality control to report it. This is to avoid manipulation,
the top management. Under Quality Management is Quality and bias in the results for quality control. Sometimes this is where
Assurance that ensures the quality policy is being achieved. the rift comes between the QC pharmacists and Manuf pharmacists.
GMP as part of Quality Assurance deals with risks that cannot Quality should be built into the product right from the start and
be tested and WILL give quality into the product, whereas QC testing alone cannot be relied on to ensure product quality.
is just a part of GMP and NOT give quality, just test the quality. - raw materials, manufacturing equipment, procedure

Bautista, N., Feria, Serrano, Ulangco 1 of 6

Quality Control: Quality Management in The Drug Industry PHA 6122 - Lecture

POTENTIAL BENEFITS DERIVED FROM A QUALITY CONTROL SYSTEM

§ C. Standard operating procedure (SOP) :
1.The system minimizes or eliminates the risk of marketing unsafe • A step by step method on how to go about a job
products. • Must spell out all information and instructions that assure that
- Following GMP eliminates the risk through QMS variations in production from day to day and week to week will be
2.It guarantees conformance to regulatory requirements. held to within acceptable established ranges
3.It guarantees product efficacy. • SOP explains our all methods on how to perform a procedure,
4.It reduces operating costs. variations that could be done, and how much of a stretch could
5.It reduces operating losses. you do with those variations to assure that no deviation will occur
- No product recalls, returns or reprocessing in reference to the SOP
6.It produces higher employee morale. • READ THE SOP to become prepared for situations that may arise
- Pride from a quality company that produces quality products
7.It motivates the pharmaceutical/medical professions to sell or
§ D. Finished product specification:
prescribe the product. • all characteristics that affect the proper performance, purity,
safety, and stability of the product
- Trust in the quality of the product
• tolerances may be minimum, maximum, or both, depending on
the nature of the situation
COST OF QUALITY
used within a total quality management or performance § E. Packaging material standard:
improvement program • Set for everything that goes around the product, primary
packaging materials and secondary packaging materials (i.e.,
§ Failure costs (costs of non-quality) bottles, cans, aluminum foil, cellophane, jars, caps, cap liners,
• are those associated with getting things wrong. They can be labels, printed inserts, cartons, wrapping papers, and shipping
tangible costs, such as the cost of rejects or “reworks” cases.)
“reprocessing costs”, or they can be intangible costs, such as lost - The units may have to run on a high-speed line.
sales and damage to image from the loss of consumer trust or o In a manufacturing company where automated machines are
problems with the regulatory authorities. responsible for labeling and packaging, It is a given that they
§ Appraisal costs are able to withstand the stress of a high-speed line. They
• are those associated with checking that things were done should not be the cause for a “stuck-up” of packaging
correctly. This is testing the quality of the products and services. materials. Packaging materials should be compatible in the
It should be emphasized that this is not value-adding activity of packaging procedure.
itself; it is merely an historical measurement of what has already - They may involve a complicated assembly
happened; serves as proof that the product has quality. o Packaging should be able to handle these types and more
§ Prevention costs o Bottling, capping, labeling, boxing
• are the costs associated with making sure that things will be done o Sometimes sealed by plastic wraps, plastic seal
right. This is the one activity of the three that can be considered - The package may be functional.
to be value adding; emphasized and where you want to put up o Must be able to contain and compatible with product
your money into rather than failure and appraisal costs. - The package must be completely compatible with the product.
o This is why there are stability tests prior to marketing in
SPECIFICATION determining the stability of the product and packaging
together. They should be compatible in such a way that the
• A specification is defined as a list of tests, references to analytical
product should not degrade because of the packaging
procedures, and appropriate acceptance criteria, which are
material
numerical limits, ranges, or other criteria for the tests described.
- The package must protect the product and assure its stability,
- This does not mean that all test will come from the USP or an
o The packaging material should not be able to degrade the
established monograph. There could be test, in-house
product where it protects it and assures its stability.; This
procedures, FDA analytical procedures what is important that it
coincides with the previous two bullet points
is referenced. These tests must be validated.
- The package must ship well.
- This specification where we look for what tests we should do to
o “dapat alam mo malayo ang mararating ng iyong packaging”
the product and where will the procedures be coming from and
what the acceptance criteria are. § F. Testing methods:
• "Conformance to specifications" means that the drug substance • testing procedures must be standardized so that they yield results
and/or drug product, when tested according to the listed analytical of comparable precision and accuracy in the hands of different
procedures, will meet the listed acceptance criteria. operators and laboratories
- ALL should be met in the specification • tests must be validated to ensure precision and accuracy on
application
SPECIFICATIONS FOR A DRUG PRODUCT
STANDARD
§ A. Formula • A standard is a document that provides requirements,
• concise and precise statement of the ingredients that comprise
specifications, guidelines or characteristics that can be used
the product
consistently to ensure that materials, products, processes and
• with the percentage and/or weight of each
services are fit for their purpose.
• is a complete list of ingredients with its corresponding amount
• Standard encompasses your specifications.
whether in weight, volume or percentage.
• ISO International Standards ensure that products and services
• Formulation
are safe, reliable and of good quality.
- Statement of how much active ingredient is present per dosage
• ISO 9000 family addresses various aspects of quality
form of product
management
§ B. Raw material specification • ensure that products and services consistently meet customer’s
• characteristics of all materials that go into the product requirements, that quality is consistently improved and that the
• each raw material must be tested for their quality that MUST be system is being operated effectively
met
• the permissible range of purity of each ingredient
• USP, NF, BP, Merck Index, etc.

2 of 6
Quality Control: Quality Management in The Drug Industry PHA 6122 - Lecture

§ ISO 9001 QUALITY VARIATION

• The organization shall establish, document, implement and • Happens when you are not following regulatory standards
maintain a quality management system and continually improve • Normal in drug production but should be minimized
its effectiveness in accordance with the requirements of this • Sometimes if Quality Variations are outside the specified limits,
International Standard. then we can encounter defects or defective products
• States that for you to be able to be accredited by the ISO • DEFECT
company, you must have an established QMS which should be - an undesirable characteristic of a product
documented, implemented and maintained . - a failure to conform to specifications
1. The quality management system documentation shall include: - pertains to the characteristic that does not conform to the
a. Documented statements of a quality policy and quality specification (e.g. color, dosage strength, consistency of liquid)
objectives, • DEFECTIVE
b. A quality manual, - A unit of a product itself, which contains one or more defects
c. Documented procedures required by this International
• Ex: tablet with green coloration which was not intended to have
Standard,
- Green coloration is the defect while the tablet is a defective
d. Documents needed by the organization to ensure the
product
effective planning, operation and control of its processes,
and
DEFECTS
e. Records required by this International Standard
- First thing that you have to do is prove that you have a QMS by 1. According to measurability:
documenting a. Variable defect – a defect which can be measured directly by
2. The organization shall conduct internal audits at planned instruments (Ex: tablet weight, tablet diameter, tablet friability,
intervals whether the quality management system assay, dosage strength)
- Conforms to the planned arrangements to the requirements of b. Attribute defect – a defect which cannot be measured directly
this International Standard and to the quality management by instruments, however can still be identified as defects since
system requirements established by the organization, and they do not pass your standards. It shows mainly the
conformance or nonconformance of the material to
- Is effectively implemented and maintained.
specifications. This is usually exemplified by the color. (Ex:
- To be able to meet the requirements, you must have an internal
Color, label appearance, taste).
audit
o Internal audit: you have an auditor from your company who • How will you express taste if you do not have an instrument to
has a manner of checking your QMS at a planned interval. measure taste? Expressing the defect for variable defects is easy
since you are able to know how far the measurement is for the
• The organization shall continually improve the effectiveness of
standard, but for attribute defects, you are unable to tell how far
the QMS through the use of the quality policy, quality objectives,
the measurement is from the standard
audit results, analysis of data, corrective and preventive actions
2. According to seriousness or gravity:
and management review
a. Critical defect – a defect which may endanger life or property
- It is a part of the internal and external audit to use the results and may render the product non-functional. (Ex: glass shards
of the audit to improve by identifying the areas that need
inside the syrup)
improvement or changing
b. Major defect – a defect which may affect the function of the
- CAPA (Corrective Action, Preventive Action) object and therefore, may render the product useless. (Ex: If
o Corrective Action: If you see an error in this particular item, packaging materials don’t perform their intended function);
what would be the corrective action that you have also a performance defect
implemented? c. Minor defect – a defect which does not endanger life nor will
o Preventive Action: If there was a chance to have an error, it affect the function but nevertheless remains a defect since it
what would be the preventive action you would do? is outside the prescribed limits. (Ex: color of label and taste)
3. According to nature:
STANDARDS TO BE FOLLOWED INA MANUF COMPANY a. Ocular defect – a defect that is visible (Ex: present of
1. Pharmacopeial standards precipitates in your solution)
• found in published monographs b. Internal defect – a defect which is not seen although present;
• USP/NF, BP, EP, PP only seen once you have an instrument that can measure it
• identity, physical tests, purity tests, alcohol content, assay and (Ex: pH of your solution, subpotent assay of solution)
several other characteristics that you would want to test for that c. Performance defect – a defect in function; pertains to
particular product or dosage form products with function (Ex: suppository’s function is to melt at
2. In-house standards body temp., if it doesn’t melt, that’s a performance defect since
• Unofficial in a way that is not published, but it is official in the it is unable to perform and carry out its function); a
manufacturing company performance defect is also a major defect,
• generated by the manufacturer
• allow flexibility dependent on how the company wants the ERRORS
products to appear (e.g. round dosage form, heart shaped dosage • source of defects
form, brown syrup, orange syrup, red syrup) • may be due to chance or assignable causes such as: materials,
• mandatory in compliance to GMP even if it is unofficial since GMP machines, methods and men
says that whatever your standards are, you must follow them
3. Regulatory standards VARIATION IN…
• mandated by the regulatory agencies
• FDA (Philippines), WHO, US FDA
§ Materials
- Variation between suppliers of same substance. (Ex: ordering
• for registration purposes
the same substance from different suppliers)
- Variation between batches from same supplier; different
batches are produced differently even if they come from the
same supplier.
- Variation within a batch; it is inevitable that there will be
variation between batches.

3 of 6
Quality Control: Quality Management in The Drug Industry PHA 6122 - Lecture

§ Machines ANALYTICAL LABORATORY

- Variation of equipment for the same process; you have the • should be in an accessible area and protected from noise and
same process and procedure, but you have two different vibration common to manufacturing operations
machines (Ex: two tableting machines) - In the analytical laboratory, there are several instruments that
- Difference in adjustment of equipment. (Ex: calibrated and are sensitive to noise and vibration which can affect the results
uncalibrated equipment) of the analysis
- Aging and improper care. (Ex: if the machine is too old, • perform physical and chemical analysis
sometimes the quality is affected) - gravimetric and volumetric analysis (wet classical method)
§ Methods - handling instruments (instrumental method)
- Inexact procedures. (Ex: if the pharmacist is inexperienced and
the procedure lacks in detail) BIOLOGICAL TESTING LABORATORY
- Inadequate procedures (sometimes there are procedures in the • staff should be well trained and experienced in both simple and
monograph that don’t itemize everything since these steps are complex microbiological procedures and biological interactions
implied) • possess a high degree of skill and judgment in order to perform
- Negligence by chance (you were unable to notice that there the job
has been negligence in your method) • veterinarian is recommended to supervise the care and
§ Men maintenance of the various species of animals used in the tests
- Improper working conditions. (Ex: unairconditioned area, hot - As an analyst in the biological testing lab, you will be handling
environment, sweat/hair/nails/dead skin cells mixing into the several animals to test for sensitivity, effectivity
drug product) • The functions of this laboratory are:
- Inadequate training, and understanding. (Ex: if the personnel’s 1. To perform and evaluate microbiological and
work/task was not trained or it was not explained to them) pharmacological assays, sterility, pyrogen and
- Dishonesty, fatigue and carelessness. bacteriological tests, irritation, safety or acute toxicity tests.
o Dishonesty: Kapag napagod na, minsan nakakalusot pa, 2. To conduct environmental monitoring.
“sige okay na nga yan”. However, if the dishonesty • Sterile conditions should be provided for areas where biological
endangers the life of the user, dishonesty is unacceptable tests are conducted.
o Fatigue and carelessness: sometimes coming from improper - Manufacturing firm should have a sterile area or laminar flow
working conditions (Ex: Personnel’s environment or work hood or a room that will provide sterile conditions for the tests
time) • Noise should be precluded from areas where animals are used.
- Animals are also sensitive to noise so if they will not become
ORGANIZATION OF QUALITY CONTROL stable or acclimatized
Quality Control Sections • An animal house should be maintained as a separate unit from
the main laboratory, if necessary.
• Materials inspection section
• Analytical laboratory
• Biological testing laboratory § MICROBIOLOGICAL TESTS
• Specifications and analytical development 1. Antimicrobial Effectiveness Testing
• Quality coordinating office - to demonstrate the effectiveness of antimicrobial protection or
ensure the efficacy of the preservatives that are placed in our
drug products
- Fungi: Candida albicans, Aspergillus niger,
Bacteria: Escherichia coli, Pseudomonas aeruginosa, and
Staphylococcus aureus
- Culture Media: Soybean-Casein Digest Broth or Agar for E.
coli, P. aeruginosa, and S. aureus, and Saboraud Dextrose
Agar or Broth for C. albicans and A. niger
2. Microbial Limit Test
MATERIALS INSPECTION SECTION - is for the estimation of the number of viable aerobic
• Inspectors are alert individuals who had experience and who are microorganisms present
familiar with the physical characteristics of the materials they - for freedom from designated microbial species in
sample and are well versed in sampling techniques pharmaceutical articles of all kinds, from raw materials to the
• The functions of this section are: finished forms
1. To sample and examine all raw materials received. - also tests if there is an absence or presence of microbial
2. To sample and conduct physical tests on: species that we do not want on our drug product
o All shipments of packaging materials o Ecoli in oral drug products since these can infect the GIT
o All manufacturing, filling and packaging operations o Fungi in topical products since fungi can thrive in our skin
3. To maintain periodic examination on the quality of inventories and reproductive orifices
throughout all phases of storage, shipping and distribution. o Staphylococcus aureus, Escherichia coli, Pseudomonas
o If there are materials that are not used and are just stored for aeruginosa, and Salmonella
a long period of time, inspectors also perform periodic exams - Culture Media: pH 7.2 Phosphate Buffer, Fluid Soybean–
to these stored materials Casein Digest Medium, or Fluid Lactose Medium
4. To perform an audit which is independent of the work done by 3. Sterility Tests
production personnel - applied to substances, preparations, or articles which,
o Production personnel will also be conducting inspection according to the Pharmacopeia, are required to be sterile
during the production of the product which is outside the of - If your product is a sterile product, it must be tested for sterility
auditor from the work of the inspector of the materials - Techniques:
inspection section i. Membrane Filtration
• Inspection stations are placed in the area of operation o products pass through the membrane filter
- (Ex: warehouse, manufacturing and packaging areas) o use membrane filters having a nominal pore size not greater
than 0.45 µm

