Practical Pharmaceutical Engineering E-Book

Gary Prager

• Herausgeber: John Wiley & Sons
• Kategorie: Fachliteratur
• Sprache: Englisch

Seitenzahl: 1197

Veröffentlichungsjahr: 2018

Beschreibung

A practical guide to all key the elements of pharmaceuticals and biotech manufacturing and design Engineers working in the pharmaceutical and biotech industries are routinely called upon to handle operational issues outside of their fields of expertise. Traditionally the competencies required to fulfill those tasks were achieved piecemeal, through years of self-teaching and on-the-job experience--until now. Practical Pharmaceutical Engineering provides readers with the technical information and tools needed to deal with most common engineering issues that can arise in the course of day-to-day operations of pharmaceutical/biotech research and manufacturing. Engineers working in pharma/biotech wear many hats. They are involved in the conception, design, construction, and operation of research facilities and manufacturing plants, as well as the scale-up, manufacturing, packaging, and labeling processes. They have to implement FDA regulations, validation assurance, quality control, and Good Manufacturing Practices (GMP) compliance measures, and to maintain a high level of personal and environmental safety. This book provides readers from a range of engineering specialties with a detailed blueprint and the technical knowledge needed to tackle those critical responsibilities with confidence. At minimum, after reading this book, readers will have the knowledge needed to constructively participate in contractor/user briefings. * Provides pharmaceutical industry professionals with an overview of how all the parts fit together and a level of expertise that can take years of on-the-job experience to acquire * Addresses topics not covered in university courses but which are crucial to working effectively in the pharma/biotech industry * Fills a gap in the literature, providing important information on pharmaceutical operation issues required for meeting regulatory guidelines, plant support design, and project engineering * Covers the basics of HVAC systems, water systems, electric systems, reliability, maintainability, and quality assurance, relevant to pharmaceutical engineering Practical Pharmaceutical Engineering is an indispensable "tool of the trade" for chemical engineers, mechanical engineers, and pharmaceutical engineers employed by pharmaceutical and biotech companies, engineering firms, and consulting firms. It also is a must-read for engineering students, pharmacy students, chemistry students, and others considering a career in pharmaceuticals.

Leseprobe

Table of Contents

Cover

Preface

1 US Regulations for the Pharmaceutical Industries

1.1 Introduction

1.2 The FDA: Formation of a Regulatory Agency

1.3 FDA’s Seven Program Centers and Their Responsibility

1.4 New Drug Development

1.5 Commercializing the New Drug

1.6 Harmonization

1.7 Review Process of US NDA

1.8 Current Good Manufacturing Practice in Manufacturing, Processing, Packing, or Holding of Drugs

1.9 Compliance

1.10 Electronic Records and Electronic Signatures

1.11 Employee Safety

1.12 US EPA

1.13 Process Analytical Technology

1.14 Conclusion

References

Further Reading

2 Pharmaceutical Water Systems

2.1 Pharmaceutical Water Systems Basics

2.2 Pharmaceutical Water Equipment

2.3 Thermodynamics Interlude

2.4 Heat Transfer for Pharmaceutical Water Production

2.5 Evaporation

2.6 Ion Exchange Systems

2.7 Reverse Osmosis

2.8 cGMP Design and Facility Maintenance Considerations for Pharmaceutical Water Systems

References

Further Reading

3 Heating, Ventilating, and Air Conditioning

3.1 Fundamentals of HVAC Electrical Systems

3.2 Design Considerations

3.3 Cleanrooms

References

Further Reading

4 Pressure Vessels, Reactors, and Fermentors

4.1 Introduction

4.2 Safety Relief Valves and Rupture Discs

References

Further Reading

5 Reliability, Availability, and Maintainability

5.1 Introduction to RAM

5.2 The Role of Reliability

5.3 The Role of Maintainability

5.4 The Preventive Maintenance Program

5.5 Human Factors

5.6 The Role of Availability

5.7 Basic Mathematics for Reliability, Availability, and Maintainability

5.8 Series and Parallel Configurations

5.9 Spares and Replacement Parts

References

Further Reading

6 Parenteral Operations

6.1 Introduction

6.2 Parenteral Definitions, Regulations, and Guidelines

6.3 Lyophilization

6.4 Lyophilizer Maintenance Issues

References

Further Reading

7 Tableting Technology

7.1 Introduction

7.2 The Role of the FDA in the Manufacturing, Processing, Packing, and Holding of Drugs: The Relationship Between Regulations and Pharmaceutical Engineering

7.3 Tablet Blending Operations

7.4 Tableting Operations

7.5 Coating

7.6 Capsules

References

Further Reading

8 Corrosion and Passivation in Pharmaceutical Operations

8.1 Corrosion

8.2 Corrosion and Corrosion Protection in Pharmaceutical Operations

8.3 General Corrosion Protection in Pharmaceutical Operations

8.4 Corrosion‐Resistant Metals and Alloys

8.5 Passivation and Rouging

8.6 General Corrosion Protective Measures

8.7 Pourbaix Diagrams

References

Further Reading

9 Pharmaceutical Materials of Construction

9.1 Introduction

9.2 Materials Selection and Performance Requirements

9.3 Advantages and Disadvantages of Stainless Steels and Polymers for cGMP and Non‐cGMP Pharmaceutical Applications

9.4 Disposal of Single Use Components

9.5 Performance Considerations for Pharmaceutical Materials of Construction

9.6 Practical Piping Calculations

References

Further Reading

10 Commissioning and Validation

10.1 Introduction to Commissioning and Validation

10.2 Commissioning

10.3 Validation

10.4 Process Validation

10.5 Electronic Records and Electronic Signatures

10.6 Comparison Between Commissioning and Validation

References

Further Reading

11 Topics and Concepts Relating to Pharmaceutical Engineering

11.1 Preliminary Concepts

11.2 Introduction to Six Sigma

11.3 Process Analytical Technology

11.4 Quality by Design

References

Further Reading

Index

End User License Agreement

List of Tables

Chapter 02

Table 2.1 Pharmaceutical water quality standards.

Table 2.2 Concentration of strong acid (HCl) and strong base (NaOH) and pH/pOH.

Table 2.3 Altitude and the boiling point of water.

