PROCESS VALIDATION OF LOPINAVIR + RITONAVIR

(100 + 25 mg) ANTIRETROVIRAL COMBINATION

TABLET
ACADEMIC GUIDE
Mrs. M.A.NAGRAS
Assistant Professor

INDUSTRIAL GUIDE
Mr. NAGESH PATIL
Sr.manager QA dept.
Emcure pharmaceuticals
Hinjewadi, Pune.

SCOP
VADGAON (BK), PUNE-041

PRESENTED BY
Kaustubh V. Kandharkar
th SEMESTER)
M.Pharm (IVth
DEPARTMENT OF QUALITY ASSURANCE
TECHNIQUES
SINHGAD COLLEGE OF PHARMACY
VADGAON (BK), PUNE-041

Definition of process validation:

As per FDA - process validation is defined as establishing documented

evidence which provides a high degree of assurance that a specific process,
method will consistently produce a product meeting Predetermined
specifications and quality attributes.
According to new 21CFR guideline Process Validation is defined as the collection and evaluation of data, from
the process design stage throughout production, which establishes scientific
evidence that a process is capable of consistently delivering quality
products.

The New Guidance Promotes:

1) Modern manufacturing principles

2) Process improvement
3) Innovation
4) Risk Assessment and mitigation

Types of Validation:

Types of Process Validation:

1)
2)
3)
4)

Prospective Validation
Retrospective Validation
Concurrent Validation
Revalidation

Stages of Process Validation:

ed
u
n
i
nt s
o
C
3. r o c e s n
P catio
ifi
r
e
V

Process
Validation
Phases

1.
P
D ro c
es es
ig s
n

2. Process Qualification

The 3 stages of Process Validation

(By 21 CFR Guidelines)
1.Process Design: The commercial process is defined during this stage based on
knowledge gained through process development activities.
2.Process Qualification: During this stage, the process design is confirmed as
being capable of reproducible commercial manufacturing. Including qualification
of the facility, utilities and equipment.
3.Continued Process Verification: Maintenance, continuous verification, and
process improvement. On-going assurance that routine production process
remains in a state of control. Assessed by collecting and monitoring information
during commercialisation.
7

Reasons for validation :

Customer satisfaction
Customer mandated- provision for securing new business
Product liability- conformance to product specification must be maintained
Reduction product cost
Supportive data
Assurance of quality
Economics: Reduction of quality cost
Safety
Better customer quality
10) Regulatory requirement
1)
2)
3)
4)
5)
6)
7)
8)
9)

Literature survey :
Title

Details

Summary

Industrial process validation of solid

dosage form

Styabrata Jena, Arjun G,Anil Kumar

international journal of
pharmaceutical review & research
2010

Quality is always an
imperative prerequisite when
we consider any product.
Therefore, drugs must be
manufactured to the highest
quality levels.

Studies in Prospective Process

Validation of Cimetidine
Tablet Dosage Form

Vandana B. Patell* , Minaxi R.

Rathwal and Kandarp Patel2
International Journal of Research in
Pharmaceutical and Biomedical
Sciences ISSN: 2229-3701

The processes include raw

material and equipment
inspections as well as inprocess controls.

http://www.emea.europa.eu

Lopinavir and ritonavir are

protease inhibitors (PI)
indicated for the treatment of
HIV infection.

Robert A Nash & Alfred H

Wachter,pharmaceutical process
validation,Ed.no. 3 Vol 129 Marcel
Decker, Inc, New York 23

process validation is defined

as establishing documented
evidence which provides a
high degree of assurance9 that

Scientific discussion lopinavir +

ritonavir tablets (Kaletra)
Process Validation

Topic

Details

Summary

The Tablet Formulation of

Lopinavir/Ritonavir Provides
Similar Bioavailability to the SoftGelatin Capsule
Formulation With Less
Pharmacokinetic Variability
and Diminished Food Effect

Abbott, Abbott Park, IL; and SOLIQS,

Abbott GmbH & Company,
Ludwigshafen, Germany.
Cheri Enders Klein, PhD,* Yi-Lin Chiu,
PhD,* Walid Awni,

Lopinavir, an HIV protease

inhibitor, is co formulated
with ritonavir to enhance
the bioavailability and
pharmacokinetics of
lopinavir.

Process Validation: an Essentiality

in the Pharmaceutical Industry

Guidance for process validation :

General principles & practices US
FDA 2008

Each step of the production

process is validated than we
can assure that the final
product is of the best
quality.

An overview of pharmaceutical
Mahesh B. Wazade*, Sheelpriya R.
process validation and process
Walde and Abhay M. Ittadwar .
control variables of tablets
IJPSR (2012), Vol. 3, Issue 09
manufacturing processes in industry

scientific discussion lopinavir +

ritonavir tablets.

