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www.wjpr.net Vol 7, Issue 11, 2018. 1270

Chaudhari et al. World Journal of Pharmaceutical Research

PROCESS VALIDATION OF SOLID ORAL DOSAGE FORM OF

TRANDOLAPRIL TABLET 1 MG

Monika Ola, Rajveer Bhaskar, Pratiksha Rathi and Lalita Chaudhari*

1Department of Pharmaceutics and Pharmaceutical Quality Assurance, R. C. Patel Institute of

Pharmaceutical Education and Research, Karwand Naka.

2Shirpur, Dhule District, Maharashtra 425 405, India.

3Department of Quality Assurance ACP, Chikhli, Buldana District, Maharashtra 443201,

India.

ABSTRACT

The concept of validation was first proposed by Food and Drug

Administration officials in 1970 in order to improve the quality of

pharmaceuticals as well as different life saving products. Process

validation is important to establish documented evidence which

provides a high degree of assurance that a specific process for

manufacturing of tablets will consistently produce a product meeting

its pre-determined specifications and quality attributes. This study

contributes to validation of all the steps while manufacturing of

Trandolapril tablets. The different steps include in this study are,

Sifting, Milling, Dry mixing, Granulation, Drying, Blending,

Lubrication, compression, and Packing. While validation of all the

steps different critical parameters were studied and found satisfactory

as it fulfills acceptance criteria. We mainly focused on validation

parameters like, Particle size distribution while sifting and milling,

blend uniformity while blending and lubrication, LOD while drying,

hardness, thickness, disintegration, dissolution, friability, average

weight, group weight are studied after compression, Packing material were also checks for its

quality. All results were found within acceptance limit.

KEYWORDS: Solid Dosage form, Process Validation, Trandolapril Tablet, Quality

management.

World Journal of Pharmaceutical Research SJIF Impact Factor 8.074

Volume 7, Issue 11, 1270-1305. Research Article ISSN 2277– 7105

Article Received on

12 April 2018,

Revised on 02 May2018,

Accepted on 23 May 2018

DOI: 10.20959/wjpr201811-12544

*Corresponding Author

Lalita Chaudhari

Department of

Pharmaceutics and

Pharmaceutical Quality

Assurance, R. C. Patel

Institute of Pharmaceutical

Education and Research,

Karwand Naka.

[email protected],

[email protected].,

[email protected],

[email protected]

mailto:[email protected]






INTRODUCTION

Validation has proven to be an important tool for quality management of pharmaceuticals.

According to ISO 9000:2000, Validation is defined as,

“Confirmation, through the provision of objective evidence, that the requirements for a

specific intended use or application have been fulfilled”. In contrast with Verification,

Validation rather focuses on the question whether a system can perform its desired functions.

This review is an attempt to prove that it as essential tool for quality management in

pharmaceuticals industry.

Validation is concepts that have been evolving continuously since its first formal appearances

in United States in 1978. The concept of validation has expanded through the years to

encompass a wide range of activities from analytical methods used for the quality control of

drug substances and products to computerized system for clinical trial, labeling or process

control. The word “validation” simply means assessment of validity or action of proving

effectiveness.

Importance of Validation[2]

The most compelling reasons to optimize and validate pharmaceutical production and

supporting processes are quality assurance and cost reduction. The basic principles of quality

assurance have as their goal and the production of articles that are fit for their intended use.

It deepens the understanding of processes, decreases the risks, processing Problems, and

assures the smooth running of the process.

It decreases the risks of defect costs.

It decreases the risks of regulatory non-compliance.

A fully validated process may require less in- process control and end product testing.

It optimizes the process.

It gives assurance of quality and safety.

Need of Validation[3,4]

If Process validation does not carried out then following problems can occur. i.e.

Low process capability

1. Scrap, Rework, or Recall

2. Protracted production cycle times and low capacity utilization.

3. Resolution of process related problems slow and difficult.



4. High cost of compliance.

There is a Risk of

1. Drug shortages.

2. Releasing a poor quality product.

3. Recall.

4. Delay in approval of new drugs.

5. Quality problems confounding clinical trial data.

So, to minimize these problems Process validation is carried out.

Major Phases in Validation[2,5]

The activities relating to validation studies may be classified into three

Phase 1: This is the pre- validation Qualification Phase which covers all activities relating to

product research and development, formulation pilot batch, establishing stability condition

and storage, and handling of in-process and finished dosage forms, equipment qualification,

installation qualification, master production document, operational qualification and process

capacity.

Phase 2: This is the process validation phase. It is designed to verify that all established limit

of the critical process parameter are valid and that satisfactory product can be produced even

under the worst condition.

Phase 3: Known as the validation Maintenance phase, it requires frequent review of all

process related documents, including validation of audit reports, to assure that there have

been no changes, deviations, failures and modifications to the production process and that all

standard operating procedures (SOPs), including change control procedures, have been no

changes/deviations that should have resulted in requalification and revalidation. A careful

design and validation of systems and process controls can establish a high degree of

confidence that all lots or batches produced will meet their intended specifications. It is

assumed that throughout manufacturing and control, operations are conducted in accordance

with the principle of good manufacturing practice (GMP) both in general and in specific

reference to sterile product manufacture.[6]



Scope of Validation[2,7]

Pharmaceutical validation is a vast area of work and it practically covers every aspects of

pharmaceutical processing activates; hence defining the scope of validation becomes a really

difficult task. A systematic look at the pharmaceutical operations will point out at least the

following areas for pharmaceutical validation, e.g. Instrument Calibration, Process Utility

services, Raw materials, Packaging materials, Equipment, Facilities, Manufacturing

operation, Product Design, Cleaning, Operators etc.