4 of 6
Quality Control: Quality Management in The Drug Industry PHA 6122 - Lecture

a. cellulose nitrate filters are used for aqueous, oily, and 3. Biological Reactivity Tests, In Vitro
weakly alcoholic solutions - Done for elastomeric plastics and other polymeric materials
b. cellulose acetate filters are used for strongly alcoholic that are used to contain the drug products, esp. for sterile
solutions. products or parenteral products that are used in plastic
o Filter the solution/sterile product then get the filter and place materials as their containers
it over your culture media and allow the bacteria to grow for - designed to determine the biological reactivity of mammalian
a period of time cell cultures following contact with the elastomeric plastics
ii. Direct inoculation of the culture medium and other polymeric materials with direct or indirect patient
o the preparation to be examined is directly inoculated into the contact or of specific extracts prepared from the materials
culture medium under test
o if the product to be examined has antimicrobial activity, carry - Plastics can leak their components through the product and this
out the test after neutralizing this with suitable neutralizing materials can induce reactivity from our cells like allergic
substance or by dilution in a sufficient quantity of culture reactions from human cells
medium - Prior to releasing the product in the market, we would want to
o Ex: if the product to be tested is an antibacterial, definitely it know if the packaging materials of the drug product are reactive
should kill bacteria in itself. to the human cells
o It doesn’t mean there’s no bacteria present if there is no - In vitro: testing is performed on petri dishes first prior to testing
colony formed, giving a false negative result it in vivo
§ Neutralize the antibacterial property of your product and if a. Agar Diffusion Test
there’s any bacterial present, it would still grow even if the o designed for elastomeric closures in a variety of shapes
product tested is an antibacterial o the agar layer acts as a cushion to protect the cells from
- Culture Medium: mechanical damage while allowing the diffusion of leachable
o Fluid Thioglycollate Medium for anaerobic bacteria chemicals from the polymeric specimens
o Soybean-Casein Digest Medium or both fungi and aerobic o mammalian cells are suspended in an agar for protection
bacteria. from mechanical damage
o polymeric (plastic) specimens will be embedded in the agar
§ BIOLOGICAL TESTS as well so that if there will be materials that will leach, they
1. Antibiotics-Microbial Assay can react with the human cells
a. Cylinder-Plate or ‘‘Plate’’ Assay o Leaching: components of the packaging material would
o diffusion of the antibiotic from a vertical cylinder through a interact with the drug product
solidified agar layer in a petri dish or plate to an extent such b. Direct Contact Test
that growth of the added microorganism is prevented entirely o Difference with agar diffusion test: Direct contact test is
in a circular area or ‘‘zone’’ around the cylinder containing a without an agar layer to protect the mammalian cells,
solution of the antibiotic therefore having no protection from mechanical damage
o An agar is inoculated with microorganisms. The cylinders are o for materials in a variety of shapes
then placed vertically into the agar, Then, the antibiotics are o allows for simultaneous extraction and testing of leachable
placed inside the cylinder. If the microorganisms in the plate chemicals from the specimen with a serum- supplemented
are susceptible to the antibiotics, then the growth will be medium
prohibited around the cylinder of the particular antibiotic. o not appropriate for very low- or high-density materials that
o Zone of Inhibition: There would be a zone of clear agar could cause mechanical damage to the cells
indicating no growth around the cylinder of the antibiotic, o Extreme materials should not be used for the direct contact
meaning that your antibiotic is effective against that test
organism. The c. Elution Test
b. Turbidimetric Method o for the evaluation of extracts of polymeric materials
o depends upon the inhibition of growth of a microbial culture o It is not the piece of plastic that will be embedded in the
in a uniform solution of the antibiotic in a fluid medium that is culture medium, rather the components of the plastic
favorable to its rapid growth in the absence of the antibiotic. material will be extracted and the extract will be eluted into
o Effectivity of the antibiotics is being tested based on the the medium that will react with the mammalian cell culture
turbidity of the medium o allows for extraction of the specimens at physiological or
o The more turbid the culture medium, the higher number of nonphysiological temperatures for varying time intervals
bacteria, the less effective is the antibiotic and vice versa o appropriate for high-density materials and for dose-response
evaluations
2. Bacterial Endotoxins Test o easier determination of the reactivity of the cells to the
- Also called LAL (limulus amoebocyte lysate) test particular dose of the extract
- to detect or quantify endotoxins from Gram-negative bacteria o Dose response evaluation may be done (gaano kadaming
using amoebocyte lysate from the horseshoe crab (Limulus extract ng plastic and mag iinduce ng reaction from the
polyphemus or Tachypleus tridentatus) mammalian cells?)
- The amoebocyte lysate from the horseshoe crab is retrieved
and then allowed to react to the product that is suspected to 4. Biological Reactivity Tests, In Vivo
have endotoxins - designed to determine the biological response of animals to
- techniques: elastomerics, plastics, and other polymeric material with
1. gel-clot technique, which is based on gel formation direct or indirect patient contact, or by the injection of specific
o If you place LAL with the endotoxin, gel will be formed extracts prepared from the material under test
2. turbidimetric technique, based on the development of a. Systemic Injection Test
turbidity after cleavage of an endogenous substrate o to evaluate systemic responses to the extracts of materials
o If you place LAL with the endotoxin, turbidity will be formed under test following injection into mice
3. chromogenic technique, based on the development of color b. Intracutaenous Test
after cleavage of a synthetic peptide-chromogen complex o to evaluate local responses to the extracts of materials under
o If you place LAL with the endotoxin, color will be produced test following intracutaneous injection into rabbits
c. Implantation Test
o for the evaluation of plastic materials and other polymeric
materials in direct contact with living tissue
5 of 6
Quality Control: Quality Management in The Drug Industry PHA 6122 - Lecture

5. Pyrogen Test
- To limit to an acceptable level the risks of febrile reaction in the
patient to the administration, by injection, of the product
concerned
- Tests if it will contain pyrogenic materials that will induce febrile
reactions
- involves measuring the rise in temperature of rabbits following
the intravenous injection of a test solution
- dose not to exceed 10 mL per Kg injected IV within a period of
not more than 10 minutes
- In the first testing, 3 rabbits are used first
o if no rabbit shows an individual rise in temperature of 0.5º or
more = absence of pyrogens
- if any rabbit shows an individual temperature rise of 0.5º or
more = continue the test using five other rabbits
o if not more than three of the eight rabbits show individual
rises in temperature of 0.5º or more and if the sum of the
eight individual maximum temperature rises does not exceed
3.3º (both conditions should be met) = absence of pyrogens

SPECIFICATIONS AND ANALYTICAL DEVELOPMENT

• To coordinate with research, product development, production,
sales and management towards improvement of a product.
• To establish specifications for raw and packaging materials if
there is no monograph to follow.
• To validate existing and tentative procedures of testing.
- If you are developing tests, this department should validate
them
• To develop new assay methods for in-house use.
- If not following pharmacopeial procedures, assay methods
must be developed for your company
• To develop and improve specifications for quality characteristics
of the final product being manufactured.

QUALITY COORDINATION OFFICE

• a should be accessible to all manufacturing and packaging
operations since documentation is its main responsibility
• all the documents produce in the production of a product should
be stored here
• Functions:
1. To maintain and store records that represents the history of the
batch from start to finish.
2. To be able to furnish data that will aid in analyzing product
performance in the market.
3. To 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.
4. To call the attention of the appropriate development group any
aspect that provides a basis for improvement of a product for
consideration and action.
5. To provide data that give specific and legal status, i.e., data
generated from the use of recognized standard compendia.
6. To maintain and develop SOP’s.

END OF REVIEWER

6 of 6
 Inspection & Sampling Quality Control
Asst. Prof. Rhona P. Ramos, MSc. PHA 6122
November 29, 2020 Lecture

INSPECTION AND SAMPLING 2. MEASUREMENT OF THE PRODUCT;

ACCEPTANCE - actual inspection (performing the inspection or analysis)
• basic quality function of deciding whether the product conforms to 3. COMPARISON OF THE PRODUCT WITH SPECIFICATION;
specifications - comparison of the results of the product with the specification
• If it conforms, you have to accept. If it does not conform, you have o Ex: Assay Procedure Specification– NLT 95% and NMT
to reject. 105%; Assay result after measurement: 99%
§ In comparison to the specification, this would mean that
• Inspection is the primary step to arrive at a decision, and the
99% is within the specification.
primary step of quality control.
o Comparison means looking at the specification and
• Quality control is composed of three major steps: inspection,
determining whether the result is within the specification;
analysis, and action. Inspection is the first thing to do.
§ below or above your specification
• Inspection is comparison of certain attributes/characteristics and 4. JUDGMENT AS TO CONFORMANCE;
dimensions of a product which is then compared to a specification
- after comparison, look at your specification if it is within the
to find out if the product is within the prescribed limits.
specification, then you now judge it if it conforms or not
§ 2 TYPES OF INSPECTION - in judgment, express if it conforms or not
• Attributes and variables basically have the same principle. - within specification: conforming, outside specification: non-
1. INSPECTION BY ATTRIBUTES conforming
- characteristics cannot be measured 5. DISPOSITION OF THE PRODUCT;
- the item is classified simply as conforming or nonconforming - disposition refers to your decision; what would you do after
with respect to a specified requirement or set of specified knowing if it conformed or not conformed
requirements, or the number of nonconformities in the item is - do not interchange comparison (result is within or outside
counted specification), judgment (within: conforming, outside: non-
- judging by its conformance and nonconformance to the conforming), and disposition (conforming: accept, non-
specification conforming: reject)
- At the end of your inspection, you will end up with the number - disposition: decision on what will you do next upon the
of non-conformities on your population or on your lot judgment of conformance- acceptance or rejection
2. INSPECTION BY VARIABLES - if you judge that it conforms, then following your disposition
- inspection by measuring the magnitude of a characteristic of an now, would be to accept it
item o if it conforms to the specification, that is your judgment, then
- magnitude of a characteristic: how long, how heavy, how strong you accept; if it does not conform, then reject
your tablets will be o disposition refers to action or decision taken upon making a
judgment
ACCEPTANCE INSPECTION 6. RECORDING OF THE DATA OBTAINED.
• may be applied - quality control and quality assurance would always be in
- to incoming materials, documentation
o deliveries or raw materials delivered to the company or - you always have to record your data because that's the only
manufacturing plan thing that you can prove that you have done something so you
§ need to be inspected to be accepted have to document all your data
- to partially finished product at various intermediate stages of
manufacturing process (in-process inspection), INSPECTION METHODS
o in-process items or in-process products that you have to 1. 100% INSPECTION
inspect - inspect all of the units
§ Ex: when tableting and an intermediate product of tablets - formidable task
would be granules, - not always successful because it has several disadvantages
1. Before tableting it or before transforming the lot to a o Ex: If you produce 100,000 tablets in a day, following 100%
tablet then you have to granulate them first. inspection, you will inspect 100,000 tablets and you will not
2. Prior to compressing the granules in the tablets, you be very sure that the result would be very good
have to inspect your granules first if they will pass a - sometimes would degenerate into a superficial 100%
particular specification inspection
- to the final product. o sufficient money, time and staff are not available
o The product will not be released into the market unless they o it would be superficial wherein you just have to browse your
have passed your inspection. products and then accept it or reject it
• Acceptance may also be carried out by the purchaser of the o it would not be specific; it would not be inspection by the
manufactured product. detail anymore
- true for those that are engaged in toll manufacturing o must have sufficient money to do 100% inspection every time
o When they have a toll manufacturer, prior to accepting the o the more tests are done, the more resources are consumed;
product that the toll manufacturer will provide them, then they and the time and staff are not available, thus, it would need
have to inspect first their products. a lot of time from your staff and manpower– without these, it
§ Inspection consists of several steps: would degenerate into superficial inspection
1. INTERPRETATION OF THE SPECIFICATION; - not viable if the inspection method necessitates destructive
- there are several types or several ways in which specifications testing
are presented and the inspector must know how to interpret o destructive testing: destruction of the product upon
them analysis (e.g., if it is a dissolution method, therefore, you
- interpretation of specifications would mean understanding first have to dissolve the tablets, and if 100% inspection will be
what the specification would need you to do done in dissolution, then all tablets must be dissolved)
- Disadvantage: not practical and illogical

