Sterile Pharmaceutical Products

Process Engineering Applications

Kenneth E. Avis, KennethE. Avis

• Publisher: Routledge
• Year: 2018
• eBook ISBN: 9781351413862
• Topic: Medicine
• Subtopic: Pharmacology

Sterile Pharmaceutical Products: Process Engineering Applications addresses the key concepts and applications of the sterile pharmaceutical manufacturing industry. It covers elements of the design, installation, validation, and usage of critical processes associated with sterile product manufacture. From water systems to clean-in-place systems, to sterile powder handling and robotic applications in sterile production environments, this book addresses the issues of system implementation, integration, and operations. Written by recognized experts and peer reviewed for accuracy, all chapters include references to supplemental resources and numerous illustrations.

   1   

INTRODUCTION

Kenneth E. Avis

The University of Tennessee

This first volume in this series will address process engineering factors applicable to the manufacture of sterile pharmaceutical products. Frequently, processing decisions in the manufacture of these products are made by pharmaceutically trained individuals who have little or no experience or insight into engineering principles. Conversely, engineers called upon to implement engineering principles in a pharmaceutical processing operation may lack an essential understanding of pharmaceutical dosage form principles in order to properly design and fabricate the equipment or facilities required to achieve a high quality pharmaceutical product. Consequently, resulting communication gaps may cause development delays, costly redevelopment efforts, or even an inadequate plan of operation. Further, complications may be augmented by the inherently unique and critical requirements for the manufacture of sterile dosage forms of drugs. In addition, the FDA’s requirements for Good Manufacturing Practices (GMPs) in sterile product manufacturing may not be known or understood by the most skilled engineer.

There are numerous books and literature references available oriented to the pharmaceutical principles and practices required for the manufacture of high quality sterile products. However, there is an almost complete lack of reference material oriented to the engineer. This book is intended to help alleviate this lack of practical information for the process engineer.

The properties essential for sterile dosage forms of drugs are much more stringent than for most other drug dosage forms. They must have a purity level that approaches perfect freedom from chemical, physical, and biological contaminants, as close as current technology allows. They must be biologically sterile (i.e., free from the presence of detectable living microorganisms and from associated pyrogenic contaminants). Physical particles must be controlled to a low level with complete freedom from visible particles.

Pharmaceutical quality control is responsible for controlling the required purity of starting formulation ingredients, but process engineers have a major responsibility for designing and operating the process so that contaminants are not introduced and that high-purity standards for the product are achieved during the manufacturing process. These are usually summarized as “good manufacturing practices” or, simply, GMPs.

The process engineer may not be familiar with the full implications of GMPs, for there is a highly important legal aspect. The term Good Manufacturing Practices is also applicable to the regulations promulgated by the FDA. These regulations must be adhered to by the pharmaceutical industry in the manufacture of pharmaceutical products, including sterile dosage forms of drugs. Further, when a pharmaceutical manufacturer describes the process to be used in the manufacture of a product in a new drug application (NDA), once this is approved by the FDA the process cannot be changed without notification and/or approval by the FDA. The process engineer must understand these legal obligations, even though there are experts in the pharmaceutical company who are responsible for monitoring these matters and communicating with the FDA. The regulations do not prevent process improvements, but improvements can only be implemented after proper channels of notification and/or approval with the FDA have been followed.

CHAPTER CONTENTS

Following the introductory chapter, there are eight chapters that each address a different engineering aspect of sterile product processing. Chapter 2, “Engineering Control of the Aseptic Filling Environment,” by Howard Leary, focuses on the enclosure in which aseptic processing is to be carried out and on the machines used to process the product. It is recognized that no enclosure can be designed and operated free from all living microorganisms. Therefore, the goal is to minimize the presence and continuance of living microorganisms. This chapter first addresses the enclosure and what is required to control the environment in which aseptic processing can be successfully carried out. The problems associated with ingress and egress of people and supplies are given necessary consideration. A large portion of the chapter addresses the design and operation of the machinery used for aseptic filling. Not only must the machinery be designed so that it can be effectively cleaned and sanitized, but it must be resistant to the caustic nature of sanitizing and sterilizing agents. Other machinery issues addressed include the desired characteristics of bearings, gears, electric motors, drives, control panels, and machine supports. Stainless steel fabrication and welding and its maintenance are also discussed. Design and maintenance for both bioburden and particulate control receive special attention. Thus, the engineer is given insights into many issues that are critical to the design and operation of an aseptic processing environment.

Chapter 3 is entitled “Air Handling Systems for Cleanroom Control.” A large volume of air must be cleaned and conditioned as it is moved into clean rooms, both to meet the needs of operators present and to contribute significantly to the aseptic control of the environment. The systems used to accomplish this are called heating, ventilating, and air conditioning (HVAC) systems. Brian Moore draws many details from his extensive experience to provide a very practical chapter with 22 illustrative figures and drawings. He begins by defining terms and discussing the general characteristics of pharmaceutical clean rooms. He then progresses to the concepts for HVAC systems, descriptions of air handling units, and the design and construction of ductwork. He provides extensive material on HVAC system controls and on system testing, commissioning, and validation. This chapter is very thorough and detailed and will provide the engineer with much useful information. The author concludes the chapter with a brief look into the future for HVAC systems.