Process Validation[2,14]

“Process validation” is defined by the U. S. Food and Drug Administration (USFDA) as,

“Establishing 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 attributes”

Types Of Process Validation[6,11,12,19,7,8,21]

There are three types of process validation as follows

1) Prospective Validation: It would normally be expected that process validation be

completed prior to the distribution of a finished product that is intended for sale.

2) Concurrent Validation: Where this is not possible, it may be necessary to validate

processes during routine production.

3) Retrospective Validation: Processes which have been in use for some time without any

significant changes may also be validated according to an approved protocol.

Different Steps of Process Validation for Tablet Manufacturing

Sifting, Mixing & Blending, Granulation, Drying, Milling, Lubrication, Compression are the

steps which are important to validate during process validation of tablet dosage form

including all the critical parameters of each step.

MATERIALS AND METHOD

Materials

All material used of USP/NF/IH grade and chemicals used in the analysis in the study were of

analytical grade. Following are the active pharmaceutical agent and excipients used in

experimental work.



List of Ingredients

Table No.1: List of Ingredients.

Sr. No. Ingredients Category Manufacturer Company

1. Drug Trandolapril API AurobindoPharma Limited, India

2. Lactose monohydrate NF Diluent DMF

3. Starch (corn starch) NF Diluent Roquette

4. Croscarmellose sodium NF Disintegrant FMC

5. Hypromellose USP Binder Dow Chemical

6. Ferric oxide (Red &Yellow Iron

818802) NF+IH Colorant Sensient

7. Povidone USP Binder BASF

8. Sodium strearylfumarate NF Lubricant Standard Chem

Analysis report of all the raw material was checked and approved raw material was used.

List of Equipments used

List of manufacturing equipments and their qualification status are described in the following

table.

Table No 2: List of equipments.

Sr.No. Manufacturing

stage Equipment’s

Manufactured

By Qualification

1 All applicable stages Weighing Balance

Jay Pan

Qualified Mettler Toledo

A&D co Ltd

2 Sifting Vibratory Sifter Gansons Qualified

3 Wet Granulation Rapid Mixer Granulator

(150L) Saral Qualified

4 Binder Preparation Pneumatic Stirrer Fluidyne Qualified

5 Drying Fluid Bed Dryer

(60kg) Saral Qualified

6 Milling Co-mill R.P.Products Qualified

7 Milling Lifting and tippling device Saral Qualified

8 Blending Piller Blender

(Capacity 150 L) R.P.Products Qualified

9 Compression

Rotary compression machine Kilian Qualified

Combo de-duster and Metal

Detector Kramer Qualified

10 Tablet inspection Tablet Inspection Machine Accura Qualified

Qualified equipments were used for processing and no failure observations noted during

operation of the equipment’s.



List of Instruments Used

List of Instruments and their qualification status are described in the following table.

Table No 3: List of Instruments.

Sr.No. Instruments Manufactured By Qualification

1. Electronic Balance Mettler Toledo Qualified

2. Moisture analyzer Mettler Toledo Qualified

3. USP Dissolution apparatus Electrolab Qualified

4. Tapped density apparatus Electrolab Qualified

5. Malvern Master Sizer Hydro 2000 S Qualified

6. Hardness tester Schleuniger Qualified

7. pH Meter Thermo scientific Qualified

8. HPLC Shimadzu Qualified

9. Friability test apparatus Electrolab Qualified

10. IR Shimadzu Qualified

11. Water Content by Karl Fisher Metrohn Qualified

12 Melting point apparatus Mettler Toledo Qualified

13 Degasser Electrolab Qualified

14 Angle of repose apparatus Electrolab Qualified

15 Polarimeter Rudolph research analytical Qualified

Qualified instruments were used for processing and no failure observations noted during

operation of the instruments.

List of Primary Packaging Materials

Primary packaging material used in Trandolapril tablets USP described as follows:

Table No. 4: Packaging Components.

Sr. No. Ingredients Function Vendor

1. 60cc ROUND OPAQ HDPE

Bottle Primary packaging Triveni Polymers

2. 033MM CR Closure with Hs123-

35 PRT Kerr Primary packaging BPREX Pharma

3 Silica gel Schet 1g Absorbent Multisorbtechnologies

4 Pharma grade polyster: coil 9G-

Carolina Absorbent

Carolina Adsorbent

Cotton USA

Assessment of critical parameters

Rational for selection of non-critical and critical steps and its process parameters for

validation are given as follows:



1. Stage :- Dispensing

Equipment: Weighing Balance

Fig. No.1: Weighing Balance for weighing.

Make-Mettler Toledo

Critical Variable- Weight variation

Critical Parameters- Showing weight variation

Rationale- Weighing balance should be calibrated to meet the desired product specification.

2. Stage:- Sifting

Equipment: Vibratory Sifter

Fig. No 2: Vibratory Sifter for sifting.

Make- Gansons

Critical Variable: Particle Size distribution of sifted materials.

Critical Parameters

Particular sieve number

Sieve integrity before and after use.



Rationale: - To ensure uniform particle size distribution of sifted input material.

