Preface

The FDA's concern with contamination of nonpenicillin drug products with those that contain penicillin and the cross-contamination of drug products with potent steroids or hormones are the main reasons behind the concept of cleaning validation in pharmaceutical industries. This has led to the formation of GMP regulations (part 133.4) in 1963, according to which all the equipment used in pharmaceutical industries to manufacture, fill, and pack drug products must be maintained in a clean and orderly manner. Of course, the main rationale for requiring clean equipment is to prevent the contamination or adulteration of drug products. Hence, the idea of cleaning validation in pharmaceutical industries is not new. The purpose of this manual is to provide a generic format for a Cleaning Validation Plan for pharmaceutical companies along with validation protocols for the most commonly used equipment in various manufacturing areas and their sampling points, using a pharmaceutical manufacturing site with both sterile and nonsterile operations as the case facility. The Cleaning Validation Manual has been organized as a database to train the manpower involved in the development, manufacturing, auditing, and validation of biopharmaceuticals on a pilot scale, leading to scaled-up production. Considerable thought, care, guides, and learning elements were forged to create the Cleaning Validation Manual.

Over the last decade, considerable information has been published referring to advancements in explaining the cleaning validation approach. Cleaning approaches are based on information provided in internationally recognized books and the author's own experience. This volume will serve as a valuable training reference guide that will be referred to repeatedly.

The Cleaning Validation Manual is divided into sections (CLV-1 to CLV-44).

Section CLV-1 gives a brief overview of how to establish a cleaning validation program, cleaning validation norms, advantages and disadvantages of using certain types of equipment, products, facilities, dosage forms, and the basic principles of products and equipment grouping.

In Sections CLV-2 to CLV-16, reference is made to introduction (of cleaning validation), scope and approach, cleaning validation team members and responsibilities, cleaning validation philosophy, strategies and methodology, planning phase, execution phase, analytical testing and reporting phase, equipment description, facility description, utilities description DI, WFI, steam, compressed air, utilities monitoring and microbiological control, equipment cleaning materials/detergent description, microbiological cleaning of equipment surface, solubility of active materials in water, and toxicity of active materials.

Sections CLV-17 to CLV-20.10 provide the cleaning validation product grouping matrix (tablet-capsule PPS), the product/equipment train matrix (tab-cap PPS), the worst-case product matrix (tab-cap PPS), and validation protocols with corresponding cleaning procedures (fluid bed dryer, mixer, granulation machines, powder bins, tablet press [three types], sieves, powder-filling machines, encapsulation machines [two types], film-coating machines, and sugar-coating machines).

Sections CLV-21 to CLV-23 provide the cleaning validation product grouping matrix (syrup), the product/equipment train, and the worst-case product for syrups.

The cleaning validation product grouping matrix, the cleaning validation product/ equipment train, and the worst-case product for suspension are described in Sections CLV-24 to CLV-26.

Sections CLV-27 to CLV-29 refer to the cleaning validation product grouping matrix (drops), the product/equipment train, and the worst-case product in hypothetical drops.

Sections CLV-30 to CLV-32 refer to the cleaning validation product grouping matrix (cream/ointment), the product/equipment train, and the worst-case product for cream and ointment.

Sections CLV-33 to CLV-35 refer to the cleaning validation product grouping matrix (suppositories), the product/equipment train, and the worst-case product for suppositories.

Sections CLV-36 to CLV-36.4 provide validation protocols for manufacturing vessels, bin-washing stations, syrup-holding tanks, filling stations, and the filtration assembly.

Sterile area equipment cleaning validation is referred to in Sections CLV-37 to CLV-39.6 starting from the cleaning validation product grouping matrix (sterile product), the cleaning validation product/equipment train matrix, validation protocols, freeze dryer, mobile tanks, filtration assembly, preparation tanks, preparation vessel, and filtration and filling. Section CLV-40 refers to the cleaning validation tentative plan.

In Section CLV-41, a matrix is provided to document cleaning validation and sampling, and testing status. The regulatory guidelines of the Food and Drug Administration (FDA), United States Food and Drug Administration (USFDA), World Health Organization (WHO), and European Medicines Agency (EMEA) are referred to in Sections CLV-42 to CLV-42.4. Information about the sampling tools is provided in Section CLV-43. Recommended readings are provided in Section CLV-44.

The ready-to-use Cleaning Master Validation Plan and protocols in combination with the regulatory guidelines provide a good source of training material for experienced and inexperienced practitioners in pharmaceutical and biotechnology industries.

Pharmaceutical industries are regulated worldwide to be in compliance with Current Good Manufacturing Practices (CGMP) and Good Laboratory Practice (GLP) principles, with particular focus on cleaning validation and cross-contamination issues.

The Cleaning Master Validation Plan and 24 protocols can be downloaded from the CD and adopted directly or with minor changes. The ready-to-use protocols allow end users to record all raw hard data.

Each company is required to create a definite cleaning matrix based on the product mix. The Cleaning Master Validation Plan and protocols available in this manual enable end users to understand the principles and elements of the cleaning approach and sampling techniques and provide documentation language ranging from the generic to the specific.

Compliance with FDA regulations is essential for companies intending to export their products to the United States and Europe. As a result, only a few companies are able to seek approval for export, one of the reasons being the absence or inadequacy of a Cleaning Master Validation Plan.

The information provided in the CD-ROM includes valuable tools for active pharmaceutical ingredients that are used in developing matrices for a cleaning Validation Master Plan to achieve FDA, GMP, ICH, EMEA, and GLP compliance. The manual is especially relevant to trainers, quality assurance personnel, engineers, validation designers, internal and external auditors, technical training managers, and anyone interested in developing a cleaning qualification documentation matrix in the healthcare industry.

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