Basics For QA

INTERVIEW PREPARATION FOR IPQA
Equipment name Model Calibration

Digital balance Make-contech In house-Quarterly ,whenever we required
Capacity-220 gm Party-One year(Micro vision)
Working capacity-100mg-100 Accuracy
gm Linearity-Acceptance Criteria: Correlation
Least count-0.001gm coefficient should not be less than 0.99.
TOLERANCE LIMIT :±
0.1% OF STANDARD Precision-Acceptance criteria: RSD of 05 replicate
WEIGHT weighing should be less than 0.5 %.
%RSD = Std. Dev. X100 = -------- = -----
Average
Eccentricity-Pan position
Uncertainty Value = 2 × Std Dev. = --------
=
10
The uncertainty valve should not be more than 0.001
Hardness tester Make- ELECTROLAB EBT- In house-Quarterly , whenever we required
2PL Party-one year
Capaccity-800 N Verification performs at the start of shift.
Tolerance Limit Thickness-10 mm s.s gauge
(± 0.2 mm) Limit-10.00 (09.80-10.20)
Tolerance Limit
(± 100g)
Limit-4.90-5.10 kg
Disintegration Electrolab ED-2L 1)Thermostat calibration
apparatus Temperature of bath
Temperature of medium
2) calibration of display
Limit-plus minus 2 second
Time-1,3,,5,15,30,60,120 min
3) Number of strokes
Limit-29-32 cycles
Criteria-plus minus 2 cycles
4) Distance traveled by shaft
Limit-53-57 mm.
Friability test Electrolab-EF-2W Number of rotation-100/minute
apparatus Stopwatch
Tachometer
Time
Rotation
Rpm
Criteria-(± 2)
Time-4 min (± 5 second)
Calibrations IH External agencies
Vernier caliper NA Yearly or whenever required
(Mitutoyo)
DT Quarterly or whenever Yearly or whenever required

(Electrolab-ED-2L) required
Sieve shaker NA Half yearly

(Electrolab-EMS-8)
Moisture analyzer NA yearly

(35) OHAUS
TDA quarterly Half yearly

(ETD-1020)
INPROCESS CHECKING LINE CLEARANCE

Line Clearance:-
➢ Avoid cross contamination.
➢ Prevent mix-ups.
➢ Facilitate proper reconciliation of batch materials.
➢ Achieve smooth and trouble free operations.
Granulation Logbooks:-
➢ (AHU, Pressure differential, temp and Humidity, equipment cleaning
logbooks, Sieve logbook, FBD bag logbook)
Granulation cleaning area
➢ SIFTER-
➢ Visually check S.S sieve, dome, discharge chute and inner, outer
surfaces of Vibro sifter
Checklist for RMG/ Saizoner Mixer Granulator (SMG) and Inline Cone
Mil
➢ RMG, Multi-mill, FBD, Blender and utensils.
➢ Floor and walls are cleaned,
➢ Door and windows are cleaned.
➢ AHU grills, dust extractor hoods are cleaned.
➢ All materials of previous product are removed.
➢ Ensure about the favorable environmental condition of the working
area.
Checklist for Fluid bed dryer (FBD)
➢ Bowl lifting chamber.
➢ Inlet air duct and supporting clamp.
➢ Check inlet and outlet temperature
➢ Dutch sieve
➢ Sampling port.
➢ finger bag holder
➢ Pressure tubes (FBD Ring).
Lifting and Positioning device (LPD)
Checklist for In Process Container (IPC)
COMPRESSION ➢ Cleaning status of compression machine.
➢ All materials of previous product are removed
➢ Rinse sample intimation slip
area.
➢ All parts of compression machine i.e. hopper, turret, dies, Ejection plate
& punches are cleaned.
➢ metal detector,
➢ Challenge test Perform by using
1)Ferrous-0.3mm
2)Non-Ferrous-o.4mm
3)S.S-0.4 mm
➢ De-duster.
➢ LPD(lifting positioning devise) cleaning,
➢ Cleaning of return air riser filters.
➢ Floor and walls are cleaned, Door and windows are cleaned.
TABLET ➢ Sorting table and trays are cleaned
INSPECTION ➢ Floor and walls are cleaned.
area.
TABLET COATING ➢ All parts of coating machine are cleaned.
➢ Rinse sample approved intimation
➢ Check Solution preparation materials
➢ Check type of coating
1)Aqueous-by using water
2)Non aqueous-Propylene glycol, ethylene chloride,
IPA, HPMC.
➢ Floor and walls are cleaned.
➢ Machine(make and model)
➢ Inlet air temp-50-70
➢ Out let temp-30-50
➢ Bed temp-40-50
➢ Spray rate-2-4 Kg
➢ Gun distance-30-40 cm
➢ Peristaltic pump-8-12 RPM
➢ Atomizing air pressure-100-400 kg/cm2
➢ Pan speed-2-6 RPM
➢ Baffle type-baffle 3
➢ Type of gun-Anesta (3/5 gun)
➢ Nozzle diameter of gun-1 mm
➢ Pattern of air flow-laminar/uniform
➢ Gun to gun distance-18 cm
➢ Type of pump used –peristaltic pump
➢ Diameter of feed tube- 15 mm
➢ Inlet air damper -(% open)
➢ Exhaust air damper-(% open)
➢ Negative air pressure inside pan (during operation)
➢ Air flow or velocity-(CFM or m3/hr) 2500-3500
➢ Total solution spraying on tablet
➢ Total time require to spray coating solution.
➢ Type of solution-For aqueous solution (30 liter)
▪ HPMC 5 CPS-3.145 KG
▪ TALCUM-2.145 KG
▪ TITANIUM DI OXIDE-1.145 KG
▪ DM WATER-30 LITER
▪ PEG-6000-0.315 GM
▪ Solution stir-45 minutes
For non aqueous solution(100 LITER)

• HPMC15 CPS-3.500 KG
• TALCUM-2.500 KG
• TITANIUM DI OXIDE-1.200 KG
• METHYLENE CHLORIDE-66 LITER
• IPA-33 LITER
• PROPYLENE GLYCOL-0.350 LITER
CAPSULE SECTION
• Magzime
• Race way
• Upper setting punch
• Lower setting punch
• Plunger
• Push plate
• Upper mould
• lower mould
• locking pin
• Rejection pin
• Ejection pin
• Dosing plate
• Powder/pellet filling plate
• Auger
➢ Rinse sample approved intimation
DIFFERENT SIZES OF CAPSULE AND THEIR EMPTY CAPSULE WT.-

• 000-125 mg
• 00-110 mg
• 0-95 mg
• 1-75 mg
• 2-65 mg
• 3-50 mg
• 4-40 mg
• 5-35 mg
PACKING ➢ Areas should be cleared and cleaned.
➢ Check the previous batch product packing material
➢ Rinse sample approval intimation slip.
➢ Check approved label of tablet received from production.
➢ Checked type of stereo
Grooved or Flat
➢ Check tablet drum received from production department and also check
PTN and do entry on inward and outward logbook.
➢ Check status on board
➢ Check environmental condition in area.
➢ Check the all logbooks
➢ Check packing material and also cross check control number of packing
material and quantity by using packing material issue slip.
➢ Check the proof.
➢ Check Change part and their number. Entry on change part logbooks.
• Hopper
• Chute
• Guide track
• Channel
• Forming roller
• Sealing roller
• Printing & Cutter gear.
Types of Tablet:-
IP BP USP
Uncoated Uncoated Compressed/molded
Film Coated Coated Plain Coated
Enteric Coated Gastro Resistant (Enteric Delayed Release

Coated)
Dispersible Tablet Dispersible Tablet Dispersible Tablet
Modified Release Tablet Modified Release Tablet Extended Release Tablet
Soluble Tablet Soluble Tablet Soluble Tablet
Effervescent Tablet Effervescent Tablet Effervescent Tablet
For use in mouth (Chewable, For use in mouth (Chewable, Chewable/Buccal, Sublingual
Lozenges, Sublingual) Lozenges, Sublingual)
Orodispersible Orodispersible Orodispersible
Standards for Tablets:-
IP BP USP
Content of Active Ingredient Content of Active Ingredient Content of Active Ingredient
Uniformity of weight Uniformity of weight Weight Variation
Uniformity of Content Uniformity of Content Uniformity of Content
DT DT DT
Dissolution Dissolution Dissolution
1) Content of Active Ingredient: -
1) Assay of Active
2) 20 tabs: - Limits 90% to 110%
2) Uniformity of Weight/Wt Variation:-

20 tabs, calculate avg. wt NMT 2 deviate, none twice the limits.
Weight Variation Limits:-
1) For Tablets
IP/BP Limit USP
80 mg or less 10% 130mg or less
More than 80mg or 7.5% 130mg to 324mg

Less than 250mg
IP Limit
250mg or more 5% More than 324mg
Less than 300mg 10%
300mg or More 7.5%

2) For Capsule:-
Friability Test:-
This test is additional to check crushing strength of tablet by this test one can check Capping
&/or Lamination.
USP limit is 0.5 to 1%. W/w
Rotation: - 25 rpm or 100 rotations
Time- 4 min.
Uniformity of Content or Content Uniformity:-
IP: - Active less than 10mg or 10%,
BP: - Active less than 2 mg or 2%,
USP:- Active less than 25mg or 25%.
-10 tabs limit NMT 1 tab deviate 85 – 115% & none outside 75 – 125% of the Avg value/IP/BP/USP
(Relative Standard Deviation less than or equal to 6%),
- If 2 or 3 individual values are outside the limits 85 – 115% of the Avg value, & none outside 75 – 125%
repeat for 20 tabs.
- Complies when 30 tabs NMT 3 of the individual values are outside the limit 85 – 115% of the Avg
value, and none outside 75 – 125%.
Disintegration Time:-
Uncoated Tablet NMT 15 min, in water with Disc 370C ± 20C
Coated Tablet NMT 30 min, In water with Disc for Film Coated Tab, and NMT 60
min Other than Film coated tablet
Enteric Coated Tab Intact for 1 hr in 0.1 N HCl & disintegrate within 2 hr in Mixed 6.8
Phosphate buffer. According to USP 1 hr in Simulated gastric fluid,
then in Simulated Intestinal Fluid.
Dispersible/Soluble Within 3 min in water at 250C ± 10C (IP) & 15 – 250C (BP)
Orodispersible Within 1 min
Effervescent Tab 5 min in 250 ml water at 20 – 300C (IP) & 5 min in 200 ml water at
15-250C (BP)
Buccal & Sublingual Not Applicable but dissolve within 15 – 30 min.
DT Apparatus:- Mesh Aperture:- 2mm (#10), Cycles:- 28 – 32 cycles/min, 50 – 60 mm distance from

bottom & top, Temp of water 370C ± 20C. If 1 or 2 tabs fail, repeat for 12 tabs.
Solubility:-
BP SOLUBILITIES
Very soluble less than 1 part
Freely soluble from 1 to 10 parts
Soluble from 10 to 30 parts
Sparingly soluble from 30 to 100 parts
Slightly soluble from 100 to 1000 parts
Very slightly soluble from 1000 to 10,000 parts
Practically insoluble more than 10,000 parts
Approximate quantity of solvent by volume for one part of soluble by

weight. For example, 1g of a very soluble substance dissolves in less than 1ml
of solvent (1gm/ml).
Compressibility Index
(Carr’s Index):- Angle of Repose:-
Tapped Density – Bulk Density x 100 θ = tan-1(h/r)
Tapped Density
Flow property C.I (%) Hausner’s ratio
Excellent ≤10 1.00 – 1.11
Good 11 – 15 1.12 – 1.18
Fair 16 – 20 1.19 – 1.25
Passable 21 – 25 1.26 – 1.34
Poor 26 – 31 1.35 – 1.45
Very poor 32 – 37 1.46 – 1.59
Very, very poor >38 >1.60
Flow property Angle of repose (degrees)
Excellent 25 – 30
Good 31 – 35
Fair-aid not needed 36 – 40
Passable – may hang up 41 – 45
Poor – must agitate, vibrate 46 – 55
Very poor 56 – 65
Very, very poor >66

Bioavailability:-
The rate and extent to which the active ingredient or active moiety is absorbed from a drug
product and becomes available at the site of action. For drug products that are not intended to be absorbed
into the bloodstream, bioavailability may be assessed by measurements intended to reflect the rate and
extent to which the active ingredient or active moiety becomes available at the site of action.
ANDA - Abbreviated New Drug Application.
IND – Investigational New Drug Application.
NDA – New Drug Application.
According to the BCS, drug substances are classified as follows:
Class I - High Solubility, High Permeability

Class II - High Permeability, Low Solubility
Class III -High Solubility, Low Permeability
Class IV - , Low Solubility Low Permeability
• A drug substance is considered HIGHLY SOLUBLE when the highest dose strength is soluble in
< 250 ml water over a pH range of 1 to 7.5.
• A drug substance is considered HIGHLY PERMEABLE when the extent of absorption in humans
is determined to be > 90% of an administered dose, based on mass-balance or in comparison to an
intravenous reference dose.
• A drug product is considered to be RAPIDLY DISSOLVING when > 85% of the labeled amount
of drug substance dissolves within 30 minutes using USP apparatus I or II in a volume of < 900
ml buffer solutions.
DISSOLUTION DETERMINATION
• USP apparatus I (basket) at 100 rpm or USP apparatus II (paddle) at 50 rpm.

• Dissolution media (900 ml): 0.1 N HCl or simulated gastric fluid, pH 4.5 buffer, and pH 6.8
buffer or simulated intestinal fluid.
• Compare dissolution profiles of test and reference products using a similarity factor (f 2).
AN ASSAY OF TABLET TYPES
Immediate Release Uncoated Tablets: Usually no taste/stability issues.

Coated Tablets: For taste/stability/identification (coated with water-soluble/dispersible polymer–
mixture of hydroxypropyl cellulose/hydroxypropylmethyl cellulose); coating readily ruptures in GI tract.
Enteric-Coated Tablets: For drugs inactivated or destroyed in the stomach or for those causing irritation
to the gastric mucosa; tablet passes through the stomach but disintegrates in the intestines where
absorption takes place. Excipients used for enteric coating include cellulose acetate phthalate, mixtures of
fats and fatty acids, etc.
Multiple Compressed Tablets: Multiple-layered tablets manufactured by using more than one
compression cycle. Each layer contains a different drug and each may be colored differently.
Controlled Release Tablets: Improved therapy, less toxicity, improved patient compliance—using
polymers such as methacrylates.
Sublingual Tablets: Small, flat ovals such as nitroglycerin. They are ideal tablets for absorption of drugs
which are destroyed by gastric juice or undergo first pass metabolism.
Chewable Tablets: Disintegrate rapidly when chewed for patients with swallowing difficulty (children,
elderly) and when there is no access to water. Most commonly used for multiple vitamins and antacids.
Effervescent Tablets: In addition to the active, this product form contains sodium bicarbonate and citric
acid. When water is added the ensuing chemical reaction forms carbon dioxide, which acts as a
disintegrant and produces effervescence that hastens dissolution (antacids).
The defects related to Tablet Process
1) Capping:
• It is partial or complete separation of the top or bottom of tablet due air-
entrapment in the granular material.
Reason:
• Capping is usually due to the air–entrapment in a compact during
compression, and subsequent expansion of tablet on ejection of a tablet from a
die
Causes
• Large amount of fines in the granulation
• Too dry or very low moisture content (leading to loss of proper binding
action).
• Not thoroughly dried granules.
• Insufficient amount of binder or improper binder
• Insufficient or improper lubricant.
• Granular mass too cold.
• Poorly finished dies
• Deep concave punches or beveled-edge faces of punches.
• Lower punch remains below the face of die during ejection.
• Incorrect adjustment of sweep-off blade.
• High turret speed
Remedies
• Remove some or all fines through 100 to 200 mesh screen
• Moisten the granules suitably. Add hygroscopic substance e.g.: sorbitol,
methyl- cellulose or PEG- 4000
• Dry the granules properly
• Increasing the amount of binder
• Adding dry binder such as pre-gelatinized starch, gum acacia, powdered
sorbitol, PVP, hydrophilic silica or powdered sugar.
• Increase the amount of lubricant or change the type of lubricant
• Compress at room temperature
• Polish dies properly. Investigate other steels or other materials.
• Use flat punches
• Make proper setting of lower punch during ejection.
• Adjust sweep-off blade correctly to facilitate proper ejection.
• Reduce speed of turret (Increase dwell time).
2) Lamination:
• It is separation of tablet into two or more layers due to air-entrapment in the
granular material.
• Is the separation of a tablet into two or more distinct horizontal layers
Reason:
• Air–entrapment during compression and subsequent release on ejection.
• The condition is exaggerated by higher speed of turret.
Causes
• Oily or waxy materials in granules.
• Too much of hydrophobic lubricant.
• Magnesium-stearate
• Rapid relaxation of the peripheral regions of a tablet, on ejection from a die.
• Rapid decompression
Remedies
• Modify mixing process. Add adsorbent or absorbent.
• Use a less amount of lubricant or change the type of lubricant.
• Use tapered dies, i.e. upper part of the die bore has an outward taper of 3° to
5°.
• Use pre-compression step. Reduce turret speed and reduce the final
compression pressure
3) Chipping:
• It is due to very dry granules.
• Chipping‘is defined as the breaking of tablet edges, while the tablet leaves the
press or during subsequent handling and coating operations.
Reason:
• Incorrect machine settings, especially miss-set ejection take-off.
Causes
• Sticking on punch faces
• Too dry granules.
• Too much binding causes chipping at bottom.
• Groove of die worn at compression point.
• Barreled die (center of the die wider than ends)
• Edge of punch face turned inside/inward.
• Concavity too deep to compress properly.
Remedies
• Dry the granules properly or increase lubrication.
• Moisten the granules to plasticize.
• Add hygroscopic substances.
• Optimize binding, or use dry binders.
• Polish to open end, reverse or replace the die.
• Polish the die to make it cylindrical
• Polish the punch edges
• Reduce concavity of punch faces. Use flat punches.
4) CRACKING
Small, fine cracks observed on the upper and lower central surface of tablets, or
very rarely on the sidewall are referred to as Cracks‘.
Reason:
It is observed as a result of rapid expansion of tablets, especially when deep
concave punches are used.
Causes
• Large size of granules.
• Too dry granules.
• Tablets expand.
• Granulation too cold.
• Tablet expands on ejection due to air entrapment
• Deep concavities cause cracking while removing tablets
Remedies
Reduce granule size. Add fines.
Moisten the granules properly and add proper amount of binder.
Improve granulation. Add dry binders.
Compress at room temperature.
5) Sticking:
• It is the adhesion of granulation material to the die wall
Reason:
• Improperly dried or improperly lubricated granules.
Causes
• Granules not dried properly.
• Too little or improper lubrication.
• Too much binder
• Hygroscopic granular material.
• Oily or way materials
• Too soft or weak granules.
• Concavity too deep for granulation.
• Too little pressure.
• Compressing too fast.
Remedies
• Dry the granules properly. Make moisture analysis to determine limits.
• Increase or change lubricant.
• Reduce the amount of binder or use a different type of binder.
• Modify granulation and compress under controlled humidity.
• Modify mixing process. Add an absorbent.
• Optimize the amount of binder and granulation technique
• Reduce concavity to optimum.
• Increase pressure.
• Reduce speed.
6) Picking:
• It is the removal of material from the surface of tablet and its adherence to
the face of punch.
Reason:
• Picking is of particular concern when punch tips have engraving or
embossing letters, as well as the granular material is improperly dried.
Causes
• Excessive moisture in granules.
• Too little or improper lubrication.
• Low melting point substances, may soften from the heat of compression and
lead to picking.
• Low melting point medicament in high concentration.
• Too warm granules when compressing.
• Too much amount of binder.
• Rough or scratched punch faces.
• Bevels or dividing lines too deep.
• Pressure applied is not enough; too soft tablets.
Remedies
• Dry properly the granules, determine optimum limit.
• Increase lubrication; use colloidal silica as a polishing agent‘, so that
material does not cling to punch faces.
• Add high melting-point materials. Use high meting point lubricants.
• Refrigerate granules and the entire tablet press.
• Compress at room temperature. Cool sufficiently before compression.
• Reduce the amount of binder, change the type or use dry binders
• Polish faces to high luster.
• Design lettering as large as possible.
• Plate the punch faces with chromium to produce a smooth and non-adherent
face.
• Reduce depths and sharpness.
• Increase pressure to optimum
7) Binding:
• These problems (are due to more amount of binder in the granules or wet
granules.
Reason:
• Binding is usually due to excessive amount of moisture in granules, lack of
lubrication and/or use of worn dies.
Causes
• Too moist granules and extrudes around lower punch.
• Insufficient or improper lubricant.
• Too coarse granules.
• Too hard granules for the lubricant to be effective.
• Granular material very abrasive and cutting into dies.
• Granular material too warm.
• Sticks to the die.
• Poorly finished dies.
• Rough dies due to abrasion, corrosion.
• Undersized dies. Too little clearance.
• Too much pressure in the tablet press
Remedies
• Dry the granules properly.
• Increase the amount of lubricant or use a more effective lubricant.
• Reduce granular size, add more fines, and increase the quantity of lubricant.
• Modify granulation. Reduce granular size.
• If coarse granules, reduce its size.
• Use wear-resistant dies.
• Reduce temperature.
• Increase clearance if it is extruding.
• Polish the dies properly.
• Investigate other steels or other materials or modify granulation.
• Rework to proper size. Increase clearance.
• Reduce pressure. Or Modify granulation.
8) MOTTLING
• Mottling‘is the term used to describe an unequal distribution of colour on a
tablet,
Reason:
• One cause of mottling may be a coloured drug, whose colour differs from
the colour of Excipient used for granulation of a tablet.
Causes
• A coloured drug used along with colorless or white-coloured Excipient.
• A dye migrates to the surface of granulation while drying.
• Improperly mixed dye, especially during Direct Compression
• Improper mixing of a coloured binder solution.
Remedies
• Use appropriate colorants.
• Change the solvent system, Change the binder, Reduce drying temperature
and Use a smaller particle size.
• Mix properly and reduce size if it is of a larger size to prevent segregation.
• Incorporate dry colour additive during powder blending step, then add fine
powdered adhesives such as acacia and tragacanth and mix well and finally
add granulating liquid.
•
9) Double Impression
• It is due to free rotation of the punches, which have some engraving on the
punch faces.
Reason:
• At the moment of compression, the tablet receives the imprint of the punch
Cause
• Free rotation of either upper punch or lower punch during ejection of a
tablet.
Remedies
• Use keying in tooling, i.e. inset a key alongside of the punch, so that it fits
the punch and
• Prevents punch rotation.
• Newer presses have anti-turning devices, which prevent punch rotation.
•
10) BLISTERING
• It is local detachment of film from the substrate forming blister.
Reason:
• Entrapment of gases in or underneath the film due to overheating either
during spraying or at the end of the coating run. The Cause and Remedy
Of Blistering
Cause
• Effect of temperature on the strength, elasticity and adhesion of the film.
Remedy
• Use mild drying condition.
11) BLOOMING
• It is defect where coating becomes dull immediately or after prolonged
storage at high temperatures.
Reason:
• It is due to collection on the surface of low molecular weight ingredients
included in the coating formulation. In most circumstances the ingredient
will be plasticizer. The Cause And Remedy Of Blooming
Cause
• High concentration and low molecular weight of plasticizer.
Remedy
• Decrease plasticizer concentration and increase molecular weight of
plasticizer.
ORANGE PEEL/ROUGHNESS
• It is surface defect resulting in the film being rough and nonglossy.
Appearance is similar to that of an orange
Reason:
• Inadequate spreading of the coating solution before drying.6The Causes and
Remedies Of Orange Peel/Roughness
Causes
• Rapid Drying
• High solution viscosity
Remedies
• Use mild drying conditions.
• Use additional solvents to decrease viscosity of solution.
Official Standards as per I.P. / B.P. / U.S.P.
COMPARISON OF DIFFERENT PHARMACOPOEIAL QUALITY CONTROL TESTS
PHARMACOPOEIAS TYPE OF TABLET TESTS TO BE PERFORMED

Content of active ingredients
BRITISH Disintegration
For all tablets
PHARMACOPOEIA Uniformity of content
Labeling
Disintegration test
Uncoated tablet
Uniformity of weight
Disintegration test
Effervescent tablet
Disintegration test
Coated tablet
Gastro resistant tablet Disintegration test
Modified release tablet Uniformity of weight
Tablet for use in mouth Uniformity of weight
Disintegration test
Soluble tablet
Disintegration test
Dispersible tablet Uniformity of dispersion
Uniformity of container content
Content of active ingredient

Uncoated tablet Uniformity of weight
Uniformity of content
Disintegration test
INDIAN
Enteric coated tablet Disintegration test
PHARMACOPOEIA
Uniformity of dispersion
Dispersible tablet
Disintegration
Soluble tablet Disintegration test
Disintegration/ Dissolution / Dispersion

Effervescent tablet
test
UNITED STATES Physical tests applicable Bulk density /Tapped density of powder
PHARMACOPOEIA to tablet formulation Powder fineness
Loss on drying
Disintegration test
Tablet friability
Dissolution test
Drug release testing
Uniformity of dosage form
Container permeation test
Labeling of inactive ingredients
1. Q. How many Tablets shall be taken for checking friability?
Ans:For tablets with unit mass equal or less than 650 mg, take sample of whole tablets
corresponding to 6.5g.For tablets with unit mass more than 650mg,take a sample of 10 whole
tablets
2. Q. What is the formula for calculating weight loss during friability test?
Ans: %Weight loss = Initial Weight - Final Weight X 100

Initial Weight
3. Q. What is the pass or fail criteria for friability test?

Ans: Generally the test is run for once. If any cracked, cleaved or broken tablets present in
the tablet sample after tumbling, the tablets fails the test. If the results are doubtful, or weight
loss is greater than the targeted value, the test should be repeated twice and the mean of the
three tests determined. A mean weight loss from the three samples of not more than 1.0% is
considered acceptable for most of the products.
4. Q. What is the standard number of rotations used for friability test?
Ans: 100 rotations
5. Q. What is the fall height of the tablets in the friabilator during friability testing?
Ans: 6 inches.Tablets falls from 6 inches height in each turn within the apparatus.
6. Q. Why do we check hardness during in process checks?
Ans: To determine need for the pressure adjustments on the tableting machine.Hardness can
affect the disintegration time.If tablet is too hard,it may not disintegrate in the required period
of time. And if tablet is too soft it will not withstand handling and subsequent processing such
as coating,packing etc.
7. Q. What are the factors which influence tablet hardness?
Ans: 1.compression force
2.Binder quantity(More binder more hardness)
3.Moisture content
8. Q. Which type of tablets are exempted from Disintegration testing?
Ans: Chewable Tablets
9. Q. Which capsule is bigger in size - size '0' or size '1'?
Ans: '0' size
10. Q. What is the recommended temperature for checking DT of a dispersible tablet?
Ans: 25 ±10C (IP) & 15 – 250C (BP)
11. Q. What is mesh aperture of DT apparatus?
Ans: 1.8 -2.2mm (#10)
13. Q. What are the pass/fail criteria for disintegration test?
Ans: If one or two tablets/capsules fails to disintegrate completely, repeat the test on another
12 additional dosage units. The requirement is meet if not fewer than 16 out of 18
tablets/capsules tested are disintegrated completely.
14. Q. What are the recommended storage conditions for empty hard gelatin capsules?
Ans: 15 - 250C & 35 -55% RH
15. Q. Which method is employed for checking “Uniformity of dosage unit”?
Ans:
A.)Content uniformity
B.) Weight Variation
Weight variation is applicable for following dosage forms;
Hard gelatin capsules,uncoated or film coated tablets,containing 25mg or more of a drug
substance comprising 25% or more by weight of dosage unit.
16. Q. What is the recommended upward and downward movement frequency of a basket-
rack assembly in a DT apparatus?
Ans: 28 – 32 cycles per minute.
17. Q. When performing the ‘uniformity of weight’ of the dosage unit, how many
tablet/capsule can deviate the established limit?
Ans: Not more than two of the individual weights can deviates from the average weight by
more than the percentage given in the pharmacopeia,and none can deviates more than twice
that percentage.
Weight Variation limits for Tablets
IP/BP Limit USP

80 mg or less ±10% 130mg or less
More than 80mg or Less than 250mg ±7.5% 130mg to 324mg
250mg or more ±5% More than 324mg
Weight Variation limits for Capsules
IP Limit
Less than 300mg ±10%
300mg or More ±7.5%
18. Q. What needs to be checked during inprocess QA checks?

Ans:
a.) Environmental Monitoring
b.) Measured values obtained from the process equipment (ex:temperature,RPM etc.)
c.) Measured values obtained from persons (ex:timmings,entries etc.)
d.) Process attributes (Ex:weight,hardness,friability etc.)
19. Q. What precautions shall be taken while collecting inprocess samples ?
Ans: While collecting inprocess samples, avoid contamination of the product being sampled
(Don’t collect samples with bare hands) & avoid contamination of sample taken.
20. Q. In a tablet manufacturing facility ‘positive’ pressure is maintained in processing area
or service corridors?
Ans: In tablet manufacturing facilities, pressure gradients are maintained to avoid cross
contamination of products through air. Usually service corridors are maintained under
positive pressure with respect to processing areas.
21. Q. If sticking observed during tablet compression what may the probable reason for the
same?
Ans:
1.If the granules are not dried properly sticking can occur.
2.Too little or improper lubrication.
3.Too much binder
4.Hygroscopic granular
22. Q. What checks shall be carried out, while calibrating DT apparatus?
Ans: While calibrating DT apparatus, following checks shall be performed.
1.) Number of strokes per minute (Limit:29-32 cycles/min)
2.) Temperature by probe & standard thermometer
(Limit: 37 ± 1 OC).
3). Distance travelled by basket (Limit:53 -57mm)
22 Q.Why granuation is important

To improve powder flow.
To improve compressibility.
To reduce fines.
To control the tendency of powders to segregate.
To control density.
To capture and fuse small quantities of active
Material.
23. Q. What is In process checks?
Ans: In process checks are checks performed during an activity,In order to monitor and,if
necessary,to adjust the process to ensure that product confirms to its specification.
24. Q. What is the difference between disintegration and dissolution?
Ans: Disintegration is a disaggregation process, in which an oral dosage form falls apart in to
smaller aggregates.(Disintegration time is the ‘break up’ time of a solid dosage form).
Where as dissolution is a process by which solid substance enters in the solvent to yield a
solution.It is controlled by the affinity between the solid substance and the solvent.
In other word disintegration is a subset of dissolution.
25. Q. What is the difference between calibration and Validation?

Ans: Calibration is a demonstration that, a particular
Instrument or device produces results with in specified limits by comparisons with those
produced by a reference or traceable standard over an appropriate range of measurements.
Where as Validation is a documented program that provides high degree of assurance that a
specific process, method or system consistently produces a result meeting pre-determined
acceptance criteria.
In calibration performance of an instrument or device is comparing against a reference

standard. But in validation such reference standard is not using.
Calibration ensures that instrument or measuring devices producing accurate results. Whereas
validation demonstrates that a process, equipment, method or system produces consistent
results (in other words, it ensures that uniforms batches are produced).
26. Q. Why do we calibrate a qualified equipment/instrument on definite intervals?