Table 2.4 Comparison of temperature systems for pure water.

Table 2.5 Common pharmaceutical piping parameters.

Table 2.6 Equivalent pipe diameters.

Table 2.7 Friction loss in pipe fittings and valves in terms of equivalent feet of straight pipe.

Table 2.8 Comparisons of published and calculated flow rates (Schedule 40 piping).

Table 2.9 Common values of the ideal gas law constant (

R

).

Table 2.10 Thermal conductivity of purified water system components.

Table 2.11 Dimensions of common heat exchanger tubes for pharmaceutical water.

Table 2.12 Feedwater concentrations for fouling and scaling minimization of RO membranes.

Table 2.13 Properties of saturated steam.

Chapter 03

Table 3.1 Efficiency of various induction motors.

Table 3.2 Motor slip and motor size relation.

Table 3.3 Horsepower and motor horsepower and associated frame size.

Table 3.4 Heat generated from lighting sources.

Table 3.5 Equipment heat load.

Table 3.6 People density.

Table 3.7 Noise evaluation variables.

Table 3.8 Noise criterions (NC) at selected frequencies.

Table 3.9 Permissible noise exposures.

Table 3.10 HVAC design criteria.

Table 3.11 ISO 14644‐1 selected cleanroom standards for particles/m

3

.

Table 3.12 Recommended action levels for microbial contamination.

Table 3.13 Surface sampling.

Chapter 04

Table 4.1 Yield strengths of selected steels for pharmaceutical pressure vessels.

Table 4.2 Weld joint efficiency values.

Table 4.3 Summary of pharmaceutical reaction kinetics information.

Table 4.4 Comparison of reactor heat transfer coefficients equipped with jackets and coils.

Table 4.5 Relief device designations and corresponding orifice areas.

Table 4.6 Surface area formulas for pressure vessel heads.

Chapter 05

Table 5.1 Part failure modes [5, 6].

Table 5.2 Maintainability design characteristics [8].

Table 5.3 Characteristics of humans and machines [8].

Table 5.4 Failure data for operating components [14].

Table 5.5 Component repair times.

Chapter 06

Table 6.1 Guidelines to parenteral drug products.

Chapter 07

Table 7.1 Common pharmaceutical tablet and capsule excipients and their function.

Table 7.2 Common test values for the angle of repose for pharmaceutical powders.

Table 7.3 Relative flowability [5].

Table 7.4 Common pharmaceutical powder particle sizes by diameter.

Table 7.5 Relevant design/operating parameters for twin shell blenders.

Chapter 08

Table 8.1 Electromotive series of metals.

Table 8.2 Factors influencing corrosion in solution.

Table 8.3 The galvanic series of metals and alloys.

Table 8.4 Properties of selected stainless steels.

Table 8.5 Techniques for corrosion elimination.

Chapter 09

Table 9.1 Some nonstandard stainless steels and their application.

Table 9.2 Mechanical property ranges of copper alloys [15].

Table 9.3 Mechanical and thermal properties of copper at ambient conditions.

Table 9.4 Copper tubing service data.

Table 9.5 Standard piping designations with pharmaceutical applications.

Table 9.6 The composition of ASTM A106, Grade B carbon steel.

Table 9.7 Properties of selected high performance piping polymers and 304 stainless steel.

Table 9.8 Recommended pipe hanger spacing for stainless steel and selected high performance polymeric piping (Sch 40).

Table 9.9 Allowable stress correction factors for PFTE and PVDF plastic piping.

Chapter 10

Table 10.1 Fume hood installation commissioning guideline.

Table 10.2 Installation qualification identification equipment identification template, IQ.

Table 10.3 Equipment components template, IQ.

Table 10.4 Hardware identification template, IQ.

Table 10.5 Software identification template, IQ.

Table 10.6 Utility identification template, electrical, IQ.

Table 10.7 Validation test equipment template, IQ.

Table 10.8 A–documentation template, IQ.

Table 10.8 B–drawings template, IQ.

Table 10.9 Maintenance template, IQ.

Table 10.10 Template for operator training, OQ.

Table 10.11A Standard operating procedures (SOP’s) template.

Table 10.11B Criticaland non critical instruments template*, OQ.

Table 10.12 Critical and non critical instruments template* (continued).

Table 10.13 Test procedure, OQ.

Table 10.14 Alarm and interlock verification*.

Table 10.15 Operational qualification summary template, OQ.

Table 10.16 Test procedure, PQ.

Table 10.17 Deviation log template.

Table 10.18 Deviation report template.

Table 10.19 Signature log template*,

Table 10.20 Computer system validation evaluation.

Table 10.21 Part 11 electronic records: Electronic signatures risk evaluation.

Table 10.22 Criticality assessment rating.

Table 10.23 System criticality rating.

Table 10.24 Comparison Between Commissioning Plans and Validation Protocols.

Chapter 11

Table 11.1 Cumulative normal distribution.

Table 11.2 Standard deviation versus defects per million opportunities (DPMO).

Table 11.3 Comparison of capability index with failures, ppm.

Table 11.4 Factors, levels, and treatments for smaller DOE programs.

Table 11.5 Selected process analytical technology (PAT) evaluation parameters and current tools.

Table 11.6 Overview of standard pharmaceutical operations and quality by design.

List of Illustrations

Chapter 02

Figure 2.1 Moody friction factor chart.

Figure 2.2 Centrifugal pump.

Figure 2.3 Single‐pass heat exchanger.

Figure 2.4 Multipass U tube heat exchanger.

Figure 2.5 Forced circulation evaporator.

Figure 2.6 Mechanical vapor recompression evaporator.

Figure 2.7 Typical reverse osmosis membrane.

Figure 2.8 Flow diagram of a reverse osmosis system.

Chapter 03

Figure 3.1 Standard psychometric chart.

Figure 3.2 Modular cleanroom.

Chapter 04

Figure 4.1 Typical pressure vessel.

Figure 4.2 Weld joint categories.

Figure 4.3 Schematic diagram of a pharmaceutical production reactor.

Figure 4.4 Diagram of a typical bioreactor.

Figure 4.5 Typical power number vs. agitated Reynolds number.

Figure 4.6 Typical industrial pharmaceutical fermentor.

