Mark Witcher is senior consultant at Brevitas Consulting, witchermf@aol.com

Mark Witcher


	Submitted: Jan. 3, 2019. Accepted: Jan. 28, 2019

To rapidly achieve high-quality pharmaceutical manufacturing processes, the industry must focus on developing prospective, management-based approaches instead of retrospective performance-based measures that are too slow to drive the necessary innovation and continuous improvement. FDA’s voluntary consensus standards initiative may provide the opportunity for establishing and evolving important prospective product development methods.

	Regulatory agencies, including FDA, have switched from a management-based to a performance-based regulatory strategy. The stated reason for the change is “to give the industry enough flexibility to manage and improve quality on its own” in hopes of a several order-of-magnitude advance in performance using continuous improvement (1). The need for improving performance is caused by the industry’s ongoing failure to reliably supply patients with high-quality products resulting in many shortages and recalls due to industry-wide manufacturing quality levels around two to three-sigma (two-sigma is roughly a 30% failure rate) (1,2). In simple terms, a poorly performing industry is being told by regulatory agencies to “fix thyself.”

	A case can be made that the shift has left the industry adrift in the rough seas of rapidly advancing medical technology without the necessary methods to keep up. The shift in regulatory strategy places a huge, but necessary burden on the industry to develop their own sophisticated, prospective, management-based methods required to achieve Six Sigma quality levels (roughly three failures/million attempts) typically found in many other industries while developing increasingly complex products and therapies. 

	Management-based approaches must be prospective if they are to be effective for developing and manufacturing future high-quality products. Performance-based approaches, particularly regulations, are retrospective measures of quality. Unless the management-based methods are effective, feedback from performance-based methods that depend on initial or past failures to improve performance will be slow to improve the industry’s performance. For pharmaceuticals, high performance must be achieved from the very beginning using prospectively developed control strategies. Further, these better methods must be developed and improved in collaboration with regulatory agencies to ensure the methods will have a perceived high likelihood of actually producing the initial results necessary to support regulatory actions for licensure and commercial manufacturing. The collaboration must also ensure that the methods’ results are consistent with existing regulations. A possible method for the industry collaborating with regulatory agencies is being developed around the voluntary consensus standards (VCS) draft guidance (3). 

	The best path for developing better industrial methods is likely to expand and supplement the existing management-based regulations developed before the shift in regulatory strategy. Old regulatory guidelines have been carefully written to avoid prescribing how approaches should be executed from a fear of establishing standardized methods that might prevent better approaches from being developed through continuous improvement. Only the industry, with the assistance of regulatory agencies, can prospectively develop and, most importantly, continue to evolve new and better methods and approaches to achieve excellence for ever-increasing product and manufacturing challenges.

	This article reviews and suggests improvements to a few of the important management-based regulatory guidelines that currently drive pharmaceutical development and manufacturing. 

	The ICH Q8 guidance contains important foundational concepts for prospectively managing the development of high-quality processes necessary for making high-quality products. However, these concepts are defined vaguely as “what” and “why” and must be expanded or industrialized, perhaps using the VCS route, to achieve their intended goal of guiding the industry. For example, quality-by-design (QbD) is defined in ICH Q8 as:

A systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management 

	This mechanistic-free definition has led to widely varying interpretations and implementations of QbD. A study commissioned by FDA concluded that the vague definition has led to many problems within the industry and regulatory agencies on how QbD can and should be used (5). Insights into the regulatory goals of QbD have been described, but again these goals focus mostly on a regulatory perspective of past performance (setting specifications, process capability, and change control) rather than methods for achieving excellence from the very beginning (6).

	A more mechanistic description has been proposed as working-quality by design (wQbD) by the following definition:  

To achieve a well-defined goal during the design stage, iteratively apply science and engineering methods to anticipate, identify, understand, and resolve problems that will be encountered during testing, operating, and verifying the goal over its entire lifecycle 

	This definition describes the use of thought experiments combined with testing mathematical and experimental models within a larger design algorithm, such as the design stage of the lifecycle process development and validation paradigm described in FDA’s 2011 process validation guidance (8). As will be discussed, wQbD drives the systematic use of prospective quality risk management (QRM), operations research (OR), and design of experiments (DoE) methods to build effective control strategies for controlling risks and improving process performance. 

	The results of the wQbD methods must be assembled and stored in a comprehensive process model for internal and regulatory communications. ICH Q8 defines the all-important process model as the design space described by the definition:

The multidimensional combination of interactions of input variable (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality. 

Working within the design space is not considered as a change. Movement out of the design space is considered to be a change and would normally initiate a regulatory post approval change process. Design space is proposed by the applicant and is subject to regulatory assessment and approval 

	The first sentence is the functional definition while the remainder are three increasingly significant policy statements intended to provide emphasis and guidance. Again, no mechanism is provided. The three policy statements provide a tantalizing look into the possibilities of sophisticated management-based regulations. Implementation of these policies, however, remains unlikely given the regulatory shift and the recent draft of ICH Q12 that describes comprehensive change control (9).

	The regulatory design space is defined primarily in terms of the following two ICH Q8 definitions:  

A physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality. 

A process parameter whose variability has an impact on a CQA and therefore should be monitored and controlled to ensure the process produces the desired quality 

	Defining the design space in terms of the CQAs and CPPs is sufficient for regulating the performance of a process, but when used to design and clearly define manufacturing processes, the limited definitions have led to a great deal of confusion and uncertainty. Much clearer definitions of process inputs and outputs are required to build control strategies (10). 