Serrano, Ulangco 1 of 7
Quality Control: Inspection & Sampling PHA 6122 - Lecture
2. SAMPLING INSPECTION • 1 group of samples from a population
- Sampling may be defined as the process of removing an - Inspection and determine number of defects. Compare to a
appropriate number of items from a population in order to make standard or a limit of acceptable number of defects. There
inferences to the entire population. should a standard that limits you on the max of defects.
o Sampling is the actual removal of the items / samples from a If it does not exceed- accept
population - If exceeds: do not accept
o Inferences/conclusions are made to the entire population § Schematic operation of double sampling method.
using only the tested samples
- A producer’s risk (α) is the probability of rejecting a good
batch, whereas a consumer’s risks (β) is the probability of
accepting a bad batch.
o the 2 risks above are the downside or the disadvantages of
sampling inspection
o how is a good batch being rejected, and a bad batch being
accepted? – from the producer's point of view, you have the
probability of rejecting a good batch, and that is when
sampling is not performed correctly (you make a conclusion
based on the sample which is applicable to the entire
population) – meaning, if you got bad samples, then the
result would be rejection of the entire population/products,
o however, in real life the samples are only the bad ones, not
the entire population (this results from your sampling method
which may have been poorly used, which results to a
rejection of the good batch) – a waste of money (producer's
risk) • 2 batches of samples and 2 acceptance numbers
o in consumer's risk, if poor sampling method is used, you can - Inspection sample n1 and determine number of defects from
get the best of your samples, accepting it, thus accepting the first group. If it does not exceed 1st acceptance number, accept.
entire population (in real life, the samples are the only good If exceeds 2nd acceptance number reject.
ones, not the entire population, hence if the products are - But what if in between the numbers. Inspect second group of
already released in the market, they would eventually reach samples. Determine TOTAL number of total number of defects
the consumers which are in bad condition) from 1st and 2nd batch of samples. If does not exceed 2nd
o both risks result from a bad sampling method acceptive number, then accept. If not then, reject.
- Population (N) is the totaling of all actual or conceivable items
of a certain class under consideration.
o population: the entire batch that you are sampling
§ Schematic operation of multiple sampling method.
- Sample (n) is a portion of a material collected according to a
defined sampling procedure. The size of any sample should be
sufficient to allow all anticipated test procedures to be carried
out, including all repetitions and retention samples.
o sample: portion of the population; withdrawn from the
population; must be sufficient enough for you to perform all
the test procedures necessary for the acceptance of the
batch/population
- A random sample is a sample chosen in such a manner that
one object has a good chance of being selected as another. It
is a sample in which the different fractions of the material have
an equal probability of being represented.
o random sample is one of the best way to the sampling
inspection
o random sampling: when all of your population has a
good/same probability of being selected as a sample; all
must be well-represented
§ Schematic operation of single sampling method

• Several groups of inspection sample and several acceptance

numbers.
• Inspection and determination of defect on first group of samples,
If 1ast AC – accept. If 1bst AC – Reject.
• If in between, proceed to second group of samples. Inspect and
determine defects. If 2ast AC – accept. If 2bnd AC – Reject.
• If in between get 3rd batch of sample Inspect and determine
defects. If 3ast AC – accept. If 3bnd AC – Reject.
Continued until 7th sampling as necessary

2 of 7
Quality Control: Inspection & Sampling PHA 6122 - Lecture
EXERCISE § DIP TUBES
1. Using the double sampling method, 3 defectives were found - Used for sampling liquid and topical products
during the first sampling. Give the disposition of the lot. Table - When you press the two horizontal bars at the top,
showing the criteria with normal inspection for lots consisting 501- the bottom part of it will open and contain the
1,200 pieces of items. Sampling n Cum. n Ac Re Double First 50 50 liquid and topical products
1 4 Second 50 100 4 5 - Should be made of an inert material, such as
• two group of samples polypropylene or stainless steel
• no stated defects found on second batch sampling thus assumed o Inert materials are used since liquid products
none were found tend to be more reactive to your tools. We want
• 1st sampling AC is 1 and 4 where it is inbetween them then to avoid your drug products from reacting to
proceed to 2nd AC number. your tools
• 2nd sample does not exceed 1st AC then this is accepted. § WEIGHTED CONTAINERS
Table showing the criteria with normal - For taking samples (liquids) from large
inspection for lots 501-1,200 pieces of items tanks & storage vessels
Sampling n Cum. n Ac Re - Designed such that it can be opened at
Double the required depth
First 50 50 1 4 o Ex: if procedure required you to take
sample from the middle of a very large
Second 50 100 4 5 tank
2. After the fourth sampling, four defectives were found. The yield of o The required depth may be at the
the fifth sampling was three defectives more. Is the lot approved or middle, bottom or top, whatever the
rejected? sampling method indicates.
Table showing the criteria with normal - The container is weighted in such a way
inspection for lots 501-1,200 pieces of items that when you place your bottle onto the
Sampling n Cum. n Ac Re liquid, dapat lumubog siya. Since the
bottle is hollow, it would float, so it must
Multiple
be weighted to allow it to sink.
First 20 20 * 3
- There must be a way to easily pull off the
Second 20 40 0 3 cap once the bottle reaches the required
Third 20 60 1 4 depth, such as a cork
Fourth 20 80 2 5 § THIEVES
Fifth 20 100 3 6 - Used when taking samples
Sixth 20 120 4 6 from deep containers of solids
1. Plug thief – one slot only
Seventh 20 140 6 7
2. Chamber thief – several
• Multiple sampling slots
• Number of samples per batch (n) = 20 - A big rod that has slots in
• Cumulative number is the total number of sample as they move between
on through the sampling - When dipped in a deep
• On the fourth sampling, there were four defectives found. container of solids (powder or grains), pwedeng pumasok yung
- Acceptance: 2, Rejection: 5 powdered material into the slots
o 4 is in between, it exceeds your acceptance but it does not - The slots are designed in such a way that you can get samples
exceed your rejection, therefore you must proceed to the fifth from the bottom, middle and top of container
sampling
§ SIMPLE BAG-SAMPLING SPEARS / “BURIKI”
• On the fifth sampling, 3 defectives more were detected.
- For taking samples (solids and
- Get the total number of defects: grains) from bags or sacks
o 4 (from the fourth) and 3 (from the fifth) = 7 defectives
- Maximum external diameter of
- Acceptance: 3, Rejection: 6 about 12 mm
o 7 defectives have exceeded the rejection number,
- 40-45 cm in length
o therefore the lot must be rejected
- Tapered type of sampling
• If only 2 defectives were found on the fifth
spear penetrates bags easily
- 4 (from the fourth) + 2 (from the fifth) = 6 defectives
- Once the tool is inserted into
o The lot must still be rejected
the sack, nabubutas yung sack
• If the lot number is equal to the rejection number, the lot must be pero bumabalik din siya once it
rejected is withdrawn from the sack
- Once you pierce the sack or
SAMPLING TOOLS bag using the spear, paghila
• Used to withdraw samples mo non, makakakuha ka ng
§ SCOOPS sample from the bag
- Small containers of solid materials - There are several types of spears:
- A scoopful of sample should be taken in one 1. Closed spear for large grains such as maize
single movement 2. Closed spear for small grains such as wheat
- Only used for solid materials 3. Open spear
- For manufacturing, it should be made of metal 4. Double tube spear / Thief

3 of 7
Quality Control: Inspection & Sampling PHA 6122 - Lecture
SAMPLING PLAN
• For inspection and sampling, a sampling plan is needed SAMPLE SIZE CODE LETTERS
• A guide on how you will do your sampling
• A definite working rule regarding size and frequency of sample
and the basis for acceptance or rejection
• Requires three numbers specified
- N (population/batch size)
- n (sample size)
- c/Ac (Acceptance number)
§ AQL (ACCEPTANCE QUALITY LEVEL/LIMIT)
- The maximum percent defective (or maximum number of
defects per hundred units) that are for purpose of sampling
inspection, can be considered satisfactory as a process
average
o Defects and defective are two different terms
§ Defectives: units with defects • Gives you the sample size code letters
§ Defects: characteristics • Lot size: basis depends on the batch or population size
o percent and per hundred units are the same, so the only • Special Inspection levels vs General Inspection levels
difference is defective and defects • General Inspection level should be followed unless it was
o When dealing with serious defects, you must be counting the specifically noted to follow the Special Inspection level
number of defectives because those are serious defects • Special Inspection level is used
§ Even if only one defect is found on the defective, it should - If you cannot tolerate a smaller sample size
be counted - If you are not able to provide many samples for inspection
o If the defect is only trivial, like having defects on different
• General Inspection level:
parts of a defective product, then the number of small defects
- Level I : Reduced
should be counted instead of the number of defectives
o When dealing with serious defects, you will be more - Level II : Normal
inquisitive, more stricter than with trivial defects which you - Level III : Tightened
are more lenient with • Example: Batch size is 5,000 following Inspection Level II,
o The inspector will assign lower AQL (more strict) for serious therefore Sample Size Code Letter is K. If Inspection Level I is
defects, and higher AQL (more lenient) for trivial defects followed, your Sample Size Code Letter is H.
o Lower than 10 as AQL for serious defects, and higher than • Then from identifying the sample size code letters, you proceed
10 for trivial defects to the Military Standard Tables
- The acceptance criteria for serious defects should be more
severe than for trivial defects MILITARY STANDARD TABLES
§ REDUCED INSPECTION
DIFFERENT SAMPLING PLANS
1. n plan / square root system
n = 1 +ÖN
- if N is less than or equal to 4, then every container is sampled
o if the population or batch size is 4 or lower, do not use this
formula. Instead, consider all the containers to be sampled
- the n plan is not statistically based and should be used only as
a guiding principle
o by practice, this is what is performed in the industry
2. government/military sampling plan
- uses the master tables which give sample sizes, acceptance
and rejection numbers
- necessary to know whether normal, tightened, or reduced
inspection schemes are to be followed
- Normal, tightened and reduced inspection only differ based on
the number of samples
o Tightened: new manufacturer or a manufacturer that you
don’t trust but have no other choice but to get supplies from
them
§ new manufacturer: new supplier of raw materials; have to
be stricter, having a tight inspection with them since you
do not know the reputation of your supplier
o Reduced: if you have a supplier with a good reputation and
is tried and tested to have quality products
§ Fewer number of samples will be needed compared to the
normal or tightened inspection
§ You want your suppliers to be classified under reduced
inspection because smaller samples would mean less
expense and less time for inspection
o Normal: the supplier is at the stage of transitioning from
tightened inspection to normal inspection. Once the supplier
is okay for normal inspection, they may be promoted to
reduced inspection; if there was no type of inspection
scheme mentioned in the problems, normal inspection is
followed

4 of 7
Quality Control: Inspection & Sampling PHA 6122 - Lecture
§ TIGHTENED INSPECTION SAMPLE PREPARATIONS
1. Crude drugs
2. Purified raw material
3. In-process items: intermediate products
4. Finished products
5. Packaging materials: used for packaging
• Crude drug vs. Purified Raw Material
- Crude drug: those that originate from plant materials
(Ex: luya powder, ginger powder, onion extract, malunggay
leaves, banaba leaves, turmeric roots)
- Purified Raw Material: In chemical substance form already, not
plant in origin
(Ex: piperacillin, paracetamol, sulfuric acid)

CRUDE DRUGS
• BULK MATERIAL
1. Gross sample – number of containers to be opened for
sampling(e.g. drums/ cartons)
if 100 drums came, not all will be opened
TABLE
N n
§ NORMAL INSPECTION 5 or less All
6-50 5
>50 (rounding up to the nearest multiple of 10) 10%
Ex. 51->60 = 6 99->100 = 10
2. Laboratory sample (sum of lab sample and retention sample)
o top, middle, end – pooled together then quartered
§ Opposites are discarded while the other is used as
samples
o grain probe (seeds)
3. Test sample (final sample)
o Quartering
4. Retention sample
o Portion from test sample

• RETAIL PACKAGES
1. Gross sample
• Sample Size Example: o Each wholesale container – 2 consumer packages
1) Batch Size: 5,000; Sample Size Code Letter: K; § One box – 10 products – get two
Inspection Level: II; therefore, the sample size is 125 o Small batches (1-5 boxes) – 10 consumer packages
2) Batch Size: 5,000; Sample Size Code Letter: K; 2. Test sample
Inspection Level: I; therefore, the sample size is 20 o From pooled sample – quartering
• AQL Example:
(remember that the lower the AQL, the stricter the inspection) PURIFIED RAW MATERIAL
1) Inspection Level II; Sample Size Code Letter: K; AQL of 0.65;
therefore your acceptance # is 1 and your rejection # is 3 1. Gross sample is computed using the n plan
2) Inspection Level II; Sample Size Code Letter: K; AQL of 15; 2. Test sample
therefore your acceptance # is 21 and your rejection # is 22 - The amount of sample for one complete analysis of all tests
- Comparing AQL 0.65 and AQL 15, there is a big difference - Dependent on the number of tests required in the drug
between the acceptance and rejection number with the same monograph
sample size - Identification and Solubility tests are reported on pooled
- If the inspector assigned 0.65 as the AQL, it could be because sample [ Qualitative]
they noticed a serious defect in the products - Quantitative tests are performed twice
o Even if the inspector only noticed 2-3 defects, that would be o Assay, related compounds, Dissolution, Disintegration, etc.
a rejected population - Example :
o Since the AQL is below 10, you are counting the number of Identification - 0.5g
defectives Assay – 2g x 2 = 4g
- If the inspector assigned an AQL which is higher than 10, the Impurities – 1.5g x 2 = 3 g
number of defects are being counted and not the defectives Total Test Sample = 7.5 g
o Even if there are a lot of defects, these are only trivial 3. Laboratory sample is equal to three times the amount of sample
• If you acceptance and rejection number falls on an arrow, then it for one complete analysis
is pertaining to the number that the arrow is pointing to LS = TS X3 example: 7.5 x 3 = 22.5
4. Retention sample is two times the amount of sample for one
- Ex: Inspection Level II, Sample Size Code Letter: G
AQL of 0.01, then your acceptance # is 0 & the rejection # is 1 complete analysis
o For future references
• Rejection number is the acceptance number plus 1 so there is no
RS = TS x 2 example: 7.2 x 2 = 15
in between. Anything passed the acceptance # is the rejection #.