Figure 4.7 Diagram of a safety relief valve.

Figure 4.8 Standard rupture disc.

Figure 4.9 Wetted wall perimeter factor as a function of vessel liquid level.

Chapter 05

Figure 5.1 Bathtub curve.

Figure 5.2 Reliability, availability, and maintainability (RAM) nomograph [7].

Chapter 06

Figure 6.1 Pressure/temperature phase diagram.

Figure 6.2 Schematic diagram of a freeze‐dryer.

Chapter 07

Figure 7.1 Typical roller compaction feed system.

Figure 7.2 Production scale roller compaction unit.

Figure 7.3 Test sieve shaker device.

Figure 7.4 Patterson Kelly 50 ft

3

twin shell blender.

Figure 7.5 Typical manufacturing tablet press.

Figure 7.6 Schematic profile of a tablet press. (A) Powder feed mechanism – The blended mix is fed to the tablet press by gravity feed from the top of the tablet press. (B) Die. (C) Lower cam – The lower cam pushes the upper punch further into the die. (D) Wipe off mechanism – This blade removes excess powder from the die/punch surface. (E) Mass control cam – Fills the powder to the required die volume. (F) Lower compression roll – Moves lower punches vertically upward to the die cavity. (G) Upper compression roll – Moves upper punches downward to the die cavity. (H) Raising action – Upward movement of punch subsequent to passing over the upper compression roll (G). (I) Lower cam action – Upper movement of lower punch subsequent to lower punch passing over lower compression roll. This action causes the tablet to be flush with the upper die. (J) Tablet ejector device – The function of this device is to eject the tablet from the die with the completed tablet collecting in a container outside the tablet press enclosure.

Figure 7.7 Typical tablet pan coater.

Figure 7.8 Flowchart for gelatin manufacturing.

Figure 7.9 Empty gelatin capsule sizes.

Figure 7.10 Process of filling gelatin capsule.

Chapter 08

Figure 8.1 Formation of zinc ions in dilute acid.

Figure 8.2 Corrosion conditions.

Figure 8.3 Corrosion at the anode and formation of hydrogen gas.

Figure 8.4 Concentration cell corrosion formation.

Figure 8.5 Pourbaix diagram of water.

Figure 8.6 Pourbaix diagram for aluminum.

Figure 8.7 Pourbaix diagram for chromium.

Chapter 09

Figure 9.1 Molecular structure of bis(2,4‐di‐

tert

‐butlylphenyl)phosphate.

Chapter 10

Figure 10.1 Specification 262813 (Division 26, Subsection 2813): Fuses.

Chapter 11

Figure 11.1 Gaussian distribution (bell‐shaped curve).

Figure 11.2 Relationships between accuracy and precision.

Figure 11.3 Differences between accuracy and precision.

Figure 11.4 Process losses and the target value.

Figure 11.5 The effect of consistently hitting the target and the goalpost analogy to production specifications.

Guide

Cover

Table of Contents

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Practical Pharmaceutical Engineering

Gary Prager

Livingston, NJ, US

This edition first published 2019© 2019 John Wiley & Sons, Inc.

All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by law. Advice on how to obtain permission to reuse material from this title is available at http://www.wiley.com/go/permissions.

The right of Gary Prager to be identified as the author of this work has been asserted in accordance with law.

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Limit of Liability/Disclaimer of WarrantyIn view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of experimental reagents, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each chemical, piece of equipment, reagent, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. While the publisher and authors have used their best efforts in preparing this work, they make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives, written sales materials or promotional statements for this work. The fact that an organization, website, or product is referred to in this work as a citation and/or potential source of further information does not mean that the publisher and authors endorse the information or services the organization, website, or product may provide or recommendations it may make. This work is sold with the understanding that the publisher is not engaged in rendering professional services. The advice and strategies contained herein may not be suitable for your situation. You should consult with a specialist where appropriate. Further, readers should be aware that websites listed in this work may have changed or disappeared between when this work was written and when it is read. Neither the publisher nor authors shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages.

Library of Congress Cataloging‐in‐Publication Data

Names: Prager, Gary, 1943– author.Title: Practical pharmaceutical engineering / Gary Prager.Description: First edition. | Hoboken, NJ : John Wiley & Sons, 2019. | Includes index. |Identifiers: LCCN 2017058784 (print) | LCCN 2018005908 (ebook) | ISBN 9781119418849 (pdf) | ISBN 9781119418719 (epub) | ISBN 9780470410325 (cloth)Subjects: LCSH: Pharmaceutical technology. | Biochemical engineering. | Production engineering.Classification: LCC RS192 (ebook) | LCC RS192 .P73 2018 (print) | DDC 615.1/9–dc23LC record available at https://lccn.loc.gov/2017058784

Cover design by WileyCover image: © hakkiarslan/Getty Images

Preface

The purpose of this text is to serve several purposes. The main intent is to provide a working knowledge for personnel involved in various aspects of pharmaceutical operations with technical and engineering tools to address tasks not necessarily related to their particular expertise. For instance, a chemist dealing with quality control issues can, after using the information contained in parts of Chapter 3 (Heating, Ventilating, and Air Conditioning (HVAC)), have the basic tools to deal with germane HVAC issues, should he be selected to represent the quality control user on a team responsible for design, construction, and installation of an HVAC system for a quality control laboratory. At a minimum the information provided should allow one to have a basic understanding of issues that may arise during the contractor/user briefings.

As a practical source of material for dealing with common engineering issues that arise, the intent is to also provide a basis to deal with resolving common situations encountered in pharmaceutical operations; it is not intended to present esoteric problems and/or situations requiring detailed resolutions and solutions. Such complex technical problems are not often encountered in “real‐life” situations. The majority of the examples are based on everyday working situations. The need to design and size a bioreactor is performed by vendors, and the installation, commissioning, and validation are generally the responsibility of the owner/operator. Consequently, details such as verifying motor sizing and performance are typically common concerns of the user; knowing how to quickly determine motor revolutions per minute (rpm) during validation is more of a common task than detailed design of a shell and tube heat exchanger, albeit a knowledge of both topics are important for successful results.

