MODULE 6│PHARMCHEM 4

QUALITY ASSURANCE & QUALITY CONTROL

QUALITY ASSURANCE & QUALITY CONTROL 4. Material Safety Data Sheet (MSDS)
• Contains information on the potential health effects of
I. BASIC PRINCIPLES exposure to chemicals and on safe working procedures
when handling chemical products
A. DEFINITION OF TERMS
D. SAMPLING
1. Quality
• The process of removal of an appropriate number of items
• Totality features or conformance to specifications of a (n) from a population (N)
product • Sampling Plan:
• Ensures that products: 1. MIL-STD-105E (Military Standard) – most common
• Are fit for their intended use (old); master tables
• Safe 2. ANSI/ ASQ Z1.4-2008 – most common (new)
• Compliant with the requirements of the marketing 3. Square Root System – easier (use in exam) n= √N + 1
authorization
E. CONTROL CHARTS
2. Total Quality Management (TQM)
• Graphs on which the quality of the product is plotted as
• A combined team effort to develop, produce, market, manufacturing is actually proceeding
distribute, and control products that are safe and will be
effective for the time they remain in the marketplace. Upper control line

Sample Statistics
Upper warning line
3. Quality Assurance (QA)
Target
• Totality of the organized arrangements made with the Lower warning line
objective of ensuring that products are of the quality Lower control line
required for their intended use 1 2 3 4 5
• Wide ranging concept that covers all matters individually or Sample Number
collectively influence
Types:
4. Current Good Manufacturing Practice (CGMP) 1. p-Chart – proportion of defectives
• Part of quality assurance which ensures that products are 2. np-Chart – non-proportion (number of defectives)
consistently produced and controlled to the quality 3. X Bar Chart – used for measurable characteristics
standards appropriate for their intended use
Warning limit – alerts the operator to closely monitor the process
5. Quality Control Action limit – alerts the operator to stop the process and do
• Part of CGMP concerned with sampling, specifications, corrective action
testing, organization, documentation and release
procedures (PIC/S Guidelines – QA → CGMP → QC) F. VALIDATION AND QUALIFICATION

6. Product Quality Review (PQR)
• Regular periodic quality reviews of all registered drug
products to verify consistency of the existing process and to
identify product and process improvements
7. Quality risk Management (QRM)
• A systematic process for the assessment, control,
communication, and review of risks to the quality of the
product
1. Validation – the action of proving and documenting that any
process, procedure or method actually leads to the expected results
2. Qualification – the action of proving that premises, systems or
equipment work correctly and actually lead to expected results.
G. PRODUCT DEFECTS
• Non-conformance to a standard or requirement

B. QUALITY UNIT Classification of Product defects:

• An organizational unit independent of Production which 1. According to Magnitude

fulfills both Quality Assurance and Quality Control
responsibilities
QA Unit
• Ensures the quality
policies are followed
• Audit and monitoring
• Primary contact with
regulatory agencies
• Prepares SOPs
QC Unit
• Conducts sampling and
testing of RM & FP
• Inspects PM components
• Preforms environmental
monitoring
a. Critical Defect – may endanger life of patient
b. Major Defect – does not endanger life of patient put affects
the function of the product
c. Minor Defect – does not endanger life of patient and does
not affect the function of the product
2. According to Measurability
a. Variable Defect – measured by an instrument
b. Attributive Defect – measured by inspection

C. DOCUMENTS 3. According to Nature

a. Ocular Defect – can be seen by the naked eye
1. Monograph b. Internal Defect – cannot be seen by the naked eye
• Specifies all the tests to be conducted on a material and the
expected results H. PRODUCT RECALL

2. Standard Operating Procedure (SOP) • Removal of product from the market because it is either
• Step-by-step instruction for doing a particular task or activity defective or potentially harmful

3. Certificate of Analysis (COA) Classification of Product Recall:

• Shows the actual result of all tests conducted on a material
to show compliance with standards 1. Class I Recall – may cause death or serious adverse
health consequences

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 2. Class II Recall – may cause temporary/ medically b. Accelerated Studies
reversible adverse health consequences • Designed to increase the rate of chemical degradation by
3. Class III Recall – not likely to cause adverse health using exaggerated storage conditions
consequences • Testing Period: 0, 3, 6

I. STABILITY STUDIES c. Stress Testing

• Elucidates the intrinsic stability of the drug substance and
1. Stability identify the likely degradation products
• Capacity of a drug to remain within specification • Carried out under more severe conditions
• Minimum Acceptable Potency: 90%
II. RAW MATERIAL QUALITY CONTROL (RMQC)
Physical
A. HANDLING OF RAW MATERIAL

Quarantine – status of materials which are isolated physically while

Therapeutic Chemical a decision is awaited on their release, rejection or reprocessing
• All quarantine materials are labeled with YELLOW color
• Materials that conform to tests are labeled with GREEN color
• Materials that are rejected are labeled with RED color