Ans: An equipment or instrument can ‘drift’ out of accuracy between the time of
qualification and actual use.So it is recommended to calibrate and recalibrate the measuring
devices and instruments on predetermined time intervals, to gain confidence on the accuracy
of the data.
27. Q. Why do we consider three consecutive runs/batches for process validation? Why not
two or four?
Ans: The number of batches produced in the validation exercise should be sufficient to allow
the normal extent of variation and trends to be established and to provide sufficient data for
evaluation and reproducibility.
First batch quality is accidental (co-incidental),
Second batch quality is regular (accidental),
Third batch quality is validation (conformation).
In 2 batches we cannot assure the reproducibility of data, 4 batches can be taken but the time
and cost are involved.
28. Q. Position of oblong tablets to be placed in hardness tester to determine the hardness?
Lengthwise / widthwise?
Ans: Position of oblong tablets should be length wise because the probability of breakage is
more in this position.
How to Calculate the Air Changes Per Hour (ACH)

29
First of all determine the velocity of the air below the HEPA filter in feet per minute. It is
determined at the four corners and the center of the filter and the mean of the five readings
are determined.
V = (V1+V2+V3+V4+V5)
5
V = Velocity observed at each point
Now calculate the area of the filter by multiplying the length and width of filter in feet.
A=lxw
l = length of HEPA filter
w = width of HEPA filter
Calculate the total air volume per minute supplied in the clean room by the following
formula:
T=AxV
A = Area of HEPA filter in square feet
V = Average air velocity in feet per minute
Calculate the total air in the room multiplying the length, width and height of the room in
feet.
Volume = L x W x H
Now we can calculate the Air Changes per hour using the following formula:
Air Changes per Hour = T X 60
Volume
Related: Cleanroom Validation
Requirement of number of air changes per hour for any room depends on the class of the
room. Cleanliness of any clean room is maintained by the air changes per hour. More air
changes per hour are required for the better clean room class then the lower one.
Related: Prevention of Cross- contamination by HVAC System
More air changes per hour are required to maintain the area where dust is generated as in
granulation and tablet compression areas. In these areas dust is to be removed in a short
period, hence more air changes per hour are required. Following is the list of the air changes
per hour in different classes of classified area.
Cleanroom Class ISO Class Required Air Change per Hour

100 ISO 5 240-480
1,000 ISO 6 150-240
10,000 ISO 7 60-90
100,000 ISO 8 5-48
Why 70% Isopropyl Alcohol is used as Disinfectant in Pharmaceuticals?
why 70% isopropyl alcohol is used for disinfection of hands and equipment surface instead of
100% in pharmaceuticals.
70% isopropyl alcohol is most commonly used disinfectant in pharmaceutical industries. The
important thing is that only 70% solution of isopropyl alcohol acts as a disinfectant killing all
surface microorganisms. It is used to disinfect hands and equipment surface in
pharmaceuticals.
70 % isopropyl alcohol kills microorganisms by dissolving plasma membrane of the cell wall.
Plasma membrane of gram negative bacteria consist of thin layer of peptidoglycon that easily
destroyed by the alcohol.
Water is also required to denature the proteins of cell membrane and acts as a catalyst in the
reaction. Contact time of the alcohol with the organism also play an important role. A 70%
solution of alcohol takes more time in evaporation from the surface, increasing the contact
time. Therefore, 70% isopropyl alcohol fulfills the both requirements.
100% isopropyl alcohol coagulates the protein instantly creating a protein layer that protects
the remaining protein from further coagulation. Due to the organism is not killed but remains
in dormant stage. While 70% isopropyl alcohol penetrates in the cell wall at slower rate and
coagulates the all protein of the cell wall and microorganism dies.
Thus 70% IPA solution in water is more effective then 100% absolute alcohol and have more
disinfectant capacity.
Following points should be considered while using 70% Isopropyl Alcohol:

1. 70% Isopropyl Alcohol should be prepared on daily basis.
2. Preparation should be done in controlled area by production.
3. Freshly prepared 70 % IPA should be used.
4. For the preparation of the 70% IPA, purified water should be used.
5. The bulk container (used for distribution) of the 70% IPA should have the label with the
details like name, prepared on, prepared by and checked by. While the small container label
should have the details like name, prepared on and prepared by.
6. The prepared 70 % IPA should be analyzed chemically and microbiologically (by
membrane filtration method).
SOP for Challenge Test of Solid Flow Monitor in Fluid Bed Dryer
5.0 PROCEDURE:
5.1 Before dispensing getting the approval sign on duplicate book for issuance of req. Quantity of Starch powder for challeng e test of SFM by the HOD
production, HOD quality assurance & the initiator itself, Issue the required quantity of starch powder from stores dept.
5.2 Ensure the proper cleaning of FBD, FBD Bag & Solid Flow Monitor Probe before and after the test is over.
5.3 Sprinkle the 50 gm starch powder over the finger of the tied FBD bag in Fluid Bed Dryer.
5.4 Start the machine in manual mode, the powder on the top of the FBD bag will go out from the FBD, SFM will sense the blown powder & machine
has to
stop with the display on the MMI that Solid Flow Monitor tripped, carried out the same test three times to get the final confirmation that the SFM is
working properly.
5.5 Same procedure to follow in the Auto Mode to check the proper working of SFM.
5.6 In case the machine will stop in the in process with the MMI display that SFM tripped then ensure the quantity of material loss get the challenge
test
done with the new bag as per procedure mentioned above before restarting the FBD for drying the running product.
NOTE:
· The Solid Flow Monitor Challenge Test will be conducted on Monthly basis.
· The Solid Flow Monitor cleaning should be ensure on product changeover by Operator/ Production Pharmacist/ Officer
· Solid Flow Monitor Challenge Test will always be taken by giving the intimation to Engineering Dept so that they will clean the SFM from Service side.
Shipping Test Test for the condition of the product

after you send it somewhere. Upon
return the product condition indicates its
ability to withstand the stress of
transportation.
Tablet Thickness 1. Important to maintain uniformityproducing
identical tablets.
2. Packaging operations (tablets are
counted based on a column in which a
certain number fit)
3. Measured by a caliper +- 5%
depending on size of tablet.
Varying tablet thickness depends on granulation, compression
pressure, &/or speed of tablet
compression
Tablet Weight in Dosage Units the volumetric fill of the die cavity
determines the weight of the tablet.
weight checked routinely during
compression.
USP Weight variation allowance for
uncoated tablets
Applies when tablet contains 25mg or
more of drug comprising 25% or more of
the weight of the tablet.
Procedure for weight variation test 1. weigh 20 tablets individually and take
average weight
2. No more than 2 tablets can differ from
the avg weight by the percents given and
none can be as far off as double the %
130mg or less allowed weight variation 10% difference, none can be double the
percent, and only 2 tablets are allowed to
differ from average by %.
130-324 mg allowed weight variation 7.5% difference
more than 324mg allowed weight
variation
5% difference
allowed average weight variation 130mg or less - 10%
130mg-324mg - 7.5%
over 324 mg - 5%
Content Uniformity of tablets to ensure that the tablets contain the
amount of drug claimed on the label,
with little variation among the tablets.
USP Content Uniformity Test applies to both coated and
uncoated tablets and all capsules that
are intended for oral route containing
25mg or less of drug substance that
comprises 25% or more (by weight) of
tablet/capsule.
Exemption Tablets with a Content Uniformity
requirement are exempt from Weight
Variation Test
Tablet Disintegration Tests Measure the time required for a group of
tablets to disintegrate into particlesunder
set of conditions. QA Test to
ensure that tablet
formulation/disintegration is same from
batch to batch.
Dissolution Test Measures the amount of time required
for API% in tablet to dissolve under a set
of conditions. need satisfactory
dissolution characteristics in successful
tablets because drug absorption and
bioavailability needed for drug to be in
dissolved state.
Dissolution Test Evaluates.... Bioavailability of the drug...It is a QA tool
to make certain the tablets are made
similarly from batch to batch and that
the batches are similar to initial tablets
used to test clinical effectiveness and
formulation.
COMPRESSION BASIC CONCEPT-
• Filling- Formulation is overfilled at the compressing station

• Metering-Overfill is removed
• Compression-Tablet is formed by pressure of punches within die
• Ejection- Tablet is ejected from die
• Dwell time: Time at maximum force.
• Consolidation time: Time to maximum force.
• Ejection time: Time during which ejection occurs.
• Residence time: Time during which the formed compact is within the die.
• Contact time: Time for compression and decompression, excluding ejection time.
• Hopper: It is used to hold the materials (drug or the drug with Excipient/ granules) to be
compressed and supply the material to the die and removes the tablet after its
compression
• Dies: Dies defines the shape and the size of the tablet by allowing the lower and upper
punch to come close together to compress the material.
• Lower and upper punches: These are used for compressing of the materials (drug or the
drug with Excipient/ granules) within the dies.
• Cam track: This is the component used for guiding the movement of the punches.
• Capacity regulator: To adjust the position of the lower punch to accommodate the
required quantity of materials by the die.
• Ejection regulator: To adjust the position of the lower punch, so that its highest position
is at par with the surface of the die.
• Driving wheel: It helps in the movement of the lower punch, the upper punch and hopper
shoe and also checks their movement.
• Hopper- The hopper holds the granules/powder mixture (API plus Excipient) that are to
be compressed into tablet.
• Dies cavity – This is where the powder granules is compressed into tablets and it
determines.
➢ The diameter of the tablet.
➢ The size of the tablet
➢ To some extent the thickness of the tablet.
• Feed paddle – Helps to force the feed/ the granules into the dies especially during faster
rotation.
• Punches – This comprises the upper and the lower punches. They move within the die
bore to compress granules into tablets.
• Lower cam track – This guides the lower punch during the filling stage so that the die
bore is over filled to allow accurate adjustment.
• Cam tracks – This guides the movement of both the upper and lower punches.
• Dept of fill/capacity control – This adjusts the lower punch track during the latter part of
the fill stage to ensure that the appropriate quantity of granules remains within the die
prior to compression.
• Recompression rollers – This roller gives the granules an initial compression force to
get rid of excess air that might be entrapped in the die.
• Main compression – This roller applies the final compression force needed for the
formation of tablet.
• Ejection cam– Guides the lower punch upwards facilitating the ejection of tablet from
the die cavity after compression.
• Take-off Blade – This is fitted in front of the feeder housing and it deflects the tablet
down the discharge chute.
• Discharge chute – This is where the tablet after being deflected by the take-off blade
passes through for collection.
• Head: The end of the punch that guides it through the cam track of tablet machine during
rotation.
• Head flat ﴾Dwell Flat﴿: The flat area of the head that receives the compression force
from rollers ﴾in upper punches﴿ and determines the weight and ejection height ﴾in lower
punches﴿.
• Outside head Angle: The area gets in touch with the roller prior to head flat, while
compression.
• Inside Head Angle: This is the area, which pulls down the lower punches after ejection
and lifts the upper punches after compression.
• Neck: The relived area between the head and barrel, which provides clearance for the
cams.
• Barrel: This area guides the punch ﴾while going up and down﴿ with reference to turret
guides.
• Stem: The area of the punch opposite the head, beginning at the tip and extending to the
point where the full diameter of the barrel begins. If the chamfer is present the barrel
usually reaches its full diameter just above the chamfer.
• Tip: This determines size, shape & profile of the tablet.
• Tip face: This area of punch is where the tablet is formed. Good surface finish is
required here to bet quality tablets.
• Working length: This distance between bottom of the cup and the head flat is called as
working length which determines weight and thickness of the Tablet.
• Overall length: Distance between top of the cup and the head flat.
• Key Angle: The relationship of the punch key to the tablet shape. The keys position is
influenced by the tablet shape, take‐off angle, and turret rotation.
• Domed Heads: Increases the dwell time and hence help to achieve the better tablet
hardness.
• Dwell time: The time punches spends below the pressure roller while rotating in the
machine.
Common stages occurring during compression

Stage 1: Top punch is withdrawn from the die by the upper cam Bottom punch is low in
the die so Powder falls in through the hole and fills the die
Stage 2: Bottom punch moves up to adjust the powder weight-it raises and expel some powder
Stage 3: Top punch is driven into the die by upper cam Bottom punch is raised by lower cam
both punch
Heads pass between heavy rollers to compress the powder
Stage 4: Top punch is withdrawn by the upper cam Lower punch is pushed up and expels the
tablet is
Removed from the die surface by surface plate
Stage 5: Return to stage 1
Tablet compaction pressure
For a flat-faced tablet, compaction pressure is calculated simply by
Dividing the force applied by the die area: where Cp is the compaction pressure and is A the area
of the die. As mentioned earlier, at the same compression force, punch diameter has an
exponential effect on compaction pressure. For example, 400kg of compression force on a 3mm
punch produces four times the pressure as 400kg on a 6mm punch.
For tablets that are not flat-faced, the cross-sectional area of the die is still normally used.
Different mesh sizes and mesh to micron conversion

➢ 40-400 mesh sieve used in pharmaceuticals manufacturing during shifting and milling of
raw materials.
➢ Mesh-no of opening in one linear inch of any sieve or screen
➢ 10 no sieve-10 opening-thick wire
➢ 400 no sieve-400 opening- thin wire
➢ Fineness of any sieve or screen depends upon the width of the wire used.
➢ Fine sieve above 400 mesh-particle describe in micron
Types of powder according to particle size
A) Mono disperse powder-all particle in same size.
B) Poly disperses powder-Particles of different size.
Methods of particles size determinations
A) Microscopy-TEM , SEM, Light microscope

B) Sieving
C) Sedimentation
D) Coulter counter
E) Surface method
F) Fluid classification method
G) Laser light scattering method
H) X-ray diffraction method
I) Cascade method
Surface area determination
A) Adsorption method
B) Air permeability method
Powder flow property
A) % compressibility-
Ability of powder to decrease the volume under pressure.
TD-BD/TD*100
B) Hausner ratio
TD/BD
C) Angle of repose
Is the maximum angle between the surface of pile of powder and horizontal plane?
Factor affecting flowability of powder
A) particle size and particle size distributions-

Particle size smaller than 10 micron gives stickiness to materials
B) density and porosity-
More density and less porosity gives better flow
C) hygroscopicity-
Reduce flow rate because it increase adhesive and cohesive force.
D) Electrostatic charge-
More electrostatic charge so reduce flowability.
Method of improving flowability
A) By adding of glidant-
Flow can improve by reducing the cohesive and adhesive force
A) By size reduction or by addition of fine
B) By removing static charge
C) By deification with the help of slugging.
D) By use auger feed equipment
E) By adding of flow activator
F) By use of spray drying
What is mean by change control?

Means when change is being made in any process or procedure it is reported by change control
procedure and that is approved by company authority or Qa head
Applicable to Departments:
➢ Regulatory Affairs
➢ Pharma Development
➢ Packing Material Development
➢ Quality Assurance
➢ Quality Control
➢ PPIC
➢ Warehouse
➢ Production (Manufacturing) Production (Packaging)
➢ Maintenance
➢ I.B.D.
➢ Production-
➢ Change in location
➢ Change in equipment
➢ Change in batch size
➢ Engineering-
➢ Change in any equipment
➢ Critical part of any equipment
➢ Design layout
➢ R AND D
➢ Change in specification of RM PM finish product
➢ Addition /deletion of any RM in product
➢ Change in quantity of RM in product
➢ Change in shelf life
➢ Change in storage condition
➢ Change in stability protocol
➢ QC
➢ Change in method of analysis
➢ Change in sampling plan
➢ QA
➢ Change in sampling plan/quantity of sample
➢ Change in documents and sop
➢ Change in validation protocol
➢ CLEANING PROCEDURE
➢ Change in cleaning agent
➢ Change in cleaning aids
➢ Change in cleaning steps
Sr. No.
Nature of Change Responsibility
1 RM, PM , Bulk & FP Specifications , Test Q.A. Manager
Procedures, Manufacturing procedures,
Change in Active Pharma Ingredient
suppliers, Change in Shelf life
2 Changes in FDA Licence, Label claim General Manager, Q.A. Manager

Changes
3 Computer Hardware & Software Electronic Data Processing

Manager
4 Manufacturing Process ,Equipment & Warehouse In charge, Maintenance

Support Systems , Utilities ,Materials Manager, Production Manager &
General Manager
5 Analytical Equipment Q.A. Manager
6 Impact of the proposed change on the Q.A. Manager

validation status of the process &
regulatory affairs
7 Scheduling & tracking of the proposed Q.A. Manager

changes & periodic review before release
of the impacted product
8 Resource required for the Proposed General Manager, Production

Changes Manager, QA Manager
DEVIATION-
Deviation is a process that is not mentioned in sop. It is a process that performs the outside of the
process or sops.
TYPES
Planned-
Planned deviation is that deviation from the procedure that are planned and we know
before they occur.
Example-calibration or validation is not carried out as per schedule due to delay for various
reasons.
Unplanned
in case of unplanned deviation the failure of procedure, utility, material, equipment or
any system is occurred.
Critical deviation-
➢ Manufactured instructions are not followed,
➢ Wrong batch detail are printed,
➢ SOP or method not followed during analysis.
Major-
➢ line clearance is not taken from QA
➢ Physician sample wrongly printed with price
Minor-
➢ Raw material is received in a damage container
➢ Manometer reading in the sampling booth are crossed the action limit.
Area of deviation
➢ SOP
➢ Documentation
➢ In process
➢ Environmental control
➢ Training
➢ Maintenance
➢ Cleaning
➢ Cross contamination
➢ Equipment
➢ Raw material
➢ Packing material
➢ Process failure
➢ Less yield
➢ Labeling
IMPACT OF DEVIATION
➢ Same batch
➢ Other product
➢ Quality/safety
➢ Yield related
➢ Equipment trend
➢ Validation
➢ Document
➢ Stability
➢ Other batch
Sr. No. Planned Deviation Explanation
1. Change in batch size Increase/ decrease in batch size as per work order
2. Out lab test for existing equipment External testing in case of critical equipment failure
3. Change in RM/PM To increase the yield
4. Change in storage conditions Change in the stability samples storage etc.
Sr. No. Unplanned Deviation Explanation
1. Power failure Due to power breakdown
2. Cycle time Blending time increase / decrease
3. Yield Spillage etc.
4. Presence of foreign particle During Visual inspection
5. Misprinting While batch coding/printing
6. Online rejection (excessive) Printing/coding rejection
7. Parametric process change Additional process

What is the difference between deviation and change control? What situations we can raise
the deviation and change control
➢ Deviation is not permanent but change control is permanent
➢ Deviation is a process in which we have to perform a task that is not mentioned in the
SOP
➢ Change control is a procedure in which we have to make a permanent change in the
Document, procedure or method, by raising 3 consecutive deviations which is approved
by the concerned departments and authorized by QA.
➢ Deviation is the temporarily reviewed effort to a change by short listed concerned
persons.
➢ Change Control is the integrated effort of several responsible departments to make a
change permanently.
➢ Change control is a addition process of current and new process or method or
equipments, like: 1>new sop preparation 2> upgrade previous sop or method or process
for better gmp compliance. It may be temporary or permanent, and depends on
requirement of particular department through QA and intimation should be sent to all
concern departments for this change.
➢ Deviations are two types one is planned deviation and another is unplanned deviation.
➢ Planned deviations are two types
➢ One is temporary and another is permanent.
➢ Temporary deviations are approved by QA then u proceeds.
➢ Permanent deviations are must be reviewed by related departments and approved by QA
through change control procedure.
➢ There are two types of deviation
➢ one is minor and another is critical,
➢ Minor deviation is approved by QA where as Critical Deviation are filled by Concerned
departments with Corrective and preventive Action, than it is reviewed by Head-API and
R&D and put their comments and finally reviewed and approved by QA for any
particular Batch.
➢ Change Control Proposal denotes any permanent and temporary change in
process/equipments or method and before raising the CCP it should be data oriented
along with proper Justification and Corrective and preventive action.
➢ If changes are critical than technical group i.e. President and Regulatory Head are also
involved for this.
➢ Change control is a planned activity to bring about changes in document/process/method.
➢ It can be for shorter period of time or it can be permanent.
➢ It must be intimated to all the concerned departments for official approval of
Change Control.
➢ Deviation is an aberration from the given procedure which is done intentionally or
unintentionally
➢ A deviation can be divided into critical & non critical.
➢ Effects of critical deviations should be accessed through investigation & Corrective &
Preventive Actions.
Types and sizes of capsules
Soft gelatin capsule-
➢ Called as soft gel
➢ Manufactured at single piece of capsule shell
➢ Suitable for non aqueous solution-oil
HARD GELATIN CAPSULE

➢ Consist of two parts-body and cap
➢ Dry in nature active ingredient filled in dry form
size Lock length External

diameter
5 smallest 11.1 4.91
4 14.3 5.31
3 15.9 5.82
2 18 6.35
1 19.4 6.91
0 21.7 7.65
00 23.3 8.53
000 biggest 23.26.14 9.91
WORKING AND PRINCIPLE OF RMG
➢ Formation of granules by whirling rising and tumbling motion of the materials

➢ It is used to mix the pharmaceuticals ingredient and make a granules before compression
.impeller and chopper are main responsible for wet granulation
IMPELLERS
➢ fix at the bottom dome shaped S.S
➢ It has two full blades and two half length blades
➢ Small blade lifts the materials and full blade push the materials to mix well
➢ This impeller break up the wet mass into small pieces and granules
CHOPPER
➢ Small blades located at the bottom of the dome.
➢ Rotate at high speed-1440/2880 RPM
➢ Chopper cut the wet lumps for material into small size
DISCHARGE PORT
➢ Located horizontally at the bottom of dome
➢ Granules unloaded through discharge port
➢ Discharge port open by compressed air 3-5 kg/cm2
IMPORTANCE OF MIXING TIME IN BLENDINGUNIFORMILITY
➢ Particle size
➢ Density of the materials-segregation of material at higher density
➢ Interaction of the materials-interaction between drug and excipients may cause the de-
mixing of materials
Difference between humidity and relative humidity-(limit-40-60 %)

Humidity
➢ Amount of moisture or water present in the air in the form of water vapour
Relative humidity
➢ Percentage of the moisture in the air at particular specific temperature.
Factors that contribute to quality products:
• Starting materials and packaging materials

• Validated processes
• Personnel
• Procedures
• Equipment
• Design and quality of premises
• Manufacturing environment
The manufacturing environment is critical for product quality
• Light
• Temperature
• Humidity
• Air movement
• Microbial contamination
• Particulate contamination
• Uncontrolled environment can lead to product degradation
What are contaminants?
• Contaminants are Products or substances other than product manufactured
• Foreign products
• Particulate matter
• Micro-organisms
• Endotoxins (degraded micro-organisms)
• Cross-contamination is a particular case of contamination
Cross-contamination can be minimized by:
o Personnel procedures
o Adequate premises
o Use of closed production systems
o Adequate, validated cleaning procedures
o Appropriate levels of protection of product
o Correct air pressure cascade
What can HVAC do?
HVAC system performs four basic functions:
➢ Control airborne particles, dust and micro-organisms – Thru air filtration using high
efficiency particulate air (HEPA) filters.
➢ Maintain room pressure (delta P) – Areas that must remain “cleaner” than surrounding
areas must be kept under a “positive” pressurization, meaning that air flow must be from
the “cleaner” area towards the adjoining space (through doors or other openings) to
reduce the chance of airborne contamination. This is achieved by the HVAC system
providing more air into the “cleaner” space than is mechanically removed from that same
space.
➢ 3. Maintain space moisture (Relative Humidity) – Humidity is controlled by cooling air

to dew point temperatures or by using desiccant dehumidifiers. Humidity can affect the
efficacy and stability of drugs and is sometimes important to effectively mould the
tablets.
➢ Maintain space temperature - Temperature can affect production directly or indirectly by