3. Stage:- Dry mixing & Wet Granulation

Equipment: Rapid Mixer Granulator

Fig. No. 3: Rapid Mixer Granulator for granulation.

Make- Saral

Capacity- 150 L

Critical Variable:-Speed of Impeller and Chopper

Critical Parameters: -Impeller speed

-Chopper Speed

Rationale: To obtain the homogeneity of granulation process and physical properties of

granules uniformity for compression.

4. Stage: Drying

Equipment: - Fluidized Bed Dyer

Fig. No.4: Fluidized Bed Dyer for drying.



Make- Saral

Capacity- 60 Kg

Critical Variable: -Temperature

Critical Parameters: -Inlet temperature

: -Outlet temperature

5. Stage:- Milling

Equipment: - Co-mill

Fig. No. 5.5: Co-mill.

Make- Saral

Critical Variable: - Temperature

Critical Parameters: - Speed of Co-Mill Screen used

6. Stage:- Blending

Equipment: - Pillar Blender Bin

Fig. No. 6: Pillar Blender Bin for Blending.



Make- R. P. Products

Capacity- 150L

Critical Variable: - Blending time (with lubricant)

Blending speed

Critical Parameters

Blending time

Blending speed

Assay

Bulk and Tap density

Sieve Analysis

Blend Uniformity

7. Stage:- compression

Equipment: - Rotary compression machine.

Fig.No. 7: Rotary compression machine.

Make- Kilian

Critical Variable

Force Feeder speed

Compression Machine Speed

Compression force



Critical Parameters

1) Dissolution

2) Uniformity of dosage unit

3) Friability

4) disintegration

METHOD

Process flow chart

A] INTRA-GRANULAR PART:

INGREDIENTS PROCESS DESCRIPTION TESTS PERFORMED

RAW MATERIAL

QUANTITY

VERIFICATION

[Weighing Balance]

1. Lactose Monohydrate

NF/IH

SIFTING

[Vibratory Sifter- 60 mesh]

1. Drug X SIFTING


1. Sifted Drug X and

2. Sifted Lactose

Monohydrate NF/IH

in 1:1 proportion

PRE-MIXING (MANUAL)

AND SIFTING (Twice)


1. Sifted Lactose

Monohydrate NF/IH

and

2. Sifted Drug premix

in 1:1 proportion

PRE-MIXING (MANUAL)

AND SIFTING


1. Remaining Lactose

Monohydrate

CO-SIFTING


1. Red Iron Oxide IH

2. Part quantity of

Starch NF

MIXING (MANUAL)

AND SIFTING (Twice)


1. Remaining quantity

of Starch NF

SIFTING


1. Hypromellose USP and

2. Croscarmellose Sodium

SIFTING





NF

1. Povidone USP and

2. Purified water USP

BINDER PREPARATION

[S.S. Container and Stirrer]

Sifted (Order-wise)

1. Hypromellose USP

and Croscarmellose

Sodium NF (Half

quantity)

2. Drug X-Lactose

Monohydrate

powder mix

3. Color-Starch

Concentrate

4. Starch NF

5. Hypromellose USP

and Croscarmellose

Sodium NF

(Remaining

quantity)

DRY MIXING

[Rapid Mixer Granulator- 150

L]

[Mixing time- 15:00 Minutes:

Seconds]

[Impeller: Slow, Chopper: Off]

1.Blend Uniformity

1. Binder Solution

2. Purified Water USP

WET GRANULATION

[Rapid Mixer Granulator- 150

L]

Binder/P. Water Addition-

Impeller: Slow, Chopper: Slow

Wet mixing-

Impeller: Fast, Chopper: Fast

DRYING

[Fluid Bed Dryer - 60 kg]

Air Drying Time: 05 Minutes

Inlet Air Temperature: 60°C ±

5°C

(55 - 65°C)

1. Loss on Drying (%

w/w)

1. Dried Granules

SIFTING OF DRIED

GRANULES


1. Oversized Granules

MILLING AND SIFTING

OF

OVERSIZE GRANULES

[Co-Mill- 1.0 mm S. S.

Screen]

[Vibratory Sifter- 30 mesh S.S.

Sieve]




Milling Speed: Slow/Fast

[Milling and sifting to be done

till all materials passed

through 30 mesh S.S. Sieve]

B]EXTRA

GRANULAR PART:

1. Sodium

StearylFumarate

SIFTING OF EXTRA-

GRANULAR MATERIAL


1. Sifted Sodium

StearylFumarate

2. Approximately 2 kg

of sized granules

MIXING (MANUAL BY

TURNING TWICE) AND

SIFTING


1. Sized Granules

2. Sodium

StearylFumarate and

Sized granules pre-

mix

LUBRICATION

[Pillar blender- 150 L]

[Mixing time- 05:00

Minutes: Seconds]

[Blender Speed- 05 rpm]

1. Description

2. Composite Blend

Assay

3. Blend Uniformity

4. Bulk density

5. Tapped Density

6. Compressibility index

7. Hausner’s ratio

8. Particle

size distribution

9. Angle of repose

COMPRESSION [Tablet Compression Machine,

Deduster and Metal Detector]

[Punch Specification: 6.0 mm

round, standard concave

punches, UP "H01" and LP

“L” and “U” on either side of

scoreline]

1. Description

2. Weight of 20 tablets

3. Uniformity of weight

4. Thickness

5. Tablets Breaking force

6. Disintegration Time

7. Friability

8. Dissolution

9. Uniformity of dosage

unit (By content

Uniformity)

Complete analysis as

per finished product

release specification



Process Description

1.0 Dispensing

1.1 The required quantities of ingredients were dispensed as per raw material requisition

sheet.

