MODULE 6: QA/QC

Mr. Jemar Wilian N. Labausa.

BREX Review Center
 QA / QC
- Totality of characteristics or
features of a product that bears on its
capacity to satisfy stated or implied needs.

QA - sum total of the organized arrangements

made w/ the object of ensuring that products will
be consistently of the quality required by their
intended use

QC
- part of GMP concerned w/ sampling, specifications,
testing, organization, documentation & release
procedures
Documentation
Kapag hindi documented, hindi po
nangyari
Itis the linkage between written records of
action taken and the quality operation
Allthe tests to be conducted on a product and
raw materials and/or appropriate references
containing DETAILS OF PROCEDURE and
EXPECTED RESULTS vs ACTUAL RESULTS
MONOGRAPH
Document that specifies all
the tests to be conducted on
a product and/or appropriate
references containing details of
procedure and expected result.
Certificate of
analysis
A document containing the result of all
tests conducted on a specific material or
product to show compliance or non-
compliance with established standards or
specifications approved by responsible
personnel
 QA Departmental Functions
Assures policies are followed inept to economic
issues associated with manufacturing and
distribution of product.
Cooperate with regulatory agencies and final
authority for product acceptance or rejection
Helps
to identify and prepare necessary
SOPs relative to control of quality
Auditand Quality monitoring to determine if
operations have adequate systems, facilities &
written procedures.
 QC Functions
Testing
and Acceptance of only highly quality
raw material, representative samples.
IP tests against criteria.
Monitorsenvironmental conditions (depends
on products)
Control packaging components
 3 Main Areas of QC (Analytical tests)
RMQC
IPQC
FPQC
RMQC
For Parenterals:
Identification Test: Active Ingredient
Solvent: Water for injection (Pyrogen Test)
Glass: Water Attack Test (Type II)
Rubber: Durometer Test
IPQC:
VOLUME FILL
FPQC
Done on final products on its FINAL
DETECTION OF PARTICLES Container
 Stability extent in which the substance
remain within specified limits and
throughout its period of storage
Capacity of drug to remain within specifications:
P-HYSICAL
C-HEMICAL
M- ICROBIOLOGICAL
T- OXICITY
T- HERAPEUTIC EFFECT
Established to assure identity, strength, quality and purity
* products must have same properties & characteristics
from the time of manufacture up to use of product by patient
* Minimum Acceptable Potency level: ---- nlt 90%
 Acceptable Stability
Timein storage and use in which a particular formulation in
container remains within P, C, Toxicological and
Bioavailability specifications.
Stable Product
One that retains its requisite:
P: one that retains its physical prop including Appearance, Palatability,
Unifomity, Dissolution, Suspendability
C: retain its chemical integrity & LP w/in specified limits
M: retain its sterility
T: No significant inc in toxicity occurs
T: therapeutic effects remains unchanged
Stability protocols
 problem
Active 1 65 mg (limits 95-105%)

Active 2 15 mg (limits 90-110%)

Active 3 122 mg (limits 90-110%)

initial 3 mos 6 mos 12 mos 24 mos 36 mos 48 mos

Active 1 67.60 67.00 66.80 65.40 63.06 67.98 61.79

Active 2 15.00 14.94 14.90 14.21 14.01 13.67 13.38

Active 3 128.30 126.00 124.10 117.76 113.30 110.60 109.5

questions
1. Determine the minimum and maximum limits
of each active based on the specifications
Active 1
61.75-68.25
Active 2
13.5- 16.5
Active 3
109.8-134.2
 questions
What is the shelf life of the formulation?
A. 24 mos
B. 12 mos
C. 36 mos
D. 48 mos
questions
What would be the expiry date of a
product manufactured on Dec. 22,
1994?
A. Dec. 22, 1997
B. Dec 22, 1996
C. Dec. 22, 1998
D. Dec. 22, 1995
 Expiration Date
Time
in which the preparation will remain
stable when stored under a recommended
condition
Harmful Events
Decrease
in therapeutic activity of
preparation to below some arbitrary content
Appearanceof toxic substances formed as
degradation product
 Errors in Estimating Expiration Date
Type 1
ALPHA ERROR
SETTING TOO EARLY
Type 2
BETA ERROR
SETTING TOO LATE
 QC TESTS OF 2. Identity tests
PHARMACEUTICAL Physical: REFRACTIVE
DOSAGE FORMS INDEX, OPTICAL
ROTATION
General Test
Classification: Chemical: visible reactions
1.Packaging
Material type: 3. Physical properties
PLASTIC/GLASS Gross: COLOR, ODOR,
Special properties: CONSISTENCY,
TRANSPARENT, DIMENSIONS
COLLAPSIBLE, EASY TO
DRAIN
Integrity: TIGHTNESS,
LEAK-FREE

