QC/QA 6.

Product Quality Review (PQR)

OUTLINE • regular periodic quality reviews of
I. Basic Principles all registered drug products to verify
II. Raw Material Quality Control consistency of the existing process
(RMQC) and to identify product and process
III. Packaging Material Quality Control improvements.
(PMQC). 7. Quality Risk Management (QRM)
I. BASIC PRINCIPLES • a systematic process for the
A. DEFINITION OF TERMS assessment, control,
1. Quality communication, and review of risks
• totality features or conformance to to the qualitv of the product
specifications of a product B. QUALITY UNIT
• Ensures that products: • An organizational unit independent
of Production which fulfills both
• Are fit for their intended use Quality Assurance and Quality
• Safe Control responsibilities.
• Compliant with the CA UNIT
requirements of the • ensures that quality policies
marketing authorization • are followed
2. Total Quality Management (TQM) • audit and monitoring
• A combined team effort to develop, • primary contact with
produce, market, distribute, and regulatory agencies
control products that are safe and • prepares SOPs
will be effective for the time they QC UNIT
remain in the marketplace • conducts sampling and
3. Quality Assurance (QA) testing of RM & FP
• totality of the organized • inspects PM components
arrangements made with the • performs environmental
objective of ensuring that products • monitoring
are of the quality required for their C. DOCUMENTS
intended use 1. Monograph
4. Current Good Manufacturing Practice • specifies all the tests to be
(cGMP) conducted on a material and the
• part of QA which ensures that expected results
products are consistently produced 2. SOP
and controlled to the quality • step-by-step instruction for doing a
standards appropriate to their particular task or activity
intended use 3. COA
5. Quality Control (QC) • shows the actual results of all tests
• part of cGMP concerned with conducted on a material to show
sampling, specifications, testing, compliance with standards
organization, documentation, and 4. MSDS
release procedures
 • contains information on the • non-conformance to a standard
potential health effects of exposure or requirement
to chemicals and on safe working • Classification:
procedures when handling chemical 1. According to Magnitude
products a. Critical Defect - may endanger
D. SAMPLING life of patient
• the process of removal of an b. Major Defect - does not
appropriate number of items (n) endanger life of patient but
from a population (N) affects the function of the
• Sampling Plans: product
1. MIL-STD-105E - most common C. Minor Defect - does not
(old) endanger life of patient & does
2. ANSI/ASQZ1.4-2008 - most not affect the function of the
common (new) product
3. Square Root System - easier (use 2. According to Measurability
in exam) a. Variable Defect - measured by
E. CONTROL CHARTS an instrument
• graphs on which the quality of the b. Attributive Defect – measured
product is plotted as manufacturing by inspection
is actually proceeding 3. According to Nature
• Types: a. Ocular Defect - can be seen by
1. p-Chart - proportion of defectives the naked eye
2. np-Chart-non-proportion b. Internal Defect - cannot be
(number) of defectives seen by the nakedeye
3. X Bar Chart - used for measurable H. PRODUCT RECALL
characteristics • removal of product from the market
• Warning Limit – alerts the because it is either defective or
operator to closely monitor the potentially harmful
process • Classification of Product Recall:
• Action Limit – alerts the operator 1. Class I Recall - may cause death
to stop the process and do or serious adverse health
corrective action consequences
F. VALIDATION & QUALIFICATION 2. Class I Recall - may cause
1. Validation - the action of proving temporary/medically reversible
and documenting that any process, adverse health consequences
procedure or method actually leads 3. Class III Recall - not likely to
to the expected results. cause adverse health
2. Qualification - the action of consequences
proving that premises, systems or I. STABILITY STUDIES
equipment work correctly and 1. Stability
actually lead to expected results. • capacity of a drug to remain within
G. PRODUCT DEFECTS specification
• Minimum Acceptable
 • Potency: 90% b. Accelerated Studies
• Drug products are mainly o designed to increase the rate
decomposed by: of chemical degradation by
a. Hydrolysis using exaggerated storage
o Prevented by reduction or conditions
elimination of water from o Testing Period: 0, 3, 6
the preparation c. Stress Testing
b. Oxidation • elucidates the intrinsic
o Prevented by antioxidants stability of the drug
(ex: Vit C & E) substance and identify the
c. Photolysis likely degradation products
o Prevented by using light- • carried out under more
resistant containers severe conditions
2. Shelf-life (tgo) II.Raw Material Quality Control (RMQC)
• period of time during which a A. HANDLING OF RM
product is expected to remain within o Quarantine - status of materials
specification which are isolated physically while a
• estimated using the Arrhenius decision is awaited on their release,
equation rejection, or reprocessing
3. Expiration Date o All quarantined materials are
• time or date prior to which a labeled with
product is expected to remain stable o YELLOW color
and after which it must not be used o Materials that conform to
• calculated using this formula: tests are labeled with GREEN
o Expiration Date = color
Manufacturing Date + Shelf- o Materials that failed or are
life rejected are labeled with
4. Stability Studies RED color
• used to estimate the shelf-life of a o Warehouse Distribution Practices:
drug product 1. First in-First out (FIFO)
• evaluated over time in the same o In this technique, the rule is
container closure to move first the stocked
• system in which the drug product is products or the products
marketed that are brought in first
• based on ASEAN Guidelines on 2. First expiry-First out (FEFO)
Stability Studies o In this technique, the
• Climatic Zones products whose expiration
dates are approaching are
moved out of the warehouse
first
B. IDENTIFICATION TEST
o to confirm the identity of a chemical
• Types of Stability Studies substance
o Methods:
 1. Chemical Methods
o Color reactions
o Precipitation
o Evolution of gas
2. Instrumental Methods
o Spectroscopy
o Chromatography
C. ASSAY
o to determine the amount of API or
biologic activity
o Methods:
1. Chemical Assay
o Titrimetry D. LIMIT TEST
o Instrumental methods o to measure small amounts of
2. Biologic Assay impurities in a RM
o Animal assay o Types of Impurities:
o Microbial assay 1. Gross Impurities - dirt or insoluble
a. Animal Assay matter
2. Biological Impurities -
microorganism
3. Chemical Impurities - by-products,
degradation products, reagents,
catalysts, ligands, heavy metals, or
residual solvents
o Examples:
b. Microbial Assay
o Methods:
1. Cylinder Plate Method
o uses a cylinder or paper
disc impregnated with
the sample, placed on a
solidified nutrient E. PHYSICAL TESTS
medium in a Petri dish o can be used for identification and
o based on the diameter of determination of concentration of a
the zone of inhibition component
2. Turbidimetric Method o may also be used to determine the
o uses a test tube filled with presence of impurities
fluid nutrient medium, 1. Specific Gravity
where the test organism is o the ratio of the density of a
inoculated substance to that of a
o based on measurement of reference substance at 25 °C
transmittance o measured using a
pycnometer or Mohr
Westphal balance
 o Alcohol: measured using a § Method IC:
hydrometer at 15.56 °C Coulometric
2. Refractive Index (n)
o ratio of the velocity of light in air to
the velocity of light in the substance
at 25°C
o represented by the formula:

