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The author outlines the key concepts of ISPE's recently revised Baseline Pharmaceutical Guide for New and Renovated Facilities. This article is part of a special supplement on Excipients and Solid Dosage.
Oral solid dosage (OSD) forms are the most common dosage forms for patients worldwide, and the use of OSD forms (i.e., tablets, capsules, or powders) is likely to increase as access to medical care expands on a worldwide basis. As a result, OSD production in established markets such as the United States and Western Europe is likely to increase as is production in emerging markets such as India, China, Brazil, Mexico, and South Korea. Pharmaceutical companies may make product internally or use contract manufacturers, which use multipurpose production facilities. At the same time, highly active and highly hazardous substances are becoming more and more part of drug development and, therefore, of manufacturing processes. The term highly hazardous substances refers to cytotoxic, cytostatic, teratogenic, mutagenic, or retrotoxic products. These factors have changed the picture of pharmaceutical production in recent years and will continue to play a role in global pharmaceutical production in the future.
To address these issues, the International Society for Pharmaceutical Engineering (ISPE) released a revised Baseline Pharmaceutical Engineering Guide for New and Renovated Facilities–Volume 2 Oral Solid Dosage Forms in November 2009 (1). More than 30 industry professionals worked on the OSD guide for more than five years through a partnership with the US Food and Drug Administration and European Medicines Agency (EMA) to develop a common understanding and interpretation of good manufacturing practice (GMP) requirements for production facilities. The purpose of the ISPE OSD guide is to support the design and construction of renovated and new facilities.
The recently revised ISPE OSD guide has several key elements:
Proper balance of facility design and procedures.To achieve the proper balance of facility design and procedures, the guide addresses each GMP issue by facility design as well as through procedural control, facility layout, containment, and barrier technologies. This approach allows the flexibility to design for appropriate levels of protection or containment while avoiding costly designs that may result in no significant improvement in quality and efficacy of the drug product, or protection of personnel. For example, based upon an assessment of contamination risk within a tableting room, one or more of the following may be applied to prevent contamination:
Risk-based approach.The risk-based approach involves using innovative manufacturing science and technology to assess, mitigate, and control the potential hazard in a manufacturing process that affects the quality of the drug product. As an example, using statistical data analysis in conjunction with process analytical technology (PAT) for continuous process monitoring and control can lead to higher quality product. Sharing such risk-mitigation strategies with FDA may be beneficial (2).
Non-GMP technologies. Some facility-design requirements arise from decisions made to address non-GMP issues or preferences of the manufacturer such as operator safety or strategic-operating decisions. These non-GMP-driven technologies often affect facility-design features aimed at achieving GMP compliance (3). With proper planning, both GMP and non-GMP risk assessments may be completed in parallel, enabling key drivers for capital investment to be included in the project scope.
Contamination risk. The level of protection is based on the risk of contamination as assessed by the manufacturer. Assessment criteria include:
Design conditions and operating range. Operating conditions are based upon product-acceptance criteria while design set points and conditions are target values for the engineering designer to achieve. For example, a blending room may have a setpoint of 40% relative humidity (RH) and a design range of 30–50% RH, but the product in that room may be unaffected by humidity in the range of 20–70% (i.e., validated product-acceptance criteria). The acceptable operating range for the room is therefore 20–70%, not 30–50%. Additionally, nonproduct requirements such as human comfort are also criteria in the design (4).
GEP.GEP is defined as engineering practices that are applied throughout the business to provide organization and control, balance risk and cost, and deliver appropriate and effective solutions. GEP describes an engineering-management system that is expected in a pharmaceutical enterprise but not mandated by good practice quality (i.e., GxP) regulations. GEP recognizes that all systems in a facility undergo some form of commissioning, which include inspection, testing, and documentation based on agreed protocols. Direct-impact systems require enhanced documentation, which includes an enhanced design review, and quality-assurance (QA) inspection and approval that are appropriate and acceptable to regulators. GEP capitalizes upon the suggestion that manufacturers engage all stakeholders (i.e., engineers, managers, operators, and QA experts) early in the planning, design, construction, commissioning, and qualification phases to ensure that systems are documented only once (5, 6).
