process validation of oral non steroidal anti …

PROCESS VALIDATION OF ORAL NON STEROIDAL

ANTI-INFLAMMATORY DRUG: IBUPROFEN 400 mg TABLET

By MANOJ BHIVSEN KOTHULE

B.Pharm.

DISSERTATION SUBMITTED TO

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,

KARNATAKA, BANGALORE.

IN PARTIAL FULFILLMENT FOR

THE AWARD OF THE DEGREE OF

MASTER OF PHARMACY

IN

QUALITY ASSURANCE

Under the Guidance of

Dr. MD. SALAHUDDIN M.Pharm.,Ph.D

Professor,

DEPARTMENT OF QUALITY ASSURANCE,

V.L.COLLEGE OF PHARMACY, RAICHUR – 584 103

-2011-

i


BANGALORE, KARNATAKA.

DECLARATION BY THE CANDIDATE

I hereby declare that this dissertation/thesis entitled “PROCESS VALIDATION

OF ORAL NON STEROIDAL ANTI-INFLAMMATORY DRUG-

IBUPROFEN 400 mg TABLET” is a bonafide and genuine research work carried out

by me under the guidance of Dr. MD SALAHUDDIN Professor, Department of Quality

Assurance, V. L. College of Pharmacy, Raichur in partial fulfillment of the requirement

for the award of degree of MASTER OF PHARMACY in QUALITY ASSURANCE.

Date:

Place: Raichur MANOJ BHIVSEN KOTHULE

iii



CERTIFICATE BY THE GUIDE

This is to certify that the dissertation entitled “PROCESS VALIDATION


IBUPROFEN 400 mg TABLET” is a bonafide research work done by

MANOJ BHIVSEN KOTHULE in partial fulfillment of the requirement for the award

of degree of MASTER OF PHARMACY in QUALITY ASSURANCE under my

Guidance.

Date:

Place: Raichur Dr. MD SALAHUDDIN M.Pharm., Ph.D

Professor V.L.College of Pharmacy, Raichur-584103

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ENDORSEMENT BY THE HOD, PRINCIPAL/HEAD OF THE INSTITUTION

This is to certify that the dissertation entitled “PROCESS VALIDATION


IBUPROFEN 400 mg TABLET” is a bonafide research work done by

MANOJ BHIVSEN KOTHULE Under the guidance of Dr. MD SALAHUDDIN in

partial fulfillment of the requirement for the degree of MASTER OF PHARMACY in

QUALITY ASSURANCE.

Date: Place: Raichur Dr. S. M. SHANTAKUMAR M.Pharm.,Ph.D Professor & Principal,

V.L. College of Pharmacy, Raichur-584103.

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COPYRIGHT

DECLARATION BY THE CANDIDATE

I hereby declare that the Rajiv Gandhi University of Health Sciences, Karnataka

shall have the right to preserve, use and dissemination this dissertation / thesis in print or

electronic format for academic / research purpose.

Date: Place: Raichur MANOJ BHIVSEN KOTHULE

© Rajiv Gandhi University of Health Sciences, Karnataka

vi

ACKNOWLEDGEMENTS

I am thankful to the Almighty for his blessings in fruitful completion of this dissertation. On the occasion of presenting this thesis, it is my privilege to express my sincere

thanks to my respected and esteemed research guide Dr. MD SALAHUDDIN Professor,

Department of Quality Assurance, V. L. College of Pharmacy, Raichur who has provided

excellent guidance, valuable advice, shared intelligent thoughts and inculcated

discipline. I am highly indebted to him for his valuable presence, which helped me to

complete this work successfully.

Words cannot express my feelings towards our beloved Principal

Dr. S. M. SHANTAKUMAR. I render my grateful respects and sincere thanks to him, for

his valuable help and providing me the necessary facilities to carry out this work with

great ease and precision.

I wish to express my honest thanks to Dr. Mayur YC Formerly Professor and

HOD, Dr. Somashekar Shyale Formerly Professor, Dr. Y. ANAND KUMAR Professor

& HOD, Sri. N. SREENIVASULU Professor, Dr. B. RAJEEVA Associate Professor &

Smt. Hafsa Mohammadi Assistant Professor.

This work is dedicated to my beloved grandparents, Late. Nanasaheb

Mahadev Kothule & Smt. Ambai Nanasaheb Kothule for their great contribution in my

life.

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Today what I am is all due to my most beloved, highly respectable parents, Mr. Kothule

Bhivsen Nanasaheb and Mrs. Kothule Mandakini Bhivsen who formed part of my

vision and taught me good things that really matter in life.

I am grateful to my seniors Mr. Nandkumar Shivghan, Mr. Kalidas

Dawalbaje, Mr. Sachin Warpe, Mr. Shrikant Raje, Mr. Mahadev Jadhav, colleagues

Mr. Hangergekar Sachin, Mr. S. Srinivas, Mr. Venu, for the cooperation and moral

support during the course of my study.

I express my heartful thanks to my classmates, Mr. Amit Malani, Mr.

Devidas Rakthe, Mr. Mahesh dasime, Mr. Nagadileep p., Mr. Deelip Kumar Gaur, Mr.

Uday Krishna T, Mr.Rajesh, Mr.Pawan, Mr.Srikanth, Mr.Abhilash, Mr.Arun,

Mr.Sunil, Mr.Virpakshi, Mr.Vivek, Miss. M. Saritha, Miss. Shevtha avani for their

valuable help and kind co-operation during my thesis work.

I will failing in my duties if I forget my friends, Mr. Kailash Khatod, Mr.

Samadhan Kuperkar, Mr. Prasen Suradkar, Mr. Mahesh Khalane, Mr. Anand Giri,

Kapil Jinturkar, Mr. Parag Joshi, Mr. Ramesh Zodge, Navnath , Prafulla , Dhiraj ,

Sandip.

It is indeed a difficult task to acknowledge the services of all those who have

extended their valuable assistance directly or indirectly. I sincerely thanks to all of them.

(MANOJ BHIVSEN KOTHULE)

viii

LIST OF ABBREVATIONS

QA : Quality Assurance

QC : Quality Control

GMP : Good Manufacturing Practice

cGMP : Current Good Manufacturing Practice

FDA : Food & Drug Administration

SOP : Standard Operating Procedure

WHO : World Health Organization

USFDA : United States of Food & Drug Administration

CFR : Code of Federal Regulation

DQ : Design Qualification

IQ : Installation Qualification

OQ : Operational Qualification

PQ : Performance Qualification

BMR : Batch Manufacturing Record

BPR : Batch Packaging Record

LOD : Limit of Detection

LOQ : Limit of Quantification

NLT : Not Less Than

NMT : Not More Than

HVAC : Heating Ventilation and air condition

AHU : Air Handling Unit

RPM : Rotation Per Minute

RSD : Relative Standard Deviation

AU : Area Under curve

BU : Blend Uniformity

DCB : Double Cone Blender

AQL : Acceptable Quality Limit

RMG : Rapid mixer granulator

RT : Retention Time

APPROX : Approximately

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ABSTRACT

Background and objective: The objective of the study is to form a basis for written

procedures for production and process control which are designed to assure that the drug

Ibuprofen 400 mg coated tablet have the identity, strength, quality and purity they purport

of are represented to possess. It is done by checking and controlling the critical in process

parameters and by evaluation of finished product. So for that purpose a specific method is

selected and performed the validation of preferred process.

Method: Three consecutive batches of Ibuprofen 400 mg tablet manufactured as per the

Batch Manufacturing Record. Collected samples at different stages like for sifting,

blending, compression, coating, and for packaging operation as mentioned in the

sampling plan for individual process. Then sent for analysis, each parameter is analyzed

and tested as per specifications and recorded the results, which were found within the

limits.

Results: The results suggest that the all parameters are within the limits. The

manufacturing process parameters like sieve integrity, appearance, bulk and tapped

density, blend uniformity and assay by using HPLC, all physical parameters like weight

variation, hardness and thickness, disintegration time, friability, coating parameters,

packaging parameters are found within the limits. So the manufacturing process intended

for further batches.

Conclusions: The process is validated as per specifications. Overall manufacturing

processing parameters are analyzed and compared with the standard specifications, found

within the limit also the packing process is well within the limit and it was concluded as

the parameters mentioned above validated as per BMR and BPR. The process validation

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data of Ibuprofen tablets reveals that there was no significant variation between batch to

batch and all the process variables were studied. Therefore it can be concluded that the

process of Ibuprofen tablet for the batch size 3.12 Lac stands Validated.

Key words: Ibuprofen, magnesium stearate, sodium starch glycolate, sodium lauryl

sulphate, alginic acid, povidone, cellulose microcrystalline, PVAP, starch, double cone

blender, multimill, cadpress, sejong coater.

xi

TABLE OF CONTENTS

Content Page no.

CHAPTER I :

INTRODUCTION 01

Review of literature 17

Aim and Objective 27

Drug Profile 29

CHAPTER II:

METHODOLOGY 43

Materials and methods 43

List of equipments used 44

Process flow chart 45

Product composition for three batches 46

Assessment of critical process parameters 47

Checklists 48

Method 52

CHAPTER III:

RESULTS & DISCUSSION 68

Sifting 68

Blending (Prelubrication) 69

Blending (Lubrication) 70

Slugging and milling 74

Compression 76

Coating 100

Packaging operation 107

Discussion 108

CHAPTER IV:

CONCLUSION, SUMMARY & BIBLIOGRAPHY 111

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LIST OF TABLES

Table

No. Contents

Page

No.

1 Parameters and source for testing 15

2 Details of material specification for core tablet 43

3 Details of material specification for coated tablet 43

4 List of equipments 44

5 Details of material for core tablet 46

6 Material required for coating 46

7 Assessment of Critical Process Parameter 47

8 Checklist for cleaning of CAD37 compression machine 48

9 Checklist for cleaning of Dedusting unit (CIP/(EMACH) 49

10 Checklist for cleaning of metal detector. 49

11 Checklist for cleaning of vibro sifter 50

12 Checklist for cleaning of multimill 50

13 Checklist for cleaning of DCB 51

14 Sampling and testing plan for sifting 52

15 Physical parameters & acceptance criteria during sifting 52

16 Sampling and testing plan for prelubrication 53

17 Physical parameters & Acceptance criteria after pre lubrication 53

18 Sampling and testing plan for blend uniformity 54

19 Testing parameters and acceptance criteria after lubrication 54

20 Chromatographic condition 56

21 Sampling and testing plan after slugging 57

22 Testing parameters & acceptance criteria after slugging 57

23 Sampling and testing plan for core tablet 59

24 Testing of physical parameters for core tablet 60

25 Chromatographic condition for core tablet 61

26 Coating parameters 62

27 Sampling and testing plan after coating 63

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28 Finished product analysis for coated tablet 63

29 Chromatographic condition for coated tablet 65

30 List of Equipments for Packing Operation 67

31 Parameters for blister packing 67

32 Sifting % sample retained result of three batches 68

33 Sieve integrity for three batches after sifting 68

34 Appearance of powder after sifting 68

35 Results of Bulk Density for three batches after pre lubrication 69

36 Results of Tapped Density for three batches after pre lubrication 69

37 Appearance of three batches after pre lubrication 69

38 Appearance of three batches of lubricated blend 70

39 Details of three batches for blend uniformity 70

40 RT & area of Ibuprofen standard 72

41 RT & area of Ibuprofen Blend 73

42 % sample retained test after sifting for Batch A 74

43 % sample retained test after sifting for Batch B 74

44 % sample retained test after sifting for Batch C 74

45 Sieve Integrity after sifting 75

46 Results of Bulk Density for three batches of lubricated blend 75

47 Results of Tapped Density for three batches of lubricated blend 75

48 Weight variation: Batch A 76

49 Hardness and thickness for batch A 77

50 Physical parameters at different speeds compressed tablet Batch A 78

51 Weight variation: Batch B 79

52 Hardness and thickness for batch B 80

53 Physical parameters at different speeds compressed tablet Batch B 81

54 Weight variation: Batch C 82

55 Hardness and thickness for batch C 83

56 Physical parameters at different speeds compressed tablet Batch C 84

57 Weight variation at Optimum Speed: Batch A 85

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58 Hardness and thickness at Optimum Speed: Batch A 86

59 Physical parameters of tablets at Optimum Speed Batch A 87

60 Weight variation at Optimum Speed: Batch B 88

61 Hardness and thickness at Optimum Speed: Batch B 89

62 Physical parameters of tablets at Optimum Speed Batch B 90

63 Weight variation at Optimum Speed: Batch C 91

64 Hardness and thickness at Optimum Speed: Batch C 92

65 Physical parameters of tablets at Optimum Speed Batch C 93

66 Assay of compressed tablet Batch A 94

67 RT & area of Ibuprofen Batch A 95

68 Assay of compressed tablet Batch B 96

69 RT & area of Ibuprofen Batch B 97

70 Assay of compressed tablet Batch C 98

71 RT & area of Ibuprofen Batch C 99

72 Weight variation: Batch A, B, C (coated) 100

73 Thickness and diameter for coated tablets Batch A, B, C 101

74 Percentage weight gain After Coating 102

75 Physical coating parameters for three batches 102

76 Assay of coated tablets: Batch A, B, C. 103

77 RT & area of coated tablets 104

78 AQL (Acceptable quality limit) for finished product analysis 105

79 Parameters for blister packing 107

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LIST OF FIGURES

Fig. No. Contents Page No.

1 Structural formula of Ibuprofen 29

2 Process flow chart 45

3 Container 53

4 Double Cone Blender 55

5 Sejong Coater 64

6 Operation of Blister packing 66

7 Blank graph by using HPLC 71

8 Standard graph of ibuprofen A, B, C, D, E 71

9 Blend uniformity for by HPLC: Batch A, B, C 72

10 Comparative Blend uniformity for Batch A, B, C 73

11 HPLC graph of ibuprofen core tablet: Batch A 94

12 Comparative Assay of compressed tablet: Batch A 95

13 HPLC graph of ibuprofen core tablet: Batch B 96

14 Comparative Assay of compressed tablet: Batch B 97

15 HPLC graph of ibuprofen core tablet: Batch C 98

16 Comparative Assay of compressed tablet: Batch C 99

17 HPLC graph of ibuprofen coated tablet: Batch A, B, C 103

18 Comparative Assay of coated tablet: Batch A, B, C 104

xvi

Department of Quality Assurance, V.L.C.P.Raichur. 1

1. INTRODUCTION

1.1 QUALITY ASSURANCE1:

Is a wide ranging concept covering all matters that individually or collectively

influence quality of a product. It is the totality of the arrangements made with the

object of ensuring that pharmaceutical products are of quality required for their

intended use. Quality assurance therefore incorporates GMP and other factors, such as

product design and development.

1.1.1 Significance and applications of QA in Pharmaceutical Industry:

The system of quality assurance appropriates the manufacture of pharmaceutical

products & should ensure that;

a) Medicinal products are designed and developed in a way that takes account of

the requirements of Good Manufacturing Practice (GMP), Good Laboratory

Practice (GLP) and Good Clinical Practice (GCP).

b) Production and control operations are clearly specified in a written form and

GMP requirements are adopted.

c) Managerial responsibilities are clearly specified in job descriptions.

d) Arrangements are made for the manufacture, supply and use of the correct

starting and packaging materials.

e) All necessary controls on starting materials, intermediate products, bulk

products and other in-process controls, calibrations, and validations are carried

out.

f) The finished product is correctly processed and checked according to the

defined procedures.

g) Pharmaceutical products are not sold or supplied until the authorized persons

have certified that each production batch has been produced and controlled in


accordance with the requirements of the marketing authorization and any other

regulations relevant to the production, control and release of pharmaceutical

products.

h) Satisfactory arrangements exist to ensure as far as possible, that the

pharmaceutical products are stored by the manufacturer, distributed and

subsequently handled so that the quality is maintained throughout their shelf-

life.

i) There is a procedure for self-inspection and/or quality audit that regularly

appraises the effectiveness and applicability of the quality assurance system.

j) Deviations, incidents, change control, market complaints are reported,

investigated and recorded.

k) There is a system for approving changes that may have an impact on product

quality.

l) Regular evaluations of the quality of pharmaceutical products should be

conducted with the objective of verifying the consistency of the process and

ensuring its continuous improvement.

1.2 VALIDATION2:

“VALIDATION is defined as a documented procedure for obtaining, recording and

interpreting data required to show that a process will consistently comply with

predetermined standards.”

Validation is a scientific study of process:

1 To improve that the process is consistently doing what it is supposed to do (i.e.

that the process is under control)


2 To demonstrate the process variables, acceptable limits for these variables and

to set up appropriate in-process controls.

1.2.1 Types of Validation:

1) Process Validation: As per US Food and Drug Administration (1987): Process

Validation is establishing documented evidence which provides a high degree of

assurance that a specified process will consistently produce a product meeting its pre-

determined specifications and quality characteristics.

The basic principles of quality assurance;

The production of articles that is fit for intended use.

Quality, safety and effectiveness must be designed and built into the product.

Quality cannot be inspected or tested in to the finished product.

Each step of the manufacturing process must be controlled to maximize the

probability that the finished product meets all the quality and design

specification.

It includes;

1. Prospective validation

2. Concurrent validation

3. Retrospective validation

4. Revalidation.

2) Facility Validation: It should include planning, documentation, construction and

testing to design specifications and cGMP requirements.