1.2 The weights and Q.C batch numbers of dispensed ingredients were checked and verified.

2.0 Sifting

2.1 Dispensed quantity of Lactose Monohydrate NF was sifted through 60 mesh S.S. sieve

using vibratory sifter.

2.2 Dispensed quantity of Drug X was sifted through 40 mesh S.S. sieve by manually.

2.3 Step 2.2 sifted Drug X was mixed together with sifted Lactose Monohydrate of step 2.1

geometrically in 1:1 proportion.

2.4 Step 2.3 mixed material was sifted through 60 mesh S.S sieve manually.

2.5 Step 2.4 material was again sifted through 60 mesh S.S. sieve manually.

2.6 Lactose Monohydrate from step 2.1 & drug premix were mixed geometrically in 1:1

proportion in polybag and sifted through 60 mesh S.S. sieve manually.

2.7 Step 2.6 drug premix was sifted with remaining quantity of step 2.1 Lactose Monohydrate

through 60 mesh S.S sieve manually.

2.8 Ferric Oxide NF+IH (Red Iron 800416) was mixed with total Qty of Starch NF and sifted

twice through 100 mesh S.S. sieve.

2.9 Remaining Starch NF was sifted through 60 mesh S.S. sieve on vibratory sifter.

2.10 Hypromellose IP was sifted through 40 mesh S.S. sieve on vibratory sifter.

2.11 Croscarmellose Sodium NF was sifted through 40 mesh S.S. sieve on vibratory sifter.

3.0 Binder Preparation

3.1Povidone USP was dissolved in purified water using stirrer to get approximately 20%

W/W solution in S.S. container.

3.2 Continued stirring till clear solution is formed.

Total Stirring Time: 16 Minutes

4.0 Wet Granulation

4.1 Dry mixing

4.1.1 Sifted material of step 2.10 and step 2.11 were loaded into RMG approximately half

Qty. followed by Drug X – Lactose monohydrate powder mix of step 2.7, colour concentrate

of step 2.8, sifted remaining Starch of step 2.9 and remaining Qty. of step 2.10 & 2.11.



4.1.2 The content of RMG were mixed for 15 minutes at agitator slow speed and chopper off.

4.2 Binder addition

4.2.1 Added step 3.2 Povidone solution into RMG content for 2 min. with slow agitator &

slow chopper.

Impeller Ampere – 12.6 A (slow)

Chopper Ampere – 2.2 A (slow)

4.3 Wet mixing

4.3.1The content of RMG was mixed by addition of purified water for 1 min.

Impeller Ampere – 8.6 A (fast)

Chopper Ampere – 2.2 A (fast)

4.3.2 Continued the granulation for 1 min.

Impeller Ampere – 8.3 A (fast)

Chopper Ampere – 2.2 A (fast)

4.3.3 After satisfactory granulation content of RMG were discharged with impeller and

chopper at fast speed in FBD bowl.

5.0 Drying

5.1 The content of FBD bowl were air dried under FBD with following parameters:

i) Air drying time - 5 minutes

ii) Inlet Temp. – 26.7⁰C

iii) Outlet Temp. – 20.5⁰C

iv) FCD – 30%

5.2 Further material in FBD bowl was dried with steam drying for 10 minutes.

i) Inlet Temp. – 58.8⁰C

ii) Outlet Temp. – 28.4⁰C

iii) FCD – 30 (8 min) ; 25 (2 min)

iv) LOD - 4.07%

FBD was stopped and LOD was checked which was found more than the specified limit (i.e.

Between 2.0-3.5% at 105⁰C), hence again drying was continued.



5.3 Steam drying was continued for 3 minutes.

i) Inlet Temp. – 58.8⁰C

ii) Outlet Temp. – 37.5⁰C

iii) FCD – 25%

iv) LOD - 2.13% (within limit; hence drying stopped)

Total air drying time – 05 min

Total steam drying time – 13 min

LOD: Top – 2.02% ; Middle – 2.37% ; Bottom – 2.45%

6.0 Sifting of dried granules

6.1 Dried granules of step 5.3 were sifted through 30 mesh S.S sieve fitted on Vibratory

Sifter and collected in double polybag lined IPC as under size granules.

Quantity of oversize granules- 6.96 kg.

Quantity of undersize granules- 22.24 kg.

7.0 Milling

7.1 Above oversize material was milled through 1.0 mm S.S. screen fitted on co-mill at

milling speed of 25 Hz and collected in double polythene bag lined container. This milled

material was then sifted through 30 mesh S.S. sieve and undersize and oversize materials

were collected separately in double polythene bag lined containers.

Total Weight of Oversize Granules- 1.30 kg

7.2 Above oversize material was again milled through 1.0 mm S.S. screen fitted on co-mill at






















7.6 Above oversize material was then passed by manually pressing through 30 mesh S.S.

sieve fitted on vibratory sifter.

7.7 All undersize granules were loaded in 150 L capacity pillar blender bin.

8.0 Lubricant sifting

8.1 Dispensed quantity of Sodium Stearyl Fumarate was sifted through 60 mesh S.S. sieve

using vibratory sifter and collected in a double polythene bag lined container.

