Engineering Considerations for the cGMP Manufacture of Hemp and Hemp Products

March 11, 2020
Laura Breit

,
Jeffrey Breit

Volume 3, Issue 2

Columns | <b>Extraction Science</b>

This column discusses some of the most important considerations involved in the GMP certification process.

As the global hemp industry continues to mature, the rules and regulations that encompass the space are constantly evolving. Hemp businesses preparing for success and scaling for future growth have a variety of best practices to consider, but one set of regulations becoming increasingly important in the early stages is current good manufacturing practices (cGMPs or GMPs). GMPs are the rules and regulations that ensure the quality, safety, and efficacy of food or pharmaceutical products by addressing all aspects of the production process. GMP certification is becoming paramount for hemp extraction facilities looking to remain competitive and align with international industry standards. This column discusses some of the most important considerations involved in the GMP certification process.

With the passing of the 2018 U.S. Farm Bill, which allowed for the federal legalization of hemp production and interstate transport, consumer products containing hemp-derived compounds such as cannabidiol (CBD) have continued to expand in number and scope. CBD health, nutrition, and food products are readily accessible through a number of retail and online outlets and the variety and number of these products is continuing to increase (1,2). The use of hemp-derived compounds such as CBD will likely continue to expand into other markets. For instance, CBD usage is currently being evaluated for pharmaceutical applications (3–5), which will likely serve to increase the rigor at which producers of hemp and hemp-derived compounds manufacture their products. 

Manufacturers of hemp-derived products are evaluating quality certification programs such as current good manufacturing process (cGMP) manufacturing strategies to differentiate their products from competitors, enable the use of hemp raw materials in high quality or high margin products, and to access highly regulated industries like pharmaceutics. The use of cGMP manufacturing and subsequent certification programs such as the ISO 9000 and ISO 9001 series of standards allow raw materials and finished goods to be used in quality defined and controlled consumer and pharmaceutical products. 

As the boutique and industrial hemp production and extraction industries mature and expand into other applications, there has been a growing interest in cGMP certification for food grade processes. For example, cGMP principles have been applied to a number of hemp processes and products including:

  • CBD production

  • Finished consumer goods containing CBD

  • Terpene isolation and use

A quick side note on good agricultural practices (GAP) versus GMP: GAP are the precursor to GMP. This will ensure the safe, hygienic, and quality production of the agricultural product (that is, propagation and cultivation) prior to manufacturing (6).

Messaging from the U.S. Food and Drug Administration (FDA) describes cGMP practices as, “providing for systems that assure the proper design, monitoring, and control of manufacturing processes and facilities” (7,8). To summarize statements made in the Code of Federal Regulations (CFR) 21 Parts 110 and 117, the FDA describes the content of a cGMP system in food grade manufacturing to include the following principles:

  • A review and qualifications of a cGMP system

  • The definition and applicability of a hazard analysis and risk-based evaluation strategies of manufacturing and production processes

  • Supply chain considerations from raw materials through finished goods and after-market monitoring

  • The establishment of defined and followed practices that lead to the production of a consistent product

  • Considerations in process and finished goods qualification and validation strategies, supported by rational characterization strategies

Generally, the information outlined in CFR 21 Part 117 may be concisely described as knowing what comprises your product, understanding your process and product, and knowing what process attributes define your product. Collectively, these concepts help owners and operators understand and control important aspects (often defined as key or critical process parameters) of product manufacturing and enable a quality evaluation and control strategy to minimize defects and variability in finished goods. The principles presented in the FDA and other expert documents on the topic of cGMP principles can best be described as general guidelines and typically include aspects of a cGMP system that are required for cGMP qualification, but do not explicitly lay out a cGMP plan for the hemp industry because every process is product-specific. 