 4. Limit tests
Gross: DIRT, INSOLUBLE MATTER
Chemical: TRACE METAL, DEGRADATION
PRODUCT
Biological: VISIBLE MICROORGANISM
5. Potency tests: to determine conformance
to LC
Instrumental: HPLC, UV, SPECTRO,
POLARIMETER, GC
Chemical: TITRIMETRIC
Biological: LIVE ANIMALS

6. DF specific tests
 ADULTERATION
Debasement of article
1.Sophistication 3. Admixture
- true adulteration - addition of an article to another
through accident, ignorance,
- addition of inferior material to any
carelessness
article
Ex: Sarsaparilla root with some soil
eg: teatree oil
4. Spoilage:
safflower -
- quality destroyed by action of
2. Substitution
microorganism
- entirely different is used in place
5. Deterioration
of the one requested.
- quality impaired by abstraction,
eg: Japanese anise
destruction of valuable constituents
due to environmental agents,
insects
QC Procedures
Tablets
Parenterals
Non-sterile
 a. Hardness
- crushing strength
-determine resistance to shipping, abrasion, or breakage under
storage, transportation, handling before usage
- Rule of Thumb Crude Method
*tablet is of proper hardness if it was firm enough to break
with a sharp snap when held between 2nd and 3rd fingers,
using thumb as fulcrum.
To
determine the need for possible adjustments on tabletting
machine
Too hard MAY NOT DISINTEGRATE
Too
soft ADD BINDERS, WILL NOT WITHSTAND
HANDLING
A. TABLET HARDNESS
- CRUSHING STRENGTH
1. STOKES HARDNESS - SPRING
TESTER(MONSANTO) - BASED ON COMPRESSING
TABLETS BETWEEN 2 JAWS
2. STRONG COBB - AIR PUMP
3. PFIZER HARDNESS - HARD PLIERS
4. ERWEKA TESTER - SUSPENDED WEIGHTS
5. SCHLEUNIGER TESTER - MOST WIDELY USED
- ELIMINATES OPERATOR VARIABILITY
- HORIZONTAL POSITION

ORDINARY uncoated tab- 4-10KG

SL, CHEWABLE 2-3KG
BUCCAL 8-10KG
Stokes Monsanto

Strong-Cobb

Pfizer Hardness Tester

25
Erweka Tester

Schleuniger Tester 26
 B.
TABLET FRIABILITY EVALUATES THE ABILITY
TO WITHSTAND ABRASIONS, PACKAGING,
HANDLING AND SHIPPING (USES ROCHE
FRIABILATOR)
Settings: 25 rotations per minute, 4 minutes is equivalent
to 100 revolutions
Number of samples: Tablet weights equal to or less than
650 mg, take sample equal to 6.5 g/
more than 650 mg, take 10 whole tablets
Acceptance Criteria: not more than 1.0% LOSS
 C.
TABLET THICKNESS USES
VERNIER CALIPER (<5%STD.
THICKNESS) or Micrometer caliper
DISINTEGRATION
- TABLET ADMIN. BY MOUTH
- BASKET RACK ASSEMBLY
- 6 CYLINDRICAL TUBES
- 10 MESH WIRE
Stage Sample Criteria
- 37+/- 2 deg C
- PASS IF NONE REMAINED, 1 6 Should
ONLY IMPALPABLE CORE disintegrate
SPECIFICATION:
2 + 12
A. PLAIN UCT AND CAPSULE: 30MINS TABLETS 16/18
B. ENTERIC- 1 hr.
C. BUCCAL- 4HRS.
D. SL- 3 MINS.