3) Equipment Qualification: It involves qualifying the design, installation,

operation, instrumentation, control system and performance of the equipment.

4) Services Validation: This involves qualification activities like:

Environmental control system e.g. HVAC, AHU

Water storage & Distribution system.


Compressed air system.

Steam distribution system etc.

5) Analytical Method Validation: It involves evaluation of product quality attributes

through testing to demonstrate reliability is being maintained throughout the

lifecycle and that the precision, accuracy, specificity, LOD, LOQ, linearity,

selectivity have not been compromised.

6) Cleaning Validation: It involves the cleaning procedure, so as to give a high

degree of assurance that the given cleaning process results in equipment/area

having product contamination below the acceptable level.

7) Vendor Qualification: It involves the qualification of the vendor who provides the

active material and the excipients required for formulation by conducting audits

8) Computer Validation: It involves validating the software used for automation or

testing purposes.

1.2.2 Validation protocol3:

A written plan stating how validation will be conducted including test parameters,

product characteristics, production equipment and design points on what constitutes

acceptable test results.

The protocol should specify a sufficient number of replicate process runs to

demonstrate reproducibility and provide an accurate measure of variability among

successive runs. The test condition for these runs should encompass upper and lower

processing limits and circumstances, including those within standard operating

procedures, which pose the greater chance of process or product failure compared to

ideal conditions. Such conditions have become widely known as “worst case”

conditions or “most appropriate challenge conditions”.


Worst case: A set of conditions encompassing upper and lower processing limits and

circumstances, including those within standard operating procedures, which pose

greater chance of product failure when compared to ideal conditions, such conditions

do not necessarily include product or process failure.

The main headings of validation protocol includes:

Objective, purpose, scope of study and responsibility,

Product and process details,

Experimental plan,

Sampling and testing plan

Acceptance criteria

Reference documents.

Elements of Validation4:

I. Equipment and process

a) Equipment : Installation qualification (DQ, IQ, OQ & PQ)

b) Process : Performance qualification

c) Product : Performance qualification

II. System to assure timely revalidation

III. Documentation

I. Equipment and process: The equipment and process should be designed and/or

selected so that product specifications are consistently achieved. This should be done

with the participation of all appropriate groups that are concerned with assuring a

quality product. E.g. engineering design, production operations and quality personnel.

a. Equipment: Design qualification: User requirements should be considered when

deciding on the specific design of a system or equipment. A suitable supplier should

be selected for the appropriate system or equipment (approved vendor).


Installation qualification: Installation qualification studies establish confidence that

the process equipment and ancillary systems are capable of consistently operating

within established limits and tolerances.

The phase of validation includes

Examination of equipment design.

Determination of calibration.

Adjustment requirements.

Maintenance.

Identifying critical equipment features that could affect the process and

product

Operational qualification: Systems and equipment should operate correctly and their

operation should be verified in accordance with an operational qualification protocol.

Critical operating parameters should be identified.

Operational qualification should include verification of operation of all system

elements, parts, services, controls, gauges and other components

b. Process: Performance qualification: The purpose of performance qualification is to

provide rigorous testing to demonstrate the effectiveness and reproducibility of the

process.

Each process should be defined and described with sufficient specificity so that

employees understand what is required. Parts of the process, which may vary so as to

affect important product quality, should be challenged.

c. Product: Performance qualification: Product performance qualification activities

apply only to medical devices.

II. System to assure timely revalidation: There should be a quality assurance

system in place, which requires revalidation whenever there are challenges in


packing, formulation, equipment or process which could impact on product

effectiveness characteristics and whenever there are changes in product

characteristics.

The quality assurance procedures should establish the circumstances under which

revalidation is required. The extent of revalidation will depend upon the nature of

changes and how they impact upon different aspects of production that had previously

been validated.

III. Documentation: It is essential that the validation program is documented and

that the documentation is properly maintained.

Approval and release of the process for use in routine manufacturing should be based

upon a review of all validation documentation, including data from the equipment

qualification, and product/package performance testing to ensure compatibility with

the process.

For routine production, it is important to adequately record process details (e.g. time,

speed, temperature & equipment used) and to record any changes which have

occurred. A maintenance log can be useful in performing failure investigations

concerning a specific manufacturing lot.

1.2.3 Regulatory requirements of Validation:

The Food, Drug and Cosmetic Act (FDC Act) defines drug as

(Clause A) articles recognized in the Official U.S. Pharmacopeia, Official

Homeopathic Pharmacopoeia of the U.S, Official National Formulary or any

supplement to any of them;

(Clause B) articles intended for use in the diagnosis, cure, mitigation, treatment or

prevention of disease in man or other animals;


(Clause C) articles (other than food) intended to affect the structure or any function

of the body of man or other animals and

(Clause D) articles intended as a component of any articles specified in clauses A, B

or C.

Based on the above definition, active ingredients, excipients, coloring agents,

flavors and in-process materials are components of a drug and therefore are subject to

the same drug laws in the FDC Act. One such law, Section 501(b) declares a drug to

be adulterated if the method used in or the facilities or controls used for its

manufacture, processing, packing or holding do not confirm too or not operated or

administered in conformity with current good manufacturing practice (cGMP) to

assure that the drug meets the requirements of this act to the safety, has the identity

and strength which meets the Quality and purity characteristics that it represented to

possess.

The prime objective of anyone working in a pharmaceutical plant whether in

production or quality control is to manufacture consistently products of the requisite

quality at the lowest possible cost. Quality requirements are defined by the user’s

need for product safety, efficacy and ease of use. All the key elements of a validation

program should be clearly defined and documented in a validation master plan or

equivalent documents. It should contain precise data of:

• Validation policy

• Organizational structure of validation activities

• Summary of facilities, systems, equipment and process to be validated

• Documentation format to be used for protocols and reports

• Planning, scheduling and change control

• Reverence to existing documents.


1.2.4 Pre-requisites for successful validation5:

There are some tools or elements that are required for conducting effective

validations. Each are presented and discussed in the following sections.

Understanding: Perhaps the single most important element required is a good

understanding of what validation is. This understanding activity goes beyond the basic

definition of validation, beyond the concept of “requiring a minimum of three runs”.

This understanding must be anchored by sufficient years of practical experience and

knowledge. It will permit sound and logical decisions even under most intense

situations.

Communication: One of the best methods of improving environment understanding

is through communication. Communication is essential for any activity that requires

more than one resource to complete. This point is understandable considering that

conducting effective validation involves multi-departments.

Experience: A firm must have resources with solid validation experience to get

success in their validation program.

Co-operation and Focus: Multiple departments that some times interact during the

course of executing validation program are project management, accounting, quality

control, project engineering, process engineering, quality assurance, facilities,

regulatory etc should have a commendable co-operation.

Resources: Resources means personnel who will plan and execute equipment on

which validations will be performed on materials with which to conduct validations.

Laboratories that will perform necessary analysis should provide necessary funding

for the validations and allocate sufficient time to perform validations. Validations can

often begin, but cannot be completed if any one of these resources is missing.


Budget: It is important to understand that a successful validation must be done to

completion. Typically, it should not be limited by a budget assembled by personnel

who have no appreciation for what is required to successfully complete validation.

Further, it is important to understand that validations cost money.

Plan: Conducting validations within most companies will involve a number of

departments and disciplines. These disciplines need a perfect plan in order to get good

team synergy.

Training: Training is essential for any successful validation. Typically this training

initiates in the validation group. It is essential that the lead validation resource for a

given validation project initiate, facilitate, coordinate and/or communicate the need

for resource training as required by validation event.

Standard Operating Procedures (SOPs): SOPs capture activities that routinely

occur within an organization. Departments charged with abiding by or following these

SOPs must first be trained against these SOPs.

Quality Control Lab Support: During most validations, some laboratory testing will

be required. In most cases this testing is handled by the QC group. QC is expected to

provide results in timely manner. So often, the wait for the receipt of analytical results

cases the entire validation project to come to halt. Because validations are based on

the results obtained.

1.2.5 Significance of validation in Pharmaceutical Industry:

1. Assurance of Quality: Without validation, which implies a process that is well

understood and in state of control, confidence in the quality of product manufactured

is impossible. GMPs and validation, two concepts that cannot be separated are

essential to quality assurance. Frequently the validation of a process will lead to

quality improvement in addition to better quality assurance.


2. Process optimization: To optimize the process for maximum efficiency while

maintaining quality standards is a natural consequence of this scientific study of

process variables and their control.

3. Cost reduction: Experience and common sense indicate that a validated process is

a more efficient process and a process that produces less reworks, rejects, wastage and

so on. Validation is fundamentally a good business practice.

4. Government regulation: Validation is considered to be an integral part of GMP’s

essentially worldwide compliance with validation requirements is necessary for

obtaining approval to manufacture and to introduce new products.

1.3 PROCESS VALIDATION6:

Process validation is defined by various regulatory agencies as given below:

USFDA defined process validation as “Establishing documented evidence (through

protocols and master plans) which provides a high degree of assurance (repeated

trials challenging full) that a specific process will consistently produce (range of

process variables and collecting multiple samples) a product meeting its

predetermined specifications and quality attributes (documented approved

acceptance criteria and product/process specifications derived from R&D or re-

validation work).”

The WHO cGMP’s defines process validation as “Establishing documented

evidence, which provides a high degree of assurance that a planned process will

consistently perform according to the intended specified outcomes”.


1.3.1 Types of process validation

The various types of process validation are outlined below:

1) Prospective validation: Prospective validation is a requirement and therefore it

makes validation an integral part of a carefully planned, logical product/process

developmental program. In prospective validation an experimental plan called the

validation protocol is executed (following completion of the qualification trials)

before the process is put into commercial use. This is normally carried out in

connection with the introduction of new drug products and their manufacturing

processes.

The formalized process validation program should never be undertaken unless and

until the following operations and procedures have been completed with satisfactory.

The facilities and equipment in which the process validation is to be conducted to

meet cGMP requirements (completion of installation qualification).

The operators and supervising personnel who will be “running” the validation

batches should have an understanding of the process and its requirements.

The design, selection and optimization of the formula have been completed. The

qualification trials using pilot lab batches have been completed in which the critical

processing steps and process variables have been identified and the provisional

operational control limits for each critical test parameter have been provided.

Detailed technical information on the product and the manufacturing process has

been provided, including documented evidence of product stability.

Finally at least one qualification trial of a pilot production batch has been made and

shows upon scale up that were no significant deviations from the expected

performance of the process.


This type of validation activity is normally completed prior to the distribution and

sale of the drug product.

2) Retrospective validation:

For a product to be considered for retrospective validation it must have a stable

process; that is one in which the method of manufacture has remained essentially

unchanged for a period of time. The first step in the product selection process is

therefore to obtain a summary of changes in the method of manufacture. In most

companies such information is part of the master batch record file or Annual product

review (APR). Then a time interval is selected that represents the last 20 to 30

batches. Products for which there is no record of a change in the method of

manufacture or control during this period can be regarded as candidates for validation.

The 20 to 30 batch rule originates from control chart principals which consider 20 to

30 points that plot within the limits as evidence of a stable process. Once this criterion

is met the number selected is actually somewhat arbitrary, as there is no one number

that is correct for every product.

The second step in the product selection process addresses the situation in which a

change in the method of manufacture or control was implemented during the last 20

or so production batches. In general a history of any one of the following changes to

the method of manufacture and control should be fully investigated before any

decision is made to validate retrospectively:

1. Formulation changes involving one or more of the active ingredients or key

excipients.

2. Introduction of new equipment not equivalent in every respect to that previously in

use


3. Changes in the method of manufacture that may affect the product’s characteristics.

4. Changes to the manufacturing facility.

• This is chosen for established products whose manufacturing processes are

considered stable.

• Prior to undertaking Retrospective validation, where in the numerical in

process and/or end product test data of historic production batches are

subjected to statistical analysis, equipment, facilities and subsystems used in

connection with the manufacturing process must be qualified and validated in

conformance with cGMP requirements.

• The source of data for this type of validation may include batch documents,

process control charts, maintenance logbooks, process capability studies,

finished product data, including trend data and stability data.

• Batches selected for retrospective validation should be representative of all

batches made during the review period including any batches that fail to meet

the specification.

3) Concurrent validation:

This involves in-process monitoring of critical processing steps and end product

testing of current production can documented evidence to show that the

manufacturing process is in a state of control such validation documentation can be

provided from the test parameter and data sources disclosed in the selection on

retrospective validation.


The following tests required to demonstrate that the process is in a state of control.

Table 1: Parameters and source for testing.

S.No. Parameter Source

1 Average weight, potency, Content uniformity, End product testing

2 Blend uniformity, Moisture content,

Weight variation, Tablet hardness In-process testing

4) Revalidation:

Revalidation provides the evidence that changes in a process introduced

intentionally/unintentionally do not adversely affect process characteristics and

product quality.

Revalidation may be required in following cases:

1. Change in formulation, procedure or quality of pharmaceutical ingredients

2. Change in equipment, addition of new equipment and major breakdown

3. Major change of process parameters

4. Change in site

5. On appearance of negative quality trends

6. Significant increase or decrease in batch size

Revalidation remains an important validation option and should be considered

whenever the continued state of control and reliable performance of the

manufacturing process are in doubt.

1.3.2 The regulatory basis for process validation7, 8:

Once the concept of being able to predict process performance to meet user

requirements evolved, FDA regulatory officials established that there was a legal

basis for requiring process validation. The ultimate legal authority , which states that a

drug is deemed to be adulterated if the methods used in or the facilities or controls


used for its manufacture, processing, packing or holding do not conform to or were

not operated or administrated in conformity with cGMP. Assurance must be given

that the drug would meet the requirements of the act and pass the safety, identity and

strength and meet the quality and purity characteristics that it purported or is

represented to possess. The section of the act sets the premise for process validation

requirements for both finished pharmaceuticals and active pharmaceutical ingredients,

as active pharmaceutical ingredients are also deemed to be drugs under the act.

The cGMP regulations for finished pharmaceuticals 21 CFR 210 and 211 were

promulgated to enforce the requirements of the act. Which states: “There shall be

written procedures for production and process control designed to assure that the drug

products have the identity, strength, quality and purity they purport or it is represented

to possess.”


1.4 REVIEW OF LITERATURE:

Mourao SC et al9 investigated sodium diclofenac (SD) release from

dosage forms has been studied under different conditions. However no dissolution

method that is discriminatory enough to reflect slight changes in formulation or

manufacturing process, and which could be effectively correlated with the biological

properties of the dosage form, has been reported. This study sought to develop three

different formulae of SD-containing matrix tablets and to determine the effect of

agitation speed in its dissolution profiles. F1, F2 and F3 formulation were developed

using hypromellose (10, 20 and 30%, respectively for F1, F2 and F3) and other

conventional excipients. Dissolution tests were carried out in phosphate buffer pH 6.8

at 37 °C using apparatus II at 50, 75 or 100 rpm. Dissolution efficiency (DE), T50 and

T90 were determined and plotted as functions of the variables agitation speed and

hypromellose concentration. Regarding DE, F2 showed more sensitivity to variations

in agitation speed than F1 and F3. Increasing hypromellose concentration reduced DE

values, independent of agitation speed. Analysis of T50 and T90 suggests that F1 is less

sensitive to variations in agitation speed than F2 and F3. Most discriminatory

dissolution conditions were observed at 50 rpm. Results suggest that the comparison

of dissolution performance of SD matrix tablet should take into account polymer

concentration and agitation conditions.

Andreas SL et al10 studied powder mixing as an important operation

routinely used in many industries including pharmaceuticals. The quality of products

depends on certain operating conditions such as the equipment, technical parameters

and formulation. In this work an operational qualification of powder mixing during

large scale production in a pharmaceutical industry was performed. A simple and

practical protocol was followed. Using a V-blender and dry powder mixing, the


operation was tested to illustrate the effect of mixing time on the homogeneity of the

drug in the mixture, demonstrating that this parameter can be used as a secure

parameter to control this pharmaceutical operation on a large scale during batch

production and using an off-line monitoring technique.

Sinka IC et al11 studied preferred drug delivery system tablets which

are manufactured using high speed rotary presses where the powder material is

compressed in a die between rigid punches. Compression represents one of the most

important unit operations because the shape, strength and other important properties

of the tablets are determined at this time. These properties are dictated not only by the

characteristics of the powder constituents (which are determined by the properties of

the constituents, mixing and granulation), but also by the selection of process

parameters imposed by production machinery. This paper focuses on the die fill and

the compaction parameters. As a result of combined interactions between the material

behavior during compaction, powder–die wall friction and process parameter during

die fill and compaction, the resulting tablets are in general non-homogeneous. X-ray

computed tomography is employed to characterize the internal density distribution in

tablets. The effect of tablet structure on friability, erosion and disintegration behavior

is examined.