Lopinavir/Ritonavir 100mg/25mg
tablets WHOPAR part 6 11/2009,
version 1.0

The challenge for the

pharmaceutical industry is
to streamline and/or
simplify validation without
sacrificing product quality.

Lopinavir/Ritonavir tablets
100 mg/25 mg is indicated
for the treatment of infected
children weighing 10 kg or
more who are infected10with

AIM:
To study the Process Validation of Lopinavir + Ritonavir
(100 + 25 mg) Anti Retroviral tablets.

OBJECTIVE:
To evaluate the manufacturing process of Lopinavir + Ritonavir
(100 + 25 mg) antiretroviral tablets to provide documented evidence that
the manufacturing process is capable of producing a product meeting its
predetermined quality attributes consistently.

11

Plan of work:

12

General check points & Precautions :

Equipments to be used in the manufacturing process are already qualified.
Preventive maintenance of process equipments is completed as per the established schedule.
All the Instruments to be used for in process testing are in calibrated state and working satisfactorily.
All the Input materials used for manufacturing of a product are approved and released from QC
department for use.
All the manufacturing operations to be carried out at temperature 20 5 00C and at 30-60% Relative
humidity.
Avoid direct contact with material.
Wear dust mask, safety goggles and hand gloves during manufacturing operations.
Material from the previous batch/product removed from equipment and area of manufacturing
operation.
13

INSTRUMENTS AND EQUIPMENTS:

EQUIPMENTS

Make

Rapid mixer granulator (250 L)

Anchor mark

Vibratory sifter 20/30

Anchor mark

Hot melt extruder

Thermo fisher scientific

Chilled jacketed cad mill

Cad mach

pillar type blender Conta blender

Anchor mark

Compression machine Legacy 6100

Pam pharmaceuticals & allied

machineries

Dedusting & deburring machine with metal detector

Techno four

Auto coater

Neo cota 50D 30

Bulk packing machine

Thermo fisher scientific

Analytical Instruments

Make

H.P.L.C

Waters

Dissolution apparatus

Electro lab

14

Hot Melt Extruder :

15

Advantages of Hot Melt Extrusion :

Problems

Solved by HME

Poor bioavailability due to poor API

solubility

Use of HME enhancement of

dissolution

Poor stability during process cause by

hydrolysis

Use of HME as alternative to wet

agglomerates

Unreliable sustained release action

Use HME to prepare sustained release

dosage form

Poor stability or tolerability of API in

the stomach

Use of HME to prepare enteric dosage

form

Poor taste of the API

Use of HME to prepare taste-masked

dosage forms

16

Drug Profile :
Drug Lopinavir :
Structure
Category

Antiretroviral

Class

HIV Protease Inhibitors

Mol. Wt.

628.8008

Melting point

124 to 127 0 C

Half life

5-6 hrs

Metabolism

Hepatic cytochrome P450 system

Excretion

Mostly fecal
17

Drug Ritonavir :
Structure

Category

Antiretroviral

IUPAC Name

HIV Protease Inhibitors

Mol. Wt.

720.944

Melting Point
Half life

120 to 122 0 C
3-5 hrs

Metabolism

Hepatic cytochrome P450 system

Excretion

Mostly fecal
18

DESCRIPTION OF MANUFACTURING PROCESS AND

PROCESS CONTROLS
(For Lopinavir + Ritonavir Tablet (100 + 25 mg) USP)

19

Process flow diagram

Raw materials

Process
Dispensing of raw material

Lopinavir, ritonavir copovidone, colloidal silicone

dioxide

Sifting

Sorbiton monolaurate

Granulation

Monotane 20 PHA

Hot melt extrusion

Size reduction ( Milling)

Colloidal silicone dioxide IP

Sodium stearyl fumarate USP/NF

Lubrication
sifting
Compression

Opadry yellow , purified water IP

coating
Packaging

20

20

Manufacturing Formula :
Ingredients

Use

A) Granulation
Drug Lopinavir (API)

Antiretroviral

Drug Ritonavir (API)

Antiretroviral

Copovidone

Binder

Colloidal silicon dioxide

Lubricant

Sorbitan Monolaurate

Surfactant

Sodium stearyl fumarate

Lubricant

B) Coating of Tablet
Opadary yellow

Coating agent

Purified water

Solvent for coating

21

Product Composition : lot no. 1

Sr.no.

Name of material

Quantity per tablet Quantity per batch

in mg.
in kg.

