Practical Pharmaceutical Engineering

Gary Prager

• Publisher: Wiley
• Year: 2018
• Print ISBN: 9780470410325
• eBook ISBN: 9781119418719
• Edition: 1
• Topic: Biological Sciences
• Subtopic: Biotechnology
• Index: Biological Sciences

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 ofhow 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 ofHVAC 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.

1
US Regulations for the Pharmaceutical Industries

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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

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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 ...

Table of contents

• Cover
• Table of Contents
• Preface
• 1 US Regulations for the Pharmaceutical Industries
• 2 Pharmaceutical Water Systems
• 3 Heating, Ventilating, and Air Conditioning
• 4 Pressure Vessels, Reactors, and Fermentors
• 5 Reliability, Availability, and Maintainability
• 6 Parenteral Operations
• 7 Tableting Technology
• 8 Corrosion and Passivation in Pharmaceutical Operations
• 9 Pharmaceutical Materials of Construction
• 10 Commissioning and Validation
• 11 Topics and Concepts Relating to Pharmaceutical Engineering
• Index
• End User License Agreement