5 of 7
Quality Control: Inspection & Sampling PHA 6122 - Lecture
IN-PROCESS ITEMS § n= ÖN +1
1. Gross sample is withdrawn on a time basis or as portions of § Ö14+1= 4.74 (no decimal points in counting containers)
batch § Round up whenever determining the number of samples.
- Time basis example: 7am then 9am then 11am It’s better to have an excess than being deficit on number
- Portions of a batch example: middle, start, or end of the batch of samples so always round up.
2. Laboratory sample is based on GMP, in-house or § n= 5
pharmacopeial requirement b. If the shipment consists of 2 drums with one batch number
- Dependent on the amount of tests performed for the in-process and 12 drums with another batch number, give the sample
items size for each batch.
§ Give the sample for each batch numbers.
FINISHED PRODUCTS § If there are deliveries with 2 different batch numbers,
separate inspection must be performed
• Determined by the requirements of the analytical procedure that § Based on the n plan, if there is only 4 or less drums,
will be used to test the product inspect all. <4 = inspect all
- Dependent on the tests performed for the in-process items § First batch= N= 2 drums, n= 2 drums
• A unit to be sampled may be regarded as the transport container § Second batch= N= 12 drums, n= 5 drums (4.46, round up)
- How they are transported can be the test sample 6. In acceptance sampling under the ABC standard, single
• Required number of unit dosage forms is then withdrawn from any sampling is to be used with Inspection Level II, for a batch of
individual container in the selected transit 100,000 pieces of labels. Give the acceptance criteria for normal
- For example, get a unit container and get a sample from that sampling if the AQL is 1.5.
container o 100,000 inspection level II sample size code: N
o Normal inspection code N, sample size: 500
PACKAGING MATERIALS o AQL 1.5: Acceptance number= 14, Rejection number= 15
• Gross sample is computed using the n plan 7. Explain how a sample size of 5 units with an AQL of 150 can
- Same with purified raw material have an acceptance number of 14.
• Laboratory sample is determined using the military standard for If you have a high AQL, then you are just counting the number
attributes of defects whether it is seen in just one unit or multiple units.
One unit can have several defects; it can contain 150 defects.
Since it has trivial defects, you can have acceptance number of
EXERCISES
14 for just 5 units because the AQL is high. You are just looking
1. For a shipment of 100 labels, the acceptance limit is 25 defects;
for trivial defects because your AQL is 150. You are just counting
9 defects were found during sampling.
defects, not the number of defectives.
- 25 is the maximum number of defects
8. Fifty sacks of 25 kg each of Psidium guajava folium were
a. What is the batch size?
received for sampling. Calculate the gross sample and gross
§ 100
delivery.
b. Give the sample size code letter. (Inspection level is not
o Psidium guava folium - type of material: crude drug; plant in
indicated, so choose normal)
origin
§ F
o Gross sample of purified material differs from that of the
c. What is n using the military standard tables?
crude drug
§ 20
o Since this is a crude drug, the gross sample is based from
d. Give the AQL.
the table
§ 25 (Given in the problem)
o If gross sample is being computed, the number of containers
§ In practice this is not being questioned because you as the
is considered
inspector should be the one to determine the AQL.
o Population here would be the total number of containers
e. What is Ac using the military standard tables?
delivered
§ Acceptance number: 10
o N = 50 sacks; n = 5 sacks (gross sample)
f. What is the disposition?
o gross delivery = no. of containers x no. of units/container
§ There were only 9 defects and this did not exceed 10, so
§ gross delivery = 50 sacks x 25kg
disposition is to accept.
§ gross delivery = 1250 kg
2. What is the Ac if Re is 23?
9. Seventy cans of Powdered Luya Rhizome were received by
o Rejection number= Acceptance number + 1, therefore,
the warehouse. Inspection of the containers shows that 67 had
Acceptance number= Rejection number – 1
the lot number R12-04 printed on the label while 3 cans were
o Ac= 22
identified with a lot number of R15-04. How much is the gross
3. Solve for the batch size if n is 4 using the square root system.
sample?
o n = 1+ ÖN o powdered luya rhizome: crude drug
o N= (n – 1)2 o N = 67 cans
o N= 32 o in getting the gross sample of crude drug, we base it on the
o N= 9 table, then for more than 50 containers, we round it up to the
4. For an AQL of 0.15, what is the maximum number of defects nearest tens, thus 67 cans would be rounded up to 70 cans
acceptable for 10,000 pieces of cartons? § then the sample size is 10% of the 70 cans
o Sample size code for 10,000/ acceptance code: L § hence, n = 7 cans
o Normal inspection sample size for L: 200 o for the lot with 3 cans, population with less than 5 would just
o AQL for 0.15: Acceptance number = 1 be the same for the sample size
5. Fourteen drums of Muriatic acid were received in the § thus, N = 3 cans; n = 3 cans
warehouse. 10. Given below is the list of tests n eeded to measure the quality
Muriatic acid type of product: Purified raw material (not a plant of Piperazine Citrate USP:
material, not a crude material) Identification : Chemical reaction 0.220g
a. If the shipment has the same batch number in all drums, how Solubility 4.0g
many drums should be sampled? Water 1.09
§ How many drums need to be opened to get the sample Primary Amines and Ammonia 0.5g
(Gross sample) Assay 0.2g
§ When dealing with purified raw materials and asked for the
gross sample, use the n plan.

6 of 7
Quality Control: Inspection & Sampling PHA 6122 - Lecture
a. How many grams of the material are needed for one
complete analysis?
§ what is being asked? : the test sample for one complete
analysis
§ in one complete analysis, we have what we call
"quantitative test" which is performed twice
§ in general, identification and solubility are qualitative tests
(not performed twice; remained as it is)
§ water: 1.083g x 2 = 2.166
§ 1º amines and ammonia: 0.5g x 2 = 1.0
§ assay: 0.2g x 2 = 0.45
§ FINAL ANSWER (total): 7.786g
b. How much is the laboratory sample?
§ test sample x 3
§ 7.786g x 3 = 23.358g
c. How much is the retention sample?
§ test sample x 2
§ 7.786g x 2 = 15.572g
11. One hundred sixty-four cases of glass bottles of 30mL, each
containing 12 dozens, were subjected to acceptance
sampling. Determine the following:
a. gross sample
§ gross sample : no. of containers
§ N = 164 cases (population)
§ gross sample of a packaging material would be computed
using "n plan", thus, n = square root of N
§ n = square root of 164 cases, or
§ n = 14 cases (rounded up) - this is the gross sample
b. laboratory sample size
§ no. of units to be sampled
§ for laboratory sample size, the population differs from the
gross sample's population
§ for gross sample, population is the no. of cases, while for
laboratory sample, population is the no. of units
§ getting the no. of units first, 164 cases each containing 12
dozen (12 bottles x 12 = 144 bottles), thus
§ N = 144 bottles x 164 cases, or
§ N = 23,616 bottles
§ now, laboratory sample is determined using the master
table based on the population, thus, sample size code
letter: M, then normal inspection, hence,
§ n = 315 bottles (sample size)
§ those 315 bottles will be obtained from the 14 cases to be
opened (gross sample)
§ if the question is "how many bottles are to obtained from
the gross sample (14 cases)?", just divide: 315 bottles/14
cases = 22 to 23 bottles per case
c. If cracks in some bottles were noted,
§ for cracks, the basis would be, is it serious or trivial?
§ serious defect: critical and major defects (e.g., cracks in
the bottle, a major defect, which affects the function of the
bottle)
§ trivial defect: minor defects
1) what AQL should be considered: 0.65 or 65?
§ since cracks is under major defect, which is under serious
defect, AQL is 0.65
2) what is the acceptance number?
§ based on the master table and the AQL: 5
3) what is the rejection number?
§ 6
§ based on the master table and the AQL: 5
3) what is the rejection number?
§ 6

7 of 7
 Controls Quality Control
Asst. Prof. Rhona P. Ramos, MSc. PHA 6122
November 29, 2020 Lecture

CONTROLS
1. Material Control
2. Manufacturing Control
3. Packaging Control
4. Distribution Control
5. Environmental Control

MATERIAL CONTROL
Two types of materials that need to be inspected in the
manufacturing industry:
1. Raw Materials
2. Packaging Materials
§ RAW MATERIALS
- Ingredients intended for use in the manufacture of drugs and
cosmetics and also those that may not appear in the final
product
- This is exemplified by solvents that are used in dissolving a
particular active ingredient that may eventually be evaporated.
o For example, water that is used for wet granulation that
would be evaporated eventually after granulation.
- These are the things that may not appear in the final product
but still part of the raw materials and should be inspected
• MATERIAL FLOW (from the raw materials to the actual use of
these materials for production)

- QUARANTINE
o Quarantine Sticker
§ Upon reception and once the RTR is accomplished, the
material will be stored in the quarantine area where it will
be attached with a quarantine sticker which is usually
colored yellow.
o samples taken (for analysis)
o Examined or Tested
- RECEPTION § In here the samples will be taken for analysis so the
o “Receipt of the deliveries” samples will be examined or tested dependent on the type
o Examined visually of material and on a pharmacopeial, an in-house or a
§ the inspector or the warehouse personnel will examine the regulatory standard.
packages visually; he or she will check whether there are o Decision Stickers
leakage or breakage § After the results are out, the decision stickers will now be
§ Upon inspection, the inspector or the warehouse pasted
personnel will examine the packages visually so he or she - APPROVED
will check whether there are leakage or breakages on the o Properly handled and stored
outside packaging § if the material has passed the acceptance criteria of all the
§ Check the integrity of the packages such as boxes if there tests that are done with the material then it will be moved
are leaks or labeling materials with folds (in bulk and not into an approved materials area or section and in there, it
necessarily in detail because this is only upon the will be properly handled and stored dependent on the
reception of the material or delivery). required storage condition and handling of the material
o Distinctive receiving number o FIFO (First In First Out)
§ The warehouse personnel will also be giving distinctive § Materials that are the same with the new materials
receiving number which will put a history on that delivery delivered would be rotated wherein the first materials that
indicating the date when the package was received and in are there must be the first ones to be dispensed (first in,
what condition it was delivered. first out) to the production area so that the old materials
§ This will serve as a tracking device so that if there are will not be stocked.
problems encountered, it would easily be traced back. § The principle followed is the same with the stock rotation
o (Receiving Tally Report) RTR of community and hospital pharmacies, FIFO is followed
§ a document that the warehouse personnel will fill out upon so that expiration of materials would be avoided.
the receipt of the material. o Approval Sticker
§ There are information here that needs to be filled out § Putting an approval sticker is a must. This is usually a
regarding the material that is delivered and then this will green sticker.
be double checked by the quality manager. § There are several ways on pasting an approval sticker. It
§ accomplished in 4 copies: 1 copy will remain at the can be totally covered. Since it already has a quarantine
warehouse, 1 copy will be at the QC Department, 1 copy sticker, once it is transferred to the approved materials
will be give in to the purchasing and 1 copy will be given section, it would get another sticker. They may cover the
to the Accounting Department. existing quarantine sticker completely/fully or only half of
it (quarantine sticker is still visible despite being pasted
over).

Serrano, Ulangco, Bautista, Feria 1 of 7

Quality Control: Controls PHA 6122 - Lecture
§ Other manufacturing companies would totally remove the - Covers the application with a given torque of a threaded lug-
quarantine sticker to avoid confusion and a new approved style closure to a container
sticker would be pasted. o Applicable to bottles with closure na pinapaikot (roll-on type
- REJECTED closure)
o If materials are not approved, it will be stored in the rejected - Measures the torque required to unscrew the closure from a
materials section container
§ should be in Lock-and-Key for it not to be used o The goal is to have bottles and closures that are effective, in
accidentally such a way that there are no leakages during handling,
§ To control the accidental use of rejected materials transportation, and storage but can still be unscrewed by the
o Materials must be identified and controlled person who will use it.
o Materials must be pasted with a Rejection Sticker (Color red) - SI unit: Newton-meter (force x distance)
- RE-EVALUATION - Imperial unit: inch-pound
o If the materials in the approved materials section were not - Also tests the performance of automatic capping machines
immediately used due to high amount of stock or if the o not only the result of the capping machine is determined, but
production using this material was stopped, re-evaluation of also the actual capping machine itself
the status of materials must be done. o probably during validation of a particular machine, the
o Done after prolonged storage of the material effectivity of the capping machine is observed
o Use of reassay date (determined dependent on the stability - measuring any tendency for threaded or lug-style closures to
of the product/materials) loosen during storage or shipment of the package
§ Monthly or prior to use - Highly unstable materials o you do not want the closures to be loosened up during
§ Every 6 months - Vitamins and Flavors storage or shipment
§ Every 12 months - Active Ingredients, Dyes or colorants - measuring the force required to break hard plastic and overturn
§ Every 24 months - Highly stable active ingredients or "strip" soft plastic and metal closures
together with some excipients - measures the force required to open up the nebules (hard
§ PACKAGING MATERIALS plastics) and also the foil packs/ blister packs (since these need
1. PHYSICAL TESTS force whenever it is opened)
a. Light Transmission Test c. LEAK TEST
b. Torque Test - has 3 methods:
c. Leak Test 1) Dye bath
d. Water Vapor Transmission Test o containers are subjected to vacuum or pressure while
2. PHYSICO-CHEMICAL TESTS immersed in bath
a. Chemical Resistance o principle: if there is a leak in the ampule, usually when
b. Moisture Permeation immersed in a bath, liquid will enter the ampule
c. Thermal Analysis o in order to check if there will be liquids to enter the ampule,
d. Nonvolatile Residue the bath must be colored in the first place
e. Residue on Ignition o usually the dye that is being used is methylene blue, thus,
f. Heavy Metals if the bath is blue, and if there is leak in the ampule, blue
g. Buffering Capacity liquid must enter the ampule
3. BIOLOGICAL TESTS 2) Liquid loss
a. Biological Reactivity Tests, In Vitro o involves pulling a vacuum, but without the dye, resulting in a
b. Biological Reactivity Tests, In Vivo loss of liquid
1. PHYSICAL TESTS o principle: outwards movement of the liquid from the ampule
a. LIGHT TRANSMISSION TEST o if there is leak in the ampule, there will be liquid loss upon
- Test for containers intended to provide protection from light or the pulling using the vacuum
offered as a light-resistant container 3) High voltage detection
o Amber bottles are light resistant containers. They must be o involves very costly electronic equipment, which applies a
tested if they can really protect the containers from light using high voltage across the length of the ampule
UV-Vis Spectrophotometer because light coming from the o high voltage across the length of the ampule is applied, and
environment is UV light. then the area with high voltage is observed if there is a
- Select sections to represent the average wall thickness presence of leakage from the ampule
- Spectrophotometer 2. PHYSICO-CHEMICAL TESTS
- Amount of light transmitted in the region of 290-450nm a. CHEMICAL RESISTANCE
o At the most, UV wavelength range - determines the resistance to water attack of new (not
- ACCEPTANCE CRITERIA previously used) glass containers
- degree of attack is determined by the amount of alkali released
from the glass
o we know already that glasses or containers sometimes leach
their components
o leaching: the integrity of the container breaks out, and the
component of the container (whether glass or plastic) reacts
with its contents
o plastics have higher probability of leaching than glasses
o however, we could not avoid leaching in glasses, specifically
if we are placing aqueous solutions / water-based solutions
in the bottles, since water can attack bottles
§ Dependent on the nominal size of the containers and how o component of glasses: alkali or basic materials, that is why
they are sealed the degree of attack will be dependent on how much alkali is
§ Flame-sealed: ampules and nebules released from the glass (we do not want that)
§ Closure-sealed: products with closures or gaps o the more basic our endpoint would be, the higher the degree
§ Expressed in percentages of light transmitted of attack
b. TORQUE TEST