Documentation. Appropriate documentation throughout the project for ensuring the equipment and facility is fit for its intended use is a key element of GEP. Documentation should be reviewed, approved by appropriate subject matter experts, updated in a timely fashion, and stored in a secure location for retrieval (1).
Cost factors for an oral solid-dosage manufacturing facility
Major elements of the OSD guide
The OSD guide is subdivided into chapters that cover the following: regulatory philosophy; product protection, product, and processing; architectural and facility design; process support and utilities; heating, ventilation, and air-conditioning (HVAC) systems; electrical requirements; control and instrumentation; and other considerations. The appendixes provide insight into cost factors for OSD manufacturing (see sidebar, "Cost factors for an oral solid-dosage manufacturing facility") and outline the quality risk-management process and tools (see sidebar, "Quality risk management) (1).
Quality risk management
Regulatory philosophy. Regulation of the pharmaceutical industry is conducted by national and international agencies such as FDA, EMA, and Japan's Ministry of Health, Labor, and Welfare (MHLW). The key legislative and regulatory provisions in the US are set forth in the US Food, Drugs, and Cosmetics Act (FD&C Act), and GMP requirements are specified in the US Code of Federal Regulations Title 21 (i.e., 21 CFR 210 and 21 CFR 211) (7, 8). In Europe, the EU Directive 2003/94/EC requires medicinal products to be manufactured in accordance with current good manufacturing practices (CGMP), which is set out in EudraLex Volume 4: EU Guidelines to Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use (9, 10). In Japan, GMP is required for manufacturing and marketing approval under Article 14.2, Paragraph 4 of Japan's Pharmaceutical Affairs Law (11). GMP requirements for OSD facility design are in the MHLW ordinance, Regulations for Buildings and Facilities for Pharmacies (12).
These regulatory provisions are a framework for the basic requirements within OSD facilities to ensure product quality and operator safety during the manufacturing process. OSD facilities may be designed and constructed to operate under different production scenarios. The products manufactured in OSD facilities may vary in dosage form and degree of product hazard. The equipment used to produce OSD forms can range from open-type manual processing to enclosed and highly automated processing. The different types of processing can lead to numerous possible facility layouts, all of which are governed by the same basic GMP requirements for the design, construction, and validation of OSD facilities and equipment. To meet these requirements, the facility should:
OSD facilities have common issues across the different unit operations and product types. Dust containment often presents a design challenge for OSD forms, particularly with highly hazardous active ingredients. The ISPE OSD guide is intended to help establish consistent and minimum parameters for facility design, which address these concerns and meet GMP requirements. The guide provides guidance on risk-based approaches, product-protection requirements, design concepts for product protection, process-control concepts, and commissioning, qualification, and validation (1, 3, 5, 6, 13–19).
Each manufacturer should define the level of control, protection, and validation appropriate to each manufacturing operation based upon a sound understanding of the critical product and process parameters and determine the risk of product contamination to the product mix within each manufacturing area. When existing facility renovations or modifications are made or manufacturing procedures are changed, these changes should be evaluated in advance to determine how they may affect patient safety and product quality. Appropriate change-control procedures should be followed in making any change to qualified equipment, systems or validated processes. Depending upon the extent of the change and its potential to affect patient safety and product quality, the governing regulatory agency may require notification or prior approval of a change before it is implemented. Understanding the potential impact of a proposed change and the corresponding regulatory requirements is critical to maintaining facilities, equipment, and processes in a qualified and validated state (1).
Product protection.The ISPE Baseline Guide Risk-MaPP (i.e., Risk-Based Manufacture of Pharmaceutical Products, Rev. C is under technical review by FDA) describes a scientific risk-based approach for the prevention of cross-contamination. The guide will, on a case-by-case basis, determine the need for dedicated or segregated facilities in the manufacture of pharmaceutical products (4, 13).
