INTRODUCTION

This chapter provides an overview of the regulatory requirements of current Good Manufacturing Practices (cGMPs) and describes the importance of cGMPs when designing engineering processes within a pharmaceutical facility. All pharmaceutical manufacturing companies have similar objectives related to the planning, designing, building, validating, and maintenance of their facilities, including the following: (1) design, delivery, and maintenance of manufacturing support facilities, utilities, process equipment, and automation controls so that they perform as intended to meet business objectives, such as capacity, yield, operational efficiency, and reliability; (2) development of a production process that can repeatedly produce a quality product; (3) creation of a quality system necessary to meet regulatory as well as business requirements; and (4) project and process deliveries that are within budgets and schedules. These objectives need to comply with regulations while retaining a highly competitive position.

MANAGED AND INTEGRATED APPROACHES TO PROJECT DELIVERY

Achieving the objectives listed above requires both a managed and an integrated approach to project delivery. A managed approach uses written plans, schedules, budgets, definitions of responsibilities, and well-understood document structures to run a project successfully, while meeting objectives and regulatory expectations. An integrated approach considers regulatory, safety, environmental, operational, and project controls. Significant benefits of an integrated approach are realized when project teams apply this approach to all dimensions of a project. These benefits include (1) an increased focus on product and process knowledge, (2) the delivery of high-quality equipment, (3) an increase in project efficiency as risks are prioritized, (4) improvement in the equipment and system start-up, and (5) the results associated with the creation of regulatory compliance documentation.

RISK MANAGEMENT

A good understanding of the risks that equipment and systems present to product and process helps to ensure the development of adequate design, mitigation, and control plans that ultimately increase product quality. Product development, process development, and technology focus the information needed by the engineering design team. Understanding the relationship between equipment and system design facilitates conclusive troubleshooting if product quality defects occur (Figure 2.1).

All project risks need to be continuously assessed and controlled, including business risk, contractor performance risk, safety risk, environmental risk, and risk to the patient. Design and manufacturing practice regulations are the basis for controlling these risks. A pharmaceutical engineer focuses on analyzing, controlling, and managing the risks to the patient that may be present in the design of the manufacturing process, equipment, utilities, facilities, and automation.

GLOBAL REGULATORY ENVIRONMENT

The intention of global regulations is a harmonized approach, which has resulted in a better understanding of the expectations of various national authorities. Efforts by the International Conference on Harmonisation (ICH), the American Society for Testing and Materials (ASTM) International, and regional regulatory authorities, such as the Food and Drug Administration (FDA) and the European Medicines Agency (EMA), to align approaches toward regulatory compliance have been highly successful. The expectations of regulators are as follows: (1) Design, operating, and quality decisions are based on scientific knowledge of the product and process; that is, the attributes of the product necessary to deliver the desired effect to the patient are known. Scientific knowledge of the process means that the manufacturing process parameters necessary to achieve those product attributes are also known. (2) Risks to the patient should be understood and managed, and this understanding should be used to drive the design, the operation, and the quality system of the manufacturing operation. (3) A comprehensive quality system should be implemented. For purposes of designing, verifying, and maintaining process, equipment, and systems, the processes defined by this chapter meet the expectations of a modern quality system.

For a project to meet regulatory deliverables, the following three aspects related to the impact on the patient need to be considered: (1) defining and verifying that critical quality attributes and critical process parameters can be met; (2) analyzing risks to the patient and verifying that they have been adequately controlled; and (3) planning, managing, and documenting qualification and validation efforts, with independent oversight by the quality unit at key points in the process. These three aspects should be the basis for how the specification, design, and validation life cycle process is to be implemented on different projects. A brief overview of several regulatory bodies and industry organizations that shape the requirements related to good pharmaceutical manufacturing design, build, and validation practices is provided below.

FOOD AND DRUG ADMINISTRATION

The FDA is an agency within the U.S. Department of Health and Human Services. It consists of the Office of the Commissioner and four directorates overseeing the core functions of the agency: medical products and tobacco, foods and veterinary medicine, global regulatory operations and policy, and operations.

The FDA is responsible for protecting public health by ensuring that foods (except for meat from livestock, poultry, and some egg products, which are regulated by the U.S. Department of Agriculture) are safe and properly labeled and by ensuring that human and veterinary drugs, vaccines, and other biological products and medical devices intended for human use are safe and effective. In addition, the FDA protects the public from electronic product radiation and ensures that cosmetics and dietary supplements are safe and properly labeled. The FDA is also responsible for advancing public health by helping to speed up innovations that make medicines effective, safe, and affordable and by helping the public get accurate, science-based information on medicines and foods to maintain and improve their health. Additionally, the FDA has the responsibility for regulating the manufacturing, marketing, and distribution of tobacco products to protect the public health and to reduce tobacco use by minors.

