Handbook of Pharmaceutical Manufacturing Formulations, Third Edition: Volume Three, Liquid Products Sarfaraz K. Niazi (Author)

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Manufacturing Formulations
Volume Three, Liquid Products
Manufacturing Formulations,
Third Edition
Volume Three, Liquid Products
Sarfaraz K. Niazi
CRC Press
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To August P. Lemberger
Dean August P. Lemberger passed away in 2010; he gave me my first teaching job at the University
of Illinois when I was still working on my thesis. He served as the dean at Illinois and Wisconsin.
Contents
Preface to the Series—Third Edition......................................................................................................................................... xxv
Preface to the Series—Second Edition....................................................................................................................................xxvii
Preface to the Series—First Edition.........................................................................................................................................xxxi
Preface to the Volume—First Edition................................................................................................................................... xxxiii
Author...................................................................................................................................................................................... xxxv
PART I Regulatory and Manufacturing Guidance
Chapter 1 Manufacturing Considerations in Liquid Formulations........................................................................................... 3

I. Introduction................................................................................................................................................... 3
II. Facilities........................................................................................................................................................ 3
III. Equipment...................................................................................................................................................... 4
IV. Raw Materials................................................................................................................................................ 4
V. Compounding................................................................................................................................................ 5
VI. Microbiological Quality................................................................................................................................ 5
VII. Oral Suspensions........................................................................................................................................... 6
VIII. Product Specifications................................................................................................................................... 6
IX. Process Validation......................................................................................................................................... 6
X. Stability......................................................................................................................................................... 6
XI. Packaging...................................................................................................................................................... 6
Chapter 2 Oral Solutions and Suspensions............................................................................................................................... 9

I. Introduction................................................................................................................................................... 9
II. Facilities........................................................................................................................................................ 9
III. Equipment...................................................................................................................................................... 9
IV. Raw Materials................................................................................................................................................ 9
V. Compounding................................................................................................................................................ 9
VI. Microbiological Quality.............................................................................................................................. 10
VII. Oral Suspension Uniformity........................................................................................................................ 10
VIII. Product Specifications................................................................................................................................. 10
IX. Process Validation....................................................................................................................................... 10
X. Stability....................................................................................................................................................... 11
XI. Packaging.................................................................................................................................................... 11
Chapter 3 The FDA Drug Product Surveillance Program...................................................................................................... 13

I. Background.................................................................................................................................................. 13
II. Implementation............................................................................................................................................ 13
A. Objectives............................................................................................................................................ 13
B. Strategy................................................................................................................................................ 13
1. Biennial Inspection of Manufacturing Sites................................................................................. 13
2. Inspection of Systems................................................................................................................... 14
3. A Scheme of Systems for the Manufacture of Drugs and Drug Products.................................... 14
III. Program Management Instructions............................................................................................................. 15
A. Definitions........................................................................................................................................... 15
1. Surveillance Inspections............................................................................................................... 15
2. Compliance Inspections................................................................................................................ 15
3. State of Control............................................................................................................................. 15
vii
viii Contents
4. Drug Process................................................................................................................................. 16
5. Drug Manufacturing Inspection................................................................................................... 16
B. Inspection Planning............................................................................................................................. 16
C. Profiles................................................................................................................................................. 16
IV. Inspectional Observations........................................................................................................................... 16
A. Investigational Operations................................................................................................................... 16
1. General�� 16
2. Inspection Approaches�� 17
3. System Inspection Coverage�� 17
4. Sampling�� 20
5. Inspection Teams�� 20
6. Reporting�� 20
V. Analytical Observations.............................................................................................................................. 21
A. Analyzing Laboratories....................................................................................................................... 21
B. Analysis............................................................................................................................................... 21
VI. Regulatory/Administrative Strategy............................................................................................................ 21
Chapter 4 Changes to Approved NDAs and aNDAs.............................................................................................................. 23

I. Introduction................................................................................................................................................. 23
II. Reporting Categories................................................................................................................................... 23
III. General Requirements................................................................................................................................. 23
IV. Assessing the Effect of Manufacturing Changes........................................................................................ 24
A. Assessment of the Effects of the Change............................................................................................ 24
1. Conformance to Specifications..................................................................................................... 24
2. Additional Testing......................................................................................................................... 24
B. Equivalence......................................................................................................................................... 24
C. Adverse Effect..................................................................................................................................... 25
V. Components and Composition..................................................................................................................... 25
VI. Manufacturing Sites.................................................................................................................................... 25
A. General Considerations....................................................................................................................... 25
B. Major Changes (Prior Approval Supplement)..................................................................................... 25
C. Moderate Changes (Supplement—Changes Being Effected)�� 26
D. Minor Changes (Annual Report)......................................................................................................... 26
VII. Manufacturing Process................................................................................................................................ 26
C. Moderate Changes (Supplement—Changes Being Effected)............................................................. 27
VIII. Specifications............................................................................................................................................... 28
IX. Package........................................................................................................................................................ 30
X. Labeling....................................................................................................................................................... 31
Contents ix
XI. Miscellaneous Changes............................................................................................................................... 32