8.2 Approximately 2 kg undersize granules and sifted Sodium Stearyl Fumarate were mixed

together manually in polybag by turning twice.

8.3 Above mixed material was sifted through 30 mesh S.S. sieve using vibratory sifter,

collected in a double polythene bag lined container and added to blender bin of step 7.7.

9.0 Blending

9.1 The contents in blender bin were mixed for 05 minutes at 5 rpm using pillar blender.

Sampling was performed as per sampling plan provided in sampling protocol (Die used-

0.3 mL round shaped Die).

9.2 Unloading of Lubricated Blend into in-process container.

10.0 Compression

10.1 Above lubricated blend was compressed using double rotatory compression machine.

At initially stage of compression sticking was observed on upper surface of tablets,

subsequently punches were cleaned, then compression was continued and further no

sticking was appeared on tablet surface. During compression in-process tests were



performed at minimum machine speed, maximum machine speed and also at start, middle

and end of compression run. Tablet parameters at these stages were checked for in-

process tests and found complying with the specified limits.

Steps Involved in Process Validation of Trandolapril Tablets[23]

1) Sifting (correct Mesh Size),

2) Mixing and Blending (dry mixing, binder addition, wet mixing, in-process control

checks etc.),

3) Granulation (Binder addition, Mixing time) done using Rapid Mixer Granulator and

samples were collected from 10 sampling locations as given in following diagram.

Figure No. Schematic Diagram of RMG.

4) Drying (LOD), by using Fluid Bed Dryer and samples for in process control checks were

collected from 7 different locations as shown in following Diagram.

Figure No. Schematic Diagram of Fluid Bed Dryer



5) Sizing and Milling (Mesh Size), done using Co-Mill.

6) Lubrication (Blending Time, Blending Speed), performed using Bin Blender and samples

were collected from 10 different locations as shown in following diagram.

Figure No. Schematic Diagram of Bin Blender.

7) Compression (Hardness, Speed, in process checks like Appearance of tablet, group

weight, Average weight, Uniformity of weight, Thickness, Hardness, Length, width, and

Friability etc), done using Rotary compression machine. Collected 54 tablets from each

interval; make a composite sample from initial, middle, and end. For the study 20 tablets

were considered as whole composite.

Table No. 9: Acceptance criteria during compression.

Test Acceptance criteria

Appearance Pink, round, biconvex, uncoated tablets

Group weight -----

Uniformity of weight ± 5% of theoretical average weight

(95.000 to 105.000 mg)

Average weight 2.000 g ± 3% (1.940 to 2.060 g)

Thickness 3.10 ± 0.20 mm (2.90 mm to 3.30 mm)

Hardness 60 ± 20 N (40 N to 80 N)

Friability NMT 0.8%

Disintegration Time NMT 15:00

Assay 95 to 105%



Different Defects Related To Tablets

Tablets were checked for following defects after compression:

Capping, Lamination, Chipping, Cracking, Sticking, Picking, Binding, Mottling, Double

impression, Bridging, Erosion, Twinning, Peeling, Frostin, Orange peel etc.

Pack Profile

The compressed tablets were packed in the container as follows:

33mm-66cc WM heavy weight round HDPE bottle containing 100tablets with and CR

closure (33-400) PP with induction heat sealed HS123 printed liner.

Equipment Evaluation

All the equipments which were used in the manufacturing of Trandolapril tablets evaluated as

per requirement and found satisfactory.

The equipments are as follows:

Mixer/granulator, Blender, Dryer, Mills etc.

RESULT AND DISCUSSION

1. Results for Sifting

Table: Sifting Results.

Batch No. Integrity of Sieve Before Integrity of Sieve After

A1 Complies Complies



Trandolapril, Hypromellose IP and Croscarmellose Sodium NF was sifted through sieve #40

on vibrosifter. Lactose and Sodium Stearyl Fumarate sifted through sieve #60. Ferric Oxide

NF+IH and starch through sieve #100.

Integrity of sieve before use and Integrity of sieve after use was checked and found

complying with specifications.

2. Results for Dry mixing

Table: Blending mixing time.

Assessment Parameters Observation

Mixing Time 15min

Speed of RMG Slow



The raw materials were mixed for 15minutes in RMG at slow speed with knife in forward

direction.

Table: Blend Uniformity Results.

Sample % Assay (Acceptance Criteria: 90% to 110% RSD : NMT 5%)

(Time :15 min)

B.No. A1 B.No. A2 B.No. A3

T1 99.4 97.1 95.1

T2 104.8 99.0 101.8

M1 99.5 100.6 95.2

M2 105.4 95.9 96.3

B1 103.6 93.3 91.9

B2 104.7 98.1 96.4

Min. 99.4 93.3 91.9

Max. 105.4 100.6 101.8

Mean % 102.9 97.3 96.1

RSD % 2.8 2.6 3.1

6 locational samples have been collected by using sampling rod and tested for blend

uniformity by using HPLC.

Batch No A1: Minimum value was 99.4%, maximum value was 105.4%, mean value was

102.9 and RSD was found to be 2.8.

Batch No. A2: Minimum value was 93.3%, maximum value was 100.6%, mean value was


Batch No. A3: Minimum value was 91.9%, maximum value was 101.8%, mean value was


Process parameters comply with the requirements as given in the protocol.

All the results of Blend uniformity were found within the acceptance criteria as per approved

specifications.

Table: Bulk Density Results.

Acceptance

criteria

Batch

No.