MEDIA: WATER, SIMULATED GASTRIC

FLUID, INTESTINAL FLUID
TYPE OF TABLET MEDIUM TIME
UNCOATED Water, 37C 2 30 MINS
TABLETS
BUCCAL TABLETS Water, 37C 2 4 HOURS
SUBLINGUAL Water, 37C 2 3 MINUTES
TABLETS
ENTERIC COATED Water, RT 5MINUTES
TABLETS Simulated Gastric AFTER 1 HOUR:
Fluid, 37C 2 NO SIGN OF
DISINTEGRATION
Simulated Intestinal 1 HOUR
Fluid, 37C 2
 problem
Test solution: Gastric Juice TS
Average tablet weight: 600 mg
Label claim: 500 mg
Tolerance:
Sample 85% Absorbance Weight
1 0.279 601
2 0.274 600
3 0.246 602
4 0.251 598
5 0.211 598
6 0.248 604
standard 0.434 --
answers
Sample Absorbance Weight % label claim

1 0.279 601 96.42

2 0.274 600 94.70

3 0.246 602 85.02

4 0.251 598 86.75

5 0.211 598 72.93

6 0.248 604 85.71

standard 0.434 --
problem
Concentration of standard: 0.3mg
Dilution factor: 2500
Q: 85%
 problem
Formula for % label claim

% label claim = Abs(sample) x concentration(Std) x dilution factor x 100

Abs(standard) x label claim
questions
1. What is the % label claim
adjusted to tablet weight for
sample #1
A. 95.15
B. 96.43
C. 98.01
D. 87.09
E. 81.98
questions
2.What is the % label claim adjusted
to tablet weight for sample #2?
A. 94.70
B. 98.00
C. 72.01
D. 86.71
E. 99.04
questions
3. What is the % label claim adjusted
to tablet weight for sample #3?
A. 84.74
B. 86.75
C. 85.02
D. 88.78
E. 90.57
questions
What is the % label claim adjusted to
tablet weight for sample 6?
A. 73.17
B. 67.04
C. 66.67
D. 85.71
E. 79.24
 S Acceptance Criteria
DISSOLUTION
S1 6 Each unit is nlt Q + 5%
- 1 SX/ VESSEL
- 37+/- 0.5degC S2 6 Average of 12 is equal to
or greater than Q, no
unit is less than Q -
1- BASKET (CAPSULE) 15%
2- PADDLE (TABLETS) S3 12 Average of 24 is equal
3- RECIPROCATING to or greater than Q,
CYLINDER not more than 2 units
4- FLOW THROUGH CELL are less than Q-15%,
no unit is less than Q
- 25%
USP Apparatus 1 and 2
USP Apparatus 3 and 4
Reciprocating Disk Flow-through Cell
44
45
DISSOLUTION APPARATUS
1- BASKET (CAPSULE)
2- PADDLE (TABLETS)
3- RECIPROCATING CYLINDER
4- FLOW THROUGH CELL
5- PADDLE OVER DISK
6- ROTATING CYLINDER
7- RECIPROCATING HOLDER/ DISK
USP DISSOLUTION APPARATUS
1 ROTATING BASKET
- Most common
- has cylindrical stainless-steel basket and shaft assembly
- For dissolution studies of capsule, suppositories and tablets that have low
density
- temp: 37 deg C
- 100rpm
- 900 mL of 0.1M HCl is used to simulate the pH of the gastric acid fluid.

2 PADDLE
- Paddle and shaft are used as the stirring element
- paddle coated with teflon
- 50rpm for tablet, 25rpm for suspension
3 RECIPROCATING CYLINDER
- Consist of set of flat bottomed cylindrical glass vessels equipped with a
reciprocating cylinder
- for drug containing microparticulate formulations designed for sustained-
release.
4 FLOW-THROUGH CELL
- Consist of reservoir of dissolution medium that is pumped into a flow cell
containing the sample
- - for sustained release and controlled-release dosage form

5 PADDLE OVER DISK

- Suitable for measurement of drug release from topical and transdermal dosage
form such as patches
6 CYLINDER METHOD- modified form of apparatus no.1
- For testing transdermal patches
- Instead of basket a stainless steel cylinder is used as a holder
- 32deg C

7 RECIPROCATING DISK METHOD

- Used for testing release of drug from transdermal system
- consists of motor drive assembly that reciprocates the system vertically.
- 30rpm
Weight Variation
Calculation:
% Wt. variation = actual wt. per sample/average wt. x 100

Take 20 tablet and weighed individually.