Ehlers H et al12 studied the surfaces of ibuprofen particles, were

modified by coating the particles with diluted aqueous hydroxypropyl methylcellulose

(HPMC) solution in an instrument top-spray fluid bed granulator. The objective was

to evaluate whether an extremely thin polymer coating could be an alternative to

granulation in enhancing powder flow and processing properties. The studied

variables were inlet air temperature and spray rate. The treated powders showed a

clear improvement in flow rate as measured with a flow meter designed for powders


with poor flow properties. The particle size was determined using optical microscopy

and image analysis. The particle size, size distribution and circularity of the treated

and untreated ibuprofen batches showed no difference from each other. Consequently

the improvement in flow properties can be attributed to the trace amounts of

hydroxypropyl methylcellulose applied onto the particle surfaces. In conclusion,

fluidized bed particle thin-coating (PTC) alters the surface of ibuprofen powder

particles and improves the flow properties of ibuprofen powder with changes in

neither particle size, size distribution nor morphology.

Cora LA et al13 carried out the analysis of physical phenomena that

occurs during tablets disintegration has been studied by several experimental

approaches; however none of them satisfactorily describe this process. The aim of this

study was to investigate the influence of compression force on the tablet by

associating the AC Biosusceptometry with consolidated methods in order to validate

the biomagnetic technique as a tool for quality control in pharmaceutical process.

Tablets obtained at five compression levels were submitted to mechanical properties

tests. For uncoated tablets, water uptake and disintegration force measurements were

performed in order to compare with magnetic data. For coated tablets, magnetic

measurements were carried out to establish a relationship between physical

parameters of the disintegration process. According to the results, differences between

the compression levels were found for water uptake, force development and magnetic

area variation measurements. ACB method was able to estimate the disintegration

properties as well as the kinetics of disintegration process for uncoated and coated

tablets. This study provided a new approach for in vitro investigation and validated

this biomagnetic technique as a tool for quality control for pharmaceutical industry.


Moreover, using ACB will also be possible to test these parameters in humans

allowing to establish an in vitro/in vivo correlation.

Bodson C et al14 study by keeping goal to apply the process Analytical

Technology FDA's initiative in Pharmaceutical tablet manufacturing. Near Infrared

Spectrophotometry (NIRS) was used as a non-destructive, very fast technique

requiring no sample preparation. Direct compression powder blends containing

Diltiazem HCl as a model drug were pressed into tablets for the calibration and the

validation steps. First, a partial least squares model was built to calibrate the NIR

spectrometer. Then, this model was validated and compared with a validated UV

spectrophotometry reference method. For this comparison, the Bland and Altman's

statistical method was applied. The manufacturing process was validated by

producing three batches at three different concentration levels. The NIR analysis of

these batches was performed during 3 days. This study shows that NIRS can be used

to validate the whole manufacturing process and not only as an analytical method for

tablets assay. NIRS is an interesting tool to show possible variations during the

manufacturing process which could lead the finished product to fall outside of

specifications.

Furlanetto S et al15 investigated experimental design was utilized to

simultaneously investigate the effect of varying the type of diluent (insoluble Calcium

phosphate or water-soluble Arabic gum) and the diluents/matrix ratio on the drug

release behavior from both lipophilic or hydrophilic (hydroxyl propyl methyl

cellulose) matrix tablets ketoprofen, theophylline and sodium sulphadiazine were

selected as model drugs on the basis of their respectively very low, medium and high

water-solubility in order to evaluate the influence of this parameter as well. The

selected response variables were the dissolution efficiency (i.e. the area under the


dissolution curve) after one and six hours and the time necessary to dissolve 10%

drug. Tablets obtained by direct compression of drug-diluent-matrix ternary mixtures

prepared according to the experimental plan provided for by an asymmetric screening

matrix were tested for drug release properties using a USP paddle apparatus. Graphic

analysis of the effects allowed identification for each examined drug of the

formulation factors active on the selected responses and determination of the proper

level of the variables to be selected for the response improvement. The different

results obtained with the three examined drugs pointed out the role of the drug

solubility in determining the influence of formulation parameter on drug release rate

from matrix tablets.

Le VNP et al16 investigated the impact of the process on drug particle

size. We chose Ibuprofen which is practically insoluble in water, as granulometry

greatly influences its dissolution rate. He developed an original method using a laser

granulometer to assess the size of ibuprofen within a blend before and after

granulation and then compression. Wet granulation was performed with a Lodige and

a Diosna granulator. The granules were then compressed. The evolution of ibuprofen

particle size after these operations was checked. Two grades of ibuprofen differing in

size were studied: ibuprofen 25 and ibuprofen 50. After the wet granulation of

ibuprofen 50 with a Lodige or a Diosna granulator, a decrease in size was observed.

This could be caused by shocks occurring in the granulator. On the other hand, after

compression of the granules, ibuprofen particle size increased and was greater than

that measured before granulation. Compression could induce some fragmentation of

ibuprofen associated with the plastic deformation and then, under pressure, a

closeness of the fragments or deformed particles which could bind or associate with

one another because the melting point of ibuprofen is not very high. In the case of


ibuprofen 25, the same phenomena were observed after compression. But, after

granulation, particle size was not modified. There was little breaking of ibuprofen

articles in the granulator because they are much smaller than those of ibuprofen 50.

This work shows the impact of the process on drug particle size when producing

tablets. The method developed made it possible to differentiate and measure the size

of ibuprofen particles in a blend.

Walker GM et al17 investigated the influence of process parameters on

the fluidized hot melt granulation of lactose and PEG 6000 and the subsequent tablet

pressing of the granules. Granulation experiments were performed to assess the effect

of granulation time and binder content of the feed on the resulting granule properties

such as mass mean granule size, size distribution, granule fracture stress, and granule

porosity. These data were correlated using the granule growth regime model. It was

found that the dominant granule growth mechanisms in this melt granulation system

were nucleation followed by steady growth (PEG 10–20% w/w). However, with

binder contents greater than 20 % w/w, the granulation mechanism moved to the

“over-wet massing” regime in which discrete granule formation could not be

obtained. The granules produced in the melt fluidized bed process were subsequently

pressed into tablets using an industrial tablet press. The physical properties of the

tablets: fracture stress, disintegration time and friability were assessed using industry

standards. These analyses indicated that particle size and binder content of the initial

granules influenced the mechanical properties of the tablets. It was noted that a

decrease in initial granule size resulted in an increase in the fracture stress of the

tablets formed.

Santos H et al18 studied compaction and compression of xanthan gum

pellets and were evaluated the drug release from tablets and characterized. Two types


of pellets were prepared by extrusion-spheronisation. Formulations included xanthan

gum, at16 % (w/w), diclofenac sodium or ibuprofen, at 10% (w/w), among other

excipients. An amount of 500 mg of pellets fraction 1000–1400 m were compacted in

a single punch press at maximum punch pressure of 125 MPa using flat-faced

punches (diameter of 1.00 cm). Physical properties of pellets and tablets were

analyzed. Laser profilometry analysis and scanning electron microscopy of the upper

surface and the surface of fracture of tablets revealed that particles remained as

coherent individual units after compression process. Pellets were flatted in the same

direction of the applied stress evidencing a lot of the original curvature of the

spherical unit. Pellets showed close compressibility degrees (49.9% for pellets

comprising diclofenac sodium and 48.5% for pellets comprising ibuprofen). Xanthan

gum pellets comprising diclofenac sodium experienced a reduction of 65.5% of their

original sphericity while those comprising ibuprofen lost 49.6% of the original

porosity. Permanent deformation and densification were the relevant mechanisms of

compression. Fragmentation was regarded as non-existent. The release of the model

drug from both type of tablets revealed different behaviors. Tablets made of pellets

comprising ibuprofen released the model drug in a bimodal fashion and the release

behavior was characterized as Case II transport mechanism (release exponent of

0.93). On the other hand, the release behavior of diclofenac sodium from tablets made

of pellets was anomalous (release exponent of 0.70). For the latter case, drug diffusion

and erosion were competing mechanisms of drug release.

Aman W et al19 investigated the formulation and the manufacturing

process can significantly influence the photo stability of tablets. Investigations of

various formulation and manufacturing process were done with tablets containing

nifedipine and molsidomine as highly light sensitive drugs. The effect of relevant


formulation factors are stated. Whereas the particle size of the drug substance and the

choice of the lubricant had no effect, the drug content, the compression diluent and

geometric alterations significantly affected the photoinstability. Depending on the

formulation drug losses varied between 30 and 55% after 12 h irradiation in a light

testing cabinet. Manufacturing parameters like compression force and direct

compression versus granulation showed less serious influences nevertheless, photo

stability changes up to 10% were registered.

Rambali B et al20 studied miconazole buccal tablets were prepared via

a dry granulation process. By applying a factorial design, the roll compactor

parameters (compaction force, gap between the rolls, type of the rolls (smooth,

ribbed) and the sieve aperture) were optimized for the tablet strength. The compaction

force and the roll type significantly affected the tablet strength. Afterwards, a quarter

fractional factorial designs was applied, consisting of the four compactor parameters

and additionally the compression pressure, in order to optimize these parameters for

the dissolution profile and the buccal bio-adhesion characteristics (bio-adhesive force

and energy). In order to evaluate the dissolution profiles properly the similarity factor

between sample and a zero-order release reference profile was used. The compression

pressure and the roll type significantly affected the dissolution profile. The sieve

aperture had a significant effect on the buccal adhesion properties and the compaction

force had a significant effect on the dissolution profile and the bio-adhesive energy.

The gap between the rolls affected the bio-adhesive force significantly.

Rekhi GS et al21 studied by keeping objective to examine the influence

of critical formulation and processing variables as described in the AAPS/FDA

Workshop II report on scale-up of oral extended-release dosage forms, using a

hydrophilic polymer hydroxypropyl methylcellulose (Methocel K100LV). A face-


centered central composite design (26 runs + 3 center points) was selected and the

variables studied were: filler ratio (lactose: dicalcium phosphate (50:50)), polymer

level (15/32.5/50%), magnesium stearate level (1/1.5/2%), lubricant blend time

(2/6/10 min) and compression force (400/600/800 kg). Granulations (1.5 kg, 3000

units) were manufactured using a fluid-bed process, lubricated and tablet (100 mg

metoprolol tartrate) was compressed on an instrumented Manesty D3B rotary tablet

press. Dissolution tests were performed using USP apparatus 2, at 50 rpm in 900 ml

phosphate buffer (pH 6.8). Responses studied included percent drug released at Q1 (1

h), Q4, Q6, Q12. Analysis of variance indicated that change in polymer level was the

most significant factor affecting drug release. Increase in dicalcium phosphate level

and compression force was found to affect the percent released at the later dissolution

time points. Some interaction effects between the variables studied were also found to

be statistically significant. The drug release mechanism was predominantly found to

be Fickian diffusion controlled (n=0.46–0.59). Response surface plots and regression

models were developed which adequately described the experimental space. Three

formulations having slow, medium and fast-releasing dissolution profiles were

identified for a future bioavailability/bioequivalency study. The results of this study

provided the framework for further work involving both in vivo studies and scale-up.

Holgado MA et al22 investigated the release behaviour of carteolol

hydrochloride matrix tablets was investigated as a function of filler nature (PEG 6000

and lactose), type of wetting liquid (12.5% and isopropanol-acetone mixture 6:4) and

mode of filler incorporation. The values of the technological parameter suggest that

hardness was the most significantly affected by the three formulation factors

considered. The strongest influence over the technological parameters was exerted by

the mode of filler incorporation. The kinetic data conformed with the Higuchi square


root equation, except for the lots containing mannitol and isopropanol-acetone

mixture that conformed to a first-order plot. The lot containing Emcompress® and

isopropanol-acetone mixture displayed acceptable linearity with both plots. Therefore,

a non-linear regression procedure and reduced time method were used to define with

precision the kinetic model followed by this formulation. Release parameters such as

the Higuchi rate constant, and dissolution efficiency were calculated. Lots containing

mannitol presented more rapid release rates due to the high solubility of this filler. On

the other hand, the use of PEG 6000 as diluent significantly decreased drug release.

The influence of technological parameter on the release of these systems was also

examined, an inverse relationship between hardness and dissolution efficiency being

found.


1.5 AIM AND OBJECTIVE:

1.5.1 Aim: The main purpose behind process validation is to provide documented

evidence that the manufacturing process of Ibuprofen 400 mg coated tablet meets the

predefined control parameters.

This involves in-process monitoring of critical processing steps and end product

testing of current production can document evidence to show that the manufacturing

process is in a state of control.

1.5.2 OBJECTIVE:

The objective of the study is to form a basis for written procedures for production and

process control which are designed to assure that the drug Ibuprofen 400 mg coated

tablet have the identity, strength, quality and purity they purport of are represented to

possess.

• To check the critical steps in the manufacturing of Ibuprofen 400 mg coated tablet.

• To provide documented evidence, so that this would give high degree of assurance

that this specific process will consistently produce Ibuprofen 400 mg coated tablets

meeting its predetermined specification and quality characteristics.

• Quality, safety and efficacy would be designed and built into the product.

• To control each step of the manufacturing process to maximize the probability that

the finished product meets all quality and design specifications.


1.5.3 Experimental plan:

Validation Procedure:

Three consecutive batches of Ibuprofen 400 mg tablet shall be manufactured

as per the Batch Manufacturing Record.

Collect samples at different stages of processing as mentioned in the sampling

plan for individual process.

Send the samples to Quality Control Laboratory for analysis as per testing

plan.

Monitor and record the results of critical control variables and response

variables as mentioned in the process parameter table for individual operation.

During the processing of the batches, Current GMP shall be followed.

Compression machine evaluation: Verify the tablets parameters at maximum

and minimum speed of machine, then set the parameters for target speed and

verify the parameters well within the limits, then check the physical

parameters of the tablets.

In case any deviation(s) are observed they must be noted down in the

deviation report immediately. The deviation must be noted in succession

throughout the process along with the corrective action.

A validation report shall be prepared upon the execution of this protocol and

testing of the validation samples.


1.6 DRUG PROFILE:

IBUPROFEN23, 24

Category: Anti-inflammatory; Analgesic.

Description: White or almost white, crystalline powder or colorless crystals; odor,

slight.

Solubility: Freely soluble in acetone, in chloroform, in ethanol (95%) and in ether;

practically insoluble in water. It dissolves in dilute solutions of alkali hydroxides and

carbonates.

Chemical Formula: Chemically it is (RS)-2-(4-isobutylphenyl) propionic acid.

Empirical formula of Ibuprofen: C13H18O2

Structural formula of Ibuprofen:

Fig.1 Structural formula of Ibuprofen

C COOH

CH3

H

CH2CHCH3

CH3

Molecular Weight: 206.28

Storage Should be stored at room temperature, between 15-30°C (59-86°F).

Standards: Ibuprofen contains not less than 95.0 per cent and not more than 105 % of

C13H18O2, calculated with reference to the dried substance.

Mechanism of Action: Ibuprofen is an NSAID which is believed to work through

inhibition of cyclooxygenase enzyme (COX), thus inhibiting prostaglandin synthesis.

There are at least 2 variants of cyclooxygenase (COX-1 and COX-2). Ibuprofen

inhibits both COX-1 and COX-2. It appears that its analgesic, antipyretic, and anti-


inflammatory activity are achieved principally through COX-2 inhibition; whereas

COX-1 inhibition is responsible for its unwanted effects on platelet aggregation and

the GI mucosa.

Side Effects: The most common side effects from ibuprofen are rash, ringing in the

ears, headaches, dizziness, drowsiness, abdominal pain, nausea, diarrhea, constipation

and heartburn. Ibuprofen may cause ulceration of the stomach or intestine and the

ulcers may bleed. Sometimes ulceration and bleeding can occur without abdominal

pain, and black tarry stools, weakness, and dizziness upon standing (orthostatic

hypotension) may be the only signs of a problem. NSAIDs reduce the flow of blood to

the kidneys and impair function of the kidneys. The impairment is most likely to

occur in patients with preexisting impairment of kidney function or congestive heart

failure and use of NSAIDs in these patients should be done cautiously. People who

are allergic to other NSAIDs, including aspirin, should not use ibuprofen. Individuals

with asthma are more likely to experience allergic reactions to ibuprofen and other

NSAIDs.25, 26


PHARMACEUTICAL INFORMATION OF ADDETIVES:

Povidone 27-29:

Chemical Name : 1-Ethenyl-2-pyrrolidinone homopolymer.

Empirical Formula : (C6H9NO)n Molecular Weight : 2500–3000000.

Functional Category: As a pharmaceutical aid (tablet binder, coating agent,

dispersing and suspending agent).

Description: Povidone occurs as a fine, white to creamy-white colored, odorless or

almost odorless, hygroscopic powder. Freely soluble in acids, chloroform, ethanol

(95%), ketones, methanol, and water; practically insoluble in ether, hydrocarbons, and

mineral oil.

Typical Properties

Acidity/alkalinity : pH = 3.0–7.0 (5 % w/v aqueous solution).

Density (bulk) : 0.29–0.39 g/cm3 Density (tapped : 0.39–0.54 g/cm3

Density (true) : 1.180 g/cm3 Melting point : softens at 150 °C.

Moisture content : povidone is very hygroscopic, significant amounts of moisture

being absorbed at low relative humidities.

Stability and Storage Conditions: Povidone darkens to some extent on heating at

150 °C, with a reduction in aqueous solubility. However, since the powder is

hygroscopic it should be stored in an airtight container in a cool dry place.

Alginic acid30-34:

Chemical Name : Alginic acid Empirical Formula : (C6H8O)n.

