By Greg Weilersbacher, Eastlake Quality Consulting
Annex 15 of the EU GMP Guidelines defines “change control” as: “A formal system by which qualified representatives of appropriate disciplines review proposed or actual changes that might affect the validated status of facilities, systems, equipment or processes.” The FDA’s own guidances refer to change control as “…managing change to prevent unintended consequences.” In practice, however, many companies limit change control to documentation such as batch records, SOPs, protocols, and specifications, while change control for equipment and facilities, if done at all, is minimized and handled in isolation. That is, when new equipment arrives, it is installed and connected to utilities without prior input and approval from facilities, engineering, validation, and quality. While many in the industry may conceptually understand change control for equipment and facilities, most people lack the knowledge to apply this control to highly sophisticated equipment and the utilities to which they connect. This article is the first in a two-part series providing a detailed framework that can be used by companies in the design of compliant equipment change control procedures.
The Scope Of Change Control
Equipment change control (ECC) applies to equipment from all departments (GMP and non-GMP) that connect to the facility’s GMP utilities. This includes utilities such as electrical, water systems, drainage, clean gases, venting/exhausting of heat and fumes, equipment cooling, clean steam, GMP servers and networks, HVAC, and any system that has direct or indirect impact on cleanroom operations. Why include non-GMP equipment in ECC? The answer is simple: shared utilities.
If you are one of the fortunate ones, your company’s research and development (R&D) departments are located in buildings with utilities dedicated to research activities. The rest of us, however, must share buildings and utilities between development and GMP operations. As such, any time a piece of equipment (R&D or GMP) is connected to a shared utility, it has the potential to affect the performance of other equipment connected to the utility. It also has the potential to damage the utility. This is why ECC is so important and where it shows its value. One of the biggest errors you can make is assuming that the utility you intend to connect to is dedicated to R&D.
Equipment change control can be grouped into six primary stages, each with several sub-stages: (1) Determining the equipment utility/IT requirements, (2) Pre-installation assessment, utility evaluation, and remediation, (3) Assessing the impact of equipment installation and operation on the validation of the utility, (4) Equipment installation, validation/calibration, (5) Review/approval of turnover packages, executed validation data/reports, and release of equipment for GMP use, and (6) Evaluation of effectiveness of the equipment change control.
Stage 1: Understanding The Utility And IT Requirements For New Equipment
This is the starting point for ECC and is one of the most important steps. Before the equipment is purchased, you must detail the equipment’s utility requirements. “Before you purchase” must be emphasized here, because all too often the cost of purchasing the equipment doubles, as does the commissioning timeline when utility upgrades and other related equipment purchases are needed to ensure proper operation of the equipment you wish to buy.
The answer can be found from several sources, including the owner’s manual or directly from the equipment manufacturer. The manufacturer often can provide specification sheets that detail the equipment’s requirements for electrical, venting/exhausting, heat dissipation or cooling, water quality, clean gases, clean steam, drainage, and explosion proofing. The spec sheet should also include a list of materials of construction that are critical for product contact equipment used in GMP manufacturing. It is important to determine the requirements for each utility when the equipment is operating at full capacity. Your company’s engineers and facility mechanics can be a great resource in helping you come up with an exhaustive list.
An often-overlooked need is the connections to GMP servers and networks. Equipment configured with outputs that can be connected to GMP servers is now the norm for new instruments. This represents one of several elements in ensuring data integrity of electronic records. However, problems are often encountered when purchasing used and refurbished equipment that the manufacturer originally designed as stand-alone equipment without networking capabilities. Data integrity compliance does not vanish when equipment cannot connect to validated networks. It creates compliance issues for which your company must develop a plan to address.
Stage 2: Comparison Of Equipment Requirements To The Capabilities Of Utilities
For facilities personnel to determine whether an electric utility is capable of meeting the needs of your new equipment, they will first need to know where it will be installed. Seems obvious, right? Wrong. Too often, those who purchase equipment don’t know exactly where the new equipment will be installed. A common response is that “the equipment will be put in one of the cleanrooms.” That’s a problem. It’s highly likely that each cleanroom is not configured exactly the same in terms of type of power available and the number of connections. If the equipment requires a significant power draw, the circuit panel will need to be evaluated to ensure that not only is the panel fed by the right power supply but also that the panel is balanced (i.e., the total amperage requirements of the electrical equipment in a shared-neutral installation are distributed equally among the number of available electrical circuits servicing the installation). Obviously, the equipment purchaser is not the right person to make this determination. This is an important element of change control: Subject matter experts (an electrician or competent facilities technician in this case) must be enlisted to make technical assessments on critical parameters.