o where i= angle of incident ray

o measured using an Abbe

refractometer

3. Optical Rotation (a)

o measure of its ability to rotate an
incident plane of polarized light o Method I: Azeotropic Distillation
o may be dextrorotatory or § based on distillation of
levorotatory water with toluene/
o measured using a polarimeter xylene
4. Solubility § uses a toluene-moisture
apparatus
o Method Ill: Gravimetry
§ based on loss on drying
at 110-120 °C for
inorganic materials and
105 °C for organic
materials
5. BP-MP III.Packaging Material Quality Control
o indicates presence of impurities (PMQC).
6. Loss on Drying A. TESTS FOR GLASS
o determines the amount of volatile 1. Hydrolytic Resistance (Leaching)
matter driven off after drying o Old SP Tests
7. Water Determination
o Method I: Karl-Fischer Titrimetry
o based on the rxn of water
and KFR
o KFR Components:
a. Powdered Glass Test
§ Sulfur dioxide
§ lodine o Sample: crushed Type I and
§ Pyridine Type III glass
§ Anhydrous Methanol o Method: Acid-base titration
o Types: with 0.02 N H,SO VS using
§ Method IA: Direct
§ Method IB: Residual
 methyl red as indicator

b. Water Attack Test

o Sample: inner surface of
Type Il glass
o Method: Acid-base
titration with 0.02 N
H,SO, VS using methyl
red as indicator
c.Surface Glass Test
o Sample: inner surface of
Type I and Ill glass
o Method: Acid-base
titration with 0.1 N HCI
VS using methyl red as
indicator
• New USP Tests

2. Light Transmission
• for colored glass containers
• Limit: NMT 10% at any wavelength
in the range of 290 to 450 nm
3. Arsenic
• for Type I or Type Il glass container
• Method: same w/ limit test for As
• Limit: NMT 0.1 ug per g

B. TESTS FOR PLASTIC

1. Biological Reactivity Tests In Vivo

2. Biological Reactivity Tests In Vitro