Lopinavir IP

100.0

7.790

RitonAVIR IP

25.0

1.899

Copividone usp / nf

443.665

33.302

Colloidal silicone dioxide IP

6.660

0.503

Sorbiton monolaurate

32.500

2.475

Colloidal silicone dioxide

4.175

0.301

Sodium steryl fumarate

6.000

0.432

618.0

44.496

Total core tablet

22

Sr.no.

Name of
material

Quantity per
tablet in mg.

Quantity per
batch in kg.

b) Coating of
tablet
8

Opadry yellow 15.450

0799 x 2 =
1.558

Purified water
Ip

4.40 x 2 =
8.80

NA

Product composition same for lot no. 2,3.

23

Processing of Batch Lot :

Step 1. Dispensing - As per bill of raw material.
Equipments needed LAF, Weight Balance, containers
Step 1. Sifting Vibratory sifter through #40. check physical integrity of sieve
before after use
Step 3.Granulation Load sifted ingredient in RMG mix for 10 min. with
impeller at fast speed and chopper off .check mixing time & speed of
impeller
Step 4. Hot Melt Extrusion (HME) Feed rate 4.5 kg to22 kg/hr. screw rpm
100 675 rpm torque 30 to 60 %
Step 5. Size reduction - Fit 3.0 mm screen to cad mill & mill the extrudates at
fast speed & knife forward. sift the milled granules through #30 sieve to
vibratory sifter

24

Step 6. Lubrication Sift colloidal silicone dioxide IP & sodium stearyl

fumarate through #40 sieve. Load granules in 150 L cage bunker attach
it to pillar type conta blender & mix for 5 min. blender speed at 12 rpm
in manual mode
Step 7. Compression single rotary 37 station Legacy 6100
upper punches : 16 x 9 mm oval shape
lower punches : 16 x 9 mm 26
Dies: : 16 x 9 mm oval shape
Step 9. Dispensing of Coating Material
Step 10. Preparation of Film Coating purified water + opadry yellow large
lump formation avoided. Stir for 45 min. filter through muslin cloth. Use
coating solution within 24 hours.
Step 11. Coating by Neo cota. Coating of tablet to be done to a weight gain
of about 2.5 %
Step 12. Packaging As per market requirement.

25

Assessment of critical process parameters :

26

Sr.no
.

Process step

Process parameter
setting

rationale

Checks

critcal steps

Raw material

NA

Raw material used are

procured from approved
vendors

NA

No

Dispensing of
raw material

Dispense raw material as

per bill of raw material

Process does not have

variable effect on product
quality when defined
operating procedures are
followed

Balance
calibration before
dispensing
operation to be
done

No

Sifting

Sift lopinavir, ritonavir,

copovidone, colloidal
silicone dioxide through
#40 sieve

Process involves breaking

of agglomerates if any

Physical integrity
of sieve before &
after use

No

Granulation

Dry mixing in rapid mixer

granulator 250 L with the
addition of sorbiton
monolaurate

Mixing time to ensure

proper mixing

Mixing time, speed

of impeller &
chopper

Yes

Hot melt
extrusion

H.M.E

Process involves formation

of hot melt extrudates

Feed rate, screw

rpm, zone temp.
% torque

Yes

Size reduction

Mill extrudes through chill

jacketed cad mill using 3.0
mm screen. Sift the
granule s through #30
sieve

Process involves breaking

of extrudes to have
uniform size of granules

Physical integrity
of sieve before &
after use &
Feed rate

Yes

Sifting of extra
granular
ingredients

sift the colloidal silicone

dioxide & sodium lauryl
fumarate through #40
sieve

Process involves breaking

of soft agglomerates if any

Physical integrity
of sieve before &
after use &
Feed rate

No

27

Sr.no.

Process
step

Process parameter setting

Rationale

Checks

Critical steps

Lubrication

Lubrication of granules with sifted

colloidal silicon dioxide & sodium
lauryl sulfate for 5 min. by keeping
the conta blender speed at 12 rpm

Mixing time to
ensure proper
mixing proper
lubrication
required to
achieve optimum
compression
properties for final
blend

testing as per
sampling plan

Yes

Compressi
on

Compress the tablets at optimum

speed using compression machine
legacy 6100 single rotary 37 station

To set the
compression
parameters & to
achieve required
compressed
weight

Testing as per
sampling plan

yes

10

Coating

Coating of tablets to be done to a

weight gain of about 2.5 %

To set the coating

parameters & to
achieve required
coating weight
gain

Testing as per
sampling plan

yes

12

Packaging

As per batch packaging records

To evaluate
packaging
parameters

Testing as per
sampling plan

yes

28

Sampling plan:
Process stage

Sample id

Sampling details & quantity

Lubrication

1 LG 01 to 1 LG
30

30 unit dose samples, 10 samples Blend uniformity

in triplicate shall be collected out Testing on pooled
of which one set of 10 samples
sample
shall be analyzed
Assay, Loss on drying
Collect a pooled sample of 200mg