	To more completely describe the performance of a manufacturing process, both the product and the process’s behavior during product manufacturing are required. An alternative method of describing process outputs, previously proposed by the author (10,11), are:

Use the ICH Q8 definition, except it refers to the product material produced by each unit operation in the manufacturing process. In the case of the final process, the output CQAs would describe the final product. 

A process output that measures or indicates the performance of the process (e.g., temperature, pressure, viability, yield, etc.) that results in all the product’s CQAs. For complex biopharmaceutical products, measuring and controlling CPRs is required to control both unknown or unmeasurable CQAs as well as the known and measurable CQAs. If appropriate, a measurable CQA can be used as a CPR (10). A CPR is an output parameter using the above CPP regulatory definition. Clearly describing the performance of a process as a CPR focuses the development activities on the important aspects of controlling the process’s behavior to achieve maximum control over product quality. 

	With respect to defining input parameters, the regulatory definition of the various input CCPs should be divided into the proposed following three categories (10,11):

Input parameters used to define and manipulate the process during development and operation. Examples of COPs include media composition, buffer concentrations, mixing rates, gas addition rates, etc. COPs used to control the performance of the process in real-time based on measuring CPRs in a feedback control loop are called critical control parameters (CCPs). 

Material attributes of the raw material input used by the process to make a product. CMPs are the same as a critical material attributes (CMAs). Thus, a series of processes are connected by the transfer of output material described by CQAs from one process that become the input material described by CMP/CMAs to the next process (6,11). 

These parameters (sometimes called critical design parameters) define the equipment. Examples of CEPs include volumes, materials of construction, agitator type, heat transfer area, and so on. These parameters are part of the equipment’s user requirements specifications (URS) when the equipment is designed, selected, and acquired during engineering. 

	When designing process systems, separating the three types of input parameters is important because they play different roles in determining the performance of the process. These parameters also contribute different risk input threats to the performance of the process and are controlled using different control strategies (10). Using the expanded definitions results in a well-structured design space (11). 

	ICH Q9-QRM is the regulatory guideline most urgently in need of rapid improvement and ongoing evolution (12). Too many times, regulatory guidance defaults to “do a risk analysis” to solve a problem or define a control strategy. Although ICH Q9 clearly states the “what and why,” the methods included in the document do not provide a viable foundation for the “how.” The methods described in ICH Q9 focus on process analysis (e.g., wishbone diagrams, failure mode and effect analysis, hazard analysis critical control point). Although an execution risk’s severity from a process can be described easily in a variety of ways (e.g., cost, supply impact), the highly subjective element of uncertainty, or likelihood of the risk’s realization, is not properly addressed by these methods. Improper handling of uncertainty frequently leads to confusion and misleading results (13,14). 

	The failure to deal quantitatively with uncertainty often leads to the risk analysis falling prey to the precautionary principle, which can be defined here as an overemphasis on the impact of the risk’s severity without properly considering the risk’s probability as a result of inadequate information or poor analysis methods of the likelihood of the risk’s realization (15). The industry desperately needs effective quality risk management methods that are prospective, theoretically consistent with using probabilities to describe uncertainty, mathematically sound, easy to use by all practitioners, and expandable to an appropriate level of detail for analysis and control based on the risk’s severity (16–18).

	FDA’s 2011 process validation guidelines

	Arguably the most important guidance for developing control systems using QRM is FDA’s 2011 process validation guidelines (8). The document provides an important paradigm for developing and manufacturing products. The paradigm can be used to develop virtually any process from procedures or facility designs to unit operations (10,16,18). The guidance is unusual because it is very close to a prescriptive “how” paradigm. The approach is aligned with the four basic questions for any undertaking: “Do what?”, “How to do it?”, “Will it work?”, and “Did it work?” (10). Any analysis method that does not address all four questions is incomplete. If the four questions are correctly asked and answered, particularly in a systematic, documented fashion using wQbD to answer the second question, success is highly likely. 

	FDA’s 2011 process validation guidelines describe three stages (8):

The commercial manufacturing process is defined during this stage based on knowledge gained through development and scale-up activities. 

During this stage, the process design is evaluated to determine if the process is capable of reproducible commercial manufacturing. 

Stage 3: Continued process verification. 

Ongoing assurance is gained during routine production that the process remains in a state of control. 

	Although the above stages provide a good foundation, they do not adequately cover the four basic lifecycle questions necessary to provide a complete development paradigm for building excellence. They also lack mechanisms for their execution. A more complete lifecycle can be divided into planning stages for prospectively building the process along with its control strategies, followed by execution stages for retrospectively assuring initial and ongoing performance based on data. The execution stages provide the foundation for the performance-based regulations and are most effective when the process’s established conditions and quality metrics are intrinsically defined and incorporated during the planning stages. 

	Briefly, the expanded process validation lifecycle paradigm can be described as planning stages (Stage 0 and 1) for prospectively building and documenting the foundation for manufacturing and execution stages (Stage 2 and 3) for retrospectively proving and documenting initial and ongoing success based on predefined comprehensive performance criteria described in the well-structured design space. The stages are described as follows:

Establish clear product and process requirements, goals, and objectives to define success during the execution stages.

Using wQbD, DoE, and prospective QRM to systematically develop control strategies and performance criteria within a well-structured design space to test, qualify, operate, control, and verify all process inputs and outputs required to manufacturing high quality products. 

Execute a documented prospective testing program that ensures the process will work during Stage 3.

Operate and control the process using the control strategies defined and designed in the planning stages while assuring and documenting successful performance using prospectively defined performance criteria (10). 