Sample

size

Untapped bulk

density

Tapped bulk

density

To record A1 30 g 0.63 0.71

To record A2 30 g 0.59 0.72

To record A3 30 g 0.63 0.71



One 30g composite sample have been collected and tested for bulk density (Tapped &

Untapped) by using bulk density tester.

Batch No. A1: The results for untapped bulk density were found to be 0.63 and for tapped

bulk density 0.71.


bulk density 0.72.


bulk density 0.71.

Process parameters comply with the requirements as per given in the protocol.

3. Results for Drying

Table: LOD Results.

Sample Acceptance

criteria

Weight

reuired (g)

LOD in %w/w

B.No.

A1 B.No.

A2

B.No.

A3

T1

2.0– 3.5 % w/w 2 – 5 g

2.44 2.59 2.53

T2 2.28 2.81 2.59

M1 2.43 2.57 2.83

M2 2.44 2.82 2.60

M3 2.39 2.68 2.42

B1 2.42 2.65 2.63

B2 2.40 2.75 2.55

Average 2.4 2.69 2.59

Granulated wet mass were transferred to FBD from RMG and dried for 10 minutes. 7

locational samples 2–5gm were collected as per sampling locations by using sampling rod

and tested for LOD by putting the sample in LOD bottles and dried it in Oven for specified

time at specified temperature.

Batch No. A1: From the top 2 portion LOD results were found to be 2.44% and 2.28%, From

middle portion 2.39-2.44% and from bottom portion 2.42% and 2.43%. Average value for

LOD was found to be 2.4%.









Process parameters comply with the requirements as given in the protocol. All the results of

LOD were found within the acceptance criteria as per approved specifications.

4. Results for Milling

Table: PSD Results.

Sieve size Acceptance criteria % w/w Retention


20#

To record

0.0 0.0 0.0

60# 32.3 31.0 33

80# 49 46 49

120# 67 62 66

200# 81 79 82

% w/w passed through

200# To record 16 17 18

Particle size of the milled granules were checked by passing it through various sieves i.e. 20#,

60#, 80#, 100#,120# &200# by using sieve shaker.

Batch No. A1: PSD results are as follows:

From the sieve size 20# 0.0 % sample retention were observed, from sieve size 60# 33%

sample retention were observed, from sieve size 80#.49% sample retention were observed,

from sieve size 120# 67% sample retention was observed, from sieve size 200# 82% sample

retention were observed and 16% sample was below sieve size 200#.



sample retention were observed, from sieve size 80# 46% sample retention were observed,


retention were observed and 17% sample was passed through sieve size 200#.



sample retention were observed, from sieve size 80# 49% sample retention were observed,


retention were observed and 18% sample was passed through sieve size 200#.




5. Results for Lubrication

Table: Blending mixing time.

Assessment Parameters Observation

Mixing Time 5 min

Speed of Bin blender 5rpm

Milled granules were transferred to Bin blender and mixed for 15 minutes at slow speed after

that Lubricant was added and again mixed for 5 minutes at 5rpm speed.

Table: Blend Uniformity Results.

Sample % Assay (Acceptance Criteria: 90% to 110% RSD : NMT 5%)

(Time : 5 min)


T1 103.0 98.7 98.4

T2 99.9 98.9 100.0

T3 100.3 99.1 98.4

T4 99.5 104.3 97.9

M1 100.1 98.5 98.3

M2 104.3 99.0 101.1

M3 103.0 99.6 98.1

B1 107.5 105.4 100.5

B2 97.6 100.7 100.9

B3 101.2 98.8 97.8

Min. 97.6 98.5 97.8

Max. 107.5 105.4 101.1

Mean% 101.6 100.3 99.1

RSD% 2.9 2.5 1.3

10 locational samples have been collected by using sampling rod and tested for blend

uniformity by using HPLC.

Batch No. A1: From the top portion results were found between 99.5-103.0%, from middle

portion 100.1-104.3% and from bottom portion 97.6-107.5%, minimum value was 97.6%,

maximum value was 107.5%, mean value was 101.6 and RSD was found to be 2.9.










All the results of Blend uniformity were found within the acceptance criteria as per approved

specifications.

Table: Assay Results of Lubricated granules.

Acceptance Criteria: 95.0 % - 105.0%

B. No. A1 B. No. A2 B. No. A3

98.0 % 98.9 % 97.6 %

Lubricated granules were withdrawn from each batch and tested for Assay by using HPLC.

The assay result for batch No A1, A2, A3 was found to be 98.0%, 98.9%, 97.6% respectively.

All the results were found within specification limit.

6. Compression

A. Hardness Variation

Table: Results of hardness variation (Batch- A1, A2, A3).

Test Acceptance Criteria --- Low

Hardness

High

Hardness

Appearance

Pink, round, biconvex,

uncoated tablets with

“L”& “U” on either side

of breakline on one side&

“H01”. on the other side.

--- Complies Complies

weight of 20

tablets

2.000g ± 3.0 %

(1.940 – 2.060 g)

Min. 2.000 2.003

Max. 2.015 2.005

Uniformity of

Weight (mg)

±5% of theoretical

average weight

(95.00-105.00mg)

--- 0.1008 0.1005

D. T. (min: sec.) NMT 15:00 --- 2.10 3.40

Thickness 3.10mm ± 0.20mm

(2.90-3.30mm)

Min. 3.30 3.12

Max. 3.36 3.15

Avg. 3.33 3.14

Hardness 60±20N

(40 – 80 N)

Min 29 80

Max. 40 99

Avg. 35 91

Friability NMT 0.8 % w/w -- 0.092 0.076

Assay 95% to 105% --- 96 98



Lubricated granules were compressed by using rotary compression machine. During

compression cycle samples were collected at min/max hardness.

