The advancement of drug development techniques coupled with the need to deliver potentially life-changing therapies to patients efficiently has made the commercial facility design process increasingly challenging. DPS Group's Eric Quarnstrom explains
Once a new therapy is proven safe and effective, it is critical that the production process is scaled up to commercial manufacturing volumes, both for the affected patient population and the overarching business. It is well known that manufacturing at a larger scale for therapies such as generic small molecule medicines and vaccines drives the cost of production down, which allows the manufacturer to offer the product to market at a lower and more competitive cost, making it more accessible and affordable to patients.
This environment of fast-paced drug development has put immense pressure on manufacturing facilities to expedite bringing these new products to market. After identifying a market share for a new product, manufacturers often face significant obstacles on the road to receiving capital funding approval to build a new facility or renovate an existing manufacturing area. It is common for pharmaceutical companies to engage with a design partner, and work through the development of front-end design studies, only to find that the facility’s total-installed-cost (TIC) is well above their initial budget. This outcome can disrupt construction schedules, delay product introduction to the market, and in some cases, cancel the project entirely.
The environment of fast-paced drug development has put immense pressure on manufacturing facilities to expedite construction
Evaluating and defining key characteristics and strategies when initiating front-end engineering of a cGMP manufacturing facility will help pharmaceutical manufacturers ensure their facility design meets both their immediate and long-term needs, as well as their budget and schedule goals.
Product characterisation is critical in defining facility and process equipment requirements, which can greatly impact a manufacturing facility’s TIC and its production capacity or throughput. The following considerations and high-level examples are a starting point for effectively vetting a facility’s requirements.
Target Markets: Where will the product be distributed? For example, Europe, the US, and Japan each have a separate regulatory body with distinct governing documents. While many requirements are similar or equivalent, critical differences can significantly impact a facility's design requirements.
Product Type: What type of drug product or drug substance does the facility intend to produce? Examples of product types can include CAR-T cell therapies, oligonucleotides, monoclonal antibodies (mAbs), microbiome therapies, antibody-drug conjugates, vaccines, and blood plasma-based therapies. Each product type comes with its own set of risks, such as cross-contamination or hazards to the facility operators and environment. For example, regulations and guidance documents for certain products may suggest that they be manufactured in separate buildings to protect operators and other products from biological hazards and contamination.
Single vs multi-product: While a multi-product facility gives a manufacturing operation flexibility to produce different products at different times using the same equipment and areas, this can significantly increase the complexity of cleaning requirements and cleaning validation efforts. It is vital to product quality that risks associated with product-to-product contamination are minimised.
Known hazards: Does the manufacturing process involve using flammable, combustible, toxic, or biologically hazardous materials? Characteristics of the product and materials used in the production process can quickly increase the cost of a new or renovated facility and any necessary production and support equipment. For example, the above-mentioned hazards can independently require single-pass air in the room(s) where the hazardous materials are manipulated, resulting in higher heating and cooling operating costs. This consequently increases the facility utility equipment and piping sizes compared to a typical building that recirculates a small percentage of air. The geographic location must also be considered, as single-pass air handling units are also exposed to higher risks of freezing on days significantly colder than average winter conditions.
The storage and use of flammable and combustible materials must comply with the relevant codes and design standards such as the International Building Code (IBC) and National Fire Protection Association (NFPA). Additional fire walls, fire protection systems, control areas, or hazard-classified areas may be required if flammable or combustible materials are above the maximum allowable quantity. Additionally, if a process utilises flammable or combustible materials with open or closed (contained) manipulations, the equipment and rooms housing these operations may require intrinsically safe or explosion-proof ratings to minimise the risk of fires and explosions.
Similarly, using toxic or highly toxic materials can require using specific containment equipment, such as fume hoods or containment isolators, to protect operators from health hazards. The requirements are typically driven by a material’s level of potency and its categorisation within an operator exposure banding or level system (OEB/OEL). Additional testing is required to determine the level of toxicity if the OEB level of material mixes are unknown.
Biologically active materials used in production processes are assigned a Bio-Safety Level (BSL), which impacts facility and equipment design. One example is the method of inactivating or killing live biological material contained within residual production solutions. The requirements for inactivation can vary from organism to organism.
Defining these product characteristics as early as possible in a design process is imperative to ensure the appropriate engineering controls are deployed to mitigate risks of product cross-contamination, containment of hazardous materials, and personnel safety. Their impact on facility cost can be substantial, and typically these requirements cannot be relaxed.
In addition, to clearly define the facility process and equipment parameters upfront, there are several design and delivery approaches that aid in successfully bringing a product to market.
Clearly establish and communicate the facility’s target budget. Whether the facility intends to produce “in-house” products or operate as a Commercial and Development Manufacturing Organisation (CDMO), it can be difficult to forecast the product portfolio for a facility that requires initial capital funding approval early in the design process. This approval is oftentimes well before many design details are determined. If the initial capital investment is known, it can be hugely beneficial to communicate a target facility budget to the facility engineering partner. This allows the design team to direct focus on options that fall into the budget at the onset of design. It also allows more effective use of LEAN tools like Target Value Design (TVD) for early and more frequent communication of the facility cost estimate throughout the design process. The design team and facility owner can use this data to track how design decisions impact initial facility cost trends.
Knowing the target budget also opens discussions on soft costs required for cGMP facilities, such as Commissioning, Qualification and Validation (CQV), design and construction management fees, and external consultant fees to support gaps in Owner Team expertise. These costs are often overlooked by companies moving from R&D to clinical and commercial manufacturing.
Utilising discrete event simulation software is another useful tool that can be leveraged in the initial design stages. These tools are used to take input data from the manufacturing operation to estimate product throughput from a single manufacturing line or an entire facility. It can also help to estimate facility support functions such as warehouse space requirements, utility consumption, production headcount, and facility operating costs. These simulation tools improve the accuracy of early design efforts and prevent significant cost over or under estimation.
Utilising discrete event simulation software is another useful tool that can be leveraged in the initial design stages
TVD and simulation tools allow manufacturers to evaluate opportunities for phased construction. It is common for new CMO/CDMO facilities to aspire to produce a wide range of product types as early as possible to cater to as many potential clients as possible. This often results in more manufacturing lines and built-in flexibility, which inevitably increases the initial facility capital investment. With a clear understanding of the project budget and potential phasing options, facility owners can focus initial efforts on products that are most likely to be approved for commercial distribution.
In a new multiproduct facility, it may make commercial sense for the capital investment to build an initial construction phase with only one manufacturing line while leaving an adjacent empty “shell space” within the facility. This shell space would be reserved for additional manufacturing lines to be installed during future construction phases. The facility owner could then fund the build-out of future manufacturing lines with revenue earned from the products generated by the initial phase’s manufacturing line.
Another example of a phased construction strategy is to expedite the build-out of a facility’s shell and core support spaces. This can allow for earlier construction of the building exterior and, in some cases, office, warehouse, and utility spaces. The early phased shell and core construction can occur in parallel with the design of the cGMP manufacturing areas that often require more design development time.
Clarity on key product characteristics is a vital step in arming facility decision-makers with the data required to make informed design and financial decisions. Partnered with design tools and delivery strategies, owners can evaluate opportunities and better balance initial capital investment with the facility’s projected revenue. Expensive design rework and cost-cutting exercises on the back-end of a design phase can also be avoided. Consequently, ensuring a faster road to capital funding approval and product to market.