2 of 7
Quality Control: Controls PHA 6122 - Lecture
- GLASS TYPES - then, the containers must be categorized as tight and well-
closed containers
1) Tight containers
o if not more than 1 of the 10 test containers exceeds 100mg
per day per L in moisture permeability, and none exceeds
200mg per day per L
o if the criteria above is not met, it is well-closed containers
2) Well-closed containers
o if not more than 1 of the 10 test containers exceeds 2000mg
o looking at the composition of the glasses, all of them are per day per L in moisture permeability, and none exceeds
alkali (we do not want that to leach in the solution) 3000mg per day per L
- again, to determine if there is leaching, chemical resistance test o if there exceeds 3000mg per day per L, the closure is not
is performed effective anymore in terms of moisture permeation
- Two types of test done under chemical resistance test: - based on the definition, tight containers will provide more
1) Powdered Glass Test - Types 1 and 3 protection from moisture compared to well-closed containers
o the glass or the bottle is pulverized, and then water is added,
then autoclave for some time, then the amount of alkali that MANUFACTURING CONTROL
is leached from the glass is observed • Procedures are embodied in four important documents designed
2) Water Attack Test - Type 2 to explain why and how the products are made.
o done in the whole container (not pulverized); the whole 1. Manufacturing monographs
container is added with water, autoclaved, then you decant 2. Batch records
the water inside then test for its alkalinity 3. Standard operating procedures (SOPs)
o done in type 2 because they are "treated soda-lime glass", 4. Quality control monographs
which differs in type 3 (not treated); in type 2, the treatment • These are documents that needs to be within the vicinity of the
is only in the inner surface of the bottle manufacturing laboratory
§ thus, if the treatment is only in the inner surface, and the 1. MANUFACTURING MONOGRAPHS
integrity of the treatment is only there, therefore you have
- The manufacturing monograph is the basic document from
to perform the test in the bottle as a whole; pulverizing type where the master formula and batch production records are
2 glass will result to being the same with type 3 glass since based.
the integrity of the treatment is lost
- Cannot be changed
- Titration is done to determine the amount of alkali released
- 3 groups of documents which includes the
from the glass
1) master formula records
o since the sample (alkali) is basic, then the standard must be
o contains the particular formula of the product
acidic, therefore the titration is direct acidimetry
o list of ingredients and excipients with corresponding amount
o the acid should be 0.02N sulfuric acid
o kept in a secured documentation room, duplicated, or
b. MOISTURE PERMEATION
photocopied only whenever a job order is issued.
- add dessicant (anhydrous calcium chloride) to 10 containers 2) master production documents - would have production
(test containers) and glass beads to the remaining 2 containers processes
(control containers) 3) master packaging documents - would have production
o 12 containers in total processes
o the dessicant (anhydrous calcium chloride) is placed in the 2. BATCH RECORDS
dessicator to maintain the relative humidity which is at
- all records generated during the course of producing a batch of
75±3%
quality-controlled product
o to maintain that humidity, saturated solution of sodium
- can be changed slightly towards formula, processes,
chloride must be added inside the dessicator, placed at
packaging and manufacturing processes. Little tweaks are
23±2ºC
documented in batch records.
- dessicator at 23±2ºC and 75±3% relative humidity
o Ex. Adding acids to reach desired pH level
- after 336 ±1 hours (14 days), record the weight of the individual
- completed documents permit reconstruction of the history of
containers
the product
o recording of the containers must be done before and after
o these are all records upon production, which can be
the storage
reviewed upon when looking into the batch number. This is
- used to test the integrity of the closure of the bottle how it permits reconstruction.
- (1000/14V) [(TF - Ti) - (CF - Ci)] o includes batch production records, batch packaging records,
o rate of moisture permeability must be computed in mg/day/L and batch control records (RTR, quarantine report, sampling
using the formula above frequency, sample taken, resample request, testing
o V = volume of the container, which is also to be measured frequency, disposition, certificate of disposal, stickers).
for 5 containers 3. STANDARD OPERATING PROCEDURE (SOP)
§ the 5 containers are filled up to the brim, then closed, then
- generated to explain in detail the reason behind a procedure
opened again to decant the contents, and then measured and proper sequence of steps to be done, and how equipment
using a graduated cylinder are to be operated for maximum performance.
§ the average of the 5 containers will be used for the value
- If there is an uncertainty in how a task is done in a laboratory,
of V
you can always refer to the SOP
o "1000" is used to convert mL into liters, since the unit must
4. QUALITY CONTROL MONOGRAPH
be per liter
- The quality of each and every component used in the
o (1000/14V) is multiplied to the test containers minus the
manufacture of the product is assured by testing these in
control containers
accordance with the specifications and methods provided by
o the rate moisture permeability of all 10 test containers must
the quality control monographs.
be computed individually, since it has to be evaluated
individually - When referring to a test procedure to determine the quality of
o at the end of the computation, we have 10 rate moisture the product, you can refer to the quality control monograph
permeability

3 of 7
Quality Control: Controls PHA 6122 - Lecture
§ PRESERVATION OF SAMPLES AND RECORDS 3. Tablet coating [Coated Tablets]
• This is the way of preserving records and samples - Average weight
• RESERVE SAMPLE - Color and coating finish
- at least twice the quantity necessary for all required tests of § LIQUID PREPARATION
identity, quality, purity and strength is set aside for preservation - Clarity
• COMPLETE RECORDS - pH
- related to the control, use, production, distribution, & complaint. - Solubility
- maintained to permit reconstruction of the history of the - Specific Gravity
product. - Assay
- Ex: if there is a product complaint, or a particular product must - Viscosity
be checked on how it was produced § SEMI-SOLID PREPARATION
• In general, ISO Standards recommends, records and samples - Active material dispersion
are retained for a period of 5 years.
- pH (excluding ointments)
• Local FDA recommends - Viscosity
1. Components:
o At least 2 years after the distribution of the last lot of product PACKAGING CONTROL
incorporating the component has been completed; or
o 1 year after the expiration date of this last lot incorporating Packaging and labeling operations are controlled to assure that the
the components finished product is properly identified with a~
2. Finished Products • CONTROL CODE
o At least 2 years after lot distribution is completed, or - during packaging a code is assigned for that packaging batch
o 1 year after the expiration date of the product. as a reference number to go back into.
3. Records - permits construction of the history of the product
o Drugs: as above - to prevent mix-ups and errors ; always put codes
o Cosmetics: At least 3 years after manufacture is completed. • LINE CLEARANCE
• ICH Guideline recommends - facilities are cleared out of package finished products and
1. Active pharmaceutical ingredient (API) batch packaging materials of the previous run.
o reserve samples - Before placing another bulk/ labeling/ box material, clear out
o should be retained for 1 year after the expiry date of the the material line first that were used from the previous run to
batch assigned by the manufacturer, or for 3 years after prevent mix ups and errors
distribution of the batch, whichever is the longer. - Products which are similar in appearance, containers or
2. Records labeling are not processed simultaneously on adjacent or
o All production, control, and distribution nearby lines unless these operations are separated by a
o should be retained for at least 1 year after the expiry date of physical barrier.
the batch • PACKAGING RECONCILIATION
3. APIs with retest dates - done after the packaging operation is completed.
o records should be retained for at least 3 years after the batch
is completely distributed.
• Determine the best guideline to be used. Document kept up to 10
§ IPQC Tests for Packaging Control
1. encoded batch and expiry date
years would keep a lot of space. Have standards to be followed o only encoded during packaging run
to be proved especially when being inspected to have no o not encoded on packaging material like bottles or labels until
problems. it’s not used to prevent wastage.
o one of the crucial steps during packaging
IN-PROCESS QUALITY CONTROL 2. count or measure in finished pack minimum fill (net weight/net
During processing, the quality of the product at various stages of content of the packaging)
production is audited by quality control. 3. label appearance and adhesion
• to determine if the product meets specifications throughout the 4. bulk material identification (there must be a code for the bulk
entire processing period and particularly during critical stages of material showing that it is indeed the material needed for
manufacturing packaging on that day)
• Before proceeding to another step of manufacturing, perform 5. cap torque
IPQC tests first. Every step of the way must be tested if these are 6. seal integrity of strip or blister pack
critical stages. 7. correctness of first and last packages
• Prevents producing a finished product that does not pass the
acceptance criteria. DISTRIBUTION CONTROL
• IPQC shows the quality of intermediate products to prevent re- • Finished products pending disposition should be separately
manufacturing of a finished products. stored from finished goods which have been approved by quality
§ SOLID PREPARATION (TABLET) control for distribution to avoid mix up
- Uncoated Tablets: only tablet granulation and compression • STOCK CARD
1. Tablet granulation - Documentation for products from production to warehouse or
- Assay finished products to be placed in the warehouse for distribution
- Granule size - Indicates a beginning & ending inventory within a certain period
- Moisture content (crucial, also a factor of compression) - Name of the product, Lot number, Date received from
2. Compression production area, quantity received, expiration date, & pack size
- Average weight - Beginning inventory: quantity received; how much was
- Diameter received from production (ex: # of boxes of a certain product)
- Disintegration - Once the product is to be distributed, list the date, invoice
- Dissolution number, quantity issued, balance, and issued by
- Friability o Ex: from 1000 boxes, 100 boxes were delivered to a
- Hardness community pharmacy, leaving a balance of 900 boxes
- Thickness - Name of the person who received the product is not included,
only the invoice number
4 of 7
Quality Control: Controls PHA 6122 - Lecture
REJECTION AND REUSE OF MATERIALS
REJECTION
• If the result is rejected or outside the acceptance criteria
• Intermediates and APIs failing to meet establish specifications
- Quality control personnel will determine if it can be reprocessed
or reworked
• Final disposition should be recorded.
- If upon testing, it can still be reprocessed, then the it must be
recorded that it can still be reprocessed, the same if rejected

REPROCESSING
• DISTRIBUTION CARD • Intermediate or API (including those rejected) that can be used
- A better way to retrace the history of a product for reprocessing
- Of great value in recalls because you know where you have - Introducing the intermediate or API back into the process and
distributed the product reprocessing by repeating a crystallization step or other
appropriate chemical or physical manipulation steps
- Just one step of the process is looked into again

REWORKING
• An investigation into the reason for non-conformance should be
performed
- Several steps of the process are looked into again
• Subjected to appropriate evaluation, testing, stability testing if
warranted, and documentation to show that the reworked product
is of equivalent quality to that produced by the original process in
terms of quality
- Must be able to prove that the reworked product is of the same
• The difference between a stock card and distribution card is that quality as the products that underwent the original process
in the distribution card, the name of the customer and the address
of where it was distributed are indicated, so that in cases of drug RECOVERY OF MATERIALS AND SOLVENTS
product recalls, there is a history of where the batch was
distributed • Reactants, intermediates, or the API
- Approved procedures must exist for the recovery
ENVIRONMENTAL CONTROL - Recovered materials must meet specifications suitable for their
intended use
• Checking if you adequate ventilation, air filtration and exhaust o Tested again to check if required specifications are met
systems provided within your manufacturing laboratory
• Solvents
- Environment must be designed and constructed to minimize
- Recovery procedures are controlled and monitored to ensure
risks of contamination and cross-contamination
that solvents meet appropriate standards before reuse or co-
- Include equipment for control of air pressure, microorganisms mingling with other approved materials
(if appropriate), dust, humidity, and temperature, as
appropriate to the stage of manufacture RETURN
o All these must be checked to know the condition of your
environment • Intermediates or APIs
• PROCESS WATER - Should be reprocessed, reworked, or destroyed, as appropriate
- Water that is used during the entire processing of your product o Depending on the quality of how the product was returned
- Should at a minimum, meet World Health Organization (WHO) - Records should be maintained
guidelines for drinking (potable) water quality o Name and address of the consignee
- Test for the ff: o Intermediate or API, batch number, and quantity returned
o Physical/chemical attributes o Reason for return
o Total microbial counts o Use or disposal of the returned intermediate or API
o Presence or absence of objectionable organisms and/or
endotoxins COMPLAINTS AND RECALLS
• There must be dedicated production areas, specifically for • Handled by the Quality Coordinating Office/QMS of the
materials that are: manufacturing laboratory
o Highly sensitizing/Highly reactive materials • All quality related complaints, whether received orally or in writing,
§ Materials that can frequently induce allergic reactions, should be recorded and investigated according to a written
such as penicillin & cephalosporins (which contains beta procedure
lactams) are produced in different building since they are • The following information must be documented
highly sensitizing materials - Name and address of complaint;
§ Different equipment and wardrobe are utilized in order to - Name (and, where appropriate, title) and phone number of
avoid cross-contamination person submitting the complaint;
o Material of an infectious nature or high pharmacological - Complaint nature (including name & batch number of the API);
activity or toxicity - Date complaint is received;
§ Production of these products, such as oncology products - Action initially taken (including dates and identity of person
are also separated since these are highly toxic, or use a taking the action);
material of infectious nature - Any follow-up action taken;
- Prevent cross-contamination from personnel, materials, etc - Response provided to the originator of the complaint (including
date response sent); and
- Final decision on intermediate or API batch or lot
• Records of the complaints should be retained

