Introduction

- Quality is the combination of attributes or characteristics of a product which, when compared to a standard, serves
as a basis for measuring the uniformity of the product and determines its degree of acceptability.

QUALITY CONTROL

- Quality control is a tool, which gives the assurance that a product conforms to standards and specifications
through a system of inspection, analysis, and action.
- Quality Control (QC) is used to describe the functions within the total control effort responsible for on-line or in-
process testing
- Quality is everybody’s business.
- Quality control system is established at the conception of a new product, during production of the batch, and
during distribution of the commercial package.
- This system is a combination of those administrative and technical procedures, which must be used to produce
and deliver a safe, pure, and effective product to the end user.

QUALITY ASSURANCE

- Quality Assurance (QA) has been used to describe the overall organizational body designed to assure product
quality, while the title.

 The potential benefits derived from a quality control system are as follows:
1. The system minimizes or eliminates the risk of marketing unsafe products.
2. It guarantees conformance to regulatory requirements.
3. It guarantees product efficacy.
4. It reduces operating costs.
5. It reduces operating losses.
6. It produces higher employee morale.
7. It motivates the pharmaceutical/medical professions to sell or prescribe the product.

ORGANIZATION OF QUALITY CONTROL

- Part of a manufacturing firm is a defined organization. Each segment of this organization is expected to fine-
tune its functions and responsibilities. An effective coordination is called for among its personnel, equipment,
building and inventory of materials. All these activities are performed towards the production of a drug or
cosmetic of the highest standard and at the lowest cost.
o In a manufacturing firm, it is a common to have the following divisions under a general manager:

1. Finance
2. Production
3. Quality Assurance (Quality Control)
4. Marketing (optional in a third party contract manufacturer)

- All manufacturing must be done in compliance with Current Good Manufacturing Practice (CGMP). For this
reason, Administrative Order No. 220, s. 1974 is included in the Appendix in its entirety.
- In enforcing CGMP to achieve the desired goal of delivering a safe, pure and effective product at the lowest
cost to the consumer, a specific group must be organized to be the core of the company’s quality audit
program. Thus, the quality control department is organized to maintain quality of products to a prescribed
level.

REF. QUALITY CONTROL II

By: Norma V. Lerma and Marina O. Osi
 - Each pharmaceutical or cosmetic company has an organizational structure, which differ somewhat from those
if other companies in scope and responsibilities. Fig. 1-2 shows a typical organization within the quality
control department.

Materials Inspection Section

- Inspectors are alert individuals who had experience and who are familiar with the physical characteristics of the
materials they sample and are well versed in sampling techniques. The functions of this section are:

1. To sample and examine all raw materials received.

2. To sample and conduct physical tests on:
a. All shipments of packaging materials
b. All manufacturing, filling and packaging operations
3. To maintain periodic examination on the quality of inventories throughout all phases of storage, shipping
and distribution.
4. To perform an audit which is independent of the work done by production personnel?

- Inspection stations are placed in the area of operation, viz., warehouse, manufacturing and packaging areas.

Analytical Laboratory

- The analytical laboratory should be in an accessible area and protected from noise and vibration common to
manufacturing operations.

- In order to perform physical and chemical analysis, the analysts should know the usual gravimetric and volumetric
analysis. Furthermore, they should be skillful in handling instruments for ultraviolet and infrared spectrophotometry,
non-aqueous titrimetry, autoanalysis, polarography, x-ray diffraction, x-ray fluorescence, spectrophotoflourimetry,
radioactive tracer techniques and chromatography, viz.: column, gas, paper, thin layer and high performance liquid
chromatography.

Biological Testing Laboratory

- The staff in a biological testing laboratory should be well trained and experienced in both simple and complex
microbiological procedures and biological interactions. They should possess a high degree of skill and judgment in
order to perform the job. A veterinarian is recommended to supervise the care and maintenance of the various species
of animals used in the tests. The functions of this laboratory are:
1. To perform and evaluate microbiological and pharmacological assays, sterility, pyrogen and bacteriological
tests, irritation, safety or acute toxicity tests.
2. To conduct environmental monitoring.

- Sterile conditions should be provided for areas where biological tests are conducted. Noise should be precluded
from areas where animals are used. An animal house should be maintained as a separate unit from the main
laboratory, if necessary.