fostering the growth of microbial contaminants on workers.
HVAC Validation TEST

➢ Air velocity test
➢ No of air changes per hour
➢ Filter integrity test
➢ Non viable air borne particle count test
➢ Viable air borne Particle count test
➢ Air flow pattern Test
➢ Air pressure differential Monitoring
➢ Temperature & Relative Humidity Monitoring
➢ Recovery time study
HVAC consist of
➢ Air conditioning
➢ AHUs
➢ Dehumidifier/Heater
➢ Filter (pre/HEPA)
➢ Dust extractor
➢ Ducting
➢ Supply fan
➢ Smoke detector
➢ Damper
➢ Humidity/temperature/pressure sensor.
➢ Bag filter
➢ Heating/cooling coil.
➢ Acceptance criteria: Specific criteria for results of either process monitoring or a test.
Criteria are defined
➢ in a validation or qualification protocol and must be met in order for the process to be
considered
➢ validated or the equipment to be qualified.
➢ Accuracy: The accuracy expresses the closeness of agreement between the value which is
accepted either
➢ as a conventional true value (in house standard) or an accepted reference value
(international standard
➢ e.g. Pharmacopoeial standard) and the value found (mean value) obtained by applying the
test
➢ procedure a number of times. Accuracy provides an indication of systematic errors.
➢ Analytical procedure: The analytical procedure refers to the way of performing the analysis.
It should
➢ describe in detail the steps necessary to perform each analytical test. This may include but
is not limited
➢ to: The sample, the reference standard and the reagents preparations, use of the apparatus,
generation of
➢ the calibration curve, use of the formulae for the calculation, etc.
➢ Bias: The error between the observed mean of the analytical method and the true value
(nominal value).
➢ Bias may be positive (yielding high results) or negative (yielding low results). There may
also be no
➢ difference, in which case bias is zero.
➢ Calibration: The set of operations that establish, under specified conditions, the
relationship between
➢ values indicated by an instrument or system for measuring (especially weighing), recording,
and
➢ controlling- or the values epresented by a material measure, and the corresponding known
values of a
➢ reference standard. Limits for acceptance of the results of measuring should be established.
➢ Change control: A formal process in which changes to equipment, systems, procedures, or
processes are
➢ proposed by individuals or units planning to implement them. The changes are reviewed by
qualified
➢ representatives of Quality Assurance and other appropriate disciplines to determine
whether they will
➢ effect the status of the validation or qualification. The reviewers shall determine whether it
is required to
➢ validate the system or take other action necessary to maintain the validated state of the
system.
➢ Coefficient of determination (R2): The ratio of the variation explained by a fitted model to
the total
➢ variation. The larger the coefficient, the better the fit. If 95 WHO/VSQ/97.02 the fitted
model is linear,
➢ the coefficient is the square of the correlation coefficient.
➢ Coefficient of variation (CV): The percentage variation in a set of numbers relative to their
mean. CV is
➢ often referred to as the Relative Standard Deviation (RSD).
➢ Control: Controls resemble the unknown in composition and are assayed at the same time
under the
➢ same test conditions by the same method. The results of these tests are used in calculating
the mean and
➢ standard deviation of the test. Controls are used to measure accuracy.
➢ Correlation coefficient (r): The square root of the Coefficient of Determination. A measure
of the
➢ closeness of observations to a straight line. The closer the coefficient is to ±1, the stronger
the linear
➢ relationship.
➢ Critical areas: Areas where sterilized products or container/closures are exposed to the
environment.
➢ Critical parameter: An operating variable that identifies the conditions under which a
product is
➢ manufactured and must be controlled in order to obtain desired or specified product
attributes.
➢ Critical process: A process that may cause variation in the quality of the pharmaceutical
product.
➢ Critical surfaces: Surfaces which come into contact with sterilized product or
containers/closures.
➢ D value: The time (in minutes) at a given temperature needed to reduce the number of
microorganisms
➢ by 90%.
➢ Freeze/thaw stability: A validation of a given drug sample’s ability to undergo multiple
freezing and
➢ thawing steps. A single drug sample is frozen and thawed multiple times. After each
freeze/thaw cycle,
➢ an aliquot is removed. This is repeated until samples that have been frozen 0-5 times are
obtained.
➢ All aliquots are assayed in triplicate and values are compared to determine stability of the
drug
➢ compound.
➢ Front-to-back: Aliquots of a single sample are assayed at different physical positions in the
assay; that is,
➢ they are handled near to or far from (in time) control samples. Values are compared to
determine if
➢ different intra-assay handling affects the observed concentration.
➢ Installation qualification (IQ): Documented verification that, at the time of installation,
equipment and
➢ equipment-related systems (i.e., support systems or utilities) comply with the
recommendations of the
➢ manufacturer, as well as with design specifications, system specifications, and appropriate
codes.
➢ Intermediate precision: Intermediate precision expresses within laboratories’ variations.
Different days,
➢ different analysts, different equipment, etc.
➢ Intra-assay precision: Repeatability is also termed intra-assay precision.
➢ Limit of detection (LOD): The lowest amount of analyte in a sample which can be detected
but not
➢ quantitated as an exact value. The LOD is mostly a parameter of limit tests.
➢ Limit of quantitation (LOQ): The quantitation limit of an individual analytical procedure is
the lowest
➢ amount of analyte in a sample which can be quantitatively determined with suitable
precision and
➢ accuracy. The quantitation limit is a parameter of quantitative assays for low levels of
compounds in
➢ sample matrices, and is used particularly for the determination of impurities and/or
degradation
➢ products.
➢ Linearity: The linearity of an analytical procedure is its ability (within a given range) to
obtain test
➢ results which are directly proportional to the concentration (amount) of analyte in the
sample.
➢ Lot-to-lot precision: The precision of multiple determinations of a single sample analyzed
in various
➢ runs using different lots of material such as assay components, test animals, and wash
buffers.
➢ Operating range: A range for an operating variable, defined by an upper and lower limit,
which is
➢ permitted in the validated process.
➢ Operational qualification (OQ): Documented verification that equipment or equipment
systems
➢ perform in accordance with manufacturers specifications and process requirements and
that the
➢ appropriate GMP systems (e.g., training, calibration, and maintenance, etc.) are in place.
➢ Overkill sterilization process: A process which is sufficient to provide at least a 12 log
reduction of
➢ microorganisms having a minimum D value of 1 minute.
➢ Performance qualification (PQ): Documented evidence that a process step, total
integrated process
➢ system, or analytical method performs as intended and that it produces an in-process
material, product,
➢ or test result that consistently meets appropriate specifications and the requirements
defined in the
➢ protocol. It is important that clear and specific acceptance criteria be established for each
critical
➢ parameter.
➢ Precision: The precision of an analytical procedure expresses the closeness of agreement
(degree of
➢ scatter) between a series of measurements obtained from multiple sampling of the same
homogeneous
➢ sample under the prescribed conditions. Precision may be considered at three levels:
Repeatability,
➢ intermediate precision and reproducibility (q.v.). Precision should be investigated using
homogeneous,
➢ authentic samples. However, if it is not possible to obtain a homogeneous sample it may be
investigated
➢ using artificially prepared samples or a sample solution. The precision of an analytical
procedure is
➢ usually expressed as the variance, standard deviation, or coefficient of variation of a series
of
➢ measurements. Precision provides an indication of random errors.
➢ Process system: The combination of process equipment, procedures, and support systems
(e.g. HVAC,
➢ air, environmental control, etc.) that has been assembled to effect a specific process.
Procedures include
➢ GMP support procedures (e.g. training, calibration, and maintenance) that must be in place
and
➢ practiced in order to remain in compliance with regulations.
➢ Prospective validation: The execution and documentation of pre-approved test protocol,
which is
➢ designed to prove that a process performs as intended, prior to the release of a
manufactured product for
➢ distribution. A minimum of three batches of product is required. If reduced batch sizes are
➢ manufactured, each must be at least one-tenth the production batch size or 100,000 units,
whichever is
➢ larger.
➢ Protocol: A documented plan, which is reviewed and approved prior to execution, for the
test of a
➢ process, system, or piece of equipment. Upon completion, the protocol and results serve as
the basis for
➢ the documentation that the process performs as intended.
➢ Proven acceptable range (PAR): A range for an operating variable throughout which it
has been
➢ demonstrated and documented that a process consistently yields acceptable product. The
PAR must
➢ include the defined operating range and may extend beyond that range. It should be
determined during
➢ the process development phase and demonstrated during validation. The PAR may be
expanded
➢ through the product life cycle with appropriate validation protocol, supporting data, and
➢ documentation.
➢ Qualification: A documented procedure which demonstrates that a piece of equipment or
process is
➢ designed, installed, and operated properly. (Generally equipment is validated by installation
➢ qualification, operational qualification, systems by installation, operational and
performance
➢ qualification. Process validation and Performance Qualification are often synonomously
used).
➢ Range: The range of the test procedure is the interval between the upper and lower levels
of analyte
➢ (including these levels) for which the procedure has been demonstrated as suitable with
precision,
➢ accuracy and linearity using the method as written.
➢ Reference standard: Any material of known identity and purity or potency. An official
reference
➢ standard is one obtained from an official source such as BP, or USP, or WHO. A house
reference
➢ standard may be obtained by thorough characterization for identity and purity or potency
relative to an
➢ official reference standard, or by determination of absolute purity by other techniques.
Depending on the
➢ intended use (qualitative or quantitative) and the nature of the assay, a greater of lesser
degree of purity
➢ is acceptable.
➢ Repeatability: Repeatability expresses the precision under same conditions: same analyst,
same
➢ apparatus, short interval of time, identical reagents.
➢ Reproducibility: The reproducibility expresses the precision under different conditions for
instance:
➢ laboratories, reagents from different sources, analysts, days, apparatus from different
manufacturers, etc.
➢ Reproducibility expresses the precision between laboratories (collaborative studies, usually
applied to
➢ standardization of methodology).
➢ Revalidation: The verification of the performance of the method following a change in the
material
➢ analyzed for the methodology used. These changes should not adversely affect the results
obtained
➢ relative to the original method.
➢ Robustness: See ruggedness.
➢ Ruggedness: The degree of reproducibility of test results obtained by the analysis of the
same samples
➢ under a variety of minor modifications to the standard test conditions, such as different
assay
➢ temperatures, mobile phase compositions, flow rates, or injection volumes. Ruggedness is
test results of
➢ operational and environmental variables of the method, Ruggedness also includes broader
concepts
➢ checked through a collaborative study: the lack of sensitivity of results to changes in
equipment,
➢ laboratory, and analyst. Also called robustness.
➢ Selectivity: See specificity.
➢ Sensitivity: For physicochemical assays, the ability to detect small differences in
concentration (the ratio
➢ of the change in response of the method to the change in concentration of the analyte, or the
slope of the
➢ analytical calibration curve).
➢ For non-physicochemical assays (e.g. biological assays), the incidence of true positive
results obtained
➢ when a test is used for animals known to have the disease or condition.
➢ Sensitivity = True Positive x 100
➢ True Positive + False Positive
➢ Specificity:
➢ 1) Specificity is the ability to assess unequivocally the analyte in the presence of
components which may
➢ be expected to be present. Typically these might include impurities, degredants, matrix, etc.
This
➢ definition has the following implications:
➢ Identity test: To ensure the identity of an analyte.
➢ Purity tests: To ensure that all the analytical procedures performed allow an accurate
statement of the
➢ content of impurities of an analyte, i.e., related substances test, heavy metals, residual
solvents content,
➢ etc.
➢ Assay (measurement of content or potency): To provide an exact result which allows an
accurate
➢ statement on the content or potency of the analyte in a sample.
➢ 2) The specificity of a method is its ability to measure accurately and specifically the analyte
in the
➢ presence of components that may be expected to be present in the sample matrix. A method
may be
➢ “specific” for one or more components of a mixture, but “non-specific” for others. Specificity
may often
➢ be expressed as the degree of bias of text results obtained by analysis of samples containing
added
➢ impurities, degradation products, related chemical compounds, or placebo ingredients,
when compared
➢ to test results from samples without added substances. The bias may be expressed as the
difference in
➢ assay results between the two groups of samples. Specificity is a measure of the degree of
interference
➢ (or absence thereof) in the analysis of complex sample mixtures.
➢ Standard deviation (SD): The square root of the variance.
➢ Sterilization filter (for liquid): A filter which, when challenged with the microorganism.
Pseudomonas
➢ diminuta, at a minimum concentration of 10/7 organisms per cm2 of filter surface, will
produce a sterile
➢ effluent.
➢ Test procedure: The test procedure is the total operation necessary to perform the
➢ Analysis of an analyte: preparation of the sample, of the reference substances or
preparations, of the
➢ reagents, use of the apparatus, calibration curve, formulae for the calculation, number of
replicates and
➢ operating procedure for the replicates etc.
➢ Trueness: Accuracy is sometimes termed trueness.
➢ Validation plan: A documented plan (Validation Master Plan) that describes the policy,
philosophy,
➢ strategy, and methodology for validating a site, process, or product. The plan can be used as
an
➢ executive summary within a company or to introduce regulatory personnel to a validation
project. The
➢ plan should identify responsibilities, as well as equipment and processes requiring
qualification or
➢ validation. It also may include schedules for an overall process.
➢ Validation program: An organized effort designed to provide assurance that all equipment
is qualified
➢ and processes are validated and that these qualifications and validations are maintained
according to
➢ current industry practice and regulatory requirements.
➢ Validation: The documented act of proving that any procedure, process, equipment,
material activity, or
➢ system actually leads to the expected results.
➢ Variance (Var): A measure of the dispersion of the points about their mean. The standard
deviation, that
➢ is, the square root of the variance, is also used as a measure of dispersion.
➢ Worst case: A set of conditions encompassing upper and lower processing limits and
circumstances,
➢ including those within standard operating procedures, which pose the greatest chance of
process or
➢ product failure when compared to ideal conditions. Such conditions do not necessarily
induce product
➢ or process failure.
Annual Review – An evaluation, conducted at least annually, that assesses the quality standards
of each drug product to determine the need for changes in drug product specifications or
manufacturing or control procedures
CAPA – Corrective and preventive action: A systematic approach that includes actions needed to
correct (“correction”), prevent recurrence (“corrective action”), and eliminate the cause of
potential nonconforming product and other quality problems (preventive action) (21CFR
820.100)
Continual Improvement – Ongoing activities to evaluate and positively change products,
processes, and the quality system to increase effectiveness
Correction – Repair, rework, or adjustment relating to the disposition of an existing discrepancy
Corrective Action – Action taken to eliminate the causes of an existing discrepancy or other
undesirable situation to prevent recurrence
Customer – A person or organization (internal or external) that receives a product or service
anywhere along the product’s life cycle
Discrepancy – Datum or result outside of the expected range; an unfulfilled requirement; may be
called non-conformity, defect, deviation, out-of-specification, out-of-limit, out-of-trend
Harm – Damage to health, including the damage that can occur from the loss of product quality
or availability
Non-conformity – A deficiency in a characteristic, product specification, process parameter,
record, or procedure that renders the quality of a product unacceptable, indeterminate, or not
according to specified requirements
Preventive Action – Action taken to eliminate the cause of a potential discrepancy or other
undesirable situation to prevent such an occurrence
Product/Service – The intended results of activities or processes; products/services can be
tangible or intangible
Quality – A measure of a product or service’s ability to satisfy the customer’s stated or implied
needs
Quality Assurance – Proactive and retrospective activities that provide confidence that
requirements are fulfilled
Quality Control – The steps taken during the generation of a product or service to ensure that it
meets requirements and that the product or service is reproducible
Quality Management – Accountability for the successful implementation of the quality system
Quality Objectives – Specific measurable activities or processes to meet the intentions and
directions as defined in the quality policy
Quality Plan – The documented result of quality planning that is disseminated to all relevant
levels of the organization
www.pharmatechbd.blogspot.com
Quality Planning – A management activity that sets quality objectives and defines the
operational and/or quality system processes and the resources needed to fulfill the objectives
Quality Policy – A statement of intentions and direction issued by the highest level of the
organization related to satisfying customer needs. It is similar to a strategic direction that
communicates quality expectations that the organization is striving to achieve.
Quality System – Formalized business practices that define management responsibilities for
organizational structure, processes, procedures, and resources needed to fulfill product/service
requirements, customer satisfaction, and continual improvement
Quality Unit – A group organized within an organization to promote quality in general practice
Risk – The combination of the probability of occurrence of harm and the severity of that harm
Risk Assessment – A systematic process for organizing information to support a risk decision
that is made within a risk management process. The process consists of the identification of
hazards and the analysis and evaluation of risks associated with exposure to those hazards.
Risk Management – The systematic application of quality management policies, procedures, and
practices to the tasks of assessing, controlling, communicating, and reviewing risk
Senior Management – Top management officials in a firm who have the authority and
responsibility to mobilize resources
Stakeholder – An individual or organization having an ownership or interest in the delivery,
results, and metrics of the quality system framework or business process improvements
Verification – Confirmation, through the provision of objective evidence, that specified
requirements have been fulfilled. (Reference: The ASQ Auditing Handbook, 3rd edition, ASQ
Quality Audit Division, J.P. Russell, and Editor)
Validation – Validation is a documented evidence which provides a high degree of assurance
that a specific process, method or system will consistently produce to the required specification in
accordance with accepted standards of cGMP.
Active pharmaceutical ingredient (API) - Any substance or mixture of substances intended to
be used in the manufacture of a pharmaceutical dosage form and that, when used in the
production of a drug, becomes an active ingredient of that drug. Such substances are intended to
furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment
or prevention of disease, or to affect the structure and function of the body.
Contamination - The undesired introduction of impurities of a chemical or microbiological
nature, or of foreign matter, into or onto a starting material, or intermediate or finished product
during production, sampling, packaging or repackaging, storage or transport.
Cross-contamination - Contamination of a starting material, intermediate product or finished
product with another starting material or product during production.
Excipient- A substance, other than the active ingredient, which has been appropriately evaluated
for safety and is included in a drug delivery system to:
— aid in the processing of the drug delivery system during its manufacture;
— protect, support or enhance stability, bioavailability, or patient acceptability;
— assist in product identification; or
— enhance any other attribute of the overall safety and effectiveness of the drug during storage or
use.
Expiry date - The date given on the individual container (usually on the label) of a drug product
up to and including which the product is expected to remain within specifications, if stored
correctly. It is established for each batch by adding the shelf-life to the date of manufacture.
Labelling - The action involving the selection of the correct label, with the required information,
followed by line clearance and application of the label.
Manufacture - All operations of purchase of materials and products, production, quality control,
release, storage and distribution of finished products, and the related controls.
Material - A general term used to denote starting materials (active pharmaceutical ingredients
and excipients), reagents, solvents, process aids, intermediates, packaging materials and labelling
materials.
Packaging material - Any material, including printed material, employed in the packaging of a
pharmaceutical product, but excluding any outer packaging used for transportation or shipment.
Packaging materials are referred to as primary or secondary according to whether or not they are
intended to be in direct contact with the product.
Pharmaceutical product - Any medicine intended for human use or veterinary product
administered to food-producing animals, presented in its finished dosage form or as a starting
material for use in such a dosage form, that is subject to control by pharmaceutical legislation in
both the exporting state and the importing state.
Production - All operations involved in the preparation of a pharmaceutical product, from receipt
of materials, through processing, packaging and repackaging, labelling and relabelling, to
completion of the finished product.
Retest date - The date when a material should be re-examined to ensure that it is still suitable for
use.
Storage - The storing of pharmaceutical products and materials up to their point of use.
Supplier - A person providing pharmaceutical products and materials on request. Suppliers may
be agents, brokers, distributors, manufacturers or traders. Where possible, suppliers should be
authorized by a competent authority.
Calibration (old)
The performance of tests and retests to ensure that measuring equipment (e.g. for temperature,
weight, pH) used in a manufacturing process or analytical procedure (in production or quality
control) gives measurements that are correct within established limits.
Calibration (new)
The set of operations that establish, under specified conditions, the relationship between values
indicated by an instrument or system for measuring (especially weighing), recording, and
controlling, or the values represented by a material measure, and the corresponding known values
of a reference standard. Limits for acceptance of the results of measuring should be established.
Computer validation
Documented evidence, which provides a high degree of assurance that a computerized system
records data correctly and that data processing complies with, predetermined specifications.
Concurrent validation
Validation carried out during routine production of products intended for sale.
Cleaning validation
Documented evidence to ensure that cleaning procedures are removing residues to predetermined
levels of acceptability, taking into consideration i.e. batch size, dosing, toxicology, equipment
size, etc.
Design Qualification (DQ)
Documented evidence that the premises, supporting utilities, equipment and processes have been
designed in accordance with the requirements of GMP.
Good Engineering Practices
Established engineering methods and standards that are applied throughout the project lifecycle to
deliver appropriate, cost-effective solutions.
Installation Qualification (IQ)(old)
IQ is the documentary evidence to verify that the equipment has been built and installed in
compliance with design specifications.
Installation Qualification (IQ)(new)
The performance of tests to ensure that the installations (such as machines, measuring devices,
utilities, manufacturing areas) used in a manufacturing process are appropriately selected and
correctly installed and operate in accordance with established specifications.
Working document QAS/03.055/Rev.2
Operational Qualification (OQ)(old)
OQ is the documentary evidence to verify that the equipment operates in accordance with its
design specifications in its normal operating range and performs as intended throughout all
anticipated operating ranges.
Operational Qualification (OQ)(new)
Documented verification that the system or subsystem performs as intended over all anticipated
operating ranges.
Performance Qualification (PQ)
PQ is the documentary evidence, which verifies that the equipment or system operates
consistently and gives reproducibility within defined specifications and parameters for prolonged
periods. (The term “process validation” may also be used.)
Process validation (See Validation)
Documented evidence, which provides a high degree of assurance that a specific process will
consistently produce a product meeting its pre-determined specifications and quality
characteristics.
Prospective validation
Validation carried out during the development stage by means of a risk analysis of the production
process, which is broken down into individual steps; these are then evaluated on the basis of past
experience to determine whether they may lead to critical situations.
Qualification (new)
Action of proving and documenting that any premises, systems and equipment are properly
installed, and/or work correctly and lead to the expected results. Qualification is often a part
(Initial stage) of Validation, but the individual qualification steps alone do not constitute process
validation.
Retrospective validation
Involves the examination of past experience of production on the assumption that composition,
procedures, and equipment remain unchanged.
Revalidation (old)
Involves the repeat of the initial process validation to provide assurance that changes in the
process and/or in the process environment, whether intentional or unintentional, do not adversely
affect process characteristics and product quality.
Revalidation (new)
Repeated validation of an approved process (or a part thereof) to ensure continued compliance
with established requirements.
Standard operating procedure (SOP)
An authorized written procedure giving instructions for performing operations not necessarily
specific to a given product or material but of a more general nature [new] (e.g. equipment
Working document QAS/03.055/Rev.2 operation, maintenance and cleaning; validation; cleaning
of premises and environmental control; sampling and inspection). Certain SOPs may be used to
supplement product-specific master and batch production documentation.
Validation (new)
Validation is a documented evidence which provides a high degree of assurance that a specific
process, method or system will consistently produce to the required specification in accordance
with accepted standards of cGMP.
Validation Protocol (VP)(old)
The VP is a written plan stating how validation will be conducted, including test parameters,
product characteristics, production equipment and decision points on what constitutes acceptable
test results.
Validation Protocol (or plan) (VP)(new)
A document describing the activities to be performed in a validation, including the acceptance
criteria for the approval of a manufacturing process - or a part thereof - for routine use.
Validation Report (VR)(old)
The VR is a written report on the validation activities, the validation data and the conclusions
drawn.
Validation Report (VR)(new)
A document in which the records, results and evaluation of a completed validation programmed is
assembled. It may also contain proposals for the improvement of processes and/or equipment.
Validation Master Plan (VMP)
VMP is a high level document that establishes an umbrella validation plan for the entire project
and summarizes the manufacturer’s overall philosophy and approach, to be used for establishing
performance adequacy. It provides information on the manufacturer’s validation work
programmed and defines details of and time-scales for the validation work to be performed,
including stating the responsibilities relating to the plan.
Verification
The application of methods, procedures, tests and other evaluations, in addition to monitoring, to
determine compliance with the GMP principles.
Worst case
A condition or set of conditions encompassing upper and lower processing limits and
circumstances, within SOPs, which pose the greatest chance of product or process failure when
compared to ideal conditions. Such conditions do not necessarily include product or process
failure.
Air lock-
A small room with interlocked doors, constructed to maintain air pressure control between
adjoining rooms (generally with different air cleanliness standards). The intent of an aseptic
processing airlock is to preclude ingress of particulate matter and microorganism contamination
from a lesser-controlled area.
Alert Level-
An established microbial or airborne particle level giving early warning of potential drift from
normal operating conditions and triggers appropriate scrutiny and follow-up to address the
potential problem. Alert levels are always lower than action levels.
Action Level-
An established microbial or airborne particle level that, when exceeded, should trigger
appropriate investigation and corrective action based on the investigation.
Aseptic Manufacturing Area-
The classified part of a facility that includes the aseptic processing room and ancillary clean
rooms. For purposes of this document, this term is synonymous with “aseptic processing facility”
as used in the segregated segment context.
Aseptic Processing Facility-
A building, or segregated segment of it, containing clean rooms in which air supply, materials,
and equipment are regulated to control microbial and particle contamination.
Aseptic Processing Room-
A room in which one or more aseptic activities or processes is performed.
Asepsis-
A state of control attained by using an aseptic work area and performing activities in a manner
that precludes microbiological contamination of the exposed sterile product.
Bioburden-
The total number of microorganisms associated with a specific item prior to sterilization.
Barrier-
A physical partition that affords aseptic processing area (ISO 5) protection by partially separating
it from the surrounding area.
Biological Indicator (BI)-
A population of microorganisms inoculated onto a suitable medium (e.g., solution, container or
closure) and placed within appropriate sterilizer load locations to determine the sterilization cycle
efficacy of a physical or chemical process. The challenge microorganism is selected based upon
its resistance to the given process. Incoming lot D-value and microbiological count define the
quality of the BI.
Clean Area-
An area with defined particle and microbiological cleanliness standards.
Clean room-
A room designed, maintained, and controlled to prevent particle and microbiological
contamination of drug products. Such a room is assigned and reproducibly meets an
appropriate air cleanliness classification.
Component-
Any ingredient intended for use in the manufacture of a drug product, including those that may
not appear in the final drug product.
Colony Forming Unit (CFU)-
A microbiological term that describes the formation of a single macroscopic colony after the
introduction of one or more microorganisms to microbiological growth media. One colonyforming
unit is expressed as 1 CFU.
Critical Area –
An area designed to maintain sterility of sterile materials. Sterilized product, containers, closures,
and equipment may be exposed in critical areas.
Clean Zone-
See Clean Area.
Critical surfaces-
Surfaces that may come into contact with or directly affect a sterilized product or its containers or
closures. Critical surfaces are rendered sterile prior to the start of the manufacturing operation,
and sterility is maintained throughout processing.
Decontamination-
A process that eliminates viable Bioburden via use of sporicidal chemical agents.
Disinfection-
Process by which surface Bioburden is reduced to a safe level or eliminated. Some Disinfection
agents are effective only against vegetative microbes, while others possess additional capability
to effectively kill bacterial and fungal spores.
Depyrogenation-
A process used to destroy or remove pyrogens (e.g., endotoxin).
D value-
The time (in minutes) of exposure at a given temperature that causes a one-log or 90 percent
reduction in the population of a specific microorganism.
Dynamic-
Conditions relating to clean area classification under conditions of normal production.
Endotoxin- A
Pyrogenic product (e.g., lipopolysaccharide) present in the bacterial cell wall. Endotoxin can lead
to reactions in patients receiving injections ranging from fever to death.
Gowning Qualification- A program that establishes, both initially and on a periodic basis, the
capability of an individual to don the complete sterile gown in an aseptic manner.
HEPA filter-
High efficiency particulate air filters with minimum 0.3 μm particle retaining efficiency of 99.97
percent.
HVACHeating,
ventilation, and air conditioning.
Intervention-
An aseptic manipulation or activity that occurs at the critical area.
Isolator- A decontaminated unit, supplied with Class 100 (ISO 5) or higher air quality, that
provides uncompromised, continuous isolation of its interior from the external environment (e.g.,
surrounding cleanroom air and personnel). There are two major types of isolators:
Closed isolator systems exclude external contamination from the isolator’s interior by
accomplishing material transfer via aseptic connection to auxiliary equipment, rather than use of
openings to the surrounding environment. Closed systems remain sealed throughout operations.
Open isolator systems are designed to allow for the continuous or semi-continuous ingress and/or
egress of materials during operations through one or more openings. Openings are engineered
(e.g., using continuous overpressure) to exclude the entry of external contamination into the
isolator.
Laminar flow-
An airflow moving in a single direction and in parallel layers at constant velocity from the
beginning to the end of a straight-line vector.
Operator- Any individual participating in the aseptic processing operation, including line set-up,
filler, maintenance, or other personnel associated with aseptic line activities.
Overkill sterilization process- A process that is sufficient to provide at least a 12 log reduction of
microorganisms having a minimum D value of 1 minute.
Pyrogens-
A substance that induces a febrile reaction in a patient.
Sterile Product- For purposes of this guidance, sterile product refers to one or more of the
elements exposed to aseptic conditions and ultimately making up the sterile finished drug
product. These elements include the containers, closures, and components of the finished drug
product.
Sterilizing grade filter-
A filter that, when appropriately validated, will remove all microorganisms from a fluid stream,
producing a sterile effluent.
Quality Control Unit-
An organizational element with authority and responsibility as defined by 211.22.
Unidirectional flow-
An airflow moving in a single direction, in a robust and uniform manner, and at sufficient speed
to reproducibly sweep particles away from the critical processing or testing area.
Terminal sterilizationwww.
pharmatechbd.blogspot.com
The application of a lethal agent to sealed, finished drug products for the purpose of achieving a
predetermined sterility assurance level (SAL) of usually less than 10-6 (i.e., a probability of a no
sterile unit of greater than one in a million).
ULPA filter-
Ultra-low penetration air filter with minimum 0.3 μm particle retaining efficiency of 99.999
percent.
Validation-
Establishing documented evidence that provides a high degree of assurance that a specific process
will consistently produce a product meeting its predetermined specifications and quality
attributes.
or
Validation is a documented evidence which provides a high degree of assurance that a specific
process, method or system will consistently produce to the required specification in accordance
with accepted standards of cGMP.
Quarantine: The status of starting or packaging materials, intermediates or bulk or finished products
isolated
physically or by other effective means while a decision in awaiting on their release or refusal or rejection
or
reprocessing. On the other hand, the status of materials, intermediates or products set apart while awaiting
a
decision on their suitability for reprocessing or for sale or distribution.
Segregation: Segregation means separating or setting apart. It is the process to separate materials or
products
according to their nature for avoiding mix-up and easy traceability. The process, which takes place in, the
formation of germ cells in which is each gamete receives only one of each pair of genes. Separation of
one
product from other product to avoid contamination and mix-up.
Ambient Temperature: Ambient temperature means the temperature surround us. In a pharmaceutical
industry, this temperature range between 25ºC – 30ºC. Ambient conditions to be 30ºC where as other
provisions accepted 25ºC – 30ºC. Ambient in the immediate location usually a reference to temperature or
humidity.
Cold/Cool Temperature: A temperature range between 2º C – 8º C is called cool temperature and cold
temperature range between 8º C – 15º C.
Cold Chain Product Temperature: The temperature is which the raw materials of a product its
manufacture, storage, distribution up to prescription is done within 2ºC – 8ºC is known as cold chain
product
temperature
Control Condition Temperature: The temperature between 20ºC – 25ºC is known as control condition
temperature or control room temperature.
Batch: A defined quantity of starting material, packaging material or product processed in one process or
series of processes so that it could be expected to be homogeneous. Batch means a specific quantity of a
drug
or other materials that is intended to have uniform character and quality within specified limits and is
produced according to a single manufacturing order during the same sycle of manufacture.
Batch no.: A distinctive combination of numbers and/or letters which specifically identifies a batch or lot
on
the labels, the batch records, the certificates of analysis etc. A designation in number or letters or
combination
there of that identifies the batch and permit the tracing of the complete history of a batch, including all
stages
of its production, control, distribution and dispensing.
Component: Component means any ingredient intended for use in the manufacture of a drug product
including those that may not appear in such drug product. Any product contains more than one material
and
each material is called component.
Drug – Product: ‘Drug Product’ means a finished dosage forms (e.g. Tablet, Capsule, Solution etc.) that
contains an active drug ingredient generally but not necessarily in association with inactive ingredients.
The
term also includes a finished dosages form that does not contain an active ingredients but is indeed to be
use
as a placebo. Any substance or mixture of substances that is manufactured, offered for sale or presented
for
use in (1) the treatment, mitigation, cure, prevention or diagnosis of disease, abnormal physical state or
the
symptoms there of in man or animal or (2) the restoration, correction or modification of organic functions
in
man or animal.
Active Ingredients: Active ingredient means any component that is intended to furnish pharmacological
activity or other direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease or to
effect
the structure of any function of the body of man or other animals the term includes those components that
may undergo chemical change in the manufacture of the drug product in a modified form intended to
furnish
the specified activity or effect.
Excipient: Excipients are the additives used to convert pharmacologically active compounds in a
pharmaceutical dosage forms suitable for administration of patients. Excipient is non-drug component of
a
pharmaceutical formulation. Excipients include diluents, binders and adhesive, fillers, disintegrants,
lubrications, glidents, flow promoters, colors, flavours and sweetness. The general notice on excipient
state
that any substances added in official preparation shall not interfere with the assays and tests of the
pharmacopoeia. It shall be innocuous shall have no a verse influence on the therapeutic efficacy of the
active
ingredient. Excipients are those substances which are not biologically active and are mainly used along
with
the active ingredient of a drug product to make the product more stable e.g magnesium stearate, Starch,
Purified talc etc.
Inactive Ingredient: ‘Inactive ingredient’ means any component other than an active ingredient. Inactive
ingredient states that any substances added in official preparation shall not interfere with the assay and
test of
the Pharmacopeia. Inactive ingredient usually makes up the major portion of the final dosage form.
Bulk Product: Any products, which has completed all processing stages up to, but not including final
packing. Any processed product, which still has to undergo the packing operation in order to become a
finished product. The product following purification, but before final formulation. It is obtained form a
bulk
harvest, and is kept in a single container and used in the preparation of the final dosage form.
Finished Product: A medicinal product, which has undergo all stages of manufacturing operations
including
packaging in its final container and labeling.
In Process Materials: In process material means any material fabricated compounded, blended or
derived by
chemical reaction that is product for and used in the preparation of the drug product. All substances,
whether
active or inactive or whether they remain unchanged or become altered, that are employed in the
manufacture
of drugs.
Strength: Strength means the concentration of the drug substances (for e.g. weight/ weight, weight /
volume
or unit dose and or the potency of a drug product). A quantitative measure of active ingredient as well as
other
ingredients requiring quantitation such as alcohol and preservatives.
Potency: Potency means the therapeutic activity of the drug product as indicated by appropriate
laboratory
tests or by adequately developed and controlled clinical data. The potency of drug is indicated on the
label.
Potency may be expressed in terms of units of a reference standard, as in 100 IU of vitamin E, or in
weight,
weight equivalent or percent of active ingredient. The potency of drug is some times referred to as the
strength of the drug.
Efficacy: Property of drug to active the desired response. A manufacture has to prove both safety and
efficacy
for the FDA to approve a new drug application. It is a term used to know the response of any drug
produced
whether optimum or not. A product must be biological effective as it is claimed to be from its dosage
form the
drug itself is required to be biologically available to the recipients.
Theoretical Yield: ‘Theoretical Yield’ means the quantity that would be obtained at any appropriate
phase of
manufacture, processing or packing of a particular drug product, based upon the quantity of components
to be
used, in absence of any loss or error in actual production.
Actual Yield: ‘Actual Yield’ means the quantity that is actually produced at any appropriate phase of
manufacture, processing or packing of a particular drug product. On the other hand the quantity that is
actually produced at any phase of production of a particular drug product from a given amount of
ingredient.
Representative Sample: Representative Sample means a sample that consists of a number of units that
are
drawn based on rational criteria such as random sampling and intended to assure that the sample
accurately
portrays the material being sampled. A sample accurately portraying the lot, the batch or the total amount
of
materials being sampled.
Validation: The documented act of proving that any process, procedure, equipment, material, activity,
system
or mechanism used in manufacture or control can achieve the describe and intended result. It is an
intended
part of Quality Assurance. The action of proving a high degree of assurance that a specific process will
consistently produce a product meeting its predetermined specification and quality attributes validation
includes installation qualification, operating qualification and performance qualification activities.
Revalidation: Revalidation means the repetition of the validation process or a specific portion of it. When
there is change in validation process or any main factors affecting product quality consideration should be
given whether revalidation is necessary.
Media Fill: It is the method of evaluating effectiveness of an aseptic process by filling container with
culture
medium instead of the product, incubating the containers and checking for microbial growth. At least
3000
articles should be used in media fill and the accepted limit 0.1%. It is the method validation intended for
sterile area for a particular number of people.
Biological Indicator: Biological indicator generally is highly resistant bacterial spores present in greater
number then the normal contamination of the product and with equal or greater resistance than normal
microbial flora in the products being sterilized. Biological indicators are standardized preparation of
resistant
organisms, usually in sporulating form, of one species used for the validation of sterilization, while
Bacillus
stearothermophilus is preferred for steam sterilization. Biological indicator are those organisms used to
indicate a particular condition. The term most commonly applied for coliform bacteria e.g. Ecoli or
streptocoecus facealis indicat the degree of water pollution due to faecal contamination. Biological
indicators
should be considered only as an additional method for monitoring the sterilization. If they are us used,
strict
precautions should be taken avoid transferring microbial contamination from them.
Non Biological Indicator: non biological indicator are those substances or chemical agents which
indicates a
particular condition either by change in colors or by the change of their present state. e.g. Sterilization
step is
a kind of non biological indicator which shows brown color after completion of a successful moist heat
sterilization cycle.
OTC Drug: Over the Counter drug. OTC drugs are those drugs which can be used without the
prescription of
a registered physician.
HVAC: Heating, Ventilation, Air conditioning system is used for temperature and humidity control with
in a
manufacturing environment. It include air handling units air distribution network, air cooling and heating
system, air filtration, equipment control system, monitoring and alarm device. HVAC system are an
integral
part of clean room design. The primary purpose of an HVAC system is to provide a specific set of
environmental conditions required for the manufacturing process.
Back Sipnonage: Back sipnonage is the process to prevent the back flow of water or other unusual
liquids. It
is a one way system to pass the water outside. Back sipnonage means back flash of water.
Material / Product Traceability: It is the process to trace all materials and products in all stages of
manufacture and distribution. All aspects of the procedure including calibration, specification of the
reagents
and other operational parameters are well defined. The measurement should be on sound chemical and
physical principles described in the literature and thoroughly tested. It should always be possible to trace
back
all the relevant information about a pre tested sample as and when necessary. Traceability is the most
prominent concept used by analytical chemist to characterize quality of measurements. It is the chain of
comparison from measurements back to the standard of same kind by reference to which one can estimate
the
uncertainly of the results.
HEPA: High Efficiency Particular Air Filter (HEPA) is a filtering system. HEPA filter capable of
retaining
99.97 percent of particles as small as 0.3 μm. It is a disposable, extended media dry type filter in a rigid
frame.
LAF: Laminar Air Flow is the flow of air currents in which streams do not intermingle the air moves
along
parallel flow lines, used in LAF hold to provide air free of microorganism over the work area. It can
deliver
clean air in vertical, horizontal direction. Movement of an entire body of air with in a confined area with
uniform velocity along parallel flow lines without turbulence.
Class 100: Area where maximum no. of particles per cubic ft 0.5 μm and large much no exceed 100 is
called
class 100. Class 100 condition means that no more than 100 particles / ft3 of size 0.5 μm shall be found in
that
particular area detected by a electronic particle counter. Particle count not to exceed a lot of 100 particles
per
cubic feet of a size 0.5 μm and large size.
DOP Test: Dioctyl Pthanate test is used to determine the integrity of HEPA filters. The test uses a
heterogeneous dioctylphthalate aerosol having the following approximate light scattering mean droplet
size
99%, less than 3.0 μm, 50% less than 0.7μm and 10% less than 0.4μm. The test is used to test the HEPA
filters for leaks. The DOP aerosols of 0.28 μms – 0.4 μms size are introduced upstream of the filter and
leaks
are detected down stream with an aerosol photometer. The aerosol is generated by a mechanical aerosol
generator.
Optical Density: Optical density is the measure of the concentration of a solute in solution, obtained by
measuring the degree to which the solution absorbs light of a particular wavelength. It can be used to
measure
the concentration of bacterial, proteins, DNA or RNA in solution. The optical density, d20
20, of a substance is
the ratio of the mass of a given volume of the substance to the mass of an equal volume of water bath
weighed
at 20°. The optical relative density is determined with precision indicated in the monograph. The optical
density expressed in kgm-3, d20
20, = 1.00180 × 10-3 p20
Optical Rotation: The optical rotation of a substance is the angle through which the plane of polarization
is
rotated, when polarized light is passed through a chemical substance, if liquid or solution of the
substance, if
solid substance are described as dextrorotatory or Levorotatory according to whether the plane of
polarization
is rotated ‘clock wise or anticlock wise’, respectively as determined by viewing towards the light source .
Dextrorotation is designated (+) and Levorotation is designated (-). The optical rotation, α, unless other
wise
specified, is measured at the wavelength of the sodium D line (589.3 nm) at a temperature of 20° in a
layer 1
dm thick determine the angle of rotation of the substance being examined at 19.5° to 20.5°. So rotation of
a
plane of polarized light by a chemical compound clock wise (+) or counter clock wise (-) with respect to a
light source. The optical rotation determination is a method for the measurement of the angular rotation of
the
sample using a polarimeter.
UV Sterilization: Ultraviolet light sterilization is used mainly to sterilize heat sensitive materials and
products and to reduce microbial load in air, pure water or surface within processing environment. The
germicidal light is emitted at wave length of 2537 Aº and the effectiveness is dependent on the intensity
of
radiation & time of exposure. To kill micro-organism by ultra violet rotation. UV radiation at 254 – 256
nm is
the bacterial effect.
Fumigation: Fumigation is the process to reduce microbial load in a particular area by using KMnO4 or
HCHO fumes for specified time. To kill micro-organism by 40% formaldehyde fumigation at 60% RH.
The
use of poisonous fumes or gases to destroy living organisms. Fumigants are relatively ineffective against
bacteria and viruses. To make smoke which is used in disinfeeting a room. Fumigate substance such as
formation used to produces fumes which are lethal to insects & rodents.
Depyrogenation: To kill pyrogen by heating at 200º C - 250º C is called Depyrogenation. It is the process
in
which dry heat at 250º C for 30 minutes or 200º C for 1 hour is used to remove pyrogens from
equipment’s
and containers used for sterile product. Time is also a factor for killing pyrogens.
Accuracy: Accuracy defines the agreement between the true value and the value found in the testing. The
closeness of the result obtained during measurement or analysis to the true value. Bias is a systematic
deviation from the true value. It normally refers to the difference between the mean of the set of results of
analysis of the unknown are compared with the results obtained from the analysis of standards or
reference
materials. Accuracy expresses closeness of agreement between the value, which is accepted either as a
conventional true value or an accepted reference value and the value found. Accuracy can be determined
by
comparing the results with those obtained using an alternative method which has already been validated.
Accuracy may be determined by applying the procedure to samples of the material to be examined that
have
been prepared with quantitative accuracy. For analytical methods there are two possible ways of
determining
the accuracy; the so- called absolute method and the comparative method.
Precessions: Precession defines the closeness of agreement between a series of measurements obtained
from
multiple sampling of the same homogeneous sample under the prescribed conditions. It is a measure of
degree
of repeatability or reproducibility under normal conditions. Precision may be defined as the concordance
of a
series of measurements of the same quality. Accuracy expresses the correctness of a measurement, and
precession the reproducibility of a measurement. Precession always accompanies accuracy, but a high
degree
of precession does not imply accuracy. The degree of variation between individual tests results when the
method is used separately to separate sample drawn from the same homogeneous batch of material. This
will
includes variation between analysis between days between tests on the same prepare extract of a given
sample, between extracts and between laboratories conducting the same test. Precession is usually
expressed
as a standard deviation or coefficient of variation.
Repeatability: Repeatability express the precession under the same operating conditions over a short
interval
in time. It is relating to testing performed over a short time interval. This is the precession of the method
when
repeated by the same analyst, same test method and under same set of laboratory condition with in a short
interval of time, the only difference being the sample. The repeatability of any test procedure is required
to be
assessed by caring out complete separate determination or separate samples of the same homogeneous
batch
of material under normal condition. This is the criteria of concern for compendia assay procedures.
Reproducibility: Reproducibility expresses the precession between laboratories. It relates to the
collaborative
studies between laboratories. This evaluation is the measure of the robustness of the method since many
variables are involved-different facilities, different equipment, different analysts different reagents. This
is a
key element in analytical verification and conformation that a new laboratory obtained equivalent result to
the
originator laboratory. When the subject method is carried out by different conditions on different
daysvariability
of analytical results as function to equipment etc. using the samples from same homogeneous batch
problems connected with reproducibility of the test results are naturally compounded when tests are
performed in different countries. When discussing confidence in test results a major concern is assuring a
sufficient degree results with the high degree of precession and be described in reproducibility.
Robustness: Robustness of an analytical procedure is a measure of its capacity to remain unaffected by
small,
but deliberate, variations in method parameters and provides an indication of its reliability during normal
use.
It is the ability of the procedure to provide analytical results of acceptable accuracy and precision under a
verity of conditions. It is a measure of the extent to which the result obtained from separate putatively
identical samples of the same homogeneous batch of material are influenced by changes in operational or
environment condition but are constant with the specification and down for procedure.
Linearity: The linearity of an analytical procedure is its ability to procedure results that are directly
proportional to the concentration of analyte in the samples. Linearity applies only to methods involving
quantification and involves the demonstration of a linear response over the range being evaluated. Exam.
An
assay method may be evaluated only over the range of 85 – 115% of the specification since any results
outside of these values would be out of specification. Linearity is ability of the method of elicit test results
that are directly proportional to the concentration of analyte.
Sensitivity: Sensitivity is the capacity of the test procedure to record small variation in concentration. It is
the
slope of the calibration curve. A more general use of term to encompass limit of detection and or limit of
quantitation should be avoided. The limit of detection is the lowest detectable quantity at the most
sensitive
instrument setting.
Limit of Quantitation: the limit of quantitation is the lowest concentration of analyte in a sample that
may be
determined with acceptable accuracy and precession when the required procedure is applied. It is
measured by
analyzing samples containing known quality of the analyte and determining the lowest level at which
acceptable degree of accuracy & precession are attainable. In many cases the limit of quantitation is
approximately twice the limit of detection. Concentration below the minimum quantifiable limit (MQL)
should not be used in data interpretation. Standard curves should not be extrapolated below MQL.
CFU: Colony Forming Units. Colony Forming Units are the no. of microbes that can replicate of form
colors
. Multiplication of bacterium on a solid surface results in the formation of colony visible to the necked
eye. It
takes generally 16 – 24 hours.
Dehumidification: It is the process to reduce the humidity of a particular area using a dehumidifier. A
dehumidifier is a unit, which absorbs the moisture content of the air. The function of dehumidifier is to
remove moisture in the vapor state from an air stream. After moisture has been removed the air stream
then
may contact a product to be direct or may be used as a mass of air entering a space where humidity
control is
needed.
WFI: Water for injection is intended to a high degree of chemical purity and to be free from pyrogenic
substances and endotoxin. It is prepared by distillation or reverse osmosis. It must be clear, colorless and
odorless having pH within the range of 5.0 to 7.0. Water for injection is a water for the preparation of
medicines for parenteral administration, when water is used as a vehicle and for dissolving or diluting
substance or preparation for parenteral administration. Water for injection is a pyrogenic distilled water.
DM Water: DM Water stands for Deminaralized water. The water free from materials is called
Deminaralized water. Deminaralized water are purified water from which the minerals are removed by
ion
exchange method. It is clean liquid, colorless and tasteless. Potable Water: Potable water is dunking
water,
treated by the local authority or an site, is suitable for human consumption. Water which are free of
pathogens
and toxic substances, odorless, i.e. in a state safe for drinking and other use are called potable water. It is
generally used for tape water or the water which drink is must meet pharmacopoeia requirement.
Conductivity: Conductivity is an electrolytic conductance and the conducting compounds are
electrolytes.
Acid Bases and Salts conduct electricity. Conductivity is the electric conducting ability of a substance. It
is
the ability of metals to conduct electric current. In case of chemical compound, it is the ability to conduct
electricity by virtue ion present. Measuring electrical resistance and calculating conductivity, which is the
reciprocal of the resistance, determine conductivity. Its unit Ohm/cm.
TDS: TDS means Total dissolve solid. The amount of solid present in dissolved state in DM or
Tape water. Tape water, DM water have pharmacopieal requirement for TDS.
Regeneration System: Regeneration means the regaining of previous condition. It means to gain the
original
strength of anything by define protocol. In DM water plant by exchanging the cationic anionic reaction,
the
resin regains its in initial states. The exchange depends on activity series. During absorption of mineral,
the
resin looses its absorbing capacity and a layer forms on resin by the accumulation of materials. Thus after
a
period of time the resin requires regeneration by red alarm on the display board. The machine shows red
alarm on the basis of conductivity e.g. The range is (0.1 – 1.0) μs. It is exceeds the machines shows
continuously red alarm to stop the supply of DM water and to go for regeneration.
Manufacturing: The complete set of activities to produce a drug comprising of production and quality
control from acquisition of all materials through processing and subsequent packaging to the release for
distribution of the finished product. The complete cycle of operations involved in the production from
receipt
of materials, through processing and packaging, to release as a finished product. All operation of purchase
of
materials and products, Production, quality Control, release, storage, distribution of medicinal products
and
related control.
Reprocessing: The reworking of all or part of batch of product of an unacceptable quality from a defined
step
of production in order its quality may be rendered acceptable by one or more additional operations.
Reprocessing or reworking may be required for many reasons the most common causes are potency
adjustments, failure to meet physical parameters, non uniform blending etc. Reprocessed batch must be
thoroughly tested to make sure that its meets the required specifications.
Campaign basis: Different products prepare in the same area, sharing same facilities with proper
cleaning
method or validation. Production on a campaign basis may be acceptable for other spore forming
organisms
provided that the facilities are dedicated to this group of products and no more than one product is
processed
at any one time. The campaign manufacturing (e.g. Sharing the same facilities between manufacture of
two or
more different products) with fulfillment of validated clean down approach, is regarded as the minimum
effort
to avoid cross-contamination. Such procedure obviously will demand a highly motivated work force.
During
“campaign manufacturing” or any routine manufacturing, the process control measures will help solve
major
risks of cross-contamination.
Consistency: An acceptable number e.g. five successive batches of final dosage form should be
characterized
as fully as possible to determine consistency of composition. Any differences between one batch and
another
should be as the basis for produce specification.
Master formula: A document stating the starting materials, with their quantities, to be used in the
manufacture of a medicinal product, together with a description of the manufacturing operation including
details of specific in process controls, but normally excluding packaging information. A document or set
of
documents specifying the starting materials with their quantities & the packaging material together with a
description of the procedure and precautions required to produce a specified quantity of finished products
as
well as the processing instructions including the in-process control.
BMR: Batch Manufacturing Record. A document stating the materials used and the operation carried out
during the processing of a given batch including details of in process control. It should be based on the
master formula and be complied as the manufacturing operation process. After completion of stability
study,
PDD prepare batch manufacturing record on the basis of product formula and product specification for
manufacturing process validation. BMR contents product name, strength, Batch no, Batch size, Quantity,
Quantity of raw material, code no, QC reference no, Calculation on potency, manufacturing procedure,
temperature, humidity, time, Yield of different stage etc.
BPR: Batch Packaging Record. A document stating the bulk product and packaging material used and the
process carried out during the packaging of a given batch with details in process control. It should be
based on
the master formula & packaging instruction and be complied during the packaging operation. BPR
contents
Product name, strength, Batch no, Batch size, Pack size, MRP, Mfg. date, Exp. Date, Outer box /
Shipping
carton size etc.
Stability Study: It is the study which is used to determine appropriate storage condition and self life
stability
study is observed to determine the self life of a product i.e. how much time the product remain stable in
the
market and confirms with product specification meet the pharmaceutical limit. Stability study observed by
two methods. (i) Accelerated storage test. (ii) Storage test method
Accelerated S. Study: A test performed to determine the rate of degradation of drugs or other substance
to
product the self life of the product. The study is performed by accelerating the degradation process by
increasing temperature, humidity or light and determine the corresponding rate of degradation of a drug
substance or drug product by using exaggerated storage condition. The purpose is to determine kinetic
parameters, to predict the tentative expiration dating period. The term “accelerated” is often used
synonymously with “stress testing”. To predict the stability of a new product the accelerated testing
approach
is a doped. Degradation of the product by adopting various extreme storage conditions such as higher
humidity and higher temperature as mentioned earlier. For a simple product where the decomposition is
constant over a temperature range and the order of reaction kinetics is also known, it is relatively easier to
calculate the t½ (half life) and t90 (10% decomposition). For the first order reaction kinetics the equation
for
0.693 0.105
t½ = -------------- and t90 = -------------
k1 k1
where k1 is the rate constant for the 1st order reaction. So when the rate constant and the order
of reaction of a drug substance is known the self life (t90) can be easily calculated. The equation
will obviously differ for a different order of reaction.
Real Time S. Study: Real time stability study is done by storing the product at ambient condition through
out
its self life after launching.
Mfg. Date: A date fixed for the individual batch including the completion date of manufacture. A
specified
date for the individual batch including the date of bulk product manufacture.
Exp. Date: A date fixed for each individual batch before which the batch iii meets the required standard
specifications for quality. A specified date for the individual batch based on the stability of the product,
beyond which it may fail to meet the required quality input for its intended use “Expiry Date” in relation
to a
medicinal product means the date after which the product should not be used. If the expiration date
includes
only a month and a year, it is expected that the product will meet specifications through the last day of the
month.
Pre Formulation: It is one step a head of final formulation. Pre formulation is the common physico-
chemical
tests; such as meeting point, thermal analysis, polymorphic studies, Stability etc. Usually carried out for
newly synthesized drug.
Recipe: Recipe is a list of active ingredients and excipients of a drug, which is to be submitted to drug
administration for approved. To produced quality product the step; to taken in account at standard chain is
mainted is called be Recipe on the other hand it can be described an predefined protocol to manufacture
drugs.
Annexure: Annexure is the approved recipe or license obtained of a drug form drug administration. It is a
document which stats the total Recipe of any product approved by appropriate Drug Control Authority.
The
formulation so approved by the regulatory Drug Authority.
DAR No.: “DAR NO” means Drug Administration Registration Number. DAR No. is a specific
combination
of numbers or approval given by the drug administration to manufacture a product.
Self – Inspection: Self-inspection means to assess myself and opportunity for improvement with respect
to
guidelines like GMP ISO9001 FDA or National regulatory discipline. Self-inspection is to evaluate the
manufactures with GMP in all aspects of production and quality control. Self-inspection is required for
the
implementation of corrective action and to examine effectiveness of improved system. Self-inspection
team
consisting of at least 3 members who are expert in their own fields and familiar with GMP.
Pressure vessel: It is a closed vessel to which pressure is added to transfer the solution either through
filter or
directly in to the fined closed vessel form which filling and sealing is done. A vessel which is used to
filter
sterile product by using wet gas pressure.
Membrane filter : Membrane filter which is used in sterile filtration of parenteral products. It is a
cellulose
ester membrane use for filtration process to remove microorganisms from liquid. The pore size of the
membrane filter may range from 0.2μ to 0.45μ. A 0.22μ filter is considered a sterilizing filter. Filter
medium
produced from cellulose derivatives of polymeric materials. Membrane filters, which have discrete
uniform
passages that penetrate from one side of the media to the other can be regarded as fine, uniform
capillaries.
Membrane filter holders accept membranes from 13 to 293 mm in diameter.
Bubble pt. Test: The bubble point test is a popular single point physical integrity test for dise filter
membrane. Nondestructive integrity test of a filter membrane based on the amount of pressure required to
force air through a wet porous membrane has a specific bubble point. A test at a pressure of 20
pounds/squire
inch is sufficient to detect leaks. Membrane filters, which have discrete uniform passages that penetrate
from
one side of the media to the other, can be regarded as fine uniform capillaries. The bubble point test is
based
on the fact that when these capillaries are full of liquid, the liquid is held by surface tension. The
minimum
pressure required to force the liquid out at the capillary pressure is higher in the case of a small pore than
in
that of a large pore. The same is true for pores in a membrane. The bubble point pressure is governed by
the
following equation 4γcosθ
P = K ------------------
D
P = Bubble point pressure
K = Shape correction factor
D = Pore diameter
γ = Surface tension of the liquid
θ = Liquid-to-membrane contact angle
Pre Filter: Filter that traps gross particulate matter. Pre filters are located upstream from other filters (e.g.
HEPA filter) and have a lower collection efficiency than the other filters. Pre filter is the filter which is
used
before final and main filtration.
Intermediate Filter: Intermediate Filter present between the final filter and pre filter.
HEPA Filter: The HEPA (Highest Efficient Particulate Air) filter is disposable, extended-media dry type
filter in a rigid frame. HEPA filter capable of retaining 99.97 percent of particles as small as 0.3
micrometers.
The filter medium is very fine glass fibers mounted in a rigid frame. The HEPA filter sometimes called
the
absolute filter.
Air Vent Filter: It is a filter used to vent air from a closed vessel during with drawls sterile solution from
or
entry of sterile solution in to the vessel to protect product from being contamination. In a 0.2 micro pore
size
filter which is used to administration sets for intravenous solutions when air elimination though
manipulative
procedures in inefficient.
Sparkler Filter: Sparkler filter is the electric filter for liquid product. It is the filter generally used to
liquid
product filtration purpose in order to get sparkling filtrate. Sparkler filter is a special type of filter in
which
liquid is passed through cloth/coarse paper positioned between two net plates one after by pressure.
Press Filter: It is the most versatile of filters since the number of type of filter sheets can be varied to suit
a
particular requirement. It can be used for coarse to fine filtrations, and any special conduct arrangement
for
multistage filtration with in single press. The filtrate equipment in which filter pad is used by pressure. It
is a
simplest kind of pressure filter, which is used for filtration of liquids by using high pressure. Filter presses
are
used for a high degree of classification of fluid and for the harvesting of cake. It can be used for coarse to
fine
filtration. The press filter is the most versatile of filters and it is the most economical filts per unit of
filtering
surface which can be used for coarse to fine filtrations. The normal range of flow of this filter is three
gallons
per minutes per square foot of filter surface at pressures of up to 25 psi.
Filter Aid: It is special type of filter medium which is used to forms a fine surface deposit that screen out
all
solids preventing them from contacting and plugging the supporting filter medium.
Microbial Alert Level: Microbial alert level is that the level of microorganism that shows a potential
drift
from normal operating condition. On the other hand Microbial levels which, when exceeded should result
in
an investigation to ensure that the process is still with in control. Exceeding alert level is not necessary
ground
for corrective action but it should at least prompt a documented follows up investigation. It’s a control
limit
for environmental monitoring level.
Microbial Action Level: It is the level of microorganism that when exceed requires immediate follow up
and necessary corrective action. Microbial levels in the controlled environment which, when exceeded
should
trigger an investigation and corrective action based on the investigation. Action limit is to allow
corrective
measures without affecting the batches or production.
Time Limitations on Production: It is the actual time needed or total time needed to complete a batch of
product with respect to standard machine specification, man power and other equipments.
Pyrogen: In Greek word “Pyrogen” means “Production of fever” any substance that produces a fever.
Pyrogens are products of the metabolism or portions of the protein coat of bacteria. The most potent
pyrogens
are often found as contaminations in paranteral drugs, thus drugs are tested for pyrogenicity with the
rabbit
test or limulus lysate test fever is a response to fever including substance called pyrogens including
bacterial
endotoxins, that enter the blood as a result of the death of microorganisms or are released by phagocytic
blood
cells.
LAL: LAL stands for “Limulus Amoebocyte Lysate” test. This test determines the presence or the
concentration of endotoxin in products. It is the bacterial indotoxin test reagent. LAL test used to detect
minute quantities of bacterial endotoxins and other pyrogens using an extract from the circulting
amebocytes
from the horseshoe crab (limulus polyphemus). Aspect of validation based on endotoxin despruction is
the
extration of dried endotoxin from the commodity for testing by the Limulus Amebocy Lysate( LAL test).
Endotoxin: Bacterial Endotoxin or pyrogen is metabolic products of living micro-organism or the dead
micro-organism causing a specific pyretic response upon injection. It is the part of Gram –ve bacterial cell
wall, also known as lipopoly succharide (LPS). It is liberated when the cell wall of the bacteria ruptures or
broken down.
Rabbit Test: Rabbit test is also called pyrogen test. Test of pyrogen based on temperature rise in rabbits
following the intravenous infection of a test solution. The pyrogen test is a method to test the existence of
pyrogens by using rabbits. The test is carried out on a group of three rabbits. If two or three rabbits show
an
individual rise of 0.6° or more above the respective control temperature. The test shall be considered as
positive when the pyrogen test is positive the sample is considered to be rejected.
Leak Test: Test performed in ampoules, tablet and capsule blisters either by dye immersion under
pressure or
by high capacitance method to detect leaks. It is performed in ampoules to detect on incomplete seal,
capacity
pores or tiny creaks. The test uses dyes or pressure to disclose leaked. This is performed to determine the
lot
average weight loss or leakage as measured over time loss is due to leakage of CPCS through the valve
seals
USP requirements are usually adopted. One product recall has occurred due to excessive leakage rates.
Air Locks: An enclosed space with two or more doors, which is interposed between two or more rooms
e.g.
of differing classes of cleanliness, for the purpose of controlling the air flow between these rooms when
need
to be entered. Each area having different qualities of environment or different air pressures, in the latter
case it
can be termed a “Pass through hatch”. An air lock can also by the “anteroom” too clean room in which
sterile
goods are handled.
Air Shower: A high speed flow of air, helps to sweep of particles and microorganism from garments and
body.
Air Curtain: Air curtain created between two temperature difference room. A current of air directed
around a
patient so that air that would normally circulate around and contaminate the patient is blocked by the
curtain
of air which is used in isolating patients from dust-borne bacteria or allergens.
Positive Pressure: Positive pressure are the pressure created in the aseptic production area to avoid
contaminated air pass in. It gradually decreases in the successive rooms. It is used to prevent
contaminated air
from flowing in to the clean room. Positive pressure areas should be used to process sterile products but
negative pressure in specific areas at point of exposure of pathogens is acceptable for containment
reasons.
Differential Pressure: Differential Pressure means the pressure difference between two adjacent rooms.
Different of air pressure between two rooms with in the sterile area this may very from 10 – 25 pressure.
Depyrogenation Temperature: Depyrogen means free from Pyrogen an a parenteral drug. The
temperature
at which the Ptrogen are killed Depyrogenation temperature are dry heat at 200ºC for one hour and 250ºC
for
half an hour.
Moist Heat Temperature & Pressure for Sterilization: Sterilization by moist heat is suitable only for
water-wettable materials and aqueous solution both temperature and pressure should be used to monitor
the
process. The moist heat temperature for sterilization is 121ºC and the pressure for sterilization is 15Ibs
pressure/square inch.
Air Velocity: It is the air speed generated by laminar air flow equipment. The air velocity is LAF work
bench
is 70-110 feet/ min. Air velocity is detected by anomometer. Measurement of the velocity of air flow in a
controlled environment to demonstrate that the air systems balanced and capable of delivering sufficient
air
volumes to maintain a minimum cross sectional velocity. Recommended air speeds are 0.30 meters per
second for vertical and 0.45 meters per second for horizontal flow.
Positive Controls: Positive controls is a culture medium which is used for sterility test is checked for its
efficacy to support growth of different organism by adding 10-100 cfu of m gm. This is known as positive
control.
Negative Controls: Negative controls are the culture media without addition of product sample or
microbial
challenge. The –ve control as used to velocity the sterility of the medium before during and after the
incubation period of the sterility tests.
Challenge Test: Microbial challenge test of a filter is the ability of a filter to retain particles or
microorganisms involving filtration. The test means of determining the bacterial retention properties of
the
system. For Example hot doptet is a challenge test for HEPA filter. On the other hand in microbial
challenge
test a standardized culture containing a large number of small microorganisms such as pseudomonas
diaminula, is fillered and the presence of bacteria in the filtrates, indicate the failure of the filter. This is
sensitive test because of the large number of organism used and because the organisms self-replicate &
allow
even low numbers of bacteria that might pass through a filter.
Preservative Deactivation Test: In pharmaceutical preservative is commonly used to prevent microbial
growth. This test is carried out for particle to cheek that any bacteriostatic and fungiotatic activity of the
article do not adversely affect the reliability of the test. The preservative can be deactivated either by
dilution
or using suitable chemical agent like easeir peptone, polisorbate 80 etc.
UCL (Upper Control Limit): UCL denotes Upper Control Limit. It is the maximum limit permitted
either in
weight or volume or potency of a product above which the weight or volume or potency of the product
will
not accepted. It is the manufactures in-house limit. Example: The upper control limit of a APA tablet is
663
mg where as its control points 650 mg.
MCL (Middle control Limit): MCL denotes Middle control Limit. It is the desired weight or volume or
potency of a product. For example 650 mg is the MCL of APA tablet.
LCL (Lower Control Limit): It is the lowest limit accepted either weight or volume or potency of a
product.
For example if standard weight of APA tablet is 650 mg and in house limit is 2% than lower control limit
is
637 mg.
ATCC (American Type Culcuture Collection): ATCC stands for American Type Culcuture Collection.
It is
a institution which gives a specific number to different organisms based on the variation of the strain.
LVP (Large Volume Parenteral): “Large Volume Parenteral” means a terminally sterilized aqueous
drug
product packaged in a single dosage container with a capacity 100 ml or more and intended to be
administered or used in man. It includes intravenous infusions, irrigating solutions, peritoneal dialysates
and
blood collecting units with anticoagulant. Single dosage form that is intended for parenteral use and is
packaged in containers holding 100 ml or more. It is commonly used to refer to injection only but the
definition includes irrigation solutions, peritoneal dialysates and blood collecting units with anticoagulant.
Containers containing 100 ml or more of the injectable solution is termed as large volume. They are
usually
used by the intravenous route.
SVP: Small Volume Parenteral include an extremely wide range of preparations and containers-closures.
Small Volume Parenterals are the drug packed in a container of not more than 100 ml in volume. They are
a
diverse and heterogeneous group of drugs. This category of parenterals include Ampoules of 1 ml, 2 ml, 3
ml
and vials of 2 ml, 5 ml, 10 ml etc. They may be suitable for intramuscular, intravenous, intra dermal,
subcutaneous, intra spinal, intra-cisternal or intrathecal use.
Particle: Particles are the substances which are either biological or non biological origin, with observable
length width and thickness i.e, dust particle, talc, bacteria and fungi etc. A very small piece or part of
matter, a
tiny fragment or trace is particle. One of several subatomic components of the nucleus of radioactive
elements
such as alpha and beta particles. Particles are biological or non biological origin.
Source of Particulate Matter: The source of particulate matter are Man, Machine, Materials, Garments,
walls, ceiling, floor etc.
Oral Liquid: Oral liquid are liquid preparations intended for oral administration that contain ore or more
substances with or without flavoring, sweetening or coloring agents dissolved in water. Liquid for oral
use are
usually solutions emulsions or suspensions containing one or more active ingredients in a suitable vehicle.
Some liquids for oral administration may consist of liquid active ingredients.
Suspension: A suspension is a preparation of finely divided undissolved drugs, dispensed in a liquid
phase. It
is a two phase dosage system in which a finely divided solid in mixture with, but not dissolved in a fluid.
Suspension are usually liquid preparation which are prepared by adding suspending agents or other
suitable
excipients are purified water or oil to splid drugs.
Emulsion: Emulsion are usually liquid preparation which are prepared by addition emulsifying agent and
purified water to liquid drugs. It is two phase system in which are liquid is dispersed in the form of small
droplets through ought another liquid. It is a stable mixture of two immiscible liquids combined with
surfactants to change there compatibility with stabilizers that increases viscosity.
External Liquid: External liquid are the liquid preparation which are used externally on the skin and not
to
take orally. External liquid is the liquid preparation other than oral liquid. It is used external body like
kevilon, Savlon, Detol etc.
Topical Preparation: It is the soft semisolid preparation for external application to the skin or mucous
membrane for systemic fungal or bacterial infection. It is a preparation which are most commonly used
are
ointments and lotion. A number of topical medicaments are applied to the skin, eye, nose, throat, ear and
vagina etc. These are the dry or semisolid preparation used in external body like Neocin powder and
another
antibiotic powder etc.
Dry Powder for Suspension: Dry powder for suspension are preparations of finely powdered drug
intended
for suspension in liquid vehicles. They are generally reconstituted with recommended volume of purified
water. A dry mixer of an Antibiotic e.g. Ampicillin, whenmixed with one or more suitable buffers,
preservatives, stabilizers, sweetening agent and suspending agents suitable for reconstitution are called
dry
powder for suspension. It is also called dry syrup. Powders are preparation in powdered form. Powders
are
usually prepared by uniformly mixing drugs with or without diluents, binders, disintegrators or other
suitable
excipients by a suitable method to produce a pulverized or finally granulated form. If necessary coloring
agents, aromatic agents, flavoring agents etc may be added
Suppository: Suppositories are solid preparation intended to insertion in to the rectum, urethra or vaginal
cavity. Suppositories are usually prepared by molding uniform mixers of drugs and bases in to a suitable
shape. Suppositories melt or soften at body temperature or dissolve slowly in the secretions. Suppositories
are
usually prepared by by mixing drugs with fat-type bases water-miscible bases or other suitable materials.
A
semisolid substance for introduction in to the rectum, vagina or urethra where it dissolves. It often suffers
as a
vehicle for medicines to be absorbed. Commonly shaped like cylinder or cone and made of soap,
glycerinated
gelatin or cocoa butter.
Ointment: Ointment are usually homogeneous, semisolid preparations for external application, as such
consistency that they may be applied to the skin by in unction. It is topical dosage form generally
consisting
of a hydrocarbon semisolid base, containing dissolved or suspended drugs. Ointments are usually
prepared
from fats, fatty oils, lanolin, petrolatum, paraffin, waxes, resins, glycols, higher alcohols, glycerin, water
by
mixing homogeneously other drugs with the foregoing materials as bases. Ointments are free from rancid
odor.
Cream: Semisolid emulsion system with opaque appearance. It may be a water in-oil or oil in – water
type. It
is high fat portion of milk. It is pale yellow and is used in making whipped cream. Creams are formulated
to
provide preparations that are necessary and essentially miscible with the skin secretion. They are intended
to
be applied to the skin or certain mucous membranes for protective, therapeutic or prophylactic purpose
especially where an occlusive effect is not necessary.
Purpose of Coating: Coating is like a cover of core tablets. To protect the tablet from light, moisture,
temperature and finally for the elegance of the product. Coating of a tablet using powdered granule. It is
prepared by feeding previously compressed tablets in to a special machine and compressing another
granulation layer around the preformed tablets. Oral tablet coated with a sugar or film coating. The
purpose of
coating arei)
To mask bitter and unpleasant taste and odor and color of the drug
ii) To overcome stomach or Gastric irritation
iii) To overcome decomposition of the drug
iv) To maintain prolong action
v) To make tablets shape smooth
vi) Improved esthetic qualities of the product
vii) Enabling the product to more easily swallowed by the patient and improving product stability.
viii) To provide physical and chemical protection for the drug.
ix) To incorporate another drug or formula adjuvant in the coating to avoid chemical incompatibilities
or the provide sequential drug release.
x) Modifying drug release characteristics and to improve the pharmaceutical elegance by use of
special colors and contrasting printing.
Ref. Standard: Ref. Standard are the primary standard, which are established, held distributed by the
appropriate international and national organization. Ref. standard is the material with which the test
material
is to be compared before deciding about its quality. Ref. Standards prepared by the producer should be
tested,
released and then stored in the same way as official standards. Ref. Standards may be available in the
form of
official standards.
Working Standard: Working standard are preparation in the laboratory, whose potency have been
determined by an adequate number of comparative tests in relation to the relevant primary standard.
Working
standard may be established by the application of appropriate tests and cheek at regular intervals to ensure
standardization.
LOD: Loss on drying. It is the expression of moisture content on a wet-weight basis. The loss of drying
test is
a method to measure the loss in weight of the sample when dried under the conditions specified in each
monograph. This method is applied to determine the amount of water, all or a part of water of
crystallization
or volatile matter in the sample, which is removed during the drying. The description for example not
more
than 1% (1 gm, 105º, 4 hours) in a monograph. On a wet-weight basis the water content of a material is
calculated as a percentage of the wet solid. The water lost by evaporation is read directly from the percent
LOD scale. It is assured that there are no other volatile materials present. LOD is calculated as follows:
MC: MC stands Moisture Content. It is the measurement of the moisture in a wet solid. Calculated on a
dryweight
basis. This value is referred to as moisture content or MC. The MC value change from slightly above
0% and approach infinity. MC is a for realistic value than LOD in the determination of dryer load
capacity.
SD (Standard Deviation): The standard deviation (σ) is the square root of the mean of the sum of the
square
of the difference between the value of the mean of those values and of the particular value in connection
with
the normal distribution. Statistical calculation for expressing the variability or spread of data is SD. The
larger
the spread of the numbers in a data set, the larger the standard deviation. It is the square root of the
variance.
In analytical chemistry one of the most common Statistical terms employed is the Standard Deviation of a
population of observation. This is also called the root mean square deviation as it is the square root of the
mean of the sum of the squares of the difference between the values and the mean of those values and is
of
particular value in connection with the normal distribution.
RSD (Relative Standard Deviation): The square of the standard deviation is called the variance. A further
measure of precision, known as the Relative Standard Deviation is given by: RSD = s/x Relative Standard
Deviation is Standard Deviation divided by Arithmetic mean. RSD = s/x Where S= Standard Deviation, x
=
Mean value.
GMP: Good Manufacturing Practice is that part of Quality Assurance which insure that products are
consistently produced and controlled the quality, standards appropriate to their intended use and required
by
the marketing authorization or product specification.
S.O.P.: A written authorized procedure that gives instruction for performing operation not necessary
specific
to a given product or materials, but of amore general nature (e.g. Equipment operation, maintenance and
cleaning, cleaning of premises and environmental control, sampling and inspection, etc) Certain standard
operation procedure may be used to supplement the product specific master and batch production
documentation.
Method Validation: Method validation is the process used to confirm the analytical procedure employed
for
the specific test is suitable its intended uses.
Master Formula: Documents used in pharmaceutical manufacturing generally containing the name,
description, strength of a product, batch size, a complete test of ingredients, quantities of ingredients,
specification of each ingredients used in product, theoretical yield, manufacturing and control instruction,
containers labeling and packing materials.
Stability study: It is the study to determine the self-life of a product how much time the product remain
stable in the market and confirm with product specification meet the pharmacopoeia limit.
Specification: A document giving a description of a starting material, packing material, intermediate bulk
or
finished product in terms of its chemical, physical and biological characteristics.
In process control: Tests, Cheeks and measurements made during the course of manufacture that result
and
product will comply with its specification.
Can any deviation be changed into the change control?

