By Herman F. Bozenhardt and Erich H. Bozenhardt
One of the most exciting and rewarding efforts in the biopharmaceutical business is to take an idea and turn it into a unique lifesaving therapy. For some, our role is to engineer, design, and eventually build a facility for that new therapy. Most of these facilities will house new processes and new technologies and will enter clinical trials as soon as the manufacturing capability is ready. All these factors add up to a new need for speed of execution and, as such, scope precision, facility definition, and execution decisiveness are vitally important.
The unfortunate reality of the industry is the engineering discipline and technical skills needed to execute this type of project are generally absent within a startup organization. This is common and to be expected since these young organizations are built around discovery scientists, their ideas, patents, and technologies. All these technologies evolved from lab-scale development in biotech labs, universities, and hospitals. Many times, these characteristics of the typical fledgling biotech carry over and impact the design and construction of a facility, such as:
- R&D-focused management has little knowledge of what it takes to develop a commercially viable process. The R&D mentality believes only in bigger and bigger lab equipment, which may not provide the scale or efficiency in terms of true process development. Open processes with manual handling, lab centrifuges, use of solvents/chloroform/surfactants, and batch processing dependent on the position of the BSC (biosafety cabinet) to the refrigerator and back to the incubator are the most common production concepts.
- Lack of familiarity with industrial systems and equipment makes processes tedious and lengthy.
- Processes are envisioned as parallel trains of laboratory practices that are usually inefficient, limit production, and abound with contamination.
- Quality assurance and quality control are foreign concepts and are seen as obstacles to real progress.
- Validated sterility and sterile filtration are new concepts.
- Biosafety, biosecurity, and basic industrial safety concepts are not in consideration and again are thought to be impairments to real progress. There often is a clear false sense of security based upon small-scale exposure and working in a university or hospital environment.
The above realities ultimately are corrected with familiarization with industrial processes, coupled with a strong and independent development effort.
Company Culture Hurdles
There also are obstacles that require organizational change, and these challenges are more difficult to implement:
- The nature of the up-start by itself forces academically oriented personnel out of their comfort zone and pushes them into the industrial world with which they are not familiar. This manifests itself in resistance to the necessary process changes, quality “oversight,” and many of the regulatory aspects of our business.
- The new biotech organizations are always funded by “other people’s money,” such as venture capitalists and private organizations. With a general intolerance for failure/missing deadlines/overrunning budgets, these organizations are always in a position to question, oppose, and control the CEO. The funders often have a CFO internally in the organization to control and “observe” the cash flow, which creates an interesting dynamic.
- The CEO and senior company officers have “sold” the concept of success to the investors, so they feel the pressure imposed by the investors and realize the source of the funds can end their venture instantly. Yet simultaneously, the senior staff realize the immense wealth they could enjoy if they are successful. This sets up a very volatile dynamic that can force budget decisions, and scopes often change quickly.
- Given the needed technical transformations required and the normal lengthy process to bring a product to market, most up-start biotechs have no intention of building the company and instead are hoping for an opportunity to sell the company to a larger firm that could sell and market the product. This can keep the culture stifled in an academic mode and prevent the evolution that needs to take place.
In addition to technical and organization obstacles, biotech startups often face numerous manufacturing complications:
- Displaying the technology and its ability to bring their products to Phase 1 and Phase 2 clinical trials is critical to any successful path. This means the products must be both safe and efficacious, manufactured according to the GMPs, and will be administered to humans. This realization must be a known corporate goal.
- The next biggest challenge facing a company and its product is manufacturing scale. With often unknowns such as potency, number of doses in the therapy, product yield, product presentation, etc., equipment and, ultimately, the facility are challenges to scale accurately. Also, the consideration of market penetration is key; how many clinics and patients at all phases will need to be served? This further complicates the answer to “how much and how big?”
- All the validation, manufacturing, and quality data must be “regulatory ready” and, from processes to data collection, must be converted from R&D mode to GMP mode. This brings into play automation, data integrity, and 21 CFR Part 11.
Make Written Commitments To Address The Challenges
Based upon the above complexities of investment, culture, and manufacturing realities, the engineering of a process and facility becomes a daunting challenge. The engineer and manager of such an effort must force the following decisions, committed to in writing:
- A known feasible, safe, and closed process
- Process utilities such as gases/WFI, etc. and temperature ranges
- Maximum use of single use systems (SUS) to provide for future flexibility
- Maximum upper and minimum lower limits on process scale must be estimated
- Process time duration must be estimated from receipt of materials to final form
- Definition of BL-1, BL-2, or BL-3 of any organisms and OSHA classification of any potent compounds
- What are the bounds of the investment funds and what is on hand now to begin with (engineering, pre-con, build out, and continuous quality verification [CQV])?
- What is the timeline of the build promised to the investors?
- What are the month-to-month cash flow allowances?
The realities of designing and building a facility for a company without any significant credit history or financial background put the entire build on a peculiar footing, particularly with vendors of large equipment. Due to the continuing level of activity in the pharmaceutical business, the following are some cash flow and commitment realities of today:
- All equipment suppliers will require 50% of the purchase price upon purchase order, regardless of delivery date, and the final 50% within 30 days of delivery. These make for large cash flow events.
- Expect receiving lower priority from major equipment suppliers and longer than advertised delivery. This is natural as the vendors and suppliers take care of their larger established clientele first.
- Anticipate delayed start-up and CQV services with vendors servicing larger clients and, in some cases, not performing their services at all for smaller “one-time” clients.