Specification and Analytical Development

- This section should have firm background not only in the principles of quality control and analytical procedures but
also in manufacturing, research, product development and in statistics in order to perform the following functions:

1. To coordinate with research, product development, production, sales and management towards improvement
of a product.
2. To establish specifications for raw and packaging materials.
3. To validate existing and tentative procedures of testing.

REF. QUALITY CONTROL II

By: Norma V. Lerma and Marina O. Osi
 4. To establish specifications based on validated procedures.
5. To develop new assay methods for in-house use.
6. To develop and improve specifications for quality characteristics of the final product being manufactured.

Quality Coordination Office

- This section should be accessible to all manufacturing and packaging operations since documentation is its main
responsibility. The functions of this section are:

1. To maintain and store records that represent the history of the batch from start to finish. These records
include the batch and master formula records, raw material analytical records, printed and packaging material
inspection reports and retention files.
2. To be able to furnish data that will aid in analyzing product performance in the market. These documents are
the stability studies and returned goods reports.
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 scientific and legal status, i.e., data generated from the use of recognized standard
compendia. This is essentially a function of the distribution section or warehouse.
6. To maintain and develop SOP’s.

HIGHER MANAGEMENT

Scientific V.P. Manufacturing V.P.

Research &
Development Purchasing

Production
Quality
Control
Warehouse

Materials Inspection Section Maintenance

Analytical Laboratory

Biological Testing Laboratory

Specifications & Analytical

Development

Research on one manufacturing company and be able to give the organizational chart

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By: Norma V. Lerma and Marina O. Osi
STANDARDS AND SPECIFICATIONS

 Quality is the combination of attributes or characteristics of a product which, when compared to a standard,
serves as a basis for measuring the uniformity of the product and determines its degree of acceptability
 Quality characteristics are interpreted by descriptive words and measurements. Characteristics are
subject to variation.
 Quality variation which is not confined within a specific range, tolerance or limit, will grow to uncontrolled
magnitude and will encourage the proliferation of errors; thus producing a defective product.
 To avoid producing a defective product, standards and specifications are developed to serve as a basis for
accepting or rejecting a product. In a product, these must cover the following points:

1. Formula. This is concise and precise statement of the ingredients that comprise the product, together with
the percentage and/or weight of each.

2. Raw material specification. This should enumerate the characteristics of all the materials that go into the
product and the permissible range of purity of each ingredient. Deviation beyond this range may be
expected to cause failure of the product to function as planned or, at least, result in an undesirable lack of
uniformity. Standard compendia like the USP, NF, BP, BPC, Merck Index, etc., provide this valuable
information.

3. Standard operating procedure. This is a step by step method on how to go about a job. It must spell out
all information and instructions that assure that variations in production from day to day and week to week
will be held to within acceptable established ranges.

4. Finished product specification. This should cover all characteristics that affect the proper performance,
purity, safety and stability of the product. Tolerances may be minimum, maximum, or both, depending on
the nature of the situation.

5. Packaging material standard. This should be set for everything that goes around the product, i.e., bottles,
cans, aluminum foil, cellophane, jars, caps, cap liners, labels, printed inserts, cartons, wrapping papers,
and shipping cases. Packaging must be considered with the following points in mind:

a. The units may have to run on a high-speed line.

b. They may involve a complicated assembly.
c. The package may be functional.
d. The package must be completely compatible with the product.
e. The package must protect the product and assure its stability.
f. The package must ship well.

6. Testing Methods. These are indispensable in assuring conformity to standards. Since they play such a
vital role, testing procedures must be standardized so that they yield results of comparable precision and
accuracy in the hands of different operators and laboratories. The tests must be validated to ensure
precision and accuracy on application.

Official References:
United States Pharmacopoeia and National Formulary
Japan Pharmacopeia
British Pharmacopeia
European Pharmacopeia
International Pharmacopeia

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An overview of USP/NF
 The United States Pharmacopeia (USP) is the official public standards-setting authority for all prescription
and over-the-counter medicines, dietary supplements, and other healthcare products manufactured and
sold in the United States.
 USP sets standards for the quality of these products and works with healthcare providers to help them
reach the standards. USP's standards are also recognized and used in more than 130 countries. These
standards have been helping to ensure good pharmaceutical care for people throughout the world for more
than 185 years.
 USP is an independent, science-based public health organization. As a self-sustaining nonprofit
organization, USP is funded through revenues from the sale of products and services that help to ensure
good pharmaceutical care.