Compression

Initial, middle end 100 tablets are to be sampled at

at optimum speed initial, middle end of tablet
& hardness
compressed at optimum speed &
hardness

Physical parameters
dissolution

compression
machine speed

Pooled sample at
optimum speed &
hardness

Assay, dissolution

100 tablets are to be sampled as

polled sample at optimum speed
& hardness

Tests

29

Conti.
Process stage

Sample id

Sampling details &

quantity

Tests

Coating

Pooled sample

Collect 1 polled
sample after
unloading of coated
tablets sampling
quantity 100 tablets

Description ,assay ,
Dissolution

Packaging

One pooled sample

collected during the entire
batch packing . Sampling
quantity as per finished
product specification

Sampling quantity as
finished product
specification

Packaging
parameters from
Batch
manufacturing
records

30

Acceptance criteria :
Stage

Test

In Process Checks

Lubrication

Description

White to off white granular powder

Blend uniformity

Relative standard deviation not more than 5 %

Assay

Not less than 90% & not more than 110 % of

labeled amount of ritonavir & lopinavir

Description

White to off white uncoated oval tablets debossed

with E/M on one side & 25 other side

Dissolution

Not less than 70 % of labeled amount of ritonavir IP

is dissolved in 120 min.
Not less than 70 % of labeled amount of lopinavir IP
is dissolved in 120 min.

Compression

Coated tablets Assay

Notless than 90% & not more than 110 % of labeled

amount of ritonavir & lopinavir IP
31

Schematic sampling plan of Conta

blender :

Fig : Sampling device

32

Sampling locations:
Top

Bottom

Centre

1 left front 3 left front 5 right

front

7 right
back

1,11,21

3,13,23

5,15,25

7,17,27

2 left front

4 left back

6 right
front

8 right
back

2,12,22

4,14,24

6,16,26

8,18,28

9 middle

10 bottom

9,19,29

10,20,30

33

Procedure:
1) Obtain 3 unit dose samples from conta blender (cage

bunker) from each position as shown in above figure and

as described in table given below
2) Use appropriate sample thief with the appropriate die to

obtain samples with net weight of 1 x to 3 x times the

target weight
3) Use labeled & weighed sample containers submit the

sample to quality control department for testing along with

appropriate technical information sheet

34

Experimental

35

Summary of Process
Parameters:
Processing stage

Critical process parameters

Recommended limit(s)/range(s)

Coating

Outlet temperature

26C to 38C

Peristaltic pump speed

10 RPM to 20 RPM

Total Air Pressure

5 kg/cm2 to 15 kg/cm2

Drug Coating

93.0% to 102.0%

Barrier Coating

93.0% to 102.0%

Enteric Coating

93.0% to 102.0%

Yield

36

Results & discussion:

Results of blend uniformity:

37

Sample Id

Blending %
content of
Ritonavir

Blending %
content of
Ritonavir

Batch no. 1

Batch no. 2

Batch no. 3

Batch no. 1

Batch no. 2

Batch no. 3

97.5

98.0

99.4

102.1

100.2

100.0

98.3

98.4

99.4

102.9

100.6

100.1

98.3

98.3

99.0

100.7

100.3

99.7

98.2

97.6

99.1

100.8

99.7

100.6

98.2

98.8

99.0

100.7

100.8

100.6

98.6

98.5

99.6

103.1

100.7

100.1

98.5

99.0

99.3

100.0

101.1

100.0

98.8

98.6

99.3

100.3

100.8

99.8

98.3

98.0

99.4

102.8

100.3

100.2

10

98.4

98.4

99.4

103.1

100.4

100.1

Average

98.3

98.3

99.3

102.8

100.5

99.9

Min.

97.5

97.6

99.0

102.1

99.7

99.6

Max.

98.8

99.0

99.6

103.3

101.1

100.2

RSD.

0.4

0.4

0.2

0.3

0.4

0.2

38

Analytical data of pooled sample at the stage of

lubrication:
Sr.
no.

Test

Acceptance criteria

Test Results
Batch no. 1

Batch no. 2

Batch no. 3

Description

White to off white

powder

White to off
white powder

White to off
white powder

White to off
white powder

Bulk density

Record the results

0.57 g/ml

0.56 g/ml

0.57 g/ml

Tapped density

Record the results

0.74 g/ml

0.72 g/ml

0.74 g/ml

Sieve analysis

For information only

# 40 : 9.3 gm

# 40 : 10.8

# 40 : 10.1

Assay (Ritonavir)

NLT 90.0 % & NMT

110.0 %

98.5 %

98.4 %

99.9 %

Assay (Ritonavir)

NLT 90.0 % & NMT

110.0 %

103.1 %

100.3 %

100.4 %

Loss on drying

For information only

0.7 %

1.5 %

1.3 %
39

Analytical data of tablets compressed at optimum

speed :
Test

Acceptance criteria

Test Results
Initial

Middle

End

Description

White to off white

uncoated oval tab.