Warehouse Distribution Practices:

Toxicologic Microbiologic
1. First in-First out (FIFO)
• In this technique, the rule is to move first the stocked
• Drug products are mainly decomposed by: products or the products that are brought first
a. Hydrolysis 2. First expiry-first out (FEFO)
• Prevented by reduction or elimination of water • In this technique, the products whose expiration dates
from the preparation are approaching are moved out of the warehouse first.
b. Oxidation
• Prevented by antioxidants (ex: Vit. C & E) B. IDENTIFICATION TEST
c. Photolysis
• Prevented by using light-resistant containers • To confirm the identity of a chemical substance

2. Shelf-life (t90) Methods:

• Period of time during which a product is expected to remain
within specification 1. Chemical Methods
• Estimated using the Arrhenius equation • Color reactions
• Precipitation
• Evolution of gas

2. Instrumental Methods
• Spectroscopy
• Chromatography
3. Expiration Date C. ASSAY
• Time or date prior to which a product is expected to remain
stable and after which it must not be used • To determine the amount of API or biologic activity
• Calculated using this formula
𝐸𝑥𝑝𝑖𝑟𝑎𝑡𝑖𝑜𝑛 𝐷𝑎𝑡𝑒 = 𝑀𝑎𝑛𝑢𝑓𝑎𝑐𝑡𝑢𝑟𝑖𝑛𝑔 𝐷𝑎𝑡𝑒 + 𝑆ℎ𝑒𝑙𝑓 − 𝑙𝑖𝑓𝑒 Methods:
4. Stability Studies 1. Chemical Assay
• Used to estimate the shelf-life of a drug product • Titrimetry
• Evaluated over time in the same container-closure system in • Instrumental methods
which the drug product is marketed
• Based on ASEAN Guidelines on Stability Studies 2. Biologic Assay
• Climatic zone • Animal Assay
• Microbial Assay
Climatic Zone Type of Climate Temperature Humidity
Zone I Temperate 21 ± 2℃ 45 ± 5% Animal Assay
(Canada,
Drug Animal used Drug Animal Used
Germany, Russia)
Zone II Mediterranean/ 25 ± 2℃ 60 ± 5% Digitalis Pigeon Chorionic Female Rat
(USA, Japan, Subtropical Gonadotropin
Italy, France, Tubocurarine Rabbit Vasopressin Male Rat
Australia) Insulin Rabbit Oxytocin Chicken
Zone III Hot and dry 30 ± 2℃ 35 ± 5% Glucagon Cat PTH Dog
(Iraq, Jordan) Corticoprin Rat Heparin Sheep
Zone IVA Hot and humid 30 ± 2℃ 65 ± 5% Cod Liver Oil Rachitic Rat Protamine SO4 Sheep
(UAE, Saudi
Arabia) Microbial Assay
Zone IVB Hot and very humid 30 ± 2℃ 75 ± 5% Methods:
(Philippines
and other Asian
Cylinder Plate Method
countries)
• Uses a cylinder or paper disc impregnated with sample,
placed on a solidified nutrient medium in a Petri dish
Types of stability Studies
• Based on the diameter of the zone of inhibition
a. Long-term Studies
Turbidimetric Method
• Conducted under normal conditions
• Uses a test tube filled with fluid nutrient medium, where the
• Testing period: 0, 3, 6, 9, 12, 15, 18, 24, 36
test organism is inoculated
• Based on measurement of transmittance