5 of 7
Quality Control: Controls PHA 6122 - Lecture
• Immediate corrective action should be given • Bulk product: Actual Yield = 2990L
• Product recall procedure QC Sample = 3 x 250mL = 750mL ≃ 0.75L
o Who should be involved in evaluating the information - Once able to produce the bulk product, it is your actual yield
§ If the product is already released to the market/retailers, - The QC Sample is taken by the QC inspector
the public should know 1. How much is the % gross yield?
§ If the product is still in distribution, there is no need for the o Gross yield: everything produced (including the QC sample)
public to know "#$%&' )*+',-./ 0&12'+
§ % gross yield = 8 100
o How a recall should be initiated 34+56+$*#&' 7*+',
;<<=>-=.@A>
§ Ex: Announcement to the public = 8 100 = 99.69%
B,===>
o Who should be informed about the recall 2. Compute for the % net yield
§ If public, or only on the distribution level o Net yield: what you have produced w/o the QC sample
o How the recalled material should be treated § % net yield =
"#$%&' )*+',
8 100
§ Can the recalled material still be reprocessed or 34+56+$*#&' 7*+',
;<<=>
reworked? = 8 100 = 99.67%
B,===>
§ Assessed by the QC inspector 3. How much is the % total loss?
- if unable to correct and must be recalled from the market o QC sample is already considered as a loss
• In the event of a serious or potentially life-threatening situation, o % total loss = 100% minus % net yield
local, national, and/or international authorities should be informed § % total loss = 100% - 99.67%
and their advice sought = 0.33%
- PH authority in terms of drug products: FDA 4. Is the manufacturing loss within normal limits? Why?
- If the result is life-threatening or serious, the FDA’s advice must o Limit: 99% yield or NMT 1% loss
be sought to spread the information regarding the particular o Yes, it is within limits since the %total loss is NMT 1% and
product since the net yield is 99.67% which is more than 99% yield
§ Manufacturing is within normal limits
EXERCISE ON PRESERVATION OF RECORDS
• First thing to be calculated is how long do we preserve the records EXERCISE ON PACKAGING RECONCILIATION
or documents for drug products • Part of the packaging control
• Retention of records • Packaging of already manufactured bulk products

Batch records of the syrup manufactured today are to be retained. Production of Multivitamin Syrup (cont. of the previous ex.)
If the product has a shelf life or 3 yrs and distribution will be • Batch Size / Theoretical Yield (TY): 3000 L
completed at the end of next year, determine the ff: • Bulk Product Actual Yield (AY): 2990 L
1. Expiration date • Packaging breakdown (breakdown of where you will be
Date of manufacture + Shelf life packaging your bulk product):
November 18, 2020 + 3 years = November 2023 25,000 bottles x 15 mL
o In writing expiration dates, only the month and year are 15,000 bottles x 60 mL
needed 14,375 bottles x 120 mL
2. Last day when medication can be taken • Packaging Limits: 98% yield or NMT 2% loss (cumulative: all
Last day of the month losses from manufacturing to packaging)
November 30, 2023 • Finished Product
3. 3 possible retention periods for the documents Fill Volume Net Yield QC samples
o ISO Guidelines and local FDA guidelines can be followed 14.98 mL 24850 bottles 24 bottles
o ISO Guideline: 60.25 mL 14390 bottles 12 bottles
1) 5 years from the date of manufacture
120.15 mL 14286 bottles 10 bottles
o Local FDA Guidelines: same as retention period of drug
2) 2 years after distribution and - 15mL bottles
o Average fill volume is 14.98mL for the 15mL bottles
3) 1 year after expiration
§ since there are many 15mL bottles, the average fill volume
o Convert the guidelines into actual dates
ISO Guideline: was computed instead
o Net Yield: Instead of 25,000 of 15mL bottles, only 24,850
1) Date of manufacture: Nov 2020 → Nov 2025
bottles were produced
Local FDA Guideline
§ QC samples are not included in the count
2) Date of Distribution: End of next year → Dec 2023
3) Expiration Date: Nov 2023 → Nov 2024 o QC Sample: 24 bottles
o If given the chance to choose which retention period to - 60mL bottles
follow, choose whichever is the shortest since there is a o Average fill volume: 60.25mL
guideline basis o Net Yield: only 14,390 bottles of the 60mL bottles were
December 2023 produced instead of 15,000 bottles
o Why keep it for a longer time if you can keep it for a shorter o QC Sample: 12 bottles
time? There will be more space in storage to retain other - 120mL bottles
documents. o Average fill volume: 120.15mL
o Net yield: 14,286 bottles were produced instead of 14,375
bottles
EXERCISE ON BULK PRODUCT RECONCILIATION
Production of Multivitamin Syrup o QC Samples: 10 bottles
• Batch size / Theoretical Yield(TY) = 3000L • Actual yield and Qc Sample (converting bottles to liters)
Total amount of bottles x fill volume = volume packaged
- If tasked to manufacture 100,000 bottles of 30mL of
multivitamin syrup - Total volume of packaged multivitamin syrup =
o 14.98 mL x (24,850 +24) x 1/1000 = 372.61L
- 100,000 bottles x 30mL = 3,000,000mL ≃ 3000L multivitamin
o 60.25 mL x (14,390 +12) x 1/1000 = 867.72L
syrup
o 120.15 mL x (14,286+10) x 1/1000 = 1,717.66L
- Only in theory, not actual o 372.61L + 867.72L + 1717.66L = 2957.99 L
• Manufacturing Limit = 99% yield or NMT 1% loss
- You should produce 99% of what you are wanting to produce

6 of 7
Quality Control: Controls PHA 6122 - Lecture
1. What is the % gross yield? § 172 cases x 144 bottles in each case = 24,768 bottles
"#$%&' )*+',-./ 0&12'+ o To get the number of loose bottles, minus the total number
§ % gross yield = 8 100
34+56+$*#&' 7*+', of bottles to the number of bottles in the 172 cases
;<A@.<<>
= 8 100 = 98.60% § # of loose bottles = 24,874 bottles – 24,768 bottles
B,===>
2. How many liters were lost during the filling and packaging run? = 106 loose bottles in the last case
TY manuf BPAY fill & pack FPAY c. How many labels were used?
3000 L 2990 L 2957.99L o Labels are used in: total number of labels =
10L 32.01L § the total number of bottles (24,874 bottles)
- Theoretical yield (TY) is 3000L then after manufacturing, the § one label each is required to be pasted on each case (173
Bulk product actual yield (BPAY) is 2,990L (this is the amount cases) and;
that was actually produced. § one label for the batch record
- From TY to BPAY, there was a 10L manufacturing loss (this is o total number of labels = 24,874 + 173 + 1 = 25,048 labels
not the loss in question, the loss we need is the volume lost d. What is the %wastage?
during the filling and packaging, aka the packaging loss) o Since there were no labels left (balance of label is zero),
- After producing the bulk product, we have the finished product however, only 25,048 labels were used, but 25,500 labels
actual yield (FPAY) which are the already bottled products were issued. So the remaining labels that weren’t used
- From Bulk Product (2990L), 2957.99L were bottled which is probably broke since it was mentioned that were was a
considered as the FPAY. balance of zero labels, this is what is considered as the
- BPAY minus FPAY is the volume lost during filling and wastage
# EL GFWKGO MOOIKR \# EL GFWKGO IOKR
packaging o % wastage = 8 100
# EL GFWKGO MOOIKR
o 2990L – 2957.99L = 32.01L ;A,A== GFWKGO \;A,=TZ GFWKGO
§ 8 100 = 1.77% wastage
- For the packaging run, we also have to consider the ;A,A== GFWKGO
manufacturing loss e. Did the labeling run meet the specification?
- When we are computing for the packaging loss, we also have o The maximum wastage is 3%,
to consider the manufacturing loss because it is a cumulative o Yes, labeling run meets the specifications since 1.77% is
loss less than 3%
- Total volume already lost
o 32.01L + 10L = 42.01L as the liters lost
DEDFG HEGIJK EL GMDKNO GEOD
o x 100
FPDIFG QMKGR
T;.=U>
§ 8 100 = 1.4% loss
B,===>
3. Is the packaging run within limits?
- Packaging loss: Not more than 2% loss cumulative
- 1.4% loss is still within limits since it is less than 2%
4. Assume that:
• 25,500 x 15mL labels were issued
• One label each is required to be pasted on each case of 144 filled
bottles (whether complete or not)
- Your bottles are placed in a case, so each case contains 144
bottles.
- The cases have one label each (whether complete or not),
meaning that regardless if the case is full or if it contains loose
bottles inside them
• Balance of label is zero
- Meaning no labels were left and there were no more extra
labels
• One label specimen for attachment to batch record
• Maximum wastage for packaging material is 3%
- This serves as the limit for the packaging material
- Maximum wastage should not be more than 3%
a. How many cases are used?
o All the cases mentioned may be full or not full
o Remember that QC samples should be labeled as well,
therefore include QC samples in the computation for
packaging reconciliation
o First, count the number cases that were used
§ The number of 15mL bottles that were filled:
24,850 for net yield + 24 for QC sample = 24,874 bottles
o Then, determine how many cases would contain 24,874
bottles.
§ Each case will contain 144 bottles
# EL WEDDGKO LMGGKR
§
# EL WEDDGKO MX KFPY PFOK
;T,Z@T WEDDGKO
= = 172.74 cases ≃ 173 cases
UTT WEDDGKO/PFOK
§ This means that 172 cases are full of 144 bottles, and 1
case (the 173rd case) is not full, containing the loose
bottles. However, the total number of cases used is still
173 cases.
b. How many loose bottles are there?
o How many bottles are in the last case?
o First, compute how many bottles were in the 172 cases

7 of 7
 ASEAN Guideline on Stability Study of Quality Control
Drug Product
Asst. Prof. Rhona P. Ramos, MSc. PHA 6122
December 2, 2020 Lecture

STABILITY o VARIATIONS: Major and Minor (refer to ASEAN Guideline

• The ability of an active ingredient or a drug product to retain its article for the definitions)
properties within specified limits throughout its shelf life. o For conventional dosage forms: at least two pilot scale
• an essential factor of quality, safety and efficacy of a drug product batches
- physical (like hardness, dissolution rate, phase separation, § Immediate release dosage forms (conventional)
etc.) o For critical dosage forms: three primary batches (two of the
- chemical (formation of high risk decomposition substances) three batches should be at least of a pilot scale; the third
batch may be smaller)
- microbiological
o PRIMARY and PILOT SCALE batches are different.
STABILITY STUDY § Primary- stability testing
§ Pilot Scale- smaller than production batches (refer to the
• Purpose: to establish a shelf-life and label storage instructions article for definition)
applicable to all future batches of the drug product manufactured
and packaged under similar circumstances
§ Testing Parameters
- After stability testing
• biased towards more stressful rather than less stressful
conditions - physical, chemical, biological and microbiological attributes,
preservative content (e.g. antioxidant, antimicrobial
- give more stress on your product than less stress during
stability study because this will provide a margin of error in preservative), and functionality tests (e.g., for a dose delivery
system)
favor of the patients because the product underwent a stressful
environment during stability study - appearance, assay and degradation products should be
evaluated for all dosage forms
- to provide a margin of error in favor of the patients
- microbial quality of multiple-dose sterile and non-sterile dosage
- to increase the likelihood of identifying substances or
forms should be controlled storage orientation of the product,
formulations that pose particular stability problems
o so that during the stability study, you may already identify the i.e., upright versus inverted, may need to be included in a
protocol
formulations that are not really stable so you must be biased
o If you are also testing for the integrity of the container closure
towards more stressful conditions
system, you must orient the product in an inverted or upright
• to determine the shelf-life
form. You can store it upright or inverted.
- the time period of storage at a specified condition within which
the drug product still meets its established specifications § Testing Frequency
• consists of a series of tests in order to obtain an assurance of
stability of a drug product
- when conducting stability studies, it consists of a series of tests
to obtain an assurance of a drug product
- a drug product is stable: maintenance of the specifications of
the drug product packed in its specified packaging material and
stored at the established storage condition within the - long term studies
determined time period o every 3 months over the first year, every 6 months over the
o you have to contain the product in its final container; in a second year, and annually thereafter through the proposed
container that your consumer will buy and use. You do not shelf-life
have to put it in a special container for it to be stable. o FIRST YR (every 3 mos): 0 mo.(initial testing for baseline),
• general conditions for long term stability testing in the ASEAN 3rd mo., 6th mo., 9th mo., 12 mo. Testing
region are the Zone IVB conditions (30oC/75% Relative Humidity) o SECOND YR: every 6 mos.(after 12th, proceed to 18th mo.),
- Philippines: Zone IVB then 24th month.
o THIRD YR & ONWARDS: after 24th, proceed to 36th month
§ STABILITY STUDIES o long term shelf-life; long term stability study (ex. 3 yrs shelf
1. Long Term life, 3 yrs stability study)
2. Accelerated o LONG TERM TESTING
§ Stability studies under the recommended storage
DESIGN condition for the re-test period or shelf life proposed (or
approved) for labeling.
• How you are going to perform the stability study
§ Do this throughout your shelf life
§ Photostability Testing - accelerated studies
- Exposing drug products to the effects of light o a minimum of three time points, including the initial and final
- should be conducted on at least one primary batch of the drug time points
product if appropriate o only 3 testing frequency (0 mo., 3rd mo., 6th mo.)
o Primary Batch: A batch of a drug product used in a stability o done for at most 6 months with 3 time points (initial, middle,
study, from which stability data are submitted in a registration final testing)
application for the purpose of establishing a re-test period or o ACCELERATED TESTING
shelf life, respectively. § Studies designed to increase the rate of chemical
§ Batch for stability study degradation or physical change of a drug substance or
§ Selection of Batches drug product by using exaggerated storage conditions as
- For NCE: at least three primary batches part of the formal stability studies.
o New chemical entities (new substances) § Get all the samples needed for all the testings (physical,
- For Generics and Variations chemical testing, etc.)
§ Manufacturers proceed first to accelerated testing so that
they know what to propose for shelf life
Serrano, Ulangco, Bautista, Feria 1 of 5
Quality Control: ASEAN Guideline on Stability Study of Drug Product PHA 6122 - Lecture

