Current Good Manufacturing Practices
U. S. Food and Drug Administration (FDA)
When designing a manufacturing facility that produces pharmaceutical products, whether generated from a chemical or biological synthesis route, the FDA’s cGMPs regulations provide minimal guidance. The cGMPs outline facility requirements and the requirements for the documentation of manufacturing procedures. The FDA’s approach toward the written regulations has been to indicate the results that a manu-facturing process must attain, not the method(s) to achieve these results. Basically, the FDA tells a manufacturer what must be done, but not how to do it. This fact has led to a variety of interpretive solutions to achieve the desired results relative to facility design. Utilizing this approach enables technologies to develop processes that can more effectively achieve the desired goals and objectives set forth by the Agency.
The FDA issues regulations in the Code of Federal Register (CFR) 21. The applicable regulations that include facility and equipment requirements can be found in the following:
Number Title
21 CFR 210 Current Good Manufacturing Practices in Manufacturing, Processing, Packaging, or Holding of Drugs, General 21 CFR 211 Current Good Manufacturing Practices for Finished
Pharmaceuticals
21 CFR 600 Biologics Products, General 21 CFR 820 Quality Systems Regulations
The applicable sections of the regulations for finished pharmaceuticals are found in 21 CFR 211, Subpart C—Buildings and Facilities and 21 CFR, 211 Subpart D—
Equipment. A review of several of the pertinent paragraphs will illustrate this point.
Paragraph 211.42 delineates the features for the design and construction of facilities:
§ 211.42 Design and construction features.
(a) Any building or buildings used in the manufacture, processing, packing, or holding of a drug product shall be of suitable size, construction, and location to facilitate cleaning, maintenance, and proper operations.
(b) Any such building shall have adequate space for the orderly placement of equipment and materials to prevent mixups between different components, drug
2. Current Good Manufacturing Practices 27
product containers, closures, labeling, in-process materials, or drug products, and to prevent contamination. The flow of components, drug product con-tainers, closures, labeling, in-process materials, and drug products through the building or buildings shall be designed to prevent contamination.
(c) Operations shall be performed within specifically defined areas of adequate size. There shall be separate or defined areas for the firm’s operations to prevent contamination or mixups as follows:
(1) Receipt, identification, storage, and withholding from use of components, drug product containers, closures, and labeling, pending the appropriate sam-pling, testing, or examination by the quality control unit before release for manufacturing or packaging;
(2) Holding rejected components, drug product containers, closures, and labeling before disposition;
(3) Storage of released components, drug product containers, closures, and labeling;
(4) Storage of in-process materials;
(5) Manufacturing and processing operations;
(6) Packaging and labeling operations;
(7) Quarantine storage before release of drug products;
(8) Storage of drug products after release;
(9) Control and laboratory operations;
(10) Aseptic processing, which includes as appropriate:
(i) Floors, walls, and ceilings of smooth, hard surfaces that are easily cleanable;
(ii) Temperature and humidity controls;
(iii) An air supply filtered through high-efficiency particulate air filters under positive pressure, regardless of whether flow is laminar or nonlaminar;
(iv) A system for monitoring environmental conditions;
(v) A system for cleaning and disinfecting the room and equipment to produce aseptic conditions;
(vi) A system for maintaining any equipment used to control the aseptic conditions.
(d) Operations relating to the manufacture, processing, and packing of peni-cillin shall be performed in facilities separate from those used for other drug products for human use. [43 FR 45077, Sept. 29, 1978, as amended at 60 FR 4091, Jan. 20, 1995]
The paragraph on lighting states:
§ 211.44 Lighting.
Adequate lighting shall be provided in all areas.
On ventilation systems:
§ 211.46 Ventilation, air filtration, air heating and cooling.
(a) Adequate ventilation shall be provided.
(b) Equipment for adequate control over air pressure, micro-organisms, dust, humidity, and temperature shall be provided when appropriate for the manu-facture, processing, packing, or holding of a drug product.
(c) 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 adequate to control contaminants.
(d) Air-handling systems for the manufacture, processing, and packing of penicillin shall be completely separate from those for other drug products for human use.
The regulations dealing with equipment requirements are written in a similar fashion. For example:
§ 211.63 Equipment design, size, and location.