 USP's contributions to public health are enriched by the participation and oversight of volunteers
representing pharmacy, medicine, and other healthcare professions as well as academia, government, the
pharmaceutical industry, health plans, and consumer organization
 Many other countries require the use of high-quality standards such as USP's to assure the quality of
medicines and related products. USP disseminates its standards to pharmaceutical manufacturers,
pharmacists, and other users through its USP–NF and other publications, official USP Reference
Standards materials, and Pharmacopeial Education courses.
 USP also conducts verification programs for dietary supplement ingredients and products. These programs
involve independent testing and review to verify ingredient and product integrity, purity, and potency for
manufacturers who choose to participate

 The USP–NF is a single-volume combination of two official compendia, the United States Pharmacopeia
(USP) and the National Formulary (NF).

 Monographs for drug substances and preparations are featured in the USP. Monographs for dietary
supplements and ingredients appear in a separate section of the USP. Excipient monographs are in the
NF.

 A monograph includes the name of the ingredient or preparation; the definition; packaging, storage, and
labeling requirements; and the specification.

 The specification consists of a series of tests, procedures for the tests, and acceptance criteria.
These tests and procedures require the use of official USP Reference Standards.

 Medicinal ingredients and products will have the stipulated strength, quality, and purity if they conform
to the requirements of the monograph.

 Tests and procedures referred to in multiple monographs are described in detail in the USP–NF
general chapters.