§ Example: Philippines’ normal condition: 30oC, Generic Products

exaggerated: 40oC
§ Hastened degradation but also fast testing
§ After accelerated testing, you can now predict shelf life
and can proceed to long term testing. At this point, you
already know the length of your long term testing because
you know your proposed shelf life.
§ Storage Conditions
- drug product should be evaluated under conditions to test its
thermal stability and, if applicable, its sensitivity to moisture
or potential for solvent loss.
- LONG TERM – IMPERMEABLE
o Relative humidity is not specified because the product is
contained in an impermeable container (water vapor cannot
pass through)
- Stress Testing
o Necessary for analytical method validation, pharmaceutical - generic products are almost the same with NCE products,
formulation, identifying and monitoring potential degradants however, we can have long term stability testing for 6 months
during stability testing if we are dealing with conventional dosage forms and stable
o purposive drug substances
- however, for critical dosage form or unstable drug substances,
the minimum time covered is still 12 months
- in generic products, it can be shortened if you are testing
conventional and stable drug substances, and you can use
minimum of 2 batches for this type of dosage form
- for accelerated, it is still 6 months, and you can still use 2
batches for conventional dosage form and stable drug
substances
Major Variation (MaV)

- Impermeable Containers
o glass ampoules, aluminum/aluminum blisters, High Density
Polyethylene (HDPE) or glass bottles fitted with metal or
HDPE closures
o can be conducted under any controlled or ambient relative
humidity condition
o there is no limit for relative humidity
- Semi-Permeable Containers (Aqueous-Based Products)
o evaluated for potential water loss
o can be carried out under conditions of low relative humidity

- for major variations, same storage conditions. the difference

would be the minimum time covered
- for long term, you can use 6 months
- for conventional, minimum of 2 batches will be used; for critical,
minimum of 3 batches– same with accelerated
Minor Variation (MiV)

- for minor variation, you can have a minimum of 3 months

- 2 batches for conventional, and 3 batches for critical (6months)

2 of 5
Quality Control: ASEAN Guideline on Stability Study of Drug Product PHA 6122 - Lecture

§ In-Use Stability • Significant change at accelerated condition

• to provide information for the labelling on the preparation, storage - significant change is observed during your testing: in
conditions and utilization period of multidose products after accelerated or long term, different intervals of testing are
opening, reconstitution or dilution of a solution present, from 0, 3months, 6months, 9months, 12months,
• should be determined over the period of the proposed in-use - occurs between 3 and 6 months’ testing at the accelerated
shelf-life storage condition
- these are drug products that are multiple-dose products that - the proposed shelf-life should be based on the long term data
differs from its original shelf-life once it is opened available at the long term storage condition
- there are medicines that have and expiration date of 2 years, o meaning, if you have seen a significant change during your
but once it is opened, usually it should only be consumed within testing of accelerated condition, whether it is 3months or
2 weeks inside the refrigerator for example, or 4 weeks outside 6months storage, you have to propose the shelf-life based
the refrigerator, depending on the drug product on long term data
- meaning, once that multi-dose containers are opened, its shelf- o if a significant change is present in a proposed shelf life using
life changes, and that is what we call "in-use stability testing", accelerated storage or accelerated studies, it is never
wherein the shelf-life is determine using that test given/proposed
• performed at intermediate time points and at the end of the o you can only propose a shelf-life if a significant change is not
proposed in-use shelf-life on the final amount of the drug present in accelerated stability testing
remaining in the container - significant changes:
o 1. A 5% change in assay from its initial value, or failure to
• minimum of two batches, at least pilot-scale batches
meet the acceptance criteria;
§ Container Closure System § we know that assays have acceptance criteria
• should be conducted on the dosage form packaged in the § if a drug product is assayed after 3 months or after 6
container closure system proposed for marketing (including, as months, and it does not meet the acceptance criteria, then
appropriate, any secondary packaging and container label) that is significant change already
- stability testing must be done to the final packaging where the § meaning, if that is significant change, you now proceed to
product will be placed in long-term stability testing already
• packaging materials are classified as semi-permeable or § thus, you do not continue the accelerated since you
impermeable depend on the packaging material characteristics cannot propose a shelf-life using that data anymore
such as thickness and permeability coefficient § or 5% change from its initial value; for example your initial
- examples for impermeable containers are already provided (by assay value is 105%, then for the assay of 3 months, you
maam) have 95% then that is more than 5% change, which is
- if containers are not included in the list, then those are your already a significant change
semi-permeable containers o 2. Any degradation product exceeding the acceptance
§ Evaluation criterion;
- after testing, data should be evaluated § aside from the assay, you also have to test for the
• Data Presentation degradation product
§ if there is degradation product that does not meet the
- Data for all attributes should be presented in an appropriate
acceptance criteria, then that is also a significant change
format (e.g., tabular, graphical, narrative) and an evaluation of
o 3. Failure to meet the acceptance criteria for appearance,
such data should be included in the application.
physical attributes, and functionality tests (e.g. colour, phase
o If you are applying for let's say product registration, you have
separation, resuspendability, caking, hardness, dose
to present your data for stability
delivery per actuation); however, some changes in physical
- If a statistical analysis is performed, the procedure used and
attributes (e.g., softening of suppositories, melting of
the assumptions underlying the model should be stated and
creams) may be expected under accelerated conditions and
justified.
as appropriate for the dosage form.
• Extrapolation of Data § you have to check for the physical attributes of the product,
- the practice of using a known data set to infer information about its appearance, and functions/functionality test
future data sets § you have to check, for example, if it is normal for the
o this is where prediction of shelf-life becomes present, suppository to melt if it is accelerated (probably yes, since
especially in accelerated stability testing since you will only if it is accelerated, that is 40ºC, and suppositories should
do this for 6 months, but you need to propose the shelf-life melt at 37ºC, so you have to expect them to soften or melt
for 1 year or 2 years for example– that is what you call at those temperatures
extrapolation o 4. Failure to meet the acceptance criteria for pH;
- consider the possible worst-case situation at the time of batch o 5. Failure to meet the acceptance criteria for dissolution for
release 12 dosage units (capsule or tablet).
o it is always safe for you to propose shelf-life much shorter • General Statistical Approaches
than its actual shelf-life, since it is better to safely propose
- employed to analyze the long term primary stability data in an
than try to propose a "stable product" although in real life it original application
is not
- purpose of this analysis is to establish, with a high degree of
- assumes that the same change pattern will continue to apply confidence, a shelf-life during which a quantitative attribute will
beyond the observed range of available long term data
remain within acceptance criteria for all future batches
- always be verified by additional long term stability data as soon manufactured, packaged, and stored under similar
as these data become available circumstances
o extrapolation of data is done for accelerated testing because
- Regression analysis is considered an appropriate approach to
you are proposing a longer shelf-life compared to what you evaluating the stability data for a quantitative attribute and
have performed
establishing a shelf-life.
o say for accelerated, you performed only for 6 months, but
- In general, the relationship between certain quantitative
you proposed for 1 year or 2 years, so you have to verify that
attributes and time is assumed to be 1 linear
using long-term stability testing
o that is why the statistical analysis that is used or the
- extrapolated shelf-life may be up to twice, but should not be statistical tool in stability is regression analysis
more than 12 months beyond, the period covered by long term
data

3 of 5
Quality Control: ASEAN Guideline on Stability Study of Drug Product PHA 6122 - Lecture

o this is an example of a data that is analyzed using regression

analysis
o at x-axis: time in months
o y-axis: assay in % labeled claim
o then you also have regression line, then you get upper
confidence limit around the regression line
o you also have upper and lower acceptance criterion
o when you are proposing shelf-life, the acceptance criteria is
95%-105%
o for example the acceptance criteria of the assay is 95%-
105%, you always have to look at its lower acceptance
criterion: "at what month will it arrive to its lower acceptance
criterion?"
o at this graph, if we will look at the regression line, it will cross
95% at around month 35-36, thus, that would be 3 years
o however, since you have upper and lower confidence limit, if
you will look at its lower confidence limit, it is much earlier to
cross its lower acceptance criterion (around 30th month),
hence, its shelf-life is much shorter if lower confidence limit
is used
§ meaning, when you are proposing a shelf-life, it is always
important to look at its lower confidence limit, since it is
much dangerous (as a manufacturer) if you will propose a
shelf-life that is much longer than its actual shelf-life
§ since you do not really know the shelf-life; you are just
proposing
o based on its regression line, its shelf-life is around 36
months, but when lower confidence limit is used, it becomes
30 months
§ if you are the manufacturer, "which proposal is much safer,
36 months or 30 months?" of course it is much safer to use
the shelf-life for 30 months

• The following slides (images) are the decision tree regarding the
proposal of shelf-life.

4 of 5
Quality Control: ASEAN Guideline on Stability Study of Drug Product PHA 6122 - Lecture

• Statements/Labeling
- storage statement should be established for the labeling in
accordance with relevant national/regional requirements
- based on the stability evaluation

Recommended labelling statements for Drug Products

o during storage, shipment and distribution of the Drug

Products, the current good practices (GDP) for
pharmaceutical products are to be observed

o depending on the pharmaceutical form and the properties of

the drug product, there may be a risk of deterioration due to
physical changes if subjected to low temperatures, e.g.
liquids and semi-solids. Low temperatures may also have an
effect on the packaging in certain cases. An additional
statement may be necessary to take account of this
possibility.

- “ambient conditions” or “room temperature” should be avoided

o during labeling, these terms should be avoided, because we
know that, especially here in the Philippines, we have
different ambient and room temperatures and if you want to
state the product at a certain temperature, do not use "store
at room temperature" because it varies
o you have to explicitly state the temperature that your product
should be stored at
- recommendations should also be made as to the utilization
period and storage conditions after opening and dilution or
reconstitution of a solution
o this is done or given using the data that is gathered in the "in-
use stability testing"

End of Reviewer

5 of 5
 Statistical Process Control Quality Control
Asst. Prof. Rhona P. Ramos, MSc. PHA 6122
December 4, 2020 Lecture

STATISTICAL PROCESS CONTROL (SPC) SPC Tools

• use of statistical techniques to measure change in systems • tools that are used to check the quality of the system
• one method of monitoring quality in pharmacy practice § Histogram
• useful tool because a key determinant of quality in products and - graph that displays frequency distributions for unique
services is consistency categories of measure
• SPC is the one that can measure the consistency in the quality of - in here, what we can see is the frequency (how many; how
our products often; the magnitude of the measurement)
• inconsistencies - useful for determining the overall shape of the data, data
- can be identified to improve quality by using statistical analysis distribution, and variation in data
- can be distinguished if acceptable or unacceptable using SPC
tools
- we have to determine if inconsistencies can be accepted or not

Rationale
• Repeated measurements of the same process within a system
will have variable outcomes over time.
- common-cause variation
- special-cause variation
§ COMMON-CAUSE VARIATION
- always present within a system
- consists of modest changes that occur randomly
o differences in individual pharmacists and technicians, patient
populations, situations, and chance
§ for example, in a manufacturing laboratory, there are two
different pharmacists (or pharmacy technicians that help
the pharmacists in producing the products) manufacturing
the products, thus, their quality of products are different
§ for differences in patient population, for example, in a Figure 1. (Bar graph) Time in minutes for new prescriptions to be
community pharmacy, there are different types of filled in a community pharmacy Number of new prescriptions
population (customer)– a variation within the system
§ any situation or chance that are different from one day to - in here, we can see the frequency distribution– which
the other prescription is the most filled on a particular time range
- this type of variation cannot be removed - the most filled prescription ranges within 21-25 minutes
- a predictable pattern of variation emerges; hence, not a
problem
§ Pareto Chart
- a type of histogram, categorizes data according to the most
- As long as the system stays the same, common-cause
frequent issues on the left to the least frequent issues on the
variation stays the same.
right
- A system is considered to be in a state of statistical control
- in here, it is arranged from the most frequent to the least
when only common-cause variation is present.
frequent
§ SPECIAL-CAUSE VARIATION - The Pareto principle, states that 80% of your quality output
- occurs when there is an interruption to the regular process comes from 20% of what you do, is the foundation for the chart.
o due to a deliberate event or an unexpected occurrence - since the most frequent and the least frequent is already
§ deliberate event: probably, laying-off a pharmacist identified, you know where to focus already
(tinanggal mo yung pharmacist), hence, the quality of the - assist in deciding which issues should be emphasized for
product changes, or the process becomes slower problem-solving, thereby having a larger impact on quality
§ unexpected occurence: for example, there is a natural improvement
calamity/flood, at hindi agad napalitan yung pharmacist for - usually used when you want to identify or list problems
his/her shift, and the pharmacist is already tired that there
becomes variation in the services, thus, an unexpected
occurence that gives special-cause
- could be desirable or undesirable
o desirable: for example, you hired a new
pharmacist/personnel, thus, the service becomes faster
o undesirable: most of the time, it is undesirable
§ mostly not on the positive side
§ this is the type of variation that you must always observe
in order for it to be corrected
- not predictable, and it fluctuates over time
- When this type of variation is present, the system is considered
to be out of the state of statistical control. Figure 2. Types of dispensing problems