	The key to achieving very high product quality is to prospectively build a foundation during the planning stages using wQbD and QRM for the retrospective assurance of performance during execution by building highly effective control strategies, including integral measures of performance.

	If the industry and regulatory agencies are to achieve FDA’s 21st century goals, the focus must be on developing and continuously improving prospective methods for developing new products and their manufacturing control strategies (19). While the existing management-based regulatory guidelines (ICH Q8 and Q9 and FDA 2011 process validation, etc.) are a good start, they must be improved significantly into straightforward methods necessary to achieve Six Sigma levels of performance to reliably supply all patients with high-quality products. Building and working with such methods will require a great deal of courage on the part of the pharmaceutical industry. Regulatory agencies and the pharmaceutical industry will have to work together, possibly using voluntary consensus standards, to build the methods along with the collective trust to efficiently develop, launch, and manufacture the many challenging products of the future. 

528 (1–2) 354–9 (2017).
	2.    J. Wechsler, 

Draft Guidance for Industry, CDER’s Program for the Recognition of Voluntary Consensus Standards Related to Pharmaceutical Quality 

Guidance for Industry: Q8 (R2) Pharmaceutical Development

, Rev. 2 (November 2009).
	5.    FDA, 

Final Deliverable for FDA Understanding Challenges to QbD Project, Understanding Challenges to Quality by Design 

(Dec. 18, 2009).
	6.    L. X. Yu, et al. 

16 (4) 771–783 (2014).
	7.    M. F. Witcher, 

Guidance for industry: Process Validation: General Principles and Practices

, Rev. 1, (January 2011).
	9.    ICH, 

Q12 Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management Core Guideline, 

Draft version (endorsed on Nov. 16, 2017).
	10.  M. F. Witcher, 

online, DOI:10.12665/J17OA.Witcher.0416 (Sept. 5, 2018).
	11.  M. F. Witcher, 

online, DOI:10.12665/J132.Witcher (Summer 2014).
	12.  FDA, 

Guidance for Industry: Q9 Quality Risk Management 

The Failure of Risk Management: Why It’s Broken How to Fix It 

(Wiley & Sons, 2009).
	14.  L.A. Cox, D. Babayev, and W. Huber; 

25 (3)  651-662 (2005).
	15.  C. R. Sunstein, 

Laws of Fear–Beyond the Precautionary Principle 

(Cambridge University Press, 2005).
	16.  M. F. Witcher, 

online DOI/10.12665/J16OA.Witcher (Sept. 25, 2017).
	17.  M. F. Witcher, “Understanding and Analyzing the Uncertainty of Pharmaceutical Development and Manufacturing Execution Risks using a Prospective Causal Risk Model” (submitted to 

2019).
	18.  M. F. Witcher, “Building Control Strategies to manage Pharmaceutical Development and Manufacturing Execution Risks using an Expanded Lifecycle Process Development and Validation Paradigm” (submitted to 

Pharmaceutical CGMPs for the 21st Century-a Risk Based Approach 

	Mark F. Witcher, PhD is senior consultant at Brevitas Consulting, 


	Vol. 43, No. 7
	July 2019
	Pages: 34–37

	When referring to this article, please cite it as M. Witcher, “Improving Prospective Product Development Methods Derived from Management-Based Regulatory Guidelines," 

Articles

To rapidly achieve high-quality pharmaceutical manufacturing processes, industry must develop prospective, management-based approaches instead of retrospective performance-based measures. 

Improving Prospective Product Development Methods Derived from Management-Based Regulatory Guidelines

initiative of “a maximally efficient, agile, flexible pharmaceutical manufacturing sector that reliably produces high-quality drugs without extensive regulatory oversight” is crucial to the biopharmaceutical industry reaching its long-term strategic business goal-efficiently and reliably supplying patients with high quality products (1). Realizing this goal has three primary objectives:

maximally efficient, agile, flexible manufacturing resulting in the rapid development of a wide variety of challenging new products and assuring delivery of these products to all patients who need them.

typically viewed as assuring performance of all manufacturing operations approaching six-sigma quality levels, or approximately three failures per million operations attempted (1).

Without extensive regulatory oversight: 

creating a relationship between regulatory agencies and manufacturing organizations that results in minimal need for regulatory oversight based on past performance.  

	The multi-purpose facility (MPF) composed of a matrix of segregated flexible operating spaces described in previous articles is specifically designed to achieve these three objectives (2,3). The ability to accomplish these objectives is the result of the MPF’s capability to use common control strategies to simultaneously operate a wide variety of multi-product processes at different scales and capacities without the need to modify the facility’s layout or control strategies.  

	A pharmaceutical manufacturing facility can best be described as an enterprise defined by three elements:

 unit operations (UOs), grouping of UOs into logical operating units (LOUs), process equipment, components, instruments, automated process control systems, input and in-process materials, and products.

 buildings, environmental systems, layouts, operational flows, logistical support, utility systems, and other building control systems such as the building management system (BMS).

 practices, procedures, people (training, discipline, and qualification), maintenance systems, and automated procedural control systems (e.g., manufacturing execution systems, electronic batch records, etc.) that control the facility and process elements.

	The enterprise can be summarized as “the process operating inside the facility under the control of the infrastructure” (4,5). 

	The conventional approach to building and operating manufacturing facilities is to design the facility and infrastructure elements around the process’s equipment and operating requirements. If the process UOs are implemented in large, fixed stainless-steel (SS) equipment, the process must be integrated into the facility by hard-piped systems. The infrastructure is then planned and assembled specifically to control the integrated process LOUs within the facility, thus creating a unique manufacturing enterprise. In most cases, these one-of-a-kind facilities required extensive regulatory inspection and oversight for approval. Continued evolution of process formats and product technologies makes replicating these enterprises to achieve standard facility designs and infrastructures for new products nearly impossible.