Product and processing.The ISPE OSD guide provides guidance on process and equipment choices for OSD forms in new or renovated pharmaceutical manufacturing, formulation development, and pilot-plant operations, which includes associated equipment pertinent to product quality and facility design. Material characteristics and properties, material handling, cleaning, and maintenance are also addressed. The guide also considers the application of PAT and manufacturing execution systems (MESs). The guide uses decision trees to evaluate the options to a baseline operation and equipment-training selection for various process requirements and material types (14). Separate guides from ISPE offer differences between European, Japanese, and US practices as they relate to active pharmaceutical ingredients (20) and for packaging, labeling, and warehousing facilities (in draft form as of publication of this article).
Architectural considerations. The ISPE OSD guide provides requirements to be considered for OSD facility design and construction for building programs, building layouts, space definition, details, and finish materials. These aspects of the facility are developed in the context of CGMP, risk, and process requirements to establish baseline guidance and parameters (15).
Process support and utilities.The ISPE OSD guide discusses the categorization of mechanical systems used in OSD pharmaceutical manufacturing. There are two broad categories: process-support systems and utility systems. The guide discusses the categorization of mechanical systems using a risk-based approach methodology to offer a robust methodology for the identification of process support and utility systems. The guide also provides a method for the determination of system applications and the selection of resulting commissioning and qualification strategies with relevant examples for each type of system. Other considerations that impact system design, including user requirements, engineering-design elements, and start-up requirements also are addressed. The discussion also focuses on GEP for utility-system design. Approaches for multiple-use requirement scenarios also are addressed. A listing of typical OSD utility systems is provided with general descriptions and requirements for each system (5).
HVAC. The ISPE OSD guide provides the GMP requirements for HVAC systems. It provides guidance on the design of HVAC systems based upon clearly defined user requirements (e.g., level of product protection, product and process requirements, and architectural design). Non-GMP requirements, such as operator protection, expectations on monitoring, energy efficiency, and safety requirements, also are addressed (16).
HVAC systems can help mitigate risks, both GMP and non-GMP risks. HVAC designers should understand CGMP regulatory requirements and also be familiar with industrial HVAC requirements as defined in various documents by the American Society of Heating, Refrigeration and Air-Conditioning Engineers and the American Conference of Governmental Industrial Hygienists. Knowledge of all local construction codes, the National Fire Protection Association standards, environmental regulations, and Occupational Safety and Health Administration regulations is assumed. The design and installation of the HVAC system should comply with these requirements and all applicable building, safety, hygiene, and environmental regulations (16).
Electrical requirements.The most important issues to be addressed in an OSD facility from an electrical perspective are:
Although the degree of electrical requirements may differ based upon the level of protection required, the cleanability of the exposed electrical equipment is the primary concern of electrical systems in an OSD facility (17).
Electrical-power-distribution systems do not directly affect the quality of OSD drugs and hence are not critical systems and are not subject to regulatory oversight and validation requirements. The equipment that produces and controls the pharmaceutical processes and provides clean and controlled environments for the manufacturing areas for OSD pharmaceutical drugs, however, requires a source of electric power and an electrical-power-distribution system that is reliable and maintainable (17).
A properly designed electrical distribution system should provide reliable electricity to the OSD pharmaceutical equipment. The ISPE OSD guide provides design and maintenance criteria to assist in the proper design of an electrical system to provide reliable electrical service (17).
Control and instrumentation.The guide addresses control-and-instrumentation systems for OSD manufacturing facilities. It focuses on facility and environment controls that affect patient safety and product quality and the major topics that drive decisions regarding the design and setup of process-control systems (PCSs). The objective is to provide design guidance, which results in cost-effective system designs that are capable of being qualified (18).
Control-and-instrumentation systems are used in many facility systems. They may be deemed to affect patient safety and product quality if they control, monitor, or record a critical process parameter or directly affect a critical quality attribute. Components of control-and-instrumentation systems are also considered critical if they come into direct physical contact with the product (18).