Ans-Only planned deviations are changed into change controls.
What is the difference of vacuum pressure and vapor pressure?
Vaccum pressure is negative pressure exerted under space that is partially
exhausted by artificial means at respective temperature (such as an air pump).
Vacuum pressure is measured relative to ambient atmospheric pressure. It is
referred to as pounds per square inch (vacuum) or psiv.
Vapour pressure is the pressure exerted by vapour in thermodynamic equilibrium

with its condensed phases (solid or liquid) at a given temperature in a closed
system. Its unit is Pascal (Pa).
In Stability testing if significant change occurs then what will be the action plan?
If it is at Development stage, then Formulation change or packaging change shall
be done if it at Exhibit batch study, then that should be addressed as OOT/OOS
and same should be investigated. Then shall go for change in formulation or
packaging. If it is at commercial batches then same should be addressed as
OOS/OOT and should investigate. Based on study product should recall
What do you mean by MKT ﴾Mean Kinetic Temperature﴿ in stability?
Mean Kinetic Temperature is defined by the USP as "the single calculated
temperature at which the total amount of degradation over a particular period is
equal to the sum of the individual degradations that would occur at various
temperatures. Thus, MKT may be considered as an isothermal storage temperature
that simulates the non isothermal effects of storage temperature variations. It is not
a simple arithmetic mean. MKT is calculated from temperatures in a storage
facility.
How to select HPLC column for a particular product?
If sample is basic then use BDS column & if acidic then use ODS column. the
column selection is depends upon the polarity of the sample or drug if in case the
drug is highly polar choose highly non-polar column (c18,c8) if in case the drug is
low polar choose the low non-polar column (cyno,c4)
sample polar then take --- non-polar column
sample non-polar then take ---polar column
It depends upon the properties and nature of analyze because selection of column
means selection of stationary phase. Furthermore it also depends on the type of
product i.e. multiactive (more than one active), needs a better resolution of peaks
by increasing column length.
What is the composition of a C18 column?
Octadecyl carbon chain bonded silica
What is validation, validation protocol and validation master plan?
Validation: Action of proving and documenting that any process, procedure or
method actually leads to the expected results.
VP: The VP is a written plan stating how validation will be conducted, including
test parameters, product characteristics, and production equipment and decision
points on what constitutes acceptable test results.
V M P: VMP is a high level document that establishes an umbrella validation

plan for the entire project and summarizes the manufacturer’s overall philosophy
and approach, to be used for establishing performance adequacy. It provides
information on the manufacturer’s validation work programmed and defines
details of and time-scales for the validation work to be performed, including
stating the responsibilities relating to the plan.
How much the minimum recovery should be in swab sampling?
85% is minimum limit for the swab recovery. General Limit is 85%-115%
What is the acceptance criterion for detergent washing?
Acceptance criteria: NMT 10ppm
What do you mean by LOD and water content?
LOD is the loss during drying of sample as per prescribed conditions which gives
loss (presence) of all evaporating solvents along with water. It is the dry base.
While water content gives the moisture present in the sample only. It is anhydrous
base.
What do you mean by Q+5 in dissolution?
Q is the specification limit (the mean of individual tablets tested should be not less
than Q) of the dissolution test.
Q+5 is the criteria for which the dissolution passing with 6 tablets at S-1 stage
(optimum release).:
What should be the sampling point in dissolution test?
There is no specific recommendation for sampling in
dissolution test. It is recommended that a specimen should
be withdraw from a zone midway between the surface of the
Dissolution Medium and the top of the rotating basket or
blade, not less than 1 cm from the vessel wall.
Where multiple sampling times are specified, replace the

aliquots withdrawn for analysis with equal volumes of fresh
Dissolution Medium at 37°C or, where it can be shown that
replacement of the medium is not necessary, correct for the
volume change in the calculation.
Specimens are to be withdrawn only at the stated times

within a tolerance of ± 2%.
Which will give more drug release paddle or basket in dissolution?
Paddle will be the best option as we know greater the surface area, greater will be
the volume of water-better for dissolution.
What is the difference between Drug Purity and Drug Potency?
Potency is a measure of drug activity expressed in terms of the amount required to
produce an effect of given intensity.
Purity is a measure of the amount of API present in a sample compared to those of

related substances, impurities, residual solvents, etc.
What should be the minimum limit of a working standard?
All values may comply with the predefined specifications. It’s
no need that its assay closes to 100%.
What is the storage condition for reference standard?
It is depend on the nature of the material. Most of the
standards are store at Room Temperature. Some Standards
which are degradable at Room Temperature, those are store in
Refrigerator or Freezer. Liquid stage standards are store
depends on it stability at various conditions.
Why we use the placebo in analysis?
Placebo consist of Excipient other than active ingrediant.While performing assay
or RS we analyze placebo to find out if there is any interference of Excipient with
main drug analysis. So that method is accurate.
How can you fix the known and unknown impurity limit for any drug substance?
The limits for a known impurity shall be fixed based on the
toxicology data of the impurity and the dosage of the drug
product; where as for the unknown impurity is based on the
dosage of the product.
How do we choose HPLC or Gas chromatography for a sample analysis?
It is based on.
Polarity
volatility
thermo stability
solubility......
Why 3X sampling plan are implemented in process validation?
3 sampling plans are implemented in process validation because the results are
1-accidental
2-co incidental
3-conformational
some times there might be chances for 4th batch also but it is cost effective and
time consuming process.
What is the difference between temporary change control and deviation?
In Short,
Deviation is an unplanned change
Change Control is a planed change after assessing the
impact on the other functions.
Why we use toluene for resolution in UV calibration?

Bcoz toluene gives maxima and minima at 266nm and 269nm to
check resolution in UV calibration and we use hexane as
diluents because it has no UV absorbance.
What is pooled sample and why it is required in dissolution test?
it is the primary requirement, the sample should completely expose to dissolution
media at all the surfaces....Pooled sample is in completely exposure to the
dissolution fluid....That's why we use basket apparatus for the floating samples. in
order to know how much drug is dissolved or disintegrated in the dissolution
medium
Why we use disodium tartare for determination of factor in Karl ficher.
Karl Fischer titration method is used to for the
titrimetric determination of water in samples. Because of
KF reagent undergoes the slow deterioration, the reagent
has to be standardized frequently, before going for the
water determination in sample.
Disodium Tartrate is used as a primary standard substance

for the standardization because of the following properties:
1. Available in a stable crystalline hydrate form

2. Its water content is close to theoretical value
3. Substances in nearly 100% purity
4. More favorable gravimetric factors
5. Stable at extreme humidifies
6. It is relatively insoluble in absolute methanol
7. Its water content is rapidly and quantitatively titrated
to a sharp end point
What are closely monitor parameters in stability study?
Temperature and humidity
What does u mean by MACO & NOEL?
MACO-max allowable carries over
NOEL-no observed effect leve; both of them are set limits for cleaning validation
Composition of c18column
Octa di acyl silane
How to select columns for specific products

Polarity, Electrical charge, Molecular size.
Normal phase is recommended for water sensitive compounds/geo metric
isomers/cis-transisomers/chiral compounds/class separations Reverse phase
for non polar /polar/ ionizable /non ionizable molecules Gel permeation for large
size compounds like polymers Ion exchange for resins
4) Define validation/validation protocol/validation master plan
Validation protocol:-
it is written plan describing the process to be validated ,including production

equipment & how validation to be conducted
Validation master plan:

it was also called as VMP which is one of important document in GM regulated
industries. it outlines the principles involved in qualification of facility, defining
areas &systems to be validated & provides written programmed for achieving &
maintaining qualified facility with validity processes
Validation:
it was defined as collection & evaluation of data from the process design
stage through commercial production which establishes scientific evidence that the
process is capable of producing quality product consistently
What is process validation?

Establishing documented evidence with high degree of assurance that specific
process will consistently produce a product meeting its predetermined
specifications & quality characteristics
What does u mean by MKT? MKT
Is an expression of cumulative thermal stress experienced by a product at varying
temperatures during storage & distribution?
Temp & humidity required for tablet compression?

Temp: - NMT 30
Humidity: - 45 +/- 5
8) What is humidity & relative humidity?

Humidity- it was amount of water vapour in air Relative humidity - the
amount of water vapour present in air expressed as % of amount needed for
saturation at the same temp
9) What is vaccum & vapour pressure?
Vaccum pressure
It was a pressure below normal atmospheric pressure which will be used to
remove air from surrounding ex: vaccum pumps
Vapor pressure
- It was pressure exerted by a vapor in thermodynamic equilibrium with its
condensed phases (solid/liq) at a given temp in closed system
10) What are stability zones & climatic conditions?
Zone-1: great Britain/north Europe/Canada/Russia (temp-21

RH-45%) (Moderate region)
Zone-2: USA/Japan/South Europe (temp-25 RH-60%) (Subtropical region)
Zone-3: Iran/Iraq/Sudan (temp- 30 RH- 55%) (Hot region)
Zone-4: Brazil/Ghana/Indonesia /Nicaragua/Philippines (temp-30 RH -70%)

(Tropical region)
11) What does u mean by bracketing & matrixing in stability studies?
Bracketing
: It was design of stability schedule such that at any time point only the samples on
extremes e.g. of container size/dosage strength are studied
Matrixing
: It was statistical design of stability schedule only a fraction of total number of
samples is tested at any sampling point. At a subsequent sampling point, different
sets of samples of total numb would be tested
12) What is limit of cleaning validation?

It should be visually clean & no residue should be visible after cleaning No
more than 10 ppm of product will be appear in another product No more than 0.1%
of normal therapeutic dose of one product will appear in max daily dose
of subsequent product
13) What is lod & water content LOD:

it is loss of weight expressed as w/w resulting from water & volatile matter of any
kind that can be driven off under specified conditions
WATER CONTENT:
It is the amount of water to be present in a sample of drug compounds
14) What is the difference between LOD & Water content Lod:
It was determined by heating the sample below its melting point in an oven & it
includes all volatile matter including water content & solvents
Water content:
It was determined by KF titration & it consist only water content
15) What are difference b/w calibration& validation& qualification?
Calibration
- The set of operations that establish under specified conditions the
relationship b/values indicated by an instrument or system for measuring and
corresponding values of ref.standerd
Validation
Action of proving & documenting that any process actually & consistently leads to
expected results
Qualification
- action of proving & documenting that any premises ,systems & equipments are
correctly installed & lead to expected results
16) DEFINE CAPA

Corrective and preventive actions
17) In Kf Titration Why We Have to Use Di Sodium Tartrate

Both water & di sodium Tartrate is generally used for standardization of kf reagent
as we going to check capacity of 1ml of kf reagent to neutralize water. Hence
water content in standardization is very imp one .as di sodium Tartrate contains
15.66% of hydrate it was recommended for standardization instead of water
18) What is formula of kf standardization
Weight of sample x 1000/ titration volume
19) what type of columns are used in GC
Capillary & open tubular columns
20) Any deviation can be changed into change control
Yes planned deviations
21) Why we shouldn’t dispatch reprocess material to export
Becoz there may be chances out of specification of product like increase in

impurity than its limit
22) What is the difference between sonication & homogenization?
Sonication is the process of making soluble of UN dissolved particles by degassing

while homogenization is the process of making uniform solution
24) What is the procedure to prepare placebo
Take all raw materials other than active ingredient & mix it
25) What is stationary phase?
It was substance inside of a column through which mobile phase flows during
separation process
26) What does u mean by end capping?
A column is said to be end capped when a small silyating agent is used

to bond residual silanolgroups on packing surface
27) How much min recovery should be in swab sampling?