Engineering, Design, And Construction Recommendations
Based upon these realities, the following comprise some basic guidance on engineering, design, and building the new plant:
- The “budget” may not be the final budget! With the reality of managing cash flow at a startup, each part of the design must be isolated into scope sections (plant sections) and phases of the build that can be executed separately. This means extra effort (time and cost) in the detailed engineering phase to articulate an incremental suite-by-suite and process section-by-section investment. Recognize that this analysis will cost more investment funds, as each incremental build will bear the cost of re-mobilization. This means every process suite, every parallel process, and every redundant system needs to be priced out for future inclusion, delay, or deletion.
- Bringing on a building constructor at the conclusion of conceptual design is critical to cross check the engineering build estimates and to guide the concept of the incremental build. This in no way means value engineering (VE) and cutting the quality of the build. On the contrary, the new biotech facilities and processes will be under greater scrutiny by the regulators, investors, and potential buyers.
- Get all the major equipment vendors on board at the conclusion of conceptual design. This ideally means placing the purchasing deposits and getting into their build schedule. This reality turns the schedule into a pull planning exercise on when is the latest date that funds can be committed and still meet the project timeline. With the purchase order placement, the build schedule and delivery dates are committed in writing. Your team will use that schedule to support the factory acceptance test (FAT), site acceptance test (SAT), and CQV activities.
- Leverage the construction firm’s contacts and relationships with the heavy infrastructure vendors (HVAC, boilers, chillers, etc.). They should be able to secure the best delivery and cost. The same goes for leveraging the design engineer’s connections and contacts for various plant equipment.
- Use a large, top-tier engineering firm and construction firm to execute your design/build effort, but never the same firm for both. You need constant cross checking on costs, execution techniques, and schedule. The larger firms have capacity for staffing, credibility with vendors, and the ability to start and stop as the investment dictates. The well-capitalized firms typically won’t be distressed or walk away if you are delayed in paying, because they have financial backing. However, starts and stops risk continuity in the project team as personnel maybe assigned to other projects.
- Change control will be a major issue as the processes develop (and change), demands from investors accelerate or slow down, or a new product or process is introduced. Each phase of the project needs a meticulous control log with change order, cost impact, schedule change, and cash flow change. Have the CEO and CFO sign each one.
- It is important to move quickly in the engineering phase in order to answer investment questions and make strategic decisions about what the scope of the build includes. The engineering lead needs to have a solid scope document (that matches the investor’s scope statement) to start with and provide a direction to the engineering firm’s team. The conceptual design phase needs to be more extensive than the typical since we need a better than the typical +/- 25% estimate and will have multiple capital deferral options. The conceptual design phase must select and size all the large equipment (WFI skid, HVAC AHUs, backup generator, autoclave, etc.) and get it on order. This can cut the build cycle time by months.
- Most biotech processes are composed of multiple processing skids and use disposable technologies to varying extents. It is at this point that two decisions need to be made:
- 1) Select and place on order the major systems (bioreactor skid(s), TFF skids, chromatography systems, etc.) that provide the required scale either as a single unit or as multiples of smaller units (to accommodate incremental cost-effective scale-up).
- 2) With the key equipment and their costs defined, the project can shorten or potentially eliminate the basis of design (BOD) stage.
Once detailed design is started, the focus needs to shift to early release drawings and documents for the next critical path items, typically the architectural features. From there, each critical path discipline should be scheduled for release in its order in the project’s critical path.
- It is another critical point to assure the biotech organization has a QA head and to synchronize with them on the commissioning approach, which places a great emphasis on checkout by the suppliers, vendors, and builders.
- The final most interesting aspect of the design and build is the education and orientation of the scientific core of the company. Too many startups have neglected to have someone working on environment, health, and safety (EHS) issues — to address the realities of compliance and regulation, safety/biosafety, biosecurity, OSHA, and the do’s and don’ts of a construction site. Building permits can very quickly generate questions from the local authorities about what the intent of the facility is and how it impacts the community.
Fledgling biotech companies are a breed of organization that has emerged over the last decade, driven by computing technology, better understanding of the human genome, the availability of venture capital, and the drive to improve human life. This new type of organization is very different from the traditional Big Pharma or the larger biotechs that are well funded. These organization are financially fragile, and they can ultimately become controlled by demanding fund managers who see these organizations as just another investment in the portfolio. The engineer who manages this must be aware and adjust their thinking and employ some new tactics to document all costs and impacts, reduce schedule, and maintain quality. While this may seem a common set of objectives, it is necessary to do this while working within the culture and be ready for a scope change or cut at a moment’s notice.
About the Authors
Herman Bozenhardt has 44 years of experience in pharmaceutical, biotechnology, and medical device manufacturing, engineering, and compliance. He is a recognized expert in the area of aseptic filling facilities and systems and has extensive experience in the manufacture of therapeutic biologicals and vaccines. His current consulting work focuses on the areas of aseptic systems, biological manufacturing, and automation/computer systems. He has a B.S. in chemical engineering and an M.S. in system engineering, both from the Polytechnic Institute of Brooklyn.
Erich Bozenhardt, PE, is the lead process engineer for regenerative medicine operations at United Therapeutics. He has 14 years of experience in the biotechnology and aseptic processing business and has led several biological manufacturing projects, including cell therapies, mammalian cell culture, and novel delivery systems. He has a B.S. in chemical engineering and an MBA, both from the University of Delaware.