This approach is particularly relevant since the era of in‐house process engineering and design is becoming more and more irrelevant in pharmaceutical operations, as evidenced by the diminishing need for corporate design specifications and design standards and outsourcing of detailed design projects.

As a result of this redirection of assets, the emphasis on pharmaceutical engineering is now more project oriented rather than process design and modifications performed by in‐house engineering operations. For instance, preparation of P&IDs is, for the most part, the responsibility of the contractor, consultant, or system vendor, ergo, the emphasis on quick and practical results.

While intended as a practical tool for practical pharmaceutical operations, this text can be envisioned as an instructional tool for an undergraduate engineering course that can augment standard coursework such as unit operations, thermodynamics, organic chemistry, biochemistry, and reaction kinetics, when considering a pharmaceutical engineering introductory course. An instructor could devise related exercises that can conform to the existing curricula (creation of appropriate exercises could also be a one or two credit graduate problem).

Since many pharmaceutical engineering courses are evening classes, the instructor could have the proposed problems be compatible with the requirements and interests of the students.

This approach would “customize” the course content.

Of course, the intent of this text is to provide an informative, useful source for many existing and evolving areas of pharmaceutical and biotechnology operations. Hopefully, it can serve as a beginning point for projects and/or a refresher for others.

While this text is authored and not edited, a great deal of assistance by others was required for completion. My friend and longtime associate, Stuart Cooper, PE, is a major reason impetus for this task. His detailed commentary to my input and his IT skills are truly masterful. Stu, my heartfelt thanks for your contributions. Also, special thanks to William B. Jacobs, PhD, whose regulatory knowledge helped make a more cohesive product. The contribution by Robert Bracco of Pfizer helped make his tableting operations input a more complete presentation.

Professor Angelo Perna, Professor Deran Hanesian, and Ed May of NJIT also assisted with their content advice and encouragement.

A special “thanks” is in order for my Wiley editors and staff, Bob Esposito, Michael Leventhal, Beryl Mesiadhas, and Vishnu Narayanan for their input and monitoring of this text.

Often, there is one person who can influence your life significantly as both a teacher and mentor. In my life this individual was the late Dr. T.T. Castonguay of the University of New Mexico Chemical Engineering Department. In addition to forcing us to master the basics, his “life lessons,” integrated with class work, served as a foundation for many alums; thanks, Doc., and, of course, a bittersweet thank you to my late wife Robin. Despite her condition, she always managed to keep me focused on this task; I’ll always miss you.

1US Regulations for the Pharmaceutical Industries

CHAPTER MENU

Introduction

The FDA: Formation of a Regulatory Agency

FDA’s Seven Program Centers and Their Responsibility

New Drug Development

Commercializing the New Drug

Harmonization

Review Process of US NDA

Current Good Manufacturing Practice in Manufacturing, Processing, Packing, or Holding of Drugs

Compliance

Electronic Records and Electronic Signatures

Employee Safety

US EPA

Process Analytical Technology

Conclusion

References

Further Reading

1.1 Introduction

In brief, the Food and Drug Administration (FDA) is tasked with protecting the public health of residents of the United States. It is not the only agency within the government that can identify with that goal, but it is the agency that is responsible for ensuring citizens safe, efficacious access to an array of products that include food, drugs, and medical devices. The scope of this chapter is to concentrate on the pharmaceutical aspects of the FDA’s mission; however, it is important to understand the structure of the agency, its history, and its role in the regulatory arena.

In an ideal world, there would be no need for oversight, as all actions would be for the general good of society as a whole, as opposed to individual gain at the unfair expense, be it monetary, health, or some other metric, of others. That is not a political statement, but rather leads to an understanding that most regulations, and certainly the establishment of most of regulatory agencies, come about as the result of egregious acts that call for remedy. That is not to say that organizations have not been created as advisory advocates for industries, independent of scandal, as in the creation of the US Pharmacopeia (USP [1]) in 1820 and the Association of Official Agricultural Chemists (now AOAC International [2]) in 1897; however, the establishment of regulatory agencies historically has been reactive rather than proactive.

It would be naïve, however, to suggest that regulatory agencies, including the FDA, are independent of political influence; they are not, nor can they be, given the structure of our legal system. The centerpiece of our legal system is the US Constitution, which establishes the structure of our country and also defines how we self‐regulate. The legislative branch, working within the framework of the Constitution, establishes federal statutes (or legislations) that reinforce the principles of the Constitution and establish control of our society. The rules and proposed rules, as well as notices of federal agencies and organizations, executive orders, and documents are published daily in the Federal Register.

The Code of Federal Regulations (CFR) is the codification of the rules posted in the Federal Register. It is updated once each calendar year and issued quarterly. There are currently 50 titles in the CFR, with 21 CFR covering Food and Drugs. This codification is meant to clarify regulations, denoting the intent of the legislation passed. However, as might be expected, the regulations are subject to interpretation. Ultimately, disputes about the interpretation of legislation, as well as its constitutionality, are clarified by the Judicial Branch, which reviews specific complaints or disputes and can elect to apply its opinion narrowly to the specific dispute or as an overarching opinion having much broader impact. At the time of publication, the CFR can be accessed online at http://www.ecfr.gov/cgi‐bin/ECFR?page=browse. This, as well as any other online address in this text, is subject to change.

The crafting of statutes, the codification of the legislation, and the interpretation of both the intent and the scope of regulations are all subject to the vagaries of human judgment and influence; hence the previous statement that regulatory agencies are subject to political influence. Reviewing the timeline of the formation of the FDA as provided on its own website (http://www.fda.gov/AboutFDA/WhatWeDo/History/Milestones/ucm128305.htm) illustrates the difficulty of establishing regulation in the face of competing influences. Be that as it may, once the regulations and regulatory agencies are established, there has historically been remarkable resistance to the politicization of the agencies themselves. The “greater good” prevails.

1.2 The FDA: Formation of a Regulatory Agency

The seminal event that led to the formation of the precursor to the FDA was the discovery of adulterated antimalarial drugs (quinine) being imported into the United States at time when malaria was a major health concern. In 1848 Congress required US Customs Service inspectors to stop the importation of these drugs when it passed the Drug Importation Act, effectively sealing off the United States from unscrupulous overseas manufacturers. Almost 50 years later, it was again the US Customs Service that was tasked, at importers expense, with the inspection of all tea entering the United States when the Tea Importation Act of 1897 was implemented.