General limit 85-115% but in swab sampling it should be 85%
28) What are closely monitor parameters in stability study?
Temp & humidity

29) What is photo stability?
It was study performed to evaluate & demonstrate that light exposure doesn’t result in
unacceptable change in new drug substances
31) What is the wave length of polarimeter lamp?
589.3 nm
32) In stability testing if significant change occurs what will be the action plan
During stability testing the term “significant change “is used only in case of drug
products .when it
Occurs then do the out of trend analysis
33) What should be the min level of working standard?
All values may complied to predefined specifications .it’s no need that its assay
close to 100%
34) How we fix validity period of volumetric solution & re-standardization

due date
Protocol shall be prepared for to establish the re standardization date

for volumetric solution. Date shall be fixed on the basis
of standardization study of volumetric solution on fixed or predefined in
protocol interval e.g.: 1/2/3/7/15 days etc. the % rsd shall be NMT 0.2% at
all intervals
35) What is DT for dispersible tablets?
3mins
36) What should be the sampling point in dissolution testing?
There is no specific recommendation for sampling in dissolution test. It is

recommended that specimen should be withdraw from a zone midway between
surface of dissolution medium &top of rotating basket
/blade NLT 1cm from vessel wall where multiple sampling times are specified,
replace the aliquots withdrawn for analysis with equal volumes of dissolution
medium at 37 or where it can be shown that replacement of medium is not
necessary, correct for the volume change in calculation Specimens are to be
withdrawn only at stated times within tolerance of +/-2%
37) What is DT for enteric coated tablets?
2 hrs in gastro intestinal simulated fluid & 1 hr in phosphate buffer
38) What is DT for coated tablets?
30-45 mins
39) What is the difference between method validation & verification?
Method validation
It is validation of method we adopt
Method verification
: Its high degree of assurance to verify
40) What is the difference between drug purity & potency?
Purity: it is the absence of unwanted substances like impurities & contaminants

Potency: it is a measure of drug activity measured in terms of amount of drug
required to produce an effect
.
41) Why pooled sample is required in dissolution test
It is the primary requirement, the sample should completely expose to dissolution

media at all surfaces .pooled sample is in completely exposure to dissolution fluid that’s
why we use basket apparatus for floating tablets.
42) Which will give more drug release paddle or basket dissolution?
Paddle as we know greater the surface area greater will be volume of water better
for dissolution
43) Which gases are used in GC
Helium & nitrogen
44) What is the difference between polarimeter lamp & ir lamps?
Polarimeter lamp emits the polarized light which in range of visibility (400-
700nm) while it lamp emits radiation in ir range (I -1000 micro meters)
45) What is the difference b/w temp change control & deviation?
Temp change control: it’s planned change after assessing the impact on other
functions Deviation: unplanned change
46) What is the difference b/w uniformity of content & content of uniformity?
Both terms are same & they are analyzed by individual assay
47) What is limit of friability of tablets?
Friability is used to determine physical strength of tablet during packing &

transporting with help of friabilator. For this test accurately weigh 10 tabs & place
them in rotating drum of friabilator at 25 rpm& it was rotated for 100 times & then
remove the tabs & weigh the tabs now. The sample fails test if anyone of them
cracked /cleaved/broken. If the wt loss is >1 % then test will be repeated so 1%
weight variation will be acceptable in friability of tabs
48) What is the relative response factor in related substances?
It is resonance of peak with respect to main peak response
49) How do we choose hplc /GC for sample analysis?

Depending upon compound nature, degradation, polarity, solubility, molecular
weight, volatile nature, thermal degradation etc
50) What is recovery factor?
It is used for cleaning validation by following formula% recovery = area

of individual swab level x STD dilution/area of corresponding STD
solution sample dilution x 100
51) Define pka
It’s an equilibrium constant used for dissociation of weak acid, & also known as
acid ionization constant
What is friability?
Ans: The percentage of loss mass of a solid dosage form after 100 times revelation in 4 minutes due to
friabilizer is
called Friability. A maximum loss of mass (obtained from a single test or from the mean of 3 tests) not
greater than 1.0
per cent is considered acceptable for most products.
2. Why it is important test for a solid dosage form?
Ans: It is also called breaking strength of the solid dosage form. It is important incase of transport of solid
dosage form
like tablet. The successful coating of tablet is also depending on the friability of the tablet.
Friability is important for Coating, Blistering and Transport stage.
3. How we are determined friability?
Ans: Use a drum, with an internal diameter between 283-291 mm and a depth between 36- 40 mm, of
transparent
synthetic polymer with polished internal surfaces, and subject to minimum static build-up. One side of the
drum is
removable. The tablets are tumbled at each turn of the drum by a curved projection with an inside radius
between
75.5-85.5 mm that extends from the middle of the drum to the outer wall. The outer diameter of the central
ring is
between 24.5-25.5 mm. The drum is attached to the horizontal axis of a device that rotates at 25 ± 1 rpm.
Thus, at
each turn the tablets roll or slide and fall onto the drum wall or onto each other.
For tablets with a unit mass equal to or less than 650 mg, take a sample of whole tablets corresponding as
near as
possible to 6.5 g. For tablets with a unit mass of more than 650 mg, take a sample of 10 whole tablets. The
tablets are
carefully dedusted prior to testing. Accurately weigh the tablet sample, and place the tablets in the drum.
Rotate the
drum 100 times, and remove the tablets. Remove any loose dust from the tablets as before, and accurately
weigh.
4. What is the unite of friability?
Ans : There is no unit for friability its explain only by percentage.
Hardness
5. What is hardness?
Ans:Required energy for break a Solid dosages form on their edge.
6. What is the unit of hardness?
Ans: KG, Newton ,Kilo poise
What is pH?
Ans: pH/pOH is the negative logarithm of Hydrogen ion/Hydroxyl ion concentration. Mathematically it may
be
represented as followspH
= - log [ H+ ].
pOH = - log [OH+ ]
10. Why pH is important in pharmaceuticals?
Ans: pH is important in pharmaceuticals because some active ingredient is stable in one pH and degrades
in another
pH. So incase of product stability pH is an important factor.
Buffer action
Ans: The resistance of buffer solution to changes in hydrogen ion concentration upon the addition of small
amount of
acid or alkali is termed buffer solution
Dissolution
13. What is dissolution?
Ans: The process by which the solid particle or medicament are dissolve in suitable solvent for ease of
absorption.
14. Difference between Dissolution and assay?
Ans: Dissolution is the amount of drug released in a certain period of time from a dosage form on the other
hand
Assay is the amount of drug that is contained by a unit dosage form of medicament. The amount of drug
that is
contained by a unit dosage form of medicament may not be released completely after a certain period
of time.
15. Why it is important character of a tablet & capsule?
Ans: Tablet & Capsule are solid dosage form. Unless dissolve the content of the Tablet or Capsule in a
suitable solvent
it cannot be reached in the systemic circulation by absorption. For this reason dissolution is important
character of
Tablet & Capsule that is solid dosage form. Simulated Gastric Fluid (SGF) & Simulated Gastro Intestinal Fluid
(SIGF) are
widely used as dissolution media.
16. The dissolution media of tablet and capsule? Why it is different?
Ans: The commonly used dissolution media of tablet & capsule are Simulated Gastric Fluid (SGF) &
Simulated Gastro
Intestinal Fluid (SIGF). They are deferent because some drug are dissolve in Gastric pH and some drug are
dissolve in
intestinal pH.
17. Working procedure of dissolution
Under Monographs of the British Pharmacopoeia in Appendix XII B1, the following conditions using the
basket or
paddle apparatus are preferred.
— rotation speed:100 rpm (basket), 50 rpm (paddle)
— dissolution medium volume: 900 ml
— dissolution medium composition: aqueous, commonly 0.1M hydrochloric acid or phosphate buffers of
pH 6.8 to 7.6
— number of units tested: 6 (plus 6, if a retest is required).
The number of units tested is specified in Appendix XII B1; other conditions are specified in the relevant
individual
monographs.
What is disintegration? Importance in pharmaceuticals dosage form?

Ans: Breakdown of unit solid dosage form or larger granules into smaller one (smaller than 2 mm). In most
cases
dissolution is directly proportional to the disintegration. More faster the solid dosage form disintegrates,
more faster it
dissolve and goes into the systemic circulation and gives the therapeutic response.
20. Official limit of different types of tablet?
Ans: The official limit of disintegration for uncoated Tablet is not more then 15 minutes and for coated
Tablet is not
more then 30 minutes. For enteric coating it 2 hrs remains intake in Gastric Simulated Fluid and after that
disintegrate
in Intestinal Simulated Fluid within 1 hrs)
Viscosity
21. What is viscosity? The unit of viscosity
Ans: The dynamic viscosity or viscosity coefficient h is the tangential force per unit surface, known as
shearing stress t
and expressed in pascals, necessary to move, parallel to the sliding plane, a layer of liquid of 1 square
metre at a rate
(v) of 1 metre per second relative to a parallel layer at a distance (x) of 1 metre.
The kinematics viscosity v, expressed in square metres per second, is obtained by dividing the dynamic
viscosity by the
density expressed in kilograms per cubic metre, of the liquid measured at the same temperature, i.e. v =
h/r. The
kinematics viscosity is usually expressed in square millimeters per second.
A capillary viscometer may be used for determining the viscosity of Newtonian liquids and a rotating
viscometer for
determining the viscosity of Newtonian and non- Newtonian liquids.
Density : Resistant of a fluid to flow.
1. What is validation? What is the importance of validation in pharmaceutical industry?

Validation is a documented evidence which provides a high degree of assurance that a specific process,
method or
system will consistently produce to the required specification in accordance with accepted standards of
cGMP.
Importance of Validation :
a) In pharmaceutical industry the validation is required for national or international regulations
b) Validation is a part of integrated requirements of a quality system
c) Validation meets the consistency of quality product in all stages
2. What do you mean by Prospective, Retrospective and Concurrent validation?
Prospective : A prospective process validation states that three consecutive marketed batches are
manufactured &
tested as per prospective process validation SOP. Validation data has generated by validation committee.
When all data
are fully satisfied then this product are released for sale & called this process is validated to use routinely
in
production.
Retrospective : A retrospective process validation are performed by documenting all the historical
information of
existing 10 products using trend analysis data in QCMS system & its ensures that the existing process is
under control.
Concurrent validation : Concurrent validation is carried out during routine production. This method is
effective only if
the development stages have resulted in a proper understanding of the fundamental of the process. Some
manufacture
refers the concurrent validation as Prospective process validation.
3. Write the basic requirements of cGMP/GLP?
Good Manufacturing Practice is that part of Quality Assurance which ensures that products are
consistently produced
and controlled to the quality standards appropriate to their intended use and as required by the Marketing
Authorization or product specification.
Good Manufacturing Practice is concerned with both production and quality control. The basic
requirements of GMP
are that -
a. appropriately qualified and trained personnel;
b. adequate premises and space;
c. suitable equipment and services;
d. correct materials, containers and labels;
e. approved procedures and instructions;
f. suitable storage and transport;
4. What do you mean by DQ, IQ, OQ, & PQ ?
Design Qualification (DQ): documented verification that the proposed design of the facilities, equipment,
or systems is
suitable for the intended purpose.
Installation Qualification (IQ): documented verification that the equipment or systems are installed or
modified &
comply with the approved design of the manufacturer’s recommendations and/or user requirements.
Operational Qualification (OQ): documented verification that the equipment or systems are installed or
modified &
perform as intended throughout the anticipated operating ranges.
Performance Qualification (PQ): documented verification that the equipment and ancillary systems are
connected &
can perform effectively and reproducibly based on the approved process method and specifications.
5. Define complaint & recall.
All quality related complaints of a product from the market should be recorded & investigated
accordingly to a
written procedure.
Recall is the removal from the market of specified batches or all batches of a product. A recall situation
can result from
information entering a company in various ways:
• Customer complaints – these may be so serious as to initiate a recall. An example could be the
evidence of a lack of sterility
• GMP deviations/results of a failure investigation
• The result from the QC stability programme
• Request by the regulatory authorities
• Result of an inspection
• Known counterfeiting or tampering
• Adverse drug reaction (ADR) reported, leading to a recall decision (however, an ADR does not
automatically lead to a recall).
6. Define Corrective Action & Preventive Action ?
Preventive Action : In order to prevent occurrence the potential action has to be taken from non
conformity,
defect or other undesirable situation.
Corrective Action : Action has to be taken to eliminate the detected non conformity or other undesirable
situation.
7. What is In Process Control ? Why it is important ?
To ensure the product conformation of its specification, checking & monitoring are performed during
production. The controlled of the environment or equipment may also be regarded as part of in process
controlled.
Importance : It is important to adjust the process to assure that the product confirms to it final
specification.
8. What is Sanitation & House keeping?
Sanitation : It is the hygienic control on manufacturing process including personnel, premises, equipment
& material
handling.
Housekeeping is the practice of keeping the workplace clean, tidy & free of potential hazards. Correct
housekeeping is
practised before, during & after the task is completed.
9. What is self inspection?
Self inspections should be conducted in order to monitor the implementation and compliance with Good
Manufacturing Practice principles and to propose necessary corrective measures.
10. Define Stating Materials, Intermediate , Bulk & Finished Products :
Stating Materials : A starting material is known as raw material or an API. A substance is a defined
quality which used
in production of a pharmaceutical product & non-pharmaceutical product excluding packaging material.
Intermediate : A partly processed material that must undergo the further manufacturing steps before a
bulk product.
Bulk Product : Any product that has completed all processing steps up to but not including final
packaging.
Finished Products : A medicinal product, which has undergone all stages of manufacture including
packaging.
11. What is sampling? What standards are used for sampling?
Sampling should be conducted according to written procedures. Sampling Process are obtain from
finished
material, in-process material, raw material or components for assessment with a view to determining the
properties of
the universe from which they were drawn.
Sampling plan -
Specific design indicating number from each lot or batch are inspected & determined the acceptability the
lot or batch.
Military Standard 105E is frequently used for determining statistical sample size.
12. Write the differences between documents & records.
Documents : Documentation is a controlled written procedure, policy, forms or other pieces of paper as
defines a
company requirement. & describe how what to do.
Records : When data or results providing evidence of activities performed then it is record.
13. When and where revalidation is required ?
Revalidation means that the original validation program should be repeated at a predetermined frequency.
This work is
carried out 3 years interval & any change of critical steps or process.
i. Changes in raw materials (Physical parameters such as viscosity, density, moisture & Particle size
distribution)
may affect the products & process
ii. Changes in the sources of active raw materials manufacturer
iii. Changes in the packaging materials (Primary packaging/Closure system)
iv. Changes in the processes (e.g. mixing time, dry time, drying temp.& batch size)
v. Changes in the equipment (e.g. addition of automatic electric system)
vi. Changes in the plant or facility
vii. Variation revealed by trend analysis.
14. What are critical, major and minor defects of a product ?
Critical defect : Critical defect are those defect which can be life-threating & which require the company
to take
immediate action by all responsible means as soon as the defect becomes apart whether in or out of
business hours.
Example : 1. Products labeled with incorrect name.
2. Counterfeit or deliberately tampered with product/
3. Microbiological contamination of a sterile product
Major defect : Major defect are those defects which may put the patient at some risk but. Which are not
life-threating
Example : 1. Any labeling/leaflet misinformation which represents a significant hazard to the patient
2. Microbial contamination of non-sterile product with some risks.
Minor defect : Minor defect are those defects which present only a minor risk to the patient. Any batch
recall or
product withdrawal would normally be initiated a few days.
Example : 1. Readily visible isolated packing faults
2. Contamination which may cause spoilage or dirt & where there is minimal risk to the patient
15. What is sterilization? Mention the duration sterility test.
Sterilization is a process or technique to remove bacteria and all types of viable microorganism.
Duration : 14 days
16. Write the types of Sterilization.
Type of Sterilization:
Terminal Sterilization
1) Steam Heat sterilization
2) Dry Heat sterilization
Others sterilization
3) Gas sterilization
4) Sterilization by ionizing Radiation
5) Sterilizing by Filtration
6) Aseptic Processing
17. Write the functions & use of HVAC system.
Functions and use of HVAC
Heating, Ventilating and Air conditioning system is used for temperature and humidity control with in a
manufacturing
environment. It includes air handling units, air distribution network, air-cooling and heating system, air
filtration,
equipment control system, monitoring and alarm decreases
18. What is SOP? Why it is needed ?
SOP (Standard Operating Procedure)
A written approved procedure which gives instruction for performing operation not necessarily specific to
a given
product or material but of a more general matter (e.g. equipment operation, maintenance and cleaning of
premises, and
environmental and sampling and inspection).
Purposes: To describe the method for writing procedures for all general operations.
19. What do you mean by critical processing steps ?
Describes a process steps, process condition, test requirement or other relevant parameter or items that
must be
controlled within predetermined criteria to ensure that the API meets its specification.
20. Write the conditions of sterilization by Autoclave & DHS.
Condition of sterilization by Autoclave & DHS
121 0 C 15 lbs pressure per square inch 15 minutes
200 o C for 1 Hour.
21. What are the points to be checked during validation of DHS/ Autoclave?
Points to be checked during validation of DHS/Autoclave
Checked by biological indicator (Bacillus sublitis) and endotoxin indicator for DHS
Checked by biological indicator (Bacillus stearothermophilus).
21. What is Clean Room & Aseptic Area?
Clean Room
A room in which the concentration of airborne particles is controlled to meet specified airborne
particulate cleanliness
class. In addition, the concentration of microorganisms in the environment is monitored; is cleanliness
class defined is
also assigned a microbial level for air, surface, and personnel gear.
Aseptic Area
Any area in an aseptic process system for which airborne particulate and microorganism levels are
controlled to
specific levels appropriate to the activities conducted within that environment.
22. What is Air lock?
Airlock: An enclosed space with two or more doors, which is interposed between two or more rooms,
e.g. of differing
classes of cleanliness, for the purpose of controlling the airflow between those rooms when they need to
be entered. An
airlock is designed for use either by people or for goods and/or equipment.
23. What Is Site Master File ?
Site Master File
Site Master File is prepared by the manufacturer and contains specific information about the quality
assurance, the
production and/ or quality control of pharmaceuticals manufacturing operations carried out at the named
site and any
closely integrated operations at adjacent and nearby buildings. If only part of a pharmaceuticals operation
is carried out
on the site. A site master file need only describe those operations that is analysis packaging etc.
24. How to sanitize the Water Supply lines?
Sanitize the water supply lines
Sanitize by Steam flush and Chlorinization.
25. How to clean the Product Manufacturing Vessels?
Wash the vat with portable water. Rubbing the vat & lid with 1% sodium lauryl sulphate & then washing
the inner side
& outside with potable water. Washing the vat by hot water & then rinsing the vat with DM water.
Rubbing the vat
with 70% IPA.
26. How to clean the Product Manufacturing Vessels?
Vessels wash with Potable Water, then wash with 2% sodium laural sulphate, Hot water, Potable water
swab with 70%
IPA, finallay swab by cotton cloth.
27. What are the differences between Sanitization and Sterilization?
Sterilization
Sterilization is a process or technique to remove bacteria and all types of viable microorganism.
Duration: 14 days
Sanitization
Reduction the number of micro-organism to a safe or relatively safe level as determined by applicable,
regulations or
the purpose of application
28. What is 1° & 2° Standards?
1° Standard: A substance that has been authentic material should be of high purity.eg. K2Cr2O7,KI.
2° Standard: A substance of established quality and purity by comparison with primary reference
standard and used
as a reference standard for routine laboratory analysis.
29. What are the parameters of Analytical Method validation?
Accuracy, Precision, Specificity, Detection Limit, Quantitation Limit, Linearity & Range, Ruggedness &
System
suitability Testing.
30. Write short note on gram +Ve & gram –Ve bacteria ? which one is more pathogenic ?
Gram +Ve Bacteria
Gram +Ve bacteria are those that are stained dark blue or violate by gram staining. This is contrast to
gram –Ve .
Gram –Ve Bacteria
Gram –Ve bacteria are those bacteria that do not retain crystal violate dye in the gram staining protocol.
Gram –Ve bacteria is more pathogenic than gram +Ve.
31. Write Air classification on cleanliness of parentral preparation.
Air Classification on cleanliness of parentral preparation
Grade At Rest In Operation
Maximum permitted particles/ m3 = or above
0.5 μ 5μ 0.5μ 5μ
Grade A 3500 0 3500 0
Grade B 3500 0 350000 2000
Grade C 350000 2000 3500000 20000
Grade D 3500000 20000 Not Defined
32. Mention Moist Heat Sterilization period and temperature.
Moist Heat sterilization
Temperature : 1210 C
Duration : 15 minutes
Pressure : 15 lbs Pressure/Square inch
33. Which type of water are used in sterile preparation.
Water for Injection(Bulk)-
Characters-A clear, colorless, odorless and tasteless liquid.
Nitrates-Not more than 0.2 ppm
Heavy metals-Not more than 0.1 ppm
Conductivity-Conductivity at 20°C not more than 1.1 μS.cm-1.
Microbial Contamination-Total viable aerobic count should less than 10 micro-organism per 100 ml.
Absence of E.
Coli, Salmonella, Staphylococcus aureus & Pseudomonas.
Bacterial endotoxins-Less than 0.25 IU per ml.
34. What is the source of Endotoxin ? Write the source of Microbial Contamination of Product.
Source of Endotoxin
Gram –Ve bacterial cell wall.
Source of microbial contamination of a product
Person, Water, Air, RM, Rubber stopper, Glass Vial and Garments
35. Write the full meaning of DOP & HEPA and its efficiency.
DOP : Dioctyl Phthalate .Dioctyl Pthanate test is used to determine the integrity of HEPA filters.
HEPA: High Efficiency Particulate Air .High Efficiency Particular Air Filter (HEPA) is a filtering
system. HEPA filter
capable of retaining 99.97 percent of particles as small as 0.3 μm. It is a disposable, extended media dry
type filter in a
rigid frame.
Efficiency: 99.97%
36. What is QC and QA of a product ?
QA & QC are closely related, but they are different concepts. Quality Assurance Section is the total
organization made
with the objective of ensuring that pharmaceutical products are of the quality required for their intended
use .QA
therefore incorporates GMP and other factors such as product design and development, GLP and GCP.
Quality control is the process where the product is actually executed and the expected behaviour is
veritied by
comparing with the actual behaviour of the software under test. All the testing types like black box
testing, white box
testing comes under quality control.
Quality assurance is done before quality control. www.pharmatechbd.blogspot.com
37. What are the basic requirements of premises of pharmaceuticals production Area?
Premises of Manufacturing Area
1. Dedicated facilities
2. Logical flows of materials and people.
3. Adequacy of working space and orderly and logical positioning of equipment.
4. Interior surfaces smooth, crack-free and easy to clean.
38. What are the basic requirements of premises of pharmaceuticals product & RM Storage Area?
Premises of RM store Area
1. Storage areas of sufficient capacity
2. Clean, dry and maintained within acceptable temperature limit
3. QC sampling area with GMP standard
4. Segregated areas for rejected recalled and returned materials
5. Separate areas for highly active hazardous narcotics materials
Premises of Manufacturing Area
1. Dedicated facilities
2. Logical flows of materials and people.
3. Adequacy of working space and orderly and logical positioning of equipment.
4. Interior surfaces smooth, crack-free and easy to clean.
39. What is training ? Why it is needed ?
Training: Training is a tool/way to know something to increase our knowledge or skill.
Importance of training:
Training helps to provide an opportunity and broad structure for the development of human resources
technical and
behavioral skills in an organization. It also helps the employees in attaining personal growth.
40. What are the functions of Qualified and key personnel in a Pharmaceutical Industry ?
I. A qualified person must ensure that each batch has been produced & tested/ checked in accordance with
the
directives & marketing authorization
II. A qualified Person musr certify in a register or equivalent document as operations are carried out &
before
any release that each production batch satisfies under the requirement of GMP
Functions of key personnel in a Pharmaceutical Industry:
I. To ensure that the production records are evaluated and signed be an authorized person before they are
sent to
the QC department.
II. To check the maintenance of his department, premises and equipment.
III. To ensure that the appropriate validations are done.
IV. To approve or reject, as sees fit, starting materials, packaging materials. And intermediate, bulk &
finished
products.
V. To evaluate batch records.
VI. To ensure that all necessary testing is carried out
VII. To approve specifications, sampling instructions, test methods and Quality Control procedures.
VIII. To approve and monitor any contract analysis.
Difference between Incidence and Deviation
When we have any written procedure like standard operating procedure, protocol, standard
test procedure, BMR etc. and someone works against this, and then it is called deviation. It
means deviation from any written procedure that we have implemented.
Now deviation can be of two different types:
A) Planned Deviation
B) Unplanned Deviation
Planned deviations are those deviations from the procedure that are planned and we know
before they occur. For example: calibration or validation is not carried out as per schedule
due to delay for various reasons. In this case we have to fill CAPA for the same.
Unplanned deviation the failure of procedure, utility, material, equipment or any system is
occurred. We can consider it as any change from the previous or our written procedure.
Unplanned deviations may be critical, major or minor. These can be categorized on their
impact of product quality.
Critical deviations:
• Manufacturing instructions are not followed, wrong batch details are printed, SOPs
Or methods of testing not followed during analysis etc.
Major deviations:
• Line clearance is not taken from QA, physician sample wrongly printed with price, etc.
Minor deviations:
• Raw material is received in a damaged container, manometer readings in the sampling
booth are crossed the action limits etc.
Incidence is any event that can affect our product quality or not but that is against the
cGMP. For example: someone is found without gowning in the production area or any
insect is found in granulation area. These may have impact on product quality but not every
time, sometime it will not impact. These are the deviations from GMP but difference is that
these are not related to our manufacturing process. So these will not be categorized as
deviations.
Pharmaceutical Water
Introduction
Water is the one of the major commodities used by the pharmaceutical industry. It is widely
used as a raw material, ingredient, and solvent in the processing, formulation, and
manufacture of pharmaceutical products, active pharmaceutical ingredients (APIs) and
intermediates, and analytical reagents. It may present as an Excipient, or used for
reconstitution of products, during synthesis, during production of finished product, or as a
cleaning agent for rinsing vessels, equipment and primary packing materials etc. There are
many different grades of water used for pharmaceutical purposes. Several are described in
USP monographs that specify uses, acceptable methods of preparation, and quality
attributes. These waters can be divided into two general types: bulk waters, which are
typically produced on site where they are used; and packaged waters, which are produced,
packaged, and sterilized to preserve microbial quality throughout their packaged shelf life.
There are several specialized types of packaged waters,
differing in their designated applications, packaging limitations, and other quality attributes.
Different grades of water quality are required depending on the different pharmaceutical
uses.
There are also other types of water for which there are no monographs. These are all bulk
waters, with names given for descriptive purposes only. Many of these waters are used in
specific analytical methods. These nonmonographed waters may not necessarily adhere
strictly to the stated or implied modes of preparation or attributes.
Types of Water Used:

1. Non potable water:
Non-potable water is water that is not of drinking water quality, but which may still be used
for many other purposes, depending on its quality. Non-potable water is generally all raw
water that is untreated, such as that from lakes, rivers, ground water, springs and ground
wells.
Purposes:
• cleaning of outer surface of the factory
• used in garden
• washing vehicles etc
2. Portable water:
Portable water is not suitable for general pharmaceutical use because of the considerable
amount of dissolved solids present. These dissolved solids consist chiefly of the chlorides,
sulphates and bicarbonates of Na, K, Ca and Mg. A 100 ml portion of official water contains
not more than 100 mg of residue (0.1%) after evaporation to dryness on a steam bath.
Purposes:
• To use as drinking water
• Washing and the extraction of crude drugs
• Preparation of products for external use
3. Purified water:
Purified water is used in the preparation of all medication containing water except
ampoules, injections, some official external preparations such as liniments. Purified Water
must meet the requirements for ionic and organic chemical purity and must be protected
from microbial contamination. The minimal quality of source or feed water for the
production of Purified Water is Drinking Water.
Purposes:
• For the Production of non-parenteral preparation/formulation
• For the Cleaning of certain equipment used in non-parenteral product preparation
• For Cleaning of non-parenteral product-contact components
• For All types of tests & assay
• For the Preparation of some bulk chemicals
• For the preparation of media in microbiology laboratories
Preparation technique:
• Deionization
• Distillation
• Ion exchange
• Reverse osmosis
• Filtration etc.
4. Water For Injection (WFI):
Water for Injection is a solvent used in the production of parenteral and other preparations
where product endotoxins content must be controlled, and in other pharmaceutical
applications Water For Injection (WFI) is sterile, non phylogenic, distilled water for the
preparation of products for parenteral use. It contains no added substance and meets all the
requirements of the tests for purified water. It must meet the requirements of the pyrogen
test. The finished water must meet all of the chemical requirements for Purified Water as
well as an additional bacterial endotoxins specification. Since endotoxins are produced by
the kinds of microorganisms that are prone to inhabit water, the equipment and procedures
used by the system to purify, store, and distribute Water for Injection must be designed to
minimize or prevent microbial contamination as well as remove incoming endotoxins from
the starting water. Water for Injection systems must be validated to reliably and consistently
produce and distribute this quality of water.
Purposes:
• For the production of parenteral products/formulation
• For cleaning of parenteral product-contact components
• Distillation
• Reverse osmosis
• Membrane process
Storage condition:
• It can be stored for periods up to a month in special tanks containing ultraviolet lamps.
When this freshly prepared water is stored and sterilized in hermitically sealed containers, it
will remain in good condition indefinitely.
• If autoclave is not available, freshly distilled water may be sterilized by boiling the water
for at least 60 minutes in a flask stopper with a plug of purified non absorbent cotton
covered with gauze, tin-foil or stout non absorbent paper; or the neck of the flask may be
covered with cellophane and tightly fastened with cord.
5. Sterile water for injection:
Its specifications are provided in USP monograph for water for injection, sterilized and
packaged in suitable single-dose containers, preferably of type I glass, of not larger than
1000 ml size. It meets the requirements of the sterility test and pyrogen test and other tests
under purified water.
Purposes:
• Used for extemporaneous preparation compounding
• Used as a sterile diluents for parenteral products
• By distillation of water for injection (WFI)
6. Bacteriostatic WFI:
This is sterile Water for Injection containing Bacteriostatic (antimicrobial) agents. It may be
packed in single-dose containers of not larger than 5 ml size and in multiple-dose containers
of not larger than 30 ml size, the label of which indicates the name and the proportion of
added agent.
Purposes:
• Used as a diluents in the preparation of parenteral products
• By using sterile water for injection
7. Sterile water for Inhalation:
Sterile water for Inhalation is Water for Injection that is packaged and rendered sterile and is
intended for use in inhalators and in the preparation of inhalation solutions. It carries a less
stringent specification for bacterial endotoxins than Sterile Water for Injection, and
therefore, is not suitable for parenteral applications.
Purposes:
• Preparation of use in inhalators
• Preparation of inhalant solutions
• By sterilization of water for injection
8. Sterile water for irrigations:
Sterile water for irrigations is Water for Injection packaged and sterilized in single-dose
containers of larger than 1 L in size that allows rapid delivery of its contents. It need not
meet the requirement under small-volume injections.
Purposes:
• To bath and moisten body tissue
• Performing urologic procedure for surgeon
• From water for injection
Example:
• Surgical irrigation solution (Splash solution)
• Urologic irrigation solution
• Glycine solution
• Sorbitol solution
9. Water for hemo dialysis:
Water for hem dialysis is used for hem dialysis applications. It may be packaged and stored
in uncreative containers that preclude bacterial entry. The term “unreactive containers”
implies that the container, especially its water contact surfaces, are not changed in any way
by the water, such as by
leaching of container-related compounds into the water or by any chemical reaction or

corrosion caused by the water. The water contains no added antimicrobials and is not
intended for injection.
Purposes:
• For the dilution of hem dialysis concentrate solution
• From safe drinking water
10. Pure steam:
Pure steam is also sometimes referred to as “clean steam”.
Purposes:
• To remove any co-deposited impurity residues
• For air humidification in controlled manufacturing environments
• Used in steam sterilization of equipment and porous loads
• For cleaning the places where condensate directly comes in contact with official articles,
product
contact containers, and surfaces.
Water miscible solvents:

Although water miscible solvents are used in parenterals, principally to enhance drug
solubility, it is important to mention that they also serve as stabilizers for those drugs that
degrade by hydrolysis. A water miscible solvent must be selected with grade care for it must
not be irritating, toxic, or sensitizing, and it must not exert an adverse effect on the
ingredients of the formulation. Solvents that are miscible with water are:
• Dioxolanes
• Dimethylacetamide
• Butylenes glycol
• Polyethylene glycol 400 and 600
• Propylene glycol
• Glycerin and
• Ethyl alcohol
Water immiscible solvents include:

• Fixed oil
• Ethyl oleate
• Isopropyl myristate, and
• Benzyl benzoate.
Specification of Water
Specification of Distilled Water/Water for Injection
S. No Parameters Specifications
1. Appearance clear, colorless, no visible particles
2. Odor Odorless
3. pH 5.0-7.0
4. Acidity or alkalinity NMT 0.1 ml of 0.01M NaOH/Hcl
5. Chloride 0 ppm
6. Oxidizable Substances 0 ppm
7. Sulphate 0 ppm
8. Total hardness 0 ppm
9. Total dissolved solid NMT 10.0 ppm
(TDS)
10. Conductivity NMT 0.1ms
11. Microbial count 10 cfu/100 ml
II. Specification of Purified Water
2. Odor Odorless
3. pH 5.0-7.0
5. Chloride 0 ppm
7. Sulphate 0 ppm
9. Ammonia 0.2 ppm
10. Heavy metal 0.1 ppm
11. Nitrate 2.0 ppm
12. Total dissolved solid NMT 1.0 ppm
(TDS)
13. Conductivity NMT 1.0ms
14. Microbial count 100 cfu/ ml & absence of pathogenic
bacteria
III. Specification of Portable water
S. Parameters Specifications
No
2. Odor Odorless
3. pH 6.5-8.5
4. Chloride NMT 250 ppm
5. Aluminum 0.2 mg/L
6. Arsenic 0.01 mg/L
7. Fluoride 1.5 mg/L
8. Boron 0.3 mg/L
9. Sulphate NMT 400 ppm
10. Sodium NMT 200 ppm
11. Copper NMT 1.0 ppm
12. Total hardness NMT 500 ppm
13. Total dissolved solid NMT 1000 ppm
(TDS)
14. Iron content NMT 0.3 ppm
15. Turbidity (as SiO2) NMT 5.0 ppm
16. Dissolved oxygen NMT 5.0 ppm
17. Manganese NMT 0.1 ppm
18. Arsenic NMT 0.05 ppm
19. Lead NMT 0.1 ppm
20. Total alkalinity NMT 500 ppm
21. Suspended solid (Rust, 0 ppm
Mud, Particles etc)
22. Microbial count 500 cfu/ ml & absence of pathogenic
bacteria
IV. Specification of sterile Water for Injection
2. Odor Odorless
3. pH 5.0-7.0
5. Chloride 0 ppm
7. Sulphate 0 ppm
9. Ammonia 0.2 ppm
10. Heavy metal 0.1 ppm
11. Nitrate 2.0 ppm
12. Total dissolved solid
(TDS):
13. Conductivity NMT 1ms
Non-sterile Process Validation in Pharmaceuticals