Complies

Complies

Complies

Group weight of
20 tablets

12.360 gm +- 3 %

12.381 gm

12.364 gm

12.392 gm

Individual tablet
weight range

+- 5 % of Avg. wt.

588 649 mg

588 648 mg

590 651 mg

Hardness

13.0 kp +- 5 kp
Limit 8 kp to 18 kp

13.4

13.6

13.7

Thickness

5.75 mm to 0.30 mm
Limit 5.45 mm to 6.05
mm

5.84

5.85

5.84

Friability

NMT 1.0 % w/w

0.2 w/w

0.1 w/w

0.2 w/w

Disintegration
time

NMT 60 min.

32 min.

32 min.

32 min.
40

Dissolution of initial, middle, end sample:

Acceptance criteria:
Not less than 70 % of labeled amount of ritonavir IP is dissolved in 120 min.&
Not less than 70 % of labeled amount of ritonavir IP is dissolved in 120 min.

41

Tablet no.

Dissolution
results
Ritonavir Ip
Batch 1
% solubility

Batch 2
% solubility

Batch 3
% solubility

Lopinavir Ip
Batch 1
% solubility

Batch 2
% solubility

Batch 3
%
solubility

Initial

Middle

End

Initial

Middle

End

98

97

98

100

98

100

98

98

98

100

100

99

98

98

98

100

101

99

98

98

98

100

100

100

98

98

97

100

99

98

98

99

98

100

101

100

Avg.

98 %

98 %

98 %

100 %

100 %

99 %

Min.

98 %

97 %

97 %

100 %

98 %

98 %

Max.

98 %

99 %

98 %

100 %

101 %

100 %
42

Dissolution on pooled sample:

Tablet no.

Dissolution
results
Ritonavir Ip
Batch 1
% solubility

Batch 2
% solubility

Batch 3
% solubility

Lopinavir Ip
Batch 1
% solubility

Batch 2
% solubility

Batch 3
%
solubility

98

97

100

100

99

102

98

97

100

100

99

101

98

98

99

100

100

101

97

97

99

100

99

100

98

97

98

101

99

100

98

99

100

100

101

101

Avg.

98

97

99

100

99

101

Min.

97

97

98

100

99

100

Max.

98

99

100

101

101

43
102

Assay of pooled sample:

Test

Acceptance
criteria

Batch 1

Batch 2

Batch 3

Assay

NLT 90.0 % &

NMT 110.0 % of
labeled amount of
ritonavir IP

101.7 %

101.1 %

99.5 %

NLT 90.0 % &

NMT 110.0 % of
labeled amount of
lopinavir IP

98.6 %

98.1 %

101.6 %

44

Results of dissolution: low speed (20 rpm)

Tablet
no.

% Released
(Ritonavir)

% Released
(Lopinavir)

Batch 1

Batch 2

Batch 3

Batch 1

Batch 2

Batch 3

98

98

96

98

99

99

100

99

96

100

99

99

100

98

96

100

99

99

100

98

96

99

99

98

99

99

96

98

100

99

99

97

96

99

97

99

Avg.

99 %

98 %

96 %

99 %

99 %

99 %

Mini.

98 %

97 %

96 %

98 %

97 %

98%

Max.

100 %

99 %

96 %

100 %

100 %

9945
%

Results of dissolution: high speed (40 rpm)

Tablet
no.

% Released
(Ritonavir)

% Released
(Lopinavir)

Batch 1

Batch 2

Batch 3

Batch 1

Batch 2

Batch 3

99

99

96

98

100

99

99

98

97

99

98

100

100

98

96

99

99

99

100

98

98

102

100

101

99

99

97

99

99

100

100

98

96

100

98

99

Avg.

99 %

98 %

97 %

99 %

99 %

99 %

Mini.

99 %

98 %

96 %

98 %

98 %

99 %

Max.

100 %

99 %

98 %

102 %

100 %

10146
%

Coating parameters:
parameters

Range

Sub lot 1

Sub lot 2

Inlet air temp.

