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4
1.
(Product Development Recommendations for Liquid Dosage Forms)
2.
(Guide to Quality Management in the Drug Industry)
3.
(Guidelines on Process Validation of Non-Sterile Products)
4.
(Guidelines for the Manufacture of Cytotoxic Drug)

1.
(process validation)


( )


2.

(Acceptable mean range )


(worst case conditions)
(Control parameter)
(operating variables)
(Control parameter range)
2
(Calibration)
( pH )

(Certification)

-2 (Installation qualification)

(Operating variable)
(process state of control) /

(Operation qualification)

(Process parameter)

(Validation)


(Prospective validation)
(Concurrent validation)
(Retrospective validation)

(Validation protocol)
(test parameter)

(Validation change control)



(Worst case)

-33.


(1)
(2)
(3)


lot

3
(1)
(2)
(3)


4
(4)
(5)
(6)

(7)

-44. GMP


(1)
(2)

(3)

5.


6.


() (Prospective Validation)

-5

() (Concurrent Validation)

lot () ()

(1) (extensive product testing)



dose uniformity 3 lot
normal distribution, standard deviation, confidence limit inter-batch
homogeneity confidence limit



(2) (challenge or worst case)

(operating parameter) (acceptable limit)




operating range

-6
(3) (simulated process trial)

aseptic

(4) (additional process parameter


measurement)


(prospective validation)


(concurrent validation)



() (Retrospective Validation)



20-30 lot

(process parameter)

-7() (Revalidation)






7.


qualification
3
() (Installation Qualification IQ)



(calibration)

() (Operational Qualification, OQ)

placebo

-8
() (Performance Qualification, PQ)

(protocol)
(process reproducibility)

8.


Powder mixing/Preblending type of mixer and agitator; content uniformity analysis,


mixer/agitator speed; load
disintegration or dissolution of
size; method and sequence, tablets in case of final
place of adding constituents; blending with lubricant
mixing time; material
characteristics : particle size,
density, flowability,
friability, moisture content
Granulation
(Wet Kneading/Wet
Screening)

granulator equipment design


e.g., high or low shear, wet
massing time, method of

granulation end point


instrumentation, content
uniformity analysis (if

Drying

introducing binder material


into formulation, method of
adding granulation fluid, load
size, intensity of agitator,
binder addition rate,
mesh size of wet screening
tray dryer :
- weight per tray
- thickness per tray
- relative humidity of air
- velocity of air flow
- air temperature
- drying time
fluidized bed dryer :
- optimum load
- rate of air flow
- inlet air temperature
- relative humidity of the
air

Size Granulation
type of size reduction,
mesh size,
mill speed,
feed rate

required), final granule testing


e.g., granule size, density,
flowability, friability

optimum moisture (or total


volatile) content

granule size distribution,


granule density/porosity,
granule friability, flowability

Tabletting/Compression

appearance (chip, crack, dust,


compression force, press
picking of monogram) weight
speed, hopper flow/fill,
variation, dose uniformity,
dwell
hardness, disintegration/
time of compression, feeding dissolution, thickness,
rate
friability

Film Coating : Pan Coating

pan design; pan load, speed; appearance, weight


pan angle; baffles : number, uniformity, diameter and

position shape; air flow rate,


temperature, humidity;
drying cycle; spraying rate;
droplet size; spray pattern;
nozzle-to-bed distance and
angle; number of spray guns;
pumping systems; atomizing
air pressure; liquid pressure
and viscosity
Capsule Filling

type of machine, speed of


filling, filling pressure,
temperature/humidity during
filling, powder/granule
characteristics : size
distribution, density,
flowability

thickness, moisture content,


disintegration and dissolution
rate, resistance to gastric
juice (if enteric coating)

esthetic properties,
completeness of closure,
integrity of capsule,
uniformity of
weight,disintegration and
dissolution, content uniformity

Mixing of Semisolid

type, material, shape and


size of container; number,
shape and position of
agitator; percent fill;
temperature of container;
sequence, temperature and
rate of addition; machine
speed; mixing time

Dispersion/Homogenization

type of machine, bore of


homogeneity, particle size
nozzle, pressure, feed rate, distribution of solid, viscosity
type of rotor, slid width,
machine speed, temperature,
time, frequency, deaeration