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.
§ 211.65 Equipment construction.
(a) 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.
(b) 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.
The requirements in these paragraphs can be satisfied utilizing various systems.
The example provided in the chapter Introduction to this chapter discusses an approach to meeting paragraph 211.42 Design and construction features. To design a pharmaceutical facility, a designer must be thoroughly knowledgeable of industry practices and systems that have been approved by the FDA. This knowledge is obtained through education and experience. There are numerous courses sponsored by universities and professional and educational associations that can introduce an individual to the requirements of facility design. (Note: the full text of 21 CFR 210 and 211 as well as the preamble can be obtained at www.FDA.gov.)
2. Current Good Manufacturing Practices 29
European Union GMPs
The majority of manufacturing facilities located in the United States also need to meet European (EU) and local country requirements. For example, the United Kingdom GMPs are described in a publications know as the “Orange Book” due to the color of the book’s cover. A review of the EU GMPs and the UK GMPs indicates that the facility and equipment requirements in these regulations are consistent.
Other countries within the EU also have specific requirements but again these are consistent with the requirements indicated in the EU regulations. Therefore, a dis-cussion of the EU regulations is in order.
The EU has issued nine volumes constituting The Rules Governing Medicinal Products in the European Union. Of interest to the designer is Volume 4—Good Manufacturing Practices, Medicinal Products for Human and Veterinary Use. The document consists of a general section followed by product specific sections call annexes. Each of these sections contains requirements for facilities and equipment.
The EU regulations are slightly more prescriptive than the FDA’s cGMPs; however, these regulations still allow the designer a good deal of flexibility when designing a pharmaceutical plant.
Within Volume 4, Chapter 3: Premises and Equipment, covers the general requirements for these items in a similar fashion as Subparts C and D of 21 CFR 211.
For example, the first paragraph of this chapter states:
Principle
Premises and equipment must be located, designed, constructed, adapted and maintained to suit the operations to be carried out. Their layout and design must aim to minimize the risk of errors and permit effective cleaning and mainte-nance in order to avoid cross-contamination, build up of dust and dirt and, in general, any adverse effect on the quality of products.
A reading of other requirements indicates more detail than the FDA’s regulations but they are still are general in nature, allowing flexibility for the designer in providing adequate solutions to fit the specific requirements of the facility being designed.
Where the EU regulations become more prescriptive is in the annexes section.
There are 14 annexes included in the regulations covering various dosage forms as follows:
Annex Number Title
1 Manufacture of sterile medicinal products
2 Manufacture of biological medicinal products for human use
3 Manufacture of radiopharmaceuticals
4 Manufacturer of veterinary medicinal products other than immunologicals
5 Manufacture of immunologicals veterinary medicinal products
6 Manufacture of medicinal gases
7 Manufacture of herbal medicinal products 8 Sampling of starting and packaging materials 9 Manufacture of liquids, creams and ointments
10 Manufacture of pressurized metered dose aerosol prepa-rations for inhalation
11 Computerized Systems
12 Use of ionizing radiation in the manufacture of medicinal products
13 Manufacture of investigational medicinal products 14 Manufacture of products derived from human blood or
human plasma
The designer is required to perform a thorough review of the annex applicable to the type of manufacturing entity being designed. These annexes provide more detailed requirements than those presented in the FDA’s regulations. However, these annexes do include much of the same information that the FDA provides in its guid-ance documents. These annexes are not in conflict with the expectations of the FDA concerning facilities and equipment. There are additional requirements in the EU regulations for the operational aspects of the licensed facility, but these usually do not impact the design.
A good example of the additional details provided in the annexes is in the annex 1 covering sterile products. The annex contains specific information on the environ-mental classification of various operating areas (class A, B, C, and D). For example, the annex indicates that class A is to be employed for high risk operations such as filling stopper bowls, open containers, and making aspect connections. This is con-sistent with FDA expectations. The annex proceeds to provide detailed functional requirements for particulates in each of the four environmental classifications as well as recommended microbial limits to be utilized for the monitoring program in each of these areas.
While this information is more specific than found in the FDA’s regulations, it is consistent with the FDA’s guidance documents and is currently being utilized in the industry as the baseline standards.