	The fundamental goal of the MPF is to separate the process format and scale from the facility and infrastructure elements. Recent advances in process technologies, including movable single-use system (SUS) equipment, combined with significant increases in process productivity from intensification, provide options for decoupling the process UOs and their equipment from the facility and infrastructure (6). The resulting decrease in the size of the process equipment and the availability of movable SUS/SS systems both reduces the size of the facility and increases the flexibility of locating and relocating equipment within the facility’s layout.  

	One of the most important functions of the facility and infrastructure elements is to control inter-operational risks between products and processes. The presence and severity of these risks can be described by a system risk structure (SRS) (7). The SRS is basically a process flow diagram (PFD) separated by control points between all the process UOs and LOUs connected and operated for material transfer or co-located in the same operating space for the same or a different product. The SRS describes the flow of threats between the UOs for each LOU defined by the PFDs. 

	An example would be co-located bioreactors. Every operating step (setup, media loading, inoculation, operation, harvest, or clean-up, etc.) is a threat to all the other bioreactors as well as any other UOs within the same operating space. Every interaction threat could produce a risk consequence that must be either accepted based on the existing control strategies or mitigated by an improved control strategy. All the interactions between the UOs, including the bioreactors, must be controlled, including proof of control, in the form of a documented release at a control point for each step in every batch. Depending on the extent of commingling, particularly those seen in large operating spaces (i.e., ballrooms), the threat/risk interactions can require extensive procedural and scheduling control systems that may limit and interfere with operating the processes. The larger the number of UOs in an operating space, the more complex and interactive the infrastructure systems must be to assure and prove control. The MPF uses facility-based segregation to minimize the required infrastructure control systems for controlling interaction risks while maximizing the process’s operating timing options and flexibility.  

	FDA’s goals (1) are achieved by both the MPF’s flexibility and risk reduction associated with separating the manufacturing process’s scale, implementation, and capacity requirements from the facility’s layout and operating control systems. This approach also allows standardization of the facility’s controls system for manufacturing many different products over their development and launch lifecycle.  

	The facility and its control systems for each product can be evolved and perfected over the development lifecycle into a high-quality infrastructure necessary for reducing regulatory oversight requirements. Once inspected and used to establish a track record of high-quality manufacturing, an MPF can become a known and trusted facility to regulatory agencies. The MPF’s ability to execute a product’s lifecycle manufacturing requirements allows for product development, clinical, and commercial manufacturing to be efficiently accomplished in a fully integrated operating environment that can reliably develop and launch a wide range of new, high-quality products.  

The MPF is capable of quickly adapting to a wide variety of different operating scales, capacity requirements, and process formats, including the next generation of intensified continuous processes, without modifying the facility’s layout or infrastructure’s control systems.  

Because the MPF can be used over the entire product development lifecycle by a proven facility and infrastructure, the manufacturing process and procedures can evolve using expanded lifecycle process validation; working-quality by design (w-QbD); and ICH Q8-based, well-structured design space methods (8). Tech transfer is essentially eliminated because of the continuity of operating methods and personnel within the integrated MPF environment. 

 Because the facility can be used for many different processes and products without modifying either the facility or infrastructure, regulatory agencies can establish a level of earned trust with the MPF manufacturing enterprise for new products and processes based on successful high-quality performance of previous production campaigns.  

	The multi-product manufacturing facility provides a method of solving many difficult manufacturing challenges, including supporting “a maximally efficient, agile, flexible pharmaceutical manufacturing sector that reliably produces high-quality drugs without extensive regulatory oversight” (1).

www.pharmtech.com/multi-purpose-biopharmaceutical-manufacturing-facilities-part-1-product-pipeline-manufacturing

www.pharmtech.com/multi-purpose-biopharmaceutical-manufacturing-facilities-part-ii-large-scale-production

	5.   M. F. Witcher, “Introduction to Biomanufacturing,” in 

Process Architecture in Biomanufacturing Facility Design

, edited by J. Odum and M. C. Flickinger (John Wiley & Sons, Inc., 2018).

	6.   J. Odum and M. F. Witcher, “Technology’s Impact on the Biomanufacturing Facility of the Future” in 

FDA’s 21st Century goals can be realized by using a multi-purpose manufacturing facility with a flexible design that provides reliable production without extensive regulatory oversight.

How FDA’s 21st Century Goals Can Be Realized by Using a Multi-Purpose Manufacturing Facility

The biopharmaceutical industry must begin designing and building a new generation of highly capable, multi-purpose manufacturing facilities to meet the commercial manufacturing challenges of supplying the next generation of small- and large-volume products, particularly those with short commercial lifespans. Biopharmaceutical manufacturing is challenged by the uncertainty risk of anticipating and establishing the commercial capacity to supply products, including those rapidly approved using an Emergency Use Authorization (EUA) to meet pandemic and bioterrorist threats (1). As described in Part I of this article (2), the manufacturing uncertainty and risk is significantly amplified by therapies following FDA’s guidance on 

Expedited Programs for Serious Conditions

 (3). To support the adequate supply of breakthrough designated therapies, the biopharmaceutical industry can no longer afford to design and build manufacturing capacity based on each product’s process format and scale or in response to changing manufacturing capacity requirements.  