Finally, the FDA plays a significant role in the nation’s counterterrorism capability by ensuring the security of the food supply and by fostering the development of medical products to respond to deliberate and naturally emerging public health threats. The FDA’s responsibilities extend to all 50 states, the District of Columbia, Puerto Rico, Guam, the Virgin Islands, American Samoa, and other U.S. territories and possessions [1].

The FDA’s Globalization Effort

Globalization is a fact of the economic life of the twenty-first century. Markets in the United States are now composed of myriad imported goods that consumers demand. In response to problems that have been associated with imported products over the years and the value derived from leveraging the activities and resources of foreign regulatory authorities, the FDA has established a permanent in-country presence in China, India, Europe, Latin America, and sub-Saharan Africa (Figure 2.2).

Global production of FDA-regulated products has quadrupled over the last decade and continues to grow. Today, FDA-regulated products originate from more than 150 countries, 130,000 importers, and 300,000 foreign facilities. Almost 40% of finished drugs and 80% of the manufacturing of active pharmaceutical ingredients (APIs) are located outside the United States. In addition, half of all medical devices are imported. The growth in imports has been rapid and promises to accelerate.

Globalization has fundamentally altered the economic and security landscape and demands a major change in the way the FDA fulfills its mission. The FDA has transformed from a domestically focused agency to a modern public health regulatory agency fully prepared for a complex globalized regulatory environment. The agency is already increasing transparency and accountability in the supply chain, developing better enforcement and regulatory tools, encouraging greater responsibility by industry, and enhancing collaboration with international regulatory counterparts [2].

The FDA and Pharmaceutical Manufacturing

Due to globalization, the pharmaceutical engineering professional needs to consider the countries where manufacturing occurs, where product is distributed, and the product labeling requirements when designing facilities for pharmaceutical manufacturing. Various global requirements have a direct impact on project complexity, schedules, and costs. It is important for the pharmaceutical engineer to work with the regulatory and quality partners to define regulations that apply to projects, ensuring that the appropriate elements are built into the project definition and design phases. Additional information about the FDA can be found at http://www.fda.gov/.

EUROPEAN MEDICINES AGENCY

The main responsibility of the EMA is the protection and promotion of public and animal health, through the evaluation and supervision of medicines for human and veterinary use. The EMA works with a network of more than 4500 European experts and is the hub of a European medicine network comprising more than 40 national regulatory authorities. The EMA works closely with its European partners to build the best possible regulatory system for medicine in Europe and to protect the health of its citizens.

The EMA forges close ties with partner organizations around the world, including the regulatory authorities of non-European nations. These activities foster the timely exchange of regulatory and scientific expertise and the development of best practices in the regulatory field across the world [1]. Additional information about the EMA can be found at http://www.ema.europa.eu/ema/.

INTERNATIONAL CONFERENCE ON HARMONISATION

The mission of the ICH is to make recommendations toward achieving greater conformity in the interpretation and application of technical guidelines and requirements for pharmaceutical product registration, thereby minimizing the use of animal testing without compromising safety and effectiveness, streamlining the regulatory assessment process for new drug applications (NDAs), and reducing the development times and resources for drug development.

Launched in 1990, the ICH is a unique undertaking that brings together the drug regulatory authorities and the pharmaceutical industry of Europe, Japan, and the United States. Key to the success of ICH was the development and implementation of ICH Tripartite Guidelines, which were developed through scientific consensus with regulatory and industry experts. The current ICH Terms of Reference (2000) as they appear on the ICH website are listed below. Additional information about ICH can be found at http://www.ich.org/ [3].

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  To maintain a forum for a constructive dialogue between regulatory authorities and the pharmaceutical industry on the real and perceived differences in the technical requirements for product registration in the EU, USA, and Japan to ensure a more timely introduction of new medicinal products, and their availability to patients;

  
  
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  To contribute to the protection of public health from an international perspective;

  
  
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  To monitor and update harmonized technical requirements, leading to a mutual acceptance of research and development data;

  
  
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  To avoid divergent future requirements through harmonization of selected topics needed as a result of therapeutic advances and the development of new technologies for the production of medicinal products;

  
  
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  To facilitate the adoption of new or improved technical research and development approaches which update or replace current practices, where these permit a more economical use of human, animal and material resources, without compromising safety;

  
  
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  To facilitate the dissemination and communication of information on harmonized guidelines and their use to encourage the implementation and integration of common standards.

