Sterile Processing of Pharmaceutical Products

Engineering Practice, Validation, and Compliance in Regulated Environments

Sam A. Hout

• Publisher: Wiley
• Year: 2021
• Print ISBN: 9781119802327
• eBook ISBN: 9781119802341
• Edition: 1
• Topic: Technologie et ingénierie
• Subtopic: Chimie industrielle et technique

Describes the methodologies and best practices of the sterile manufacture of drug products

Thoroughly trained personnel and carefully designed, operated, and maintained facilities and equipment are vital for the sterile manufacture of medicinal products using aseptic processing. Professionals in pharmaceutical and biopharmaceutical manufacturing facilities must have a clear understanding of current good manufacturing practice (cGMP) and preapproval inspection (PAI) requirements.

Sterile Processing of Pharmaceutical Products: Engineering Practice, Validation, and Compliance in Regulated Environments provides up-to-date coverage of aseptic processing techniques and sterilization methods. Written by a recognized expert with more than 20 years of industry experience in aseptic manufacturing, this practical resource illustrates a comprehensive approach to sterile manufacturing engineering that can achieve drug manufacturing objectives and goals. Topics include sanitary piping and equipment, cleaning and manufacturing process validation, computerized automated systems, personal protective equipment (PPE), clean-in-place (CIP) systems, barriers and isolators, and guidelines for statistical procedure. Offering authoritative guidance on the key aspects of sterile manufacturing engineering, this volume:

• Covers fundamentals of aseptic techniques, quality by design, risk assessment and management, and operational requirements
• Addresses various regulations and guidelines instituted by the FDA, ISPE, EMA, MHRA, and ICH
• Provides techniques for systematic process optimization and good manufacturing practice
• Emphasizes the importance of attention to detail in process development and validation
• Features real-world examples highlighting different aspects of drug manufacturing

Sterile Processing of Pharmaceutical Products: Engineering Practice, Validation, and Compliance in Regulated Environments is an indispensable reference and guide for all chemists, chemical engineers, pharmaceutical professionals and engineers, and other professionals working in pharmaceutical sciences and manufacturing.

1
Introduction

This book is engineering driven to highlight basis of design, design criteria, and assumptions to coach and guide professionals involved in learning more about sterile manufacturing engineering and in pharmaceutical and biopharmaceutical manufacturing facilities, including operational requirements. The intent of this book is to present a simplified treatise with some very specific description of aseptic processing techniques and sterilization methods.

Sterile manufacturing engineering and process validation guides (US FDA, Guidance for Industry – Process Validation) are intended to manage risk, introduce Quality by Design (QbD), and ensure continued process reliability, consistency, and repeatability.

Sterile manufacturing guidelines are based on specific elements in the construction and installation of classified clean rooms, critical utility systems such as water for injection (WFI), solution transfer systems, powder transfer systems, and monitoring and controls, including automation of processes. Specialized technologies [1] in design of fill/finish lines of vials, cartridges, bottles for ophthalmic or otic purposes, prefilled syringes (PFSs), or ampoules, which might be filled and sealed aseptically or IV bags that are mostly terminally sterilized. In addition, considerations for personnel and material flow to prevent cross contamination are usually very well defined to separate in and out movements of sterile suites and cascading clean rooms through separate paths, including the use of path‐through transfer systems for material flow.

Overall, paying attention to the design, construction, and installation should focus on process flow and employ standardization of equipment and methodologies as much as possible. Building sustainable premises, equipment qualifications, cleaning validation, and sanitization requirements should be all in consideration as part of the design of pharma/biopharma processing. Similarly, process validation and periodic revalidation of manufacturing systems are all important stages and steps that need to be on well‐defined schedules to ensure reliability of drug production [2].

The main emphasis of clean room classifications is to quantify particle limits when rooms are in operation (dynamic conditions) for nonviable particles. In addition, microbiological limits are emphasized when classified rooms are in operation for viable particles. Media fills are conducted to certify rooms for aseptic conditions of drug products. EN ISO 14644 Methodology

Class ISO 146144‐1 (Federal Standard 209E)	Average airflow velocity, m/s (ft/min)	Air changes per hour	Ceiling coverage (%)
ISO 8 (Class 100,000)	0.005–0.041 (1–8)	5–48	5–15
ISO 7 (Class 10,000)	0.051–0.076 (10–15)	60–90	15–20
ISO 6 (Class 1,000)	0.127–0.203 (25–40)	150–240	25–40
ISO 5 (Class 100)	0.203–0.406 (40–80)	240–480	35–70
ISO 4 (Class 10)	0.254–0.457 (50–90)	300–540	50–90
ISO 3 (Class 1)	0.305–0.457 (60–90)	360–540	60–100
ISO 1–2	0.305–0.508 (60–100)	360–600	80–100

Microbiological Limits

	Recommended limits for microbial contamination
Grade	Air sample, cfu/m^3	Settle plate, Ø 90 mm, cfu/4 h	Contact plates, Ø 55 mm, cfu/plate	Glove print, 5 fingers, cfu/glove
A	<1	<1	<1	<1
B	10	5	5	5
C	100	50	25	—
D	200	100	50	—

Monitoring of classified areas is continuous whether the room is in operation or not. Particles are measured through a continuous particle monitoring computerized system under measured conditions of temperature, pressure, and relative humidity. In addition, Environmental Monitoring Systems (EMS) with automated features are fitted with alarms to control alert and action levels in classified rooms limit of operation and regulatory requirements. Microbial counts are sampled and read using settling plates both at the aseptic core and equipment surroundings inside the classified clean room. Locations of these plates and frequency of sampling are based on formal risk analysis, sampling requirements, and validation protocols.

Various technologies are employed in sterile manufacturing such as Isolator technologies, Blow/Fill/Seal, aseptic customized tubing set as needed for product specifications, and ter...

Table of contents

• Cover
• Table of Contents
• Title Page
• Copyright
• Preface
• Acknowledgments
• 1 Introduction
• 2 Sterilization
• 3 Sterile Manufacturing Facilities
• 4 Sanitary Process Piping and Equipment
• 5 Passivation
• 6 Chilled Water System
• 7 Clean‐In‐Place (CIP) Systems
• 8 Computerized Automated Systems
• 9 Personal Protective Equipment (PPE) and Process Flow
• 10 Sterile Aseptic Processing
• 11 Integrated Facility Design
• 12 Barriers and Isolators
• 13 Guidelines for Statistical Procedure
• 14 Calibration
• 15 Cleaning Validation
• 16 Validation of Filling Equipment
• 17 Manufacturing Process Validation
• Appendix A: Installation Test Plans
• Appendix B: Operational Tests Plans
• Appendix C: WFI Turbulence Flow Requirements
• Appendix D: Water For Injection (WFI) – Design Requirements
• Appendix E: Solution Transfer System (STS) – Design Requirements
• Glossary
• Nomenclature
• References
• Further Reading
• Index
• Back Cover
• End User License Agreement