In 1862, President Abraham Lincoln appointed Charles M. Wetherill, a chemist, to serve in the newly created US Department of Agriculture (USDA). The USDA housed the Bureau of Chemistry, a precursor to the FDA, where Wetherill began investigating the adulteration of agricultural products. Succeeding USDA Chief Chemists Peter Collier (1880) and Dr. Harvey W. Wiley (1883) expanded the food adulteration studies and campaigned for a federal law regulating foods. For his efforts, Dr. Wiley is regarded as the “Father of the Pure Food and Drugs Act,” having vigorously crusaded for its eventual passage.

In 1902 the Biologics Control Act was passed to ensure purity and safety of serums, vaccines, and similar products used to prevent or treat diseases in humans by licensing biologics manufacturers and regulating the interstate commerce of biologics.

The first major legislation was passed in response to growing outrage, fanned by muckraking writers, over the unsanitary conditions in meat‐packing plants and the presence of poisonous preservatives and dyes in foods. The original Food and Drug Act was passed in 1906 prohibiting interstate commerce of misbranded or adulterated foods, drinks, and drugs. The Federal Meat Inspection Act was passed the same day. The next year, the Certified Color Regulations listed seven color additives that were considered safe in food. Poisonous, colorful coal‐tar dyes were banned from foods.

From 1912 to 1933, a series of minor back‐and‐forth legislative and judicial rulings effectively increased the regulations against misleading therapeutic statements, mislabeling of contents, and other deceptive practices. Also imposed were more stringent requirements for the dispensing of narcotic substances and the qualitative and quantitative labeling of package contents. Still under the auspices of the USDA, the precursor to the FDA began to be separated from nonregulatory research, which was placed under the aegis of the Bureau of Chemistry and Soils in 1927. The beginning of the separation of regulation of meat and dairy products from FDA control began in 1930, the same year the name was officially changed to the FDA.

This new agency recommended a complete revision of the obsolete 1906 Food and Drugs Act, launching a 5‐year legislative battle. The second major regulatory revision, the 1938 Federal Food, Drug, and Cosmetic Act (FD&C) was largely passed as a result of a 1937 incident in which 107 persons were killed by consuming Elixir Sulfanilamide containing the poisonous solvent diethylene glycol. As a result, new provisions were added:

Control was extended to cosmetics and therapeutic devices.

New drugs were required to be shown to be safe

prior

to marketing.

Eliminated the need to prove intent to defraud in misbranding cases.

Provided safe levels of poisonous components that were unavoidable.

Authorized standards of identity, quality, and fill weights for foods.

Authorized inspections of manufacturing facilities.

Added court injunctions to the previously authorized penalties of seizures and prosecutions.

That same year, however, regulation of advertising of all FDA‐regulated products with the exception of prescription drugs was transferred to the Federal Trade Commission (FTC).

In 1940, the FDA was transferred from the USDA to the Federal Security Agency, precursor to the Department of Health, Education, and Welfare (HEW). In the 1940s a Supreme Court decision extended liability for violations by companies to officials responsible within the company regardless of their knowledge of the violations. Two particular amendments were passed requiring the FDA to test and certify the purity and potency of the drugs insulin and penicillin. Other legislation extended the reach of government and the maintenance of public health and confirmed the agency’s regulatory control over interstate commerce. At the end of the decade, the FDA published for the first time guidance to the industry and procedures for appraisal toxicity of chemicals in food.

In the 1950s, there was an increased oversight of both food and drug products, including their labeling. Drugs that required medical supervision were restricted in their sale, requiring a licensed practitioner to authorize purchases. The purpose for which a drug is offered was required to be on the label as part of the directions for use of that product. The factory inspection was found to be too vague and therefore was reinforced by a further amendment in 1953. The FDA increased its oversight of the safety of foods with the Miller pesticide amendment, the food additives amendment, and the color additives amendment.

In the 1960s the United States was spared of the tragedy suffered by Western European families because the drug thalidomide was kept off the US market, preventing birth defects affecting potentially thousands of babies. This success, by the FDA medical officer Frances Kelsey, aroused strong public support for stronger drug regulation. As a result the Kefauver–Harris drug amendments were passed to ensure drug efficacy and greater drug safety. These amendments required that drug manufacturers prove to the FDA the effectiveness of their products before placing them on the market. The FDA contracted with the National Academy of Sciences and National Research Council to evaluate the effectiveness of 4000 drugs that had been approved on the basis of safety alone between 1938 and 1962. Other legislation enacted in the 1960s included Drug Abuse Control Amendments, to combat abuse of stimulants, depressants, and hallucinogens, and a Consumer Bill of Rights.

In the 1970s further consumer protections were put into place with the first patient package insert for oral contraceptives that delineated the risks and benefits of taking the drug. The Comprehensive Drug Abuse Prevention and Control Act replaced previous laws and categorized drugs based on abuse and addiction potential versus their therapeutic value. Some responsibility shifted among government agencies with the Environmental Protection Agency (EPA) taking over the FDA program for setting pesticide tolerances. Regulation of biologics – including serums, vaccines, and blood products – was transferred from the National Institute of Health (NIH) to the FDA. Over‐the‐counter drug reviews began to enhance the safety, effectiveness, and labeling of drugs sold over‐the‐counter. The Bureau of Radiological Health was transferred to the FDA to protect humans against unnecessary exposure to radiation from products in the home, in industry, and in healthcare professions.

The 1980s saw the FDA revise regulations on drug testing, greatly increasing protections for subjects upon whom new drugs were tested. In reaction to deaths caused by cyanide placed in Tylenol bottles, packaging regulations requiring tamper‐resistant closures was enacted. The FDA also promoted research and marketing of drugs needed for treating rare diseases with the Orphan Drug Act. To promote competition and lessen costs, the FDA allowed the marketing of generic versions of brand‐name drugs without requiring repeating the research necessary to prove them to be safe and effective. At the same time, they gave brand‐name companies the right to apply for up to 5 years of additional patent protection for the new medicines they had developed to make up for the time lost, while the products were going through the FDA’s approval process.

