Handbook of Validation in Pharmaceutical Processes, Fourth Edition

James Agalloco, Phil DeSantis, Anthony Grilli, Anthony Pavell, James Agalloco, Phil DeSantis, Anthony Grilli, Anthony Pavell

• Publisher: CRC Press
• Year: 2021
• ISBN:
  9781000436037
• Edition: 4
• Topic: Medicine
• Subtopic: Pharmacology

Revised to reflect significant advances in pharmaceutical production and regulatory expectations, Handbook of Validation in Pharmaceutical Processes, Fourth Edition examines and blueprints every step of the validation process needed to remain compliant and competitive. This book blends the use of theoretical knowledge with recent technological advancements to achieve applied practical solutions. As the industry's leading source for validation of sterile pharmaceutical processes for more than 10 years, this greatly expanded work is a comprehensive analysis of all the fundamental elements of pharmaceutical and bio-pharmaceutical production processes. Handbook of Validation in Pharmaceutical Processes, Fourth Edition is essential for all global health care manufacturers and pharmaceutical industry professionals.

Key Features:

• Provides an in-depth discussion of recent advances in sterilization
• Identifies obstacles that may be encountered at any stage of the validation program, and suggests the newest and most advanced solutions
• Explores distinctive and specific process steps, and identifies critical process control points to reach acceptable results
• New chapters include disposable systems, combination products, nano-technology, rapid microbial methods, contamination control in non-sterile products, liquid chemical sterilization, and medical device manufacture

1Why Validation?

James Agalloco

DOI: 10.1201/9781003163138-1

CONTENTS

1.1 Introduction

1.2 Application of Validation

1.3 Why Validation?

1.4 Conclusion

1.1 INTRODUCTION

The origins of validation in the global health care industry can be traced to terminal sterilization process failures in the early 1970s. Individuals in the United States point to the Large Volume Parenterals (LVPs) sterilization problems of Abbott and Baxter, whereas those in the United Kingdom cite the Davenport Incident.¹ Each incident was the result of a nonobvious fault with the sterilization that was not detected because of the inherent limitations of the end product sterility test. As a consequence of these events, non-sterile materials were released to the market, deaths occurred and regulatory investigations were launched. The outcome was the introduction by the regulators of the concept of “Validation.”

Documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality attributes.²

The initial reaction to this regulatory initiative was one of some puzzlement; after all, only a limited number of firms had encountered difficulties, and all of the problems were seemingly associated with the sterilization of LVP containers. It took several years for firms across the industry to understand that the concerns related to process effectiveness were not limited to LVP solutions, and even longer to recognize that those concerns were not restricted to sterile products. Perhaps most unfortunate of all was the lack of enthusiasm on the part of industry. From its earliest days, validation was identified as a new regulatory requirement, to be added onto the list of things that firms must do, with little consideration of its real implications. Some firms believed validation to be little more than a regulatory fad, or a one-time activity that, once completed, could be filed away for use with inspectors. Fortunately, it was considered more objectively by those who initially attempted to perform a “validation”. The first efforts reflected what can be termed the “scientific method” of observation of an activity: (1) hypothesis/prediction of cause/effect relationship, (2) experimentation followed by (3) assembly of the results in the form of the experimental report. In the pharmaceutical validation model, this has evolved into the validation protocol (hypothesis and prediction), field execution (experimentation), and summary report preparation (documented observations).

By 1980, when it was becoming evident that validation was here to stay, pharmaceutical firms began to organize their activities more formally. Ad hoc teams and task forces that had started the efforts were gradually replaced by permanent validation departments whose reporting relationship, responsibilities, and scope varied with the organization, but whose purpose was to provide the necessary validation for a firm’s products and processes. The individuals in these departments were the first to grapple with validation as their primary responsibility and their methods, concepts and practices have served to define validation ever since.

Validation—Establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality attributes.³

The first efforts at validation were simplistic and limited in their understanding of the implications that validation actually entailed. As an example, the first sterilization validations at most firms were performed without prior qualification of the equipment. Once validation had been established as a useful discipline and something more than a passing fad, methods for its execution became substantially more formalized and rigorous.

The validation community made significant strides in clarifying the various components of a sound validation program. Perhaps most important of all was the separation of activities into two major categories: Equipment Qualification and Process Qualification. The former (sometimes divided into Installation and Operational Qualification) focused on the facilities, equipment, and systems needed for the product being processed. This is predominantly a documentation exercise, in which details of the physical components of the system are recorded as a definition of the equipment. Equipment operational capabilities are also established. This activity provides the basis for change control that supports the utility of the validation effort over time. Process Performance Qualification (also known as Process Validation or Performance Qualification) confirms the acceptability of the product manufactured in the equipment and relies heavily on the results of physical, chemical, and microbial tests of samples.