The functions of a control-and-instrumentation system may be performed in a single system or by several independent systems. The guide provides specific design advice where possible, but stresses that different operational preferences and priorities influence the preferred solution. The designer needs to consider other relevant design criteria such as safety, reliability, and maintenance. PSC encompass a wide variety of systems such as programmable-logic-controller systems, supervisory-control-and-data-acquisition systems, distributed-control systems, and MESs (18, 21).
Control systems may be complex and validation strategies should be based on a defined risk-based approach. A testing strategy should be based on a predefined estimate of the level of risk, providing traceability and information allowing critical parameters to be determined. The basis of PAT is process understanding and the application of appropriate control strategy for the critical process parameters to ensure the quality of in-process material and final drug products. A robust control system is a key component to support a PAT system implementation (18, 22).
A statistical process control (SPC) may be considered as a precursor to PAT. A control system should assist with:
At the time of this publication, PAT is only in the inception phase. The ability to connect PAT measurement devices with PCSs and to transfer related data to statistical tools is required before a regulatory filing involving PAT.
Other considerations.The ISPE OSD guide provides an overview of considerations for health, safety, and environmental factors and controlled substances (3). The guide summarizes non-CGMP risks that should be considered and provides an overview of the basic technical and procedural approaches that may be used to mitigate these risks (3). In addition to information provided in the guide, project teams should be aware of local requirements and facility policies. The guide outlines the types of non-CGMP information that should be gathered as part of an organization's risk assessment and mitigation process.
Commissioning and qualification guide
In its report, Pharmaceutical CGMPs for the 21st Century—A Risk-Based Approach, FDA outlined several key goals:
A revision of ISPE's Baseline Guide Volume 5Commissioning and Qualification is underway. The revisions seeks to support these objectives by describing an efficient and effective design, installation, and verification process that focuses on safeguarding product quality and public health. It is intended that risk management should underpin the specification, design, and verification process, and be applied appropriately at each stage.
As part of this revision, Baseline Guide Volume 5Commissioning and Qualification is being aligned with ASTM International's standard E2500, which describes a risk- and science-based approach to the specification, design, and verification of manufacturing systems and equipment that have the potential to affect product quality and patient safety.
The author would like to acknowledge ISPE for providing information in support of this article.
Richard Denk is director of the pharmaceutical department at Hecht Technologie GmbH, Schirmbeckstrasse 17, 85276 Pfaffenhofen/Ilm, Germany, firstname.lastname@example.org, tel. +49 8441 8956 18. He is a contributing writer to the International Society for Pharmaceutical Engineering's (ISPE) Baseline Pharmaceutical Engineering Guide for New and Renovated Facilities–Oral Solid Dosage Forms, a member of ISPE's Oral Solid Dosage Steering Committee, and co-chair of ISPE's Containment Steering Committee.
1. Baseline Pharmaceutical Engineering Guide for New and Renovated Facilities–Volume 2 Oral Solid Dosage Forms (ISPE, Washington, DC, 2nd ed., Nov. 2009).
2. ICH, Q9 Quality Risk Management (Geneva, Nov. 2005), Sec. 17, Reference 1.
3. "Other Considerations," in Baseline Pharmaceutical Engineering Guide for New and Renovated Facilities–Volume 2 Oral Solid Dosage Forms (ISPE,, Washington, DC, 2nd ed., Nov. 2009), Chapter 10, pp 125–148.
4. "Concepts and Regulatory Philosophy" in Baseline Pharmaceutical Engineering Guide for New and Renovated Facilities–Volume 2 Oral Solid Dosage Forms (ISPE, Washington, DC, 2nd ed., Nov. 2009), Chapter 2, pp 17–21.
5. "Process Support and Utilities," in Baseline Pharmaceutical Engineering Guide for New and Renovated Facilities–Volume 2 Oral Solid Dosage Forms (ISPE, Washington, DC, 2nd ed., Nov. 2009), Chapter 6, pp. 89–96.