	Dealing with manufacturing’s frequent presence on the critical path has led to many initiatives attempting to speed up the creation of manufacturing capacity. These efforts, however, have had minimal impact on the overall time required to plan, design, build, start-up, and validate new manufacturing capacity. Without a significant change in the approach, the availability of commercial manufacturing capacity will remain an expensive, time-consuming obstacle to launching and then supplying new products. The industry must have existing, pre-positioned, highly flexible manufacturing resources capable of manufacturing a wide variety of processes at scales necessary to supply products when they are approved. 

	Current trends in designing commercial biopharmaceutical manufacturing facilities are for large operating cleanrooms designed around specific processes where unit operations are commingled for operational convenience.  While optimum for the processes for which they are designed, they are relatively inflexible and inefficient for meeting the challenges described earlier in this article for other process configurations. Once constructed, these facilities do not provide the adaptability required for efficiently changing process scales, unit operation sequences, or segregation strategies without modifications to the facility’s layout that may significantly impact ongoing manufacturing of other products. 

	Rather than commingling many process steps, an approach that distributes the different process unit operations (UOs) into logically operating units (LOUs), as described in Part I, can provide the process and capacity flexibility necessary to quickly adapt an existing layout to the inevitable changes in product demand. Products and processes will come and go, but a multi-purpose facility remains a manufacturing asset capable of manufacturing nearly any future product at the required scale using any process developed in moveable, single-use system (SUS) equipment. 

	Using the example 11-UO, four-LOU monoclonal antibody (mAb) process defined in Part I, this article briefly describes the layout, flows, and operational control systems for commercial-scale, multi-purpose facilities. The approach uses large numbers of segregated, multi-functional cleanrooms that can be rapidly adapted, configured, integrated, operated, and when necessary, redeployed to quickly satisfy a wide variety of complex manufacturing requirements. The multi-functional layout trades some of operating convenience provided by a facility designed around a specific process for the much more important, long-term advantages of a facility that can be configured and reconfigured to a wide variety of different processes and scales necessary for increasing or decreasing operating capacity. 

operating core described in Part I (2) composed of 18 cleanroom operating areas arranged in three arms (A, B, C) with each arm containing six cleanrooms. Depending on the number of potential commercial products and their estimated manufacturing requirements, the facility’s initial capabilities can be increased substantially by increasing the number of arms and possibly increasing the number of cleanrooms per arm in the initial facility design. Additional arms can be added to 

at the top of the layout, either in the original buildout or as a follow-on expansion as Arms D and E, and if needed as Arms F and G, etc. The additional arms are supplied, operated, and controlled using the same systems and facility infrastructure as the initial design in 

	For introducing a new process, equipment is staged in the equipment preparation area located in the lower right of the layout shown in 

and moved through the primary corridors to the designated operating area. Equipment no longer needed is removed to the layout’s right via

the out corridors and then through a de-staging area. Raw materials and components are supplied to the operating areas by totes and carts via

the primary corridor. Transfer of in-process materials in small volumes is achieved using totes via

the primary corridor. For large-scale processes, a variety of options for in-process material movement are available. If the appropriate LOU adjacencies are provided, material can be transferred through walls, particularly in operating room pairs in the center of the arms. For non-adjacent LOUs and large volumes, such as for harvesting 2000-L single-use bioreactors (SUBs) to a non-adjacent area, stainless-steel tubing (with a portable clean-in-place [CIP] system) on the utility floor above the operating areas can be used to transfer the conditioned media from the SUBs to the harvest UOs. Under normal operation, personnel movement is controlled using bidirectional flow 

the primary corridor. Operating problems can be quickly and efficiently remediated using procedural controlled access to the out corridor. Waste material, used components, and equipment are removed using unidirectional flow via

the out corridor. A utility floor above the operating core contains the heating, ventilation, and air-conditioning systems, utility access (including water for injection, air, etc.), and access to operating areas for easily adding inter-room, stainless-steel tubing for transferring large volumes of media, buffers, and in-process materials. 

	The flexibility, high activity level, and complex material and personnel movement of the multi-purpose facility, especially for intensified commercial manufacturing, requires a comprehensive control strategy that assures appropriate control of all aspects of the facility, material, and process unit operations. While the layout provides significant opportunities for physical separation, appropriate procedures supported by a manufacturing execution system (MES) for controlling all people, raw material, waste, product, and in-process material flows in time and space must be fully implemented. Such procedural controls and automated support systems are well within currently available technologies and can be readily developed and implemented. 

and the process LOU strategy described in Part I (2), the capabilities of the multi-purpose layout for large-scale commercial manufacturing can be demonstrated. 

	Phase III: Launch to commercial manufacturing

is identical to the facility described in Part I for running small- and medium-scale processes for supplying product for preclinical (250-L SUB) through product launch (2000-L SUB). To demonstrate the wide variety of options for larger-scale operation, the process LOU distributions in 

	The 2000-L SUB launch process might be used for supplying late-stage Phase III clinical trials, inventory building, and product launch at the time of approval. If product demand is high, the process can be scaled out to multiple 2000-L SUBs or twinned 2000-L SUBs. If the process is properly designed and intensified using a high density and a large-volume seed train, the 2000-L SUBs can be paired and multiple SUB pairs sequentially harvested to a suitably intensified single downstream process. The flexibility of the multi-purpose facility also allows for significant media and buffer resources (support LOUs) to be added for supplying media for many large-scale seed and production SUBs along with intensified downstream processes requiring very large volumes of buffers. 

shows one possible high-capacity, commercial-scale configuration. To show an extreme scenario, the LOU distribution for a high-capacity commercial process is shown as the final process in 

. This process operates three pairs of 2000-L SUBs (located in areas B3, B4, and C3) for an effective bioreactor volume of 12000 L. The pairs are operated on a two-day staggered schedule, such that one pair of SUBs is harvested every other day to a single downstream train located in Areas C4â6. The downstream train, if intensified using large multi-cycle chromatography systems, can support three, 2 x 2000-L harvests per week. As shown in 

, three support LOUs (one media in C2 and two buffer preparation and hold located in B5 and B6) have been added to support the commercial process. Media, buffers, and large volume in-process materials are transferred by CIP-able stainless-steel tubing runs located on the utility floor above the core in addition to the movement of the other in-process materials by totes and inter-area connections via single use tubing between UOs and LOUs in adjacent rooms. Even while running a commercial-scale process, Areas A3 thru A6 are available for operating a small-scale process or a second purification train, if needed.

