Handbook of Pharmaceutical Manufacturing Formulations, Third Edition-Volume Six, Sterile Products

453 Pages·2019·7.379 MB·\453

by  Sarfaraz K. Niazi (Author)

Handbook of Pharmaceutical
Manufacturing Formulations
Volume Six, Sterile Products

Handbook of Pharmaceutical
Manufacturing Formulations,
Third Edition
Volume Six, Sterile Products
Sarfaraz K. Niazi
CRC Press
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To Dean Shamsuz Zoha
Dean Shamsuz Zoha passed away in 2010; he was the dean of pharmacy school in Pakistan
where I began my career and I had the privilege of receiving his blessings throughout my life.

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
About the Author ....................................................................................................................................................................xxxv
PART I Regulatory and Manufacturing
Chapter 1 Sterile Manufacturing Formulations Template .......................................................................................................3
I. Autoclaves ..................................................................................................................................................6
II. Aseptic Contract Manufacturers ................................................................................................................6
A. Manufacturing Formulations Template ..............................................................................................6
III. Clean-Room Design and Construction ......................................................................................................6
IV. Clean-in-Place/Steam-in-Place (CIPISIP) .................................................................................................6
V. Closure Washing and Sterilization ............................................................................................................6
VI. Consultants ................................................................................................................................................6
VII. Disinfectants and Preservatives .................................................................................................................7
VIII. Distillation Equipment ...............................................................................................................................7
IX. Engineering and Construction ...................................................................................................................7
X. Filling Machines ........................................................................................................................................7
XI. Filter Aids ..................................................................................................................................................7
XII. Flowmeters (Sanitary) ...............................................................................................................................7
XII. Freeze-Dryers (Sterilizable) .......................................................................................................................7
XIII. Microfiltration Equipment and Filters .......................................................................................................7
A. Manufacturing Formulations Template ..............................................................................................8
XIV. Pumps (Sanitary) .......................................................................................................................................8
XV. Sterile Tanks and Related Stainless Equipment ........................................................................................8
XVI. Sterility Test Equipment ............................................................................................................................8
XVII. Sterilizing and Drying Tunnels (Hot Air) .................................................................................................8
XVIII. Stoppering Machines .................................................................................................................................8
Chapter 2 Inspection of Sterile Product Manufacturing Facilities ........................................................................................11
I. Introduction .............................................................................................................................................11
II. cGMP Compliance Basics .......................................................................................................................11
A. Personnel ..........................................................................................................................................11
B. B uildings...........................................................................................................................................11
C. Air .....................................................................................................................................................11
D. Environmental Controls ...................................................................................................................11
E. Equipment .........................................................................................................................................12
F. Water for Injection .............................................................................................................................12
G. Containers and Closures ...................................................................................................................12
H. Sterilization ......................................................................................................................................12
1. Methods .....................................................................................................................................12
2. Indicators ...................................................................................................................................12
3. Filled Containers .......................................................................................................................13
I. Personnel Practices ............................................................................................................................13
J. Laboratory Controls ...........................................................................................................................13
1. Retesting for Sterility ................................................................................................................13
2. Retesting for Pyrogens ..............................................................................................................13
3. Particulate Matter Testing ..........................................................................................................13
4. Production Records ...................................................................................................................13
vii
viii Contents
III. Aseptic Processing .....................................................................................................................................13
A. Introduction ........................................................................................................................................13
B. Buildings and Facilities.......................................................................................................................14
1. Critical Area (Class 100) ..............................................................................................................14
2. Supporting Clean Areas ...............................................................................................................15
3. Clean Area Separation ..................................................................................................................15
4. Air Filtration.................................................................................................................................15
5. Design ..........................................................................................................................................16
C. Personnel Training, Qualification, and Monitoring ............................................................................17
1. Manufacturing Personnel .............................................................................................................18
2. Laboratory Personnel ...................................................................................................................19
3. Monitoring Program .....................................................................................................................19
D. Components and Containers/Closures ................................................................................................19
1. Components .................................................................................................................................19
2. Containers/Closures .....................................................................................................................19
E. Endotoxin Control ...............................................................................................................................20
F. Time Limitations ..................................................................................................................................21
G. Process Validation and Equipment Qualification ................................................................................21
1. Process Simulations .....................................................................................................................21
2. Filtration Efficacy ........................................................................................................................24
3. Sterilization of Equipment and Containers/Closures ...................................................................24
H. Laboratory Controls ............................................................................................................................25
1. Environmental Monitoring ...........................................................................................................26
2. Microbiological Media and Identification ...................................................................................27
I. Sterility Testing ....................................................................................................................................28
1. Choice of Methods .......................................................................................................................28
2. Media ...........................................................................................................................................28
3. Personnel ......................................................................................................................................28
4. Sampling and Incubation .............................................................................................................28
5. Investigation of Sterility Positives ...............................................................................................28
J. Batch Record Review: Process Control Documentation .....................................................................30
IV. Processing Prior to Filling and Sealing Operations ...................................................................................30
A. Aseptic Processing from Early Manufacturing Steps .........................................................................30