Harmonization
In the early 1990s, an international effort was begun to harmonize the require-ments for pharmaceutical manufacturing and licensing among the United States, Japan, and the European Union. The focus of the International Conference on
2. Current Good Manufacturing Practices 31
Harmonization (ICH) program is the technical requirements for pharmaceutical products containing new drugs. Since the majority of new drugs are developed in the United States, Western Europe, and Japan, it was agreed that the scope of this activity would be confined to registration in these three geographical regions.
As stated in the mission statement:
The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) is a unique project that brings together the regulatory authorities of Europe, Japan, and the United States and experts from the pharmaceutical industry in the three regions to discuss scientific and technical aspects of product registration.
The purpose is to make recommendations on ways to achieve greater harmoni-sation in the interpretation and application of technical guidelines and require-ments for product registration in order to reduce or obviate the need to duplicate the testing carried out during the research and development of new medicines.
The objective of such harmonisation is a more economical use of human, animal and material resources, and the elimination of unnecessary delay in the global development and availability of new medicines whilst maintaining safe-guards on quality, safety and efficacy, and regulatory obligations to protect public health.
The harmonization effort has resulted in several standards in the areas of quality, safety, and efficacy. Of interest is Q7A—Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients. This document provides a template for other GMP guide documents will follow. A review of this document finds that the terminology and structure are very similar to the FDA’s cGMP requirements in 21 CFR 211 and the EU GMP Vol 4. Similar harmonization efforts are underway for aseptic manufacturing and non-sterile manufacturing.
Validation
An important regulatory issue affecting the design of a pharmaceutical facility is val-idation. The FDA requires that all processes producing drug substances be validated.
The FDA’s definition for process validation, as stated in the Guideline on General Principals for Validation, is:
Establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its predeter-mined specifications and quality attributes.
This statement not only requires that manufacturing processes be validated, but the facility systems that support production as well. For example, an aseptic
processing operation requires a “clean” room. Consequently, the heating, venti-lating, and air-conditioning (HVAC) system must be validated in order to ensure that the process is truly aseptic. Furthermore, all critical utility systems (e.g., water, steam, compressed air) need to be tested to ensure proper operation. The nature of the testing that takes place during validation varies depending upon the system or piece of equipment. Certain systems are “validated” and others are “qualified.” The difference is whether or not a challenge test is conducted. Sterilization systems and procedures undergo a specific challenge to determine their adequacy. Support util-ities and HVAC systems are not specifically challenged but are determined to be operating within acceptable criteria and, therefore, are qualified. Industry and the FDA have generally agreed regarding which systems fall into each category. In general, those systems that directly affect the product are challenged, while those that support the operation are qualified. The entire documentation and testing effort is generally known as validation. (Details of this program are discussed elsewhere in this text).
The requirement for validation is delineated in 21 CFR 210 and 211 for finished drug products and 21 CFR 820 for medical devices. (The guideline mentioned above provides the specific paragraph references for validation. A complete text of the guideline can be obtained at the FDA’s web site.) The requirement for validation is included in the EU regulations in Volume 4, Chapter 5: Production, Sections 5.21 through 5.24.
The above regulatory requirements ensure that a designer, in addition to a knowledge of design, must also have knowledge of how the facility is to operate and how it is to be validated. These activities have a direct impact on the facility and equipment design. The owner needs to define the approach to validation at the begin-ning of the project. A useful tool in conveying this information is the Validation Master Plan. (VMP) This document delineates the validation program that will be utilized and is usually developed in conjunction with the design basis of the facility.
Both documents require the use of User Requirement Specifications (URS) as their foundation. These two documents are discussed elsewhere in this text.
APPROACH TO GMP DESIGN General
The non-specific requirements delineated in the regulations require a disciplined approach to the design of pharmaceutical manufacturing facilities, thus GDP. As dis-cussed inthe ISPG Baseline Guides, the foundation of this approach is the manufac-turing process(es) and the product(s) that will be produced, tested, or held in the facility under design. The majority of design decisions and design criteria should be based on the critical quality attributes of the product.