- right there and then, you can identify the problems that you
want to focus (left: make the most out of the problem)

Serrano, Ulangco, Bautista, Feria 1 of 6

Quality Control: Statistical Process Control PHA 6122 - Lecture
§ Scatter Diagram o If the variations are just fluctuating between the upper and
- show patterns in data and relationships between two variables lower and not exceeding, there will be no review of systems
for a unit analysis (e.g., a patient) (wala ka nang masyadong poproblemahin kasi this is a
- can present patterns in data in order to identify the common cause variation- it naturally happens)
relationships between two variables - Only the events outside the acceptable control limits are
- Analysis of data allows a regression line to be drawn that shows pursued.
the relationship between variables in a scatter diagram. o If you have data outside the control limit, you can now pursue
the event.
o What happened during that time period?
- The control limits are typically set at 3 SD around the mean,
which says that 99.97% of measures will fall within the control
limits.
o Get the mean of the data set then get the 3 standard
deviations below or above. 3SD are needed because this will
cover 99.97% of the data. Outside that, it will already be too
far from the mean.
- allows only meaningful changes in the process to be captured
- greater confidence that a measure observed outside of the
control limits is really due to special-cause variation
Figure 3. The relationship between pharmacy loyalty and overall o This will guide you on where to pursue the variation. Pag
patient satisfaction. Overall satisfaction lagpas na sa UCL or LCL, that’s when you’ll pursue a
special-cause variation
- for example, the two variables here are overall satisfaction and
pharmacy loyalty: you want to determine if the pharmacy loyalty
is dependent on the overall satisfaction
o you want to know the relationship between these two: if it is
linear or not
- parameter: r2
§ you have to have 0.99 r2, so that you will know if these two
variable have linear relationship

§ Run Chart
- can identify performance patterns and trends by showing how
a variable changes over time
- trend/time
- can also be used to make comparisons among trends by using
multiple variables
- basis would be "time" Figure 5. Average time in minutes for a new prescription to be
- x axis: time; and the other one is the variable that varies filled at ABC Pharmacy
- X-axis: months; y-axis: minutes
- Fluctuating, not constant.
- The green solid line is the mean and the broken red lines are
the control limits.
- In between 3rd and 4th month, you will see the drastic change.
Ask whether this is a common cause variation or a special
cause variation
o Looking at the data, this is still a common cause variation

Figure 4. Percentage of patients receiving medication counseling

prior to discharge from a hospital.

- in here the trend during the first 5 months stayed in the same
range (21% above)
- after the 5th month, which is on the 6th month, there is already
a trend that changes over time
- run chart can easily show "what is happening" over time
o saan biglang nagbago?
o saan biglang tumaas/bumaba?
§ Control chart
- a type of run chart (1 variable each for the x and y axis)
- serves as a visual aid to distinguish between common- and
special-cause variations
o main tool in identifying/ distinguishing variations Figure 6. Average time in minutes for a new prescription to be
- comprised of a series of measurements over time and three filled at XYZ Pharmacy
horizontal lines which represent the upper control limit (UCL), - Looking at the data, there are 2 data outside the limit
mean, and lower control limit (LCL) - Special cause variation: exceeded limit on the 8th and on the
- This is called control chart because it has a control limit 11th month- you can determine right away what events
- Variation that occurs between the UCL and LCL is considered happened on those months
to be acceptable and will not trigger a review of system.

2 of 6
Quality Control: Statistical Process Control PHA 6122 - Lecture
QUALITY CONTROL CHARTS
1. Attribute Chart
- Makes use of discrete data classifying the number of items
conforming and the number of items failing to conform to any
specified requirements.
o Not measured, just determining if it is within or outside the
acceptable criteria
o Conforming or non-conforming/ accepted or rejected
products/ pass or fail
o p chart (fraction-defective chart)

2. Variable chart
- Using actual records of numerical measurement on a full
continuous scale such as meter, grams, liter.
o Variables are measured data
o Scales on y-axis; time as x-axis
o X̄ (mean) and R (range) charts

EXERCISES
1. 20 sets of 10 tablets were weighed during compression at
30 min intervals. Calculate LCL and UCL and find out if the
process is statistically controlled.
a. Use the formula: to compute for standard deviation (s)
∑(' − '̅ )!
! = $
+−1
Step 1: Compute for standard deviation (s)
Mean of 10 tablets (mg)
373.3 374.1 370.0 367.9 374.1 365.1 368.0 371.1 366.9 372.5
381.5 365.1 365.8 370.0 369.7 370.6 372.8 365.2 370.3 370.4
-.- = /0 − 3! 2.- = /0 − 3!
(By using excel spreadsheet, same process for calculator)
• Transfer the 20 data sets into an excel spreadsheet
(Set #: column a, data: column b)
• Follow the formula in a long method
- Calculate first the standard deviation in a long method, using
the excel spreadsheet
i. Compute the mean of x
o (data in column b) (By using calculator, if kaya by calculator, then do it [nike])
o =average(highlight all data in column b) i. Input all the data
o Press enter ii. get the mean
ii. Compute (' − '̅ ) iii. get the difference then square
o x mean of x in column C iv. get the summation and
o Have a separate column for x minus mean of x v. by the number of data subtracted by 1.
o Do this for each individual data to get the difference of the vi. Then get the square root for the standard deviation
data minus the mean
o Add a dollar sign after the column letter so that the mean of Step 2: Calculate the upper & lower controls limits (UCL & LCL)
x will stay constant in the formula o LCL: Subtracting 3 standard deviations from the mean
o Formula for Set 1 x mean of x: =B2-B$22 (LCL = X¯ − 3s)
o Drag the lower right corner of the cell down until the last data o UCL: Adding 3 standard deviations to the mean
set so that the formula will be applied to all sets (UCL = X¯ + 3s)
Mean of 10 tablets (mg)
iii. Compute for (' − '̅ )! 373.3 374.1 370.0 367.9 374.1 365.1 368.0 371.1 366.9 372.5
o x mean of x squared in column D 381.5 365.1 365.8 370.0 369.7 370.6 372.8 365.2 370.3 370.4
o Can also be done on calculator LCL = X¯ − 3s UCL = X¯ + 3s
o =x mean of x cell^2 LCL = 370.25 − 3(3.99) UCL = 370.25 + 3(3.99)
o =C2^2 LCL = 358.3 UCL = 382.2
o Drag the lower right corner of the cell down until the last data
set so that the formula will be applied to all sets Step 3: Determine if there are any data that are beyond the
iv. Get the S (summation) lower limits or upper limits.
o sum of all the values of x mean of x squared - If there are none then the data sets are statistically controlled
o =SUM(highlight all data in column D) - If there are then the data set is not statistically controlled
v. Divide it by + − 1 • Problem for compression process
o n= number of data (for the example given, there are 20 data - Since no data is beyond the limits, the compression process is
sets, therefore n=20, n-1 = 19, which will serve as the statistically controlled.
denominator)
vi. Divide the S (summation) by + − 1 Step 4: Converting the data into a control chart
o =summation cell/n-1 cell • Mean Chart
o =D22/D23 - Plotted means of the 10 tablets
vii. Get the square root of S divided by + − 1 - Data are means
o =SQRT(summation cell) - x axis are time periods
o =SQRT(D24)

3 of 6
Quality Control: Statistical Process Control PHA 6122 - Lecture

o 15 number of inspections for 5 different vials per inspection

Mean = 370.25, LCL = 358.3, UCL = 382.2

b. Using the table, calculate the standard deviation using the o Inspection happens every 30 minutes
formula:
" a. Solve for x̄ and , R and .
δ= Step 1: Solve for Mean
#
- where R is the range o =average(highlight cells per inspection #)
o Difference between highest value and lowest value o drag for the formula in all the rows
- D is the divisor for the sample size used o verify the data by placing the cursor on the formula to check
Mean of 10 tablets (mg) if the desired data was used in the formula
373.3 374.1 370.0 367.9 374.1 365.1 368.0 371.1 366.9 372.5
381.5 365.1 365.8 370.0 369.7 370.6 372.8 365.2 370.3 370.4 Step 2: Get the Range
Step 1: Identify the highest and lowest values from the data o Find the difference of the highest and lowest values per
o Highest: 381.5; Lowest: 365.1 inspection #
Step 2: Divide the highest and lowest values by the divisor of o In one column, get the max
the sample size used =(max(highlight cells per inspection #)
o Sample size: 20 o In another column, get the small
Divisor for Estimating SD from the range (small(highlight cells,1)
Sample size (n) Divisor (D) Sample size (n) Divisor (D) § If asked which position, like third or second smallest or first
2 1.1 9 3.0 smallest, place 1 to get the pinakasmallest, if second
3 1.7 10 3.1 smallest and hinahanap, then place 2
4 2.1 25 3.5 o Then get the difference between Range Max and Range
5 2.3 20 3.7 Small
6 2.7 30 4.0 o You can also use the Compiled formula instead
8 2.8 50 4.5 =(max(highlight cells per inspection #)) – (small(highlight
Step 3: Calculate standard deviation cells,1))
" $%&.( – $+(.& o Drag the formulas for both corresponding columns
δ = ; δ =
# $., Step 3: Get the Mean of Means
δ = 4.43 o Average of all means
o Rough estimation of SD compared to 3.99 from the previous o =average(highlight all cells under mean column)
formula in (a) Step 3: Get the Mean of Means
o Average of all Ranges
2. The volume of 5 vials was determined during the filling of o =average(highlight all cells under range column)
an injectable. Determine the UCL and LCL using the
formulas below: b. Solve for LCL and UCL.
o What is being measured here is the filling process, if it is Factors for estimating 3 δ (standard deviations)
statistically controlled or not Sample size (n) Factors for x̄
Factors for chart
o Just estimations of our SD chart (A2)
D3 D4
∑(/0/̅ )7
o This equation is more accurate: ! = 6 2 0.00 3.27 1.88
30&
3 0.00 2.57 1.02
• We can have the lower and upper control limits for the means and
4 0.00 2.28 0.73
the ranges
5 0.00 2.11 0.58
6 0.00 2.00 0.48
7 0.08 1.92 0.42
8 0.14 1.86 0.37
9 0.18 1.82 0.34
= mean of means ; A2, D3, D4 = Factors ; R = Range 10 0.22 1.78 0.31
Factors for estimating 3 δ (standard deviations) Step 1: Check for the factors for 5 vials
Sample size (n) Factors for x̄ A2 = 0.58; D3 = 0.00; D4 = 2.11;
Factors for chart
D3 D4 chart (A2)
2 0.00 3.27 1.88
3 0.00 2.57 1.02
4 0.00 2.28 0.73
5 0.00 2.11 0.58
6 0.00 2.00 0.48
7 0.08 1.92 0.42
8 0.14 1.86 0.37
9 0.18 1.82 0.34
10 0.22 1.78 0.31

4 of 6
Quality Control: Statistical Process Control PHA 6122 - Lecture
Step 2: Compare all the data for the mean and ranges with your
Upper and Lower Control Limits for the mean and the range

o Control Chart can be used to help you find data that lies
outside the mean
• Range (R) chart
- Data plotted is the ranges, not the mean
- UCL and LCL of the range is plotted as well
- 1-15 on the x axis are time periods for every 30 minutes

Step 2: Compute for fraction defective (on excel)

o =(# of defective per day) / (sample size)
o On the 12th 30 minute, there is data that lies outside the limit o Drag down to get the fraction defective for all days
§ Must pursue this data that is a special-cause variation to Step 3: Get the Mean of Fraction Defectives
find out what happened during this time o =average(highlight cells under p column)
o Alternative formula:
3. A batch of ointment was filled into tubes during working =[sum(highlight cells under d column)] / [sum(highlight cells
days. 500 tubes were filled each day. The inspector under n column)]
withdrew a random sample based on the master table and
noted the number of leaking tubes below. b. Compute for average fraction defective ( )
∑4
o Filling and packaging process = ∑
3
o Population: 500 tubes per day
(on excel)
o Inspector withdrew a random sample based on the military
=[sum(highlight cells under d column)] / [sum(highlight cells
standard table
under n column)]
o Look for special-cause variation or if the process is
statistically controlled or not.
c. Calculate the LCL and the UCL through the formulas
Day No. of o Average fraction defective: 0.074
a. Compute for fraction defective (p): leaking o Number of data: 10
9 tubes
8= 1 4
+
Where: 2 6
d – number of defectives found 3 7
4 5
n – number of units inspected
5 3
6 1
o Out of the samples, you must detect the 7 6
number of leaking tubes 8 3
o Since this is an attribute chart and you are 9 2
just looking at items that are conforming or 10 0 o From these control limits, compare all your fraction
not conforming, nothing is being measured. You are simply defectives if they are outside your LCL and UCL, if anything
checking the presence or no presence of leakage, so you will is lower than LCL and higher than UCL
be able to count how many leaking tubes there are
Step 1: Identify the sample size
o If the lot size per day is 500 tube and no specific inspection
level was mention, proceed to inspection level 2 (normal
inspection)
o Sample Size Code: H, Sample size: 50
o Every day, sample size of 50 tubes are taken for inspection,
from there, you will determine the number of leaking tubes
per day

5 of 6
Quality Control: Statistical Process Control PHA 6122 - Lecture

o Fraction Defective ( ) Chart can be used to help you find

data that lies outside the mean

o LCl does not lie within the chart since it is a negative value

d. Is the crimping process statistically controlled?

o None of the values are outside the control limits, therefore
the crimping process is statistically controlled

6 of 6