Molecular Weight : 20000–240000

Functional Category: Stabilizing agent; suspending agent; sustained release

adjuvant; tablet binder; tablet disintegrant; viscosity-increasing agent


Description: Alginic acid is a tasteless, practically odorless, and white to yellowish-

white, fibrous powder. Soluble in alkali hydroxides, producing viscous solutions; very

slightly soluble or practically insoluble in ethanol (95%) and other organic solvents.

Typical Properties

Acidity/alkalinity : pH = 1.5–3.5 for a 3% w/v aqueous dispersion.

Density (true) : 1.601 g/cm3 Moisture content : 7.01 %

Viscosity (dynamic) : Viscosity increases considerably with increasing

concentration; typically a 0.5% w/w aqueous dispersion has a viscosity of

approximately 20 mPa s,

Stability and Storage Conditions: Alginic acid hydrolyzes slowly at warm

temperatures producing a material with a lower molecular weight and lower

dispersion viscosity. Alginic acid dispersions are susceptible to microbial spoilage on

storage, it should therefore be preserved with an antimicrobial preservative.

Alginic acid should be stored in a well-closed container in a cool, dry place.

Sodium lauryl Sulphate35:

Chemical Name : Sulfuric acid monododecyl ester sodium salt

Empirical Formula : C12H25NaO4S Molecular Weight : 288.38

Functional Category : Anionic surfactant; detergent; emulsifying agent; skin

penetrant; tablet and capsule lubricant; wetting agent.

Description: Sodium lauryl sulfate consists of white or cream to pale yellow colored

crystals, flakes, or powder having a smooth feel, a soapy, bitter taste and a faint odor

of fatty substance. Freely soluble in water, giving an opalescent solution practically

insoluble in chloroform and ether.

Typical Properties

Acidity/alkalinity : pH = 7.0–9.5 (1% w/v aqueous solution)


Density : 1.07 g/cm3 at 20 °C Melting point : 204–207 °C

Interfacial tension : 11.8 dynes/cm for a 0.05% w/v solution at 30 °C.

Moisture content : 45%; sodium lauryl sulfate is not hygroscopic.

Surface tension : 25.2 dynes/cm for a 0.05% w/v aqueous solution at 30 °C

Stability and Storage Conditions: Sodium lauryl sulfate is stable under normal

storage conditions. The bulk material should be stored in a well-closed container

away from strong oxidizing agents in a cool dry place.

Sodium starch glycolate36-41:

Chemical Name: Sodium carboxymethyl starch.

Empirical Formula: The USPNF 23 states that sodium starch glycolate is the sodium

salt of a carboxymethyl ether of starch, containing 2.8–4.2% sodium.

Molecular Weight: 5×105–1×106.

Functional Category: Tablet and capsule disintegrant.

Description: Sodium starch glycolate is a white to off-white, odorless, tasteless, free-

flowing powder. Sparingly soluble in ethanol (95%); practically insoluble in water. At

a concentration of 2% w/v sodium starch glycolate disperses in cold water and settles

in the form of a highly hydrated layer.

Typical Properties

Acidity/alkalinity : pH = 5.5–7.5 for a 3.3% w/v aqueous dispersion.

Density (bulk) : 0.756 g/cm3 Density (tapped) : 0.945 g/cm3;

Density (true) : 1.443 g/cm3 Melting point : chars at 200 °C.

Specific surface area : 0.24 m2/g;

Stability and Storage Conditions: Tablets prepared with sodium starch glycolate

have good storage properties. Sodium starch glycolate is stable and should be stored

in a well-closed container in order to protect it from wide variations of humidity and


temperature, which may cause caking. Swelling capacity: in water, sodium starch

glycolate swells to up to 300 times its volume.

Magnesium stearate42-45:

Chemical Name : Octadecanoic acid magnesium salt

Empirical Formula : C36H70MgO4 Molecular Weight : 591.34

Structural Formula : [CH3 (CH2)16COO]2Mg

Functional Category : Tablet and capsule lubricant.

Description: Magnesium stearate is a very fine, light white, precipitated or milled,

impalpable powder of low bulk density, having a faint odor of stearic acid and a

characteristic taste. The powder is greasy to the touch and readily adheres to the skin.

Practically insoluble in ethanol, ethanol (95%), ether and water; slightly soluble in

warm benzene and warm ethanol (95%).

Typical Properties:

Crystalline forms : high-purity magnesium stearate has been isolated as a

trihydrate, a dihydrate, and an anhydrate.

Density (bulk) : 0.159 g/cm3 Density (tapped) : 0.286 g/cm3

Density (true) : 1.092 g/cm3 Melting range : 117–150 °C

Stability and Storage Conditions: Magnesium stearate is stable and should be stored

in a well closed container in a cool, dry place.

Cellulose microcrystalline46-49:

Chemical Name : Cellulose Empirical Formula : (C6H10O5)n

Molecular Weight : (162)n Functional Category : Adsorbent; suspending

agent; tablet and capsule diluent; tablet disintegrant.


Description: Microcrystalline cellulose is purified, partially depolymerized cellulose

that occurs as a white, odorless, tasteless, crystalline powder composed of porous

particles.

Typical Properties

Angle of repose : 498 for Ceolus KG; 34.48 for Emcocel 90M.(9)

Density (bulk) : 0.337 g/cm3 Density (tapped) : 0.478 g/cm3;

Density (true) : 1.512–1.668 g/cm3 Melting point : 260–270 °C.

Moisture content : typically less than 5% w/w.

Stability and Storage Conditions: Microcrystalline cellulose is a stable though

hygroscopic material. The bulk material should be stored in a well-closed container in

a cool, dry place.

Potato starch50-54:

Chemical Name : Starch, Empirical Formula : (C6H10O5)n

Molecular Weight : (162)n.

Functional Category : Glidant; tablet and capsule diluent; tablet and capsule

disintegrant; tablet binder.

Description: Starch occurs as an odorless and tasteless, fine, white-colored powder

comprising very small spherical or ovoid granules whose size and shape are

characteristic for each botanical variety. Practically insoluble in cold ethanol (95%)

and in cold water. Starch swells instantaneously in water by about 5–10% at 37 °C.

Typical Properties

Acidity/alkalinity : pH = 5.5–6.5 for a 2% w/v aqueous dispersion.


Density (true) : 1.478 g/cm3 Gelatinization temperature: 72 °C


Moisture content : Approximate equilibrium moisture content values at 50%

relative humidity 18%.

Storage: Should be stored in well closed container.

Colloidal silica55-58:

Chemical Name : Silica Empirical Formula : SiO2

Molecular Weight : 60.08

Functional Category : Adsorbent; anticaking agent; emulsion stabilizer; glidant;

suspending agent; tablet disintegrant; thermal stabilizer; viscosity-increasing agent

Description: Colloidal silicon dioxide is submicroscopic fumed silica with a particle

size of about 15 nm. It is a light, loose, bluish-white colored, odorless, tasteless, non

gritty amorphous powder. Practically insoluble in organic solvents, water, and acids,

except hydrofluoric acid; soluble in hot solutions of alkali hydroxide. Forms a

colloidal dispersion with water.

Typical Properties:

Acidity/alkalinity : pH = 3.5–4.4 (4% w/v aqueous dispersion)

Flowability : 35.52% (Carr compressibility index)

Specific surface area : 200– 400 m2/g (Stroehlein apparatus, single point)

Storage Conditions: Talc should be stored in a well-closed container in a cool, dry

place.


PHARMACEUTICAL INFORMATION OF COATING MATERIAL:

1) Talcum powder59-61:

Chemical Name : Talc

Empirical Formula : Talc is a purified, hydrated, magnesium silicate,

approximating to the formula Mg6(Si2O5)4(OH)4. It may contain small, variable

amounts of aluminum silicate and iron Purified Talc;

Functional Category : Anticaking agent; Glidant; tablet and capsule diluent; tablet

and capsule lubricant

Description: Talc is a very fine, white to grayish-white, odorless, impalpable,

unctuous, crystalline powder. It adheres readily to the skin and is soft to the touch and

free from grittiness. Pactically insoluble in dilute acids and alkalis, organic solvents

and water.

Typical Properties

Acidity/alkalinity : pH = 7–10 for a 20% w/v aqueous dispersion.

Moisture content : talc absorbs insignificant amounts of water at 25 °C and

relativehumidity up to about 90%.

Specific gravity : 2.7–2.8. Specific surface area : 2.41–2.42 m2/g

Stability and Storage Conditions: Talc is a stable material and may be sterilized by

heating at 160 °C for not less than 1 h. It may also be sterilized by exposure to

ethylene oxide or gamma irradiation. Talc should be stored in a well-closed container

in a cool, dry place.


2) Granular Sugar62:

Chemical Name : b-D-fructofuranosyl-a-D-glucopyranoside.

Empirical Formula : C12H22O11 Molecular Weight : 342.30

Functional Category : Base for medicated confectionery; coating agent; granulating

agent; sugar coating adjunct; suspending agent; sweetening agent; tablet binder; tablet

and capsule diluent; tablet filler; viscosity-increasing agent.

Description: Sucrose is a sugar obtained from sugar cane (Saccharum officinarum

Linne’ (Fam. Gramineae)), sugar beet (Beta vulgaris Linne’ (Fam. Chenopodiaceae)),

and other sources. It contains no added substances. Sucrose occurs as colorless

crystals, as crystalline masses or blocks or as a white crystalline powder; it is odorless

and has a sweet taste.

Typical Properties

Density (bulk) :0.93 g/cm3 (crystalline sucrose); 0.60 g/cm3 (powdered sucrose). Density (tapped) :1.03 g/cm3 (crystalline sucrose); 0.82 g/cm3 (powdered sucrose). Density (true) :1.6 g/cm3 Dissociation constant :pKa = 12.62

Melting point :160–186 °C.

Moisture content :finely divided sucrose is hygroscopic and absorbs up to 1%

water.

Stability and Storage Conditions: Sucrose has good stability at room temperature

and at moderate relative humidity. It absorbs up to 1% moisture, which is released

upon heating at 90 °C.

The bulk material should be stored in a well-closed container in a cool dry place.


3) Titanium dioxide63-66:

Chemical Name : Titanium oxide. Empirical Formula : TiO2

Molecular Weight : 79.88 Structural Formula : TiO2 Functional Category : Coating agent; opacifier; pigment.

Description: White, amorphous, odorless, and tasteless nonhygroscopic powder.

Practically insoluble in dilute sulfuric acid, hydrochloric acid, nitric acid, organic

solvents and water. Soluble in hydrofluoric acid and hot concentrated sulfuric acid.

Typical Properties

Density (bulk) : 0.4–0.62 g/cm3 Density (tapped) :0.625–0.830 g/cm3

Density (true) : 3.8–4.1 g/cm3 Melting point : 1855 °C

Moisture content : 0.44%

Stability and Storage Conditions: Titanium dioxide is extremely stable at high

temperatures. This is due to the strong bond between the tetravalent titanium ion and

the bivalent oxygen ions. However, titanium dioxide can lose small, unweighable

amounts of oxygen by interaction with radiant energy. This oxygen can easily

recombine again as a part of a reversible photochemical reaction, particularly if there

is no oxidizable material available. These small oxygen losses are important because

they can cause significant changes in the optical and electrical properties of the

pigment. Titanium dioxide should be stored in a well-closed container, protected from

light in a cool dry place.

4) Calcium carbonate67-70

Chemical Name : Carbonic acid, calcium salt (1: 1)

Empirical Formula : CaCO3 Molecular Weight : 100.09

Structural Formula : CaCO3


Functional Category : Buffering agent; coating agent; opacifier; tablet and capsule

diluent; therapeutic agent.

Description: Calcium carbonate occurs as an odorless and tasteless white powder or

crystals. Practically insoluble in ethanol (95%) and water. Solubility in water is

increased by the presence of ammonium salts or carbon dioxide. The presence of

alkali Hydroxides reduces solubility.

Typical Properties

Acidity/alkalinity : pH = 9.0 (10% w/v aqueous dispersion)


Melting point : decomposes at 825 °C.

Specific surface area : 6.21–6.47 m2/g

Stability and Storage Conditions: Calcium carbonate is stable and should be stored

in a well closed container in a cool dry place.

5) Acacia71-74:

Chemical Name : Acacia

Empirical Formula : Acacia is a complex, loose aggregate of sugars and

hemicelluloses with a molecular weight of approximately

Molecular Weight : 240000–580000.

Functional Category : Emulsifying agent; stabilizing agent; suspending agent; tablet

binder; viscosity-increasing agent.

Description: Acacia is available as white or yellowish-white thin flakes, spheroidal

tears, granules, powder or spray-dried powder. It is odorless and has a bland taste.

Soluble 1 in 20 of glycerin, 1 in 20 of propylene glycol, 1 in 2.7 of water; practically

insoluble in ethanol (95%). In water, acacia dissolves very slowly, although almost

completely after two hr.


Typical Properties

Acidity/alkalinity : pH = 4.5–5.0 (5 % w/v aqueous solution)

Acid value : 2.5

Viscosity (dynamic) : 100 mPas (100 cP) for a 30 % w/v aqueous solution at 20 °C.

Stability and Storage Conditions: Aqueous solutions are subject to bacterial or

enzymatic degradation but may be preserved by initially boiling the solution for a

short time to inactivate any enzymes present; microwave irradiation can also be used.

Aqueous solutions may also be preserved by the addition of an antimicrobial

preservative such as 0.1 % w/v benzoic acid, 0.1 % w/v sodium benzoate, or a

mixture of 0.17 % w/v methyl paraben and 0.03 % propyl paraben. Powdered acacia

should be stored in an airtight container in a cool dry place.

6) Carnauba wax 75-77

Chemical Name : Carnauba wax.

Empirical Formula : Carnauba wax consists primarily of a complex mixture of

esters of acids and hydroxy acids, mainly aliphatic esters, o-hydroxy esters, p-

methoxycinnamic aliphatic esters, and p-hydroxycinnamic aliphatic diesters

composed of several chain lengths, in which C26 and C32 alcohols are the most

prevalent. Also present are acids, oxypolyhydric alcohols, hydrocarbons, resinous

matter and water.

Functional Category : Coating agent. Flash point : 270–330 °C

Description: Carnauba wax occurs as a light brown- to pale yellow-colored powder,

flakes or irregular lumps of a hard brittle wax. It has a characteristic odor and

practically no taste. Soluble in warm chloroform and in warm toluene; slightly soluble

in boiling ethanol (95 %); practically insoluble in water.


Stability and Storage Conditions: Carnauba wax is stable and should be stored in a

well-closed container in a cool dry place.

7) PVAP 78-81:

Chemical Name : Polyvinyl acetate phthalate

Empirical Formula and Molecular Weight: The USPNF 23 describes polyvinyl

acetate phthalate as a reaction product of phthalic anhydride and partially hydrolyzed

polyvinyl acetate. It contains not less than 55.0 % and not more than 62.0 % of

phthalyl (o-carboxybenzoyl, C8H5O3) groups, calculated on an anhydrous acid-free

basis. It has been reported that the free phthalic acid content is dependent on the

source of the material.

Functional Category: Coating agent.

Description: Polyvinyl acetate phthalate is a free-flowing white to off-white powder

and may have a slight odor of acetic acid. The material is essentially amorphous. It is

soluble in ethanol and methanol; sparingly soluble in acetone and propan-2-ol;

practically insoluble in chloroform, dichloromethane and water.

Typical Properties

Moisture content : 3.74%; 2.20% Density : 1.31 g/cm3; 1.37 g/cm3.

Viscosity (dynamic) : the viscosity of a solution of polyvinyl acetate phthalate:

methanol (1:1) is 5000 mPas. In methanol/ dichloromethane systems, viscosity

increases as the concentration of methanol in the system increases.

Stability and Storage Conditions: Polyvinyl acetate phthalate should be stored in

airtight containers. It is relatively stable to temperature and humidity and does not

age, giving predictable release profiles even after prolonged storage.


2.1 MATRIALS AND METHODS:

Details of material for three batches:

Table 2: Details of material specification for core tablet

S.No. Ingredients Specification.

1 Ibuprofen Drug B.P.

2 Silica colloidal Ph.Eur.

3 Potato starch Ph.Eur.

4 Povidone Ph.Eur.

5 Microcrystalline cellulose Ph.Eur.

6 Alginic acid B.P.

7 Magnesium stearate Ph.Eur.

8 Sodium lauryl sulphate Ph.Eur.

9 Sodium starch glycolate Ph.Eur.

10 Crosscarmallose Ph.Eur.

Table 3: Details of material specification for coated tablet

S.No. Ingredients Specification

1 Ibuprofen core tablets B.P.

2 PVAP Seal coat B.P.

3 Purified talcum powder B.P.

4 Granular sugar B.P.

5 Titanum dioxide B.P.

6 Calcium Carbonate B.P.

7 Gum Acacia B.P.

8 Carnauba wax B.P.

9 Purified water ……


2.2 LIST OF EQUIPMENTS USED:

Table 4: List of equipments

S.No. Equipment Capacity Batch no.

A

Batch no.

B

Batch no.