A designer must have knowledge of how the facility is to operate and how it is to be validated. The company define its approach to validation at the beginning of the project. The Validation Master Plan (VMP), the document which delineates the validation program that will be utilized, is developed in conjunction with the design basis of the facility.
2. Current Good Manufacturing Practices 33
During the development of the design basis, the manufacturing process and facility requirements are defined. These are developed through discussions with the end user, including the manufacturing, QA/QC, engineering, and the validation groups. Items addressed during this phase are:
• Establishing goals and objectives
• Preparing user Requirements Specifications (URS), process, and operational flow dia-grams
• Developing system design criteria
• Developing the facility conceptual design
Goals and Objectives
Goals and objectives of the manufacturing unit depend upon the following:
• Corporate philosophies
• Operating philosophies
• Regulatory requirements
A corporate philosophy, such as the requirement to maintain a minimum level of finished goods inventory, will directly affect the size of the warehouse and pro-duction equipment output rates. Corporations have requirements concerning capital investment. Prior to the commitment of funds, the investment must meet certain cri-teria for return on investment (ROI) and the time period within which an investment pays for itself (payback period). The inclusion of systems such as energy manage-ment and production automation, may be dependent upon their payback period. A period of two to five years for such systems is common in the industry.
An operating philosophy that encompasses the presence or absence of in-process material quarantine areas during the manufacturing operation will affect the physical size and layout of the new facility.
The cGMPs regulations place restrictions on the design of the facility. For example” Are entry and exit gowning areas required? How will material control be dealt with in a batching operation?
An understanding of these factors is essential in designing a compliant manu-facturing facility.
User Requirements Specifications, Process Flow, and Operational Flow Diagrams
In order to fully understand the expectations of the user of the manufacturing facility, it is necessary to develop the User Requirements Specifications (URS). These doc-uments delineate the requirements and expectations of the end user of the facility, equipment, and system. The designer needs to understand that the objective is to deliver a design for a licensed operation, not just a design of a building filled with equipment. The manner in which the facility, equipment, and systems are to be uti-lized forms the foundation for manufacturing operation. These documents also are utilized as the starting point in the validation effort.
A constructive technique to assist in the understanding of all aspects of the manufacturing process is the preparation of process flow diagram (PFD) and opera-tional flow diagram (OFD).
PFDs depict each unit operational step of the manufacturing process. In ana-lyzing the overall production scheme, the operation can be broken down into its basic elements.
These elements are arranged in a facility OFD that depicts the inter-relation-ships between the manufacturing process steps and other operating departments (QA, Production, In-Process Testing, etc.). In this manner, the designer can incor-porate the entire operation into the layout of the facility without inadvertently neglecting some component or preventing required interactions.
System Design Criteria
System design criteria must be established for each production and support system required by the manufacturing process. The products being manufactured form the focus for establishing design criteria. An analysis of the manufacturing process being conducted in each room/area must be completed to identify all systems that can impact the quality of the product and/or the efficiency of operations. The PFD and OFD, along with the URS, should form the basis for this analysis.
Facility Conceptual Design
The activities leading to this point have resulted in the development of a design basis for the facility. Alternative concepts can exist that will satisfy the requirements developed. These concepts need to be explored and decisions made as to which are to be used.
The conceptual designs of the manufacturing process are developed during the creation of the PFD. The concepts for the support utilities are derived when the quan-tity of the utility is known and a decision concerning the segregation of process and building utilities is reached. Once the manufacturing process and support utility con-ceptual designs are completed, the facility layout is developed.
The engineering and validation disciplines should be involved at this phase of the project to develop the approach to validation of the facility and to prepare the Commissioning Plan (CP) and the VMP.
Normally at the end of this project phase, a report is issued delineating the facility requirements and presenting the concepts that were investigated, including drawings that indicate the schematic design of the facility. This report is used for the Design Development phase of the project. At this point in time, the first draft of the VMP should be issued and the first meeting with the FDA arranged.
Prior to the meeting with the FDA, the project team should conduct a cGMP audit of the project. The purpose of this audit is to determine whether the design of the facility meets cGMP requirements and accepted industry practices. The audit should be conducted by personnel who are familiar with cGMP design practices and who are not directly involved in the project.
2. Current Good Manufacturing Practices 35