1. Principle
1.1 Process validation provides documented evidence that a process is capable of reliably
and repeatedly rendering a product of the required quality.
1.2 The principles of planning, organizing and performing process validation are similar
to those for qualification. It should be done in accordance with process validation
protocols; data should be collected and reviewed against predetermined acceptance
criteria, and reflected in process validation reports.
2. Scope
2.1 These guidelines describe the general aspects of process validation for the manufacture
of non-sterile finished products.
2.2 Normally process validation should cover at least the critical steps and parameters (e.g.
those that may have an impact on the quality of the product) in the process of manufacturing
a pharmaceutical product.
2. General
3.1 The policy and approach to process validation should be documented, e.g. in a validation
master plan, and should include the critical process steps and parameters.
3.2 Process validation should normally begin only once qualification of support systems and
equipment is completed. In some cases process validation may be conducted concurrently
with performance qualification.
3.3 Process validation should normally be completed prior to the manufacture of finished
product that is intended for sale (prospective validation).
Process validation during routine production may also be acceptable (concurrent validation).
3. Prospective validation
4.1 Critical factors or parameters that may affect the quality of the finished product should be
identified during product development. To achieve this, the production process should be
broken down into individual steps, and each step should be evaluated (e.g. on the basis of
experience or theoretical considerations).
4.2 The criticality of these factors should be determined through a “worst-case” challenge
where possible.
4.3 Prospective validation should be done in accordance with a validation protocol. The
protocol should include:
— a description of the process;
— a description of the experiment;
— details of the equipment and/or facilities to be used (including measuring or recording
equipment) together with its calibration status;
— the variables to be monitored;
— the samples to be taken — where, when, how, how many and how much
(sample size);
— the product performance characteristics/attributes to be monitored,
together with the test methods;
— the acceptable limits;
— time schedules;
— personnel responsibilities; and
— details of methods for recording and evaluating results, including statistical analysis
Been fully validated (e.g. during installation qualification and operational qualification).
4.5 Personnel participating in the validation work should have been appropriately trained.
4.6 Batch manufacturing documentation to be used should be prepared after these critical
parameters of the process have been identified, and machine settings; component
specifications and environmental conditions have been determined and specified.
4.7 A number of batches of the final product should then be produced. The number of
batches produced in this validation exercise should be sufficient to allow the normal extent
of variation and trends to be established and to provide sufficient data for evaluation.
4.8 Data within the finally agreed parameters, from at least three consecutive batches, giving
product of the desired quality may be considered to constitute a proper validation of the
process.
4.9 The batches should be of the same size, and should be the same as the batch size
intended in full-scale production. Where this is not possible, the reduced batch size should
be considered in the design of the protocol and when full-scale production starts, the validity
of any assumptions made should be demonstrated.
4.10 Extensive testing should be performed on the product at various stages during the
manufacturing process of the batches, including on the final product and its package.
4.11 The results should be documented in the validation report. As a minimum, the report
should include:
• a description of the process: batch/packaging document, including details of critical steps;
• a detailed summary of the results obtained from in-process and final testing, including data
from failed tests. When raw data are not included, reference should be made to the sources
used and where it can be found;
• any work done in addition to that specified in the protocol, or any deviations from the
protocol should be formally noted along with an explanation;
• a review and comparison of the results with those expected; and
• formal acceptance or rejection of the work by the team or persons designated as being
responsible for the validation, after completion of any corrective action or repeated work.
4.12 A conclusion and recommendation should be made on the extent of monitoring and the
in-process controls necessary for routine production, on the basis of the results obtained.
4.13 The conclusion and recommendation should be incorporated into the batch
manufacturing and batch packaging documents and/or standard operating procedures
(SOPs) for routine use. Limits and frequencies of testing and monitoring should be
specified. Actions to be taken in the event of the limits being exceeded should be specified.
4.14 Batches manufactured as part of the validation exercise, and intended to be sold or
supplied, should have been manufactured under conditions that comply fully with the
requirements of good manufacturing practice and the marketing authorization (where
applicable).
5. Concurrent validation
5.1 In certain cases, it may be appropriate to validate a process during routine production,
e.g. where the product is a different strength of a previously validated product, a different
tablet shape or where the process is well understood.
5.2 The decision to carry out concurrent validation should be made by appropriately
authorized personnel.
5.3 It is essential that the premises and equipment to be used during concurrent validation
have been previously qualified.
5.4 Prospective validation should be done in accordance with a validation protocol.
5.5 The results should be documented in the validation report.
6. Retrospective validation
6.1 Retrospective validation is based on a comprehensive review of historical data to
provide the
necessary documentary evidence that the process is doing what it is believed to do. This
type of
Validation also requires the preparation of a protocol, the reporting of the results of the data
review, a conclusion and a recommendation.
6.2 Retrospective validation is not the preferred method of validation and should be used in
exceptional cases only. It is acceptable only for well-established processes and will be
inappropriate where there have been changes in the composition of the product, operating
procedures or equipment.
6.3 Sufficient data should be reviewed to provide a statistically significant conclusion.
6.4 When the results of retrospective validation are considered satisfactory, this should serve
only as an indication that the process does not need to be subjected to validation in the
immediate future.
7. Revalidation
The need for periodic revalidation of non-sterile processes is considered to be a lower
priority than for sterile processes.
7.1 In the case of standard processes using conventional equipment, a data review similar to
that which would be required for retrospective validation may provide an adequate
assurance that the process continues to be under control. The following points should also
be considered:
— the occurrence of any changes in the master formula, methods, starting material
manufacturer, equipment and/or instruments;
— equipment calibrations and preventive maintenance carried out;
— standard operating procedures (SOPs); and
— cleaning and hygiene programmed.
8. Change control
8.1 Products manufactured by processes that have been subjected to changes should not be
released for sale without full awareness and consideration of the change and its impact on
the process validation.
8.2 Changes that are likely to require revalidation may include:
— changes in the manufacturing process (e.g. mixing times, drying temperatures);
— changes in the equipment (e.g. addition of automatic detection systems);
— production area and support system changes (e.g. rearrangement of areas or a new water
treatment method);
— transfer of processes to another site; and
— unexpected changes (e.g. those observed during self-inspection or during routine analysis
of process trend data).
Validation in Pharmaceutical Manufacturing

1. Introduction
Validation is an essential part of good manufacturing practices (GMP). It is, therefore, an

element of the quality assurance programmed associated with a particular product or
process. The basic principles of quality assurance have as their goal the production of
products that are fit for their intended use.
These principles are as follows:
• Quality, safety and efficacy must be designed and built into the product.
• Quality cannot be inspected or tested into the product.
• Each critical step of the manufacturing process must be validated. Other steps in the
process must be under control to maximize the probability that the finished product
consistently and predictably meets all quality and design specifications.
Validation of processes and systems is fundamental to achieving these goals. It is by design

and validation that a manufacturer can establish confidence that the manufactured products
will consistently meet their product specifications.
Documentation associated with validation includes:

— Standard operating procedures (SOPs)
— Specifications
— Validation master plan (VMP)
— Qualification protocols and reports
— Validation protocols and reports.
The implementation of validation work requires considerable resources such as:
• Time: generally validation work is subject to rigorous time schedules.
• Financial: validation often requires the time of specialized personnel and expensive
technology.
• Human: validation requires the collaboration of experts from various disciplines
(e.g. a multidisciplinary team, comprising quality assurance, engineering, manufacturing
and other disciplines, depending on the product and process to be validated).
These guidelines aim to give guidance to inspectors of pharmaceutical manufacturing
facilities and manufacturers of pharmaceutical products on the requirements for validation.
The main part covers the general principles of and qualification. In addition to the main part,
appendices on validation
and qualification (e.g. cleaning, computer and computerized systems, equipment, utilities
and systems, and analytical methods) are included.
2. Scope
2.1 These guidelines focus mainly on the overall concept of validation and are intended as a
basic guide for use by GMP inspectors and manufacturers. It is not the intention to be
prescriptive in specific validation requirements.
This document serves as general guidance only, and the principles may be considered useful
in its application in the manufacture and control of active pharmaceutical ingredients (APIs)
and finished pharmaceutical products. Validation of specific processes and products, for
example in sterile product manufacture, requires much more consideration and a detailed
approach that is beyond the scope of this document.
2.2 There are many factors affecting the different types of validation and it is, therefore, not
intended to define and address all aspects related to one particular type of validation here.
2.3 Manufacturers should plan validation in a manner that will ensure regulatory compliance
and ensuring that product quality, safety and consistency are not compromised.
2.4 The general text in the main part of these guidelines may be applicable to validation and
qualification of premises, equipment, utilities and systems, and processes and procedures.
More specific principles of qualification and validation are addressed in the appendices.
Semi-automatic or fully automatic clean-in-place (CIP) systems and other special cases
should be treated separately.
3. Relationship between validation and qualification

Validation and qualification are essentially components of the same concept.
The term qualification is normally used for equipment, utilities and systems, and validation
for processes. In this sense, qualification is part of validation.
4. Validation
4.1 Approaches to validation
4.1.1 There are two basic approaches to validation — one based on evidence obtained
through testing (prospective and concurrent validation), and one based on the analysis of
accumulated (historical) data (retrospective validation). Whenever possible, prospective
validation is preferred. Retrospective validation is no longer encouraged and is, in any case,
not applicable to the manufacturing of sterile products.
4.1.2 Both prospective and concurrent validation may include:
• Extensive product testing, which may involve extensive sample testing (with the
estimation of confidence limits for individual results) and the demonstration of intra- and
inter-batch homogeneity;
• Simulation process trials;
• challenge/worst case tests, which determine the robustness of the process; and
• Control of process parameters being monitored during normal production runs to obtain
additional information on the reliability of the process.
4.2 Scope of validation

4.2.1 There should be an appropriate and sufficient system including organizational
structure and documentation infrastructure, sufficient personnel and financial resources to
perform validation tasks in a timely manner. Management and persons responsible for
quality assurance should be involved.
4.2.2 Personnel with appropriate qualifications and experience should be responsible for
performing validation. They should represent different departments depending on the
validation work to be performed.
4.2.3 There should be proper preparation and planning before validation is performed. There
should be a specific programmed for validation activities.
4.2.4 Validation should be performed in a structured way according to the documented
procedures and protocols.
4.2.5 Validation should be performed:
— For new premises, equipment, utilities and systems, and processes and procedures;
— At periodic intervals; and
— When major changes have been made.
(Periodic revalidation or periodic requalification may be substituted, where appropriate,
with periodic evaluation of data and information to establish whether requalification or
revalidation is required.)
4.2.6 Validation should be performed in accordance with written protocols. A written report
on the outcome of the validation should be produced.
4.2.7 Validation should be done over a period of time, e.g. at least three consecutive batches
(full production scale) should be validated, to demonstrate consistency. Worst case
situations should be considered.
4.2.8 There should be a clear distinction between in-process controls and validation. In-
process tests are performed during the manufacture of each batch according to specifications
and methods devised during the development phase. Their objective is to monitor the
process continuously.
4.2.9 When a new manufacturing formula or method is adopted, steps should be taken to
demonstrate its suitability for routine processing. The defined process, using the materials
and equipment specified, should be shown to result in the consistent yield of a product of
the required quality.
4.2.10 Manufacturers should identify what validation work is needed to prove that critical
aspects of their operations are appropriately controlled. Significant changes to the facilities
or the equipment, and processes that may affect the quality of the product should be
validated. A risk assessment approach should be used to determine the scope and extent of
validation required.
5. Qualification
5.1 Qualification should be completed before process validation is performed.
The process of qualification should be a logical, systematic process And should start from
the design phase of the premises, equipment, utilities And equipment.
5.2 Depending on the function and operation of the equipment, utility or system, only
installation qualification (IQ) and operational qualification (OQ) may be required, as the
correct operation of the equipment, utility or system could be considered to be a sufficient
indicator of its performance (refer to Section 10 for IQ, OQ and performance qualification
(PQ)). (The equipment, utility and system should then be maintained, monitored and
calibrated according to a regular schedule.)
5.3 Major equipment and critical utilities and systems, however, require IQ, OQ and PQ.
5. Calibration and verification
6.1 Calibration and verification of equipment, instruments and other devices, as applicable,
used in production and quality control, should be performed at regular intervals.
6.2 Personnel who carry out calibration and preventive maintenance should have appropriate
qualifications and training.
6.3 A calibration programmed should be available and should provide information such as
calibration standards and limits, responsible persons, calibration intervals, records and
actions to be taken when problems are identified.
6.4 There should be traceability to standards (e.g. national, regional or international
standards) used in the calibration.
6.5 Calibrated equipment, instruments and other devices should be labelled, coded or
otherwise identified to indicate the status of calibration and the date on which recalibration
is due.
6.6 When the equipment, instruments and other devices have not been used for a certain
period of time, their function and calibration status should be verified and shown to be
satisfactory before use.
7. Validation master plan

The validation master plan (VMP) should reflect the key elements of the validation
programme. It should be concise and clear and contain at least the following:
— A validation policy
— Organizational structure of validation activities
— Summary of facilities, systems, equipment and processes validated and to be validated
— Documentation format (e.g. protocol and report format)
— planning and scheduling
— change control
— References to existing documents.
8. Qualification and validation protocols
8.1 There should be qualification and validation protocols describing the qualification and
validation study to be performed.
8.2 As a minimum the protocols should include the following significant background
information:
— The objectives of the study
— The site of the study
— The responsible personnel
— Description of SOPs to be followed
— Equipment to be used; standards and criteria for the relevant products and processes
— The type of validation
— The processes and/or parameters
— sampling, testing and monitoring requirements
—Predetermined acceptance criteria for drawing conclusions.
8.3 There should be a description of the way in which the results will be analyzed.
8.4 The protocol should be approved prior to use. Any changes to a protocol should be
approved prior to implementation of the change.
9. Qualification and validation reports
9.1 There should be written reports on the qualification and validation performed.
9.2 Reports should reflect the protocols followed and include at least the title and objective
of the study; reference to the protocol; details of material, equipment, programmers and
cycles used; procedures and
Test methods.
9.3 The results should be evaluated, analyzed and compared against the pre-determined
acceptance criteria. The results should meet the acceptance criteria; deviations and out-of-
limit results should be investigated. If these deviations are accepted, this should be justified.
Where necessary further
Studies should be performed.
9.4 The departments responsible for the qualification and validation work should approve
the completed report.
9.5 The conclusion of the report should state whether or not the outcome of the qualification
and/or validation was considered successful.
9.6 The quality assurance department should approve the report after the final review. The
criteria for approval should be in accordance with the company’s quality assurance system.
9.7 Any deviations found during the validation process should be acted upon and
documented as such. Corrective actions may be required.
10. Qualification stages

10.1 There are four stages of qualification:
— design qualification (DQ);
— installation qualification (IQ);
— Operational qualification (OQ); and
— Performance qualification (PQ).
10.2 All SOPs for operation, maintenance and calibration should be prepared during
qualification.
10.3. Training should be provided to operators and training records should be maintained.
Design qualification
10.4 Design qualification should provide documented evidence that the design
specifications were met.
Installation qualification
10.5 Installation qualification should provide documented evidence that the installation was
complete and satisfactory.
10.6 The purchase specifications, drawings, manuals, spare parts lists and details should be
verified during installation qualification.
10.7 Control and measuring devices should be calibrated.
Operational qualification
10.8 Operational qualification should provide documented evidence that utilities, systems or
equipment and all its components operate in accordance with operational specifications.
10.9 Tests should be designed to demonstrate satisfactory operation over the normal
operating range as well as at the limits of its operating conditions (including worst case
conditions).
10.10 Operation controls, alarms, switches, displays and other operational components
should be tested.
10.11 Measurements made in accordance with a statistical approach should be fully
described.
Performance qualification
10.12 Performance qualification should provide documented evidence that utilities, systems
or equipment and all its components can consistently perform in accordance with the
specifications under routine use.
10.13 Test results should be collected over a suitable period of time to prove consistency.
Requalification
10.14 Requalification should be done in accordance with a defined schedule. The frequency
of requalification may be determined on the basis of factors such as the analysis of results
relating to calibration, verification and maintenance.
10.15 There should be periodic requalification, as well as requalification after changes (such
as changes to utilities, systems, equipment; maintenance work; and movement). (See also
point 4.2.5 above and section 11 below.)
10.16 Requalification should be considered as part of the change control procedure.
Revalidation
10.17 Processes and procedures should be revalidated to ensure that they remain capable of
achieving the intended results.
10.18 There should be periodic revalidation, as well as revalidation after changes. (See also
points 4.2.5 above, point 10.21 below and section 11 below.)
10.19 Revalidation should be done in accordance with a defined schedule.
10.20 The frequency and extent of revalidation should be determined using a risk-based
approach together with a review of historical data.
Periodic revalidation
10.21 Periodic revalidation should be performed to assess process changes that may occur
gradually over a period of time, or because of wear of equipment.
10.22 The following should be considered when periodic revalidation is performed:
— master formulae and specifications;
— SOPs;
— records (e.g. of calibration, maintenance and cleaning); and
— Analytical methods.
Revalidation after change

10.23 Revalidation should be performed following a change that could have an effect on the
process, procedure, quality of the product and/or the product characteristics. Revalidation
should be considered as part of the change control procedure.
10.24 The extent of revalidation will depend on the nature and significance of the change(s).
10.25 Changes should not adversely affect product quality or process characteristics.
10.26 Changes requiring revalidation should be defined in the validation plan and may
include:
• Changes in starting materials (including physical properties, such as density, viscosity or
particle size distribution that may affect the process or product);
• Change of starting material manufacturer;
• Transfer of processes to a different site (including change of facilities and installations
which influence the process);
• Changes of primary packaging material (e.g. substituting plastic for glass);
• Changes in the manufacturing process (e.g. mixing times or drying temperatures);
• Changes in the equipment (e.g. addition of automatic detection systems, installation of new
equipment, major revisions to machinery or apparatus and breakdowns);
• Production area and support system changes (e.g. rearrangement of areas, or a new water
treatment method);
• Appearance of negative quality trends;
• Appearance of new findings based on current knowledge, e.g. new technology;
• Support system changes.
Changes of equipment which involve the replacement of equipment on a “like-for-like”
basis would not normally require a revalidation. For example, installation of a new
centrifugal pump to replace an older model would not necessarily require revalidation.
11. Change control

11.1 Changes should be controlled in accordance with a SOP as changes may have an
impact on a qualified utility, system or piece of equipment, and a validated process and/or
procedure.
11.2 The procedure should describe the actions to be taken, including the need for and
extent of qualification or validation to be done.
11.3 Changes should be formally requested, documented and approved before
implementation. Records should be maintained.
12. Personnel
12.1 Personnel should demonstrate that they are appropriately qualified, where relevant.
12.2 Personnel requiring qualification include, for example:
— Laboratory analysts;
— Personnel following critical procedures;
— Personnel doing data entry in computerized systems; and
— risk assessors.
Cleaning Validation of Pharmaceutical Equipments

The Cleaning validation is performed to demonstrate the effectiveness of procedures for cleaning to
remove residue of previous product. After the process, equipments used for manufacturing of the
product, shall be cleaned as mentioned in respective SOPs for cleaning.
Sampling procedure
Shall explain briefly the procedure for sample collection.
Analytical specification
Shall provide specifications of the applicable tests.
Method of analysis
Shall provide analytical method for the applicable tests
All the applicable tests shall be incorporated in the specification itself.
Minimally three cleaning cycles shall be monitored and validated to establish the effectiveness of
cleaning procedure.
Cleaning verification
Study of monitoring the cleaning activity before completion of the three cleaning cycles on
commercial batches of the product shall be considered as cleaning verification.
Cleaning verification / validation Acceptance Criteria:
Calculation of the Maximum Allowable Carryover (MACO)
For the calculation by considering 0.1 % Safety factor
Daily therapeutic dose Min. Batch Size of Product B

of product A in mg (in mg)
Limit (mg) = ----------------------------------- x ------------------------------------------------
1000 Max. daily therapeutic dose of
product B in (mg)
Where,
Product A – Product manufactured before cleaning
Product B – Next Product after cleaning
For considering 10 ppm as acceptance criteria.
The quantity equivalent to 10 mg/L of the batch size is considered as the acceptance criteria for the
acceptance criteria as 10 ppm.
Calculation of acceptance criteria

Calculation of acceptance criteria for swab samples
Active Ingredient Residue (For Non-dedicated equipments): Acceptance criteria based on the
following rationale for swab samples :
Calculation [Applicable to all items of common equipment in product train].
1000 D
Limit (PPM) = MACO x ---------- x -----------
C V
Where,
C – Cumulative surface area of the equipments used (in cm2).
V – Volume of solvent used to dispense swab.
1000 – Multiplication factor to convert value in mcg from mg.
D – Swabbed Surface Area in cm 2.
Calculation of acceptance criteria for Rinse samples
Active Ingredient Residue (For Non-dedicated equipments): Acceptance criteria based on the
following rationale for rinse samples:
Calculation [Applicable to all items of common equipment in product train].
1000 1
Limit (PPM) = MACO X ---------- x ------
C V
Where,
C – Cumulative surface area of the equipments used (in cm2).
V – Volume of solvent used for rinse of the same in mL per cm2 of Equipment.
1000 – Multiplication factor to convert value in mcg from mg.
Calculation of recovery factor:
% Recovery shall not be less than 75% unless otherwise specified and justified in individual
protocol of analytical method validation.
Recovery factor shall be calculated as follows:
100
Recovery factor = --------------------
% Recovery
Microbiological Quality:
a) A Total count limit, is Not more than 10 cfu/100 ml by rinse method.
b) Not more than 5 cfu / 25 cm2
Cleaning validation shall be performed on all the products. The matrix for acceptance criteria shall
be prepared when the same set of equipment is used for different products.
After addition of new product the acceptance criteria and maximum rinse volume shall be
recalculated in matrix
If the acceptance criteria is stringent than as specified.
Revalidation of cleaning procedure:
Revalidation of cleaning procedure is required if any of the following occur and revalidation of
cleaning procedure shall be performed on a minimum of three cleaning cycles.
Modification of cleaning procedure / Surface area of product contact parts of the equipment or any
modification to the equipment which has got direct bearing on product contact parts.
Change in cleaning procedure.
Change in analytical method for determination of residue.
Major non-traceable contamination occurrence.
Failure during cleaning verification / validation.
Monitor the validation status for cleaning during new product introduction.
In case of microbial analysis results of swab samples or rinse samples, no need to wait for the release
of results.
Corrective Action and Preventive Action (CAPA)

Corrective Action
Action taken to rectify, fix or correct a specific deviation, defect or undesirable situation.
Preventive Action
Action taken to eliminate the cause of deviation, defect, or other undesirable situation in
order to prevent the future occurrence of such or similar an event.
Initiation of CAPA:
1. The initiation of CAPA requires submission of source document by concerned
Department Head to QA.
2. Department Head shall decide the need for CAPA with Head QA.
3. The Department Head shall get a CAPA form issued from QA. QA shall write the source
document name and Source document number on the form before issue of form.
4. Department Head shall fill the CAPA form as under.
A) Date CAPA initiated

B) Proposed completion date
C) Select the department initiating the CAPA by making a √ marks in appropriate box.
D) Select the relevant system affected by making a √ mark in appropriate box. If none of
the systems printed are affected select not applicable. If any other system other than those
mentioned is affected,
write the system in blank spaces provided.

E) Write in brief the CAPA description from the source document and corrective and
preventive action details.
F) The Department Head shall write their name with signature and date.
5. The department head shall send the CAPA form to QA.

6. GM QA / Designee shall allot a reference number to the CAPA form and make relevant
entries in the CAPA log. Forward the CAPA form to the concerned department.
7. The CAPA shall be numbered serially in the calendar year for each department with an
identification code of department. A typical CAPA form shall be numbered as
CAPA/XXX/YYY/ZZ
Where,
XXX: department code.
YYY: serial number, commencing at 001 for each department in calendar year.
ZZ: Last digit of a calendar year.
E.g. CAPA/PRD/007/13 represents the 7th CAPA from production department in calendar
year 2013.
DEPARTMENT CODE
Prefix Department
QAD Quality Assurance Dept.
QCD Quality Control Dept.
PRD Production Dept.
WHD Ware House Dept.
ENG Engineering Dept.
HRD Human Resource Dept.
RAD Regulatory Affairs Dept.
CAPA Closure and Verification
1. On completion of actions, the department head shall certify that the proposed CAPA is
completed and implemented along with associated actions.
2. QA shall verify the implementation and completion of CAPA with review of supporting
documents and certify the same.
3. Any change proposed as a result of CAPA shall be through the SOP on Change Control
Reference of the same shall be mentioned in the CAPA format.
4. All Change Controls, Deviations, Discrepancy, Incident Reports giving rise to CAPA
shall be addressed through CAPA form.
5. All facility up-gradations / Capital purchase requirements / major changes in quality
system and compliance to regulatory commitments giving rise to CAPA shall be addressed
through CAPA form.
6. The record of each CAPA shall be maintained.
7. Copy of the completed CAPA shall be provided to the concerned Dept. Head by QA
Department Head shall compile the CAPA information and submit the summary to the
Management during GMP Committee meeting / Management Review Meeting.
8. Management shall review / verify the same quarterly in Management Review Meeting.
9. Information and documents related to CAPA drawn from internal audits, external/
Customer audits and regulatory inspections are considered confidential and can only be
made available to regulatory review when approved by Director technical and Vice
President QA.
Source documents of CAPA are identified as:

• GMP Investigations
• Deviations
• Change control
• Laboratory (OOS) Investigations
• Internal Audit Reports
• External / Customer Audits
• Annual Product Reviews
• Regulatory Inspection Reports
• Management Action Plans
• Changes in regulatory / Pharmacopoeia requirements
• Product Failures
• Complaints
• Product recall
• Returned Goods
• Incidence Reports
• Discrepancies
Deviation Control in Pharmaceuticals

1. As for as possible there should not be any deviation in either manufactuting or Pacing process.
2. Deviation may be planed and unplanned If there is any deviation then it should be categorized as
either minor or major deviation.
3. In case of minor deviation in the Manufacturing Process which does not affect the final
parameters of the product or its quality or its stability. The deviation should be authorized by
manager of production & Q.A. Department and them only carry out the process.
4. Minor batch deviation (with authorization) should be limited to the particular batch only so that
the batch may be completed.
5. After minor deviation, if the specifications of the product are changed, then the clanges should be
recorded / regularized / and authorized by Technical director.
6. In case of major deviation in the Mfg./Pkg. Process e.g.(i) any change of RM or its supplier and
its quantity per batch; (ii) any change of primary packing material or its supplier.
7. The change should be validated for three consecutive batches.
8. The change should be studied for stability purpose. In case of Loan licence party stability shall be
conducted by concerned party.
9. On the basis of validation & stability studies data the change should be authorized by Technical
Director or Q.A. Manager before its implementation in the regular batches.
10. A Detailed report about the investigation and the deviation shall be prepared & kept in file for
further reference.
Procedure for Raising deviation Report

1. Request for deviation shall be raised by manager of respective department. In the approved
format (Annexure 1) with justification for deviations.
2. The location head Technical director shall comment on the deviation.
3. Comments by Regulatory & product development deptt. Are made whether validation. Stability
study for change control required or not.
4. Decision regarding approval / non approval of the deviation shall be taken by Q.A. Manager in
case of loan licenses party or by technical director in case of Promed product.
5. Closer remark shall be made mentioning B.No. & date of completion.
Annexure -1
DEVIATION REPORT
1. Deviation Report Number ___________________
2. Name of Munufacurer ______________________
3. Product Details
Product Batch Market Pack Mfg.Date Exp.Date
No. Size.
Types of Deviation :-
Planned Unplanned
Description of
Deviation_______________________________________________________________
Stage____________________________________________________________________________
_
Observed by :-
_____________________________________________________________________
4. Justification :-
___________________________________________________________________
___________________ __________________ __________________
Mfg. Location Initiated by (Name) Signature & Date
5. Comments by Location Head :

_______________________________________________________
Location Head (Name) Signature & Date
___________________ _______________________
6. Decision by Q.A.M
Approved Not Approved
Remarks:-________________________________________________________________________
_________________ _______________________
Name Signature & Date
7. Closer Remarks:-
Date of Implementation :_____________________
Involved Batch No. : ______________________
Remark :
__________________________________________________________________________
_____________________ _______________________
Location Head QA Signature & Date
Different Types of Diffusers Used in Pharmaceutical

Clean Rooms (Controlled Area)
Air diffusers are used in clean rooms and other controlled areas to distribute the clean air
passed through the HEPA filters. Diffusers are important part of the HVAC system and play
vital role in maintenance of classified area.
Number of diffusers in a room depends upon the volume of the area, size of diffusers and
required air changes par hour. Diffusers are mounted in the ceiling of the room to distribute
the uniform air in the area and return risers should not be near the diffusers. Otherwise air
pockets will form that can increase the contamination level in the area. Place and type of
diffusers to be used should be included in the HVAC system qualification.
Generally two types of air diffusers are used in pharmaceutical industries.
1. Induction Diffusers
2. Perforated Plate Diffusers
3. Swirl Diffusers
1. Induction Diffusers: Induction diffusers are generally used in offices and therefore also
called office type diffusers. These diffusers direct the air to flow in different directions.
WHO does not recommend these types of diffusers to use in pharmaceutical processing
areas because these diffusers mix the fresh air with the contaminated room air (see
figure) and the air should be replaced with the fresh air to minimize the contamination.
In the areas where dust is liberated it is important to replace the air containing dust with
the fresh air.
2. Perforated Plate Diffusers: These are the WHO recommended and widely used
diffusers in pharmaceutical industries. They allow the air to flow in all directions
replacing the air containing dust and contamination with the fresh air from supply.
3. Swirl Diffusers: These rotating diffusers are also recommended by the WHO which
rotates during the fresh air supply allow distributing the fresh air throughout the area.
Guidelines for Preparation of VMP (Validation Master Plan)

The VMP document shall contain information on the following sections and cover all
aspects of qualifications and validations.
• Introduction
• Objective
• Scope
• Validation policy
• Validation committee
• Key personnel and manpower requirement
• Facility and equipment qualification
• Description of facility including plans
• Facility, utilities qualifications
• Description and listing of equipments
• Key acceptance criteria
• Design qualification (DQ)
• Installation qualification (IQ)
• Operational qualification (OQ)
• Performance qualification (PQ)
• Re-validation criteria
• Description and listing of protocols
• Preventive maintenance programmed
• Process validation
• Cleaning validation
• Laboratory instrument qualification
• Analytical method validation
• Computer validation
• Change control and approvals
• Validation documentation
• Validation plan and schedule
• Personnel training programmed
• Reasonable unexpected events (worst case)
• Review of VMP
• List of relevant SOPs
• Glossary of terms
The VMP shall describe the process of preparation, review and approval of protocols. The
major contents of protocol and report shall be defined to achieve uniformity in
documentation of various protocols.
VMP shall describe the process of execution, review and approval of the validation.
Key people / team responsibilities for validations shall be described.
The VMP shall be printed using format attached. Printing shall be done using the following
guidance :
The compiled VMP will have serial pagination.
Design, drawing of the facility shall be included to as annexure to elucidate description of
the facility.
VMP will be prepared by a team, reviewed by senior team and approved by GM QA & QC.
The VMP is a controlled document and will be reviewed once a year. Changes to VMP can
be made through document change control.
Sr. No. Text Font

1 Section title Arial, (size16)
2 Sub section Arial, (size 14)
3 Text matter Arial (size 11)
4 Text in table Arial with appropriate font size
5 Autocad drawing Appropriate legible size letters and
diagrams
Heating, Ventilation and Air Conditioning (HVAC) System

Validation Process
Process:
1. Perform Installation Qualification.

2. Perform general operational controls verification testing.
3. Operate system throughout the range of operating design specifications or range of
intended use.
4. Integrity test all HEPA filters with dioctylphthalate (DOP) smoke (0.3 microns).
5. Measure the average face velocity of each terminal HEPA filter. Measure the average
velocity 1 ft above the work-space exposed product areas, or exposed component areas in
all Class 100 laminar flow rooms or areas.
6. Verify that system air flows have been balanced to within ±10% of design criteria.
7. Verify that directional air flows are consistent with design drawings by verifying
relative differential air pressures.
8. Verify that each room maintains the design temperature range for three (3)
consecutive days.
9. Verify that each room maintains the design relative humidity range for three (3)
consecutive days.
10. Verify that air flow patterns within Class 100 laminar flow areas are non turbulent
and unidirectional by performing smoke-stick air flow studies and recording the test on
videotape.
11. Verify that rooms identified with particulate classifications are certified per Federal
Standard 209E for their respective classification (Class 100, 10,000, and 100,000).
12. Verify that AHUs, fans, and heat exchangers operate per design ratings.
13. Record the range of all process or equipment parameters (set points, flow rates,
timing sequences, etc.) verified during operational and performance qualifications testing.
Acceptance Criteria:
1. The system is installed in accordance with design specifications, manufacturer

recommendations, and cGMPs. Instruments are calibrated, identified, and entered into the
calibration program.
2. General controls and alarms operate in accordance with design specifications.
3. The system operates in accordance with design specifications throughout the
operating range or range of intended use.
4. HEPA filters are 99.99% efficient when tested with DOP smoke (0.3 microns).
5. All terminal HEPA filter face velocity measurements are within ±30% of the average
filter velocity.
6. The average face velocity of terminal HEPA filters servicing Class 100 laminar flow
rooms is 90 ft/min ±20%, with no points below 75 ft/min or above 105 ft/min.
6. All room supply, exhaust, and return flow rates must be within ±10% of design flow
rates.
8. Directional air flows (as determined by room differential pressure) must be consistent
with design drawings.
9. Each room must maintain the design temperature range for three (3) consecutive
days.
10. Each room must maintain the design relative humidity range for three (3) consecutive
days.
11. Air flow in Class 100 laminar flow areas must be non-turbulent and unidirectional as
demonstrated by smoke-stick studies.
12. All classified rooms are certified to meet their particulate classification per Federal
Standard 209E.
13. AHU, fan, and heat exchanger operations must meet or exceed their respective design
ratings.
Importance and Maintenance of Pressure Differential in

Manufacturing Area
Pressure differential is difference between atmospheric pressure between production area

and its surroundings. It is measured in pascal using magnehelic pressure gauge.
According to WHO guidelines on HVAC system, 10-15 pascals of differential pressure is

maintained between manufacturing and surrounding areas. Aseptic area should always be
highly pressurized than the non aseptic area and air flow should be always from the aseptic
to non aseptic area. This pressure differential is maintained by HVAC system. In tablet
production area, pressure differential helps to prevent the cross contamination. Dust
particles are generated in granulation and compression area; those can contaminate the other
products being manufactured in adjacent areas. In sterile manufacturing pressure differential
prevents entering the particles and microbes in sterile manufacturing rooms.
It is necessary to maintain the positive pressure in corridor than the tablet manufacturing
areas to minimize the cross contamination. But positive airlocks should be there before
entering the corridor while maintain the positive corridor than the manufacturing
rooms. These airlocks prevent the direct air flow form uncontrolled area to controlled areas
and helps to minimize the entrance of contaminated air into the controlled area. In sterile
manufacturing area, manufacturing room is maintained in positive pressure than the
surrounding corridor because there are more chances of microbial contamination instead of
cross contamination.
It is important to carry out the pressure differential and recovery tests at the time of HVAC
system validation. Pressure gauges should also be calibrated at the time of HVAC
validation.
It is important to have a good building construction and air tight windows and doors to
maintain the required differential pressure. Pressure drop alarms are also used these days to
indicate the low pressure in critical areas. Pressure differential may cause difficult to open
the doors, particularly in the facilities
having multi level differential pressure. Some facilities are using sliding doors to prevent
this problem but it is difficult to make the sliding doors leak proof.
Sanitation of Clean room Area in Pharmaceutical
Manufacturing
Pharmaceutical manufacturing a clean room area and it is important to clean the area
periodically. Area
should be clean after a defined period as per standard operating procedure.
Where sanitation is done by using the disinfectants, two

are more disinfectants should be used. Disinfectants may be ineffective against some of the
organisms called resistant organisms. A procedure should be developed to identify such
organisms and any effective disinfectant should be employed for such organisms.
Sanitation procedure and the disinfectant used should be validated. If any equipment is
sanitized with the disinfectant, a cleaning validation should be done for the removal of the
disinfectant. Residues of the disinfectant should be removed properly from the equipment
after cleaning.
Class A and class B area of sterile manufacturing should be sanitized with the sterile
disinfectants and detergents. Generally disinfectants are sterilized by filtration using 0.2 µ
membrane filters in sterile conditions. Hold time period of diluted disinfectant should be
validated.
Different types of disinfectants should be used in the rotation. Disinfectants should include
the sporicidal because most of the disinfectants do not have sporicidal activity and
effectiveness of these disinfectants must be validated.
Fumigation of the sterile area is a useful way to sanitize the air of sterile area. It can reduce
the microbial contamination in the air. Time of the fumigation can be validated for better
results of fumigation. Area should be de-fumigated properly before use. Hydrogen peroxide
solution with silver chloride is used in fogger for fumigate the controlled areas. It is
available in market with different brand names.
What is HEPA filter? It’s Use in Pharmaceuticals

Q. What does the term HEPA mean?
A. HEPA is an acronym for "High Efficiency Particulate Air" or "High
Efficiency Particulate Arrestance." This acronym refers to a filter that is
manufactured, tested and certified to meet Institute of Environmental Sciences
and Technology (IEST) construction, performance and certification standards
as currently published in IEST RP-CC001.3.
Q. How long have HEPA filters been in use?

