GMP or Non-GMP Washers and Sterilizers Part 2: Pharmaceutical Grade vs. Laboratory
by Marcel Dion, Director of Marketing for Washing and Steam Sterilization Systems in the Life Sciences Division of STERIS Corporation and Matt Hofacre, responsible for global applications team with STERIS Life Sciences Capital Equipment Solutions
Non-GMP or GMP Washers and Sterilizers: How to Choose article is featured in the November/December 2015 issue of Pharmaceutical Engineering®.
This three part series will present the standards and guidelines typically used by manufacturers to design and build GMP washers and sterilizers. It describes the characteristics that differentiate GMP from regular laboratory equipment. Part two will cover all of the differences between pharmaceutical grade washers and sterilizers versus laboratory.
Pharmaceutical Grade Washers and Sterilizers vs. Laboratory
The characteristics can be grouped into five categories:
- Manufacturer’s quality assurance program
- Mechanical design
- Process monitoring
- Control and software system
- Design, manufacturing, and qualification documentation
Manufacturer’s quality assurance program
The ASME-BPE standard indicates that “the manufacturer shall implement a quality assurance program describing the systems, methods, and procedures used to control materials, drawings, specifications, fabrication, assembly techniques, and examination/inspection used in the manufacturing of bioprocessing equipment.”6 A third-party certification such as ISO 900115 is generally well accepted and recognized; in some cases, however, users prefer to conduct an audit of the supplier. Such a certification is not necessarily required for regular non-GMP applications.
The ASME-BPE 2014 Part System Design (SD) provides methods and guidelines to create a design framework, using proven practices for supporting efficient cleanability and bioburden control in bioprocessing systems.7 The overall objective is to prevent contamination of drug products due to inadequate cleaning or sterilization of surfaces that come in contact with the products during their manufacturing process. While it would be challenging to attempt to summarize the entire content of ASME-BPE in this article, some sections that relate directly to the design of washing and sterilization systems used in GMP facilities can be highlighted:
SD-2.4—Fabrication: “Fabrication shall be performed in facilities where the product contact surfaces are protected from contamination.” SD-22.214.171.124—Material of construction: “Generally, materials such as 316 and 316L, stainless steel, duplex stainless steels, and higher alloys have proven to be acceptable. … When nonmetallic materials are used (e.g., polymeric materials or adhesives), the owner/user shall specify which one of these materials shall carry a Certificate of Compliance. The conformance of material shall be explicitly stated (e.g., conforming to FDA 21 CFR 177 and USP Section <88> Class VI).”
Parts MM and PM provide additional guidelines for the selection of metallic and nonmetallic materials.
SD-2.4.2—Cleanability: This section describes how equipment should be designed so that all surfaces are cleanable: “Surface imperfections (e.g., crevices, gouges, obvious pits) shall be eliminated whenever feasible, horizontal product contact surfaces shall be minimized, the equipment shall be drainable and free of areas where liquids may be retained and where soil or contaminants could collect, and areas of low flow and low velocity or impact where soil or contaminants could collect. Fasteners or threads shall not be exposed to the process, steam, or cleaning fluids. Design of corners and radius shall have the maximum radius possible for ease of cleanability (minimum 3.2 mm).” (See Figure 1.)
SD-2.4.3—Drainability: “For sterility and cleaning, gravity is an effective way to facilitate drainage. To achieve gravity drainage, lines should be pitched to designated points at a specific slope.” The recommended slope varies between 0.5% and 2%, depending on the application (Figure 2).
SD-3—Process components: This section describes how piping, connections, and fittings should be designed to be hygienic. The number of connections should be minimized; hygienic fittings should be used since threaded fittings are not recommended. Dead legs should ideally have a length/diameter ratio of less than 2 where possible. Stainless steel surfaces should be passivated, the use of blind welds should be avoided, and the design of pumps and associated connections should be hygienic (Figure 3).
Part SF—Surface finish: “Product contact surface requirements shall apply to all accessible and inaccessible areas of the systems that directly or indirectly come in contact with the designated product.” These requirements may vary from one application to another, but typically, for pharmaceutical-grade washers and sterilizers, the acceptable range varies between 20 and 30 μin Ra (0.51 and 0.76 μm).