Filtering

type, size and material of


filter; capacity; pressure/

viscosity, homogeneity,
particle size distribution of
solid active ingredient,
conductivity, pH

clarity test

vacuum; flow rate of filtrate;


temperature
Filling of Semisolids

type of filling line, rate of


weight/volume
stirring, pumping, feeding,
temperature, processing time

Filling of Liquid

type of filling line, rate of


feeding, pressure,
temperature
processing time

uniformity of volume/weight

Fluidized Bed Granulation


type and capacity of
apparatus; position, angle &
bore of nozzle; spray angle
and regime; load size;
inlet/outlet air temperature;
air flow rate; spraying rate;
spraying pressure; product
temperature; filter shaking;
drying time; climatic
condition; processing time.

granule size, bulk/tapped


density, flow property,
granule friability, residual
moisture, homogeneity


Tablets

appearance,
uniformity of weight and content
hardness,
thickness,
friability,
disintegration/dissolution time

Capsules

appearance,
uniformity of weight content,
disintegration/dissolution time

Coated Tablets

appearance/color uniformity/surface
dimensions

uniformity of weight, residual moisture,


disintegration/dissolution time, resistance to
gastric fluid
appearance, homogeneity, particle size
distribution of active ingredient (if solid),
rheological properties, rate of release, pH,
microbial contamination
appearance, density, rheological properties/
viscosity, clarity, pH,
odour/taste (if orals),
content

Ointment, Creams

Solutions

Suspensions

appearance,
density,
rheological properties/viscosity,
pH,
odour/taste (if orals),
content,
sedimentation,
particle size range and distribution,
re-dispersibility,

rate of release/dissolution
Emulsions

appearance,
density,
rheological properties,
pH,
odour/taste
content,
rate of release,
type (w/o, o/w or others),
droplet size distribution

-149.




10.
2
. (protocol) :

-
-
-
-
-
-
. (report)

-
-
-
-

-1511.









(retrospective validation)

-16-

1. Berry, I.R. Process validation of raw materials. In Berry, I.R., Nash, R.A.
editors. Pharmaceutical Process Validation. New York, Marcel Dekker Inc.
1993: 369-410.
2. Jeater, J.P., Cullen, L.F., Papariello, G.J. Organizing for validation. In
Berry, I.R., Nash, R.A., editors. Pharmaceutical Process Validation.
NewYork , Marcel Dekker Inc. 1993: 9-24.
3. Nash, R.A. The essentials of process validation. In Lieberman H.A.,
Lachman, L., Schwartz, J.B. editors. Pharmaceutical Dosage Forms : Tablets
Vol.3. New York, Marcel Dekker Inc. 1990 : 417-456.
4. Nash, R.A. Process validation : solid dosage forms. Drug. Cosm. Ind.
1981: 38-39.
5. Peck, G.E., Anderson, N.R., Banker, G.S., Principle of improved tablet production
system design. In Lieberman, H.A., Lachman, L., Schwartz, J.B., editors
Pharmaceutical Dosage Forms: Tablets vol. 3. New York, Marcel Dekker Inc.
1990: 64-70.
6. Rudolph, J.S. Validation of solid dosage forms. In Berry, I.R., Nash, R.A.
editors. Pharmaceutical Process Validation. New York, Marcel Dekker Inc.
1993: 167-188.
7. Scheer, A.J. Practical guidelines for suspension formulation. Drug Cosm. Ind.
1981 (April): 41-44.

-17-

8. Scott, R.R. A practical guide to equipment selection and operating techniques.


In Lieberman, H.A., Rieger, M.M., Banker, G.S., editors. Pharmaceutical
Dosage Forms: Dispersed Systems Vol. 2. New York, Marcel Dekker Inc.
1989: 1-71.
9. Sykes, I.K. Manufacturing. In Cartwright, A.C., Matthews, B.R. editors.
International Pharmaceutical Product Registration. Chichester, Ellis
Horwood Limited, 1994 : 90-93.
10. U.S. Food and Drug Administration. Guideline on General Principles of
Process Validation. Maryland, May 1987.
11. World Health Organization. Guidelines on the Validation of Manufacturing
Processes. Geneva, 1992.
12. World Health Organization. Good manufacturing practices for
pharmaceutical products. In WHO Expert Committee on Specifications for
Pharmaceutical Preparations. Thirty-second report. Geneva, 1992 : 27.