By Greg Weilersbacher
Despite FDA’s guidance documents on change control, “…managing change to prevent unintended consequences,” many companies limit change control to documentation such as batch records, SOPs, protocols, and specifications and only sporadically evaluate that of equipment and facilities, if it is done at all. A lack of knowledge and even conceptualization of the use of change control for equipment and facilities severely limits GMP compliance, particularly when new equipment is installed and connected.
Equipment change control (ECC) applies to equipment from all departments (GMP and non-GMP) that connect to the facility’s GMP utilities, including 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. 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 a company can make is assuming that a utility is dedicated to R&D.
Equipment change control can be grouped into six primary stages:
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 when operating at full capacity.
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 and can be a particular challenge when purchasing used or refurbished equipment.
Stage 2: Comparison of Equipment Requirements to the Capabilities of Utilities
Electrical – For facilities personnel to determine if an electric utility has the capability of meeting the needs of your new equipment, first they will 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 or assume it will be put in one of the cleanrooms. 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 the panel must also be balanced. Enlist subject matter experts to make a technical assessment on a critical parameter.
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 evaluated in comparison to the current load.
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 to protect against fire or explosion. Exhausting of solvents through non-corrosive and non-flammable ducting is key. Refer to National Fire Protection Association’s Standard 318, NFPA Standard, and local requirements for materials of construction for ducting in your area.
Heat Dissipation – Heat generated by production equipment, including drying ovens and pan coaters, can impact temperature control in GMP production suites. Keep this in mind as it can be difficult for the HVAC to maintain temperature set points and operate within validated ranges.
Cooling – Installation of process piping wrapped with non-shedding insulation is often required to deliver chilled water to its point of use in cleanrooms.
Water Quality – A variety of grades of water are used for pharmaceutical purposes. 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). When contemplating installing an additional autoclave or replacing an existing autoclave with one with larger capacity, its important to sum the consumption rates of all equipment using clean steam and those that use only reverse osmosis/de-ionizing water (RO/DI).
Clean Gases – 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, The introduction of new equipment requiring one or more clean gas 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 tanks capacity but also the length and internal diameter of distribution piping. Flow rate, pressure, and volume requirements of each piece of equipment currently installed must be evaluated in comparison with the ability of the system to keep up with demand. The last thing you want is to install a $2,000,000 spray dryer and find out that the nitrogen system and piping is too small to satisfy its consumption.
Drainage – The Most Difficult Utility to Retrofit – All drains are not created equal. Some are designed to transfer liquids to normal waste streams, others 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 equipment location?
Explosion Proofing – Pharmaceutical production equipment and cleanrooms, including those than 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 uses a “class, division” system as the basis for area classification of hazardous locations.
Cleanrooms can be protected to mitigate against the potential for explosions by ensuring that electrical outlets, lighting, sources of heat and spark are separated from their surrounding environments protecting them from dust, moisture, vapors or other contaminants. This isolation can also protect the surrounding environment from outgassing, heat, arching, air pressure leakage, electromagnetic interference and other conditions that could negatively affect process integrity and personal safety. In cases where cleanrooms can pose an explosion risk, 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.
Connecting Equipment to GMP Networks and Servers – Critical to Quality Attributes (CQA) 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 periodically tested for retrieval of data and meta data to ensure that data integrity and the principles of ALCOA are met when connecting to GMP networks.
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 site 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).
Stage 3: Assessing the impact of New Equipment on Utility Validations
If the installation and functionality of new equipment requires adding new utility points of use (POU, i.e., valves that connect the equipment to the utility) the drawings, schematics, and materials of construction detailed in the utility’s Installation Qualification (IQ) will need to be updated. Tied to this change, the Operational Qualification will likely require revision to test the functionality of the new POU and for gas system a pressure-hold challenge.
Performance qualification (PQ) – This validation phase tests the ability of the utility to perform consistently over long periods of time within tolerances deemed acceptable by the manufacturing process as a whole. This is the most important element to test when tying in new equipment to an existing utility. It asks the question: Will the utility keep up with the demand while all POU are in operation serving equipment?
Stage 4: Calibration/Validation of New Equipment
When calibrating equipment, it is important that the calibration match or exceed the intended operational range of the equipment that will be used during actual production activities. Too often, equipment is operated at RPMs, flow rates, compression forces, etc., at settings that exceed the lower or high-end calibrated range of the equipment. This is a common audit observation made in sponsor and regulatory inspections of production facilities.
Requirements for validating equipment should be detailed in a validation master plan (VMP) that outlines the quality requirements for the types of equipment already in-house.
Equipment change control should reference both the manufacturer’s validation package and the gap validations, IQ, OQ, PQ, performed. Note that in all cases, the manufacturer’s validation protocols and your internal gap validation protocols must be approved by the equipment owner, validation, and quality prior to executions. These deliverables should be documented in the equipment change control.
Stage 5: Review of Turn-Over Packages, Executed Validations/Data/Reports, Release of equipment for GMP use
This stage in the change control process is often treated as a rubber-stamp. It is, however, is an extremely critical phase were issues, gaps, deviations, deficiencies, etc are identified and remedied with input from a quality, engineering, validation, and the department owning the equipment.
A common mistake made by companies is forgetting to complete a written statement, approved by all parties including quality, that the equipment is now released for GMP use. Although all of the associated validation and calibration documentation may be approved, inspectors from regulatory agencies around the world look for this designation that the equipment is now suitable and released for GMP activities.
Stage 6: Change Control Effectiveness Check (i.e., what did we miss)
An effectiveness check is a valuable way to identify where equipment commissioning gaps and problems were found and also for formulating a plan to prevent the same issues from happening during future activities A robust change control effectiveness check, which is often neglected due to competing demands, should be built-in to the company’s equipment commissioning process as a required step.
The Take-Away
New production equipment can be exciting to the end-user. The challenge is that it is often viewed as plug-and-play: connect the equipment and we’re off and running. There is an impact on the utilities that provide electrical, gases, water, drainage, heating and cooling that serve a wide array of equipment in the GMP setting. These six stages of equipment change control provide a detailed roadmap for evaluating a facility’s current capabilities and comparison to the requirements of new equipment. With careful evaluation, planning, and direct input from engineers, validations, and quality departments the common pitfalls associated with installing new equipment can be avoided. Consult a qualified consultant for assistance in marrying the expertise of your various departments to ensure a seamless assessment of equipment and facility requirements, installation, validation of conformance and use.
Posted in Drugs, EASeNews, Issue of the Month and tagged Greg Weilersbacher.