Microbial Contamination Control in Parenteral Manufacturing

Kevin Williams

• Publisher: CRC Press
• Year: 2004
• ISBN:
  9781135536213
• Edition: 1
• Topic: Medizin
• Subtopic: Pharmakologie

This reference surveys emerging trends, concepts, and procedures used in the characterization and control of contaminants; the sterile production of traditional drugs and biologics; the design, construction, and validation of new parenteral facilities; and the monitoring of clean environments-vividly illustrating the routes by which products, proce

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Historical and Emerging Themes in Parenteral Manufacturing Contamination Control

Kevin L.Williams

Eli Lilly and Company, Indianapolis, Indiana, U.S.A.

1.1. INTRODUCTION

Man has been described as an obligate aerobe. Oxygen floods the lungs, dissolves in the bloodstream, and spills into a thousand capillaries as a great waterfall aerates a mighty river. The same blood that brings oxygen is the route of choice for many Pharmaceuticals that can only reach the innermost depths of the body via this route to dispense their therapeutic properties. The word parenteral is derived from the Greek “para” (beyond) and “enteral” (gut) because it bypasses the digestive system. This route is so effective it necessitates a level of cleanliness that approaches the absolute. A single viable organism, bacteria or virus, thusly introduced into the body evades all but the final mechanism of defense and so the medicine designed to bring life could bring infection, fever, shock, or death. Man’s war against microbes is never ultimately won. They are deeply entrenched in the air, water, and soil. The body itself is occupied: 1% or more of the human genome consists of retroviral sequences, and microbes on and in the body outnumber the cells that compose the body by 10- to 20-fold (1). Microbes are legion; ubiquitous, unmerciful, and untiring. On a personal basis, those occupying us now, or their offspring, will decompose us when we die. They can be eradicated only in small places and for a short time.

It is desirable to step back and view, even rudimentarily, the scientific, regulatory, and technological events (historical and contemporary) that contribute to the current state of complexity encompassing the control of contaminants in the manufacture of parenteral drugs. Many of the references chosen here are review articles that will facilitate basic and advanced inquiries into the relevant topics that are presented in this chapter as an overview and that contrast in that regard to the highly specialized chapters to come.

Parenterals require sterility in every case; there is no gray area in that regard. Why then is “contamination control” relevant to parenteral manufacturing? Contamination control occurs at a multitude of sites along the series of processes that lead inevitably to the final result that is a sterile product.

1.2. THE BIRTH OF MICROBIOLOGICAL THEORY

The birth of modern microbiology in the later ninenteenth century heralded by Louis Pasteur, Robert Koch, Joseph Lister, and others began the quest to clarify the bacterial causation and mechanisms of infection. Though Anton van Leeuwenhock, the “uneducated” Dutch merchant and amateur microscope maker, made detailed observations of microorganisms, even proposing a role in disease causation in letters to the Royal Society in London between 1675 and 1685, the new paradigm of microscopic life was not generally accepted as fact for at least another 200 years (2). Pasteur’s refutation of spontaneous generation, description of fermentation as a by-product of microorganisms, ideas on putrefication, and invention of pasteurization (3) dispelled many of the prevalent myths of the day, sometimes in dramatic fashion (i.e., swan-necked flask). Lister, meanwhile, elaborated his “germ theory” from Glasgow and performed the first successful antiseptic operation using carbolic acid (phenol) to steam-sterilize medical instruments. The work of Pasteur and Lister served to dispel the thought that vapors (“miasma,” or bad air as it was called) and other vague forms of suspected “contagion” by gases held any role in disease causation (4). Though Edward Jenner developed the first vaccine using the cowpox virus 100 years before Pasteur, it was Pasteur who knowingly manipulated living microbes to alter the course of disease. He heated anthrax bacilli and dried the spinal cords of rabies-infected rabbits to develop vaccines against anthrax in sheep (1881) and rabies in man (1885), respectively (5).

In the late 1870s, Robert Koch established that individual types of microbes were associated with specific diseases, including anthrax and tuber-culosis (6). Koch laid out postulates purporting the conditions that must be met prior to regarding an organism as the cause of a given disease. His postulates were as follows: (a) the organism must be present in every case under conditions explaining the pathological changes and clinical symptoms, (b) the organism must not be associated casually with other diseases, and (c) after isolation from the body and cultivation in pure culture, the organism must be able to produce the disease in animals. Koch refined tools and techniques needed to prove his postulates, including solid agar and a method of isolating singular bacterial colonies by means of a heated inoculating loop. Both tools remain staples of the microbiological trade. Koch’s methods led to the rapid identification of the specific bacteria associated with many of the infectious diseases of the late 1800s and early 1900s. The Gram stain, invented by Hans Christian Joachim Gram in 1884 (4), proved to be a most useful tool in the study of fever causation in that it split the newly discovered bacterial world into two distinct groups that, unknown at the time, included those containing endotoxin and those that did not (7). Because the cellular wall contents determined the amount of stain retained in the staining process, subsequent observations were based on cellular morphology and were not merely an arbitrary classification technique. These new theories and methods provided the a priori background for further research into the newly discovered microbial world, established the ubiquity of microorganisms as causative agents of disease, and underscored the rational processes on which to base research into aseptic technology and disease prevention and cure.