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 Antibiotic Test Organism • KFR Components:
Penicillin G Staphylococcus aureus • Sulfur dioxide – main component
Bacitracin Micrococcus luteus • Iodine – main component
Streptomycin Klebsiella pneumoniae • Pyridine
Chloramphenicol Escherichia coli • Anhydrous Methanol
Vancomycin Bacillus subtilis • Types:
• Method IA: Direct
Vitamin Test Organism • Method IB: Residual
Niacin Lactobacillus plantarum • Method IC: Coulometric
Ca Pantothenate 𝑉𝑥𝐹
Cyanocobalamin Lactobacillus leichmanii % 𝑊𝑎𝑡𝑒𝑟 = 𝑥100
𝑊𝑡
Where
V = mL of KFR
D. LIMIT TEST F = water equivalence factor
Wt = mg of sample
• To measure small amounts of impurities in a Raw Material Sample Calculation: Calculate the water content of Streptomycin
• Types of impurities: powder weighing 4.20g as sample. The water equivalence factor (F)
1. Gross Impurities – dirt or insoluble matter of the Karl Fischer reagent was found to be 5.1 and the volume
2. Biological Impurities – microorganism consumed was 11.50. The % of water is:
3. Chemical Impurities – by-product, degradation
products, reagents, catalysts, ligands, heavy metals, or 11.50 𝑥 5.1
% 𝑊𝑎𝑡𝑒𝑟 = 𝑥100 = 1.40%
residual solvents 4,200𝑚𝑔
• Examples:
b. Method II: Azeotropic Distillation
Chemical Impurity Reagent Used • Based on distillation of water Toluene or Xylene (alternative)
Heavy Metals Hydrogen Sulfide TS • Used a toluene-moisture apparatus
Arsenic Silver Diethyldithiocarbamate TS
Iron Ammonium Thiocyanate TS c. Method III: Gravimetry
Chloride Silver Nitrate TS • Based on loss on drying at 110-120°C for inorganic materials
Sulfate Barium Chloride TS and 105°C for organic materials
E. PHYSICAL TESTS III. PACKAGING MATERIAL QUALITY CONTROL (PMQC)
• Can be used for Identification and determination of A. TESTS FOR GLASS
concentration of a component
• May also be used to determine the presence of impurities 1. Hydrolytic Resistance (leaching)
• Old USP tests
1. Specific Gravity
• The ratio of the density of a substance to that of a reference TYPE Description Use Type of Test
substance 25°C I Highly-resistant, Buffered or non- Powdered Glass
• Measured using a pycnometer or Mohr-Westphal balance borosilicate glass buffered Surface Glass
• Alcohol: measured using a hydrometer at 15.56°C aqueous
parenteral
2. Refractive Index (n) II Treat soda-lime Acidic and Water Attack
• Ratio of the velocity of light in air to the velocity of light in the glass neutral aqueous
parenteral
substance at 25°C
sin 𝑖 III Soda-lime glass Non-aqueous or Powdered Glass
• Represented by the formula: 𝑛 = dry solid Surface Glass
sin 𝑟
• Where i = angle of incident ray parenteral
r = angle of refracted ray
• Measured using an Abbe refractometer a. Powdered Glass Test
• Sample: crushed Type I and Type III glass
3. Optical Rotation (α) • Method: Acid-base titration with 0.2N H2SO4 VS using
• Measure of its ability to rotate an incident plane of polarized methyl red as indicator
light
• May be dextrorotatory or levorotatory Glass Type Limit (mL of 0.02N H2SO4)
• Measured using a polarimeter Type I 1.0
Type III 8.5
4. Solubility
b. Water Attack Test
Descriptive Term Parts of Solvent Required for 1 • Sample: infer surface of Type II glass
Part of Solute • Method: Acid-base titration with 0.2N H2SO4 VS using
Very Soluble <1 methyl red as indicator
Freely Soluble 1-10
Soluble 10-30 c. Surface Glass Test
Sparingly Soluble 30-100 • Sample: inner surface of Type I and III glass
Slightly Soluble 100-1,000 • Method: Acid-base titration with 0.1N HCl VS using methyl
Very Slightly Soluble 1,000-10,000 red as indicator
Insoluble >10,000
• New USP tests
5. Boling Point – Melting Point
• Indicates presence of impurities Type Test Use
I, II, III Glass Grains Test Distinguishes Type I from Types II
6. Loss on Drying and III
• Determines the amount of volatile matter driven off after I, II, III Surface Glass Test Distinguishes Types I and II from
drying Type III
I, II Surface Etching Test Distinguishes Type I from Type II
7. Water determination
2. Light Transmission
Official Methods: • For colored glass containers
• Limit: NMT 10% at any wavelength in the range of 290 to
a. Method I: Karl-Fischer Titrimetry 450nm
• Based on the reaction of water and KFR

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3. Arsenic Cleaning sieves:
• For Type I or Type II glass container • Air jet
• Method: same with limit test for As • Liquid stream
• Limit: NMT 0.1 μg per g • Gentle brushing

B. TESTS FOR PLASTIC Endpoint for Sieving:

• Weight difference of <5%
1. Biological Reactivity Tests In Vivo • If <5% of total wt. is present on any sieve, the endpoint for
that sieve is increase to wt. change of ≤20%
Test Sample Animal • If 50% of the sample is (+) in a sieve, repeat test but insert
Systemic Injection Test Parenteral containers Albino mice a coarser sieve
Intracutaneous Test Parenteral containers Albino rabbits
Eye Irritation Test Ophthalmic containers Albino rabbits Example: Given the ff data from sieve analysis of a 71.23g sample:
Implantation Test Material in direct contact Rabbits Sieve no. Initial wt. (g) Final wt. (g) % on Total wt. Wt. Difference
with tissues 20 2.62 2.23 3.13% 14.89% ✓
40 5.64 5.19 7.29% 7.98% ✕
2. Biological Reactivity Tests In Vitro 60 20.48 19.83 27.84% 3.18% ✓
80 31.17 30.42 42.17% 2.41% ✓
Test Sample Test Organism Receiver 11.32 13.56 19.03%
Total 71.23g 100%
Agar Diffusion Test Elastomeric material Cell or Tissue
(Plastic)
Which of the ff sieves have already reached endpoint?
Direct Contact Test
Elution Test
X Sieve no. 40 (7.98% ✕)