Chapter 4 discusses “High Speed, Automated Filling of Sterile Liquids and Powders.” After addressing the scope of the chapter, William Rahe focuses on common design issues, including dose control, cleanliness, sterilizable parts, materials of construction, validation, and machine capacity sizing. In the next section the author concentrates on liquid filling with a thorough discussion of different types of metering devices. He discusses how each functions as well as the limitations and advantages of representative metering devices and components, such as peristaltic, piston, rolling diaphragm, valves, actuation, gravimetric, time-pressure, manifolds, and filling needles. The author then discusses some of the aspects of container handling. The requirements for powder filling are also addressed, focusing on four primary types, pneumatic cylinder and piston wheel, totally enclosed pneumatic pump, volumetric compression, and auger filling. The engineering considerations for operational items such as hoppers, agitators, pistons, dust containment, checkweighing, and dosing are discussed in detail. The chapter is well illustrated with 18 figures and drawings.

Chapter 5 is long and detailed on the subject of “Engineering Considerations for CIP/SIP Systems.” The expertise of the authors is clearly evident as Dale Seiberling reviews the developing principles and practices for CIP systems and Alfred Ratz for SIP systems. They provide extensive details on multiple variations of functional systems. A total of 35 detailed drawings give clarity to the systems and variations presented. The drawings alone will be extremely valuable in identifying the engineering design of a variety of CIP systems. However, coupled with the practical discussions in the text, the value for a user is very much enhanced. For example, under engineering considerations for a CIP recirculating unit, the author discusses required delivery (gal/min), delivery pressure (psig), required sequence of treatment, number of tanks required, delivery temperature, and physical space. A large section of the chapter deals with automation of the pharmaceutical or biotech process and focuses on topics such as air-operated valves, automated process piping design, air-operated valve pulsing and sequencing, and U-bend transfer panels. The SIP section focuses on topics such as steaming a tank, steaming a tank with fill/discharge piping, steaming a transfer line and filter train, and steam sanitizing a transfer line. The final section presents a discussion of various methods utilized for evaluating the results of CIP cleaning.

Chapter 6, “Engineering Considerations for Water Systems,” has been coauthored by Henry Kuhlman and Drew Coleman. Following definitions of terms and general historical background, the authors launch into pretreatment requirements, including engineering considerations for gravel beds, water softeners, carbon filters, deionizers, and reverse osmosis units. Under design considerations the authors discuss equipment sizing and selection for distillation, reverse osmosis, ultrafiltration, and heat exchange. The storage and distribution system design is given careful attention and includes topics such as point-of-use heat exchangers, standby pumps, piping materials, control requirements, storage tank vortex breakers, relief valves and rupture discs, the piping system, and safety features. A section is devoted to construction standards and procedures, including welding procedures and slope verification. A large section is devoted to validation requirements for the WFI system, including a unique, detailed example of a start-up and validation sequence. This example will be of exceptional value to the process engineer. Also of great practical value is the final section, in which the authors discuss preventive maintenance programs. Seven figures are used to illustrate the chapter.

Chapter 7 is entitled “Engineering Considerations in Sterile Powder Processes” and has been written by Alpaslan Yaman. The author begins by considering the characterization and sterilization of a bulk drug powder. He then moves to considerations affecting the handling and bulk packaging of the dry, sterile drug substance. At the conclusion of bulk packaging, the substance is ready to be divided into dispensing units. The latter process may involve other steps, such as the blending/mixing of another dry component. The author discusses the problems associated with the blending of components to a uniform mixture while maintaining sterility and freedom from particulate contaminants. Further, the author identifies the problem of segregation during the filling of the bulk mixture into dispensing containers, and discusses ways to alleviate the problem. In some instances he recommends that filling of each ingredient separately by means of double shot filling may be preferable. In the final section of the chapter he discusses environmental factors that affect finished product characteristics. He discusses the necessity for and the approach used to control factors such as humidity, electrostatic charge, oxygen level, dust containment, and particulate matter level. Twelve figures are used to illustrate this chapter.

Holly Haughney has written Chapter 8, “Engineering Considerations in Sterile Filtration Processes.” The chapter is divided into three main sections, namely, the introduction, sterile liquid filtration design and operational considerations, and sterile gas filtration process design and operational considerations. In the introduction the author gives basic information, describing membrane filters and how they function to achieve a sterile filtrate. The second section is subdivided into design and operational considerations for a filtration process. The section on design covers topics such as membrane compatibility, effluent quality, and process specifications, including maximum pressure differential, flow rate, operational temperature, and size requirements. Operational considerations include topics such as system configuration and protocol for in situ steam sterilization, plumbing needs, steam considerations, autoclaving considerations, and troubleshooting. Also included in this subsection is a discussion of the selection, design, and operational factors for integrity testing of membrane filter systems. Two specific examples of sterile gas filtration are discussed in detail: sterile filtration of fermenter air and sterile tank vent filtration. The author has presented many practical engineering details with respect to the use of membrane filters in sterile filtration processes. A unique feature of the chapter is a set of guidelines for troubleshooting each topic. Fourteen figures and drawings are used to illustrate the text.