Part MJ—Material joining: This part provides specific requirements for the joining (welding) of metallic materials. In general, welds in pharmaceutical-grade washers and sterilizers are expected to be “hygienic.”
Part PI—Process instrumentation: This section is dedicated to the definition of minimum requirements for process instrumentation in hygienic applications. In practice, the design of all instrumentation that is in contact with the washing or sterilization process has to be hygienic.
Specifications for regular laboratory washing or sterilization systems typically do not include any of these mechanical requirements.
Process monitoring for Pharmaceutical Grade Washers and Sterilizers
Section SD-5.3 of the ASME-BPE 2014 standard includes information on process-monitoring functions that are specific to washing and sterilization systems. As an example, section SD-126.96.36.199.3 indicates that the “instrumentation and control architecture should be designed to communicate, monitor, and synchronize the clean-in-place (CIP) cycle and report CIP variables.” These variables, which are very similar in clean-out-of-place (COP) washers (also referred to as parts or components washers), include parameters such as time of exposure, temperature of wash and rinse solutions, chemical concentration by conductivity or volume, final rinse water conductivity or residual cleaning chemical concentration, water flow and pressure, and rotation of spray devices. Similar requirements for sterilizers (or autoclaves) are outlined in section SD-5.3.2. It is also mentioned that provisions for recording process parameters should be included and that “recording may be achieved by paper or 21 CFR Part 11 compliant electronic means.” EN285 and HTM2010 (CFPP) have specific process monitoring requirements for temperature and pressure in steam sterilizers.
The majority of pharmaceutical-grade washers and sterilizers are equipped with advanced process monitoring systems. New technologies now make it possible to perform online monitoring of total organic carbon (TOC) content in the final rinse water of CIP or COP washing systems (Figure 4). Of course, laboratory washers and sterilizers monitor critical parameters such as time, temperature, and pressure; but as an example, basic washers typically do not monitor parameters such as conductivity of final rinse water, TOC content, or rotation of spray devices.
Control and software
For regular laboratory applications, the type of control with which the washer or sterilizer should be equipped is rarely specified. In many cases, proprietary microprocessor-based control systems are provided and accepted. Units are typically stand-alone and rarely connected to centralized supervisory control and data acquisition (SCADA) systems. However, in GMP environments, nonproprietary commercially available control platforms are generally preferred and, in many cases, interfaced with a higher-level centralized control or data management system (Figure 5). In most cases, users expect that equipment suppliers will follow GAMP guidelines.
GAMP guidance aims to achieve computerized systems that are fit for intended use and meet current regulatory requirements.8 It is also meant to provide life sciences industry suppliers with guidance on the development and maintenance of systems by following good practices.
As mentioned previously, records of process parameters must be maintained for GMP applications. While printers are still commonly used, many users now opt for electronic records, in which case, CFR Title 21, Part 114 automatically applies. “This part applies to records in electronic form that are created, modified, maintained, archived, retrieved, or transmitted, under any records requirements set forth in agency regulations.”4 Again, this type of requirement does not typically apply to regular research facilities and equipment.
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In March, the ISPE Training Institute will be conducting a Facilities, Systems & Equipment training focusing on the tools for implementing a sustainable approach to a risk-based C&Q program, integrating the new C&Q program into existing quality systems, Quality Assurance and Engineering Management Systems and defining organizational capabilities to support the new C&Q program Sign up today!
4. ———. Code of Federal Regulations, Title 21, Part 11. “Electronic Records; Electronic Signatures.” 21 August 2015. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=11.1.
6. ———. ASME BPE—2014 Bioprocessing Equipment. 2014. GR-3, p. 1.
7. ———. ASME BPE—2014 Bioprocessing Equipment. 2014. SD-1, p. 17.
8. International Society for Pharmaceutical Engineering. GAMP® 5: A Risk-Based Approach to Compliant GxP Computerized Systems. February 2008, p. 11.
15. International Organization for Standardization. “ISO 9000—Quality Management.” http://www.iso.org/iso/home/standards/managementstandards/iso_9000.htm.