𝐼𝑛𝑖𝑡𝑖𝑎𝑙 − 𝐹𝑖𝑛𝑎𝑙
IV. IN-PROCESS QUALITY CONTROL (IPQC) % 𝑊𝑡 𝑑𝑖𝑓𝑓𝑒𝑟𝑒𝑛𝑐𝑒 = 𝑥 100
𝐼𝑛𝑖𝑡𝑖𝑎𝑙
A. IPQC TESTS FOR POWDERS AND GRANULES
Types of Granules
Coarse Granule Retained at mesh 20
1. Particle size distribution analysis
Good Granule Passed Mesh 20, Retained at mesh 40
Fines Passed Mesh 20 and 40
1.1 Optical microscopy
• Diameter measurement:
2. Density
• Ferret – 2 tangents represented by longest distance
• Martin – bisect particles into halves Bulk Density Tapped Density
• Projected area of circle – circle diameter, that will
Ratio of Bulk volume (untapped) True/ Particle volume
enclose the particle powder’s 9(tapped) – denser!
• Adv: individual particles are seen (most reliable) mass and 𝑖𝑛𝑡𝑟𝑎 & 𝑖𝑛𝑡𝑒𝑟
• Disadv: 2D image only, very tedious 𝑉𝑜𝑖𝑑𝑠 ( )
its: 𝑠𝑝𝑎𝑐𝑒𝑠 𝑏𝑒𝑡. 𝑝𝑎𝑟𝑡𝑖𝑐𝑙𝑒𝑠
Method I 250mL Graduated cylinder
Method II Scott volumeter 250mL Graduated cylinder
Method III Vessel 100mL stainless steel, cylindrical

Volume types (Powder and Granules)

1.2 Sieving
• Adv: fastest • True/ Particle volume (Vp)
• Limitation: • Granule volumes (Vg) = Vp + Intraparticle spaces
• At least 25g of sample → due to particle attrition • Bulk volume (Vb) = Vg + Interparticle spaces
• Not for oily cohesive material
Density
𝑀
D(p, g, b) =
𝑉(𝑝, 𝑔, 𝑏)
Density & Mass = Directly Proportional
Density & Volume = Inversely Proportional

Porosity (E)
𝑉𝑏 − 𝑉𝑔
𝐼𝑛𝑡𝑒𝑟𝑝𝑎𝑟𝑡𝑖𝑐𝑙𝑒 𝑃𝑜𝑟𝑜𝑠𝑖𝑡𝑦 = 𝑥 100
𝑉𝑏
𝑉𝑔 − 𝑉𝑏
𝐼𝑛𝑡𝑟𝑎𝑝𝑎𝑟𝑡𝑖𝑐𝑙𝑒 𝑃𝑜𝑟𝑜𝑠𝑖𝑡𝑦 = 𝑥 100
𝑉𝑔
Sieve/ Mesh No.
• # Of square opening per linear inch 𝑉𝑏 − 𝑉𝑝
𝐵𝑢𝑙𝑘 𝑜𝑟 𝑇𝑜𝑡𝑎𝑙 𝑃𝑜𝑟𝑜𝑠𝑖𝑡𝑦 = 𝑥 100
• ↑ # = ↓ particle size 𝑉𝑏

Sieving Methods: 2.1 Bulk Density

a. Mechanical agitation Method I: Graduated Cylinder

• For particles > 75 μm • Pass 100g samples through sieve with apertures ≥ 1.0mm
into 250mL graduated cylinder without compacting
b. Air jet • Measure volume to determine density (constant wt.)
• For particles < 75 μm → light weight, < cohesive forces
• Single sieve at a time Method II: Scott Volumeter
• Measure weight to determine density (constant volume)
c. Sonic sifting
• For particles < 75 μm 2.2 Tapped Density
• With vertically oscillating column of air (that lifts the
specimen and then carries it back against mesh openings) Method I & II: Graduated Cylinder
• Difference is the drop rate
• Procedure: (tap then read the volume)
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 • 10 taps (V10) B. IPQC TEST FOR TABLETS
• 500 taps (V500)
• 1250 taps (V1250) 1. Tablet Hardness
• “Crushing strength/ breaking force”
Endpoint for Tapped Density (V500 – V1250 = ?) • Ability to withstand mechanical shocks from handling in
≤ 2mL V1250 = tapped volume manufacturing, packaging and shipping
> 2mL Repeat 1250 taps (until difference is ≤ 2mL) • Affects dissolution, and disintegration, BA
• Adjustments:
3. powder flow • Too hard (may not disintegrate in the required time period)
• Too soft (will noy withstand handling)
3.1 Angle of repose (ϴ)
• Measure of flowability Hardness Tester
• Maximum angle possible between the surface of the pile of Rule of thumb Crude method/ sharp snap (acceptable)
powder and the horizontal plane Stokes (Monsato) Spring
• 3D angle assumes by a cone-like pile of material Strong cobb Air pump/ hydraulic pressure
Pfizer Pliers (like)
Apparatus: Erweka Suspend motor-driven weight
• Fixed funnel; fixed cone (constant diameter), Free standing Schleungier/ Heberlein Motor-driven anvil crushes tablet horizontally;
most widely used (eliminates operator
cone (constant ht.), Tilting box, Revolving cylinder variability)