35 to 700 c

52 to 530 c

52 to 53 0 c

Pan speed

1 to 7 rpm

5 rpm

5 rpm

Automizer air
pressure

1.0 to 3.0 kg/cm2

2.0 kg/cm2

2.0 kg/cm2

Number of guns

2 Nos

2 Nos

2 Nos

Distance of the guns

from tablet bed

14 to 25 cm

Coating solution
spray rate

10 to 80 ml/min/gun

22 ml/min/gun

22 ml/min/gun

weight gain

2.5 %

2.6 %

2.6 %

Gun to gun distance

10 to 25 cm

18 cm

18 cm

20 cm

20 cm

47

Analytical data of pooled sample at the stage of

coating :
Test

Acceptance criteria

Description

Pale yellow film coated oval

tablet debossed with EIM on
one side & 26 on other side

Assay Ritonavir Ip

NLT 90.0 % & NMT 110.0 % of

labeled amount of Ritonavir Ip

Assay Lopinavir Ip NLT 90.0 % & NMT 110.0 % of

labeled amount of Lopinavir Ip

Test results
Batch 1

Batch 1

Batch 1

101.8 %

101.3 %

99.3 %

98.6%

98.2 %

101.4 %

48

Dissolution on pooled sample of coated tablets:

Acceptance criteria:
Not less than 70 % of labeled amount of ritonavir IP is dissolved in 120
min.&
Not less than 70 % of labeled amount of lopinavir IP is dissolved in 120 min.

49

Tablet no.

Dissolution
results
Ritonavir Ip
Batch 1

Batch 2

Batch 3

Lopinavir Ip
Batch 1

Batch 2

Batch 3

Initial

Middle

End

Initial

Middle

End

98

97

98

100

98

100

98

98

98

100

100

99

98

98

98

100

101

99

98

98

98

100

100

100

98

98

97

100

99

98

98

99

98

100

101

100

Avg.

98 %

99 %

96 %

100 %

99 %

99 %

Min.

97 %

98 %

96 %

99 %

99 %

99 %

Max.

100 %

99 %

97 %

102 %

100 %

100 %
50

Packaging observation:
Packaging
Batch. No.

Pack style

Packaging material used

for packing

1 x60 Tablets

HDPE Container ,
closure 38 mm, silica gel

1 x60 Tablets

HDPE Container ,
closure 38 mm, silica gel

1 x60 Tablets

HDPE Container ,
closure 38 mm, silica gel

51

Packaging observation:
Checks

Acceptance
criteria

Observation
Batch 1

Batch 2

Batch 3

Speed of capping
machine

Limit 30 to 40
bottles/min

56 bottles/min

60
bottles/min

62
bottles/min

Percentage induction for

induction cap sealer

Limit 70 to 95
%

90 %

90 %

96 %

Torque for capping

machine

Limit 17.26
inch

19 inch

19 inch

19 inch

Number of tablets in the

filled HDPE container

60 tablets

60 tablets

60 tablets

60 tablets

Leak test

Should pass
the test

Satisfactory

Satisfactory

Satisfactory

52

Analytical data of finished product:

53

Test

Specification

Product

Description

Pale yellow film coated oval tablet debossed

with EIM on one side & 26 on other side

Complies

Identification by
HPLC

The retention time & peak due to lopinavir &

ritonavir in assay preparation complies to that
obtained from standard preparation

Complies

Water extent

NMT 6.0 %

3.0 %

Assay

NLT 90.0 % & NMT 110.0 % of labeled

amount of Ritonavir Ip

101.8 %

NLT 90.0 % & NMT 110.0 % of labeled

amount of Lopinavir Ip

98.6 %

Any unspecified
impurity

NMT 1.0 %

Less than 1.0 %

Total impurity

NMT 2.0 %

Less than 2.0 %

Any unspecified
impurity

NMT 2.5 %

Less than 2.5 %

Total impurity

NMT 3.0 %

Less than 5.0 %

Related substance
(Lopinavir )

Related substance
(Ritonavir )

54

Results of Critical process parameters of Drug coating :

Parameters

Specifications

Equipment name

Neo cota

Equipment ID No.

Batch 1
Neo cota

Observation
Batch 2
Neo cota

Batch 3
Neo cota

CH/MC/TAB/
2009/333

CH/MC/TAB/
2009/333

CH/MC/TAB/
2009/333

Inlet air temperature

43C(35C to 70C)

53C

51C

53C

Outlet air temperature

To be recorded(C)

43C

44C

4
3C

Bed temperature

49C (44C to 54C)

50C

50C

51C

Atomization air pressure

1.0 to 3.0 kg/cm2(1.8 to 3.0)

2.0

2.0

2.0

Number of Guns

2 Nos.

Distance of the guns from

tablet bed

14 to 25 cm

20

20

20a

Coating solution spray

rate

10 to 80 ml/min/gun

22 ml/min/gun

19 ml/min/gun

19 ml/min/gun

Peristaltic pump speed

To be recorded

% weight gain
Gun to Gun distance

2.5 %( 2.0 to 3.0%)