A. Major Changes (Prior Approval Supplement)..................................................................................... 32
B. Moderate Changes (Supplement—Changes Being Effected)............................................................. 32
C. Minor Changes (Annual Report).......................................................................................................... 32
XII. Multiple Related Changes......................................................................................................................... 33
Glossary.................................................................................................................................................................. 34
Chapter 5 Formulation Considerations of Liquid Products.................................................................................................... 35

I. Solubility................................................................................................................................................... 35
II. Chemical Modification.............................................................................................................................. 35
III. Preservation............................................................................................................................................... 35
IV. Sweetening Agents.................................................................................................................................... 36
V. Flavors....................................................................................................................................................... 36
VI. Viscosity.................................................................................................................................................... 36
VII. Appearance................................................................................................................................................ 36
VIII. Chemical Stability..................................................................................................................................... 36
IX. Physical Stability....................................................................................................................................... 36
X. Raw Material............................................................................................................................................. 36
XI. Manufacturing Equipment........................................................................................................................ 37
XII. Manufacturing Directions......................................................................................................................... 37
XIII. Packaging.................................................................................................................................................. 37
XIV. Particle Size and Shape............................................................................................................................. 37
XV. Suspensions............................................................................................................................................... 38
XVI. Emulsions.................................................................................................................................................. 38
Emulsions.................................................................................................................................................. 38
XVII. Powder for Reconstitution......................................................................................................................... 40
XVIII. Nasal Spray Products................................................................................................................................. 40
A. Inhalation Solutions and Suspensions............................................................................................... 41
B. Inhalation Sprays............................................................................................................................... 41
C. Pump Delivery of Nasal Products..................................................................................................... 41
D. Spray Content Uniformity for Nasal Products.................................................................................. 42
E. Spray Pattern and Plume Geometry of Nasal Products..................................................................... 42
F. Droplet-Size Distribution in Nasal Products...................................................................................... 42
G. Particle-Size Distribution for Nasal Suspensions.............................................................................. 43
XIX. Emulsification and Solubilization.............................................................................................................. 43
XX. Complexing............................................................................................................................................... 43
XXI. Hydrophilization........................................................................................................................................ 43
XXII. Stabilizing Suspensions............................................................................................................................. 43
Chapter 6 Container Closure Systems.................................................................................................................................... 45

I. Introduction............................................................................................................................................... 45
A. Definitions......................................................................................................................................... 45
B. Current Good Manufacturing Practice, the Consumer Product Safety Commission, and
Requirements on Containers and Closures�� 45
C. Additional Considerations................................................................................................................. 45
II. Qualification and Quality Control of Packaging Components.................................................................. 46
A. Description........................................................................................................................................ 49
B. Information about Suitability............................................................................................................ 49
C. Stability Data (Packaging Concerns)................................................................................................ 50
D. Inhalation Drug Products.................................................................................................................. 50
E. Injection and Ophthalmic Drug Products.......................................................................................... 50
F. Liquid-Based Oral and Topical Drug Products and Topical Delivery Systems................................ 51
x Contents
G. Solid Oral Dosage Forms and Powders for Reconstitution............................................................... 52

1. Polyethylene Containers (USP <661>)...................................................................................... 53
2. Single-Unit Containers and Unit-Dose Containers for Capsules and Tablets (USP <671>)..............53
3. Multiple-Unit Containers for Capsules and Tablets (USP <671>)............................................. 53
H. Other Dosage Forms......................................................................................................................... 53
III. Postapproval Packaging Changes.................................................................................................................. 53
IV. Type III Drug Master Files............................................................................................................................ 54
V. Bulk Containers............................................................................................................................................. 54
Bibliography........................................................................................................................................................... 55
Chapter 7 Material for Containers.......................................................................................................................................... 57

