Case Study

Understanding The Full Scope Of A Manufacturing Facility Renovation

By Jose Gonzalez, PE, LEED AP, CRB

Understanding The Full Scope Of A Manufacturing Facility Renovation

A facility transformation begins long before the A&E and other service providers are invited to the table. Typically, a business model is used to map out and project demand for specific products, estimate product production rates, and time lines for expected product introduction and product ramp-up to match the expected demand. Several factors are considered to determine where the facility should be located: proximity to the customer pool, availability of qualified on-site resources and availability of existing infrastructure, market conditions, and regulatory climate.

Take a client located in the San Francisco Bay area as an example. Ultimately, a site was selected to manufacture an API in an existing facility. The selected facility readily met at least two of the aforementioned factors in that it had qualified human capital already on site and had room for expansion. It helped that the facility was also client-owned. The selection of an existing facility also presumed a reduced construction schedule and therefore accelerated product time to market.

Project Scope

The scope of work was to design and build a manufacturing cleanroom and ancillary support spaces for the production of an API that contained a potent compound as part of the manufacturing process. Handling and processing of the API product required adherence to additional safety measures that impacted the design of the cleanroom, some of which are described below. User requirements specifications were followed for the selection of the process equipment, utility delivery rates, and quality. In terms of the facility construction, adherence to the cleanroom URS and the HVAC URS was paramount. These specifications were produced by the A&E under the strict supervision, review, change control, and administration of the client.

Delivery method and team structure

The delivery method was a hybrid approach. The client selected a design-build strategy for just the mechanical and plumbing scope. All other disciplines were delivered using the traditional design-bid-build approach. As is common on design-build projects, a significant effort was required to determine the deliverables for hand off to the design-build contractor. Risk needed to be mitigated in terms of operational requirements and construction cost escalation to improve the chances of project success. Therefore, the mechanical deliverables were completed to the level of basic design that included completed P&IDs, equipment schedules and specs. This bounded the design and placed enough constraints to limit, and in most cases eliminate, the possibility of changes by the mechanical contractor. As previously mentioned, the availability of on-site resources was key on site selection. Client involvement was critical to move the project forward in terms of the decision-making process and in the interpretation and application of the client’s design standards. The table below illustrates a high-level overview of the resources needed to make this project possible.




Project Executive.

Project Executive

Project Executive.

Project Management

Project Management

Project Management


Discipline Leads

MEP Trades


Production Team

Cost/Schedule Estimating










Key team members were required to be on site for the duration of the design and construction phases, which lasted about three years from design to turnover for production. Being on site facilitated interaction with the client’s staff and provided the A&E with the opportunity to gain first-hand knowledge about the existing facility systems infrastructure.

Existing building composition

The building housing this expansion was comprised of offices, labs, manufacturing and support spaces, with a total of over 220,000 square feet of space. Distinctive air-handling zones existed for the offices, the labs and the manufacturing areas. Offices were served by several packaged single-zone systems. The labs and the manufacturing areas used air handlers utilizing chilled water and hot water coils.

Air handling zoning and air movement

The facility renovation converted around 40,000 square feet of existing non-manufacturing space, mostly composed of non-cGMP storage warehouse, to qualified cGMP production space. Two new air-handling systems and related exhaust fans suitable for cleanroom applications were added. As part of the air-handler zoning plan, all the ISO 7 spaces were supplied from a common air-handler system. This was possible because the facility only produced one drug product at a time. The controlled not classified (CNC) spaces were conditioned by a second and completely separate air-handler system. Air filtration of the ISO 7 areas was through ceiling-mounted HEPA filters providing at least 99.9 percent filtration efficiency. Room exhaust was through low wall grilles. Given the nature of the API, low wall returns in the critical zone contained HEPA filters identical to the supply and had provisions that allowed them to be integrity tested in place by the use of a shroud for the introduction of the challenge media. The CNC spaces, which included the initial level of gowning, were also provided with ceiling supply HEPA filters and ceiling returns without HEPA filters.

Cleanliness and environmental needs

In terms of cleanliness, the manufacturing space was design to meet ISO 7 classification in at rest condition. Entry and exit points were specified at air changes per hour that met ISO 7 requirements for this non-sterile drug product. The air change rate in the gowning rooms was set higher to promote particle capture at entry and exit points. The corridors were clean but not classified or CNC. A transition zone occurred inside the gowning room to take into account the movement between the CNC space and the ISO 7 area, as depicted in the image below. This transitional zone was physically demarked by a step-over bench that separated the clean side from the dirty side. Gowning at the entry point was downed at a level that was prescribed by the user as part of the administrative protocols to minimize both introduction of particles and cross contamination of the API from external sources. For this facility, people entering the manufacturing area from the CNC corridor downed a second layer of gowning (the first layer was downed at the entrance to the CNC space). People moving from one production suite to the next needed to follow gowning protocols at each entry and exit point.

Cleanliness plan

The API processed in the critical space was not particularly sensitive to temperature but was to the space relative humidity. Temperature was set in the range of 64 to 68 degrees Fahrenheit primarily in response to human comfort and to reduce sweating of the gowned personnel, who would introduce particles in the space. Humidification was added to the supply air to maintain the space relative humidity within allowable range. Doors between rooms were interlocked to prevent cross contamination and reduce safety issues. Visual and audible aids were placed in the critical areas to inform the user of excursions from normal operation conditions. This was a requirement given the validated nature of the facility and the hazardous material used in manufacturing the drug product.