WORLD HEALTH ORGANIZATION

The World Health Organization (WHO) is the directing and coordinating authority for health within the United Nations system. It is responsible for providing leadership on global health matters, shaping the health research agenda, setting norms and standards, articulating evidence-based policy options, providing technical support to countries, and monitoring and assessing health trends. Additional information about WHO can be found at http://www.who.int/en/ [4].

AMERICAN SOCIETY FOR TESTING AND MATERIALS INTERNATIONAL

ASTM International is a globally recognized leader in the development and delivery of international voluntary consensus standards. This organization has developed more than 12,000 ASTM standards, which are used around the world to improve product quality, enhance safety, facilitate market access and trade, and build consumer confidence. Additional information about ASTM International can be found at http://www.astm.org/ [5].

KEY PHARMACEUTICAL REGULATIONS RELATED TO DESIGN AND ENGINEERING

Different nations and different economic blocks follow regulations and guidance documents that can vary greatly in terms of specificity and detail regarding design, build, and validation expectations for pharmaceutical facilities. This section contains excerpts from the FDA, EU, ASTM International, and WHO regulations and guidance documents that relate to pharmaceutical design life cycle processes. This is not an all-inclusive list of global regulations, but it highlights the regulations that represent major global market segments. Pharmaceutical engineering professionals, with quality and regulatory personnel, should develop an understanding of the intent of the regulations and apply that to specific projects.

FOOD AND DRUG ADMINISTRATION

The FDA issues regulations in the Code of Federal Regulations (CFR) 21. The applicable regulations that include facility and equipment design requirements can be found in the following:

LIGHTING (§211.44)

The paragraph on lighting states that adequate lighting shall be provided in all areas.

VENTILATION, AIR FILTRATION, AND AIR HEATING AND COOLING (§211.46)

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  Adequate ventilation shall be provided.

  
  
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  Equipment for adequate control over air pressure, microorganisms, dust, humidity, and temperature shall be provided when appropriate for the manufacture, processing, packing, or holding of a drug product.

  
  
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  Air filtration systems, including prefilters and particulate matter air filters, shall be used when appropriate on air supplies to production areas. If air is recirculated to production areas, measures shall be taken to control recirculation of dust from production. In areas where air contamination occurs during production, there shall be adequate exhaust systems or other systems to control contaminants.

  
  
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  Air-handling systems for the manufacture, processing, and packing of penicillin shall be completely separate from those for other drug products for human use.

EQUIPMENT DESIGN, SIZE, AND LOCATION (§211.63)

The regulations dealing with equipment requirements are written in a similar fashion.

Equipment used in the manufacture, processing, packing, or holding of a drug product shall be of appropriate design, adequate size, and suitably located to facilitate operations for its intended use and for its cleaning and maintenance.

EQUIPMENT CONSTRUCTION (§211.65)

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  Equipment shall be constructed so that surfaces that contact components, in-process materials, or drug products shall not be reactive, additive, or absorptive so as to alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements.

  
  

  Any substances required for operation, such as lubricants or coolants, shall not come into contact with components, drug product containers, closures, in-process materials, or drug products so as to alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements.

Summary

Since the above requirements can be satisfied using various methods, designers must be thoroughly knowledgeable of industry practices and systems related to pharmaceutical design. There are numerous courses sponsored by universities and professional and educational associations that introduce an individual to the requirements of facility design.

To complement the regulations, the FDA has drafted several guidance documents for industry. These guidance documents represent the FDA’s current thinking on a topic. Guidance documents do not create or confer any rights for or on any person and do not operate to bind the FDA or the public. Alternative approaches from those described in the guidance can be applied if the approach satisfies the requirements of the applicable statutes and regulations. Two guidance documents related to good design practice are “Process Validation: General Principles and Practices” issued in January 2011 and “Quality Systems Approach to Pharmaceutical cGMP Regulations” issued in September 2006. The “Process Validation” document provides guidance for good design practices relating to pharmaceutical facilities and equipment, including recommendations on the team approach for process design and validation of utilities and equipment. It reinforces the expectation that project teams of subject matter experts (SMEs) from various disciplines define the project requirements and expectations throughout the project life cycle. The FDA also stresses the importance of having senior management sponsorship. Management awareness and accountability are critical for efficient decision making, removal of roadblocks, and escalation of key issues or risks. Several relevant topics within these guidance documents are outlined below.

Process Qualification

During the process qualification stage of process validation, the process design is evaluated to determine if it is capable of reproducible commercial manufacture. This stage has two elements: (1) design of the facility and qualification of the equipment and utilities and (2) process performance qualification. During process qualification, cGMP-compliant procedures must be followed. Successful completion of process qualification is necessary before commercial distribution. Products manufactured during this stage, if acceptable, can be released for distribution.