I. Glass Containers.......................................................................................................................................... 57
II. Nonplasticized Poly(Vinyl Chloride) for Containers for Noninjectable Aqueous Solutions...................... 58
III. Polyethylene Terephthalate for Containers for Preparations Not for Parenteral Use.................................. 58
IV. Nonplasticized Poly(Vinyl Chloride) for Containers for Dry Dosage Forms for Oral Administration...... 58
V. Plasticized Poly(Vinyl Chloride) for Containers for Aqueous Solutions for Intravenous Infusion............. 58
VI. Polyethylene Terephthalate for Containers for Preparations Not for Parenteral Use.................................. 58
VII. Polyolefins................................................................................................................................................... 58
VIII. Polyethylene with Additives for Containers for Parenteral Preparations and for Ophthalmic
Preparations................................................................................................................................................. 59
IX. Polypropylene for Containers and Closures for Parenteral Preparations and
Ophthalmic Preparations............................................................................................................................. 60
X. Poly(Ethylene/Vinyl Acetate) for Containers and Tubing for Total Parenteral Nutrition Preparations.............60
XI. Plastic Containers for Aqueous Solutions for Infusion............................................................................... 61
XII. Sterile Single-Use Plastic Syringes............................................................................................................. 61
XIII. Rubber Closures for Containers for Aqueous Parenteral Preparations, for Powders, and for
Freeze-Dried Powders................................................................................................................................. 62
XIV. Silicone Oil Used as a Lubricant................................................................................................................. 62
XV. Silicone Elastomer for Closures and Tubing............................................................................................... 62
Chapter 8 Stability Testing of New Drug Substances and Products....................................................................................... 63

I. Introduction..................................................................................................................................................... 63
A. Objectives of the Guideline.................................................................................................................... 63
B. Scope of the Guideline............................................................................................................................ 63
C. General Principles................................................................................................................................... 63
II. Guidelines....................................................................................................................................................... 63
A. Drug Substance....................................................................................................................................... 63
1. General�� 63
2. Stress Testing................................................................................................................................. 63
3. Selection of Batches....................................................................................................................... 63
4. Container Closure System.............................................................................................................. 64
5. Specification................................................................................................................................... 64
6. Testing Frequency.......................................................................................................................... 64
7. Storage Conditions......................................................................................................................... 64
8. Stability Commitment.................................................................................................................... 65
9. Evaluation�� 65
10. Statements/Labeling....................................................................................................................... 65
B. Drug Product........................................................................................................................................... 66
1. General�� 66
2. Photostability Testing..................................................................................................................... 66
3. Selection of Batches....................................................................................................................... 66
4. Container Closure System.............................................................................................................. 66
5. Specification................................................................................................................................... 66
6. Testing Frequency.......................................................................................................................... 66
7. Storage Conditions......................................................................................................................... 66
Contents xi
8. Stability Commitment.................................................................................................................... 68

9. Evaluation�� 69
10. Statements/Labeling....................................................................................................................... 69
Glossary.................................................................................................................................................................. 69
Bibliography........................................................................................................................................................... 71
Chapter 9 Stability Testing: Photostability Testing of New Drug Substances and Products.................................................. 73
I. General............................................................................................................................................................ 73
A. Preamble................................................................................................................................................. 73
B. Light Sources.......................................................................................................................................... 73
C. Procedure................................................................................................................................................ 73
II. Drug Substance............................................................................................................................................... 74
A. Presentation of Samples.......................................................................................................................... 75
B. Analysis of Samples................................................................................................................................ 75
C. Judgement of Results.............................................................................................................................. 75
III. Drug Product.................................................................................................................................................. 75
A. Presentation of Samples.......................................................................................................................... 75
B. Analysis of Samples................................................................................................................................ 76
C. Judgement of Results.............................................................................................................................. 76
IV. Annex............................................................................................................................................................. 76
A. Quinine Chemical Actinometry.............................................................................................................. 76
Chapter 10 Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products......................... 77
I. Introduction..................................................................................................................................................... 77
B. Background............................................................................................................................................. 77
C. Scope of the Guideline............................................................................................................................ 77
II. Guidelines....................................................................................................................................................... 77
A. General.................................................................................................................................................... 77
B. Applicability of Reduced Designs........................................................................................................... 77
C. Bracketing............................................................................................................................................... 77
1. Design Factors.................................................................................................................................. 77
2. Design Considerations and Potential Risks..................................................................................... 78
3. Design Example............................................................................................................................... 78
D. Matrixing................................................................................................................................................ 78
1. Design Factors.................................................................................................................................. 78
2. Design Considerations..................................................................................................................... 79
3. Design Examples.............................................................................................................................. 79
4. Applicability and Degree of Reduction............................................................................................ 79
5. Potential Risk................................................................................................................................... 80
E. Data Evaluation....................................................................................................................................... 80
Chapter 11 Evaluation of Stability Data................................................................................................................................... 81