C

1 Weighing balance --- Ok Ok Ok

2 Mechanical sifter 20#, 40#, 60#,

80#, 100#. T – 255 T – 255 T – 255

3 Double Cone

Blender. ---- T – 148 T – 148 T – 148

4 Multi mill ---- T – 98 T – 98 T – 98

5 Roll Compactor ---- T – 142 T – 142 T – 142

6 Compression machine 37 station

Double rotaryT – 87 T – 87 T – 87

7 Tablet deduster ---- T – 150 T – 150 T – 150

8 Metal detector ---- T – 96 T – 96 T – 96

9 Sejong coater ---- T – 117 T – 117 T – 117

10 Blister packing machine ----


2.3 PROCESS FLOW CHART:

Fig.2: Process flow chart

DISPENSING

SIFTING

BLENDING (PRE- LUBRICATION)

BLENDING (LUBRICATION)

SLUGGING

MILLING

SIFTING

COMPRESSION

PACKING

WEIGHING BALANCE

SIFTER

DCB

DCB

ROLL COMPACTOR

MULTIMILL

SIFTER

CADPRESS MACHINE CADPRESS

BLISTER PACKING


2.4 PRODUCT COMPOSITION FOR THREE BATCHES:

Table 5: Details of material for core tablet

S.No. Ingredients Qty. mg/tab. Std. Qty.(Kg)

1 Ibuprofen 400.00 125.00

2 Silica colloidal 7.08 2.212

3 Potato starch 87.74 27.42

4 Povidone 11.21 3.503

5 Microcrystalline cellulose 96.85 30.27

6 Alginic acid 10.62 3.320

7 Magnesium stearate 4.72 1.475

8 Sodium Lauryl sulphate 2.36 0.737

9 Sodium starch glycolate 14.68 4.587

10 Cross carmellose 4.72 1.475

Total weight 640.00 200.00

Coating material used for three batches: Table 6: Material required for coating

S.No. Ingredients Qty. mg/tab. Std. Qty.(kg)

1 Ibuprofen core tablets 400.00 200.00

2 PVAP Seal coat 19.81 6.190

3 Purified talcum powder 29.67 9.272

4 Granular sugar 102.5 34.75

5 Titanum dioxide 1.82 0.57

6 Calcium Carbonate 23.51 7.335

7 Gum Acacia 2.24 0.70

8 Carnauba wax 0.45 0.144

9 Purified water ….. 31 lit

Total weight 820.00 285.96


2.5 ASSESSMENT OF CRITICAL PROCESS PARAMETERS: Table 7: Assessment of Critical Process Parameter

Process Steps Critical Variables Rational Critical Parameters

Sifting Particle size distribution of sifted materials

To ensure uniform particle size distribution of sifted input material

- Appearance - Right sieve number - Sieve integrity before and after use.

Blending (Prelubrication)

Blending Time Speed of blender

To obtain uniform distribution of drug.

- Appearance - Bulk / Tapped density

Blending (lubrication)

Blending Time (with lubricant) Speed of blender

To obtain final blend uniformity for compression

- Blending time - Speed of blender - Bulk / Tapped density - Sieve analysis - Blend uniformity

Slugging Milling Sifting

Reduction and uniform particle size distribution of blended materials

To ensure uniform particle size distribution of blended material

- Screen used - Speed of multimill - Correct Sieve. - Appearance - Sieve integrity before and after use. - Bulk / Tapped density

Compression

Machine Speed: Min speed: 1600 (tab/ min ) Max speed : 2400 ( tab/ min ) Target speed: 2000 (tab/ min )

To meet the desired product specification till end of compression.

- M/C Speed - Description - Average weight - Weight Variation - Thickness - Hardness - Friability - Disintegration test

Coating

Inlet temp. Exhaust temp. Pan speed Atomization pressure Spray rate Gun distance No. of guns used

To meet the desired final product specification

- RPM of coating pan - Inlet temp. - Outlet temp. - Appearance - Weight build up - Spray Rate - Assay - Dimensions


2.6 CHECKLISTS:

Before starting of manufacturing operation the following observation should be

done:

Checklist for cleaning of CAD37 compression machine (type-A cleaning)

Equip no = T–87 Date = xxxx.

Product name = Ibuprofen 400 mg Tab. Previous product = xxxx.

Batch no = xxxx Batch no = xxxx

Table 8: Checklist for cleaning of CAD37 compression machine

S.No. Check point Status

1 Ensure that CAD-37 compression machine is switched off &

hydraulic pressure is released.

2 Check the turret hoppers & feed frames are vacuum cleaned.

Followed by wipe with clean dry lint free cloth.

3 Check that CAD37 compression machine is vacuum cleaned

from outside followed by wipe with clean dry lint free cloth.

4 Ensure that all the residue of previous product has been removed.

5 Check area for cleanliness.

6 Label the CADPRESS machine as cleaned

7 Enter the details in “Equipment usage log.”

– Satisfactory

– Unsatisfactory

NA – Not applicable

Remark – Ok


Checklist for cleaning of Dedusting unit (CIP/(EMACH) Table 9: Checklist for cleaning of Dedusting unit (CIP/(EMACH)

S.No Check point Status

1 Check that the main electrical supply is off.

2 Ensure that the cover & perforated screen, tablet outlet chamber

are vacuum cleaned & wipe cleaned with clean dry lint free cloth.

3 Ensure that dedusting unit is vacuum cleaned from outside or wipe

cleaned with dry lint free cloth.


5 Label the dedusting, unit as “CLEANED”.

6 Enter the details in equipment sequential log.

Checklist for cleaning of metal detector. Table 10: Checklist for cleaning of metal detector.

S.No. Check point Status

1 Ensure that metal detector is switched off

2 Ensure that the channels & stainless steel container are

mismatched.

3 Check the channels & body of metal detector are cleaned with

nylon brush.

4 Check that the channels & stainless steel container are vacuum

cleaned.

5

Ensure that the channels stainless steel container & body of

digital metal Detector are wipe cleaned with clean dry lint free

cloth.



8 Label the metal detector as “CLEANED”.

9 Enter the details in “Equipment usage log.”


Checklist for cleaning of vibro sifter Table 11: Checklist for cleaning of vibro sifter S.No Check point Status

1 Check that the sieve & deck rings are dismantled.

2

Ensure that the powder / granules from sieve & collection chamber

are removed.

3

Ensure that the sieve collection chamber is wiped, cleaned with dry

lint free cloth.

4

Ensure that vibro sifter is wipe cleaned from outside with clean dry

lint free cloth.

5 Ensure that sieve is free from sticky residue.

6 Check area cleanliness.

7 Label the vibro sifter as “CLEANED”.

8

Enter the details in “Equipment sequential log.

Checklist for cleaning of multimill. Table 12: Checklist for cleaning of multimill. S.No Check point Status

1 Check that discharge cover feed hopper screen & screen holding plates are dismantled.

2 Ensure that the powder/granules from screen, screen holding plate beater assembly & feed hopper are removed.

3 Ensure that the screen, screen holding plate beater assembly feed hopper & discharge cover are wipe cleaned with clean dry lint free cloth.

4 Ensure that the multimill is wipe cleaned from outside with clean dry lint free cloth.

5 Check area for cleanliness. 6 Label the multimill unit as “CLEANED”. 7 Enter the details in “Equipment sequential log.”


Checklist for cleaning of DCB Table 13: Checklist for cleaning of DCB S.No Check point Status

1 Ensure that the limit switch is detached from safety guard.

2 Ensure that all the powder from cone blender is removed.

3 Ensure that cone blender is cleaned from inside with clean dry

lint free cloth.

4 Check that the cone blender wipe cleaned from outside with

clean dry lint free cloth.



7 Label the cone blender as ‘CLEANED’.

8 Enter the details in “Equipment sequential log.”


2.7 METHODS: Procedure

2.7.1 DISPENSING: Environmental conditions were monitored during dispensing

stage. Temperature: Not more that 27 oC, Relative Humidity: Not more than 50 %,

Differential Pressure: NLT 0.4 MMWC. Ensure that weighing balance is cleaned,

calibrated and adjusted to zero. Brought materials in original packs for dispensing and

verify that all the materials bear QC approved label.

Transferred of each weighed material in to separate polythene bag and store in tightly

closed container in quarantine area.

2.7.2 SIFTING: Weighed all material separately by using calibrated weighing

balance. All materials sifted or sieved by using sieve of 20#, for uniform distribution

of particle size.

Table 14: Sampling and testing plan for sifting

Table 15: Physical parameters & acceptance criteria during sifting.

S.No Stage Sample Quantity Test Specification

Appearance White colored free flowing powder

Sieve 20# Should comply. Integrity before and after use.

Should be OK

1 Sifting 100 gm.

% powder retained

NMT 1 %

Formula: For % Powder Retained

S.No. Stage Sampling location Sample

Quantity

1 Sifting After completion of sifting pooled sample from container

100 gm


2.7.3 BLENDING (PRE LUBRICATION): The blending step involves mixing of

additives using Double cone blender. In this step transferred 281.250 kg of Ibuprofen

drug powder, potato starch 54.838 kg, microcrystalline cellulose 60.531 kg, povidone

7.006 kg. In this step the lubricating agent is not added. Then rotated the machine

DCB at speed of 24 ± 1 RPM for 15 min. After completion of mixing unloading is

done in the containers.

Table 16: Sampling and testing plan for prelubrication

Testing parameters & acceptance criteria after Blending pre lubrication:

Table 17: Physical parameters & Acceptance criteria after pre lubrication.

S.No. Stage Test Specification Appearance White colored free flowing powderBulk density 0.5–1.0 g/ml 1

Blending (Pre- lubrication) Tapped

Density 0.5–1.0 g/ml.

Sampling location: Top: 1, Middle: 1, Bottom: 1, by using sampling rod.

Fig.3: Container

S.No. Stage Sampling location Sample Quantity

1 Blend

(Prelubricated) From container 3 point pooled sampling 100gm


Formula: For Bulk Density and Tapped Density

2.7.4 BLENDING (LUBRICATION): In this step added alginic acid 6.638 kg,

magnesium stearate (lubricant) 2.950 kg, colloidal silica 4.425 kg, sodium lauryl

sulphate 1.475 kg, sodium starch glycolate 9.175 kg, Cross carmellose 2.950 kg, in

the previously blended non lubricated material. Then rotated the DCB for 3 min. at

speed of 24 ± 1 RPM. After blending unloading is done in the container.

Sampling and testing plan for blend uniformity:

Table 18: Sampling and testing plan for blend uniformity

Testing parameters and acceptance criteria after Blending lubrication:

Table 19: Testing parameters and acceptance criteria after Blending lubrication

S.No. Stage Test Specification

Appearance White colored free

flowing powder.

Blend

uniformity

100 ± 10 % (360 – 440

mg of Ibuprofen)

1 Blending

(Lubrication)

RSD NMT 5 %


1 Lubricated

Blend

From DCB. After completion lubrication

draw 12 point sample in duplicate.

X – 3X

(640 – 1920 mg)

in duplicate


Sampling Location: Double Cone Blender: 12 - Point sampling.

Fig.4: Double Cone Blender

Top samples : 3 (U1, U2, U3)

Middle samples : 5 (M1, M2, M3, M4, M5)

Lower samples : 3 (L1, L2, L3)

Bottom sample : 1 (B0)

Blend uniformity by using HPLC:

Procedure:

Preparation of mobile phase: Mixed 1000 ml of methanol to 400 ml of distilled

water and added 40 ml of Acetic acid.

Preparation of extracting solution: Mixed 1000 ml of methanol to 1000 ml of

distilled water.

Standard preparation of Ibuprofen: Weighed 200 mg of Ibuprofen and dissolved in

30 ml of extracting solution, sonicated until dissolve and made up volume to 200 ml

with extracting solution.

Sample preparation: Weighed about 320 mg ± 2.5 % fine powder of blend

equivalent to 200 mg of Ibuprofen added 30 ml of extracting solution, sonicated until

dissolve and made up volume to 200 ml with extracting solution. Filter the solution

through 0.45 µ filter. Again dilute to 10 to 25 ml of extracting solution.

Same procedure followed for individual samples.


Procedure: Injected 20 µl of blank, standard solution 1 five times, sample solution 2

times, record the chromatogram and measure the peak area of standard and sample

solution.

Chromatographic condition:

Table 20: Chromatographic condition

Formula:

AS – Average % area of standard (100 %)

AT – % Area of Ibuprofen in sample

MT – Mass of powder taken sample equivalent to 200 mg of ibuprofen.

MS – Mass of standard powder taken 200 mg.

M – Average mass X (640 mg)

P – Purity of standard Ibuprofen (99.5 %).

% Blend uniformity

X = Value from Blend Uniformity.

Column Silica – Octracarber equivalent

Wavelength 254 nm

Flow rate 1.0 ml/min

Oven temp. 30 °C

Run time 10 min.

Injection volume 20 µl


2.7.5 SLUGGING, MILLING AND SIFTING:

1] Slugging: In this process all blended material is transferred in Roll compactor,

formation of large slugs or compact mass taking place. Here sampling is not done but

selection of Roll compactor used and speed of 10–12 RPM for slugging is important

that should be same for three batches.

2] Milling: The compact mass is passed through Multimill. Where cutting of large

slugs into small granular particles takes place. The main parameters considered during

this step are screen used which is of 2.5 mm sieve and speed of multimill which is

1500 RPM.

3] Sifting: The milled material is passed through different sieves for uniform

distribution of particle size. This is done by using Vibro sifter.

Pooled sample: After sifting one pooled sample is collected from container.

Table 21: Sampling and testing plan after slugging

Table 22: Testing parameters & acceptance criteria after slugging.

S.No. Stage Test Specification

Sieve: 20#, 40#, 60#, 80#,

100#. Should comply

Sieve integrity before and

after use Should be OK

Bulk Density 0.5 to 1 g/ml

Tapped Density 0.5 to 1 g/ml

1 Sifting

% retained. NMT 30 %

from100#.


1

Slugging

Milling

Sifting

Collect one pooled sample after

completion of sifting from the

container.

100 gm

(pooled sample)


Formula:

1] Formula for % Powder Retained:

2] Formula for Bulk Density:

3] Formula for Tapped Density:

2.7.6 COMPRESSION: In this step the granules are compressed at specific force

to form a uniform shaped tablet. Compression is done by using machine Cadpress

which is double rotary having 37 stations. Compression was carried as per BMR using

standard concave shaped punches with hard chrome plated tips. Machine was set at

speed i.e. speed of 2000 tab/min this is the target speed of machine. The sample was

collected at initial, middle and end of compression at the target speed. Also the

samples are collected at minimum speed i.e., 1600 tab/min maximum speed i.e.2400

tab/min of compression.

Number of stations : 37 Type of tooling : “D” type

1] Description: Done visual inspection by collecting the pooled sample.

2] Average weight: Done by using digital balance.

Formula:

3] Disintegration time: It is done by using USP DT apparatus. Filled the beaker 900

ml with the distilled water, and adjusted the temperature about 37 ± 1 °C. Placed 6


tablets in six tubes having mesh at bottom of 0.2 mm size. Started the apparatus about

29 up and down cycles/min. and recorded the disintegration time from display after

complete disintegration of tablets.

4] Friability: Done by using Rosche friabilator. Firstly taken the weight of 20 tablets.

Then placed these 20 tablets in the friabilator chamber, and started machine at speed

of 25 RPM for 4 min. After completion of 100 revolution the tablets are collected,

dedusted and again weighed.

Formula:

W3 = W1 – W2

W1 – Initial weight of 20 tablets, W2 – Final weight of 20 tablets.

5] Thickness: Done by using vernier caliper and noted the reading directly from

screen.

6] Hardness: Done by using Schleuniger hardness tester and noted the reading

directly from screen.

Table 23: Sampling and testing plan for core tablet


1

Compression

(At target speed)

(2000 tab/min)

Initial

Middle

End

Min. speed

(1600 tab/min)

Max. speed

(2400 tab/min)

At the beginning, middle and

towards the end of

compression at target speed.

100 tablets

(from each sampling plan

)


Table 24: Testing of physical parameters for core tablet

S.No. Parameter Standards No. of tablets to be taken for

testing

1 Description

White circular,

biconvex

tablet, plane on both

sides.

As per AQL.

2 Weight of 20

tablets

12.8 gm ± 5%

(12.16 gm – 13.44 gm)20 tablets

3 Average weight 640 mg ± 2.5% 20 tablets

4 Weight variation 640 mg ± 5% 20 tablets

5 Hardness NLT 20 N (2.05

Kg/cm2) 10 tablets

6 Thickness 6.70 – 7.10 mm 10 tablets

7 Disintegration

time NMT 15 min. 6 tablets

8 Friability NMT 1 % w/w 20 tablets

9 Assay 380 – 420 mg;

100 ± 5 % 10 tablets

Assay of core tablet by using HPLC: Procedure:




distilled water.




Sample preparation: Weighed 320 mg ± 2.5 % fine powder of 20 tablets equivalent

to 200 mg of Ibuprofen added 30 ml of extracting solution, sonicated until dissolve


and made up volume to 200 ml with extracting solution. Filter the solution through

0.45 µ filter.

Same procedure followed for individual core tablet.



solution.


Table 25: Chromatographic condition for core tablet

Formula:

AS – Average % area of standard (100%).

AT – % Area of Ibuprofen in sample.

MT – Mass of individual tablet powder equivalent to 200 mg of ibuprofen.

MS – Mass of standard powder taken (200 mg)

M – Average mass of tablet 640 mg.