Calculate average weight and compare

the individual tablet weight to the
average.
 Unofficial method
Ave wt of tab % variation
<150mg + 10%
150 324mg + 7.5%
> 324mg + 5%
Criteria:
NMT 2 tab differ by more than % variation
No tab differs by more than double % variation
Official method
Stage Sample Criteria
1 10 85-115% LC
2 20 NMT 1 outside 75-125%LC
Content Uniformity Test:
Randomly select 30 tablets. 10 of these assayed
individually.
The Tablet pass the test if 9 of the 10 tablets must
contain not less than 85% and not more than 115% of
the labeled drug content and the 10th tablet may not
contain less than 75% and more than 125% of the
labeled content.
If
these conditions are not met, remaining 20 tablet
assayed individually and none may fall out side of the
85 to 115% range.
 II. Parenterals (Sterile Products)
Sterility test
Test for Pyrogens
Safety test
Particulate Matter test
Leakers test
 Sterility test
PRIMARY METHOD- Membrane filtration
Direct transfer method DIRECT INOCULATION
BIOLOGICAL INDICATOR: FOR STERILIZATION
PROCESS
Culture Media
1. Soybean Casein Digest Medium
FUNGI + AEROBIC BACTERIA:
20-25C
2. Fluid thioglycollate Medium:
ANAEROBIC BACTERIA: 30-35C
Time of Incubation
Membrane filtration: 7 days
Direct inoculation: 7-14 days
Sterilization
1. Steam: B. stearothermophilus
2. Dry Heat: B. subtilis
3. Ionizing Radiation UV: B. pumilus
B. Stearothermophilus
B. subtilis
4. Ethylene Oxide: B. subtilis
5. Membrane filtration: P. diminuta
 Test for Pyrogens
Pyrogen (Bacterial endotoxin)
Bacterial endotoxins from cell wall
of G (-)
Thermostable, not autoclavable
HMW lipopolysaccharide
* may cause fever, malaise,
chills, pain
2. Test for Pyrogens
A. Bacterial Endotoxin Test (BET) using LAL reagent
Limulus polyphemus or Tachypleus tridentatus
Two Methods:
Gel-clot formation and turbidimetric method
uses USP Endotoxin RS
measured using USP-EU
If
a gel is formed via a clotting reaction, endotoxin is present
and the sample fails the test
Turbidity testing determines the cloudiness of a solution by
measuring the loss of intensity in a light beam passing through
that solution 57
B. Pyrogen Test
Test animal: 3 healthy , mature rabbits
Dose: 10 mL per Kg unless otherwise specified
Received10mL/kg in marginal ear vein, completing injection
w/in 10 mins after start of admin
Rectaltemp recorded at 1,2,3 hrs after injection or 30mins
interval 1 hr after injection
Stage Sample Criteria
1 3 Total temp rise is NMT 1.4C
None with T rise > 0.5C

2 8 NMT 3 of 8 with T rise > 0.5C

Temp rise 0f 8 rabbits NMT 3.3C
QUIZ
1. Crude method to measure the tablet hardness.
2. Acceptance criteria for Tablet Friability
3. Temperature requirement for Disintegration Apparatus.
4. Flow through cell is USP Dissolution App. Number ___.
5. Bacterial indicator in Ethylene Oxide.
6. Reagent used in Pyrogen Test.
7. T/F. Fluid Thioglycollate is for fungi and anaerobic bacteria.
8. This is used as a quality control test for tablets containing non-potent
ingredient.
9. Total sample of Stage 3 for Dissolution Apparatus.
10. Suspended weights are present in what kind of hardness tester?
11. Dissolution Apparatus no. 5 and 6 is used for testing ____.
12. Used to measure the hardness aof plastic and rubber.
13. This is use as biological indicator in Ethylene oxide.
14. Criteria, stage 2 for Content Uniformity Test.
15. Composition of simulated intestinal fluid.
16. Number of sx for weight variation.
17. AKA reciprocating disk method.
18. Measures the tightness of the Cap.
19. Limit time for enteric tablet to disintegrate.
20. The addition of an article to another through accident, ignorance,
carelessness
Particulate Matter <788>
Presence of particles may be harmful
- Emboli phlebitis
1. Light Obscuration Particle Count Test
Electronic particle counters
constant in-process measurement
quickly identify, size and count the particles
provides trend analysis to identify the problem
DISADVANTAGE:
requires routine preventive maintenance and
calibration 63
2. Microscopic Particle Count Test
Membrane filtration
allows collection of the particles larger
than rated pore size
microscopic identification of particle
types and materials
DISDAVANTAGE:
slow counting and sizing on membrane
surface
requires top and bottom lighting to
distinguish all particles
64
Specification: (USP Limits)
For SVP
Limits (per container)
Methods 10 m 25m
Light obscuration 6000 600
Microscopic method 3000 300
For LVP
Limits (per container)
Methods 10 m 25m
Light obscuration 25 3
Microscopic method 12 2 65
 III. Non-sterile
A. Microbial Limit test
Medium
Total Aerobic T: 30-35C;
Count Duration: 2-3 days