10 to 25 cm

2.6
18 cm

2.6
18cm

2.6
55
18cm

Final batch yield and Reconciliation :

Observation
Parameters

Specifications
1

Drug Coating

Theoretical Yield

To be established

45.608 kg

45.608 kg

45.608 kg

Actual Yield

To be established

45.100 kg

45.207 kg

45.200 kg

Reconciliation

To be established

98.88%

99.12%

99.10%

56

Results of In-process analysis of Drug coating :

Results

Parameters

Acceptance Criteria

Description

Pale yellow, film coated , oval tablet debossed with

EIM on one side & 26 on other side

Complies

Identification
(By HPLC)

The retention time of the major peak in the

chromatogram of the sample preparation corresponds
to that in the chromatogram of the standard
preparation, as obtained in the assay.

Complies

Compli
es

Complies

Water content
(by KF)

NMT 6% w/w

3% w/w

2.7%
w/w

2.6% w/w

Minimu
m:
97.0%
Maximu
m:
99.9%
Average
: 98.0%
%
RSD :
0.9%

Minimum: 95.9%
Maximum : 97.0%
Average : 96.5%
% RSD : 0.3%

2
Compli
es

3
Complies

Content uniformity

(1)Mean of all results is 90% to 110% of target assay.

(2)RSD of all individual results: NMT 5.0%

Minimum : 97.1%
Maximum: 99.6%
Average : 98.0%
% RSD : 0.8%

Assay
(By HPLC)

Not less than 90.0% & Not more than 110.0 % of

labeled amount of Ritonavir IP

101.8%

101.3%

99.3%

% LOD by moisture analyzer at

105C in auto mode

For information only

0.7%

1.5 %

1.3%

Retain on #30
Between #24 and #30
Pass through #24

Particle size distribution

NMT 5%
NLT80%
NMT 5%

0.1%
98.0%
1.6%

0.1%
98.5%
1.1%

0.1%
97.8%
1.6%57

Results of Finished product analysis :

Parameters

Specifications

Description

Pale yellow, film coated , oval

tablet debossed with EIM on
one side & 26 on other side

Results
2

Complies

Complies

Complies

Complies

Complies

Complies

The retention time and the peak

due to Lopinavir & ritonavir in
Identification
(By HPLC)

assay preparation correspond to

that obtained from the standard
preparation as directed in the
test for assay.

Water content

NMT 6 % w/w

3.0% w/w

3.0% w/w

3.0% w/w

Dissolution

Stage A : NLT 75% (D) of the

labeled amount of Lopinavir IP
is dissolved in 120 min.
Stage B : NLT 75% (D) of the
labeled amount of Ritonavir IP
is dissolved in 120 min.

Stage A (min): 0.0%

Stage A (max):2.2%
Stage A (avg.):0.9%
Stage B (min):96.1%
Stage B (max):99.0%
Stage B (avg.):97.1%

Stage A
(min) : 0.0%
Stage A (max) :2.3%
Stage A (avg.) :0.7%
Stage B (min):96.5%
Stage B (max):99.4%
Stage B (avg.):97.8%

Stage A (min):0.0%
Stage A (max):0.1%
Stage A (avg.):0.0%
Stage B (min):95.4%
Stage B (max):96.9%
Stage B (avg.):96.3%

Assay
(By HPLC)

Each 100mg pellets contain l &r

USP NLT 90.0% of labeled
amount of 12.70% w/w

97.4%

98.1%

94.1%

Blend uniformity

1)Individual results should be

90.0% to 110 % of target assay.
2) Mean of all results is 95.0%
to 105.0% of target assay.
3)RSD of all individual results
NMT 5.0%

Minimum: 97.87%
Maximum: 98.6%
Average: 98.3%
%RSD: 0.3%

Minimum: 97.2%
Maximum: 98.4%
Average: 97.9%
%RSD: 0.4%

Minimum: 93.5%
Maximum: 98.7%
Average: 96.3%
%RSD: 1.9%
58

Critical process parameters and Recommended range :

Processing stage

Coating

Drying

Yield

Critical process parameters

Recommended
limit(s)/range(s)

Outlet temperature

31C to 44C

Peristaltic pump speed

10RPM to 20RPM

Total Air Pressure

5 kg/cm2to 15
kg/cm2

Total Drying time

Up to 140 minutes

Exhaust air temperature (at the end of

drying)

35C to 40C

Loss on drying (LOD)