A. The first HEPA filters were developed for the Atomic Energy Commission
during World War II for use in facilities manufacturing components for the
Manhattan (atomic bomb) project. These HEPA filters were originally
designed to capture microscopic radioactive particles too small for effective
removal by existing types of filters. HEPA filters used today are much more
efficient and economical than the products made in the 1940's.
Q. Where are HEPA filters used today?

A. HEPA filters are generally specified for applications where microscopic
airborne particles or biopollutants could cause human health or product quality
problems. Typical users include military, nuclear, pharmaceutical, electronics,
biological and medical facilities.
Q. What is it that makes HEPA filters so efficient?

A. The ultra-fine glass-fiber medium captures microscopic particles that can
easily pass through other filters by a combination of diffusion, interception and
inertial impaction. To qualify as a Type A HEPA filter, the filter must capture
at least 99.97% (9,997 out of 10,000) of particles 0.3 microns in size–about
300 times smaller than the diameter of a human hair, and 25 to 50 times
smaller than we can see. To a HEPA filter, catching a one-micron particle
(1/1,000,000 of a meter) is like stopping a cotton ball with a door screen.
Q. Are filters this efficient really necessary for IAQ applications?

A. Laser particle counter measurements typically show that more than 99% of
the particles suspended in indoor air are one micron (1/1,000,000 of a meter) or
smaller in size. EPA calls these “lung-damaging” particles, because they can
lodge deep in the lungs when inhaled. The ability of HEPA filters to capture
particles this small is what sets them apart from other types of filters.
Regulations developed by EPA, OSHA, CDC and other federal, state and local
government agencies responsible for human health and IAQ issues specify
HEPA filters for asbestos, lead and mold abatement, TB and SARS isolation
rooms and healthcare renovation projects.
Q. Are all filters made with HEPA filter media HEPA filters?
A. Manufacturing a filter with HEPA filter media does not mean that the filter
itself meets true HEPA efficiency requirements. Serious filter leakage can go
undetected if filters are not individually tested and certified at the end of the
manufacturing process. Even the tiniest pinhole leaks in the media or breach of
the seal between the media pack and the filter frame can cause the filter to fail
IEST requirements. The testing requires very specific procedures using a
thermally generated mono-dispersed aerosol and a laser particle counter. Some
regulations also require field-testing by the user prior to going into service and
periodically thereafter.
Q. Why is the testing done with a 0.3-micron particle size test aerosol?
A. Filter efficiency studies have shown that 0.3-microns is the "Most
Penetrating Particle Size (MPPS)" for HEPA filter media. Efficiency is
typically greater than 99.97% against larger or smaller particle sizes. Particles
larger than 0.3 microns are typically more easily trapped, or intercepted, by the
media. Smaller particles often lack sufficient mass to penetrate the media.
Q. Is a "HEPA Type" filter the same as a HEPA filter?

A. No. In fact, the differences are huge. According to the American Lung
Association, filters classified as "HEPA type" filters may capture as little as
55% of 0.3-micron particles (5,500 out of 10,000). By this definition, the true
HEPA filter could be more than 1,800 times as efficient as the "HEPA type"
filter.
Q. Does HEPA filter efficiency decrease as the filter gets dirty?

A. No. Unlike electronic air cleaners and other air purification technologies
that experience substantial loss of efficiency as they become dirty, exactly the
opposite typically happens with HEPA filters. In fact, the dirtier a HEPA filter
gets, the more efficient it can become.
Prevention of Cross - Contamination During Processing

• Line clearance should be performed as per SOP & check list and recorded.
• Check for absence of any starting materials, products, product residues, documents of
previous product.
• Wherever possible adopt “Closed system” while handling materials.
• Processing of only one material at a time in same cubicle.
• At every stage of processing product, material, printing material should be free from
microbial and other contaminants.
• Reduce bio burden and other contaminants by removing outer wrapping of the packaging
material in which they are delivered before being issued on the shop floor.
• Containers for filling should be cleaned before use .
• Packaging operations in packing area should be carried out with physical segregation
between packing lines.
• Proper validated systems.
• Product and product contact parts of equipment should not be directly handled with bare
hands.
• In process control may be carried out in production area, provided they do not carry any
risk for the product.
• Campaign production should be followed by appropriate cleaning in accordance with a

validated cleaning procedure.
• Materials e.g. lubricants, inks, cleaning fluids should be in containers that look
distinctively different from the containers which are used in production and should be
labeled as per their content.
• Products that have been involved in an unusual event during packaging should be re
introduced into the process only after inspection investigation and approval
by authorized personnel . Detailed records should be kept of this operation.
• Repairs and maintenance operations should not present any hazard to the quality of the
products.
Clothing
• Clothing and its quality should be appropriate for the process and the grade of the
working area.
• Linen is non shredding type. (Non linting)
• Minimise exposed body surfaces.
• Wash routinely.
• Separate washing for clothes worn during handling of sensitive products.
• Should not get contaminated by cleaning agents.
• Appropriate personnel protective equipment (PPE) should be used where applicable.
• Dedicated PPE for beta-lactum products, antibiotics, hormones, cytotoxic, drugs
manufactured from live microorganisms.
• Clothing / linen should be changed after every product change over/ breaks.
• Procedure for cleaning foot wear should be available.
• Routine environmental monitoring by particle count, active air sampling and settle plate
count to be carried out.
• Capable of repeated wear, laundering without deterioration.
Utilities and Service
• Water used in the manufacture of Pharmaceutical Products should be suitable for the
intended use.
• (Chemical & Microbial limits should be appropriate for its intended use)
Steam
free of additives.
clean steam generators may be used wherever applicable.
Compressed air
Air to be passed through appropriate filter
A high level of sanitation & hygiene should be practiced in every aspect of the
manufacture of drug product.
• Materials used for the operations such as cleaning, lubrication of equipment, pest control,
should not come in direct contact with the product. Suitable grade to be used to minimise
the health risk.
• Measure to prevent cross contamination and their effectiveness should be checked
• periodically as per procedure.
• Beta lactum products, antibiotics, hormones, cytotoxic, primary packing in dedicated area
• Active raw material of Beta lactum may be transported with other packed active materials
and excipients. The packed finished products of these drugs can be transported with other
non active finished products.
• In case of spillage or contamination during transport, entire quantity to be rejected.
• All containers of raw materials, in process materials, processed or partially processed,
partially packed, finished products to be properly labeled with product name, Batch no.,
status etc.
• "Cleaned" or "To be cleaned" label should be affixed on empty containers, with names of
the previous product.
Mix Up and Cross Contamination in Pharmaceutical

Manufacturing
Mix up
· A blend of diverse elements.
· A mistake that results from taking one thing to be another.
· A wrong action attributable to bad judgment or ignorance or inattention.
Likely Causes
· Close proximity of the two products i.e Size, shape, colour etc.
· Pack i.e Same colour combination, size and type
· Multiple products/ packs handled in the same area
· Same apparatus/ Instrument (for IPC checks) is used for multiple products.
· No proper storage/ segregation of products i.e during manufacture, sterile and non
sterile product
· During packaging and repackaging
· During dispensing
· No proper line clearance procedure followed
· Left out labels/cartons/ leaflets from previous product/ batch overprinting materials
e.g. stereos
etc. of earlier batch not removed.
· Improper labeling/ documentation
· No identification code
· No training/inappropriate training
· Failure of processing equipment
· Manual labeling/ packaging/repackaging
· Improper controls
· Rejection handling
· Improper labeling
· Reprocessing
· At vendor’s site;
-Same vendor used for printing of [packaging material at vendor’s site
-No adequate control at printer’s end.
· Lack of understanding/ communication
· Same operator handling two or more machines/ products at the same time.
· Lack of proper validation procedures
Contamination
The undesired introduction of impurities of a chemical or microbiological nature ,or of
foreign matter, into or on to a starting material or intermediate during production , sampling
, packaging or repackaging, storage or transport.
Cross Contamination
Contamination of a starting material, intermediate product or finished product with
another starting material or a product during production
Typical sources of Contamination
· Premises
· Equipment
· People
· HVAC System
· Processing Operations
· Clothing
· Utilities and Services
Risk of cross contamination

The significant of risk varies with the type of contaminant and product being contaminated.
The most hazardous contaminant are ;
· Highly sensitizing materials
· Biological preparations containing living organisms
· Hormones
· Cytotoxics etc.
Products where contaminant is more significant are;
· Injections
· given in large doses
· Over a long period of time
· Applied to open wounds
Consequences
Company
· Show cause notice
· Warning letter
· Closure of premises
· Suspension of manufacturing licence
· Withdrawal of product licence
· Monetary losses
· Frequent audits by regulatory authorities
· Market reputation / Adverse Publicity
Employee
· Suspension order
· Termination of services
· Show cause notice
· Jail / Penalty
· Monetary losses
Good Documentation Practices (GDP) in Pharmaceuticals

1. All documentation entries shall be made with indelible black ink in clear and legible
handwriting.
2. Verification of the Document made by QA by using indelible blue ink.
3. Green ink shall be used only by QA for issuance of BMR / BPR.
4. Do not leave any column in the record / document unfilled. If any column in a record
document is not applicable, write “N.A”. If no comments write nil or put ‘---‘.
5. Time should be expressed as HH.MM i.e. 2 pm should be recorded as 14.00 hrs.
6. While issuing documents and in other record books the date should expressed as
DD-MM-YY or DD.MM.YY or DD/MM/YY.
7. While approving document the date should be expressed as DD-MM-YYYY or

DD.MM.YYYY or DD/MM/YYYY.
8. If any page(s) left blank, draw a line across the page from left top to right bottom of the
page and write “CANCELLED” / “N.A.” (Not applicable) across the page and sign with
date.
9. If an entire page / paragraph is to be cancelled from a document, QA counter sign is
required.
10. No pencil entries are allowed.
11. Do not use correction fluid in any of the documents
12. All personnel shall avoid errors during data entry.
13. In case an entry error is occurred, the same shall be corrected as described below.
14. Do not overwrite the wrong entries. Cross it out with a line permitting the reading of
original entry. Clearly write the correct entry near the cross out.
15. Initial / Sign and put date, on which the correction was made. Wherever appropriate, the
reasons for correction shall be recorded.
16. If the correction is made on a date after the date of original entry, it must be corrected as
mentioned above and counter signed and dated by the supervisor or QA.
17. If an entire line / paragraph / page to be deleted from a sequential record (e.g. log book
or stock card) the following steps to be taken.
i) Cross out with a line
ii) Write a comment explaining the reason for deletion near the cross out.
iii) Initial / sign and put the date, on which the correction was made.
GMP Audit Check List- Equipment

1. Is brief description of major production and quality control lab. Equipment indicating
construction, validation and suitability of other materials (polypropylene, chrome plated
brass, PVC, non-reactive plastic materials) provided?
2. Are the equipment of appropriate design, construction and adequate size suitably located?
3. Are the equipment surfaces coming into contact with any raw material, intermediate bulk
or finished product made of inert materials (e.g. stainless steel)
4. Are the equipment properly maintained and easily cleaned?
5. Are there procedures for cleaning and maintenance available? (Indicate responsibility,
contractual details, maintenance routines which could affect product quality)
6. Are all equipment for cleaning and maintenance recorded? (Indicate type, frequency,
details of reports/modification, use of report)
7. Are all equipment properly grounded where required?
8. Is there any program for calibration of measuring equipment?
9. Is the result of the calibration documented?
10. Are all open mechanical belts, pulley, etc equipped with safety guards?
11. Are major equipment clearly marked with identifying numbers?
12. Are qualification, validation and calibration programs available for equipment used for
production, quality control heating ventilation, air conditioning (HVAC), water system,
steam, compressed air, gasses etc.?( indicate policy/protocols for qualification and
validation, revalidation, calibration and their recording)
Difference among Calibration, Validation & Qualification

A lot of pharmaceutical professionals are having a big confusion among calibration,
validation and qualification, hence I am trying to washout the confusion. I think it will make
a clear image about these three concepts.
Calibration:
The set of operations that establish, under specified conditions, the relationship between
values indicated by an instrument or system for measuring (for example, weight,
temperature and pH), recording, and controlling, or the values represented by a material
measure, and the corresponding known values of a reference standard. Limits for acceptance
of the results of measuring should be established. Always remember any reference standard
is always used in calibration.
Validation:
Action of proving and documenting that any process, procedure or method actually and
consistently leads to the expected results. It can better understand that the validation is a
documented evidence to and done to prove the consistency of the expected results of any
process, procedure or method.
Related: Validation in Pharmaceutical Manufacturing
Qualification:
Action of proving and documenting that any premises, systems and equipment are properly
installed, and/or work correctly and lead to the expected results. Qualification is often a part
(the initial stage) of validation, but the individual qualification steps alone do not constitute
process validation. Qualification is a part of validation.
Common Ways to Avoid Making the Most Frequent GMP

Errors
Many common GMP errors in pharmaceuticals can be easily avoided by following a few
simple rules.
Below I describe common mistakes (and ways to avoid them) that I’ve seen and that many
managers, supervisors, and executives have told me they have seen. I use these common
sense tips in my training classes and thought you might like to see them,
Safety First, Last, and Always

We all must observe safety rules, for our own safety and to protect the product from
contamination. We work with ultramodern equipment, in laboratories and facilities that cost
millions of dollars, and with exciting technology, nevertheless, some of the products and
materials we work with are potently bio hazardous. Electricity running through some pieces
of equipment also presents a risk. Guards, such as on packaging equipment, are there for a
reason. I always tell employees to locate eyewashes, fire extinguishers, and equipment
"emergency stop" buttons, learn your company's evacuation procedures. If you clean or do
maintenance on vessels, tanks, steam lines, or lyophilizers, learn the appropriate safety
precautions and follow them thoroughly. That includes company policy regarding work
orders and lockout and tag out procedures to ensure that the equipment is not in use before
you begin maintenance.
1. Wear personal protective equipment one common GMP mistake is not wearing your
safety glasses. Your eyes are too precious not to protect them. Always wear your safety
glasses, safety shoes, respirators, and other personal protective equipment. Take the time to
think things through. Stay alert, and trust your instincts. Avoid situations that look
potentially dangerous, and let your supervisors or others know. Read the Material Safety
Data Sheets (MSDS) for all materials that you work with.
2. Read and observe all labels and signs. I once saw an experienced operator suspect that a
vendor had changed the process on a raw material because the label "looked different" Read
all labels and signs carefully. Check for "released" stickers. Ensure that the material has not
expired and that its the correct material. Caution and warning signs in your plant should be
printed in all languages spoken in the plant
3. Be especially careful around breaks, when you are tired, called away, and so on. GMP
and safety violations occur most often right before break times, before lunch, before your
shift is over, when it's time to go home, when someone interrupts you or breaks your train of
thought, and so on. Be especially vigilant during those times. The most common injuries in
our business seem to be hand and back injuries, so use proper lifting techniques, slow down,
and think about what you are about to do before putting your hands or back at risk.
4. Wear only appropriate clothing. In most companies, supervisors are responsible for
providing on-the-job training (including training in proper attire, such as sterile gowning)
and then monitoring employees to make sure that they are wearing appropriate clothing.
One common GMP error is not wearing your lab coat while you are in the laboratory (or
visitors or contractors not wearing hair coverings, shoe coverings, lab coats, and so on).
Splashes can be dangerous and can ruin your clothes. When visiting bulk chemical plants,
don't wear designer suits or shoes.
Another common error is wearing your lab coat or plant uniform outside the building. Some
483 observations noted that employees were smoking outside of buildings while wearing
their plant uniforms. Some types of jewelry are not allowed in certain areas. Check with
your supervisor if you're not sure.
5. Keep surfaces and equipment clean. Follow approved cleaning procedures, and use
approved cleaning solutions, People have become sick and in the most serious case that I'm
aware of, have died — because cleaning was inadequate, and the cleaning process had never
been validated. One of the first things that investigators or visitors notice when they visit
your plant is the facility's general cleanliness. Don't stack cardboard boxes in the hallways.
Before you use a piece of equipment, ensure that it was cleaned by checking the "Cleaned
Equipment" tag or the equipment logbook. If possible, open the equipment and look inside
to make sure that no rinse water (or a Brillo pad!) was accidentally left behind.
6. Wash your hands. Most pharmaceutical plants have signs in the bathrooms reminding
employees to wash their hands before returning to the plant. If you've ever put your hand on
a plate and cultured the bacteria present, you know that bacteria are everywhere, in large
quantities, although omnipresent in life, they are not something that any one of us wants in
our medicines or injectables.
7. Report an Illness. I know of no other industry-other than food - that requires personnel
working over open product to notify their supervisors when they have a cold it is a GMP
requirement that employees and temporary employees do this. On those days when you're
not feeling up to par, you can be assigned to attend GMP classes, revise SOPs, or catch
up on your scintillating GMP reading, such has articles like this one.
8. Use only released raw materials, packaging components, and labels. Use no expired
materials. Under cGMPs, only released materials can be used in all clinical and commercial
lots of product. A common error is to store expired materials with current materials.
Remove, segregate, and/or destroy all expired materials.
An R&D employee once called me because he was making a master cell bank (MCB) and
was under a great deal of pressure to get it done. The process took two weeks, and he had to
ship it soon. He called to ask whether he could use unreleased ("on test" or "quarantined'')
media, I said no, that under GMPs, he must use released materials,
A few days later he called me again because the media had still not been released by Quality
Control. Could he use the unreleased media? No, I said, under cGMPs you cannot use
unreleased raw materials. The next day, I got an urgent voicemail message from him. He
said that he wanted to go ahead and use the media, even though it wasn't released, because
he was being pressured to finish the MCB. But he had just received an urgent message from
QC telling him that the media he wanted to use had failed endotoxin testing. Could he use it
anyway?
No, I explained, you cannot use unreleased or rejected material in the manufacture of
clinical or commercial lots, who says GMPs are boring?! On a positive note, he was asking
for advice. Had he made the MCB, not only would it have had to be destroyed, but he would
have wasted two weeks of his time along with the cost of the raw materials,
9. Think. Even though the pace in our industry is fast, and everyone has more to do than
they can possibly get done, everyone deserves the time to think things through.
Every time I have allowed myself to be rushed, I have made a critical mistake.
10. Always fill in the blanks. Record all requested information. If its truly not applicable,
write N/A; your initials, and the date. If pages or sections of forms are not applicable, line
through them, write N/A, your initials, and the date. The correct information must be
entered on batch records, equipment logbooks, and test result forms, otherwise, your QA
department will be checking with you soon to find out why you didn't complete the work
11. Record results as you get them. One common GMP error is to speed through documents
at the end of the day or at the end of your shift, filling in all the blanks at one time. But we
all know that it is impossible to remember what we did five minutes ago, much less eight
hours ago. You have to train yourself and your people to record results and information as
you get it - on batch records, lab notebooks, and test result forms.
12. Use Indelible Ink. The industry standard is black indelible ink because it photocopies
well and does not smear. Pencil is unacceptable because it smears easily and can be erased.
13. Banish the correction fluid. Using correction fluid is not allowed. I know of some
employees who don't even have correction fluid in their desk drawers, to avoid the
temptation to use it.
14. Line through, Initial, and date all changes. The correct way to make a change is to line
through the error once using your indelible ink pen, clearly write the correction above or
beside it, and initial and date the correction.
15. Never backdate or falsify records. Always use today's date when documenting your
work. If you do not, you are falsifying records. For example, if I made a batch of a product
today, and did not fill out a line on a batch record, a QA employee would stop by and ask
me whether I had completed that step. If I did remember completing it, I would write in the
Comments section of the document that QA had noticed that I had failed to document the
step and that I had in fact completed it. I would initial and date
my comment the day that I was writing it. Preferably, I would have an attachment or some
sort of corroborating data to back this up! The better idea is to record data when you get it.
Under no circumstances should you go back into a batch record and fill it out as though you
had filled it out properly to begin with.
16. There is no such thing as a dumb question. Better to ask and get an answer (see MCB
story above) than to assume and risk a batch, someone recently told me that a single gram of
one of their active ingredients was worth $8,000. Some larger biotech companies with
products on the market have batches worth $4-7 million each. An awful lot of money is
riding on those batches, not to mention the safety, purity, and effectiveness of the products.
It's critical that supervisors make sure their people feel comfortable asking those questions
and admitting their mistakes.
17. Take action to make things better. In all of the classes I teach, I always ask people to
take action to make things better.
Each of us sees things in our day-to-day jobs that others do not. Or we may reach a
conclusion faster than someone else. Have the courage to bring up things that need to be
improved. Be the responsible employee who picks the piece of paper from the floor rather
than steps over it.
As your move up in your career, people are going to trust you with information that is
confidential and sensitive. You must honor their confidences but also take action. For
example, if employees confide in you that they are worried about the safety of their work
area, you must immediately inform the area manager and also your Environmental Health &
Safety department coordinator in writing. The point is to not assume that the charge is
correct, but to turn it over to people who can follow up.
18. Ensure that equipment Is calibrated before using it. Equipment that must be calibrated
in a manufacturing or laboratory environment typically has an equipment calibration tag on
its front, side, or back that indicates the date the equipment was last calibrated, who did the
calibration, and when the next calibration is due. Check to make sure that your equipment is
within calibration before you use it. Otherwise, your results or measurements could be
inaccurate.
19. Record ID, part, lot, document, revision, and other control numbers. When something
goes wrong with a product lot, trying to determine the true source of the problem is often
like solving a mystery. The GMPs require that you assign and use unique numbers on each
lot of your raw materials, reagents, documents, and all lots of produced product to permit
traceability should there ever be a problem.
So when filling out a batch record or recording your results, record equipment, lot, sample,
reference sample, and document and revision numbers.
20. Do not bring food, gum, tobacco, or houseplants into production and laboratory areas. A
common GMP error is bringing drinks into a laboratory. Smoking, eating, and drinking are
prohibited in a GMP area. You do not want to have food inside a GMP area because rodents
and other pests will try to enter the f facility to get the food. A beetle can bore through 0.125
inch of solid plastic to get to food or the glucose or sucrose stored on pallets in your
warehouse. Houseplants may have insects on their soil and leaves.
21. Check your pest control devices frequently. If you use an outside pest control service,
test it by placing a plastic mouse in one of the traps. If the service doesn't find it, it's not
doing a thorough job inspecting and cleaning the traps. Because rats like to run along walls -
they do not see well, and they feel safer against a wall - rodent traps should be placed along
walls. Clean the bottom tray of insect electrocutors frequently. You may have an insect
infestation in the bottom of the tray. If a pregnant female is electrocuted, her young may
survive to feed on the remains of the dead insects inside the tray.
22. Before signing anything, check for accuracy, for completeness, and correct calculations.
In our industry, a signature is a legal and an ethical responsibility. If you have signature
authority and are asked to sign something, you must, to the best of your ability, review it
thoroughly and completely, make sure that everything that needs to be attached is attached,
and make sure that all calculations are correct. Never sign something without thoroughly
reviewing it first. Never sign something that you know to be wrong. Get it corrected and
then sign it.
23. Print clearly in logs, and fill them out completely. Fill out all logs and other documents
completely. Your handwriting must be clear and legible. If your handwriting, like mine, is
difficult to read, then print.
24. Record data directly on the appropriate form or notebook. Do not write original data on
scrap paper, napkins, or paper towels and then transfer the information to the appropriate
form or notebook. If you accidentally record your data on a piece of scrap paper, staple it to
the form or notebook, because it is original data. Always attach printouts and labels where
indicated. Never throw away original data.
25. Never simply average out-of-specification results to obtain a passing result do not
continue testing samples until you get enough that pass. As a result of the Barr case, there
has been a lot of scrutiny in this area. Every company should have an SOP that discusses
how to handle out-of- specification results and how to handle failure investigations. One
executive recently told me that he suspects that analysts were not telling their supervisor
when they got an out-of - specification result because an investigation would have to be
done. Supervisors take note: Encourage your people to tell you when they get an unusual
result, and don't punish them when they do.
26. Have another person perform double checks as Indicated In the batch record. Double
checks are required for critical steps, like weighing and adding raw materials, because
people have discovered that historically those are problematic areas. A double check means
that one person performs the work while another person observes and makes any
suggestions or corrections. Individuals then sign or initial the batch record where indicated.
GMPs require that you have sufficient staff to do this.
27. Keep shipping, receiving, and other doors closed. A common error is to leave shipping
and receiving doors open after a delivery has arrived - an open invitation for pests of all
kinds. Owls, snakes, rats, and mice have been found in warehouses looking for food, water,
and shelter. A field mouse only needs 0.25 inch to get under a door, so check the bottom of
your outside doors. If there is a gap, you could be inviting a rodent problem. Many years
ago a mouse ran across the back of a room in an older office building where I was teaching a
GMP class. (He probably wanted to make sure he met his GMP training requirement.) The
cGMPs require that you have an effective pest control program; keeping your receiving
doors closed will help.
28. During an Inspection, answer all questions honestly and directly. Do not guess or
speculate. Do not volunteer information. Refer questions that you cannot answer to your
supervisor. FDA and other regulatory agencies know that this is how employees are trained.
Don't be evasive, and don’t try to hide the truth. Don't guess, and don't state your opinion.
"If you think we're bad, you should see those guys down the hall!"
29. Report mistakes - or suspected mistakes - as soon as possible to your supervisor. I hate
to make mistakes, rd rather be perfect. But the truth is that we're all human, and human
beings make mistakes. As a supervisor, encourage your people to tell you things. Don’t
jump all over them when they do so they never do it again. And don't go looking for
scapegoats. If something goes wrong in your group, you as a supervisor or manager must
accept responsibility for the mistake see what you can reconstruct or recover, and figure out
how you can prevent the mistake from happening again.
30. Read and become familiar with all SOPs and other documents that relate to your work.
You must know your SOPs. A common 483 observation continues to be "Firm failed to
follow its own SOP." If an SOP needs to be revised, tell your supervisor and offer to help
revise it and get it approved.
Use of Ion Exchange Resins in Water Purification
Systems
Water purification is a necessary process for the water used in pharmaceutical
manufacturing because it contains a lot of suspended material as well as in the form of ions.
Turbidity and suspended solids can be removed by activated carbon filter but ions cannot be
removed by ACF. This form of ions is called hardness of water. Hardness is denoted by
Calcium and Magnesium ions. The process to remove this hardness is called softening and
water is known as soft water.
Some resins are required to remove this hardness. Generally ion exchange resins are used
for the process. These ions of hardness are taken by the resin. The resins are charged by
chemicals to release this hardness.
Ion exchange resins are white to yellow colored synthetic polymers beads of small size
ranging from 0.5-1.0 mm having the pores on their surface to trap and release the ions
easily. Important – Resins are solids but measured in liter.
Two types of ion exchange resins are used in water systems - cation-exchange resins which
release the hydrogen ions in water while trapping the ions from water and anion-exchange
resins those release OH ions in exchange of hardness ions. Thus sodium ions are released in
water and calcium and magnesium ions are attached with the resins. So the resins are
required to regenerate before use again.
Anion is the negatively charged ion and anion exchanger is regenerated by 10-15% NaOH
solution and water released from anion bed has pH between 7.5 and 9.5. Cation is positively
charged ion and anion bed is regenerated by 8-12 % hydrochloric acid solution and pH of
water released from the anion bed remains between 2 and 3.
By the process of regeneration sodium ions are attached again with the surface of ion
exchange resin to get replaced by the calcium and magnesium ions of hard water.
Can any deviation be changed into the change control?

Ans-Only planned deviations are changed into change controls.
What is the difference of vacuum pressure and vapor pressure?
Vaccum pressure is negative pressure exerted under space that is partially
exhausted by artificial means at respective temperature (such as an air pump).
Vacuum pressure is measured relative to ambient atmospheric pressure. It is
referred to as pounds per square inch (vacuum) or psiv.
Vapour pressure is the pressure exerted by vapour in thermodynamic equilibrium

with its condensed phases (solid or liquid) at a given temperature in a closed
system. Its unit is Pascal (Pa).
In Stability testing if significant change occurs then what will be the action plan?
If it is at Development stage, then Formulation change or packaging change shall
be done if it at Exhibit batch study, then that should be addressed as OOT/OOS
and same should be investigated. Then shall go for change in formulation or
packaging. If it is at commercial batches then same should be addressed as
OOS/OOT and should investigate. Based on study product should recall
What do you mean by MKT ﴾Mean Kinetic Temperature﴿ in stability?
Mean Kinetic Temperature is defined by the USP as "the single calculated
temperature at which the total amount of degradation over a particular period is
equal to the sum of the individual degradations that would occur at various
temperatures. Thus, MKT may be considered as an isothermal storage temperature
that simulates the non isothermal effects of storage temperature variations. It is not
a simple arithmetic mean. MKT is calculated from temperatures in a storage
facility.
How to select HPLC column for a particular product?
If sample is basic then use BDS column & if acidic then use
ODS column. the column selection is depends upon the polarity of the sample or
drug
if in case the drug is highly polar choose highly non-polar column (c18,c8)
if in case the drug is low polar choose the low non-polar column (cyno,c4)
sample polar then take --- non-polar column
sample non-polar then take ---polar column
it depends upon the properties and nature of analyze
because selection of column means selection of stationary
phase. Furthermore it also depends on the type of product
i.e. multiactive (more than one active), needs a better
resolution of peaks by increasing column length.
What is the composition of a C18 column?
Octadecyl carbon chain bonded silica
What is validation, validation protocol and validation master plan?
Validation: Action of proving and documenting that any
process, procedure or method actually leads to the
expected results
VP: The VP is a written plan stating how validation will be

conducted, including test parameters,
product characteristics, production equipment and decision
points on what constitutes
acceptable test results.
V M P: VMP is a high level document that establishes an

umbrella validation plan for the entire project
and summarizes the manufacturer’s overall philosophy and
approach, to be used for
establishing performance adequacy. It provides information
on the manufacturer’s validation
work programmed and defines details of and time-scales for
the validation work to be
performed, including stating the responsibilities relating
to the plan.
How much the minimum recovery should be in swab sampling?
85% is minimum limit for the swab recovery.
General Limit is 85%-115%
What is the acceptance criterion for detergent washing?
Acceptance criteria : NMT 10ppm
What do you mean by LOD and water content?
LOD is the loss during drying of sample as per prescribed
conditions which gives loss (presence) of all evaporating
solvents along with water.It is the dry base.
While water content gives the moisture present in the
sample only. It is anhydrous base.
What do you mean by Q+5 in dissolution?
Q is the specification limit (the mean of individual tablets tested should be not less
than Q) of the dissolution test.
Q+5 is the criteria for which the dissolution passing with 6 tablets at S-1 stage
(optimum release).:
What should be the sampling point in dissolution test?
There is no specific recommendation for sampling in
dissolution test. It is recommended that a specimen should
be withdraw from a zone midway between the surface of the
Dissolution Medium and the top of the rotating basket or
blade, not less than 1 cm from the vessel wall.
Where multiple sampling times are specified, replace the

aliquots withdrawn for analysis with equal volumes of fresh
Dissolution Medium at 37°C or, where it can be shown that
replacement of the medium is not necessary, correct for the
volume change in the calculation.
Specimens are to be withdrawn only at the stated times

within a tolerance of ± 2%.
Which will give more drug release paddle or basket in dissolution?
Paddle will be the best option as we know greater the surface area, greater will be
the volume of water-better for dissolution.
What is the difference between Drug Purity and Drug Potency?
Potency is a measure of drug activity expressed in terms of
the amount required to produce an effect of given intensity.
Purity is a measure of the amount of API present in a sample

compared to those of related substances, impurities,
residual solvents, etc.
What should be the minimum limit of a working standard?
All values may comply with the predefined specifications. It’s
no need that its assay closes to 100%.
What is the storage condition for reference standard?
It is depend on the nature of the material. Most of the
standards are store at Room Temperature. Some Standards
which are degradable at Room Temperature, those are store in
Refrigerator or Freezer. Liquid stage standards are store
depends on it stability at various conditions.
Why we use the placebo in analysis?
Placebo consist of Excipient other than active ingrediant.While performing assay
or RS we analyze placebo to find out if there is any interference of Excipient with
main drug analysis. So that method is accurate.
How can you fix the known and unknown impurity limit for any drug substance?
The limits for a known impurity shall be fixed based on the
toxicology data of the impurity and the dosage of the drug
product; where as for the unknown impurity is based on the
dosage of the product.
How do we choose HPLC or Gas chromatography for a sample analysis?
It is based on.
Polarity
volatility
thermo stability
solubility......
Why 3X sampling plan are implemented in process validation?
3 sampling plans are implemented in process validation because the results are
1-accidental
2-co incidental
3-conformational
some times there might be chances for 4th batch also but it is cost effective and
time consuming process.
What is the difference between temporary change control and deviation?
In Short,
Deviation is an unplanned change

Change Control is a planed change after assessing the
impact on the other functions.
Why we use toluene for resolution in UV calibration?

Bcoz toluene gives maxima and minima at 266nm and 269nm to
check resolution in UV calibration and we use hexane as
diluents because it has no UV absorbance.
What is pooled sample and why it is required in dissolution test?
it is the primary requirement, the sample should completely expose to dissolution
media at all the surfaces....Pooled sample is in completely exposure to the
dissolution fluid....That's why we use basket apparatus for the floating samples. in
order to know how much drug is dissolved or disintegrated in the dissolution
medium
Why we use disodium tartare for determination of factor in karl ficher titration?
Karl Fischer titration method is used to for the
titrimetric determination of water in samples. Because of
KF reagent undergoes the slow deterioration, the reagent
has to be standardized frequently, before going for the
water determination in sample.
Disodium Tartrate is used as a primary standard substance

for the standardization because of the following properties:
1. Available in a stable crystalline hydrate form

2. Its water content is close to theoretical value
3. Substances in nearly 100% purity
4. More favorable gravimetric factors
5. Stable at extreme humidifies
6. It is relatively insoluble in absolute methanol
7. Its water content is rapidly and quantitatively titrated
to a sharp end point
What are closely monitor parameters in stability study?
Temperature and humidity
1) What does u mean by MACO & NOEL?

MACO-max allowable carries over
NOEL-no observed effect leve; both of them are set limits for cleaning validation
2) Composition of c18column
Octa di acyl silane
3) How to select columns for specific products

Polarity, Electrical charge, Molecular size.
Normal phase is recommended for water sensitive compounds/geo metric

isomers/cis-transisomers/chiral compounds/class separations Reverse phase
for non polar /polar/ ionizable /non ionizable moleculesGel permeation for
large size compounds like polymers Ion exchange for resins4) define
validation/validation protocol/validation master plan Validation protocol :-
it is written plan describing the process to be validated ,including production

equipment & how validation to be conducted
Validation master plan:

it was also called as VMP which is one of important document in GM regulated
industries. it outlines the principles involved in qualification of facility, defining
areas &systems to be validated & provides written programmed for achieving &
maintaining qualified facility with validity processes
Validation:
it was defined as collection & evaluation of data from the process design
stage through commercial production which establishes scientific evidence that the
process is capable of producing quality product consistently
What is process validation?

Establishing documented evidence with high degree of assurance that specific
process will consistently produce a product meeting its predetermined
specifications & quality characteristics
What does u mean by MKT? MKT
Is an expression of cumulative thermal stress experienced by a product at varying
temperatures during storage & distribution?
Temp & humidity required for tablet compression?

Temp: - NMT 30
Humidity: - 45 +/- 5
8) What is humidity & relative humidity?