	If operated at capacity, the facility shown in 

would have a very high utilization rate and an annual capacity of approximately 1.5 Mtons/year (6 grams/L, 42+weeks/year, 50% purification yield). Yet, if the campaign is shortened or the process removed, the same facility without modification can be returned to running small- or medium-sized processes for other products. 

	If Arms B and C are replicated either in the initial design or by an expansion at the top of 

 as Arms D and E, the plant’s capacity can be further increased by an additional 1.5 Mtons/year. Very large-scale production of one or more products can be achieved by building multi-purpose facilities with numerous arms configured like Arms B and C. If sustained long term demand for the product is established, the large-scale process in Arms B and C can be easily transferred to a similarly designed multi-purpose facility for long-term operation and the launch facility returned to developing new processes and products. 

	Regulatory agencies continue to do much to expedite the approval of important new therapies. The biopharmaceutical industry must match these regulatory initiatives by creating a new class of manufacturing facilities capable of taking manufacturing off the critical path of launching and supplying products. Manufacturing these complex products over their entire lifecycle requires immediate access to available and qualified manufacturing facilities that can be adapted to produce a wide variety of products when they are needed using a wide range of processes. These facilities, using modern single-use systems in movable equipment within appropriately controlled multi-functional cleanrooms, are capable of quickly adapting to overcome the industry’s manufacturing challenges. Processes and products will come and go, but the facility that can readily adapt to the different processes remains essentially the same. Only existing, operationally ready facilities flexible enough to manufacture whatever is required with minimal or no modifications can rapidly and efficiently fulfill the industry’s future manufacturing challenges. 

	1. S.L. Nightinggale, J.M. Prasher, and S. Simonson, 

online, 13(7) 1046. DOI: 10.3201/eid1307.061188

Guidance for Industry:  Expedited Programs for Serious Conditions-Drugs and Biologics (Procedural) 


	Vol. 42, No. 11
	November 2018
	Pages: 42–45

	When referring to this article, please cite it as M. Witcher and H. Silver, "Multi-Purpose Biopharmaceutical Manufacturing Facilities Part II:  Large-Scale Production," 

	Mark F. Witcher, PhD is a consultant, witchermf@aol.com; and Harry Silver is senior process/facility designer at Harry Silver Designs.

A matrix of multi-functional cleanrooms can be adapted for launching products.

Multi-Purpose Biopharmaceutical Manufacturing Facilities Part II:  Large-Scale Production

The biopharmaceutical industry can no longer afford to design and build manufacturing capacity as a major part of the critical path for launching and supplying products by waiting to define the process and capacity requirements before making the decision to develop or build commercial manufacturing capacity. This two-part article describes how a facility layout composed of multi-functional cleanrooms can be used to both develop and launch new products from a pipeline (Part I) as well as support large-scale commercial manufacturing (Part II) (1). The layout strategy leverages moveable equipment using single-use component technologies to provide agile flexibility. The approach uses large numbers of segregated, multi-functional cleanrooms that can be quickly adapted, configured, integrated, operated, and redeployed as necessary to satisfy a wide variety of complex manufacturing requirements. 

	A product’s manufacturing capacity, from clinical testing through early commercial supply, can grow and contract for many reasons that are difficult to predict. Many initiatives have attempted to speed up the creation of manufacturing capacity to satisfy specific production requirements. These efforts, however, have had minimal impact on the overall time required to plan, design, build, start-up, and validate new manufacturing capacity. Without a significant change in the approach, access to manufacturing capacity will remain an expensive, time-consuming obstacle to launching and supplying new products. 

	Biopharmaceutical manufacturing’s challenges can be summarized as:

Accurately predicting capacity requirements for biopharmaceuticals, particularly those associated with changing patient requirements and market penetration over the product’s lifecycle from clinical testing to inventory building and long-term market supply, is almost impossible. 

: Continuing process evolution will result in significantly smaller, more efficient processes that will stimulate both internal and competitive biosimilar products for reducing product costs and increasing capacity. These process advances include continuous manufacturing in the form of perfusion and highly concentrated fed batch bioreactors, high cycle rate, and simulated moving bed chromatography, etc. Systems biology and specialized synthetic, purpose-built cell lines may also result in significant process changes in the future that require greater flexibility for running and adapting to new process scales, strategies, and configurations.

By using the same facility and dedicated critical personnel, tech transfer can be minimized, if not eliminated, thus increasing the likelihood of consistently high-quality products and lifecycle comparability. Such an approach is especially important for products that must be immediately approved using an Emergency Use Authorization (EUA) to remediate pandemic and bioterrorism threats (2). 

The industry’s need for more efficient and flexible manufacturing capacity is significantly impacted by FDA’s guidance, 

Expedited Programs for Serious Conditions–Drugs & Biologics

, which uses surrogate and intermediate therapeutic endpoints to accelerate the approval of breakthrough products (3). The guidance impacts manufacturing in the following ways:

		Places clinical manufacturing capacity on or near the product’s development critical path by significantly increasing the rate products can be developed, clinically tested, approved, and launched.