Acceptance Criteria:
Experimental considerations:
• Conventional and ordinary coated tablet: min 4 kg (4-10 kg)
• Base must be standardized flat surface without vibration
• SL, chewable: 2-3 kg
• Funnel must be at least 2-4cm above the cone to avoid
• Buccal: 7/8-10 kg
deformation
• MR tablets: >10 kg
ℎ
𝑇𝑎𝑛𝜃 = 2. Tablet Thickness
𝑟
• h = height of the powder cone
Importance:
• r = radius of the powder cone
• Identical appearance
• Facilitate packaging
3.2 Carr’s index
• Accuracy for tablet counting machines
• measure of compressibility
𝑉𝑏 − 𝑉𝑡 𝐷𝑡 − 𝐷𝑏
𝐶𝑙 = 𝑥 100 = 𝑥 100 Apparatus:
𝑉𝑏 𝐷𝑡 • Micrometer or Vernier caliper/ thickness gauge
*Same formula as bulk porosity
Acceptance Criteria: ± 5% of the set standard thickness
3.3 Hausner’s ration
𝑉𝑏 𝐷𝑡
𝐻. 𝑅. = = Example: Tab thickness 0.55cm x 5% / 100% = ±0.0275
𝑉𝑏 𝐷𝑏 AC = 0.5225-0.5775
Flowability 𝜽 Cl (%) HR Notes
Excellent 25-30° ≤ 10 1.00-1.11 Non-cohesive
V. FINISH PRODUCT QUALITY CONTROL (FPQC)
Good 31-35° 11-15 1.12-1.18
Test for Solid and Semisolid Dosage Forms
Fair (+ Glidant) 36-40° 16-20 1.19-1.25 Cohesive
Passable 41-45° 21-25 1.26-1.34 FPQC Tests Common to all Dosage forms:
Poor 46-55° 26-31 1.34-1.45
Very Poor 56-65° 32-37 1.46-1.59 Very cohesive • Identification
Very Very Poor ≥ 66° > 38 > 1.60 • Assay
• pH – common to SS and L
3.4 Flow through orifice
• Flow rate (measured as mass per time flowing from any A. FPQC TEST FOR TABLETS
types of containers: cylinders, funnels, hoppers)
• For free-flowing powders only 1. Friability
• determines tablet durability
3.5 Shear cell • Primary importance: No capping or chipping
• Sample:
Example: Aspirin granules were evaluated for its flow property: • ≤ 650mg: take a sx corresponding to 6.5g
Wt. of sample 100g • > 650mg: 10 whole tabs (uncoated)
Vol. of sample (untapped) – Vb 185mL • Equipment: Roche/ Vanderkaamp friabrilator
Vol. of sample (tapped) – Vt or Vp 169mL • Specification: 25 rpm x 4 mins. = 100 rev.
Wt. of sample passing through sieve # 20 – 100mg 𝑖𝑛𝑖𝑡𝑖𝑎𝑙 𝑤𝑡 − 𝑓𝑖𝑛𝑎𝑙 𝑤𝑡
Wt. of sample passing through sieve # 40 – fines, 90g retained 10g % 𝐹𝑟𝑖𝑎𝑏𝑖𝑙𝑖𝑡𝑦 = 𝑥 100
(good granules) 𝑖𝑛𝑖𝑡𝑖𝑎𝑙 𝑤𝑡
Ht. of cone formed 5cm
• Acceptance Criteria (max wt. loss)
Diameter of cone formed – 6.5cm radius 13cm • Old formulation: ≤ 1%
• New formulation: ≤ 0.8%
Compute for the ff:
a. % Good granules = (90g / 100g) x 100 = 90% Example: The ff data for friability test o a new formulation of
b. % Fine granules = (10g / 100g) x 100 = 10% Metronidazole 500mg/tab were obtained:
Average weight 592.40mg (sx size = 6.5164g)
c. Bulk density = 100g / 185mL = 0.5405g/mL
Weight of tabs after test 6.4893g
d. Tapped density = 100g / 169mL = 0.5917g/mL
e. Angle of repose = (𝜃)AOR=Shift tan 5cm / 6.5cm = 37.57°
a. How many tabs were used for the test? 6.5164g / 0.59240 =
(Fair + Glidant)
11 tabs
f. Carr’s index = ([185mL – 169] / 185) x 100 = 8.65%
b. What is % friability obtained?
(Excellent) 6.5164g − 6.4893g
g. HR = 185mL / 169mL = 1.0947 (Excellent) % 𝐹𝑟𝑖𝑎𝑏𝑖𝑙𝑖𝑡𝑦 = 𝑥 100 = 𝟎. 𝟒𝟐%
6.5164g
c. T or F. Did the batch pass the test? True