Acquired immune deficiency syndrome (AIDS) tests for blood were approved by the FDA to prevent the transmission of the causative agent to recipients of blood donations. The marketing of prescription drugs was limited to legitimate commercial channels in order to prevent the distribution of mislabeled, adulterated, subpotent, and/or counterfeit drugs to the public.

Investigational drug regulations were revised, expanding access to investigational drugs for patients with serious diseases with no alternative therapies. This trend was continued in the early 1990s as regulations were established to accelerate a review of drugs for life‐threatening diseases.

In 1994 the Dietary Supplement Health and Education Act established specific labeling requirements, a regulatory framework, and authorized the FDA to promulgate good manufacturing practice (GMP) regulations for dietary supplements. Dietary supplements and dietary ingredients were classified as food, and a commission was established to recommend how to regulate any claims appearing on the labels. As a result of this, 21 CFR part 111 Current Good Manufacturing Practice (cGMP) in manufacturing, packaging, labeling, or holding operations for dietary supplements was established.

Also in the 1990s was a relaxation of some regulations on pharmaceutical manufacturers including an expansion of allowable promotional material on the approved use of drugs. It was during this period that the FDA attempted to extend its reach to the tobacco industry, defining nicotine as a drug and smoking or smokeless tobacco products to be combination of drug delivery systems, restricting the sale of such materials to minors. The FDA was forced to rescind its rule in 2000 when the Supreme Court upheld a lower court ruling supporting a lawsuit by a tobacco company against the FDA.

In the 1990s there was increased focus on the effectiveness of drugs as influenced by gender and, in 2002, in children. This was a reaction to the discovery that drugs commonly tested on male subjects left unresolved the question of how female subjects responded to exposure to these drugs. Similarly, the safety and efficacy of drugs prescribed for children was required.

In the 2000s there was again a response to the current events. The Public Health Security and Bioterrorism Preparedness and Response Act of 2002 was designed to improve the country’s ability to prevent and to respond to public health emergencies. In response to questions about the jurisdiction of various departments within the FDA, the Office of Combination Products was formed to oversee products that fall into multiple jurisdictions, for example, medical devices that contain a drug component.

The cGMP initiative focused on the greatest risks to public health in manufacturing procedures applying a consistent approach across FDA. It also ensured that process and product quality standards did not impede innovation of new products.

In general, in this new century the FDA has continued to respond and grow in three main areas:

Responding to specific external forces, as in COX‐2 selective agents and dietary supplements containing ephedrine alkaloids as health risks. The Drug Quality and Security Act (DQSA) of 2013 in response to an epidemic of fungal meningitis linked to a compounded steroid, among other provisions, outlined steps for an electronic and interoperable system to identify and trace certain drugs throughout the United States.

The FDA increased its influence on product development (for both human and nonhuman species) by encouraging specific remedies and also by expanding how the FDA can collaborate in the process of developing therapeutic products from laboratory to production to end use. Establishment of user fees for drugs, medical devices, and biosimilar biologic agents that are targeted to fund expedited reviews.

Has promoted a continuation of improved dissemination of information to both physicians and patients.

In summary, the FDA was created out of necessity in response to events that threatened the health and safety of citizens with regard to their food and medical supplies. It has continued to oversee our food and drug supply for both humans and animals as it has evolved. Perhaps the most influential pieces of legislation were the Food and Drugs Act of 1906, the Food Drug and Cosmetic Act of 1938, the Kefauver–Harris Amendments of 1962, and a Medical Device Amendments of 1976. Until 1990 all US laws and regulations relating to medical products were in reaction to medical catastrophes. A proactive stance, with new laws and regulations written to avoid medical calamities began in the 1990s.

There are corresponding agencies around the world that operate independently according to their individual mandates from their legislative bodies. In some cases the relations in the United States are more restrictive than those agencies of other countries; in other cases the United States is less restrictive in its oversight. Given the ever‐increasing interrelationships of multinational companies and their markets, there is great impetus to align the regulatory requirements of individual countries into harmonized code. International agencies are working toward that end at this time. However, the trend in regulation, while vacillating, has been toward the more restrictive, including more detailed accountability and traceability of all products. This is likely to continue.

With the trend toward greater regulation, greater international harmonization and acceptance of the FDA as a partner in producing safe, efficacious, high‐quality products, and learning to work with this development will be most beneficial not only for the consumers but also to the manufacturers. The FDA focuses on ensuring public safety within the scope of their mandate, and it is in the best interest of all. Rather than view the FDA as an adversary to be controlled, the FDA should be viewed as a partner in product development.

1.3 FDA’s Seven Program Centers and Their Responsibility

1.3.1 Center for Biologics Evaluation and Research

This is the center within the FDA that regulates biological products for human use including blood, vaccines, tissues, allergenics, and cellular and gene therapies. Biologics are derived from living sources and many are manufactured using biotechnology. They often review cutting‐edge biomedical research, evaluating scientific and clinical data submitted to determine whether or not the products meet the Center for Biologics Evaluation and Research (CBER)’s standards for approval. The approvals may be for newly submitted biologicals or for new indications for products already approved for a different purpose.

1.3.2 Center for Drug Evaluation and Research

The Center for Drug Evaluation and Research (CDER) oversees over‐the‐counter and prescription drugs including biological therapeutics and generic drugs. For regulatory purposes, products such as fluoride toothpaste, antiperspirants and dandruff shampoos, and sunscreens are all considered to be drugs.

1.3.3 Center for Devices and Radiological Health

FDA’s Center for Devices and Radiological Health (CDRH) is tasked with eliminating unnecessary human exposure to man‐made radiation from medical, occupational, or consumer products in addition to ensuring the safety and effectiveness of devices containing radiological materials. The CDRH is particularly concerned about the lifecycle of the product from conception to ultimate disposal in a safe manner.

1.3.4 Center for Food Safety and Applied Nutrition

Center for Food Safety and Applied Nutrition (CFSAN) is responsible for ensuring a safe, sanitary, wholesome, and properly labeled food supply. It is also responsible for dietary supplements and safe, properly labeled cosmetic products. As needed, it may work in conjunction with other centers as, for example, with CDER or enforcement of the FD&C Act or products that purport to be cosmetics but meet the statutory definitions of a drug.