Capacity Of Emergency Generators — The Most Ignored Utility
Emergency generators are typically installed during facility construction and their size is reflective of only the equipment that was on-site or projected to be on-site at that time. If it is critical that the new piece of equipment is connected to an e-power circuit and the power requirements are high, it is important to evaluate the capacity of the emergency generator in comparison to the current load. It is best not to rely solely on the architectural as-built drawings, since new equipment and power connections are frequently added without redlining the as-builts. A qualified electrical contractor can install a monitor at the power source to the facility and trend the power draw over a few weeks or a month. The results should be compared to the emergency generator’s load rating and then the capacity of the generator can be compared with the power needs of the new equipment.
I recently encountered this problem in a GMP production facility where the CDMO added five large stability chambers to the QC lab for use in a sponsor’s GMP stability studies. Since ample 220-volt power supply was available in the lab and each outlet was labeled as e-power (i.e., designation that the outlet was connected to emergency power), no further actions were taken before connecting the five stability chambers to electrical power. Several months after the installation of the stability chambers, the entire city block on which the CDMO’s facility was located experienced a 10-hour power outage in the middle of the night. The next morning, quality control employees observed that the five new chambers had shut down. The investigation revealed that the electrical panel providing the 220-volt power supply to the outlets had been rerouted to a non-e-powered circuit during the remodel of the adjacent laboratory. Stability samples stored in these chambers had been compromised and the CDMO was forced to notify all affected sponsors. This highlights an important lesson: Do not trust the labeling on electrical power outlets. Use an electrician to trace electrical connections before plugging in equipment.
Exhausting Of Solvents
In pharmaceutical and biopharmaceutical cleanrooms, it is essential that every trace of any hazardous vapor be removed from a room or piece of equipment. The hazards related to exhausting solvents include fire or explosion and the resulting contamination of production, storage, and cleanroom areas by smoke or other substances released by the fire. Exhausting of solvents through non-corrosive and non-flammable ducting is key. Fluoropolymer-coated stainless-steel ducting can be more effective and safer than traditional piping. Additionally, cleanroom exhaust, fume hoods, snorkels, walk-in reactor enclosures, and biological safety cabinets (BSCs) used to store chemicals with corrosive fumes can all benefit from the use of fluoropolymer-coated stainless-steel duct, rather than pipe. Refer to the National Fire Protection Association's Standard 318, NFPA Standard, and local requirements for materials of construction for ducting in your area.
While this category does not usually receive much attention, heat generated by production equipment can impact temperature control in GMP production suites. Product drying ovens and pan coaters used for tablet coating can alter the temperature of the room in which they are located if the room is not configured for insulated ducting to remove heat. Keep this in mind, as the heat generated by production equipment can make it difficult for the HVAC to maintain temperature set points and operate within validated ranges.
Some types of production equipment, such as large production spray dryers, require connections to chilled water or stand-alone chillers that use specialized refrigerants for cooling. Installation of process piping wrapped with non-shedding insulation is often required to deliver the chilled water to its point of use in cleanrooms. Process piping installation requires the shutdown of the affected cleanrooms for pipe penetration into cleanroom walls as well as testing for refrigerant leakage.
A sponsor experienced this problem with its CDMO recently. The sponsor relied solely on its favorite CDMO to manufacture its solid oral drug product. The CDMO informed the sponsor that it had ordered a very large pharmaceutical-grade spray dryer to use for the Phase 3 product. Once the equipment was received, the engineering staff quickly realized that the spray dryer required a high-capacity chiller that was not available from the manufacturer of the spray dryer. The chiller had to be custom fabricated and had a lead time of nine months for delivery. To add insult to injury, the installation required connection to the facility’s HVAC chilled water system (invalidating a portion of the HVAC validation), 10-inch holes cut into the cleanroom walls for pipe penetrations to and from the chiller, and a cement pad poured outside of the cleanroom to place the chiller. All told, the installation of the large spray dryer, custom fabrication of the chiller, and installation of process piping doubled the projected timeline and significantly delayed the sponsor’s Phase 3 supply production date. Moral of the story: Doing your homework before purchasing equipment will save time and money and keep sponsors happy and on schedule with their corporate goals.
A variety of grades of water are used for pharmaceutical purposes and four are typically produced and used on-site at manufacturing facilities: purified, water for injection (WFI), pure steam, and water for hemodialysis. It is important to confirm the quality of water required for new equipment as well as the pressure, flow rate, and temperature requirements (as applicable). Some types of equipment, such as an autoclave, require clean steam (directly) but also indirectly reverse osmosis/de-ionized water (RO/DI), as RO/DI is typically the feed water for clean steam generators. When contemplating installing an additional autoclave or replacing an existing autoclave with one with larger capacity, it is important to sum up the consumption rates of all equipment using clean steam and those that use only RO/DI.
Nitrogen, oxygen, argon, carbon dioxide, clean compressed air, and other specialty high-purity gases are often used in pharmaceutical production settings to operate production equipment, in spray drying applications, as head space to product containers, and for fermentation, extraction, and purification. There are a wide variety of utilities that generate gases on-site and distribute them throughout the production facility to points of use in cleanrooms. Alternately, some facilities use stationary tanks that can store 6,000 liters or more and are configured with telemetry devices to alert service providers to refill the tanks before the gas (liquid or vapor phase) runs out. In either case, the introduction of new equipment requiring one or more clean gases requires an assessment of the capacity of the utility to meet the requirements of all equipment it connects to.