2. Dosage Unit Uniformity

• Ensures tabs meet specifications for potency
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Problems: 4. Dissolution
• Uneven distribution of API in powder mix/ granulation • Test for measuring the amount of time required for a given
• Segregation of powder mix/ granulation % of drug substance in a tablet to go into solution
• Tab wt. variation • Equipment: Vessel with cover, water bath maintained at
37±0.5 °C metallic drive shaft or Paddle.
2.1 Weight Variation
• ≥ 25mg API per dose and comprising ≥ 25% by wt. of
dosage unit
• Sample: 20 uncoated compressed tablets

Average Wt. Acceptance criteria

(max difference) Nmt 2 units are
< 130 mg ±10% outside AC
130 mg – 324 mg ±7.5%
> 324 mg ±5 % No unit is outside
twice the AC
Type Accessory
Example: 20 units of Metformin tabs were weighed individually and ff I Basket
data were obtained II Paddle (50 rpm)
Tab # Wt. Tab # Wt. Tab # Wt. Tab # Wt. III Reciprocating Cylinder
1 298 6 305 11 243 16 320 IV Flow-Through Cell
2 330 7 316 12 321 17 312 V Paddle Over Disk
3 312 8 307 13 340 18 315 VI Revolving Cylinder
4 250 9 291 14 315 19 341 VII Reciprocating Holder
5 318 10 280 15 318 20 301 *V-VII: TDDS
Average wt. = 306.65mg
a. Based on USP Wt Variation test, what is the acceptable wt. Inside diameter
Vessels Ht. (cm)
variation tolerance? 306.65mg x 7.5% / 100% = ±23 mg (mm)
1 160
98-106
b. What is the acceptable wt. range? 283.65-329.65 mg 2
280-300
c. T or F. based on this data, the batch has acceptable wt. 4 145-155
variation. False
• Q = % LC (amount of API released as specified in
2.2 Content Uniformity monograph)
• Ensures formulation potency • Sample: 6 units (initial); 6 units of retest (S@); 12 units on
• <25 mg API per dose and comprising <25% by wt. of final retest (S3)
dosage unit
• Sample: 10 units (assay individually); 20units on retest Stage No. Tested Acceptance criteria
• Acceptance Criteria: 85-115% API (100±5) 1 6 units • Each unit is nlt Q + 5%
2 + 6 (12) • Ave (12) is nlt Q
• No unit <Q – 15%
3. Disintegration 3 + 12 (24) • Ave (24) is nlt Q
• Measure of the time required for a tablet to break up into • Nmt 2 units <Q – 15%
small particles (for taps admin PO) • No unit <Q – 25%

Complete disintegration Example: Data for dissolution test:

• “State in which any residue of the unit, except fragments of Vessel % LC
insoluble coating or capsule shell, remaining on the screen 1 86%
of the test apparatus is a soft mass having no palpably firm 2 83%
core” 3 85%
Disintegration Test
4 86%
Equipment Basket-Rack Assembly
Media temperature 37±2 °C
5 87%
Cycles/ minute 29-32 6 85%
Media type Water, simulated gastric fluid, simulated
intestinal fluid If Q = 80%, what is the disposition for the test?
Fluid volume Upward stroke: wire mesh remains at least Q + 5%
15mm below fluid surface 80% + 5% = 85%
Disposition: Stage 2 (retest on 6 more samples)
Downward stroke: wire mesh descends nlt
25mm below the vessel
B. FPQC TEST FOR CAPSULES
Tablet type Medium Temp Time
1. DUU (WV, CU)
Uncoated/ IR
tablet 30 mins
2. Disintegration
Capsule Water 37±2 °C 3. Dissolution
SL tablet 2-3 mins
Buccal tablet 4 hrs C. FPQC TEST FOR SEMISOLID DOSAGE FORM

Tablet type Medium Temp Time 1. pH

Water Room temp 5 mins 2. Spreadability
simulated After 1hr: No 3. Spatula feel
Enteric coated
tablet
gastric fluid
37±2 °C
sign of disin. 4. Consistency (Penetrometer)
simulated 5. Viscosity (Brookfield viscometer)
1hr
intestinal fluid 6. Melting range
7. Microbial content*
• Sample: 6 units (Initial); 12 units on retest 8. Minimum fill*
Stage Sample Acceptance criteria 9. Metal particle in Ophthalmic ointments*
1 6 units Disintegrates (NONE remained on the
mesh except a soft mass with no palpable Microbial Content
firm core)
• Ophthalmic: sterile
If 1-2 didn’t disintegrate → stage 2 • Topical: (-) P. aeruginosa, S. aureus
2 + 12 units (18) NMT 2/18 fail to disintegrate • Urethral, Rectal, Vaginal: (-) molds and yeasts