NMT 1.5%w/w

Drug Coating

93.0 % to 102.0 %
59

Summary :
This report explains the details of batch quantities, equipments & analytical
results with stage wise conclusion.
Test results & data generated during the process validation studies compiled as
process validation report .
All the equipments used for the manufacturing of lopinavir + ritonavir tablets
were verified for cleaning & found within the acceptance criteria.
The process validation was performed using qualified equipments as per
instructions given in BMR & BPR
All the equipments used for manufacturing of product were verified for
cleaning and found within the acceptance criteria

60

Conclusion:
Based on all the analytical data it can be concluded that the product complies with the
acceptance criteria as per the process validation protocol
This process produces the documented evidence that the process can effectively reproduce
a product with the current approved specification & quality standards.
Coating of all three consecutive batches carried out using Neo cota equipment.
It can be concluded from results that coating of these batches using Neo cota equipment is
satisfactory.
Process validation study on consecutive three batches is successfully completed and the
manufacturing critical process parameters were validated in this study.
Test results & data generated during the process validation studies compiled as process
validation report
61

References:
1) The European Agency for the Evaluation of Medicinal Products. Guidance
2)

3)

4)
5)
6)

on Process Validation, Canary Wharf, London, 30th September 1999.

Division of Manufacturing and Product Quality. U.S. Food and Drug
Administration. Guidelines on General Principles of Process Validation,
US Department of Health and Human Services, Public Health Service,
Food and Drug Administration, 1987.
Saudi Food & Drug Administration. Drug Sector. Guidelines for Process
Validation of Pharmaceutical Dosage Forms, Kingdom of Saudi Arabia,
2010, Vol. 2, 9 13.
Haider SI. Pharmaceutical Master Validation Plan: The ultimate guide to
FDA, GMP, and GLP compliance, Informa HealthCare, 2002.
USFDA Guidance for Industry; Process Validation: General Principles and
Practices. In C. CDER, CVM (ed.), Rockville, Maryland, November 2008.
Nash RA. The Validation of Pharmaceutical Processes. Drugs and the
pharmaceutical sciences, Marcel Dekker, 1998, 3rd edition: 161-186.
62

References :
Indian Pharmacopoeia. The Controller of Publication. Ministry of Health
and Family Welfare, Government of India, New Delhi, 2007 Vol. 3, 859861
8) United States Pharmacopoeia, US pharmacopoeial Convention, Mack
Printing Rockville,2007,30th ed.: 3636.
9) British Pharmacopoeia, Her Majestys Stationary office, London; 2009,
Vol-II:780-783.
10) E.P. Commission. European pharmacopoeia, Maisonneuve, 2339,1969.
11) Dale M, The Complete Drug Reference. Parfitt K, editor, Pharmaceutical
Press, 36th edition, 1768,1999.
12) FDA Guidance for Industry Process Validation: General Principles and
Practices, January 2011.
13) FDA Guideline on General Principles of Process Validation May 1987.
7)

63

References :
15) Solanki NS Process Validation: An Essentiality in the Pharmaceutical

Industry. International Journal of Pharmaceutical Research and

development. 2011,3:8-14.
16) Sharp J. The problem of Process Validation. Pharmaceutical Journal,
1986, 236(1): 43-45.
17) Potdar MA, editor. Pharmaceutical Validation., Nirali Publication, 2 nd
edition, Pune, 2007, 8.36-8.37.
18) K kolter Hot- Melt Extrusion with BASF polymers Extrusion
compendium Page No:8-15
19) Imming P Drugs, their targets and the nature and number of drug targets.
Net Rev Drug Discov. 2006 821-34
20) Lachman L, Lieberman HA, Joseph K, Kanig: The theory and practice of
industrial pharmacy; 3rd edition: 348-352, 426.

64

Review on Industrial process validation of Tablet dosage form

International Journal of Interdisciplinary and Multidisciplinary Studies
ISSN 2348 0343 (IJIMS)
Highlights :UO 2014 Impact Factor :1.36, Fast Track Review Process.
4/29/2014
Gmail - Acceptance Letter :Kindly confirm the receipt of acceptance letter
Kaustubh Kandharkar <kaustubh.kandharkar@gmail.com>
Acceptance Letter :
Kindly confirm the receipt of acceptance letter
Editor IJIMS <editorijims5@gmail.com> Thu, Apr 10, 2014 at 11:56 AM
To: kaustubh.kandharkar@gmail.com
Dear Sir /Madam,
I am delighted to inform you that your article entitled
"REVIEW: - INDUSTRIAL PROCESS VALIDATION OF TABLET DOSAGE FORM " has
been accepted for publication in the forthcoming April issue on
recommendation of reviewers. The April issue is to be released soon.
http://www.ijims.com/guidelines.php
65

Work remaining :
UV method development of Acamprosate calcium

66

Thank You**

67