I. Introduction..................................................................................................................................................... 81
B. Background............................................................................................................................................. 81
II. Guidelines....................................................................................................................................................... 81
A. General Principles................................................................................................................................... 81
B. Data Presentation.................................................................................................................................... 82
C. Extrapolation........................................................................................................................................... 82
D. Data Evaluation for Retest Period or Shelf-Life Estimation for Drug Substances or Products
Intended for Room-Temperature Storage�� 82
1. No Significant Change at Accelerated Condition............................................................................ 82
2. Significant Change at Accelerated Condition.................................................................................. 83
xii Contents
E. Data Evaluation for Retest Period or Shelf-Life Estimation for Drug Substances or Products
Intended for Storage below Room Temperature�� 83
1. Drug Substances or Products Intended for Storage in a Refrigerator.............................................. 83
2. Drug Substances or Products Intended for Storage in a Freezer...................................................... 84
3. Drug Substances or Products Intended for Storage below −20°C................................................... 84
F. General Statistical Approaches................................................................................................................ 84
Appendices............................................................................................................................................................. 85
Appendix A: Decision Tree for Data Evaluation for Retest Period or Shelf-Life Estimation for Drug
Substances or Products (Excluding Frozen Products)....................................................................... 85
Appendix B: Examples of Statistical Approaches to Stability Data Analysis................................................ 86
B.1. Data Analysis for a Single Batch.................................................................................................. 86
B.2. Data Analysis for One-Factor, Full-Design Studies..................................................................... 87
B.3. Data Analysis for Multifactor, Full-Design Studies..................................................................... 88
B.4. Data Analysis for Bracketing Design Studies.............................................................................. 89
B.5. Data Analysis for Matrixing Design Studies................................................................................ 89
References.............................................................................................................................................................. 89
Chapter 12 Stability Data Package for Registration Applications in Climatic Zones III and IV............................................. 91
I. Introduction..................................................................................................................................................... 91
B. Background............................................................................................................................................. 91
II. Guidelines....................................................................................................................................................... 91
A. Continuity with the Parent Guideline..................................................................................................... 91
B. Storage Conditions.................................................................................................................................. 91
1. General Case.................................................................................................................................... 91
2. Aqueous-Based Drug Products Packaged in Semipermeable Containers........................................ 92
3. Tests at Elevated Temperature and/or Extremes of Humidity.......................................................... 92
C. Additional Considerations....................................................................................................................... 92
References.............................................................................................................................................................. 92
Chapter 13 EU Guidelines to Good Manufacturing Practice Medicinal Products for

Human and Veterinary Use.................................................................................................................................... 93
I. Introduction...................................................................................................................................................... 93
Part I: Chapter 1: Quality Management.......................................................................................................... 94
Principle�� 94
Quality Assurance................................................................................................................................... 94
Good Manufacturing Practice for Medicinal Products (GMP)............................................................... 94
Quality Control....................................................................................................................................... 95
Product Quality Review.......................................................................................................................... 95
Quality Risk Management...................................................................................................................... 96
Chapter 2: Personnel....................................................................................................................................... 96
Principle�� 96
General�� 96
Key Personnel�� 96
Training�� 97
Personnel Hygiene.................................................................................................................................. 97
Chapter 3: Premises and Equipment............................................................................................................... 98
Principle�� 98
Premises�� 98
Production Area�� 98
Storage Areas�� 99
Quality Control Areas�� 99
Ancillary Areas�� 99
Equipment�� 99
Contents xiii
Chapter 4: Documentation.............................................................................................................................. 99
Principle�� 99
General�� 99
Specifications for Starting and Packaging Materials............................................................................ 100
Specifications for Intermediate and Bulk Products............................................................................... 100
Specifications for Finished Products..................................................................................................... 100
Manufacturing Formula and Processing Instructions........................................................................... 100
Packaging Instructions...........................................................................................................................101
Batch Processing Records......................................................................................................................101
Batch Packaging Records.......................................................................................................................101
Procedures and Records.........................................................................................................................101
Sampling�� 102
Testing�� 102
Other�� 102
Chapter 5: Production................................................................................................................................... 102
Principle�� 102
General�� 102
Prevention of Cross-Contamination in Production�� 103
Validation�� 103
Starting Materials�� 103
Processing Operations: Intermediate and Bulk Products�� 104
Packaging Materials�� 104
Packaging Operations�� 104
Finished Products�� 104
Rejected, Recovered, and Returned Materials�� 104
Chapter 6: Quality Control�� 105
Principle�� 105
General�� 105
Good Quality Control Laboratory Practice�� 105
Documentation�� 105
Sampling�� 106
Testing�� 106
Ongoing Stability Program�� 106
Chapter 7: Contract Manufacture and Analysis�� 107
Principle�� 107
General�� 107
The Contract Giver�� 107
The Contract Acceptor�� 107
The Contract�� 108
Chapter 8: Complaints and Product Recall�� 108
Principle�� 108
Complaints�� 108
Recalls�� 108
Chapter 14 Impurities: Guideline for Residual Solvents........................................................................................................ 109