The importance of defining roles, responsibilities, and lines of communications, as well as anticipated cGMP and certification milestones during initiation of facility development, cannot be overstated. A GMP consultant can be critical to success in obtaining cGMP certification for your facility. A list of activities critical to the successful build and launch of a cGMP manufacturing facility may look something like the following:

  • Define target product profile (TPP)

  • Identify manufacturing process flow, unit operation functionality, and product and human safety attributes

  • Conceptualize brick and mortar functionality, flow and governing cGMP requirements

  • Utilize risk-based tools including process hazards analyses (PHA), risk assessments (RA), design qualifications (DQ), and validation master planning (VMP) to pre-establish critical processes and facilities influencing design, construction, and qualification criteria

  • Integrate process, product, personnel, material, waste, and airflows predicated on identified risks corresponding to cGMP requirements and good industry practice

  • Initiate cGMP conforming design and installation for architectural, mechanical, electrical, and plumbing (MEP) systems directed at mitigation of product contamination and assurance of operational safety

  • Conduct qualification and validation demonstrating the concepts, criteria, and RA stated outcomes defined in master-planning

  • Build a structured quality management system (QMS) with the appropriate depth and scope required for anticipated certifications and TPP

  • Create protocols and standard operating procedures (SOPs) to support product manufacture and QMS needs using prequalified raw material vendors, build bill of materials (BOM)

  • Integrate analytical equipment required to support raw material testing, in process checks and finished product release testing

  • Establish an acceptable certificate of analysis that is supported by finished product critical quality attributes (CQAs) and anticipated market requirements

  • Staff with trained and qualified personnel, by function, capable of demonstrating operational proficiency within the prescribed regulated environment

The Owner, Architect, and Engineer Triad

Ultimately, the responsibility of understanding and integrating the above list of topics into a comprehensive manufacturing, quality management, and cGMP certification scheme (supported by a hemp-centric business model) is the responsibility of the facility owner or senior management. To facilitate this, process owners and senior management should enlist the help of a qualified support team to help lead facility design. This support team will likely involve the owner and their team of staff that will be overseeing or operating the facility, a GMP consultant to guide the owner through the cGMP requirements and certifications, and a design team consisting of an architect, qualification and validation engineers, and mechanical, electrical, and plumbing (MEP) engineers. It is incredibly important that this complete team of experts is engaged early and often-proper coordination is key to success.

The Architect’s Role in the Design of a cGMP Facility

Architects are professionally licensed and specialize in designing the architectural components of a facility. While there are architects with more cGMP experience than others, it is ultimately the owner’s responsibility to be sure that the architect is aware of the cGMP requirements that will fall under the architect’s scope. While the architect will not direct the cGMP requirements, it is important to collaborate with an architect with design expertise in cGMP facilities. Note that oftentimes, the architect may hold the contract for the entire engineering team as well, so it will be important to define all requirements for the entire design team. Though they will vary from project to project, a few simple examples of items that the GMP consultant and owner may need to define for the architecture team are discussed in more detail below.

Product Quality Attributes and Critical Process and Facility Parameters

In the design of a GMP facility, all attributes of design and installation are focused on the mitigation of product contamination, the conduct of robust and routine product manufacture, and the safety and efficiency of operations. The conduct of risk analyses drive key considerations, which must be outlined for the architect upfront, driving fundamental aspects of facility design to include airflows and pressurization schemes, materials of construction, and equipment requirements (explored further below). During validation master-planning, a predefined set of criteria will be established to demonstrate conformance with the cGMPs, many of which influence the basis of design and installation of equipment critical to the architect and MEP engineers, with the goal of ultimately establishing cGMP conformance.

Requirements for Easily Cleanable Walls, Floors, and Ceilings

This may include fiberglass reinforced plastic (FRP), stainless steel, or polyvinyl chloride (PVC) walls and ceilings; epoxied floors, and coved bases between the wall and floor to create an impervious seal between the intersection of these two surfaces, making them easier to clean and maintain. Note: pay special attention to static charge that may build on these surfaces in classified areas containing flammable or explosive materials and operations, and work with your architect to select the best materials to meet your needs. 

Personnel Flow and Gowning Requirements

The owner will need to explain the personnel flow and gowning requirements of the facility so that the architect can take this into consideration when space planning.

Airlock or Vestibule Requirements Between Corridors and Process Rooms

These spaces are explained in more detail under the heating, ventilation, and air conditioning (HVAC) section below. The architect will need to know where airlocks are required so that they can factor them into space planning.