Design of a Facility and Qualification of Utilities and Equipment

Proper design of a manufacturing facility is required under part 211, Subpart C, of the cGMP regulations on buildings and facilities. It is essential that activities performed to ensure proper facility design and commissioning precede process performance qualification. Here, the term qualification refers to activities undertaken to demonstrate that utilities and equipment are suitable for their intended use and perform properly.

Qualification of utilities and equipment generally includes the following activities:

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  Selecting utilities and equipment construction materials, operating principles, and performance characteristics based on whether they are appropriate for their specific uses.

  
  
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  Verifying that utility systems and equipment are built and installed in compliance with the design specifications.

  
  
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  Verifying that utility systems and equipment operate in accordance with the process requirements in all anticipated operating ranges. This should include challenging the equipment or system functions while under loads comparable to those expected during routine production. It should also include the performance of interventions, stoppage, and start-up as expected during routine production. Operating ranges should be capable of being held as long as would be necessary during routine production.

Qualification of utilities and equipment can be covered under individual plans or as part of an overall project plan. The plan should consider the requirements of use and can incorporate risk management to prioritize certain activities and identify a level of effort in both the performance and documentation of qualification activities. The plan should identify the following items: (1) the studies or tests to use, (2) the criteria appropriate to assess outcomes, (3) the timing of qualification activities, (4) the responsibilities of relevant departments and the quality unit, and (5) the procedures for documenting and approving the qualification.

The project plan should also include the firm’s requirements for the evaluation of changes. Qualification activities should be documented and summarized in a report with conclusions that address criteria in the plan. The quality control unit must review and approve the qualification plan and report (§211.22).

The “Quality Systems Approach to Pharmaceutical cGMP Regulations” guidance provides a link to the regulations related to the design of facilities and equipment under Section IV: “The Quality Systems Model.” The quality systems model is described according to four major factors: (1) management responsibilities, (2) resources, (3) manufacturing operations, and (4) evaluation activities. Appropriate allocation of resources is key to creating a robust quality system and complying with the cGMP regulations.

Facilities and Equipment

Under a quality system, the technical experts (e.g., engineers and development scientists), who have an understanding of pharmaceutical science, risk factors, and manufacturing processes related to the product, are responsible for defining specific facility and equipment requirements. Under the cGMP regulations, the quality unit must review and approve all initial design criteria and procedures that pertain to facilities and equipment and any subsequent changes (§211.22[c]). Under the cGMP regulations, equipment must be qualified, calibrated, cleaned, and maintained to prevent contamination and mix-ups (§211.63, 211.67, 211.68). The cGMP regulations require a higher standard for calibration and maintenance than most nonpharmaceutical quality system models. The cGMP regulations place as much emphasis on process equipment as on testing equipment (§211.160, 211.63, 211.67, and 211.68), while most quality systems focus only on testing equipment. The full text of 21 CFR 210 and 211, as well as the preamble, “Process Validation” guidance and “Quality Systems Approach to Pharmaceutical cGMP Regulations” guidance can be obtained from http://www.FDA.gov [7, 8].

AMERICAN SOCIETY OF TESTING AND MATERIALS INTERNATIONAL

The ASTM International has issued the “Standard Guide for Specification, Design, and Verification of Pharmaceutical and Biopharmaceutical Manufacturing Systems and Equipment” (ASTM E2500-13), which governs the specification, design, and verification process. This standard is based on understanding and managing risks to the patient that may be present in the manufacturing process equipment and facilities and also ensuring that process requirements are met. It also provides guidance on how to conduct verification activities. Figure 2.3 is an introductory overview of the process. The process has four major phases and is supported by four control programs applied throughout the project.

The process is to (1) identify, collect, and manage the product, process, and other quality requirements that form the basis of the design; (2) develop the design, and assess patient risk based on scientific knowledge; (3) establish risk mitigation controls and critical aspects; (4) verify that the critical aspects are in place and acceptance criteria are met as defined in the risk assessment and final design review; and (5) review the results and accept the systems and process equipment, formally releasing them for use in manufacturing operations.

The process is performed, using good design and engineering practices and risk management and change management principles. Additional traditional project controls, such as scheduling and purchasing, should also be considered and are addressed in subsequent chapters.

This risk-based approach to specification, design, and verification provides a number of opportunities to save time and money, while improving the overall quality of the delivered process equipment and systems. This approach can meet both the letter and the intent of various international cGMP regulations, regarding equipment suitability and formal qualification when applied appropriately. When using this approach, project teams should adapt it to their particular situations, using the ASTM E2500-13 2013 standard as a guide [9].

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