Refer to sample monograph below

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An Illustrated Guide to USP Standards Using the Acetaminophen and Acetaminophen Capsules Monographs
Acetaminophen Monograph, Illustrated
1. Acetaminophen
C8H9NO2 151.17
Acetamide, N-(4-hydroxyphenyl)-.
4’-Hydroxyacetanilide [103-90-2].
2. >>Acetaminophen contains not less than
98.0 percent and not more than 101.0 percent
of C8H9NO2, calculated on the anhydrous basis. the article is specified. It is usually given as a percentage of the
3. Packaging and storage—Preserve in tight,
light-resistant containers.
4. USP Reference standards <11>—USP
Acetaminophen RS.
5. Change to read:
6. Identification
A: Infrared Absorption <197K>.
B: Ultraviolet Absorption <197U>—
1. The monograph begins with an official title, using the United
States Adopted Name (USAN), as outlined under
Nomenclature <1121>, followed by descriptive information,
including a graphic formula, chemical formula, molecular
weight, chemical names, and Chemical Abstracts (CAS)
registry number.
2. The first item, introduced by a bold-face double-chevron
symbol (>>), is the Definition. In the Definition, the content of
chemical formula, based on the Assay, calculated on the
anhydrous or dried basis. The assayed content of a synthetic
drug substance normally should not be less than 98.0 percent
and not more than 102.0 percent. The tightness of the
tolerance depends on the precision of the assay used as well
as on the ability to produce a drug substance of high purity
without incurring unreasonable costs. For articles of lesser
purity, which are derived from natural sources or fermentations,
as well as for biologics (see Biologics <1041>), the content
might be expressed in micrograms per milligram or in units per
milligram.
3. A discussion on packaging and storage is found in the
General Notices under Preservation, Packaging, Storage, and
Labeling. The proper packaging and storage conditions should
be derived and documented from stability studies on the bulk
drug. These standards are also important and applicable to
storage and repackaging within the community pharmacy.
4. The Reference Standards section notifies the analyst of the
official USP Reference Standard(s) used in the monograph and
refers to the general test chapter USP Reference Standards
<11> for additional information and instructions. Reference
Standards are supplied by USP. (See also the section on
Reference Standards in the General Notices).
5. Although technically not part of the monograph, this is a key
revision phrase, which denotes that an official revision has
occurred (see No. 6). The superscript black box is the
beginning of the change and the subscript black box with a
numeral signals the end of the change. The number at the end
denotes the Supplement that the revision becomes official.
(The official date of each Supplement is listed on the front
cover of each Supplement.) Other revision phrases include
"Add the following;" and "Delete the following:"
6. Identification tests are discussed in Procedures under Tests
and Assays in the General Notices and Requirements. They
are "…provided as an aid in verifying the identity of articles.
Such tests, however specific, are not necessarily sufficient to
establish proof of identity…Other tests and specifications in the
REF. QUALITY CONTROL II
By: Norma V. Lerma and Marina O. Osi
Solution: 5 µg per mL. 3
Medium: 0.1 N hydrochloric acid in methanol (1
in 100).
C: It responds to the Thin-layer
Chromatographic Identification Test <201>, a
test solution in methanol containing about 1 mg
per mL and a solvent system consisting of a
mixture of methylene chloride and methanol
(4:1) being used.
7. Melting range <741>: between 168° and
172°.
8. Water, Method I <921>: not more than 0.5%.
9. Residue on ignition <281>: not more than
0.1%.
10. Chloride <221>—Shake 1.0 g with 25 mL
of water, filter, and add 1 mL of 2 N nitric acid
and 1 mL of silver nitrate TS: the filtrate shows
no more chloride than corresponds to 0.20 mL
of 0.020 N hydrochloric acid (0.014%).
Sulfate <221>—Shake 1.0 g with 25 mL of
water, filter, add 2 mL of 1 N acetic acid, then
add 2 mL of barium chloride TS: the mixture
shows no more sulfate than corresponds to
0.20 mL of 0.020 N sulfuric acid (0.02%).
Sulfide—Place about 2.5 g in a 50-mL beaker.
Add 5 mL of alcohol and 1 mL of 3 N
hydrochloric acid. Moisten a piece of lead
monograph often contribute to establishing or confirming the
identity of the article under examination."
The most conclusive test for identity is the infrared absorption
spectrum (see Spectrophotometry and Light-scattering <851>).
When taken together, absorption bands characteristic of
individual functional groups are unique for a given chemical
compound with few exceptions. Conformance with both infrared
absorption and ultraviolet absorption test specifications "leaves
little doubt…regarding the identity of the specimen under
examination" (see Spectrophotometric Identification Tests
<197>). If no suitable infrared spectrum can be obtained, the
Thin-layer Chromatographic Identification Test <201> is a good
substitute. Care has to be taken to ensure that the
chromatographic system separates the article from other
closely related drug substances. When a drug substance is a
salt, identification of the base or acid used is also provided.
This is particularly important if an active principle is available in
several salt forms. Identification tests for the most frequently
used acids or bases can be found in Identification Tests—
General <191>.
7. For many organic compounds the melting range or
temperature is a convenient criterion of identity and purity.
Generally, for a melting range to be useful it should not exceed
3° or 4°. This test should not be specified when the substance
melts with decomposition; rather, such characteristics are given
in USP in the Reference Tables under Description and
Solubility.
8. If water is the only residual solvent, or if it is present as a
hydrate, it must be determined for the reasons given for
Procedures under Tests and Assays in the General Notices.
Water Determination <921> describes the various methods that
might be applicable for a given article.
9. Residue on ignition can be regarded as a purity test because
it limits contamination with inorganic matter (salts) in an organic
compound. Such contamination would not be readily detectable
by the assay, particularly a chromatographic one. It also serves
as an identity test for compounds with heavier inorganic
counterions or inorganic functional groups.
10. These tests are provided as general procedures where
limits of chloride or sulfate salts are specified.
REF. QUALITY CONTROL II
By: Norma V. Lerma and Marina O. Osi
acetate test paper with water, and fix to the
underside of a watch glass. Cover the beaker
with the watch glass so that part of the lead
acetate paper hangs down near the pouring
spout of the beaker. Heat the contents of the
beaker on a hot plate just to boiling: no
coloration or spotting of the test paper occurs.
11. Heavy metals, Method II <231>: 0.001%. 11. This limit test, which actually determines heavy metals
relative to a lead standard, should be used whenever
contamination with toxic metals introduced during the
manufacturing process is suspected. With modern methods of
synthesis and modern supplies of acids, the need for such a
test requirement seems to have lessened somewhat, at least in
developed countries, and it has been possible to lower the
limits for heavy metals in a number of articles.
12. Free p-aminophenol—Transfer 5.0 g to a 12. Toxic impurities, arising out of the synthesis or degradation
100-mL volumetric flask, and dissolve in about of an article, are those possessing undesirable biological
75 mL of a mixture of equal volumes of properties. They must be controlled by suitable tests to a level
methanol and water. Add 5.0 mL of alkaline not considered harmful. The manufacturer must notify USP
nitroferricyanide solution (prepared by concerning the presence of such impurities and should provide
dissolving 1 g of sodium nitroferricyanide and 1 methods and validation data for a limit test. Suitable limit tests
g of anhydrous sodium carbonate in 100 mL of employ either chromatographic methods or specific and
water), dilute with a mixture of equal volumes of sensitive spectrophotometric and chemical methods.
methanol and water to volume, mix, and allow
to stand for 30 minutes. Concomitantly
determine the absorbances of this solution and
of a freshly prepared solution of p-aminophenol,
similarly prepared at a concentration of 2.5 µg
per mL, using the same quantities of the same
reagents, in 1-cm cells, at the maximum at
about 710 nm, with a suitable
spectrophotometer, using 5.0 mL of alkaline
nitroferricyanide solution diluted with a mixture
of equal volumes of methanol and water to 100
mL as the blank: the absorbance of the test
solution does not exceed that of the standard
solution, corresponding to not more than
0.005% of p-aminophenol.
Limit of p-chloroacetanilide— Transfer 1.0 g
to a glass-stoppered, 15-mL centrifuge tube,
add 5.0 mL of ether, shake by mechanical
means for 30 minutes, and centrifuge at 1000
rpm for 15 minutes or until a clean separation is
obtained. Apply 200 µL of the supernatant
liquid, in 40-µL portions, to obtain a single spot
not more than 10 mm in diameter to a suitable
thin-layer chromatographic plate (see
Chromatography <621>) coated with a 0.25-
mm layer of chromatographic silica gel mixture.
Similarly apply 40 µL of a Standard solution in
ether containing 10 µg of p-chloroacetanilide