For Low Hardness: Compression results obtained are as follows:

1. weight of 20 tablets:(acceptance criteria- (1.940 – 2.060 g): 20 tablets were accurately

weighed by using calibrated balance and the results were found to be min. 2.000g and

max. 2.015g.

2. Uniformity of Weight (mg) (acceptance criteria- 95.00-105.00mg): All tablets have been

weighed accurately by using calibrated balance and the average weight were calculated.

The results were found to be 0.1008.

3. Disintegration Time: (NMT 15:00): Disintegration time was determined by the

disintegration apparatus and results were found to be 02:10.

4. Thickness (acceptance criteria- 2.90-3.30mm):

Thickness of 10 tablets was checked by using vernier caliper and the results found to be

min. 3.30mm, max. 3.36mm and avg. 3.33mm.

5. Hardness (acceptance criteria- 40 – 80 N):

Hardness of 10 tablets were tested using hardness tester and the results found to be at

min. hardness min. 29N, max. 40N, avg. 35N.

6. Friability (acceptance criteria- NMT 0.8 % w/w): Friability of tablets were checked by

using friability tester and the results found to be 0.092.

7. Assay (acceptance criteria- 95% to 105%): The assay of compressed tablets were carried

out by using HPLC and result was found to be 96%.

For High Hardness: Compression results obtained are as follows:

1. Weight of 20 tablets :(acceptance criteria- (1.940 – 2.060 g): 20 tablets were accurately

weighed by using calibrated balance and the results were found to be min. 2.003 and max.

2.005.


weighed accurately by using calibrated balance and the average weight were calculated.

The results found to be 0.1005.

3. Disintegration Time: (NMT 15:00): Disintegration time was determined by the

disintegration apparatus and results were found to be 03:40.



4. Thickness (acceptance criteria- 2.90-3.30mm): Thickness of 10 tablets was checked by

using vernier caliper and the results found to be min. 3.12mm, max. 3.15mm and avg.

3.14mm.

5. Hardness (acceptance criteria- 40 – 80 N): Hardness of 10 tablets were tested using

hardness tester and the results found to be at min. hardness min. 80N, max. 99N, avg.

91N.


using friability tester and the result found, to be 0.076.

7. Assay (acceptance criteria- 95% to 105%): The assay of compressed tablets was carried

out by using HPLC and the result found to be 98%.

The data of physical & analytical parameters carried on samples collected during low

hardness & high hardness for all three validation batches are found within the limits of

acceptance criteria.

B. Speed variation

Table 7.12 Results of Speed variation (Batch- 01, 02, 03).

Test Acceptance Criteria --- Low

Speed

High

Speed

Appearance

Pink, round, biconvex, uncoated

tablets with “L”& “U” on either side

of breakline on one side& “H01”. on

the other side.

--- Complies Complies

weight of 20 tablets 2.000g ± 3.0 %

(1.940 – 2.060 g)

Min. 1.990 2.004

Max. 1.992 2.009

Uniformity of

Weight (mg)

±5% of theoretical average weight

(95.00-105.00mg) --- 0.09941 0.10018

D. T. (min: sec.) NMT 15:00 --- 0.238 0.242


(2.90-3.30mm)

Min. 3.08 3.12

Max. 3.21 3.23

Avg. 3.16 3.19

Hardness 60±20N

(40 – 80 N)

Min 47 55

Max. 78 76

Avg. 64 66

Friability NMT 0.8 % w/w -- 0.031 0.031

Assay 95% to 105% --- 97 98


compression cycle samples were collected at min/max speed.



For Low Speed: Compression results obtained are as follows:

1. Weight of 20 tablets (acceptance criteria- 1.940 – 2.060 g): 20 tablets were accurately


max. 1.992g.


weighed accurately by using calibrated balance and the average weight was calculated.


3. Disintegration Time (acceptance criteria- NMT 15:00): Disintegration time was

determined by the disintegration apparatus and results were found to be 0.238



3.16mm.



64N.


using friability tester and the result found to be 0.031.



For High Speed: Compression results obtained are as follows:

1. Weight of 20 tablets (acceptance criteria- 1.940 – 2.060 g): 20 tablets were accurately


max. 2.009g.


weighed accurately by using calibrated balance and the average weight was calculated.



determined by the disintegration apparatus and results were found to be 0.242.



3.19mm.





66N.


using friability tester and the result found to be 0.031.



The data of physical & analytical parameters carried on samples collected during low speed

& high speed for all three validation batches are found within the limits of acceptance

criteria.

C. At optimum condition

Optimum condition means the speed of the machine and the hardness of the machine were

kept at optimum level, i.e. speed – 20rpm, hardness – 80-130N

Table: Results of compression parameters at optimum condition (Batch- 01, 02, 03).

Test Acceptance Criteria --- Initial Middle End

Appearance

Pink, round, biconvex, uncoated tablets

with “L”& “U” on either side of breakline

on one side& “H01”. on the other side.