% Assay

X = Value from assay


Wavelength 254 nm


Run time 10 min

Oven temp. 30 °C



2.7.7 COATING: Coating is done by using Sejong coater.

Preparation of syrup solution: Heated purified water to boil 31 lit. Then added

granulated sugar 34.75 kg and stirred to dissolve. Removed this syrup and weighed

16.8 kg for preparation of colour coating solution. Then remaining quantity of

solution added 7.372 kg purified talcum powder, 7.335 kg Calcium carbonate and

0.70 kg Gum acacia, mixed slowly with sugar syrup under stirring for 15 min.

1] Seal coating: Dried the Sejong coater pan at 50 °C for 5 min. and transferred the

core tablets to pan which is rolled at speed of 3 rpm and inlet temperature of 40 °C.

Applied 6.190 kg of PVAP seal coat, rolled till cores are tacky. Then added required

quantity of talcum powder. Dried at 45 °C for 20 min.

2] Sub coating: Rolled the tablets at speed of 6 rpm with inlet temperature of range

60–70 °C. Then applied dose of syrup solution and allowed the tablets until rolled out.

Then dried the tablets until become hard. Repeated this procedure until target weight

is achieved. After this the sub coated tablets are polished by using titanium dioxide

and carnauba wax.

Coating parameters:

Table 26: Coating parameters

S.No. Parameter Desired Settings

1. Pan speed (RPM) 6 RPM

2. Inlet air temperature 60 – 70 °C

3. Outlet air temperature 45 – 55 °C

4. Spray rate 40-50 gm/gun/min

5. Number of guns used 6

6. Distance of coating gun from bed 20 – 24 cm

7. Atomizing air pressure 3-5 kg/cm2


Sampling and testing plan for coating:

Table 27: Sampling and testing plan after coating

Finished product analysis and acceptance criteria for coated tablet:

Table 28: Finished product analysis for coated tablet

S.No. Parameter Standards No. of tablets to be

taken for testing

1 Description White, round, biconvex,

Sugar Coated Tablet. As per AQL.

2 Weight of 20

tablets

16.40 gm ± 5% (15.58 gm –

17.22 gm) 20 tablets

3 Average weight 820 mg± 5%

(779 to 861 mg) 20 tablets

4 Thickness 7.20 – 8.0 mm 10 tablets

5 Disintegration

time NMT 30 min 6 tablets

6 Weight Builds

Up 160 – 190 mg 20 tablets

7 Assay 380-420 mg

100 ± 5 % 10 tablets

S.No. Stage Sampling location Sample

Quantity

1 During coating

From Coating Pan

After completion of

coating, draw 5-point

samples for each lot.

100 tablets

2 Finished product

(after coating)

Pooled sample after completion of

coating from all containers.

100 tablets

(pooled

sample)


Sampling Location:

Sejong Coater: 5-Point sampling.

Fig.5: Sejong Coater

L-1) Right Back side Layer; L-2) Right Front Side Layer; L-3) Middle Layer

L-4) Left Back Side Layer; L-5) Left Front Side Layer

HPLC procedure for assay of coated tablet:




distilled water.




Sample preparation: Weighed 410 mg ± 5% powder of 20 tablets which is

equivalent to 200 mg of Ibuprofen added 30 ml of extracting solution, sonicated until

dissolve and made up volume to 200 ml with extracting solution. Filter the solution

through 0.45 µ filter.

Same procedure followed for individual coated tablet.




solution.


Table29: Chromatographic condition for coated tablet

Formula:

AS – Average % area of standard (100%).

AT – % Area of Ibuprofen in sample

MT – Mass of coated tablet powder equivalent to 200 mg of ibuprofen.

MS – Mass of standard powder taken 200 mg.

M – Average mass of coated tablet (820 mg)


% Assay

X = Value from assay


Wavelength 254 nm


Run time 10 min

Oven temp. 30 °C



2.7.8 BLISTER PACKING: This process involves packing of tablets in polythene

lined aluminum foil and PVC blister pack.

Operation of Blister packing:

Fig.6: Operation of Blister packing

Batches taken for the study : A, B and C.

Generation of process order for issuance of packing materials

Formation of blister

Transferring of packing material from PMS to staging area

Rolling and formation of foil.

Area, machine clearance from IPQA and issue the sample intimation slip to IPQA

Transferring of packing material from staging area to packing line

Transferring of Semi-finished tablets from quarantine area to packing line along with completed BMR

Formation of cartons

In process checks during packing

Filling of tablets in the sockets of foil

Transferring packed goods to BSR


Leak Test: Procedure:

1. Tied 5 blisters with rubber band.

2. Dipped in solution of 1% methylene blue.

3. Raised the pressure of vacuum 15 mmHg for 30 sec.

4. Then released the pressure after 30 min.

5. Removed the blisters and checked visually for any leakage.

Equipment Detail for Packaging Operation:

Table 30: List of Equipments for Packing Operation

S.No. Equipment Name Equipment Nos.

1. Tablet elevator P – 38

2. Rotary sealing machine P – 40

3. Mechanical embossing machine ……..

4. Non fill detection (camera) ……..

5. Automatic cartoner ……..

6. Check weigher P – 41

7. Leak test apparatus P – 125

8. Shrinker machine P – 50

9. BOPP tapping machine P – 56

Observed parameters for blister packing;

Table 31: Parameters for blister packing

S.No. Parameters Standards

1 Pack size 8 tablets

2 Blister forming Temperature 140 – 160 °C

3 Sealing temperature 175 – 180 °C

4 Speeds studied 70-100 cuts/min

5 Leak test Should comply

6 Physical evaluation Should be OK


3.1 RESULTS: Three batches each of 3.12 lac were taken for the Process validation

of Ibuprofen tablets. For each of three batches the critical steps were identified and

variables studied.

3.1.1 SIFTING: By using 20# sieves.

% sample retained for Batch A, B, C:

Table 32: Sifting % sample retained result of three batches

S.No. Batch no. Sample taken (gm) Sample retained (gm) Result

(%) 1 A 10.05 0.025 0.24 2 B 10.06 0.028 0.27 3 C 10.05 0.026 0.25

Sieve integrity for Batch A, B, C:

Table 33: Sieve integrity for three batches after sifting

Sieve Integrity Batch no. Sieve used as per BMRBefore Use After Use

A 20# OK OK B 20# OK OK C 20# OK OK

Appearance of powder: White free flowing powder

Table 34: Appearance of powder after sifting

S.No. Batch no. Appearance1 A Complies 2 B Complies 3 C Complies


3.1.2 BLENDING (prelubrication):

Bulk Density for Batch A, B, C:

Table 35: Results of Bulk Density for three batches after pre lubrication

S.No. Batch

No.

Weight of sample

(A) gm

Apparent volume

(B) ml

Bulk density

(g/ml)

1 A 10.02 15.0 0.668

2 B 10.08 15.2 0.663

3 C 10.04 15.1 0.664

Tapped Density for Batch A, B, C

Table 36: Results of Tapped Density for three batches after pre lubrication

S.No. Batch

No.

Weight

of

sample

(A) gm.

Tapped

vol. 10

tap.(ml)

Tapped

vol. 500

tap.(ml)

Tapped

vol. 1250

tap.(ml)

Final

Tapped

vol. (ml)

(G)

Tapped

density

(g/ml).

1 A 10.02 13.0 11.5 11.3 11.3 0.886

2 B 10.08 13.4 11.8 11.5 11.5 0.876

3 C 10.04 13.2 11.6 11.4 11.4 0.880

Appearance: White free flowing powder

Table 37: Appearance of three batches after pre lubrication

S.No. Batch no. Appearance

1 A Complies

2 B Complies

3 C Complies


3.1.3 BLENDING (Lubrication):

Appearance for Batch A, B, C: White free flowing powder

Table 38: Appearance of three batches of lubricated blend

S.No. Batch no. Appearance

1 A Complies

2 B Complies

3 C Complies

Blend uniformity after lubrication for Batch A, B, C:

Table 39: Details of three batches for blend uniformity

S.No. Location Batch A Batch B Batch C

1 U1 98.35 98.45 100.20

2 U2 100.21 97.26 95.24

3 U3 97.65 98.02 99.46

4 M1 98.08 97.30 99.55

5 M2 95.13 96.56 97.23

6 M3 96.02 97.04 97.45

7 M4 100.54 96.42 100.01

8 M5 98.00 97.03 98.55

9 L1 97.08 100.14 96.53

10 L2 98.80 97.25 99.23

11 L3 100.45 98.43 97.53

12 B0 99.23 98.46 100.05

13 Minimum 95.13 96.42 95.24

14 Maximum 100.54 100.14 100.20

15 Mean 98.29 97.69 98.41

16 % RSD (NMT 5%) 1.69 1.04 1.60

Acceptance Criteria: Between 90 to 110 % of Ibuprofen


BLANK GRAPH BY USING HPLC: Using solvent without active drug.

Fig.7: Blank graph by using HPLC

STANDARD GRAPH OF IBUPROFEN BY USING HPLC

Fig.8: Standard HPLC graph of ibuprofen 1, 2, 3, 4, 5.

1 2

3 4

Sample Information

Sample name Blank

Acquired method Ibuprofen


Run time 10.0 min

Vial 1

Injection 1


5

Table 40: RT & area of Ibuprofen standard

Sr.no. Name Sample name Vial Injection RT Area % Area

1 Ibuprofen Standard# 2 2 1 4.248 1111889





Mean 4.2476 1110629

100 %

DETERMINATION OF BLEND UNIFORMITY OF BLEND BY USING

HPLC: Blend Uniformity for Batch A, B, C.

Fig.9: Blend uniformity by HPLC for Batch A, B, C

Batch A: Upper 1 Batch B: Middle 1

Sample Information

Sample name Standard



Run time 10.0 min

Vial 2


Batch C: Lower 1

Table 41: RT & area of Ibuprofen Blend

Sr.no. Sample Name Vial Injection RT Area % Area

1 BU Batch A U1 3 1 4.200 1102356 99.25

2 BU Batch B M1 6 1 4.146 1101849 99.20

3 BU Batch C L1 11 1 4.130 1094568 98.55

Mean 4.158 1099591 99.00

BLEND UNIFORMITY (LUBRICATION)

Fig.10: Comparative Blend uniformity for Batch A, B, C.

Blend Uniformity

85

90

95

100

105

110

115

1 2 3 4 5 6 7 8 9 10 11 12

No. of samples

Con

tent

uni

form

ity (%

)

Min.Batch ABatch BBatch CMax.

Sample Information

Sample name BU



Run time 10.0 min


3.1.4 SLUGGING AND MILLING: Sample taken after sifting

% sample retained test: Batch A.

Table 42: % sample retained test after sifting for Batch A.

S.No. Sieve no. Sample taken (gm) Sample retained (gm) Result %

1 20# 10.0058 0.0486 00.49 %

2 40# 10.0151 0.4010 04.00 %

3 60# 10.0186 1.0117 10.10 %

4 80# 10.0064 1.4887 14.88 %

5 100# 10.0360 1.8058 17.99 %

% sample retained test: Batch B.

Table 43: % sample retained test after sifting for Batch B


1 20# 10.0060 0.0485 00.48 %

2 40# 10.0150 0.402 04.01 %

3 60# 10.0186 1.020 10.18 %

4 80# 10.0060 1.480 14.79 %

5 100# 10.0350 1.790 17.83 %

% sample retained test: Batch C.

Table 44: % sample retained test after sifting for Batch C


1 20# 10.0050 0.0470 00.46 %

2 40# 10.0000 0.3800 03.80 %

3 60# 10.0180 1.0120 10.10 %

4 80# 10.0045 1.4750 14.74 %

5 100# 10.0300 1.8500 18.44 %


Sieve Integrity for Batch A, B, C:

Table 45: Sieve Integrity after sifting

Sieve Integrity Batch no. Sieve used as per BMR

Before Use After Use

A 20#, 40#, 60#, 80#, 100#. OK OK

B 20#, 40#, 60#, 80#, 100#. OK OK

C 20#, 40#, 60#, 80#, 100#. OK OK

Bulk Density for three batches:

Table 46: Results of Bulk Density for three batches of lubricated blend

S.No. Batch No. Weight of

sample(A) gm

Apparent

volume(B) ml

Bulk density

( g/ml)

1 A 10.045 13.0 0.772

2 B 10.066 13.5 0.745

3 C 10.055 13.2 0.761

Tapped Density three batches:

Table 47: Results of Tapped Density for three batches of lubricated blend

S.No Batch No.

Weight of

sample (A)

(gm)

Tapped vol. 10

tap.(ml)

Tapped vol. 500 tap.(ml)

Tapped vol. 1250

tap. (ml)

Final Tapped vol. (ml)

(G)

Tapped density A g/ml.

1 A 10.045 12.0 11.2 11.0 11.0 0.913

2 B 10.066 12.5 11.5 11.2 11.2 0.898

3 C 10.055 12.4 11.3 11.1 11.1 0.905


3.1.5 COMPRESSION:

Physical parameters of compressed tablets at different speeds:

Weight variation: Batch A

Table 48: Weight variation: Batch A

S.No. Parameter 1600

Tab/min

2000

Tab/min

2400

Tab/min

1 638.20 649.47 628.24

2 642.55 644.65 632.25

3 632.00 642.30 628.23

4 640.24 644.64 634.11

5 630.12 648.29 638.36

6 646.22 644.10 635.42

7 635.55 646.50 635.42

8 636.24 646.80 631.24

9 642.02 650.67 638.41

10 628.08 646.39 632.18

11 628.56 646.48 627.01

12 640.35 636.42 634.56

13 638.65 648.25 630.12

14 632.13 650.29 641.01

15 630.47 644.41 625.56

16 635.21 639.30 630.23

17 628.32 647.58 628.32

18 640.56 649.32 629.50

19 635.14 645.40 636.42

20

Weight Variation

640 mg ± 5%

636.86 649.24 635.02

21 Min. 628.08 636.42 625.56

22 Max. 646.22 650.49 641.01

23 Wt. of 20 Tab. 12.71 12.92 12.65

24 Average 635.87 646.02 632.58


Hardness and thickness: Batch A

Table 49: Hardness and thickness for Batch A


Tab/min

2000

Tab/min

2400

Tab/min

1 25.12 24.21 28.02

2 29.13 25.03 26.16

3 26.02 28.32 25.31

4 26.13 28.65 26.14

5 27.00 24.13 24.13

6 24.24 30.11 28.54

7 25.31 23.31 25.78

8 30.12 25.12 24.46

9 26.10 26.10 26.63

10

Hardness

NLT 20 N (2.05 Kg/cm2)

27.06 29.50 32.85

11 Min. 24.24 23.31 24.13

12 Max. 30.12 30.11 32.85

13 Average 26.62 26.44 26.80

1 6.84 6.82 6.85

2 6.84 6.84 6.87

3 6.85 6.88 6.86

4 6.84 6.82 6.84

5 6.86 6.88 6.82

6 6.85 6.84 6.85

7 6.83 6.85 6.84

8 6.85 6.87 6.83

9 6.84 6.85 6.81

10

Thickness

6.70 – 7.10 mm

6.80 6.89 6.87

11 Min. 6.80 6.82 6.81

12 Max. 6.86 6.89 6.87

13 Average 6.84 6.85 6.84


Physical parameter at different speed Batch A: Table 50: Physical parameters at different speeds compressed tablet: Batch A

S.No. Parameter Specification 1600

Tab/min

2000

Tab/min

2400

Tab/min

1 Appearance

White,

biconvex tablet.

Plain on both

the sides.

Complies Complies Complies

2

Weight of 20

tablets

12.8 gm ± 5%

(12.16 gm –

13.44 gm)

12.71 12.92 12.65

3 Average weight

(mg)

640 mg ± 2.5%

(624 to 656 mg)635.87 646.02 632.58

4 Thickness(mm)

(Avg.)

6.70 – 7.10

mm 6.84 6.85 6.84

5 Hardness

(kg/cm2) (Avg.)

NLT 20 N (2.05

Kg/cm2) 26.62 26.44 26.80

6 Friability

(% w/w) NMT 1 % w/w 0.23 0.15 0.16

7 Disintegration

time NMT 15.0 min 1.52 2.20 2.05


Physical parameter at different speed for Batch B:

Weight variation: Batch B

Table 51: Weight variation: Batch B


Tab/min

2000

Tab/min

2400

Tab/min

1 650.12 639.45 638.23

2 644.55 641.38 639.88

3 647.56 639.56 646.41

4 640.24 640.25 639.23

5 649.65 640.39 637.46

6 648.21 638.56 640.42

7 646.47 635.12 639.27

8 648.23 639.38 636.24

9 646.88 640.36 643.22

10 637.45 637.54 640.18

11 649.12 644.00 639.21

12 645.45 638.04 634.01

13 648.42 644.45 638.56

14 639.24 646.56 641.46

15 646.01 647.25 646.40

16 648.45 645.45 640.02

17 638.56 640.46 644.62

18 640.56 645.43 648.45

19 649.42 644.00 639.42

20

Weight Variation

640 mg ± 5%

646.42 643.75 642.23

21 Min. 637.45 635.12 634.01

22 Max. 650.12 647.25 648.45

23 Wt. of 20 Tab. 12.91 12.83 12.81

24 Average 645.55 641.56 640.74


Hardness and thickness: Batch B:

Table 52: Hardness and thickness for Batch B


Tab/min

2000

Tab/min

2400

Tab/min

1 24.22 25.26 24.23

2 24.33 24.23 26.84

3 25.02 28.00 24.66

4 27.12 25.21 29.14

5 27.06 29.15 23.13

6 24.21 30.10 25.54

7 26.31 25.59 25.13

8 24.12 24.12 24.66

9 32.10 29.20 28.23

10

Hardness

NLT 20 N (2.05 Kg/cm2)

26.06 29.45 25.65

11 Min. 24.12 24.12 23.13

12 Max. 32.10 30.10 29.14

13 Average 26.05 27.03 25.72

1 6.79 6.85 6.80

2 6.87 6.83 6.86

3 6.84 6.87 6.87

4 6.82 6.85 6.83

5 6.80 6.82 6.84

6 6.83 6.86 6.84

7 6.85 6.84 6.86

8 6.82 6.86 6.85

9 6.84 6.87 6.86

10

Thickness

6.70–7.10 mm

6.88 6.83 6.84

11 Min. 6.79 6.82 6.80

12 Max. 6.88 6.87 6.87

13 Average 6.83 6.84 6.84


Physical parameters at different speeds compressed tablet Batch B:

Table 53: Physical parameters at different speeds compressed tablet: Batch B


Tab/min

2000

Tab/min

2400

Tab/min

1 Appearance

White, biconvex

tablet. Plain on both

the sides.