Containment requirements and strategies

A strategy was developed for the movement of materials and people throughout the cleanroom. Eventually, a layout of the facility was agreed upon. It is important to understand that the development of the layout was a critical factor in that the design work cannot proceed fully without a “frozen” layout. More often than not, there is a level of hesitation from the parties involved — typically on the owner side — with endorsing a final layout. It is safe to assume that even with the best intentions, changes will occur after the layout is frozen and endorsed, and design professionals can only hope for a properly managed change process. Layout development is a process that does not follow a straight line. It is seldom, if ever, a black and white type of solution. Instead, this is the part of the design that takes a great deal of effort to achieve consensus. The process is interactive, and that involves multiple steps. Teams gathered to discuss what was required (the action), and a space program is preliminary developed in response (the reaction). Unless all the stakeholders are present, which is rarely the case, this can be a time-consuming process.

Input received from the EH&S and the quality teams has to be incorporated as part of the final layout to ensure the facility meets all their criteria, and the manufactured product is safe and effective. Not involving them early in the project will be detrimental and will likely result in changes to the design and impact to the schedule. This is when discussions around containment levels and criticality of systems occur. Sophisticated clients will determine the level of risk at every step of the way. Through their risk assessment, direction is provided in regard to level of redundancy, continuity of power supply, level of primary and secondary containment, administrative protocols for people and material movement (personal protective equipment and gowning needs included). They will pay particular attention when the manufacturing processes utilize potent compounds to deliver the API. As was the case for this facility.

For this project, the layout of the facility was sectionalized taking the flow of people and material and the criticality of the space into account. Criticality was evaluated on the basis of health, safety and environment (HSE) criticality and cGMP criticality. HSE criticality involves providing the proper work environment for the handling of hazardous substances and the safety measures and protocols needed in place to protect the people in the manufacturing space and surrounding areas. cGMP HVAC criticality involved providing an adequate environment for the manufacture and protection of the API in terms of cleanliness, temperature and relative humidity of the space. The owner had definitive criteria that applied depending on criticality levels. For areas handling potent compounds, the access to the suites was through a dedicated gowning area, which contained a gowning room for entry and a separate gowning room for exit. A shower room was provided before the exit as an added safety measure. The API handled was classified as non-sterile dry powder with processing work carried inside the isolator, which was the primary safety barrier. Owner direction was to provide 10 to 15 pascal differential pressure between rooms of different cleanliness classifications and twice as much for rooms handling potent compounds, which needed to be kept negative and with a full pressure step differential (13 pascal) in relation to corridors. Various iterations where employed to meet the added challenge of the functional requirement of a shower out with a bypass. The overall scheme for people movement and pressure cascades are depicted below. Code requirements limit the amount of force that personnel should apply to open a door unassisted my mechanical means. That meant the pressure differential across rooms needed to stay within certain parameters (less than 30 to 35 pascal) and that the room layout had to work accordingly to allow for a proper and safe pressure cascade without the use of assisted door openers. In the end, the team arrived at a solution that used air “bubbles” for the entry and exit points as a secondary barrier for separating the critical spaces (see image below) from the common areas. The imposed pressure differential between the bubbles and the critical space was set to approximately 26 pascal. In addition, there was a pressure differential between the corridor and the critical space that provided an extra level of protection in the event of bubble malfunction. Safety was paramount and the design reflected that imperative. 

People flow

Pressure cascade

Critical area region

It is important to note that this example is only a fraction of the manufacturing space. Other less critical areas were treated differently, and different pressure levels were applied there.

Energy saving strategies

At the onset of the project, the goals and objectives for the project were set. Energy reduction was one of them. And the owner was pursuing this goal aggressively, not just for this project but for the rest of the existing facility as part of a separate but parallel project. Efficiency targets were provided by the client to the design team that needed to be met or exceeded. It was refreshing that this client was willing to support this effort by not value engineering out energy saving features to save money and encouraging and providing a simplified path to justification and approval of approaches that reduced use and conserved energy. This client viewed energy savings beyond simple payback analysis. Some of the salient energy savings are listed below.

At the clean space level:

  • Minimize air change rate — the largest energy saver
  • Recirculate the air from the CNC zones
  • Recirculate the air from the ISO 7 space (with additional safety features added to the mechanical design due to hazardous classification of the space)
  • Implement an occupied/unoccupied mode of operation for the cleanroom (or set back mode) to depress air changes per hour even more
  • Specify doors with low leakage rates

At the facility level:

  • Low pressure drop ductwork design
  • Heat recovery of the exhaust
  • High-efficiency plant equipment (chillers, condensing boilers, cooling tower, pumps)
  • High-efficiency central air handlers (greater than 70 percent)
  • Extended media HEPA filters
  • Variable frequency drives

These measures promoted energy saving by design and reduced operating cost, and in some instances, installed cost due to reductions in the size of the mechanical infrastructure. The facility was turned over to the local site management and has been operating as intended since the summer of 2015.

Jose Gonzalez, PE, LEED AP, is a professional registered engineer and Senior Mechanical Engineer in CRB’s San Jose office. Jose has over 20 years of experience dedicated to the planning, design and construction of advanced facilities in the science and technology sector, including biotechnology facilities, cleanrooms, research and development labs, and office buildings. His areas of expertise include design for cGMP manufacturing, critical environments, cleanrooms, research labs, and bio containment labs. Jose holds a Bachelor and Master of Science in mechanical engineering from Universidad Michoacan, Mexico, and the University of California-Davis, respectively. He is a member of ASHRAE and ISPE and is a LEED Accredited Professional.