The Engineer’s Role in the Design of a cGMP Facility

MEP engineers are professionally licensed with expertise in designing a facility’s mechanical (HVAC), electrical, and plumbing systems. MEP systems are not the manufacturing process, they are the support systems that breathe life into the manufacturing process. As a very simple definition, these systems provide energy, create the environment within which the process lives, and remove waste. It’s important to recognize that while these engineers have deep expertise in their fields, the focus of their roles and expertise is not necessarily to direct the cGMP specifications, but to create systems that meet the requirements of your cGMP specifications. As mentioned previously, the owner is responsible for determining what standards the engineers should design to. A GMP consultant can assist with this process and communication. As is true for the architecture team, while the engineering team will not direct the cGMP requirements, it is important to work with an engineering team with design expertise in cGMP facilities. Though they will vary from project to project, a few simple examples of items that the GMP consultant and owner may need to define for the engineering team include the following items described below.

Cleanroom Class

ISO classes of cleanroom vary from ISO 1 (extremely clean) to ISO 9 (clean) (see Table I). There are many requirements for each clean room class including air change rates, filter types, and filter coverage that will impact costs associated with each class. ISO 7 classification is often observed in hemp facilities, but it is the owner’s responsibility to determine the appropriate cleanroom class and convey the cleanroom class to their designers, based on information they have received from their GMP consultant. Designers can then meet the design requirements for the cleanroom class expected.

Equipment Cutsheets

You will have specific equipment that you have selected for your process. It is important that your engineers receive this information prior to beginning their design, and that the information is complete and accurate. Inaccuracies will result in extra design time and money spent.

Temperature and Humidity Requirements

While the HVAC system can ensure that the temperature and humidity requirements are met, the engineering team expects that the owner will provide these requirements.

Other Specific Requirements

There may be other requirements specific to your process or facility. As an example, many facilities will opt to keep conduit and piping behind walls to make it easier to clean the wall surfaces in the facility. However, some clients need access to piping for experimental changes. In this case, you may direct your designer to design the piping and conduit so that it is exposed within the room, yet held off the wall so that you can easily clean behind and around the piping and conduit to maintain your cGMP facility requirements.

A Word About HVAC

Your HVAC designer will be critical to the success of your cGMP facility. It is important to consider and keep in mind what your HVAC system can and cannot do (9).   

What HVAC Can’t Do

HVAC cannot clean the surfaces of a contaminated room or equipment. The SOPs defined by the owner should specifically cover cleaning protocols. HVAC cannot compensate for workers who do not follow procedures. Ensuring that staff is trained and following SOPs is critical to the success of your cGMP facility and is the owner’s responsibility. HVAC cannot be left unmaintained. If not maintained, the HVAC systems may not adequately meet your cGMP requirements.

What HVAC Can Do

HVAC can control airborne contaminants through proper air filtration. There are numerous levels of air filtration, generally stated on the minimum efficiency reporting value (MERV) measurement scale. In commercial applications, filtration will generally range from a typical MERV 8-such as what would normally be utilized in a basic residence-through MERV 20, which will meet the requirements of a cleanroom. High efficiency particulate air (HEPA) filters, which will remove 99.97% of particles whose diameter is greater than .3 μm, fall into the range of MERV 17 through MERV 20. HEPA filters are generally utilized in cleanrooms, among other applications. The air filtration level needs to be considered when selecting the HVAC systems, as the higher the MERV rating, the more air restriction there will be, so the fans need to be sized to overcome this static pressure, both with an unloaded and loaded filter. Prefilters are generally utilized prior to the HEPA filters to capture the larger particles, so as to not unnecessarily load the HEPA filter. This allows the owner to change the prefilter often (which are generally a lower cost item than the HEPA filters), and the HEPA filter less often. Pressure gauges and simple alarms can be helpful in alerting the facility’s maintenance crew that the filters need to be changed. Changing the filters at regular intervals is critical in meeting cGMP because an overly loaded filter will affect particulate capture rates and air change rates within the room, potentially causing the facility to fall out of spec. 