Total Yeasts and T; 20-25C; 5-7 days

Molds
-Enriched Media (BLOOD agar, Chocolate agar)
Specific Microorg -Selective Media (McConkey, Lowenstein, Potato
Dextrose, Saborauds)
-Differential Media (McConkey agar)
 E. Leaker test
Negativepressure within
incompletely sealed ampule while
submerged in dye solution
Dye: 1 %methylene blue
Rinse dye from outside
(+) appear blue
 Solutions
Appearance
Stability
a. Chemical degradation products,potency
b. Physical
Viscosity
Color
Clarity should remain clear under temp range: 4-47C
pH
Odor and taste
SUSPENSIONS
1. Sedimentation Volume
Vs = Vu / Vo
Where: Vu is settled volume, Vo is volume of suspension
2. Redispersibility the amount of the force necessary to redisperse particles,
-- product is subject to shaking for minimum of 10 spm
100% redispersable with minimum agitation
3. Size of particles Ideal size: 2um
Solution: <1 mcm
Colloidal: 0.1-1mcm
Suspension: >1mcm
4. Zeta Potential determines the repulsive forces between particles (INC. ZETA, SLOWER
SETTLING)
5. Rheological properties (newtonian and non-newtonian)
6. Temperature and gravitational stress tests
-- test for crystal growth at 40degC 69
1.Sedimentation volume
Ideal: F=1
No sediment is present
Caking is absent
Suspension is esthetically
pleasing
EMULSIONS
1. Test for creaming, cracking, phase separation, phase
inversion
DYE SOL (AMARANTH GREEN/SUDAN RED)
UV FLUORESCENCE
CONDUCTIVITY
COBALT CL TEST
DIRECTION OF CREAMING
2. Electrophoretic analysis
3. Particle size number analysis
4. Gravitational and temperature stress tests (50-70degC)

71
Type of tests W/O O/W

A. Dye solubility Test Amaranth green (+) (-)

Sudan red (-) (+)

B. UV Fluorescence (+) absorption (-)

Test

C. Conductivity (-) (+)

D. Cobalt Chloride Blue Pink

Test

E. Direction of Sedimentation Creaming

Creaming
GRANULES/ Powders
Powder Fineness, Particle Size
Distribution, Powder Flow
1. Particle Size Distribution
Techniques:
a. Sieving- MOST RAPID
b. Optical microscopy
c. Electron microscopy
d. Sedimentation
e. Light scattering technique
73
 1.Particle Size Distribution
*Sieving most rapid
Mesh # - # linear openings per square inch

Coarse granule : DO NOT PASS MESH NO. 20

Good granules : PASS MESH NO. 20

DO NOT PASS MESH NO. 40

Fines: BOTH PASS ON MESH NO. 20 AND 40

2. Angle of Repose <1174> measure the frictional force present in loose powder or
the index of flowability
Methods:
a. Static angle of repose (fixed funnel method, fixed bed cone, tilting box
a. Fixed funnel method
b. Fixed bed cone
c. Tilting box
b. Kinetic angle of repose (cylinder method)
Specification:
< 25 excellent
25 30 good
30 40 fair, (ADD GAL)
>40 poor
75
3.Bulk and Tapped Density <616>
measured amount of granules in
graduated cylinder or a volumeter
(Scott volumeter)
index of the ability of the powders
to flow

77
Height of Cone = 7 cm
Diameter of cone form = 14.5 cm
Compute for the Angle of repose.
What is the flowability of the powder?
A sample of powder was made to flow from a funnel, a
powder cone of 12mm from the surface was made as
well as spread of 40 cm. Determine the angle of repose.
CI, HR AND POROSITY

Weight of the sx: 120 g

Initial Volume: 100 mL
Final Volume: 80 mL
DENSITY: 1.313 g/mL

Compute for CI, HR, and POROSITY

Paracetamol = 500mg tab
Initial weight = 7 g
Final weight = 6.85 g

What is the % friability of the tablet?

Disposition of the batch?