		Increases the urgency and risks of planning commercial manufacturing capacity by stating: “When sponsor receives an expedited drug development designation, they should be prepared to propose a commercial manufacturing program that will ensure availability of quality product at the time of approval” (3).

		Increases business risks because the products are approved based on intermediate endpoints. If long-term safety or efficacy concerns occur during post-marketing confirmatory monitoring, the product may be withdrawn or sales significantly restricted. 

	The next generation of biopharmaceutical facilities must go beyond multiproduct to true multi-purpose capabilities. By facilitating the rapid scale up and, if necessary, scale-out of a process, the multi-purpose facility can be used for clinical testing, product launch, inventory building, and long-term commercial supply. Such flexibility requires facilities designed to be easily adapted to the changing manufacturing needs of a product’s process without facility modifications. These facilities must also be adaptable to many different types of processes as well as able to quickly add or remove support services, such as media and buffer preparation, based on the needs of the processes. 

	This article describes a new type of highly flexible, multi-purpose manufacturing facility layout using a matrix of multi-functional operating rooms that can be adapted and used to operate a wide variety of different processes at different scales without changes to the layout. Processes could even include final filling of small-volume or time-sensitive cellular products using movable, self-contained work-cell isolator systems with ready-to-use components. Most importantly, processes can be added, modified, or removed without impacting ongoing operation of other processes currently in the facility. 

shows a basic layout of three arms (A, B, C) divided into six non-dedicated cleanrooms (1 thru 6) per arm. The size of the 18-cleanroom operating core is approximately 23,500 ft

. Depending on the projected size of the pipeline and its estimated manufacturing requirements, the facility’s initial capabilities can be increased or decreased by changing the number of arms or the number of cleanrooms per arm during the design. Each process placed into the facility shown in 

uses only enough cleanrooms to operate the process. The remaining areas are available for other products or process activities. 

	The cleanrooms are connected by interlocking primary and out corridors supporting both bi- and uni-directional flows of equipment, material, and personnel. The layout is a mixture of Grade C and D areas with some adjacent rooms having removable walls to support larger equipment and material space requirements. 

	For introducing a new process, equipment is staged in the equipment preparation area located in the lower right of 

and moved through the primary corridors to the selected operating area. For small-scale processes, raw materials and components are supplied to the operating areas by totes and carts via the primary corridor. Transfer of in-process materials is achieved using totes via the primary corridor. Under normal conditions, personnel movement is controlled using bidirectional flow via the primary corridor. Waste material, used components, and equipment are removed using unidirectional flow via the out corridor. A utility floor above the operating core contains the heating, ventilation, and air-conditioning systems, utility access (including water for injection, air, etc.) as well as closed, stainless-steel piping inter-area connections, if needed. 

	The facility’s flexibility comes from each of the 18 multi-functional cleanroom’s ability to accommodate nearly any of the various process or support elements required to operate a process. Because of the separation provided by the many multi-functional areas, the process can be placed within the layout in a wide variety of configurations based on available adjacencies and product priorities. Recent developments in single-use systems (SUS) make it easy to move and setup the process equipment in the assigned cleanrooms, operate them, and then remove or relocate the equipment when the product’s campaign is complete. 

	The following example process demonstrates how a variety of manufacturing processes can be organized and controlled for insertion, operation, rearrangement, or removal from the layout. The example process represents a wide variety of possible processes for manufacturing proteins, nucleic acids, cells, or vaccines. 

is a typical monoclonal antibody (mAb) process composed of 11 unit operations (UOs) divided into four logical operating units (LOUs). LOUs are groups of UOs that can or should be operated together for operational convenience or inter-UO connectivity. All process UOs for manufacturing any product can be grouped into LOUs. The LOUs are then appropriately located within the layout depending on available inter-LOU connectivity options and various risk factors associated with each process step, equipment sizes, and various operational considerations such as pre- and post-viral removal steps. 

	To demonstrate the facility’s flexibility, the example process is operated at scales ranging from 250 L to 2000 L single-use bioreactors (SUBs). In addition, the facility is adapted to support different operating rates and campaign lengths by adding the necessary support resources. The flexibility and adaptability of the multi-functional areas allows for support resources to be added and removed as necessary to meet product development priorities and optimize the overall facility’s utilization rate. This ability is particularly important for intensified processes that require large amounts of media and buffers. 

	A possible portfolio of process scales, which also represents a likely scale-up sequence for developing a new mAb product, is shown in 

	A true multi-purpose facility should be able to run many small Phase I processes, several medium-size Phase II processes, and a larger-scale Phase III process when needed. To demonstrate full functionality of the multi-purpose facility concept, a high volume, commercial-scale process is described in Part II of this article (2). 

	One possible process arrangement of the three processes in 

. The placement of the LOUs within the facility is likely based on the availability of areas as they are cleared by the removal of previous processes. Although the LOUs for the 500-L SUB, Phase II process appears disjointed, raw materials and in-process materials for short clinical manufacturing campaigns can be easily transferred via the BâC primary corridor. For long or intense campaigns, the process can be rearranged within the facility as operating areas become available to provide more convenient adjacencies for inter-LOU transfer of in-process materials. If the 250-L process in Arm A is removed, the 500-L process can be moved to Arm A to provide more efficient room adjacencies. 