It was soon apparent that validation had to be more closely integrated into the mainstream of Current Good Manufacturing Practice (CGMP) operations in order to maximize its effectiveness. A number of areas can be identified as prerequisites for process or system validation. The origins of these elements can be identified in the CGMP requirements for drugs and devices (Table 1.1).⁴

TABLE 1.1 Prerequisites for Validation

• Process Development [21 CFR 820.30—Design Control]—The activities performed to define the process, product or system to be evaluated.

• Process Documentation [21 CFR 211 Subparts F—Production and Process Controls and J—Records and Reports]—The documentation (batch records, procedures, test methods, sampling plans) (software) that define the operation of the equipment to attain the desired result.

• Equipment Qualification [21 CFR 211 Subparts C—Buildings and Facilities and D—Equipment]—The specifications, drawings, checklists and other data that supports the physical equipment (hardware) utilized for the process.

• Calibration—The methods and controls that establish the accuracy of the data.

• Analytical Methods [21 CFR 211 Subpart I—Laboratory Controls]—The means to evaluate the outcome of the process on the materials

• Cleaning—[21 CFR 211.67a Equipment Cleaning and Maintenance]—A specialized process whose intent is to remove traces of the prior product from the equipment.

• Change Control—[21 CFR 211.67c Equipment Cleaning and Maintenance]—A formalized process control scheme that evaluates the changes to documentation, materials, and equipment.

With this understanding of its dependencies, validation is more easily assimilated into the overall CGMP environment rather than being something apart from it. Although firms will likely have a validation department, it must be supported by activities in other parts of the organization. For example, a poorly developed process performed using uncalibrated equipment making a product that has no standard test methods could never be considered validated. The supportive elements must be properly operated in order to result in a compliant product, and one that can be successfully validated. A later definition that addresses the larger scope of validation within the overall organization appears following:

Validation is a defined program which, in combination with routine production methods and quality control techniques, provides documented assurance that a system is performing as intended and/or that a product conforms to its predetermined specifications.⁵

1.2 APPLICATION OF VALIDATION

After its first use with LVPs in the early 1970s, the application of validation spread quickly to other sterilization processes. It was also applied for the validation of other pharmaceutical processes, albeit with mixed success. In sterilization validation and to a slightly lesser extent in processes supporting the production of sterile products using aseptic processing, there is little difficulty applying validation concepts. The apparent reasons for this are the common and predominantly quantitative criteria for acceptance of the quality attributes for sterile products. Building consensus on validation of sterile products has largely been achieved across the entire industry. There are numerous regulatory and industry guidance documents outlining validation expectations on the various sterilization processes, as well as numerous publications from individuals and suppliers.

Validation of non-sterile products and their related processes is less certain. Despite the obvious importance of cleaning procedures, cleaning validation was not publicly discussed until the early 1990s. To this day, there is lingering confusion regarding the requirements for validation of this important process. The difficulties with validation are even more complicated for pharmaceutical dosage forms. There are no widely accepted validation requirements for the important quality attributes of drug products. Although the key elements are known, e.g., dissolution, content uniformity, and potency, there are no objective standards upon which to define a validation program. The compendial standards of the various pharmacopeias are poorly suited to validation. The small sample size and absolute nature of the acceptance criteria remain problematic for direct application to large-scale commercial production. After more than 40 years, the absence of universal criteria for dosage forms is distressing.

Applying validation requirements to water and other utility systems is somewhat easier than for the pharmaceutical products themselves. Equipment qualification of utility systems is relatively easy to perform, and samples of the supplied utility (water, steam, environmentally controlled air, compressed gas, solvent, etc.) taken across the system can directly support the acceptability of the preparation, storage (where present), and delivery. Classified and other controlled environments have also proven comparatively easy to validate. Their physical elements lend themselves readily to equipment qualification, and sampling affords direct confirmation of their operational capabilities.

Biotechnology first came of age in the late 1980s into a regulatory environment that expected validation of important processes. As the first biotech products were injectable drugs, it was quite natural for firms to validate their entire production process from the onset. As a consequence, cell culture and purification processes of all types have always been subject to validation expectations. There is a substantial body of validation knowledge on these processes available. In marked contrast, the bulk pharmaceutical chemical segment of the industry was comparatively slow to embrace validation concepts. Although certainly the rigorous environmental expectations associated with many dosage forms and virtually all biotechnology processes weren’t present, the important considerations of impurity levels, by-product levels, racemic mixtures, crystal morphology, and trace solvents all suggest that there are important quality attributes to be controlled (and thus validated) as well.

Computerized systems became subject to validation requirements when they were first applied to CGMP functions in the 1980s. For ease of understanding, parallels between computerized systems and physical systems were utilized. The computer hardware can be qualified like the process equipment to which it is connected, whereas the computer software has some similarities to the operating procedures utilized to operate the equipment. This approach may be an oversimplification of the required activities for the software, but it provides some clarity to the uninitiated. Computerized syst...