Module 6 – Quality Assurance & Quality Control Page 6 of 8 RJAV 2022

Minimum fill Batch No. Volume (mL) Settled volume (mL)
• For semisolids with labeled content of nmt 150g or 150ml Batch 1 250 189
• Sample: 10 containers (assay individually); 20 containers Batch 2 250 156
on retest
a. What is the sedimentation volume of batch 1 and batch 2?
Net content = Initial wt. – Final wt. Batch 1 = 0.756
• Initial wt.: container with sample (unlabeled, cleansed, then Batch 2 = 0.624
dried) b. Which is better product based on sedimentation volume?
• Final wt.: empty container (heated at 100°C for 5 mins then Batch 1
cooled)
𝑛𝑒𝑡 𝑐𝑜𝑛𝑡𝑒𝑛𝑡
• % 𝐿𝑎𝑏𝑒𝑙𝑒𝑑 𝑐𝑜𝑛𝑡𝑒𝑛𝑡 = 𝑥 100 3. Degree of flocculation (β)
𝑙𝑎𝑏𝑒𝑙𝑒𝑑 𝑐𝑜𝑛𝑡𝑒𝑛𝑡

Acceptance criteria Each container 𝐹 𝑓𝑙𝑜𝑐 𝑉𝑢

𝛽= =
Aerosols <60g or 60ml: >90% 𝐹 𝑑𝑒𝑓𝑙𝑜𝑐 𝑉∞
≥60g or 60ml (but nmt 150g or 150ml): >95%
Non-Aerosols Net content > labeled content Suspension Flocculated Deflocculated
Particles Larger Smaller
Example: ZnO paste, with 50g LC, is subjected to minimum fill test. Uniform Varying
What is the AC? Sedimentation rate High Low
50g x 90% / 100% = 45g AC: LC nlt 90% and volume
Supernatant Clear Turbid
Metal particle in Ophthalmic ointments Sediment Porous Non-Porous (Hard
cake)
• Sample: 10 tubes (extrude contents in peri dish)
Redispersibility Yes (by agitation) No
• Heat @ 85°C for 2 hours the cool
• Invert petri dish → count metal particles using microscope
4. Redispersibility
(≥ 50 μm)
• Ideal: 100% with minimum agitation
Acceptance criteria:
5. Rheological properties: Viscosity
• Total # of metal particles in all 10 tubes is <50
• Measure of resistance to flow
• Nmt 1 tube contains > 8 metal particles
• Should not be too fluid nor too viscus (pour out readily)
Single use: must pass sterility test
6. Zeta potential
Multiple use: must pass antimicrobial effectiveness test (unless
• Repulsive forces between particles
bacteriostatic itself)
• ↑ zeta potential = ↓ Settling
VI. FINISH PRODUCT QUALITY CONTROL (FPQC)
7. Temperature and gravitational stress
Test for Liquid Dosage Forms
• T: 40°C
• Centrifugation: Crystal growth
A. FPQC TEST FOR LIQUID DOSAGE FORM
C. FPQC TEST FOR EMULSION
1. pH
1. Emulsion Type Test
2. Appearance (Color, Odor, Taste)
Dilution Test W/O O/W
3. Deliverable volume
Dye solubility Sudan red Amaranth green,
• Applicable for liquid products nmt 250mL Methyl red
• Sample size: 10 containers; 20 containers on retest UV fluorescence ✓ x
• Procedure: (Angle: 30°; prevent air-bubble formation) Conductivity x ✓
• Single unit: drain in 5 seconds Cobalt chloride Pink spots Pink
• Multiple unit: drain in ≤30 mins
2. Instability Test
B. FPQC TEST FOR SUSPENSIONS • Creaming, cracking/ breaking and phase separation/
inversion (o/w → w/o)
1. Particle size determination
3. Temperature and gravitational stress
1.1 Optical microscopy method • T: 50-70°C (then observed for instabilities)
1.2 Sedimentation rate
• Free for all particle velocity on Andreasen pipet based on D. FPQC TEST FOR STERILE DOSAGE FORMS
Stokes law (Sedimentation rate is directly proportional to
particle size)
Parenteral:
• Particle size: • SVP (≤ 100mL)
• Solution 0.1-1nm • LVP (> 100mL)
• Colloidal 1-100nm
• Suspension >100nm 1. Sterility
• Test to see absence of viable microorganisms in product
2. Sedimentation volume
• ≤10-6 microorganism
𝑉𝑢
𝐹=
𝑉𝑜 Sterilization Test Incubation Notes
Vu – settled volume
Membrane filtration 7 days Primary
Vo – suspension volume technique
Direct inoculation Soybean casein Aerobes (e.g., fungi:
Ideal: F = 1 digest medium total yeast and molds
• No sediment is present (20-25°C; 5-7days) count)
• Caking is absent Fluid thioglycolate Anaerobes (also used
• Suspension is esthetically pleasing medium in total aerobic count)
(30-35°C; 2-3days)
Example: two different batches of Amoxicillin 125mg/5mL Biological indicator Preferred for
sterilizations
suspension made under different production set-ups were compared processes
with the ff results

