There is growing attention to adoption of GMPs as it extends to the manufacturing environment; the warehouse for receiving, storage and shipping of product, and all controlled areas on the manufacturing floor. The FDA is rapidly influencing how process controls during manufacturing are put in place. These process controls include Buildings and Facilities[i] (21 CFR 211.42) which operate the HVAC system of your otherwise unprotected bulk formulated product and exposed, open product containers. The HVAC system provides conditions for low particulate air (clean air), temperature and humidity that has a direct or indirect effect on the quality, performance and stability of the product itself. For these reasons, it is critical to engineer and design HVAC systems properly. Good Manufacturing Practices are a valuable set of criteria, that when followed ensure the successful design and commissioning of your HVAC (and other) systems, resulting in years of trouble-free operations.
It starts with identifying Design and User Requirements Specifications (Performance):
- What product line(s) do you intend to produce and store?
- What are your major processing steps (think – bulk formulations, filling/packaging and testing, product ingredient and component specifications and storage conditions)?
- What capacity do you need to meet (output and throughput), and how does this relate to inventory and quantities to be on order and in stock?
- How will materials flow through the facility (process flow maps – this will help identify the need for pass-thrus, interlocks, and establishing different work zones)?
Figure 1 Example of an indoor cultivation room still under construction
By answering these questions, you will understand:
- Processing constraints, (bulk powder or powder filling), building conditions, etc.
- Bio-load conditions and demands on the air system as it relates to employees entering and exiting, man-doors and bay doors opening and closing throughout the shift, personnel training, and cleaning programs needed.
The result is considerable savings through effective mitigation and maintenance of your facility thanks to proper design, air pressure, room air flow and air changes that become built into your processes.
Regulatory requirements to ensure success
Knowing the regulatory requirements on controlled rooms and HVAC systems is an absolute prerequisite for all further steps like design, qualification and operation of controlled rooms. Here are a few regulatory references:
21 CFR 211.42 (FDA Drug GMPs)
ISO 14644 (Cleanrooms)
Local Regulations (City and State)
What do I need to be able to explain and document?
For a company to specify, purchase, install and operate a successful HVAC system it needs to be able to explain and document:
- The role of HVAC in protecting products using risk assessment to set environmental criteria.
- Each stage of the product lifecycle, from Research and Development to Manufacturing, such as: controlling cross-contamination between products.
- Capacity, flow, personnel, cleaning and maintenance, air balance and temperature control throughout the building (offices, warehouse, manufacturing floor).
- Performance (air flow, direction, filtration effectiveness, filter pressure differential (filter load), calibration of equipment, room pressure differential, positive or negative pressure, temperature, humidity, lighting, dynamic and static conditions, worst case scenarios (power outage removes air pressure).
- Types of filters (prefilters, final filters).
- System access for repair, filter replacement, main units, Roof Top Units (RTUs), ducting, calibrated recording equipment, tolerances of controllers (+ or -).
- Cleanability of surfaces, effectiveness and compatibility of chemicals and lubricants.
- Compatibility of materials (e.g. stainless-steel vs galvanized).
CapEx and OpEx Budget Considerations
HVAC systems can account for as much as half of the energy usage in facilities, a significant ongoing operating cost. Appropriate system design and critical parameter selection for efficiency by the right design and engineering firm up front can easily reduce operating costs by as much as one-third[ii] (RII, 2019). In addition to gaining significant operational efficiencies and OpEx cost savings, you will have peace of mind knowing your facility will operate as intended from day one, and be provided with appropriate qualification documentation needed to comply with authorities having jurisdiction, GMPs, as well as your internal business requirements.
In addition to the design and engineering of the HVAC system, common issues and problems in the operation and maintenance of a facility include control system monitoring, alarm management, common system construction deficiencies, cGMP documentation, maintaining an “inspection ready” state, frequency of testing and balancing, airflow visualization, air change rate and cleaning. All items need to be considered as part of the total system and operational costs.
The Site Acceptance testing (SAT) step occurs using either vendor provided IQ/OQ/PQ test protocols to assure proper site installation and performance or consider contracting a third-party validations/consulting group to write the protocols and conduct testing. All test data, (raw, in-field) and final reporting will need to be collected, evaluated, controlled and filed with the designated department, typically the Quality Unit (QU).
Figure 2 The hierarchy of fundamental documents and records that ensure a robust cGMP Quality System
The following are support programs a company needs to have in place that ensure performance of these functions and continued maintenance and support of Good Manufacturing Practices.
The overall validation program for the facility.
The calibration program is designed to ensure accuracy and reproducibility from critical instrumentation. Critical instrumentation whose measurements are utilized to make decisions in processes or systems which affect or determine efficacy or purity of a product will be calibrated in accordance with the company’s calibration requirements.
The preventive maintenance program ensures the continued maintenance of equipment and systems through regularly scheduled inspections and adjustments.
Change control is the procedure followed to assure that proposed changes to facility equipment, systems, or processes are reviewed and approved by responsible management. It is especially critical for validated systems as any changes could alter the validation status of the equipment, system or process. QU is responsible for change control on facility systems, equipment, and processes.
A revalidation program identifying which equipment/systems/processes will be developed, which defines the time frames in which revalidation activities will occur. Utility monitoring data will be evaluated on an annual basis to determine if the systems remain in a controlled, validated state.
Training is performed to ensure that personnel are trained in GMP requirements as well as production operating methods. Training will be documented and administered through the QU and human resources department.
Document control procedures provide a method for ensuring use of current documents and for tracking changes in procedures and other critical documents. Documentation control will be administered through the QU department.
Many companies take their HVAC systems for granted, that they will deliver proper temperatures, air flow, room pressure differentials and humidity control without considering the capabilities of the existing system or its limitations, condition or age. In order to depend on reliable performance of their HVAC, a company should elicit a professional engineering company. With the stated specifications of the client they can design a proper system that meets GMP requirements and significantly reduces OpEx. Once a company has chosen to operate with dependable, reliable equipment, systems and processes, within anticipated GMP regulations, they can expect sustained success in the cannabis and CBD space.