--- Complies Complies Complies

weight of 20 tablets 2.000g ± 3.0 %

(1.940 – 2.060 g) 1.9950 2.0050 1.9970

Uniformity of

Weight (mg)

±5% of theoretical average weight (95.00-

105.00mg) --- 0.10025 0.10050 0.10035

D. T. (min: sec.) NMT 15:00 --- 02:40 02:35 02:30


(2.90-3.30mm)

Min. 3.17 3.17 3.17

Max. 3.20 3.22 3.20

Avg. 3.19 3.20 3.19

Hardness 60±20N

(40 – 80 N)

Min 54 57 60

Max. 71 69 69

Avg. 63 63 64

Friability NMT 0.8 % w/w -- 0.077 0.077 0.123

Assay 95% to 105% --- 98 98.5 97


compression cycle samples were collected at Initial, Middle and End stage of compression.

At initial stage: Compression results obtained are as follows:

1. Weight of 20 tablets test (acceptance criteria- 1.940 – 2.060 g)): 20 tablets were

accurately weighed by using calibrated balance and the results were found to be 1.9950g.



2. Uniformity of weight (acceptance criteria- 95-105 mg): All tablets have been weighed

accurately by using calibrated balance and the average weight were calculated. The result

found to be 0.10025.

3. Thickness (acceptance criteria- 2.90 mm-3.30 mm): Thickness of 10 tablets were

checked by using vernier caliper and the results found to be min. 3.17mm, max. 3.20mm

and avg. 3.19mm.



5. Hardness (acceptance criteria- 40N-80N): Hardness of 10 tablets were tested using

hardness tester and the results found to be min. 54N, max. 71N and avg. 63N.





At middle stage: Compression results obtained are as follows:








and avg. 3.19mm.





6. Friability (acceptance criteria- NMT 0.8% w/w): Friability of tablets were checked by



out by using HPLC and the result found to be 98.5%.



At end stage: Compression results obtained are as follows:








and avg. 3.19mm.









The data of physical & analytical parameters carried on samples collected during initial,

middle and end stage of compression for all three validation batches are found within the

limits of acceptance criteria.

Evaluation of Finished Product

Table: Analytical Results of Finished Product.

Tests Acceptance criteria Observation

A1 A2 A3

Description

Pink, round, biconvex,

uncoated tablets with “L”& “U”

on either side of break line on

one side& “H01”. on the other

side.

Complies Complies Complies

Identification by

HPLC

The retention time of the major

peak in the chromatogram of

the test preparation corresponds

to that of the standard

preparation, as obtained in

assay.

Complies Complies Complies

weight of 20

tablets

2.000g ± 3.0 %

(1.940 – 2.060 g) 1.995 2.005 2.003



Uniformity of

Dosage Units

(by weight

variation)

Acceptance Value Not more

than 15. 8.8 8.8 8.8

Hardness 60±20N

(40 – 80 N)

Min: 56 Min: 56 Min: 56

Max: 70 Max: 72 Max: 68

Friability NMT 0.8 % 0.107 0.077 0.092

Assay 95-105 % 99 97 98.5

Water content by

KF(%W/W) NMT 7.50 6.45 6.55 6.50

Dissolution

NLT 80% Q of the labelled

amount of Trandolapril is

dissolved in 45 min.

Min: 96 Min: 97 Min: 96

Max: 99 Max: 95 Max: 98

Avg.: 98 Avg.: 96 Avg.: 97

Batch A1



2. Uniformity of dosage unit (acceptance criteria- Acceptance Value NMT 15): All tablets

have been weighed accurately by using calibrated balance and the average weight were

calculated. The result found to be 8.8.


hardness tester and the results found to be min. 56N and max. 70N.


using friability tester and the results found to be 0.077



6. Water content by KF(%W/W) (acceptance criteria- NMT 7.50): The water content was

found to be 6.45%.

7. Dissolution (acceptance criteria- NLT 80% Q of the labelled amount of Trandolapril is

dissolved in 45 min.): Dissolution was carried out and results were found to be min. 96%,

max. 99% and avg. 98%.

Batch A2











using friability tester and the results found to be 0.107




found to be 6.55%.




Batch A3











out by using HPLC and the result found to be 98.5%.


found to be 6.50%.




Visual Inspection Test

Tablets were checked for following defects after compression

Capping, Lamination, Chipping, Cracking, Sticking, Picking, Binding, Mottling, Double

impression, Bridging, Erosion, Twinning, Peeling, Frosting, Orange peel No defect were

observed on the tablets after the compression.



Packing

Result of Debottling (Assay)

Acceptance Criteria: 95.0 % - 105.0%.

Table: Results of Assay.

B. No. A1 B. No. A2 B. No. A3

102.5 102.4 102.1

Compressed tablets were packed in heavy weight round HDPE bottle.

Samples were withdrawn from each batch and tested for Assay by using HPLC.

The results of assay for Batch No. A1, A2 and A3 were 102.5, 102.4, 102.1 respectively.

All the results were found within specification limit.

CONCLUSION

The review of data shows compliance to the requirements as per the protocol hence it can

be concluded that this process validation exercise is acceptable.

Hence we concluded that the set procedure which is recommended for manufacturing of

Trandolapril tablets 1mg is followed as such. This process give the product meeting its

pre-determined specifications, quality attributes etc.

The above mentioned recommendations for individual processing step of Trandolapril

tablets 1mg are to be implemented and according to this validation batch records should

be modified.

The updated Batch Manufacturing Records & Batch Packing Records should be used for

the routine manufacturing & packing of the various batches.

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