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per mL, and allow the spots to dry. Develop the
chromatogram in an unsaturated chamber, with
a solvent system consisting of a mixture of
solvent hexane and acetone (75:25), until the
solvent front has moved three-fourths of the
length of the plate. Remove the plate from the
developing chamber, mark the solvent front,
and allow the solvent to evaporate. Locate the
spots in the chromatogram by examination
under short-wavelength ultraviolet light: any
spot obtained from the solution under test, at an
Rf value corresponding to the principal spot
from the Standard solution, is not greater in
size or intensity than the principal spot obtained
form the Standard solution, corresponding to
not more than 0.001% of p-chloroacetanilide.
13. Readily carbonizable substances 13. This nonspecific test is applied to substances that are not
<271>—Dissolve 0.50 g in 5 mL of sulfuric acid readily carbonized by sulfuric acid in order to limit the presence
TS: the solution has no more color than of concomitant impurities that are readily carbonized.
Matching Fluid A.
Change to read: 14. This limit test determines organic volatile impurities relative
14. Organic volatile impurities, Method V to a standard preparation containing chloroform, benzene, 1,2-
<467>: meets the requirements. 1 dioxane, methylene chloride, and trichloroethylene. The limits
Solvent—Use dimethyl sulfoxide as the solvent. are 50, 100, 100, 500, and 1,000 ppm, respectively. The test is
required for bulk substances and excipients that are used in
chronic-systemic administered dosage forms. The three main
analytical methods used are based on the use of gas
chromatography.
15. Assay—Dissolve about 120 mg of 15. Tolerances in the Definition are based on the Assay. They,
Acetaminophen, accurately weighed, in 10 mL therefore, should be as precise as possible. The Assay does
of methanol in a 500-mL volumetric flask, dilute not have to be stability-indicating, but the monograph, taken as
with water to volume, and mix. Transfer 5.0 mL a whole, should assure that any degradation would be detected
of this solution to a 100-mL volumetric flask, and can be limited by a chromatographic or other specific test.
dilute with water to volume, and mix. An ideal combination is a chromatographic test for ordinary
Concomitantly determine the absorbances of impurities with a precise titrimetric assay. Microbial assays for
this solution and of a Standard solution of USP antibiotics (see Antibiotics—Microbial Assays <81>) are
Acetaminophen RS, in the same medium, at a currently replaced by HPLC (see Chromatography <621>)
concentration of about 12 µg per mL in 1-cm assays, wherever possible. However, for antibiotics that are
cells, at the wavelength of maximum mixtures of several active components, the microbial assay is
absorbance at about 244 nm, with a suitable still the preferred one and is sometimes coupled with a
spectrophotometer, using water as the blank. chromatographic test to quantitate the individual components.
Calculate the quantity, in mg, of C8H9NO2 in the Biologics, proteins, and peptides may require very specialized
Acetaminophen taken by the formula: biological assays.
10C(AU/AS), in which C is the concentration in
m g per mL, of USP Acetaminophen RS in the
Standard solution, and AU and AS are the
absorbances of the solution of Acetaminophen
and the Standard solution, respectively.

REF. QUALITY CONTROL II

By: Norma V. Lerma and Marina O. Osi