HVAC can maintain room pressure differential requirements (delta P or ΔP). Proper air cascades are critical in ensuring that air flows from clean to dirty spaces, and not the other way around. Areas that must remain cleaner than surrounding areas must be kept under positive pressurization with respect to the surrounding area. This can be done in various ways. Oftentimes an airlock, sometimes referred to as a vestibule, is utilized in the entrance to the cleanroom. This is a separate room with one door opening into the main corridor and another into the cleanroom. The doors are controlled so that they cannot be opened at the same time (either by interlocks or simply by SOP). Fan filter units can be a low cost way to ensure that the pressure cascades between the main corridor, airlock, and clean room are appropriately maintained, and with the proper filtration to protect the cleanroom.

HVAC can maintain room temperature and humidity. Temperature and humidity are controlled via air handlers with cooling coils and reheat coils. There are other methods to control temperature and humidity, and your mechanical engineer can determine the best type of equipment for your application. Note that while your engineer can design and select the proper equipment to meet your temperature and humidity needs, it is the owner’s responsibility to determine the target temperature and humidity levels, as well as the acceptable range. This will vary depending on what the process needs are. Facility owners will often set a very tight temperature and humidity range. Be cautious: more stringent than required temperature and humidity requirements can result in your engineer selecting an expensive HVAC system to meet the requirements, oversizing your HVAC system, and resulting in higher than necessary utility costs to run the equipment. Be sure to select a reasonable temperature and humidity range for what your process requires.

Closing Remarks

For any project-but especially a cGMP facility­-it is incredibly important that the owner engage their internal team that will run the facility, a GMP consultant, architect, and engineering team early and often. Proper coordination is key to success. All team members must know their roles and responsibilities within the facility design process, and ultimately it is the owner’s responsibility to be sure that everything is covered in order to obtain and maintain the desired cGMP certifications.

References

  1. A. Gasparro, The Wall Street Journal, January 9, 2020,  https://www.wsj.com/articles/cloudy-regulation-slows-cbds-seep-into-food-and-drinks-11578574807
  2. M. Gauthier, HealthMJ, January 2020, https://www.healthmj.com/cbd/hemp-cbd-bubble-prices-market-growth/.
  3. https://international-cdp.com/.
  4. V. Rees, European Pharmaceutical Review, August 2019, https://www.europeanpharmaceuticalreview.com/article/96609/cannabinoids-in-pharma-series-cannabinoids-on-the-market-today.
  5. https://www.gwpharm.com/healthcare-professionals/research/cannabinoid-compounds.
  6. https://www.rhizosciences.com/gxp-good-cannabis-practices/gap-good-agricultural-practice/.
  7. U.S. Food and Drug Administration, Current Good Manufacturing Practices (CGMPs) for Food and Dietary Supplements, https://www.fda.gov/food/current-good-manufacturing-practices-cgmps-food-and-dietary-supplements.
  8. Electronic Code of Federal Regulations, https://www.ecfr.gov/cgi-bin/text-idx?SID=3f7125891958b3eb9380856f26065b5c&mc=true&node=pt21.2.117&rgn=div5.
  9. A. Bhatia, HVAC Design for Pharmaceutical Facilities (Continuing Education and Development, Inc., Stony Point, New York) https://www.cedengineering.com/userfiles/HVAC%20Design%20for%20Pharmaceutical%20Facilities.pdf.
  10. https://www.mecart-cleanrooms.com/learning-center/cleanroom-classifications-iso-8-iso-7-iso-6-iso-5/.

About the Columnists

Laura J. Breit, PE, is the founder and owner of Oregon-based firms Root Engineers and Cole-Breit Engineering. She is a professional mechanical engineer specializing in the design of HVAC, plumbing, and process systems for the cannabis industry. Since legalization in her home state of Oregon in 2014, Laura has led her team of mechanical and electrical engineers and designers on more than 100 cannabis-related projects across the country.

 

 

Jeffrey F. Breit, PhD, has more than 15 years of experience leading program development efforts for pharmaceutical and health and nutrition products. He has played a leading role in the development of both organic and cGMP compliant manufacturing facilities and processes.

 

 

 

How to Cite this Article

L.J. Breit and J.F. Breit, Cannabis Science and Technology3(2), 16–20 (2020).

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