2 Weight of 20

tablets

12.8 gm ± 5%

(12.16 gm – 13.44

gm)

12.91 12.83 12.81

3 Average weight 640 mg ± 2.5% (624

to 656 mg) 645.55 641.56 640.74

4 Thickness (mm)

(Avg.) 6.70 – 7.10 mm 6.83 6.84 6.84

5 Hardness

(kg/cm2) (Avg.)

NLT 20 N (2.05

Kg/cm2) 26.05 27.03 25.72

6 Friability

(% w/w) NMT 1 % w/w 0.31 0.23 0.38

7 Disintegration

time NMT 15 min 1.59 2.10 2.16


Physical parameter at different speed for Batch C:

Weight variation: Batch C Table 54: Weight variation: Batch C


Tab/min

2000

Tab/min

2400

Tab/min

1 635.56 649.65 650.45

2 640.55 638.48 644.08

3 631.32 642.60 636.12

4 640.24 642.65 640.05

5 630.65 638.13 638.45

6 640.10 644.21 641.20

7 631.47 649.22 647.21

8 630.21 646.64 646.48

9 642.88 642.45 644.11

10 637.45 648.73 640.70

11 641.42 648.56 646.55

12 635.40 646.85 640.65

13 636.25 648.63 647.44

14 632.28 644.89 648.70

15 641.23 649.10 643.47

16 636.36 639.22 646.20

17 632.56 648.02 647.62

18 634.24 644.25 648.46

19 636.42 646.35 649.56

20

Weight Variation

640 mg ± 5%

632.23 644.23 644.20

21 Min. 630.21 638.13 636.12

22 Max. 642.88 649.65 650.45

23 Wt. of 20 Tab. 12.71 12.90 12.89

24 Average 635.94 645.14 644.58


Hardness and thickness for Batch C:

Table 55: Hardness and thickness for Batch C


Tab/min

2000

Tab/min

2400

Tab/min

1 28.26 24.45 27.10

2 25.13 28.03 26.11

3 27.32 24.21 25.25

4 26.65 26.26 24.24

5 27.13 26.32 26.33

6 25.64 25.01 24.54

7 27.31 26.25 25.38

8 25.12 25.13 24.26

9 23.80 29.35 23.73

10

Hardness

NLT 20 N (2.05 Kg/cm2)

32.56 28.26 28.35

11 Min. 23.80 24.21 23.73

12 Max. 32.56 29.35 28.35

13 Average 26.89 26.32 25.52

1 6.86 6.87 6.85

2 6.88 6.85 6.82

3 6.85 6.88 6.88

4 6.86 6.84 6.87

5 6.81 6.85 6.86

6 6.85 6.85 6.89

7 6.89 6.82 6.84

8 6.84 6.82 6.80

9 6.86 6.88 6.86

10

Thickness

6.70 – 7.10 mm

6.78 6.84 6.80

11 Min. 6.78 6.82 6.80

12 Max. 6.89 6.88 6.89

13 Average 6.84 6.85 6.84


Physical parameter at different speed for Batch C:

Table 56: Physical parameters at different speeds compressed tablet: Batch C


Tab/min

2000

Tab/min

2400

Tab/min

1 Appearance

White, biconvex

tablet. Plain on

both the sides.


2 Weight of 20

tablets

12.8 gm ± 5%

(12.16 gm –

13.44 gm)

12.71 12.90 12.89

3 Average weight 640 mg ± 2.5%

(624 to 656 mg) 635.94 645.14 644.58

4 Thickness (mm)

(Avg.) 6.70 – 7.10 mm 6.84 6.85 6.84

5 Hardness

(kg/cm2) (Avg.)

NLT 20 N (2.05

Kg/cm2) 26.89 26.32 25.52

6 Friability

(% w/w) NMT 1 % w/w 0.32 0.11 0.24

7 Disintegration

time NMT 15.0 min 1.46 1.58 2.15


Physical parameters of tablets at Optimum Speed of 2000 tab/min.: Batch A

Weight variation: Batch A

Table 57: Weight variation at Optimum Speed: Batch A

S.No. Parameter Initial Middle End

1 649.47 641.15 645.60

2 644.65 641.32 646.40

3 642.30 632.30 643.23

4 644.64 641.03 646.30

5 648.29 641.75 635.56

6 644.10 640.36 638.80

7 646.50 640.26 642.32

8 646.80 642.20 639.42

9 650.67 639.52 642.24

10 646.39 636.30 647.25

11 646.48 640.16 639.60

12 636.42 638.05 641.26

13 648.25 633.23 644.42

14 650.29 640.28 638.36

15 644.41 636.13 636.89

16 639.30 633.32 646.42

17 647.58 635.05 645.36

18 649.32 638.23 643.44

19 645.40 640.35 641.43

20

Weight Variation

640 mg ± 5%

649.24 640.18 642.43

21 Min. 636.42 632.30 635.56

22 Max. 650.49 642.20 647.25

23 Wt. of 20 Tab. 12.92 12.77 12.84

24 Average 646.02 638.56 642.33


Hardness and thickness: Batch A

Table 58: Hardness and thickness at Optimum Speed: Batch A


1 24.21 26.55 27.10

2 25.03 26.46 25.13

3 28.32 26.01 28.75

4 28.65 33.16 24.46

5 24.13 28.36 26.36

6 30.11 23.81 26.40

7 23.31 28.23 26.12

8 25.12 24.56 30.47

9 26.10 24.58 26.48

10

Hardness

NLT 20 N (2.05 Kg/cm2)

29.50 28.42 29.56

11 Min. 23.31 23.81 24.46

12 Max. 30.11 33.16 30.47

13 Average 26.44 27.01 27.08

1 6.82 6.78 6.80

2 6.84 6.87 6.84

3 6.88 6.84 6.86

4 6.82 6.79 6.85

5 6.88 6.83 6.84

6 6.84 6.79 6.82

7 6.85 6.75 6.79

8 6.87 6.80 6.83

9 6.85 6.83 6.82

10

Thickness

6.70 – 7.10 mm

6.89 6.81 6.81

11 Min. 6.82 6.75 6.79

12 Max. 6.89 6.87 6.86

13 Average 6.85 6.80 6.82


Physical parameters of tablets at Optimum Speed: Batch A

Table 59: Physical parameters of tablets at Optimum Speed: Batch A

S.No. Parameter Specification Initial Middle End

1 Appearance

White, biconvex


the sides.


2

Weight of 20

tablets

12.8 gm ± 5%

(12.16 gm –

13.44 gm)

12.92 12.77 12.84


to 656 mg) 646.02 638.56 642.33

4 Thickness (mm)

(Avg.) 6.70 – 7.10 mm 6.85 6.80 6.82

5 Hardness

(kg/cm2) (Avg.)

NLT 20 N

(2.05 Kg/cm2) 26.44 27.01 27.08

6 Friability

(% w/w) NMT 1 % w/w 0.38 0.15 0.21

7 Disintegration

time NMT 15.0 min 1.52 2.20 1.45


Physical parameters of tablets at Optimum Speed of 2000 tab/min: Batch B

Weight variation: Batch B

Table 60: Weight variation at Optimum Speed: Batch B


1 639.45 646.06 640.41

2 641.38 635.40 641.23

3 639.56 633.42 640.23

4 640.25 647.35 642.33

5 640.39 641.75 635.50

6 638.56 646.33 637.24

7 635.12 646.23 640.46

8 639.38 644.20 638.36

9 640.36 647.44 640.50

10 637.54 636.30 638.75

11 644.00 645.80 640.23

12 638.04 642.43 641.20

13 644.45 633.85 634.45

14 646.56 640.45 638.36

15 647.25 636.13 637.05

16 645.45 633.32 637.88

17 640.46 630.56 639.36

18 645.43 646.65 635.02

19 644.00 649.46 640.53

20

Weight Variation

640 mg ± 5%

643.75 640.46 638.12

21 Min. 635.12 630.56 634.45

22 Max. 647.25 649.46 642.33

23 Wt. of 20 Tab. 12.83 12.82 12.76

24 Average 641.56 641.17 638.86


Hardness and thickness: Batch B

Table 61: Hardness and thickness at Optimum Speed: Batch B


1 25.26 26.63 28.01

2 24.23 28.81 25.56

3 28.00 28.51 26.20

4 25.21 26.23 24.58

5 29.15 24.52 24.36

6 30.10 26.01 25.12

7 25.59 33.25 25.12

8 24.12 24.05 29.40

9 29.20 27.26 27.56

10

Hardness

NLT 20 N (2.05 Kg/cm2)

29.45 24.05 25.21

11 Min. 24.12 24.05 24.36

12 Max. 30.10 33.25 29.40

13 Average 27.03 26.93 26.11

1 6.85 6.84 6.83

2 6.83 6.81 6.81

3 6.87 6.84 6.86

4 6.85 6.89 6.79

5 6.82 6.86 6.82

6 6.86 6.84 6.83

7 6.84 6.86 6.80

8 6.86 6.87 6.84

9 6.87 6.86 6.83

10

Thickness

6.70 – 7.10 mm

6.83 6.89 6.82

11 Min. 6.84 6.81 6.82

12 Max. 6.89 6.89 6.86

13 Average 6.84 6.85 6.82


Physical parameters of tablets at Optimum Speed: Batch B

Table 62: Physical parameters of tablets at Optimum Speed: Batch B


1 Appearance

White, biconvex


the sides.


2 Weight of 20

tablets

12.8 gm ± 5% (12.16

gm – 13.44 gm) 12.83 12.82

12.76


to 656 mg) 641.56

641.17

638.86

4 Thickness (mm)

(Avg.) 6.70 – 7.10 mm 6.84 6.85 6.82

5 Hardness

(kg/cm2) (Avg.)

NLT 20 N

(2.05 Kg/cm2) 27.03 26.93 26.11

6 Friability

(% w/w) NMT 1 % w/w 0.39 0.23 0.47

7 Disintegration

time NMT 15.0 min 1.45 2.19 1.58


Physical parameters of tablets at Optimum Speed 2000 tab/min: Batch C

Weight variation: Batch C

Table 63: Weight variation at Optimum Speed: Batch C


1 649.65 648.52 644.60

2 638.48 647.40 646.40

3 642.60 648.49 641.23

4 642.65 648.55 646.30

5 638.13 649.65 635.56

6 644.21 647.10 634.20

7 649.22 646.23 640.45

8 646.64 649.47 640.23

9 642.45 647.44 640.46

10 648.73 643.23 649.25

11 648.56 645.28 639.12

12 646.85 648.56 644.23

13 648.63 649.71 644.22

14 644.89 650.25 638.27

15 649.10 649.58 636.11

16 639.22 647.18 646.42

17 648.02 648.60 644.12

18 644.25 646.65 643.41

19 646.35 649.58 640.59

20

Weight Variation

640 mg ± 5%

644.23 649.12 640.43

21 Min. 638.13 643.23 634.20

22 Max. 649.65 650.25 649.25

23 Wt. of 20 Tab. 12.90 12.96 12.83

24 Average 645.14 648.02 641.78


Hardness and thickness: Batch C

Table 64: Hardness and thickness at Optimum Speed: Batch C


1 24.45 28.25 27.12

2 28.03 27.54 27.16

3 24.21 28.40 25.43

4 26.26 29.54 24.03

5 26.32 28.47 26.30

6 25.01 26.57 26.45

7 26.25 30.71 27.38

8 25.13 28.32 28.26

9 29.35 24.21 31.34

10

Hardness

NLT 20 N (2.05 Kg/cm2)

28.26 28.13 28.32

11 Min. 24.21 24.21 24.03

12 Max. 29.35 30.71 31.34

13 Average 26.32 28.01 27.17

1 6.87 6.84 6.82

2 6.85 6.83 6.86

3 6.88 6.84 6.88

4 6.84 6.89 6.87

5 6.85 6.86 6.86

6 6.85 6.86 6.80

7 6.82 6.86 6.84

8 6.82 6.87 6.85

9 6.88 6.86 6.86

10

Thickness

6.70 – 7.10 mm

6.84 6.89 6.83

11 Min. 6.82 6.83 6.80

12 Max. 6.88 6.89 6.88

13 Average 6.85 6.86 6.84


Physical parameters of tablets at Optimum Speed: Batch C

Table 65: Physical parameters of tablets at Optimum Speed: Batch C


1 Appearance

White, biconvex


the sides.


2

Weight of 20

tablets

12.8 gm ± 5%

(12.16 gm – 13.44

gm)

12.90 12.96 12.83


to 656 mg) 645.14

648.02

641.78

4 Thickness (mm)

(Avg.) 6.70 – 7.10 mm 6.85 6.86 6.84

5 Hardness

(kg/cm2) (Avg.)

NLT 20 N (2.05

Kg/cm2) 26.32 28.01 27.17

6 Friability (%

w/w) NMT 1 % w/w 0.16 0.36 0.25

7 Disintegration

time NMT 15.0 min 1.55 1.46 1.40


Assay of compressed Ibuprofen tablets at different time cycle during

compression: Batch A

Table 66: Assay of compressed tablet: Batch A

S.No. Initial Middle End

1 97.50 99.35 98.32

2 98.02 98.23 97.80

3 98.45 99.08 97.86

4 97.54 100.12 98.22

5 99.23 97.45 98.03

6 98.88 98.23 100.02

7 99.75 97.56 99.13

8 100.12 101.01 97.08

9 99.03 97.86 98.46

10 97.12 98.06 99.21

Min. 97.12 97.45 97.08

Max. 100.12 101.01 100.02

Average 98.56 98.69 98.41

RSD

NMT 4 % 1.01 1.17 0.84

Acceptance criteria: Between 95.0 to 105.0 % of labeled amount.

A) GRAPH OF IBUPROFEN CORE TABLET BY USING HPLC: Batch A

Fig.11: HPLC graph of ibuprofen core tablet: Batch A

Initial Middle


End Table 67: RT & area of Ibuprofen Batch A

S.No. Name Vial Injection RT Area % Area

1 Ibuprofen Core Initial 3 1 4.111 1098564 98.91

2 Ibuprofen Core Middle 3 1 4.225 1106523 99.63

3 Ibuprofen Core End 3 1 4.139 1101485 99.17

Mean 4.158 1102191 99.23

ASSAY OF COMPRESSED TABLET: Batch A

Fig.12: Comparative Assay of compressed tablet: Batch A

Assay of compressed tablet

90

95

100

105

110

1 2 3 4 5 6 7 8 9 10

No. of Tablets

Ass

ay (%

)


Sample Information

Sample name Core Assay



Run time 10.0 min


Assay of compressed tablet: Batch B

Table 68: Assay of compressed tablet: Batch B


1 99.90 100.26 99.19

2 99.05 97.82 98.23

3 101.03 99.88 97.02

4 98.13 100.01 100.20

5 101.14 98.05 99.56

6 98.23 101.05 100.24

7 98.84 99.13 99.25

8 100.01 97.41 101.14

9 99.23 97.98 98.65

10 97.56 99.42 99.88

Min. 97.56 97.41 97.02

Max. 101.14 101.05 101.14

Average 99.31 99.10 99.33

RSD

NMT 4 % 1.20 1.22 1.16


B) GRAPH OF IBUPROFEN BY USING HPLC: Batch B:

Fig.13: HPLC graph of ibuprofen core tablet: Batch B

Initial Middle


End

Table 69: RT & area of Ibuprofen Batch B





Mean 4.247 1114382 100.09

ASSAY OF COMPRESSED TABLET: Batch B

Fig.14: Comparative Assay of compressed tablet: Batch B


90

95

100

105

110

1 2 3 4 5 6 7 8 9 10

No. of Tablets

Ass

ay (%

)


Sample Information




Run time 10.0 min


Assay of compressed tablet: Batch C

Table 70: Assay of compressed tablet: Batch C


1 99.75 100.04 99.23

2 98.23 97.02 99.02

3 100.05 98.56 98.01

4 97.00 97.85 101.45

5 99.23 100.32 99.36

6 98.98 100.01 99.54

7 99.65 98.23 98.46

8 100.32 101.00 97.21

9 100.56 99.01 97.26

10 97.61 98.65 98.12

Min. 97.00 97.02 97.21

Max. 100.56 101.00 101.45

Average 99.13 99.06 98.76

RSD

NMT 4 % 1.18 1.24 1.25


C) GRAPH OF IBUPROFEN BY USING HPLC: Batch C

Fig.15: HPLC graph of ibuprofen core tablet: Batch C

Initial Middle


End

Table 71: RT & area of Ibuprofen Batch C





Mean 4.246 1113664 100.27

ASSAY OF COMPRESSED TABLET:Batch C

Fig.16: Comparative Assay of compressed tablet: Batch C


90

95

100

105

110

1 2 3 4 5 6 7 8 9 10

No. of Tablets

Ass

ay (%

)


Sample Information




Run time 10.0 min


3.1.6 COATING: Physical parameters.

Weight variation: Batch A, Batch B, Batch C.

