by Jeff Lewis, PE, Ryan McDonough, PE, and Eddie Skillington of DPS Group
In the engineering and design world of high-tech industries, commissioning, qualification, and validation (CQV) is an important part of building fully functional pharmaceutical manufacturing facilities. Major drug companies have this down to a science.
The CQV story can often be quite different for younger companies pursuing novel therapies. Many have emerged from a research and development lab or academic environment, often with government or venture capital funding, expecting results to happen sooner rather than later. Researchers specialize in discovery over delivery. In most cases, they haven't yet needed to consider the requirements of designing and building facilities to manufacture products at scale, nor what it may take to qualify the facility to do just that.
Working side-by-side with these novel drug companies and researchers, experienced engineers can identify and overcome hurdles that arise when facing the transfer from research to production scale. Since these companies' familiarity with facilities for pharmaceutical manufacturing can range from expert to novice, everyone involved has to be in the trenches together.
This article takes a high-level look at some of the challenges in designing novel therapy facilities – and what to keep in mind when working with engineers and designers to create these new facilities.
To build or outsource?
We are seeing unprecedented demand for and corresponding growth of novel therapies. The biopharmaceutical industry is starting to feel the pressure. Former FDA Commissioner Scott Gottlieb was quoted as saying, "We’re entering a new frontier. FDA officials predicted in 2019 that the agency will receive more than 200 investigational new drug applications per year for cell and gene therapies, and that by 2025, it expects to have accelerated to 10 to 20 cell and gene therapy approvals per year.”
While the increased use of these novel therapies are encouraging for the medical profession and those patients who may receive treatment, it puts a demand on capacity within the manufacturing space.
When producing at scale, novel drug companies realize that they must either manufacture the products themselves or outsource the manufacturing to a Contract Development and Manufacturing Organization (CDMO). The employees of early-stage companies are usually the scientists and researchers who are not typically familiar with what is required to bring a therapeutic discovery into manufacturing production. To reduce risk, these companies may be inclined to partner with the CDMOs.
As CDMOs not only work with new companies but established ones as well, the market is flooded. The current market may result in a backlog of work stretching up to 18 months or more with this saturation in mind.
As most companies cannot afford such a time delay, they may pivot back to building their own facility. For newer companies that are still expanding their qualified personnel, that’s no small feat. Facility design and construction in this context require engineering firms and the industry in general to think outside the box to streamline an established process developed over many decades.
The process is daunting for many fast-growing companies as they aren’t prepared for the sheer volume of regulations and approvals required for the start-up and operation of a manufacturing facility – particularly in qualifying and validating a facility for production.
In this fast-paced industry, it’s common for a company to kick off a project and aim to begin construction as quickly as possible, frequently overlooking the critical step of validation. When it is realized, too often, it’s too late in the project to juggle with the aggressive schedule of getting their novel therapy product to market.
The lesson here is that early engagement with engineering and design firms with GMP experience can mean the difference in months of lost time and considerable expense when building a new facility. With the high value of gene-therapy drug substances, the emphasis is on reducing the time to market from the moment a project is conceived.
Quality Risk Management, or QRM, is a systematic process that assesses risk to the quality of a drug product across its life cycle. This life cycle approach is also being applied to novel drug therapy projects to reduce schedule and cost. With QRM, key players are brought in early in the project lifecycle, to set up the planning and processes needed to integrate the project phases and to shorten the overall schedule.
The realities of validation planning for novel therapies
A facility’s Validation Master Plan (VMP) provides a road map for its compliant design and construction. It defines the execution plan needed to assure a paper trail that allows the facility to reach its ultimate goal: To meet all the requirements of the FDA, and other regulatory bodies such as EMA in Europe, to manufacture novel therapy product(s).
Establishing a VMP allows for a basis of knowledge for what may be specifically required from an engineering perspective. The facility can be designed with validation in mind, using the appropriate equipment in the appropriate locations to meet the user requirements.
It is best to create these validation planning documents early, to prevent unnecessary delays and headaches throughout the building and validation process. They typically take two to three months before specific design criteria can be addressed. The earlier specific user requirements can be established, the more successful the project will be in the long term. It should be noted, however, that the extent to which this planning can be done in advance typically comes down to the bandwidth of the client’s team.
Client bandwidth issues usually pertain to the design process itself. When an engineering firm provides an early-stage feasibility study, it is common practice to advise clients that the speed at which a project can move forward is usually limited by the client’s capacity to support the work. Design is a very time-intensive effort, so fully understanding client needs in advance leads to a more accurate and on-time scheduling.
Making changes early in the design phase is considerably less expensive than introducing changes when facility construction is already underway. Often, however, start-up novel therapy companies may not have these dedicated teams in place when a project kicks off. Individuals may be added to the group once the project is underway, which inevitably leads to additional requirements being established in real-time.