B. Aseptic Processing of Cell-Based Therapy Products (or of Products Intended for Use as
Cell-Based Therapies) .........................................................................................................................31
V. Aseptic Processing Isolators .......................................................................................................................31
A. Maintenance ........................................................................................................................................31
1. General .........................................................................................................................................31
2. Glove Integrity .............................................................................................................................31
B. D esign .................................................................................................................................................31
1. Airflow .........................................................................................................................................31
2. Materials of Construction ............................................................................................................31
3. Pressure Differential ....................................................................................................................31
4. Clean-Area Classifications ...........................................................................................................32
C. Transfer of Materials and Supplies .....................................................................................................32
1. Introduction ..................................................................................................................................32
2. Discharge .....................................................................................................................................32
D. Decontamination .................................................................................................................................32
1. Surface Exposure .........................................................................................................................32
2. Efficacy .......................................................................................................................................32
3. Frequency .....................................................................................................................................32
E. Filling Line Sterilization .....................................................................................................................32
F. Environmental Monitoring ..................................................................................................................32
G. Personnel ............................................................................................................................................32
VI. Blow-Fill-Seal Technology .........................................................................................................................33
A. Equipment Design and Air Quality ....................................................................................................33
B. Validation and Qualification ................................................................................................................33
C. Batch Monitoring and Control ............................................................................................................33
Contents ix
VII. Lyophilization of Parenterals .....................................................................................................................34
A. Introduction ........................................................................................................................................34
B. Product Type and Formulation ............................................................................................................34
C. F illing ..................................................................................................................................................34
D. Lyophilization Cycle and Controls .....................................................................................................36
E. Cycle Validation ..................................................................................................................................36
F. Lyophilizer Sterilization and Design ...................................................................................................37
G. Finished Product Testing ....................................................................................................................38
1. Dose Uniformity ..........................................................................................................................38
2. Stability Testing ...........................................................................................................................38
3. Sterility Testing ............................................................................................................................39
H. Finished Product Inspection—Meltback ............................................................................................39
VIII. High-Purity Water Systems ........................................................................................................................39
A. System Design ....................................................................................................................................39
B. S ystem Validation ...............................................................................................................................39
C. M icrobial Limits .................................................................................................................................40
1. WFI Systems ................................................................................................................................40
2. Purified Water Systems ................................................................................................................40
D. WFI Systems .......................................................................................................................................41
E. Still......................................................................................................................................................41
F. Heat Exchangers .................................................................................................................................41
G. Holding Tank ......................................................................................................................................42
H. Pumps .................................................................................................................................................42
I. Piping ..................................................................................................................................................42
J. Reverse Osmosis .................................................................................................................................42
K. Purified Water Systems .......................................................................................................................42
L. Process Water ......................................................................................................................................43
M. Evaluation Strategy .............................................................................................................................43
Relevant Guidance Documents (FDA) ..................................................................................................................43
Glossary .................................................................................................................................................................44
Bibliography ..........................................................................................................................................................47
Chapter 3 New Drug Application for Sterilized Products .....................................................................................................49
I. Introduction ................................................................................................................................................49
II. Terminal Heat Sterilization ........................................................................................................................49
A. Description of the Process and Product ..............................................................................................49
B. Thermal Qualification of the Cycle .....................................................................................................49
C. Microbiological Efficacy of the Cycle ................................................................................................50
D. Microbiological Monitoring of the Environment ...............................................................................50
E. Container/Closure and Package Integrity ...........................................................................................50
F. Bacterial Endotoxins Test and Method ...............................................................................................51
G. Sterility Testing Methods and Release Criteria ..................................................................................51
H. Evidence of Formal Written Procedures .............................................................................................51
III. Other Terminal Sterilization Processes ......................................................................................................51
A. Ethylene Oxide ...................................................................................................................................51
B. R adiation .............................................................................................................................................51
IV. Aseptic Fill Manufacturing Processes .......................................................................................................51
A. Buildings and Facilities ......................................................................................................................52
B. Overall Manufacturing Operation .......................................................................................................52
C. Containers and Closures .....................................................................................................................52
D. Procedures and Specifications for Media Fills ...................................................................................52
E. Actions Concerning Product When Media Fills Fail ..........................................................................53
F. Microbiological Monitoring of the Environment ...............................................................................53
G. Container/Closure and Package Integrity ...........................................................................................53
H. Sterility Testing Methods and Release Criteria ..................................................................................53
I. Bacterial Endotoxins Test and Method ...............................................................................................53
J. Evidence of Formal Written Procedures.............................................................................................53