I. Introduction................................................................................................................................................. 109
II. Scope of the Guideline................................................................................................................................ 109
III. General Principles....................................................................................................................................... 109
A. Classification of Residual Solvents by Risk Assessment.................................................................... 109
B. Methods for Establishing Exposure Limits..........................................................................................110
C. Options for Describing Limits of Class 2 Solvents..............................................................................110
D. Analytical Procedures...........................................................................................................................111
E. Reporting Levels of Residual Solvents.................................................................................................111
IV. Limits of Residual Solvents..........................................................................................................................112
A. Solvents to Be Avoided........................................................................................................................112
B. Solvents to Be Limited.........................................................................................................................112
xiv Contents
C. Solvents with Low Toxic Potential.......................................................................................................112

D. Solvents for Which No Adequate Toxicological Data Were Found.....................................................112
Glossary.................................................................................................................................................................112
Appendix 1 List of Solvents Included in the Guideline.....................................................................................113
Appendix 2 Additional Background...................................................................................................................115
A2.1 Environmental Regulation of Organic Volatile Solvents..................................................................115
A2.2 Residual Solvents in Pharmaceuticals..............................................................................................115
Appendix 3 Methods for Establishing Exposure Limits....................................................................................115
Chapter 15 Electronic Records and Signatures (CFR 21 Part 11 Compliance).......................................................................117

Sec. 11.2 Implementation..............................................................................................................................118
Sec. 11.3 Definitions......................................................................................................................................118
Subpart B: Electronic Records..............................................................................................................................118
Sec. 11.10 Controls for Closed Systems........................................................................................................118
Sec. 11.30 Controls for Open Systems..........................................................................................................119
Sec. 11.50 Signature Manifestations.............................................................................................................119
Sec. 11.70 Signature/Record Linking............................................................................................................119
Subpart C: Electronic Signatures..........................................................................................................................119
Sec. 11.100 General Requirements................................................................................................................119
Sec. 11.200 Electronic Signature Components and Controls........................................................................119
Sec. 11.300 Controls for Identification Codes/Passwords............................................................................ 120
Chapter 16 Product-Specific Bioequivalence Testing Protocols............................................................................................. 121
Chapter 17 Formulation Considerations................................................................................................................................. 125

1. Background................................................................................................................................................... 125
2. Ion Resin Complexes..................................................................................................................................... 125
3. Ion Exchange Resins..................................................................................................................................... 125
3.1 Drug Loading....................................................................................................................................... 126
3.2 Coating Drug–Resin Complexes......................................................................................................... 126
4. Cyclodextrins................................................................................................................................................. 127
Chapter 18 Pediatric Pharmaceutical EU Legislation............................................................................................................ 129

Background.......................................................................................................................................................... 129
The Main Points in the Regulation....................................................................................................................... 129
Implications.......................................................................................................................................................... 130
Chapter 19 Pediatric Formulations......................................................................................................................................... 133

Specific Considerations on Formulations for Neonates....................................................................................... 134
Collaboration on Pediatric Formulations............................................................................................................. 134
Conclusions.......................................................................................................................................................... 134
Bibliography......................................................................................................................................................... 135
Chapter 20 SOP and Specification to Establish Electronic Submission to Regulatory Agencies.......................................... 137
1. Purpose.......................................................................................................................................................... 137
2. Scope............................................................................................................................................................. 137
3. Definitions and Abbreviations....................................................................................................................... 137
4. Responsibilities............................................................................................................................................. 137
4.1 Information Technology...................................................................................................................... 137
4.2 Regulatory Affairs................................................................................................................................ 137
4.3 Publishing............................................................................................................................................ 137
Contents xv
5. Materials and Equipment.............................................................................................................................. 137