Humidity- it was amount of water vapour in air Relative humidity - the
amount of water vapour present in air expressed as % of amount needed for
saturation at the same temp
9) What is vaccum & vapour pressure?
Vaccum pressure
It was a pressure below normal atmospheric pressure which will be used to
remove air from surrounding ex: vaccum pumps
Vapor pressure
- It was pressure exerted by a vapor in thermodynamic equilibrium with its
condensed phases (solid/liq) at a given temp in closed system
10) What are stability zones & climatic conditions?
Zone-1: great Britain/north Europe/Canada/Russia (temp-21

RH-45%) (Moderate region)
Zone-2: USA/Japan/South Europe (temp-25 RH-60%) (Subtropical region)
Zone-3: Iran/Iraq/Sudan (temp- 30 RH- 55%) (Hot region)

Zone-4: Brazil/Ghana/Indonesia /Nicaragua/Philippines (temp-30 RH -70%)

(tropical region )
11) What does u mean by bracketing & matrixing in stability studies?
Bracketing
: it was design of stability schedule such that at any time point only the samples on
extremes e.g. of container size/dosage strength are studied
Matrixing
: it was statistical design of stability schedule only a fraction of total number of
samples are tested at any sampling point. At a subsequent sampling point, different
sets of samples of total numb would be tested
12) What is limit of cleaning validation?

It should be visually clean & no residue should be visible after cleaning No
more than 10 ppm of product will be appear in another product No more than 0.1%
of normal therapeutic dose of one product will appear in max daily dose
of subsequent product
13) What is lod & water content LOD:

it is loss of weight expressed as w/w resulting from water & volatile matter of any
kind that can be driven off under specified conditions
WATER CONTENT:
It is the amount of water to be present in a sample of drug compounds
14) What is the difference between LOD & Water content Lod :
It was determined by heating the sample below its melting point in an oven & it
includes all volatile matter including water content & solvents
Water content:
It was determined by KF titration & it consist only water content
15) What is difference b/w calibration& validation& qualification?
Calibration
- The set of operations that establish under specified conditions the
relationship b/values indicated by an instrument or system for measuring and
corresponding values of ref.standerd
Validation
action of proving & documenting that any process actually & consistently
leads toexpected results
Qualification
- action of proving & documenting that any premises ,systems & equipments
arecorrectly installed & lead to expected results
16) DEFINE CAPA

Corrective and preventive actions
17) In Kf Titration Why We Hav To Use Di Sodium Tartarate

Both water & di sodium Tartrate are generally used for standardization of kf
reagent as we going to check capacity of 1ml of kf reagent to neutralize water.
Hence water content in standardization is very imp one .as di sodium tartrate
contains 15.66% of hydrate it was recommended for standardization instead of
water
18) what is formula of kf standardization Weight of sample x 1000/ titration
volume19) what type of columns are used in gc
Capillary & open tubular columns
20) any deviation can be changed into change control
Yes planned deviations
21) why we shouldn’t dispatch reprocess material to export
Becoz there may be chances out of specification of product like increase in

impurity than its limit
22) What is the difference between sonication & homogenization?
Sonication is the process of making soluble of UN dissolved particles by degassing

while homogenization is the process of making uniform solution
24) What is the procedure to prepare placebo

Take all raw materials other than active ingredient & mix it
25) What is stationary phase?
It was substance inside of a column through which mobile phase flows during
separation process
26) What do u mean by end capping
A column is said to be end capped when a small silyating agent is used

to bond residual silanolgroups on packing surface
27) How much min recovery should be in swab sampling?
General limit 85-115% but in swab sampling it should be 85%
28) What are closely monitor parameters in stability study
Temp & humidity

29) What is photo stability?
It was study performed to evaluate & demonstrate that light exposure doesn’t result in
unacceptable change in new drug substances
31) What is the wave length of polarimeter lamp?
589.3 nm
32) In stability testing if significant change occurs what will be the action plan
During stability testing the term “significant change “is used only in case of drug
products .when it
Occurs then do the out of trend analysis
33) What should be the min level of working standard?
All values may complied to predefined specifications .it’s no need that its assay
close to 100%
34) How we fix validity period of volumetric solution & re-standardization

due date
Protocol shall be prepared for to establish the re standardization date

for volumetric solution. Date shall be fixed on the basis
of standardization study of volumetric solution on fixed or predefined in
protocol interval e.g.: 1/2/3/7/15 days etc. the % rsd shall be NMT 0.2% at
all intervals
35) What is DT for dispersible tablets?
3mins
36) What should be the sampling point in dissolution testing
There is no specific recommendation for sampling in dissolution test. It is

recommended that specimen should be withdraw from a zone midway between
surface of dissolution medium &top of rotating basket
/blade NLT 1cm from vessel wall where multiple sampling times are specified
,replace the aliquots withdrawn for analysis with equal volumes of dissolution
medium at 37 or where it can be shown that replacement of medium is not
necessary ,correct for the volume change in calculation Specimens are to be
withdrawn only at stated times within tolerance of +/-2%
37) What is DT for enteric coated tablets?
2 hrs in gastro intestinal simulated fluid & 1 hr in phosphate buffer
38) What is DT for coated tablets?
30-45 mins
39) What is the difference between method validation & verification?
Method validation
It is validation of method we adopt
Method verification
: Its high degree of assurance to verify
40) What is the difference between drug purity & potency?
Purity: it is the absence of unwanted substances like impurities & contaminants

Potency: it is a measure of drug activity measured in terms of amount of drug
required to produce an effect
.
41) Why pooled sample is required in dissolution test
It is the primary requirement, the sample should completely expose to dissolution

media at all surfaces .pooled sample is in completely exposure to dissolution fluid that’s
why we use basket apparatus for floating tablets.
42) Which will give more drug release paddle or basket dissolution?
Paddle as we know greater the surface area greater will be volume of water better
for dissolution
43) Which gases are used in gc
Helium & nitrogen
44) What is the difference between polarimeter lamp & ir lamps?
Polarimeter lamp emits the polarized light which in range of visibility (400-
700nm) while it lamp emits radiation in ir range (I -1000 micro meters)
45) What is the difference b/w temp change control & deviation?
Temp change control: its planned change after assessing the impact on other
functions Deviation: unplanned change
46) What is the difference b/w uniformity of content & content of uniformity?
Both terms are same & they are analyzed by individual assay
47) What is limit of friability of tablets?

Friability is used to determine physical strength of tablet during packing &
transporting with help of friabilator. For this test accurately weigh 10 tabs & place
them in rotating drum of friabilator at 25 rpm& it was rotated for 100 times & then
remove the tabs & weigh the tabs now. The sample fails test if anyone of them
cracked /cleaved/broken. If the wt loss is >1 % then test will be repeated so 1%
weight variation will be acceptable in friability of tabs
48) What is the relative response factor in related substances?
It is resonance of peak with respect to main peak response
49) How do we choose hplc /gc for sample analysis

Depending upon compound nature, degradation, polarity, solubility, molecular
weight, volatile nature, thermal degradation etc
50) What is recovery factor?
It is used for cleaning validation by following formula% recovery = area

of individual swab level x std dilution/area of corresponding std solution sample
dilution x 100
51) Define pka
It’s an equilibrium constant used for dissociation of weak acid, & also known as
acid ionization constant
1. What is an SOP?
A Standard Operating Procedure (SOP) is a certain type of document that describes in a step-
by-step outline form how to perform a particular task or operation. Everyone in a company
must follow the same procedures to assure that tasks are performed consistently and
correctly. Most companies have a wide variety of SOPs that describe how to do different
tasks. In many companies technicians and operators are trained in how to follow
individual SOPs and their training record specifies which SOPs they are trained on and are
authorized to use.
2. What is 21 CFR parts 11?

Title 21 CFR Part 11 of the Code of Federal Regulations deals with the Food and Drug
Administration (FDA) guidelines on electronic records and electronic signatures in the
United States. Part 11, as it is commonly called, defines the criteria under which electronic
records and electronic signatures are considered to be trustworthy, reliable and equivalent to
paper records
3. What are user requirements?
User Requirements Specification describes what users require from the System. User
requirement specifications are written early in the validation process, typically before the
system is created. It is written by the System Owner and End Users, with input from Quality
Assurance. Requirements outlined in the URS are usually tested in the
Performance Qualification. User Requirements Specifications are not intended to be a
technical document; readers with only a general knowledge of the system should be able to
understand the requirements outlined in the URS.
4. What is a validation plan?
Validation Plans define the scope and goals of a validation project. Validation
Plans are written before a validation project and are specific to a single Validation Project.
Validation Plans can include:
Deliverables (Documents) to be generated during the validation process
Resources/Departments/Personnel to participate in the validation project
Time-Line for completing the validation project
5. What is an IQ document?
Installation Qualifications are a collection of test cases used to verify the proper installation
of a System. The requirement to properly install the system was defined in the Design
Specification. Installation Qualifications must be performed before completing
Operational Qualification or Performance Qualification.
6. What is an OQ Document?
Operational Qualifications are a collection of test cases used to verify the proper functioning
of a System. The operational qualification tests requirements defined in the Functional
Requirements. Operational Qualifications are usually performed before the system is released
for use.
7. What is a PQ Document?
Performance Qualifications are a collection of test cases used to verify that a System
performs as expected under simulated real-world conditions. The
performance qualification tests requirements that were defined in the User Requirement
Specification (or possibly the Functional Requirements). Due to the nature of performance
qualifications, these tests are sometime conducted with power users as the system is being
released.
8. What is a Validation Summary Report?
Validation Summary Reports provide an overview of the entire validation project. When
regulatory auditors review validation projects, they typically begin by reviewing the
summary report. The validation summary report should include:
A description of the validation project

all test cases performed, including if those test cases passed without issue
all deviations reported, and including how those deviations were resolved
9. What is a Change Request?
Change Control is a general term describing the process of managing how changes are
introduced into a controlled System. In validation, this means how changes are made to
the validated system. Change control is required to demonstrate to regulatory authorities
that validated systems remain under control after system changes. Change Control systems
are a favorite target of regulatory auditors because they vividly demonstrate an organization
capacity to control its systems.
Q. Why water for pharmaceutical use is always kept in close loop in continuous
circulation?
A. Water is a best medium for many microorganisms, microorganism can be a highly
pathogenic which causes serious diseases(many diseases are water born), these pathogens
infect after consumption of contaminated water, microorganisms tend to settle on a surface if
water is allowed to stand in a stagnant position for few hours, these settled microorganism
form a film over the surface of vessel and piping, such film formed by microorganisms is also
called as Bio-film, bio-films are very difficult of remove, once a bio-film is formed at a
particular point then that point may form a bio-film again even after cleaning very easily as
seed from this point is may not completely get removed effectively.
Bio-films then can become a source of microbial contaminations;
therefore purified water after collection in a distribution system is always kept in a closed loop
in a continuous circulation. A continuous circulation is also not enough at some points,
therefore it is aided with high temperature range from 65 °C to 80°C, a minimum temperature
of 65 °C is considered a self sanitizing, but better assurance is obtained with a temperature of
80°C.Purified water collected should be stored in a stainless still vessel which must facilitate
distribution to the point of use in a closed loop of continuous circulation, tank should be made
of corrosion free material of construction, and must facilitate sanitization and easy cleaning.
Q. Water for pharmaceutical use shall be free cations, anions and other impurities why?
Water for pharmaceutical must be free from inorganic as well as organic impurities, minerals,
and heavy metals. Some impurities like calcium, magnesium, ferrous are responsible for
degradation of drug molecule, many Cation like ferrous and calcium magnesium act as
catalysts in degradation reaction of drug molecule, anions like chloride are highly active they
participate in nucleophilic substitution reactions, where in they break a double bond between -
C=C- in to a single bond as CL –CH-CH2- , which a reason why we observe that color dies
tend to fed in presence of chlorine as most of the dies used are diazo compounds which has
plenty of places for nucleophilic substitution reactions, which is also a reason why stability of
drug is drastically affected in presence of cations and anions from mineral origin present in
water.
Q. Water for pharmaceutical use shall be free heavy metals why?
A. Heavy metals like lead and arsenic are highly cumulative neurotoxin metals, heavy metals
are not eliminated out of our body easily like other drugs and molecules but heavy metals bind
with proteins and tend to get accumulated in fatty tissues, nerve tissue is most likely to get
damaged by heavy metals, heavy metal causes nervous tissue damage there for water must be
free from heavy metals.
Q. Brazil falls under which climatic zone?
A. Zone IVB (30 degree Celsius and 75% relative humidity)
Q. Change in the size or shape of the original container requires any stability study?
A. Change in the size or shape of the original container may not necessitate the initiation of
new stability study.
Q. Forced degradation (stress testing) and accelerated stability testing are same?
A. Forced degradation and stress testing are not same. Stress testing is likely to be carried out
on a single batch of the drug substance. The testing should include the effect of temperatures
(in 10°C increments (e.g., 50°C, 60°C) above that for accelerated testing), humidity (e.g., 75
percent relative humidity or greater) where appropriate, oxidation, and photolysis on the drug
substance. The testing should also evaluate the susceptibility of the drug substance to
hydrolysis across a wide range of pH values when in solution or suspension. Photo stability
testing should be an integral part of stress testing.
Q. According to WHO guidelines what is the storage condition of climatic zone IVa and
zone IVb?
A. Zone IV a: 30°C and 65% RH (hot and humid countries)
Zone IV b: 30°C and 75% RH (hot and very humid countries
Q. Countries come under climatic zone IVb?
A.Brazil,Cuba,China,Brunei,Cambodia,Indonesia,Malaysia,Myanmar,Philippines,Singapore,T
hailand
Q. What is the purpose of stress testing in stability studies?
A. Stress testing of the drug substance can help identify the likely degradation products,
which can in turn help establish the degradation pathways and the intrinsic stability of the
molecule and validate the stability indicating power of the analytical procedures used. The
nature of the stress testing will depend on the individual drug substance and the type of drug
product involved.
Q. What is the formula for calculating number of air changes in an area?
A. Number of air changes/hour in an area is
= Total Room Airflow In CFM x 60

Total Volume of room in cubic feet
For calculating Total Room Airflow in CFM, first calculate air flow of individual filter.
Formula is given below.
Air flow (in cfm) = Avg.air velocity in feet/Minute x Effective area of filter
Then find Total air flow. Formula is
Total Air flow = Sum of air flow of individual filter.
Air flow Velocity can be measured with the help of Anemometer.
Q. What is dead leg?
A. A dead leg is defined as an area in a piping system where liquid can become stagnant and
not be exchanged during flushing.
Q. What is the recommended bio burden limit of purified water & WFI?
A. Purified water has a recommended bioburden limit of 100 CFU/mL, and water for injection
(WFI) has a recommended bio burden limit of 10 CFU/100 mL.
Q. Brief about ICH stability guidelines?
A. Q1A- Stability testing of new drug substance & products
Q1B- Photo stability testing of new drug substances & products
Q1C-Stability testing of new dosage forms
Q1D-Bracketing & Matrixing designs for testing of new drug substances and products
Q1E-Evaluation of stability data
Q1F-Stability data package for registration applications in climatic zone III & IV
(Withdrawer)
Q. What are significant changes in stability testing?

A.
1. A 5% change in assay for initial value.
2. Any degradation products exceeds its acceptance
Criterion.
3. Failure to meet acceptance criterion for
appearance, physical attributes and functionality
Test.
4. Failure to meet acceptance criteria for dissolution
For 12 units.
Q. If leak test fail during in process checks what needs to be done?
A.
Immediately stop packing process and check for
1.Sealing temperature
2. Verify for any possible changes like foil width, knurling etc.
3. Check & quarantine the isolated quantity of packed goods from last passed in process.
4. Collect random samples & do retest.
5. Blisters from the leak test passed containers shall allow going further and rest must be
deblistered/ defoiled accordingly.
Q. How many Tablets shall be taken for checking friability?
A. For tablets with unit mass equal or less than 650 mg, take sample of whole tablets
corresponding to 6.5g.For tablets with unit mass more than 650mg; take a sample of 10 whole
tablets.
Q. What is the formula for calculating weight loss during friability test?
A. %Weight loss = Initial Weight - Final Weight X 100
Initial Weight
Q. What is the pass or fail criteria for friability test?
A. Generally the test is run for once. If any cracked, cleaved or broken tablets present in the
tablet sample after tumbling, the tablets fails the test. If the results are doubtful, or weight loss
is greater than the targeted value, the test should be repeated twice and the mean of the three
tests determined. A mean weight loss from the three samples of not more than 1.0% is
considered acceptable for most of the products.
Q. What is the standard number of rotations used for friability test?
A. 100 rotations
Q. What is the fall height of the tablets in the friabilator during friability testing?
A. 6 inches. Tablets falls from 6 inches eight in each turn within the apparatus.
Q. Why do we check hardness during in process checks?
A. To determine need for the pressure adjustments on the tableting machine. Hardness can
affect the disintegration time. If tablet is too hard, it may not disintegrate in the required
period of time. And if tablet is too soft it will not withstand handling and subsequent
processing such as coating, packing etc.
Q. What are the factors which influence tablet hardness?
A.
1.compression force
2.Binder quantity(More binder more hardness)
3.Moisture content
Q. Which type of tablets is exempted from Disintegration testing?
A. Chewable Tablets
Q. Which capsule is bigger in size - size '0' or size '1'?
A. '0' size
Q. What is the recommended temperature for checking DT of a dispersible tablet?
A. 25 ±10C (IP) & 15 – 250C (BP)
Q. What is mesh aperture of DT apparatus?
A. 1.8 -2.2mm (#10)
Q. What are the pass/fail criteria for disintegration test?
A. If one or two tablets/capsules fail to disintegrate completely, repeat the test on another 12
additional dosage units. The requirement is meeting if not fewer than 16 out of 18
tablets/capsules tested are disintegrated completely.
Q. What are the recommended storage conditions for empty hard gelatin capsules?
A. 15 - 250C & 35 -55% RH
Q. Which method is employed for checking “Uniformity of dosage unit”?
A.
A.)Content uniformity
B.) Weight Variation
Weight variation is applicable for following dosage forms; Hard gelatin capsules, uncoated or
film coated tablets, containing 25mg or more of a drug substance comprising 25% or more by
weight of dosage unit.
Q. What is the recommended upward and downward movement frequency of a basket-
rack assembly in a DT apparatus?
A. 28 – 32 cycles per minute.
Q. When performing the ‘uniformity of weight’ of the dosage unit, how many
tablet/capsule can deviate the established limit?
A. Not more than two of the individual weights can deviates from the average weight by more
than the percentage given in the pharmacopeia, and none can deviates more than twice that
percentage.
Weight Variation limits for Tablets
IP/BP Limit USP

80 mg or less 10% 130mg or less
More than 80mg or Less than 7.5% 130mg to 324mg
250mg
250mg or more 5% More than 324mg
Weight Variation limits for Capsules

IP Limit
Less than 300mg 10%
300mg or More 7.5%
Q. What needs to be checked during in process QA checks?
a.) Environmental Monitoring
b.) Measured values obtained from the process equipment (ex: temperature, RPM etc.)
c.) Measured values obtained from persons (ex: timings, entries etc.)
d.) Process attributes (Ex: weight, hardness, friability etc.)
Q. What precautions shall be taken while collecting in process samples?
A. While collecting in process samples, avoid contamination of the product being sampled
(Don’t collect samples with bare hands) & avoid contamination of sample taken.
Q. In a tablet manufacturing facility ‘positive’ pressure is maintained in processing area
or service corridors?
A. In tablet manufacturing facilities, pressure gradients are maintained to avoid cross
contamination of products through air. Usually processing areas are maintained under positive
pressure with respect to service corridors.
Q. If sticking observed during tablet compression what may the probable reason for the
same?
1.If the granules are not dried properly sticking can
Occur.
2.Too little or improper lubrication can also leads to
Sticking.
3.Sticking can occur because of too much binder or
Hygroscopic granular.
Q. What checks shall be carried out, while calibrating DT apparatus?
A. While calibrating DT apparatus, following checks shall be performed.
1.) Number of strokes per minute (Limit:29-32 cycles/min)
2.) Temperature by probe & standard thermometer
(Limit: 37 ± 1 OC).
3) Distance travelled by basket (Limit:53 -57mm)
Q. What is In process checks?
A. In process checks are checks performed during an activity, In order to monitor and, if
necessary, to adjust the process to ensure that product confirms to its specification.
Q. What is the difference between disintegration and dissolution?
A. Disintegration is a disaggregation process, in which an oral dosage form falls apart in to
smaller aggregates.(Disintegration time is the ‘break up’ time of a solid dosage form).
Whereas dissolution is a process by which solid substance enters in the solvent to yield a
solution. It is controlled by the affinity between the solid substance and the solvent.
In other word disintegration is a subset of dissolution.
Q. Why do we calibrate a qualified equipment/instrument on definite intervals?
A. An equipment or instrument can ‘drift’ out of accuracy between the time of qualification
and actual use. So it is recommended to calibrate and recalibrate the measuring devices and
instruments on predetermined time intervals, to gain confidence on the accuracy of the data.
Q. Why do we consider three consecutive runs/batches for process validation? Why not
two or four?
A. The number of batches produced in the validation exercise should be sufficient to allow the
normal extent of variation and trends to be established and to provide sufficient data for
evaluation and reproducibility.
· First batch quality is accidental (co-incidental),
· Second batch quality is regular (accidental),
· Third batch quality is validation (conformation).
In 2 batch we cannot assure the reproducibility of data,4 batches can be taken but the time and
cost are involved.
Q. Explain about revalidation criteria of AHU system?
A. AHU system shall be revalidated periodically as mentioned in the regulatory standards.
AHU shall be revalidated in following cases also.
· When basic design of AHU is changed,
· When clean room volume is changed,
· When new equipment is installed
· When a construction is carried out, that calls for reconstruction of AHU system.
Q. What needs to be checked during AHU validation?

A. During AHU validation, following tests shall be carried out
· Filter efficiency test,
· Air velocity & number of air changes,
· Air flow pattern (visualization)
· Differential pressure, temperature and RH
· Static condition area qualification
· Dynamic condition qualification
· Non-viable count
· Microbial monitoring
· Area recovery and power failure study.
Q. Position of oblong tablets to be placed in hardness tester to determine the hardness?
Lengthwise / widthwise?
A. Position of oblong tablets should be length wise because the probability of breakage is
more in this position.
Q. Explain in detail about qualification of pharmaceutical water system?
A. Qualification of pharmaceutical water system involves three phases
· Phase -1
· Phase -2
· Phase -3
Phase -1
A test period of 2-4 weeks should be spent for monitoring the system intensively. During this
period the system should operate continuously without failure or performance deviation.
Water cannot be used for pharmaceutical manufacturing in this phase. The following should
be included in testing approach.
· Under take chemical & microbiological testing in accordance with a defined plan.
· Sample incoming feed water daily to verify its quality.
· Sample each step of purification process daily.
· Sample each point of use daily.
· Develop appropriate operating ranges.
· Demonstrate production and delivery of product water of required quantity and quality.
· Use and refine the SOP’s for operation, maintenance, sanitization and trouble shooting.
· Verify provisional alert and action levels.
· Develop and refine test failure procedure.
Phase -2
A further test period of 2-4 weeks. Sampling scheme will be same as Phase – 1.Water can be
used for manufacturing process in this phase.
Approach should also
· Demonstrate consistent operation within established ranges.
· Demonstrate consistent production & delivery of water of required quality and quantity.
Phase - 3
Phase 3 runs for one year after satisfactory completion of phase-2.Water can be used for
manufacturing process during this process.
Objectives & Features of Phase -3

· Demonstrate extensive reliable performance.
· Ensure that seasonal variations are evaluated.
· The sample locations, sampling frequencies and test should be reduced to the normal
routine pattern based on established procedures proven during Phase -1 & phase - 2.
Q. What is the difference between calibration and Validation?
A. Calibration is a demonstration that, a particular
Instrument or device produces results within specified limits by comparisons with those
produced by a reference or traceable standard over an appropriate range of measurements.
Whereas Validation is a documented program that provides high degree of assurance that a
specific process, method or system consistently produces a result meeting pre-determined
acceptance criteria.
In calibration performance of an instrument or device is comparing against a reference
standard. But in validation such reference standard is not using.
Calibration ensures that instrument or measuring devices producing accurate results. Whereas
validation demonstrates that a process, equipment, method or system produces consistent
results (in other words, it ensures that uniforms batches are produced).
Q. Briefly explain about ICH climatic zones for stability testing & long term storage
conditions?
A.ICH STABILITY ZONES
Zone Type of Climate
Zone I Temperate zone
Zone II Mediterranean/subtropical zone
Zone III Hot dry zone
Zone IVa Hot humid/tropical zone
Zone IVb ASEAN testing conditions hot/higher humidity
Long term Storage condition

Climatic Zone Temperature Humidity Minimum
Duration
Zone I 21ºC ± 2ºC 45% rH ± 5% rH 12 Months
Zone II 25ºC ± 2ºC 60% rH ± 5% rH 12 Months
Zone III 30ºC ± 2ºC 35% rH ± 5% rH 12 Months
Zone IV 30ºC ± 2ºC 65% rH ± 5% rH 12 Months
Zone IVb 30ºC ± 2ºC 75% rH ± 5% rH 12 Months
Refrigerated 5ºC ± 3ºC No Humidity 12 Months
Frozen -15ºC ± 5ºC No Humidity 12 Months
Q. What is bracketing & matrixing in stability testing?

A.Both Matrixing & Bracketing’s are reduced stability testing designs
Bracketing
The design of a stability schedule, such that only samples of extremes of certain design factors
(ex:strength,package size) are tested at all time points as in full design.The designs assumes
that the stability of any intermediate level is represented by the stability of extremes tested.
Matrixing
The design of a stability schedule, such that a selected subset of possible samples for all factor
combinations is tested at a specified time point.At a subsequent time point another subset of
samples for all factor combination is tested. The design assumes that the stability of each
subset samples tested represents the stability of all samples at a given time point.
There for a given time point other than initial & final ones not every batch on stability needs
to be tested.
Q. What are the common variables in the manufacturing of tablets?
A.
· Particle size of the drug substance
· Bulk density of drug substance/excipients
· Powder load in granulator
· Amount & concentration of binder
· Mixer speed & mixing timings
· Granulation moisture content
· Milling conditions
· Lubricant blending times
· Tablet hardness
· Coating solution spray rate
PHARMA ABBEREVIATIONS
AADA: Abbreviated antibiotic drug application

ADE: Adverse drug event
ADME: Absorption, distribution, metabolism, and excretion
AHU: Air Handling Unit
ANDA: Abbreviated new drug application
ANVISA: Agência Nacional de Vigilância Sanitária (National Health
Surveillance Agency Brazil)
AP: Applicants Part (of EDMF)
API: Active pharmaceutical ingredient
APR: Annual product review (APQR – Annual product quality
review)
AQL: Acceptable quality level
AR: Analytical Reagent
ASHRAE: American Society of heating, Refrigeration and
Air Conditioning Engineers
ASM: Active Substance Manufacturer
ASMF: Active Substance Master File
AST: Accelerated stability testing
ASTM: American Society for Testing and Materials
BA/BE: Bioavailability/bioequivalence
BCS: Biopharmaceutical classification system
BET: Bacterial Endotoxins Test
BFS: Blow Fill Seal
BI: Biological Indicator
BMR: Batch Manufacturing/Processing Record
BOD: Biological Oxygen Demand
BOM: Bill of Materials
BOPP: Biaxilary Oriented Polypropylene
BP: British Pharmacopoeia
BPR: Batch Packaging Record
BRMS: Biologics Regulatory Management System
BSE: Bovine spongiform encephalopathy (mad cow disease)
CAPA: Corrective and preventive action
CBE: Changes being effected
CBER: Center for Biologics Evaluation and Research (FDA)
CCIT: Container closure integrity test
CDER: Center for Drug Evaluation and Research (FDA)
CDSCO: Central drug standard control organization (India)
CEP: Certification of suitability of European Pharmacopoeia monographs
CFR: Code of Federal Regulations
CFU: Colony Forming Unit
cGMP: Current Good Manufacturing Practices
CIP: Clean in place
CMC: Chemistry, manufacturing and controls
CMS: Continuous monitoring system
COA: Certificate of analysis
COS: Certificate of suitability
COPP: Certificate of Pharmaceutical Products
CPP: Critical Process Parameter
CQA: Critical Quality Attribute
CTD: Common technical document
DMF: Drug master file
DOP: Dioctyl Phthalate
DQ: Design Qualification
EDMF: European drug master file
EDQM: European Directorate for the Quality of Medicines
EH&S: Environmental health and safety
EIR: establishment inspection report (FDA)
EMEA: European Medicines Agency (formerly European Medicines
Evaluation Agency)
EP: European Pharmacopoeia
EPS: Expanded polystyrene
ETP: Effluent Treatment Plant
EU: Endotoxins unit
EU: European Union
FAT: Factory Acceptance Testing
FBD: Fluid-bed dryer
FDA: Food and Drug Administration, United States
FDC: Fixed Dose Combination
FEFO: First expiry first out
FG: Finished Goods
FIFO: First in first out
FMEA: Failure modes and effect analysis
FOI: Freedom of information
GAMP: Good automated manufacturing practice
GC: Gas Chromatography
GCLP: Good clinical laboratory practice
GCP: Good clinical practice
GDP: Good distribution practice
GEP: Good engineering practice
GGP: good guidance practice
GIT: Gastrointestinal Tract
GLP: Good laboratory practice
GMO: Genetically modified organism
GMP: Good manufacturing practice
GPT: Growth Promotion Test
GRAS/E: Generally recognized as safe and effective
GRP: Good review practice
HACCP: Hazard analysis critical control point
HDPE: High Density Polyethylene
HEPA: High efficiency particulate air (filter)
HPLC: High performance liquid chromatography
HSA: Health Sciences Authority, Singapore
HVAC: Heating, ventilating, and air conditioning
ICAH: International Conference on Harmonization
IH: In house
IM: Intramuscular
IND: Investigational new drug
INDA: Investigational new drug application
IP: Indian Pharmacopeia
IPA: Isopropyl Alcohol
IPS: In process control
IQ: Installation qualification
IR: Immediate release
ISO: International Organization for Standardization
ISPE: International Society for Pharmaceutical Engineering
IV: Intravenous
JP: Japanese Pharmacopoeia
KOS: Knowledge organization system
LAF: Laminar air flow
LAL: Limulus Amoebocyte Lysate
LD: Lethal dose
LD50: Lethal dose where 50% of the animal population die
LDPE: Low Density Polyethylene
LIMS: Laboratory Information Management System
LIR: Laboratory Investigation Report
LOD: Loss on drying
LOD: Limit of detection
LOQ: Limit of quantification
LR: Laboratory Reagent
LVPs: Large Volume Parenteral
MA: Marketing Authorization
MAA: Marketing Authorization Application
MAC: Maximum Allowable Carryover
MCC: Medicines control council (South Africa)
MDD: Maximum daily dose
MFR: Master Formula Record
MEDSAFE: Medicines and medicinal devices safety authority (New
Zealand)
MHRA: Medicines and Healthcare products Regulatory Agency (UK)
MOA: Method Of Analysis
MSDS: Material Safety Data Sheets
NCE: New chemical entity
NDA: New Drug Application
NF: National Formulary
NIR: Near Infra Red Spectroscopy
NON: Notice of non-compliance (Canada)
ODI: Orally Disintegrating Tablet
OQ: Operation Qualification
OSD: Oral Solid Dosage
OSHA: Occupational Safety And Health Administration
OTC: Over-the-counter
OOS: Out of specification
OOT: Out of trend
PAC: Post-approval changes
PAO: Poly alpha olefin
PAT: Process Analytical technology
PET: Preservative efficacy test
PET: Polyethylene
PIC/S: Pharmaceutical Inspection Co-operation Scheme
PLC: Programmable Logic Control
PQ: Performance Qualification
PVC: Polyvinyl Chloride
PVDC: Polyvinylidene Chloride
PW: Purified Water
QA : Quality Assurance
QC: Quality Control
QBD: Quality by design
QM: Quality Manual
QSD: Quality System Dossier
QSM : Quality System Management
QMS: Quality Management System
RH: Relative humidity
RLAF: Reverse laminar air flow
RLD: Reference listed drug
RM: Raw material
RO: Reverse Osmosis
ROPP: Roll On Pilfer Proof
RS: Related Substance
SAL: Sterility Assurance Level
SAT: Site Acceptance Testing
SDN: Screening Deficiency Notice (Canada)
SIP: Sterilization in place/Steam in place
SLS: Sodium Lauryl Sulphate
SMF: Site master file
SOP: Standard operating procedure
SPE: Society for Pharmaceutical Engineering
SUPAC: Scale-up and post approval changes
SVP: Small Volume Parenteral
TC: Thermocouple
TDS: Total Dissolved Solids
TGA: Therapeutics goods administration (Australia)
TOC: Total organic carbon
TSE: Transmissible spongiform encephalopathy
USFDA: United states foods and drugs administration
USP: United States Pharmacopeia
USP-NF: United States Pharmacopeia-National Formulary
URS: User Requirement Specification
VAI: Voluntary action indicated
VMP: Validation Master Plan
WFI: Water for injection
WHO: World Health Organization
WL: Warning letter

Basics For QA

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Basics For QA

Uploaded by

Copyright:

Available Formats

INTERVIEW PREPARATION FOR IPQA

Equipment name Model Calibration

DT Quarterly or whenever Yearly or whenever required

Sieve shaker NA Half yearly

Moisture analyzer NA yearly

TDA quarterly Half yearly

INPROCESS CHECKING LINE CLEARANCE

For non aqueous solution(100 LITER)

DIFFERENT SIZES OF CAPSULE AND THEIR EMPTY CAPSULE WT.-

Uncoated Uncoated Compressed/molded

Film Coated Coated Plain Coated

Enteric Coated Gastro Resistant (Enteric Delayed Release

Dispersible Tablet Dispersible Tablet Dispersible Tablet

Modified Release Tablet Modified Release Tablet Extended Release Tablet

Soluble Tablet Soluble Tablet Soluble Tablet

Effervescent Tablet Effervescent Tablet Effervescent Tablet

Orodispersible Orodispersible Orodispersible

Standards for Tablets:-

Content of Active Ingredient Content of Active Ingredient Content of Active Ingredient

Uniformity of weight Uniformity of weight Weight Variation

Uniformity of Content Uniformity of Content Uniformity of Content

Dissolution Dissolution Dissolution

1) Content of Active Ingredient: -

2) 20 tabs: - Limits 90% to 110%

2) Uniformity of Weight/Wt Variation:-

Weight Variation Limits:-

IP/BP Limit USP

80 mg or less 10% 130mg or less

More than 80mg or 7.5% 130mg to 324mg

300mg or More 7.5%

USP limit is 0.5 to 1%. W/w

Rotation: - 25 rpm or 100 rotations

Uniformity of Content or Content Uniformity:-

IP: - Active less than 10mg or 10%,

BP: - Active less than 2 mg or 2%,

USP:- Active less than 25mg or 25%.

Uncoated Tablet NMT 15 min, in water with Disc 370C ± 20C

Orodispersible Within 1 min

Buccal & Sublingual Not Applicable but dissolve within 15 – 30 min.

DT Apparatus:- Mesh Aperture:- 2mm (#10), Cycles:- 28 – 32 cycles/min, 50 – 60 mm distance from

Very soluble less than 1 part

Freely soluble from 1 to 10 parts

Soluble from 10 to 30 parts

Sparingly soluble from 30 to 100 parts

Slightly soluble from 100 to 1000 parts

Very slightly soluble from 1000 to 10,000 parts

Practically insoluble more than 10,000 parts

Approximate quantity of solvent by volume for one part of soluble by

Tapped Density – Bulk Density x 100 θ = tan-1(h/r)

Flow property C.I (%) Hausner’s ratio

Excellent ≤10 1.00 – 1.11

Good 11 – 15 1.12 – 1.18

Fair 16 – 20 1.19 – 1.25

Passable 21 – 25 1.26 – 1.34

Poor 26 – 31 1.35 – 1.45

Very poor 32 – 37 1.46 – 1.59

Very, very poor >38 >1.60

Flow property Angle of repose (degrees)

Fair-aid not needed 36 – 40

Passable – may hang up 41 – 45

Poor – must agitate, vibrate 46 – 55

Very, very poor >66

ANDA - Abbreviated New Drug Application.