6. "Risk-Based Approaches to Commissioning and Qualification" in Baseline Pharmaceutical Engineering Guide for New and Renovated Facilities–Volume 2 Oral Solid Dosage Forms (ISPE, Washington, DC, 2nd ed., Nov. 2009), Chapter 11, pp 149–151.
7. "Current Good Manufacturing Practice in Manufacturing, Processing, Packing, or Holding of Drugs; General," in Code of Federal Regulations, Title 21, Food and Drugs (Government Printing Office, Washington DC), Part 210.
8. "Current Good Manufacturing Practice for Finished Pharmaceuticals, "in Code of Federal Regulations, Title 21, Food and Drugs (Government Printing Office, Washington DC), Part 211.
9. European Commission, Commission Directive 2003/94/EC, "Laying down the Principles and Guidelines of Good Manufacturing Practice in Respect of Medicinal Products for Human Use and Investigational Medicinal Products for Human Use (Brussels, Oct., 2003).
10. European Commission, EudraLex (Rules Governing Medicinal Products in the European Union) Volume 4: EU Guidelines to Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use (Brussels, Oct., 2003).
11. Pharmaceutical Affairs Law (Japan's MHLW, Tokyo), Article. 14.2, paragraph 4.
12. "Regulations for Building and Facilities of Pharmacies," in Pharmaceutical Affairs Law (Japan's MHLW, Tokyo).
13. "Product Protection," in Baseline Pharmaceutical Engineering Guide for New and Renovated Facilities–Volume 2 Oral Solid Dosage Forms (ISPE, Washington, DC, 2nd ed., Nov. 2009), Chapter 3, pp 23–30.
14. "Product and Processing," in Baseline Pharmaceutical Engineering Guide for New and Renovated Facilities–Volume 2 Oral Solid Dosage Forms (ISPE, Washington, DC, 2nd ed., Nov. 2009), Chapter 4, pp 31–36.
15. "Architectural," in Baseline Pharmaceutical Engineering Guide for New and Renovated Facilities–Volume 2 Oral Solid Dosage Forms (ISPE, Washington DC, 2nd ed., Nov. 2009), Chapter 5, pp 67–88.
16 "HVAC, " in Baseline Pharmaceutical Engineering Guide for New and Renovated Facilities–Volume 2 Oral Solid Dosage Forms (ISPE, Washington, DC, 2nd ed., Nov. 2009), Chapter 7, pp 97–113.
17. "Electrical," in Baseline Pharmaceutical Engineering Guide for New and Renovated Facilities–Volume 2 Oral Solid Dosage Forms (ISPE, Washington, DC, 2nd ed., Nov. 2009), Chapter 8, pp 115–120.
18. "Control and Instrumentation," in Baseline Pharmaceutical Engineering Guide for New and Renovated Facilities–Volume 2 Oral Solid Dosage Forms (ISPE, Washington, DC, 2nd ed., Nov. 2009), Chapter 9, pp 121–124.
19. "Cost Factors in OSD Manufacturing, "Baseline Pharmaceutical Engineering Guide for New and Renovated Facilities–Volume 2 Oral Solid Dosage Forms (ISPE, Washington, DC, 2nd ed., Nov. 2009), Appendix 1, 153–155.
20. Baseline Pharmaceutical Engineering Guide–Volume I Active Pharmaceutical Ingredients (ISPE, Washington, DC, 2nd Ed., Apr. 2007).
21. "Control and Instrumentation," in Baseline Pharmaceutical Engineering Guide for New and Renovated Facilities–Volume 2 Oral Solid Dosage Forms (ISPE, Washington, DC, 2nd ed., Nov. 2009), Chapter 9, Section 17, Reference 13.
22. "Control and Instrumentation," in Baseline Pharmaceutical Engineering Guide for New and Renovated Facilities–Volume 2 Oral Solid Dosage Forms (ISPE, Washington, DC, 2nd ed., Nov. 2009), Chapter 9, Section 17, Reference 28.
23. FDA, Pharmaceutical CGMPs for the 21st Century–A Risk-Based Approach (Rockville, MD, 2004).