Strictly speaking, companies should be designing their facilities to User Requirement Specifications (URS) that minimize the risk to patient safety, which the FDA is expecting to see evidence of now. This is accomplished by understanding the drug Critical Quality Attributes (CQAs), which are preserved by controlling the Critical Process Parameters (CPPs) for each process step. This risk-based approach not only provides a roadmap for what testing is required, it greatly reduces the overall effort and time needed to qualify a new facility.
For CDMOs and CMOs which do not have defined drug substances, typical CQAs are assumed, for example, safety, integrity, strength, purity, and quality (SISPQ). When a drug is selected to be manufactured by this equipment, a risk assessment must be performed to verify that the critical design elements required for this particular drug – for example, sensors, alarms, etc. – are present in the design.
Young novel therapy companies do not always have the experience to define and design to the user requirements. GMP engineering and design firms can help establish what the client facility needs to do, how it needs to deliver their product(s), and any interim material and personnel requirements that may be required.
It's preferable to have user requirement documentation inform the design rather than basing the design on specifications, past experience and instincts. Yet, it is common for designs to be adjusted when there was no specific guidance on what the requirement might have been in the first place.
Lessons learned: Typical problems in the design process
Practical experience with novel therapy companies has uncovered some common misconceptions or knowledge gaps within those organizations. The following potential problem areas must be addressed early in the process to ensure a smooth and successful transition from design to a commissioned and qualified facility:
Insufficient understanding of what is required to manufacture products at scale. Often, novel therapy companies have several potential products in progress at once, and they are developing the manufacturing process as they go. Such flexibility and agility is prized in the field, but, it is important to temper expectations about what design flexibility means with the practical limitations of what is truly achievable.
It’s not just flexibility; it’s adaptability. The notion of flexible facilities is somewhat of a misnomer. In fact, facilities should be designed with adaptability in mind. That means the ability to make changes without having a massive impact on the facility and its operations. As a company looks at its portfolio of products, decisions must be made along the way as to which current or potential products may perform well in the marketplace and which may not. Those decisions carry a need to respond appropriately with an adaptable environment that can accommodate multimodal manufacturing.
Whether it’s pharmaceutical companies making the products or contract manufacturing organizations, the dream is to have the flexibility to produce from among several products – or in the case of CDMOs, to switch easily between various modalities (cell therapy versus gene therapy, for example). The design challenge is one of designing and building with sufficient flexibility to allow the client to adapt to market conditions as necessary.
Flexibility is not free, so plan accordingly. Flexible design can be costly in terms of time, money, and space. A designer's greatest contribution for novel therapy facilities is to guide the manufacturer in the process of narrowing their manufacturing requirements to a reasonable number of products for a given phase of production. That may call for manufacturers to make potentially difficult business decisions on how to roll out products to keep the costs appropriate to the available budget.
At the same time, the design must be future-looking enough to address current needs and the additional considerations that come with subsequent phases of production. Understanding the production volumes across phases of operations is extremely helpful in creating a strategy for future expansion. It gives the designers a target for what the client’s needs may be down the line. Future-centric designs can help prevent a company from having planning and space constraints as needs change.
It is important to design in such a way as to be able to add or remove items as necessary to support the manufacturing expansion plans. That may include taking a hard look at available space in the facility footprint that can be repurposed – with the original intended use possibly relocated elsewhere entirely. For example, suppose a facility includes a large warehouse. In that case, it may be necessary to create a design where that space may be constructed or retrofitted by adding prefabricated cleanroom pods, understanding that the warehouse function may have to be moved offsite.
Additional areas to consider when designing agility, flexibility, or adaptability into a facility for future expansion typically include mechanical, electrical, and plumbing systems, fire prevention systems, and air handling and segregation.
The demands of bringing novel therapy facilities online can be pressure-filled, with high stakes for the companies, and the engineers and designers tasked with ensuring success. The starting point can be further off than a company might expect, due to the importance of matching appropriate future-thinking designs with the company’s ever-evolving needs, both today and in years to come.
About the Authors: Jeff Lewis, Department Manager, Process Engineering, DPS Group, is a registered professional engineer with 17 years of experience leading and providing process engineering, procurement, and construction support for pharmaceutical and chemical manufacturing facilities. His experience includes facility master planning, equipment arrangement/plant layout, pharmaceutical equipment selection and specification, PFD and P&ID development, and piping design.
Ryan McDonough, Senior Vice President, Philadelphia Project Operations, DPS Group, leads the strategic direction and continued growth of DPS’ Philadelphia office. He has 20 years progressive experience in the design and management of pharmaceutical, biotechnology, and medical device processing facilities.
Eddie Skillington, Vice President, Business Development, DPS Group, has more than 18 years of industry experience in a variety of roles in the life sciences, oil and gas, chemical, power, manufacturing, and electronics industries. His technical expertise comprises instrumentation and control systems engineering, construction management, and CQV. He has hands-on experience and understanding of all discipline trades from project ideation through qualification.