1.3. HISTORICAL DEVELOPMENT AND REGULATION OF PARENTERAL DOSAGE FORMS

The manner of origin of most dosage forms is largely unknown. Early humans may have fashioned primitive injections modeled after venomous snakes or insect bites and stings (natural puncture injections). Asians inoculated for the prevention of smallpox by pricking with needles dipped in pus centuries before the technique was used in Western cultures. Jenner performed the same in 1796 using a cowpox sore (8). Sir Christopher Wren was first to inject a drug in 1657, a technique which was later used routinely by the English practitioner Johan Major in 1662. In the early 1800s, Gaspard experimented by injecting putrid extracts into dogs (9). Doctors experimented with injecting some potentially useful compounds and some bizarre and even fatal substances. Stanislas Limousin invented the ampule in 1886, and Charles Pravex of Lyons suggested the hypodermic syringe in 1853. The Royal Medical and Chirurgical Society of London approved hypodermic injections in 1867 concurrently with the first official injection (Injectio Morphine Hypodermica) published in a monograph in British Pharmacopoeia (8). Early progress in injectable therapy was slowed by fever occurrences and other symptoms associated with the crude state of early parenteral manufacturing. Exceptions existed that allowed progress, notably Ehrlich’s use of hypodermic injections of salvarsan for syphilis in 1910 (8). Martindale and Wynn proposed active manufacturing techniques to produce aseptic salvarsan in the same year that Hort and Penfold were describing the active agent in producing fevers (bacterial endotoxin) (10).

It is interesting to note that the very first parenteral applications, vaccines, were in effect contaminated solutions used to trigger the body’s immune response (rabies, tetanus, tuberculosis, smallpox). The concept of sterility was introduced at the beginning of parenteral manufacturing and was first required in the ninth revision of the U.S. Pharmacopeia in 1916 and was accompanied by an introductory chapter on achieving sterility. The only parenteral solutions included at the time were distilled water, solution of hypophysis, and solution of sodium chloride (11). The fever that accompanied early injections was believed to be due to the route of administration (i.e. the body’s response to being pricked by a needle) rather than being viewed as a drug contaminant, and it was therefore referred to as “injection fever.” In 1912 Holt and Penfold published several conclusive studies, including “Microorganisms and Their Relation to Fever” (10). The pair demonstrated that (a) the toxic material originated from gram-negative bacteria (GNB), (b) the pyrogenic activity in distilled water correlated to the microbial count, (c) dead bacteria were as pyrogenic as living ones, and (d) a rabbit pyrogen test could be standardized and used to detect occurrence of endotoxin in parenteral drugs.

The work of Hort and Penfold was largely overlooked until 1923 when Florence Seibert in the United States explored the causes of pyrogenicity of distilled water (12). She demonstrated conclusively that bacterial contamination was indeed the cause of “fever shots” (13). She determined that even minuscule, unweighable contaminants were biologically very active (14). During this time it became obvious to numerous investigators that GNB possessed a high-molecular-weight complex as part of their outer cell walls. The complex came to be called the endotoxic complex, which as a whole was thought to be responsible for the toxic, pyrogenic, and immunological response induced by GNB. Rademaker confirmed Siebert’s findings and stressed the importance of avoiding bacterial contamination at each stage of pharmaceutical production, pointing out that sterility is no guarantee of apyrogenicity (15). Nevertheless, it would be two decades before the U.S. National Institutes of Health and 14 pharmaceutical manufacturers undertook a collaborative study to establish an animal system to be used to determine the pyrogenicity of parenteral solutions. The first official rabit pyrogen test was incorporated into the 12th edition of the U.S. Pharmacopeia (USP) in 1942 (16).

A test for parenteral sterility (to support the 1916 contention that parenteral solutions should be sterile) originated in the British Pharmacopoeia in 1932 and in the U.S. Pharmacopoeia in 1936 (17). By 1936 there were 26 parenteral drug monographs in the National Formulary (NF VI), many of which were packaged in ampules (18). The methods of gauging sterility have been modified year in and year out since, but the basic concept of what sterility means has not changed. Halls lists some major limitations of the very first sterility test (17). Limitations associated with the necessity of demonstrating the lack of sterility from a quality perspective still exists in today’s test 70 years later:

1. The test presumed sterility. Even with the limitations of the sterilization technology of the 1930’s, the pharmacopoeia was presuming sterility unless nonsterility could be convincingly and conclusively demonstrated. This is rather unusual because it goes against the grain of scientific criticality to assume that a hypothesis is valid unless it can be proven otherwise. The test was ...

Table of contents

• Cover Page
• Title Page
• Copyright Page
• Preface
• Contributors
• 1: Historical and Emerging Themes in Parenteral Manufacturing Contamination Control
• 2: Microbial Origins, Microbiological Function, and Contamination Hazard Analysis in Sterile Product Manufacturing
• 3: Overview of Modern Parenteral Products and Processes
• 4: The Role of USP in the Microbiological Assessment of Parenteral Manufacturing
• 5: Sterility and Bioindicators
• 6: Biological Safety Cabinets and Isolators Used in Pharmaceutical Processing
• 7: Developing a Process for Aseptic Facility Design and Validation
• 8: Pharmaceutical Water Systems New Orientations in System Design
• 9: Airborne Contamination Control
• 10: Disinfection Practices in Parenteral Manufacturing
• 11: Sterile Filtration
• 12: Process Development of Alternative Sterilization Methods
• 13: Terminal Sterilization and Parametric Release
• 14: Raw Material Contamination Control
• 15: Endotoxin: Worst-Case Parenteral Pyrogen
• 16: Screening Active Pharmaceutical Ingredients and Excipients for Endotoxin
• 17: Viral and Prion Clearance Strategies for Biopharmaceutical Safety
• 18: Statistical Sampling Concepts
• 19: Environmental Monitoring
• 20: Prevention and Troubleshooting of Microbial Excursions
• 21: Simulation of Aseptic Manufacture
• 22: Standard Methods of Microbial Identification
• 23: Rapid Methods of Microbial Identification