Not only is it important to assess the capabilities of gas generating equipment and storage tank capacity but also the length and internal diameter of distribution piping. For example, if the internal diameter of the distribution piping is miniscule, it doesn’t matter how massive a clean compressed air system is, since it is unlikely to keep up with the demand of adding another piece of equipment. Flow rate, pressure, and volume requirements of each piece of equipment currently installed must be evaluated to determine whether the system can keep up with demand.
Drainage — The Most Difficult Utility to Retrofit
All drains are not created equal. Some are designed to transfer liquids to normal waste streams, other liquids require special treatment before going to city waste, and still other effluents must be captured and taken away for processing. Equally problematic is the location where the new equipment will reside. Does the room currently have the proper drain system with floor connections next to the intended location of the equipment? If the room does not have drains or has the wrong type of drain, be prepared to spend big dollars and allow for significant downtime to trench new drains. Note that, depending on the city or state, city permitting will likely be required for the new drainage.
Pharmaceutical production equipment and cleanrooms, including those that employ solvent handling and processing such as spray drying, are categorized in terms of their potential for explosivity. In North America, hazardous location electrical codes and standards use a “class, division” system as the basis for area classification of hazardous locations. Locations are divided into three classes and two divisions. The classes are based on the type of hazard and the explosive characteristics of the material, with the divisions being based on the occurrence of risk of fire or explosion that the material presents.
Cleanrooms can be protected against the potential for explosions by ensuring that electrical outlets, lighting, and sources of heat and spark are isolated so they are not exposed to dust, moisture, vapors, or other contaminants. This isolation can also protect the surrounding environment from outgassing, heat, arcing, air pressure leakage, electromagnetic interference, and other conditions that could negatively affect process integrity and personnel safety. In cases where cleanrooms can pose an explosion risk based on the materials that will be processed, it’s prudent to seek the advice of a qualified industrial electrician or other expert to assess the controls that are currently in place and those that need strengthening. This is particularly important for manufacturing processes in which physical containment or isolators are not used to transfer flammable materials and solvents from one piece of equipment to the next (i.e., relying solely on the cleanroom infrastructure for protection). Some types of production equipment, including specialized computers, are certified to meet the requirements of the specific class and division, thereby ensuring an extra level of protection of the process, facilities, and personnel.
Connecting Equipment To GMP Networks And Servers
Critical to Quality Attributes (CQAs) must be defined by the organization and followed by equipment owners and IT to ensure that data from equipment is automatically sent from equipment to servers, is backed up per schedule, and is periodically tested for retrieval of data and meta data to ensure that data integrity and the principles of ALCOA (attributable, legible, contemporaneous, original, accurate) are met. This requirement is often overlooked when installing new equipment.
Formal change control for new equipment, and even equipment that is moved from one location to another, must include an ALCOA assessment when connecting to GMP networks. This is particularly important when additional network data cabling is installed to accommodate the newly purchased equipment. The network architecture must be able to identify the equipment that is connected to specific data port IDs located in cleanrooms and map the equipment’s data to secured and compliant server locations. FDA warning letters for computer networks cite the failure of validation documentation to include complete updated design documentation and complete wiring/network diagrams to identify all computers and devices connected to the system. Given that networks change frequently, maintaining accurate diagrams that reflect the current configuration of the network requires revision control (i.e., formal change control). Additionally, the World Health Organization’s (WHO) guidance on validation of computer systems states that GxP computer systems and network validation should include the system physical and logical architecture and map out the relevant workflows and data flows.
Equipment change control is viewed by many as a rubber-stamp exercise designed to make quality assurance happy. This is far from the truth. Poor planning, lack of understanding of equipment utility requirements, and deficiencies in the ability of utilities to meet the needs of all equipment to which they are connected pose serious risks to GMP operations. Enlisting personnel from engineering, manufacturing, mechanical/facilities, and external contractors will help to ensure that your eyes are wide open to the challenges in front of you and the installation of new equipment goes as smoothly as possible. In the next article in the series, we will address assessing the impact of new equipment on existing utility validations, the validation of new equipment, review of turnover packages and validation reports, and the change control effectiveness check.
About The Author:
Greg Weilersbacher is the founder and president of Eastlake Quality Consulting, a GMP consulting firm based in Southern California. Over the last 25 years, Weilersbacher has held director and VP positions leading quality assurance, quality control, analytical chemistry, materials management, GMP facilities, and product manufacturing in biotech and pharmaceutical companies. His unique experiences and technical background have led to the manufacture and release hundreds solid oral, sterile, and biologic investigational products to clinics in the U.S. and abroad. Weilersbacher can be contacted at firstname.lastname@example.org.