5.1 Materials.............................................................................................................................................. 137
5.2 Equipment............................................................................................................................................ 138
6. Health and Safety.......................................................................................................................................... 138
7. Procedure....................................................................................................................................................... 138
7.1 Secure E-mail Setup............................................................................................................................ 138
7.2 Requesting a Pre-Assigned Application Number................................................................................ 138
7.3 ESG Account Setup............................................................................................................................. 138
8. References..................................................................................................................................................... 138
9. Exhibits........................................................................................................................................................ 139
Exhibit I—Pre-Assigned Application Number Request.............................................................................. 139
Exhibit II – Sample Letters of Non-Repudiation Agreement...................................................................... 139
10. Revision History.......................................................................................................................................... 139
11. ICH eCTD Specification............................................................................................................................. 139
11.1 Introduction...................................................................................................................................... 139
11.2 Background....................................................................................................................................... 139
11.3 Scope................................................................................................................................................ 139
11.4 Requirements.................................................................................................................................... 140
11.5 Change Control................................................................................................................................. 140
11.5.1 Introduction......................................................................................................................... 140
11.5.2 Process................................................................................................................................ 140
11.5.3 Procedure............................................................................................................................ 140
11.6 Approach to Documentation and Use of the eCTD Specification.....................................................141
Appendix 1: Overall Architecture...........................................................................................................................................143
Appendix 2: The eCTD Submission....................................................................................................................................... 145
Appendix 3: General Considerations for the CTD Modules............................................................................................... 149
Appendix 4: File Organization for the eCTD........................................................................................................................ 157
Appendix 5: Region-Specific Information Including Transmission and Receipt.............................................................. 201
Appendix 6: The eCTD XML Submission............................................................................................................................ 205
Appendix 7: Specification for Submission Formats.............................................................................................................. 213
Appendix 8: XML eCTD DTD................................................................................................................................................217
Appendix 9: Glossary.............................................................................................................................................................. 225
Appendix A: GMP Audit Template........................................................................................................................................ 227
Appendix B: Dissolution Testing............................................................................................................................................ 247
Appendix C: Excipients........................................................................................................................................................... 249
PART II MANUFACTURING FORMULATIONS
Liquid Formulations................................................................................................................................................................ 279