Module 6 – Quality Assurance & Quality Control Page 7 of 8 RJAV 2022

 Sterilization method
Steam/ moist heat (autoclave)
• 121°C, 15psi, 15-30
mins.
Dry heat
• For water sensitive
Ethylene oxide
• Gas sterilant
• For heat sensitive
Ionizing radiation
Sterilizing membrane filter
• Pore size: 0.2μm
• Efficiency: Bubble point
test
Biological indicator Method II: Microscopic particle count test
• Uses microscope with ocular micrometer, membrane filter
Bacillus stearothermophilus and illuminators)
6. Leaker’s test
• Negative pressure within incompletely sealed ampule while
Bacillus subtilis
submerged in dye solution (1% methylene blue)
• Ampules with color contents → discarded
Bacillus pumilus
E. ENVIRONMENTAL CONTROL TEST FOR STERILE AREAS
Pseudomonas diminuta
• Test to determine the viable and nonviable particles
suspended in air or settled on surfaces

2. Pyrogens/ bacterial endotoxins (lipid A of LPS) 1. Air sampling (Slit-to-agar-sampler)

• Organic metabolic products from G (-) bacteria which can • Air → Slit (via vacuum) → slowly rotating Nutrient Agar plate
cause fever and hypotension → Colony Forming Unit (?)
• Thermostable (non-autoclave)
Methods:
Pyrogen Test: • Agar plate exposure to the settling air microbes
• Bacterial endotoxin/ Limulus Amebocyte Lysate test (in vitro) • Rodac plates – agar plates having conves surface which
• Rabbit test (in vivo) determines microbes on surface

2.1 Bacterial endotoxin/ Limulus Amebocyte Lysate test (in 2. Media fill (process simulation testing)
vitro) • Evaluates the environment along with the process, operators
• LAL source: Horseshoe crab (Limulus polyphemus) and equipment
• Detect and quantify endotoxin from gram-negative bacteria • Sterile trypticase soy broth is filled into at least 3000 sterile
• 3 techniques: containers → incubated at 20-25°C for 14days → examined
• Gel-clot for bacterial growth
• Turbidimetric • Acceptance Criteria: nmt 0.1% of units is (+) for growth
• Chromogenic
3. Electronic/ automated particle counter
2.3 Rabbit test (in vivo) • Determines particle size by means of shadow casted by
Rabbit Test particles as it passes through a high intensity beam
Prior test - Samples: 3 healthy, mature rabbits (37±2 °C) • Disadv: nonspecific
- Apparatus: Depyrogenated at 250°C
During test - Inj. 10mL/kg TS in the ear vein, completing inj. Within
10mins after start of administration
Counter counter – Electrical resistance
- After 1 hour, record the rectal temperature (30 mins/ Gelman counter – Tyndall effect
1-hour intervals for 3 hours) Hiac/ Royco = Light blockage
AC (Non- Sum rise:
Pyrogenic) - AC 1: <1.5°C for 3 rabbits (provided NO individual 4. Membrane filtration technique
rise of ≥0.5°C + 5 rabbits • Collects particles size greater than the membrane pore size
- AC 2: ≤3.3°C for 8 rabbits (provided NMT 3 rabbits • Disadv: saturable, slow counting
have individual rise of ≥0.5°C
HEPA filter
Example: the ff data were obtained on pyrogen test in 8 rabbits • 99.97%; ≤0.3μm
Rabbit # Temp rise (°C)
• Efficiency tests:
1 02
• DOP (dioctyl phthalate) test
2 0.6
3 0.3
• Test HC (Henkel corp) emery test
4 0.5
5 0.1
6 0.2
7 0.2
8 0.4
Sum rise = 2.5°C

a. Did the individual temp rise of each rabbit comply with the
requirement? Yes (nmt 3 rabbits have temp rise of ≥0.5°C)
b. Did the temp rise comply with the requirement? Yes (Sum
rise = 2.5°C; AC: ≤3.3°C)

3. Safety/ Cytotoxicity Test

• Bioassays

4. Clarity Test
• Visual inspection; inverted to see heavy particles (can be
done @ 100% or product units or at the level of user’s
discrimination

5. Particulate matter
• Presence of extraneous mobile undissolved particles → Cx.
Emboli phlebitis
• Must be carried out in laminar airflow hood

Method I: Light obscuration particle count test

• Adv: Automatic (measure particle number and size)
• Disadv: for clear and non-viscous solutions only (not for:
emulsions, colloids, liposomal preparations)

Module 6 – Quality Assurance & Quality Control Page 8 of 8 RJAV 2022