How to Validate a Pharmaceutical Process

Steven Ostrove

• Publisher: Academic Press
• Year: 2016
• Print ISBN: 9780128041482
• eBook ISBN: 9780128096536
• Topic: Medicine
• Subtopic: Probability & Statistics

How to Validate a Pharmaceutical Process provides a "how to approach to developing and implementing a sustainable pharmaceutical process validation program. The latest volume in the Expertise in Pharmaceutical Process Technology Series, this book illustrates the methods and reasoning behind processes and protocols.  It also addresses practical problems and offers solutions to qualify and validate a pharmaceutical process. Understanding the "why is critical to a successful and defensible process validation, making this book an essential research companion for all practitioners engaged in pharmaceutical process validation. - Thoroughly referenced and based on the latest research and literature - Illustrates the most common issues related to developing and implementing a sustainable process validation program and provides examples on how to be successful - Covers important topics such as the lifecycle approach, quality by design, risk assessment, critical process parameters, US and international regulatory guidelines, and more

Section II

Stage I—Process Development

Outline

Chapter 4 Getting Started

Chapter 5 Basic Equipment and Utility Qualification¹

Chapter 6 Computers and Automated Systems

Chapter 4

Getting Started

Abstract

Planning is critical to a successful process validation program. Time must be taken to carefully plan the testing to be performed, the methods of the testing, and all of the ancillary steps needed to assure that the process is run and tested correctly. This is one of the main purposes of the validation master plan. Equipment must be readied through its qualification, calibration, preventive maintenance programs, and other quality programs. The staff needs to be trained on the process, as well as how to execute a process validation protocol. The Standard Operating Procedures (SOPs) need to be approved and available as do other support documents. The risk-based methodology to the testing and execution of the entire process chain needs to be the primary approach in design, execution, and analysis of the process validation program.

Keywords

Validation master plan (VMP); quality programs; standard operation procedures (SOP); training; risk-based; preventive maintenance

Before It All Starts

As presented in Chapter 1, “Introduction to Process Validation” process validation (PV) is a program that requires the interaction of several groups, not just one individual. Thus, the first thing that needs to be addressed is the organization and assembly of the necessary groups to plan the validation effort (Fig. 4.1). The actual plan for the validation program is documented in the Validation Master Plan (VMP). This document usually requires several months to prepare and involves the input from many different groups within the manufacturing site. Some of the main groups or departments that should be tapped for input are:

• Analytical Lab

• Engineering/Maintenance

• Metrology

• Operations

• Quality

• Regulatory Affairs

• Research & Development

• Validation

Figure 4.1 Organization chart for a process validation project.

Others may be involved for parts of the planning, for example, Health & Safety, Document Control, IT, etc., since almost every department will have some input into the program. The announcement of the project should be widely distributed and meetings publicized to allow input from all sources. A project manager or coordinator will integrate all aspects of the project and increase the likelihood that the project will run smoothly. The size of the facility, the types of products, and the experience of the staff (training) will have major impacts on the execution of the project.

Each department should provide the input necessary based on their expertise or needs. For example, the operations group will know how the equipment will be used during actual commercial production. They are the ones who will be providing the user requirements to the engineering group. The engineers will then develop the functional requirements and, subsequently, the design requirements. The functional requirements are those that set the way the equipment will operate and thus be able to perform their user requirements. The design requirements are those that are used to actually make the unit work, that includes the programming, the utility requirements, as well as all the process specifications. After the design is complete the request is sent to the purchasing department who will then request bids (with specifications) from vendors who can provide the unit of choice. Fig. 4.2 shows a general approach to a project that starts with the pharmaceutical company and moves through validation consultants and to the vendor.

Figure 4.2 General project flow.

Example

A user requirement can be the need for a blender that needs to hold 500 kg of material. The functional requirement then would specify that the unit be able to hold 750–1000 kg (Note: The unit should normally hold 50–100% more than required. This also goes for sizing the motors, etc. so as to keep the duty cycle in an effective range and extend the life of the equipment) of material, thus it would need to be XX by XX Ft². This information would then be given to the engineering group who would put the unit together allowing sufficient rotation space (Note: All equipment should be installed allowing sufficient room on all sides to service the unit). Fig. 4.3 shows a blender installation allowing sufficient room for rotation and maintenance. The need for access to all sides of the equipment applies to the utilities as well as the process equipment. In another approach, the user requirements may be turned over to the purchasing department who will then order a unit from a vendor that can provide the necessary requirements. The engineering department and the operations department prior to actually placing the order should check this request. This is also known as bid verification or bid review, which is a very important step that is often omitted due to project time constraints.

Figure 4.3 Example of a V Blender. Source: Dmitry Kalinovsky/Shutterstock.

Getting Started (After the Equipment Specifications)

Process validation cannot begin when the first commercial size batch is produced. It must start much earlier. In reality, process validation begins in the basic research stage. While basic research itself is not under Good Manufacturing Practices (GMPs), the results that are obtained there are critical to successfully completing the PV process. There is a lot of information that needs to be collected and organized prior to starting an effective process validation program. There are four major categories of documents that are needed for any successful process validation project. These are:

• VMP

• Standard Operating Procedures (SOPs)

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Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Dedication
• Author Biography
• Preface
• Acknowledgment
• About the Expertise in the Pharmaceutical Process Technology Series
• Section I: Introduction to Process Validation
• Section II: Stage I—Process Development
• Section III: Stage II—Process Development
• Section IV: Stage III—Continued Process Verification
• Section V: Other Related Activities
• Terms and Definitions
• Appendix A. 21 CFR 211
• Appendix B. Example—Short Change Control Form
• Appendix C. Additional ICH and FDA Guidelines
• Index