1.3.5 Center for Veterinary Medicine

The Center for Veterinary Medicine (CVM) regulates the manufacture and distribution of food additives, drugs, and medical devices that will be given to animals. The animals may be either for human consumption or companion animals. One growing area of interest is that of genetically modified or genetically engineered animals. The FDA has expressed an interest in regulating these animals; however, depending upon the animal species and its intended use, the FDA will regulate these animals in combination with other federal departments and agencies such as the USDA and the EPA.

1.3.6 Office of Combinational Products

Combination products are defined in 21 CFR 3.2(e) as:

A product composed of two or more regulated components, i.e. drug/device, biologic/device, drug/biologic, and drug/device/biologic, that are physically or chemically combined or mixed and produced as a single entity.

Two or more separate products packaged together in a single package or as a unit and composed of drug and device products, device and biological products, or biological and drug products.

A drug, device, or biological product packaged separately that according to its investigational plan or proposed labeling is intended for use only with an approved individually specified drug, device, or biological product where both are required to achieve the intended use, indication, or effect and where upon approval of the proposed product the labeling of the approved product would need to be changed, e.g. to reflect a change in intended use, dosage form, strength, route of administration, or significant change in dose.

Any investigational drug, device, or biological product packaged separately that according to its proposed labeling is for use only with another individually specified investigational drug, device, or biological product where both are required to achieve the intended use, indication, or effect.

1.3.7 Office of Regulatory Affairs

The Office of Regulatory Affairs (ORA) oversees the field activities of local FDA field operations. It also provides FDA leadership on imports inspections and enforcement policy, inspects regulated products and manufacturers, conducts sample analyses of regulated products, and reviews imported products offered for entry into the United States. The ORA also advises the commissioner and other officials on regulations and compliance‐oriented matters and develops FDA‐wide policy on compliance and enforcement. The ORA develops and/or recommends policy programs and plans activities between the FDA and state and local agencies.

1.4 New Drug Development

While the overall focus of this book is on the manufacture of pharmaceuticals, it is useful to understand how drugs are developed. Every new formulation must undergo a series of tests to prove it is both safe and efficacious to the consumer. The FDA estimates that it takes over 8 years, from concept to approval for public consumption of a new drug. At any stage in the investigation, or during postmarket evaluations, the drug may be deemed unsafe and restricted from market. The FDA does not actually test the drug itself for safety and efficacy, but rather reviews data submitted by the drug company sponsor.

1.4.1 Discovery

A typical drug development pathway involves the generation of large numbers of molecules of similar structures with the intention of identifying the most promising candidates for further development. The rationale behind this is that slight variations on a known structure may attenuate the behavior of the known molecule in a desirable fashion. That is to say, substitution on a well‐characterized structure may be expected to increase beneficial properties of the chemical or alternately decrease detrimental characteristics.

The discovery of a new drug involves more than formulation development. On the lab scale, research and development will determine the potential drug stability and active ingredients, as well as any other requirements. A formal protocol for nonclinical studies must be designed to establish exactly how the preclinical study will be performed, including the types of animals to be tested, the duration and frequency of the test, and how the data will be handled. Finally chemistry, manufacturing, and controls (CMC) will be established to allow larger scale production of the drug under GMP.

Scale up from bench to manufacture requires consideration of the following:

Active ingredients: identity, purity, and stability.

Raw materials specifications and identification.

Intermediate products.

Filtration and/or purification process.

Solubility, particulate size, disintegration, dissolution (for pills and capsules).

Sterility requirements.

Final drug specifications.

Dose uniformity.

Required QC tests.

Methodologies for QC assays.

Validations: QC assay method

Equipment

Cleaning

Record keeping and documentation

The pertinent area of the CFR regarding investigation into the potential of a new drug for human use is 21 CFR 312, Investigational New Drug Application (IND or INDA). In this part of the regulations, procedure requirements governing use of investigational new drugs including stipulations for the submission for review to the FDA are found.

1.4.2 Investigational New Drug Application

It is illegal to transport unapproved drugs across state lines for any purpose. Thus there exists the necessity to request an exemption from this federal statute in order to conduct clinical trials. In order to transport a new unapproved drug, an IND or INDA must be filed to get an exemption from the statute. Form 1571 can be obtained from the FDA website (http://www.fda.gov/opacom/morechoices/fdaforms/cder.html).

Required information for the submission includes the data collected from the preclinical animal pharmacology and toxicology studies, showing the safety of the proposed drug. It must be demonstrated that the manufacturer can reliably reproduce and supply consistent batches of the said drug, so information about the composition, manufacture stability, and controls for manufacture must be supplied. Finally the detailed protocols for the proposed clinical studies, including the qualifications of the clinical investigators, and commitments to obtain informed consent from the research subjects, commitments to review the study by an institutional review board (IRB), and a firm commitment to adhere to investigational new drug regulations must be submitted.

The investigation of a drug for potential human applications is initiated and overseen by a sponsor committed to properly conduct a study, be they an institution or organization, a company, or even an individual. They are responsible for the management, from start to finish, of a clinical trial. Alternately, they may provide financing for the study by investigators who will actually initiate and complete the study. The sponsor does not, however, relinquish responsibility simply by financing a project proposed by an individual investigator.

Once the required NDA is submitted to the FDA, it is assigned an IND number that is to be used in all correspondence with the FDA regarding the application. The FDA or more specifically the CDER will review the IND. The IND is reviewed on medical, chemistry, pharmacology/toxicology, and statistical bases to review the safety of the proposed study. If the review is complete and acceptable with no deficiencies, the study may proceed. If not, a clinical hold is placed on the study and the sponsor is notified, affording him the opportunity to submit new data.

INDs are not approved by the FDA. An IND becomes effective 30 days after receipt by the FDA unless a clinical hold is imposed. The clinical hold can be placed at any time and is an order by the FDA to suspend or delay a proposed or ongoing clinical investigation. The clinical hold is commonly placed upon the study for deficient study design, unreasonable risk to subjects, inclusion of an unqualified investigator, misleading investigator brochure submission, or insufficient information to assess the risk to test subjects.