Abacavir Sulfate Oral Solution............................................................................................................................ 279
Acetaminophen, Chlorpheniramine, and Pseudoephedrine Syrup....................................................................... 279
Acetaminophen Drops.......................................................................................................................................... 280
Acetaminophen Oral Suspension......................................................................................................................... 280
Acetaminophen Rectal Solution........................................................................................................................... 281
Acetaminophen Suspension................................................................................................................................. 281
Acetaminophen Syrup.......................................................................................................................................... 281
Acetaminophen Syrup.......................................................................................................................................... 282
Acetaminophen Syrup for Children..................................................................................................................... 282
Preface to the Series—Second Edition
The science and the art of pharmaceutical formulation keeps and this applies to all information contained in this
evolving as new materials, methods, and machines become book. The freedom of information act (FOIA) is an
readily available to produce more reliable, stable, and release- extremely useful conduit for reliable information and
controlled formulations. At the same time, globalization of manufacturers are strongly urged to make use of this
sourcing of raw and finished pharmaceuticals brings chal- information. Whereas this information is provided
lenges to regulatory authorities and results in more frequent free of charge, the process of obtaining the informa-
revisions to the current good manufacturing practices, regulation may be cumbersome, in which case, commercial
tory approval dossier requirements, and the growing need for sources of these databases can prove useful, particu-
cost optimization. Since the publication of the first edition of larly for the non-U.S. companies.
this book, a lot has changed in all of these areas of importance 6. Also included are the new Good Manufacturing
to pharmaceutical manufacturers. The second edition builds Guidelines (2007) with amendments (2008) for the
on the dynamic nature of the science and art of formulations United States and similar updates for European
and provides an evermore useful handbook that should be Union and WHO; it is strongly urged that the com-
highly welcomed by the industry, the regulatory authorities, panies discontinue using all old documents as there
as well as the teaching institutions. are significant changes in the revised form, and
The first edition of this book was a great success as it many of them are likely to reduce the cost of GMP
brought under one umbrella the myriad of choices available compliance.
to formulators. The readers were very responsive and com- 7. Details on design of clean rooms is a new entry that
municated with me frequently pointing out to the weaknesses will be of great use to sterile product manufactur-
as well as the strengths of the book. The second edition totally ers; whereas the design and flow of personnel and
revised attempts to achieve these by making major changes to material flow is of critical nature, regulatory agen-
the text, some of which include: cies view these differently and the manufacturer
is advised always to comply with most stringent
1. Complete, revised errors corrected and subject mat- requirements.
ter reorganized for easy reference. Whereas this 8. Addition of a self-auditing template in each volume
series has six volumes differentiated on the basis of of the series. While the cGMP compliance is a com-
the type of dosage form and a separate inclusion of plex issue and the requirements diversified across
the U.S. OTC products, ideally the entire collection the globe, the basic compliance remains universal. I
is needed to benefit from the myriad of topics relat- have chosen the European Union guidelines (as these
ing to formulations, regulatory compliance, and dos- are more in tune with the ICH) to prepare a self-audit
sier preparation. module that I recommend that every manufacturer
2. Total number of pages is increased from 1684 adopt as a routine to assure GMP compliance. In
to 2726. most instances reading the template by those respon-
3. Total number of formulations is expanded by about sible for compliance with keep them sensitive to the
30% with many newly approved formulations. needs of GMP.
4. Novel formulations are now provided for a variety 9. OTC products cross-referenced in other volumes
of drugs; these data are collected from the massive where appropriate. This was necessary since the
intellectual property data and suggest toward the regulatory authorities worldwide define this class of
future trend of formulations. While some of these drug differently. It is important to iterate that regard-
formulations may not have been approved in the less of the prescription or the OTC status of a prod-
United States or Europe, these do provide additional uct, the requirements for compliance with the cGMP
choices, particularly for the NDA preparation. As apply equally.
always, it is the responsibility of the manufacturer 10. OTC monograph status is a new section added to the
to assure that the intellectual property rights are not OTC volume and this should allow manufacturers to
violated. chose appropriate formulations that may not require
5. A significant change in this edition is the inclusion a filing with the regulatory agencies; it is important
of commercial products; while most of this informa- to iterate that an approved OTC monograph includes
tion is culled out from the open source such as the details of formulation including the types and quan-
FOIA (http://www.fda.gov/foi/default.htm), I have tities of active drug and excipients, labeling, and
made attempts to reconstruct the critical portions presentation. To qualify the exemption, the manufac-
of it based on what I call the generally acceptable turer must comply with the monograph in its entirety.
standards. The drug companies are advised to assure However, subtle modifications that are merely cos-
that any intellectual property rights are not violated metic in nature and where there is an evidence that
xxvii
xxviii Preface to the Series—Second Edition
the modification will not affect the safety and effi- therefore included, as an appendix to each volume,
cacy of the products can be made but require prior a list of all excipients that are currently approved by
approval of the regulatory agencies and generally the U.S. FDA along their appropriate levels. I suggest
these approvals are granted. that a formulator consult this table before deciding
11. Expanded discussion on critical factors in the man- on which level of excipient to use; it does not mean
ufacturing of formulations provided; from basic that the excipient cannot be used outside this range
shortcuts to smart modifications now extend to all but it obviates the need for a validation and lengthy
dosage forms. Pharmaceutical compounding is one justification studies in the submission of NDAs.
of the oldest professions and whereas the art of 14. Expanded section on bioequivalence submission
formulations has been relegated to more objective was required to highlight the recent changes in these
parameters, the art nevertheless remains. An expe- requirements. New entries include a comprehensive
rienced formulator, like an artist, would know what listing of bioequivalence protocols in abbreviated
goes with what and why; he avoids the pitfalls and form as approved by the U.S. FDA; these descrip-
stays with conservative choices. These sections of tions are provided in each volume where pertinent.
the book present advice that is time tested, although To receive approval for an ANDA, an applicant must
it may appear random at times; this is intended for generally demonstrate, among other things, equiva-
experienced formulators. lence of the active ingredient, dosage form, strength,
12. Expanded details on critical steps in the manufactur- route of administration and conditions of use as the
ing processes provided but to keep the size of the listed drug, and that the proposed drug product is
book manageable, and these are included for proto- bioequivalent to the reference listed drug [21 USC
type formulations. The reader is advised to browse 355(j)(2)(A); 21 CFR 314.94(a)]. Bioequivalent drug
through similar formulations to gain more insight. products show no significant difference in the rate
Where multiple formulations are provided for the and extent of absorption of the therapeutic ingredient
same drug, it intended to show the variety of pos- [21 U.S.C. 355(j)(8); 21 CFR 320.1(e)]. BE studies are
sibilities in formulating a drug and whereas it per- undertaken in support of ANDA submissions with
tains to a single drug, the basic formulation practices the goal of demonstrating BE between a proposed
can be extended to many drugs of same class or even generic drug product and its reference listed drug.
of diversified classes. Readers have often requested The regulations governing BE are provided at 21
that more details be provided in the Manufacturing CFR in part 320. The U.S. FDA has recently begun to
Direction sections. Whereas sufficient details are promulgate individual bioequivalence requirements.
provided, this is restricted to prototype formula- To streamline the process for making guidance
tions to keep the size of the book manageable and to available to the public on how to design product-
reduce redundancy. specific BE studies, the U.S. FDA will be issuing
13. Addition of a listing of approved excipients and the product-specific BE recommendations (www.fda.
level allowed by regulatory authorities. This new gov/cder/ogd/index.htm). To make this vital informa-
section allows formulators a clear choice on which tion available, an appendix to each volume includes
excipients to choose; the excipients are reported in a summary of all currently approved products by the
each volume pertaining to the formulation type cov- U.S. FDA where a recommendation on conducting
ered. The listing is drawn from the FDA-approved bioequivalence studies is made available by the U.S.
entities. For the developers of an ANDA, it is critical FDA. When filing an NDA or an ANDA, the filer is
that the level of excipients be kept within the range faced with the choice of defending the methods used
generally approved to avoid large expense in justi- to justify the bioavailability or bioequivalence data.
fying any unapproved level. The only category for The U.S. FDA now allows application for waiver of
which the listing is not provided separately is the bioequivalence requirement; a new chapter on this
OTC volume since it contains many dosage forms topic has been added along with details of the dis-
and the reader is referred to dosage form–specific solution tests, where applicable, approved for various
title of the series. The choice of excipients forms dosage forms.
keeps increasing with many new choices that can 15. Dissolution testing requirements are included for all
provide many special release characteristics to the dosage forms where this testing is required by the
dosage forms. Choosing correct excipients is thus FDA. Surrogate testing to prove efficacy and compli-
a tedious exercise and requires sophisticated multi- ance is getting more acceptance at regulatory agen-
variate statistical analysis. Whereas the formulator cies; in my experience, a well-designed dissolution
may choose any number of novel or classical compo- test is the best measure of continuous compliance.
nents, it is important to know the levels of excipients Coupled with chapters on waivers of bioequiva-
that are generally allowed in various formulations lence testing, this information on dissolution test-
to reduce the cost of redundant exercises; I have ing should be great value to all manufacturers; it is
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Handbook of Pharmaceutical Manufacturing Formulations, Third Edition: Volume Three, Liquid Products Sarfaraz K. Niazi (Author)