The last chapter is written by Hans Trechsel, an engineer who has been an innovator in many developments of automated liquid filling process equipment. Therefore, he is highly qualified to write on the topic, “The Development of Integrated, Automated Filling and Packaging Equipment using Hybrid Robotics.” After defining terms and introducing the topic, he launches into a discussion of the principles of machine design. This is followed by a discussion of how a product progresses through a process, using one of five methods: batch processing; indexing motion processing; continuous motion flow processing; process layout in a rotary, in-line, or reverse in-line manner; and row advance processing. The advantages and disadvantages of each method are discussed. The author then launches into a detailed discussion of an example liquid filling line. Engineers and pharmaceutical processing operators will appreciate the details given by the author for each of the operation steps: prefeeding, washing/sterilizing, sterilizing and depyrogenation, accumulating/down-bottle reject, in-feed line conveyor and starwheel, no vial–no fill, tare weighing, nitrogen flush, filling/checkweighing, stoppering, nitrogen purge and seating of stoppers, capping/sealing, rejection of bad parts, trayloading, labeling/final inspection/packaging. The author concludes the chapter with a short discussion of material selection for processing equipment. A total of 15 figures are included to illustrate the equipment discussed.

It is anticipated that the practical information provided in this book will be found to be of great value to process engineers in the pharmaceutical and biotech industries where sterile products are manufactured. Additional topics will be covered in future books in the Drug Manufacturing Technology Series.

2

ENGINEERING CONTROL OF THE ASEPTIC FILLING ENVIRONMENT

Howard R. Leary

Luciano Packaging Technologies, Inc.

OBJECTIVE AND INTRODUCTION

Aseptic environments present many limiting, restrictive conditions and requirements to the equipment that is intended to operate in them. The objective of this chapter is to consider the effects of these conditions and restrictions on the equipment, the effect of the equipment on the environment, and to describe some specific approaches that engineers use in designing package filling equipment to accommodate these concerns.

Clean rooms or isolation chambers are used to provide aseptic environments for package filling. Besides providing aseptic conditions (absence of viable microorganisms), particulate control is often part of the purpose of environmental control, either because the product (e.g., injectables) cannot tolerate particulates, or in order to keep any particulates, viable or otherwise, away from the product and package.

A clean room is large enough to contain the equipment and the people that operate within it. Laminar airflow, usually vertical and downward, washes particulates away from product and package by design. People in the room usually will be expected to sanitize the equipment in one of several ways.

Isolation chambers are built around the critical operations of the process, and are intended to exclude people except by means of gloves or half-suits. Typically, only part of a package filling machine will be enclosed—the area where sterile containers are filled and sealed.

Many of the hazards to equipment that will be discussed in this chapter provide motivation for today's interest in developing isolation technology for sterile pharmaceutical packaging applications. Equipment designers and engineers are developing ways to isolate sections of mechanisms, introduce sterile packaging material, discharge sealed containers, and achieve adequate sterilization. The high demands of pharmaceutical asepsis and its validation have made achieving effective results in isolation technology applications very challenging. A subsequent chapter will discuss isolation technology.

Hazards to the condition of equipment result from the need to sanitize or sterilize everything in the controlled area. Sanitizing is any means that cleans surfaces for the purpose of keeping bioburden under control. It is typically done by manual application of liquid disinfectant solution to machinery, walls, curtains, and other surfaces in the general area where sterile package filling is done. Sterilizing is any means of destroying all microorganisms on or in an object. Items to be sterilized are put in some enclosed processing device, in which they are treated with steam; gamma rays, electron beams, ultraviolet light, or other forms of radiation; gases such as ethylene oxide, hydrogen peroxide, or peracetic acid; dry heat; or other environments in which microorganisms cannot survive.

Any surface that is in contact with the product, or with a package component that contacts the product, must be sterilized between each production batch. These parts of the machine must be designed to permit and withstand the rigors of sterilization without deteriorating. Parts of the equipment that do not contact the product directly or indirectly must be sanitized to prevent the possible growth of organisms in the controlled area. This is typically done by direct application of liquid sanitizing agents t...

Table of contents

• Cover
• Title Page
• Copyright Page
• Table of Contents
• Foreword
• 1. Introduction
• 2. Engineering Control of the Aseptic Filling Environment
• 3. Air Handling Systems for Cleanroom Control
• 4. High Speed, Automated Filling of Sterile Liquids and Powders
• 5. Engineering Considerations for CIP/SIP Systems
• 6. Engineering Aspects of WFI Systems Design
• 7. Engineering Considerations in Sterile Powder Processes
• 8. Engineering Considerations in Sterile Filtration Processes
• 9. The Development of Integrated, Automated Filling and Packaging Equipment Using Hybrid Robotics
• Name Index
• Subject Index