Table 72: Weight variation for: Batch A, B, C.

S.No. Parameter Batch A Batch B Batch C

1 819.80 815.32 820.34

2 822.42 818.43 819.56

3 826.54 816.23 819.24

4 819.89 817.18 817.46

5 829.25 820.02 816.26

6 828.50 813.50 816.48

7 827.31 819.25 821.58

8 826.01 817.02 817.26

9 827.45 816.52 819.58

10 820.16 815.02 820.53

11 827.51 814.46 816.94

12 828.21 814.15 823.54

13 824.33 817.65 817.41

14 826.14 816.57 816.56

15 825.37 817.23 818.49

16 828.10 816.08 818.65

17 824.13 817.11 815.80

18 827.21 816.35 816.35

19 826.48 815.41 818.56

20

Weight Variation

820 mg ± 2.5%

(799.50 mg to 840.50 mg)

827.45 814.37 817.56

21 Min. 819.80 813.50 815.80

22 Max. 829.25 820.02 823.54

23 Wt. of 20 Tab. 16.51 16.32 16.36

24 Average 825.61 816.39 818.40


Thickness and diameter for coated tablets: Batch A, B, C.

Table 73: Thickness and diameter for coated tablets: Batch A, B, C.

S.No. Parameter Batch A Batch B Batch C

1 7.51 7.41 7.47

2 7.48 7.46 7.46

3 7.49 7.40 7.43

4 7.47 7.47 7.47

5 7.44 7.50 7.45

6 7.47 7.42 7.44

7 7.49 7.44 7.45

8 7.48 7.41 7.44

9 7.51 7.43 7.48

10

Thickness

7.20 – 8.0 mm

7.46 7.47 7.46

11 Min. 7.44 7.40 7.43

12 Max. 7.51 7.50 7.48

13 Average 7.48 7.44 7.45

1 13.48 13.49 13.58

2 13.60 13.52 13.54

3 13.59 13.51 13.53

4 13.57 13.57 13.56

5 13.55 13.56 13.54

6 13.54 13.54 13.50

7 13.59 13.57 13.55

8 13.54 13.54 13.52

9 13.58 13.55 13.54

10

Diameter

13.20 – 14.80 mm

13.57 13.51 13.59

11 Min. 13.48 13.49 13.50

12 Max. 13.60 13.57 13.59

13 Average 13.56 13.53 13.54


Percentage weight gain of coated tablet for: Batch A, B, C.

Table 74: Percentage weight gain After Coating

Percentage weight gain

After Coating I After Coating II S.No. Batch No.

Limit Actual Limit Actual

1 A 1.81 % 28.89 %

2 B 1.80 % 27.61 %

3 C

1.6 – 2.0 %

1.81 %

24.92 – 31.32 %

27.40 %

Physical coating parameters at optimum speed: For Batch A, B, C.

Table 75: Physical coating parameters for three batches

S.No. Parameter Specification Batch A Batch B Batch C

1 Appearance

White, round

biconvex, Sugar

Coated Tablet.


2

Weight of 20

tablets

16.40 gm ± 5%

(15.58 gm – 17.22

gm)

16.51 16.32

16.36

3 Average Weight

820 mg ± 2.5%

(799.50 mg to

840.50 mg)

825.61

816.39

818.40

4 Thickness (mm)

(Avg.) 7.20 – 8.0 mm 7.48 7.44 7.45

5 Diameter (mm)

(Avg.) 13.20 – 14.80 mm 13.56 13.53 13.54

6 Disintegration

time NMT 30 min 11.46 13.23 13.45

7

Related substances

(Complies with

B.P.)

Individual

Impurity: max .3%

Total impurity:

max 0.7%



Assay of coated tablets for: Batch A, B, C

Table 76: Assay of coated tablets: Batch A, B, C.

S.No. Batch A Batch B Batch C

1 98.34 99.56 99.53

2 98.55 97.02 99.02

3 100.12 98.33 98.54

4 97.45 97.00 101.12

5 99.13 97.88 99.07

6 98.42 100.23 99.65

7 99.36 98.12 97.68

8 97.03 101.30 97.85

9 100.33 99.01 97.80

10 97.52 98.24 98.13

Min. 97.03 97.00 97.68

Max. 100.33 101.30 101.12

Average 98.62 98.66 98.83

RSD

NMT 4 % 1.11 1.37 1.07


GRAPH OF IBUPROFEN COATED TABLETS BY USING HPLC

Fig.17: HPLC graph of ibuprofen coated tablet: Batch A, B, C.

Batch: A Batch: B


Batch: C

Table 77: RT & area of coated tablets

Sr.no. Name Vial Injection RT Area % Area

1 Ibuprofen coated Batch A 3 1 4.237 1109893 99.93

2 Ibuprofen coated Batch B 3 1 4.225 1106496 99.62

3 Ibuprofen coated Batch C 3 1 4.253 1110868 100.02

Mean 4.238 1111419 99.85

ASSAY OF COATED TABLET: Batch A, B, C.

Fig.18: Comparative Assay of coated tablet: Batch A, B, C


90

95

100

105

110

1 2 3 4 5 6 7 8 9 10

No. of Tablets

Ass

ay (%

)


Sample Information

Sample name Coated Assay



Run time 10.0 min


AQL (Acceptable quality limit) for finished product analysis.

Checklist for Product Inspection for Physical Defects of Coated Tablets

Table 78: AQL (Acceptable quality limit) for finished product analysis

Inspection No. 01 Total Sample Qty.:1250

S.No. Critical

No. of

units

observed

Major

No. of

units

observed

Minor

No .of

units

observed

1 Wrong

product 00

Partially

coated tablets 02

Adhering

surface

spots, dye

spots

04

2

Presence of

more than

one product

(mix-up)

00

Coating is not

uniform in

colour

(Mottling)

00 Picking 00

3 Wrong

embossing 00

Broken

Tablets 02 Chips 03

4

Change of

color, shade

variation

00 Crack / porous

surface 03

Rough

surface 04

Critical

(AQL:

0.015%)

Major

(AQL:

0.65%)

Minor

(AQL:

2.5%)

Batch size /

Lot size

Sample

size code

Sample

size

Acceptance Acceptance Acceptance

35001 to

150000 Nos. N 500 Nos. 0 Nos. 7 Nos. 21 Nos.

150001 to

500000 Nos. P 800 Nos. 0 Nos. 10 Nos. 21 Nos.

500001 to

and over Q

1250

Nos. 0 Nos. 14 Nos. 21 Nos.


5

Presence of

foreign

matter

00

Embedded

surface spots

or

contamination

00 Poor

embossing 00

6 Embedded

particle 00 Capping 00 Others 00

7 Others 00 Film pilling

off 00 ---

8 --- Foreign odor 00 ---

9 --- Twin tablets 00 ---

10 --- Coating

eruption 00 ---

11 --- Others 00 ---

Total units 00 Total units 07 Total

units 11

AQL:0.015

%

Pass/Fail

AQL:0.65 %

Pass/Fail

AQL:2.5

%

Pass

/Fail

BATCH STATUS: COMPLIES / DOES NOT COMPLIES


3.1.7 PACKAGING OPERATION

Blister packing:

Observation: No leakage observed.

Observed parameters for blister packing

Table 79: Parameters for blister packing

S.No. Parameters Batch A Batch B Batch C

1 Pack size (8 tablets) Complies Complies Complies

2 Physical evaluation Complies Complies Complies

3 Blister forming

Temperature 150 °C 150 °C 150 °C

4 Sealing temperature 180 °C 180 °C 180 °C

5 Leak test Complies Complies Complies

6 Speeds studied 90 cuts/min. 90 cuts/min. 90 cuts/min.


3.2 DISCUSSION:

The process validation was carried out for the batch size 3.12 Lac, which include the

validation of critical steps of manufacturing. Such as dry mixing, blending,

compression, coating and blister packing.

Sifting Stage: Sifting of API and inactive material was carried out as specified

in BMR for all the three batches. Sifting of batches carried by using 20#

stainless steel sieve.

Blending (pre lubrication): The blending was carried out by using Double

cone blender (DCB) for 15 min as per specified in Batch Manufacturing

Record (BMR), the value of bulk density and tapped density, appearance

complying with the specification.

Blending (Lubrication) : The lubricating blending was carried out by using

Double cone blender (DCB) for 03 min as per BMR, the samples for blend

uniformity were withdrawn and found that the content uniformity was well

within the limit of 90 – 110 % and the above values were in the range. The

RSD values were found to be well within the limit of NMT 5 %. The RSD

values of three batches were found to be 1.69, 1.04 and 1.60 % which were

well within the acceptable limit of NMT 5 %.

Slugging: The slugging of blended powder was carried out by using Roll

compactor for all three batches. After slugging the slugs were milled by using

multimill with speed of 1500 RPM using sieve of 2.5 mm. further the milled

slugs were passed through 20#, 40#, 60#, 80#, 1003 sieves for uniform granule

size using sifter.

Compression: The compression was carried out as per BMR by using

compression machine Cadpress 37 for all the bathes, the samples were


collected as per protocol during compression. These samples were analyzed

for physical and chemical parameters as per protocol and found that all the

physical parameters and chemical parameters of tablet were well within the

limit i.e. content uniformity 95 – 105 % and RSD NMT 4%, weight of 20

tablets 12.8 gm ± 5% (12.16 – 13.44 gm), average weight 640 ± mg 2.5 %,

thickness 6.70 – 7.10 mm, hardness NLT 20 N (2.05 kg/cm2), friability NMT

1% w/w, disintegration NMT 15 min. and all above values were within the

limit only.

The compression was carried out at different speeds of machine 1600, 2000 and 2400

tablets/minute. The samples were collected at different speeds analyzed for all

physical parameters and found that all parameters were within the limit.

The samples were collected at initial, middle, near end, at optimum speed of 2000

tab/min and found that all parameters were within the limit.

The samples tested for content uniformity, RSD and it was found that the content

uniformity is well within the limit of 95 – 105 % and RSD NMT 4% respectively.

Coating: The coating was carried out as per BMR by using Sejong coater and

also the coating parameters were mounted for three batches. One pooled

sample from each batch of Ibuprofen 400 mg tablet was collected after

completion of coating and analyzed as per finished product specifications and

found that the following were well within the limit i.e. inlet temperature 60 to

70 °C, exhaust temperature 45 to 55 °C, pan speed 6 RPM, atomization speed

pressure 3 to 5 kg/cm², spray rate 40 to 50 gm/gun/min, gun distance 20 to 24

cm. The weight buildup 24.92 – 31.32 % (160 to 190 mg) for the three bathes

respectively and which was found to be within limit.


Blister packing: The blister packing of tablets was carried out as per BPR and

found that following were well within the limit i.e. blister forming roller

temperature 140 to 160 °C, sealing roller temperature 175 to 180 °C and

machine speed 70 to 100 cuts/min. Leak test is performed and it was found

that the quality of sealing was satisfactory. Over printing details and blister

appearance were also found to be satisfactory in the final blister pack.


4.1 CONCLUSION:

Blending (prelubrication): In order to fix the satisfactory blending time,

samples were collected from the container and were analyzed. From the result

obtained it was concluded that the mixing time of 15 min was found to be

satisfactory which meets the predetermined specification and quality

attributes.

Blending (lubrication): In order to fix the satisfactory blending time, samples

were collected in DCB from the predetermined location at i.e. 12 point

location at speed of 24 RPM after 3 min. and were analyzed. After evaluating

the data it was concluded that blending of contents in double cone blender for

3 min after pre lubrication (15 min) and it was found to be satisfactory which

meets the predetermined specification and quality attributes.

Compression: In order to get satisfactory physical parameters of tablet during

compression. Samples were collected at different speeds of machine 1600

tab/min., 2000 tab/min, and 2400 tab/min. Also at initial, middle and end

sample at optimum speed of 2000 tab/min. After evaluating the data it was

concluded that compression of tablets at 2000 tab/min and was found to be


attributes.

Coating: In order to optimize coating parameters samples were collected and

tested for weight build up. From the result it was concluded that the coating at

pan speed of 6 RPM, spray rate 45 gm/gun/min and atomization pressure 3-5

kg/cm² was found to be satisfactory to get optimum weight build up and also

to meet the predetermined specification and quality attributes.


Blister packing : The blister packing of tablets, at blister forming roller

temperature 150 °C and sealing roller temperature 180 °C was found to be


attributes.

The project entitled “Process validation of oral non steroidal anti-inflammatory drug:

Ibuprofen 400 mg tablet” was carried out at Wockhardt Pharmaceutical Ltd.,

Aurangabad, Maharashtra. The study involves validating the process variables of this

product to show that the process was under control. The study was conducted on a

batch size of 3.12 Lac, which includes the validation of critical steps of manufacturing

such as dry mixing, blending, compression, coating and blister packing.

Overall manufacturing process and packing process was concluded as

validated at the parameters mentioned above as per BMR and BPR. The process

validation data of Ibuprofen tablets reveals that there was no significant variation

between batch to batch and all the process variables were studied. Therefore it can be

concluded that the process of Ibuprofen tablet for the batch size 3.12 Lac stands

Validated.


4.2 SUMMARY:

The process validation of pharmaceutical dosage form is one of the most important

regulatory requirements for pharmaceutical industry and main job of quality

assurance. Which shows the documented evidence about the quality of product by

validating the whole manufacturing process, because single critical parameter of the

process like speed of machine, time, weight etc. may affect the quality of product and

dangerous for life, so by using this concept the process validation of Ibuprofen 400

mg tablet is done, which is a non steroidal anti-inflammatory drug. For this purpose

before starting the process validation, validation team, protocol for validation and

documents are prepared then forwarded for further study.

Chapter I provide the introduction to Quality Assurance, validation, process

validation, regulatory requirements, their significance and applications, types and

elements of validation, requirements. Further chapter discusses about the review of

literatures, aim and objective, experimental plan. Then the pharmaceutical

information of the drug and additives.

Chapter II discuss in details about the materials and method required for the process

validation of Ibuprofen 400 mg tablet. Materials involves the detail information about

the quantity of each an every ingredient, details of equipments, process flow chart i.e.

how to follow the process, critical process parameters of each step, checklists for

equipments. Method involves about brief procedure about sifting, blending, slugging,

compression, coating, packing. Then the sampling, testing plan and their acceptance

criteria for each step, formulas, sampling diagrams, HPLC procedure and

requirements.


Chapter III describes the result and discussion of the thesis work. The results show

that the manufacturing process parameters of Ibuprofen 400 mg tablet complying with

the all standard parameters. The results were found well within the limits.

The physical parameters like appearance, bulk density, tapped density, % retained

powder after sifting, sieve integrity before and after use was studied for three batches

and found within the limit. The blend uniformity i.e. the uniform distribution of drug

after blending of three batches found in limit of 100 ± 10% and also RSD is NMT 5%.

The drug content was evaluated by HPLC method, where the graph shows RT of

ibuprofen blend in range of 4.130 to 4.200 and also area under curve is comparable

with standard Ibuprofen area.

The compression and coating physical parameters for three batches like weight

variation, average weight, hardness and thickness, disintegration time etc. found well

within the limits for that purpose all the three batches were evaluated carefully. Also

the analytical parameters like assay of core and coated tablet of three batches found in

limit of 100 ± 5% and RSD NMT 4 % of labeled amount of Ibuprofen, which is also

evaluated by using HPLC method. At the end of coating finished product analysis is

done by using AQL also found within the limit for three batches. Then the blister

packing operation and their parameters also found in limits, for that purpose leak test

was performed.

So after studying all parameters it was found that, all processing parameters and steps

are meeting the predetermined standard values, all found to complying with the

specifications and comparable with each other.

Chapter IV describes the brief summary and conclusion.

Last part of thesis provides the bibliography.


4.3 BIBLIOGRAPHY:

1. WHO good manufacturing practices: water for pharmaceutical use. In: WHO

Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-ninth

report. Geneva, World Health Organization 2005; (WHO Technical Report Series,

No. 929), 3: 16–17.

2. Good Manufacturing Practices for pharmaceutical products: main principles. In:

WHO Expert Committee on Specifications for Pharmaceutical Preparations.

Thirty-seventh report. Geneva, World Health Organization, 2003; (WHO

Technical Report Series, No. 908) 4: 113–139.

3. A WHO guide to good manufacturing practice (GMP) requirements. Part 2:

Validation. Geneva, Global Programme for Vaccines and Immunization, Vaccine

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