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PART I Regulatory and Manufacturing Guidance

Chapter 1 Manufacturing Considerations in Liquid Formulations........................................................................................... 3

Chapter 2 Oral Solutions and Suspensions............................................................................................................................... 9

Chapter 3 The FDA Drug Product Surveillance Program...................................................................................................... 13

Chapter 4 Changes to Approved NDAs and aNDAs.............................................................................................................. 23

XI. Miscellaneous Changes............................................................................................................................... 32

Chapter 5 Formulation Considerations of Liquid Products.................................................................................................... 35

Chapter 6 Container Closure Systems.................................................................................................................................... 45

G. Solid Oral Dosage Forms and Powders for Reconstitution............................................................... 52

Chapter 7 Material for Containers.......................................................................................................................................... 57

Chapter 8 Stability Testing of New Drug Substances and Products....................................................................................... 63

8.  Stability Commitment.................................................................................................................... 68

Chapter 11 Evaluation of Stability Data................................................................................................................................... 81

Chapter 13 EU Guidelines to Good Manufacturing Practice Medicinal Products for

Chapter 14 Impurities: Guideline for Residual Solvents........................................................................................................ 109

C. Solvents with Low Toxic Potential.......................................................................................................112

Chapter 15 Electronic Records and Signatures (CFR 21 Part 11 Compliance).......................................................................117

Chapter 16 Product-Specific Bioequivalence Testing Protocols............................................................................................. 121

Chapter 17 Formulation Considerations................................................................................................................................. 125

Chapter 18 Pediatric Pharmaceutical EU Legislation............................................................................................................ 129

Chapter 19 Pediatric Formulations......................................................................................................................................... 133

5. Materials and Equipment.............................................................................................................................. 137

PART II MANUFACTURING FORMULATIONS

Liquid Formulations................................................................................................................................................................ 279

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G. Solid Oral Dosage Forms and Powders for Reconstitution............................................................... 52

8. Stability Commitment.................................................................................................................... 68

C. Solvents with Low Toxic Potential.......................................................................................................112

5. Materials and Equipment.............................................................................................................................. 137