Once the IND is in effect, it must be maintained so that current information is submitted to the FDA. Toward this end, amendments are made to the original protocol. These may be either protocol amendments or information amendments. Three types of protocol amendments may be submitted: for a new protocol, a change in protocol or a new investigator carrying out a previously submitted protocol. Informational amendments fall outside the scope of the protocol amendments. An information amendment is any amendment to an IND application with information essential to the investigational product that is not within the scope of protocol amendments, safety reports, or annual reports. This may include new technical information or discontinuation of the clinical trial.

A written safety report that transmits information about any adverse drug experience or adverse events associated with the use of the drug is to be submitted to the FDA and all participating investigators along with Form 3500A as soon as possible, but no more than 15 calendar days after initial notification to the sponsor. In the case of serious adverse events, the report must be submitted no later than 7 days after the receipt of information by the sponsor. The sponsor will follow up and investigate all safety and relevant information and report to the FDA as soon as possible.

An annual report is to be sent to the FDA to update the IND about the progress of the investigation and all changes not reported in amendments or other reports. It should be submitted within 60 days of the calendar date that the IND went into effect.

Additionally, meetings may be scheduled with the FDA at various stages of investigation. Meetings may be held pre‐IND to discuss, for example, CMC issues. Meetings may also be held at the end of Phase I, Phase II, or pre‐new drug application (NDA).

The IND can be withdrawn by the sponsor at any time without prejudice. The FDA and all pertinent IRBs will be notified. Any remaining drugs will be disposed of by the sponsor or returned to the sponsor.

An IND may go on inactive status at the request of the applicant or the FDA if, for example, no human subjects entered the study within a period of 2 years, or if the IND remains under a clinical hold for 1 year or more. An inactive application may be reactivated if activities under the IND have recommenced. An IND that remains on inactive status for 5 years or more may be terminated.

The IND may also be terminated for cause by the FDA. Such cause may be determination that test subjects may be exposed to significant or unreasonable risk or if methods, facilities, and controls used for the manufacturing are inadequate to maintain appropriate standards for quality and purity of the proposed drug as needed for subject safety. Additional grounds for termination may be found in 21 CFR 312.44.

1.4.3 Preclinical Studies (Animal)

Before a drug can be tested on a human being, it must be shown to be safe. This can be established by compiling data from previous nonclinical studies on the drug, by compiling data from previous clinical testing or data from markets in which the drug has previously been sold, if relevant, or new preclinical studies may be undertaken. Both in vivo and in vitro laboratory animal studies are used.

These preclinical studies must be able to show any potential toxic effects under the conditions of the proposed clinical trial. The toxicity studies should include single and repeated dose studies, reproductive studies, genotoxicity, local tolerance studies, and the potential for carcinogenicity or mutagenicity. Additionally pharmacology studies to establish safety and pharmacokinetic studies to determine how the drug reacts in the body (absorption, distribution, metabolism, or excretion) may be performed.

At this stage the FDA will generally ask for a pharmacological profile of the drug, a determination of the acute toxicity in at least two species of animals, and a short‐term toxicity study. Under 21 CFR 312.23(a)(8) the basic safety tests are most often performed in rats and dogs. Selection of a safe starting dose for humans, suggestion of the target organs subject to toxic reactions, and a margin of safety between therapeutic doses of a toxic substance will be established.

Good laboratory practice (GLP) covers several different aspects of preclinical studies. An organizational chart delineating responsibilities and reporting relationships is essential. A quality assurance unit (QAU) is required to ensure that the study takes place under GLP standards. The testing facility must be of the proper size and condition to allow proper conduct of the studies. Feed, bedding supplies, and equipment must be stored separately and protected from contamination. A separate space must be maintained for the storage of test and control items. Laboratory space for routine and specialized procedures must be separated and data reports and specimens must have a separate, limited access area.

Any equipment used for data collection or assessment must be maintained, calibrated, and kept clean. Written standard operating procedures (SOPs) must be maintained for all aspects of specimen or data handling. All prepared solutions and reagents must be properly labeled with the name of the contents, the concentration, the preparer, the expiration date, the date of preparation, and the required storage conditions.

There must be a written protocol that clearly indicates the objectives and methods for the study. The study must be conducted in accordance with the approved study protocol. Proper forms will be used for the collection of data. If data is collected manually, the data must be recorded legibly and in ink, at the time it is observed or determined, with the dated signature of the person collecting the data.

1.4.4 Clinical Studies

Once the IND is in effect, clinical trials may begin. These are conducted in at least three phases under good clinical practices (GCP).

1.4.4.1 Phase I Studies

Traditional Phase I studies are the first exposure of humans to the drug and are designed to evaluate how the drug acts in the body and how well it is tolerated. The human pharmacological studies evaluate the pharmacokinetic parameters, generally in healthy volunteers who are not the target market for the drugs, although some patients may be included in Phase I studies. These studies generally start out with single dose, followed by escalated dosage and short‐term repeated dose studies. These trials are very closely monitored. Well‐designed Phase I experiments will greatly aid the design of Phase II studies.

The FDA will periodically issue guidance to industry, outlining its then current thinking on pertinent topics. Such guidance does not establish legally enforceable responsibilities but rather should be viewed as recommendations. One such guidance was issued in June 2016, jointly by the CDER and the CBER providing information for industry, researchers, physicians, IRBs, and patients about the implementation of FDA’s regulation on charging for investigational drugs under an IND for the purpose of either clinical trials or expanded access for treatment use (21 CFR 312.8), which went into effect on 13 October 2009.

Another guidance was developed by the Office of New Drugs in the CDER in 2006 was for exploratory IND studies. There exists a great deal of flexibility in existing regulations regarding the amount of data that needs to be submitted with an IND application. This guidance suggests that industry as a whole has been submitting more information for an IND than is required by regulations. The guidance sought to clarify the manufacturing controls preclinical testing and clinical approaches that should be considered when planning limited early exploratory IND studies in humans. Within the guidance the phrase “exploratory IND study” is

“intended to describe the clinical trial that:

is conducted early in Phase 1

involves very limited human exposure, and

has no therapeutic or diagnostic intent (e.g., screening studies, micro dose studies).

These exploratory IND studies precede traditional Phase I dose escalation, safety, and tolerance studies of investigational new drug and biological products.