	The 2000-L SUB Phase III/Launch process is shown in Arms B and C along with the 500-L SUB Phase II process. The Phase III/Launch process is initiated in Area B1 and proceeds through upstream operation in Areas C2 and B3, then to the downstream areas in C4 thru C6. In-process materials can be transferred directly through appropriate adjacencies or totes via the BâC primary corridor. For longer, more intense campaigns, in-process material can be transferred via stainless-steel tubing from Areas B3 (SUB-N) to C4 (Harvest). Other UO/LOU combinations are possible depending on area availability, inâprocess volumes, and equipment requirements. In Part II of this article, the same layout will be used to operate a larger-scale process necessary to supply commercial markets. 

	The biopharmaceutical industry’s greatest contribution to patients is to rapidly and efficiently develop and quickly supply new, high-quality biopharmaceuticals. Regulatory agencies continue to do much to expedite the approval of important new therapies. The biopharmaceutical industry must complement these regulatory initiatives by creating a new class of manufacturing facilities capable of taking clinical and launch manufacturing off the critical path of bringing new products to patients. Manufacturing these complex products through the development lifecycle requires immediately available and qualified manufacturing facilities that can handle a wide range of processes. These facilities, using modern single-use systems in moveable equipment within appropriately controlled multi-functional cleanrooms, are capable of quickly adapting and accomplishing the required manufacturing challenges. While processes and products will come and go, a flexible multi-purpose facility that can be readily adapted to different processes will essentially remain the same. Only existing, operationally ready facilities flexible enough to manufacture whatever is required with minimal or no modifications can efficiently fulfill the industry’s future product development challenges. 

	1. M.F. Witcher and H. Silver; “Multi-product Biopharmaceutical Manufacturing Facilities–Part II:  Large-Scale Production,” PharmTech.com, Sept. 2, 2018. 

	2. S.L. Nightinggale, J.M. Prasher, and S. Simonson, 

Guidance for Industry:  Expedited Programs for Serious Conditions-Drugs and Biologics (Procedural)

	When referring to this article, please cite it as M. Witcher and H. Silver, "Multi-Purpose Biopharmaceutical Manufacturing Facilities Part 1:  Product Pipeline Manufacturing," 

		Mark F. Witcher, PhD is a consultant, witchermf@aol.com; and Harry Silver is senior process/facility designer at Harry Silver Designs.

A multi-purpose biopharmaceutical manufacturing facility using a matrix of multi-functional cleanrooms can be adapted to efficiently meet the capacity challenges of both supplying clinical trials and launching products.

Multi-Purpose Biopharmaceutical Manufacturing Facilities Part 1:  Product Pipeline Manufacturing

	The biopharmaceutical industry must begin designing and building a new generation of highly capable, multi-purpose manufacturing facilities to meet the commercial manufacturing challenges of supplying the next generation of small- and large-volume products, particularly those with short commercial lifespans. Biopharmaceutical manufacturing is challenged by the uncertainty risk of anticipating and establishing the commercial capacity to supply products, including those rapidly approved using an Emergency Use Authorization (EUA) to meet pandemic and bioterrorist threats (1). As described in Part I of this article (2), the manufacturing uncertainty and risk is significantly amplified by therapies following FDA’s guidance on 

	Rather than commingling many process steps, an approach that distributes the different process unit operations (UOs) into logically operating units (LOUs), as described in Part I, can provide the process and capacity flexibility necessary to quickly adapt an existing layout to the inevitable changes in product demand. Products and processes will come and go, but a multiâpurpose facility remains a manufacturing asset capable of manufacturing nearly any future product at the required scale using any process developed in moveable, single-use system (SUS) equipment. 

	Using the example 11-UO, four-LOU monoclonal antibody (mAb) process defined in Part I, this article briefly describes the layout, flows, and operational control systems for commercial-scale, multiâpurpose facilities. The approach uses large numbers of segregated, multiâfunctional cleanrooms that can be rapidly adapted, configured, integrated, operated, and when necessary, redeployed to quickly satisfy a wide variety of complex manufacturing requirements. The multi-functional layout trades some of operating convenience provided by a facility designed around a specific process for the much more important, long-term advantages of a facility that can be configured and reconfigured to a wide variety of different processes and scales necessary for increasing or decreasing operating capacity. 

the primary corridor. For large-scale processes, a variety of options for in-process material movement are available. If the appropriate LOU adjacencies are provided, material can be transferred through walls, particularly in operating room pairs in the center of the arms. For non-adjacent LOUs and large volumes, such as for harvesting 2000-L single-use bioreactors (SUBs) to a non-adjacent area, stainless-steel tubing (with a portable clean-in-place system) on the utility floor above the operating areas can be used to transfer the conditioned media from the SUBs to the harvest UOs. Under normal operation, personnel movement is controlled using bidirectional flow 

, three support LOUs (one media in C2 and two buffer preparation and hold located in B5 and B6) have been added to support the commercial process. Media, buffers, and large volume in-process materials are transferred by CIP-able stainless-steel tubing runs located on the utility floor above the core in addition to the movement of the other in-process materials by totes and inter-area connections via single use tubing between UOs and LOUs in adjacent rooms. Even while running a commercial scale process, Areas A3 thru A6 are available for operating a smallâscale process or a second purification train, if needed.

	If Arms B & C are replicated either in the initial design or by an expansion at the top of Figure 3 as Arms D & E, the plant’s capacity can be further increased by an additional 1.5 Mtons/year. Very large-scale production of one or more products can be achieved by building multiâpurpose facilities with numerous arms configured like Arms B and C. If sustained long term demand for the product is established, the large-scale process in Arms B and C can be easily transferred to a similarly designed multi-purpose facility for long-term operation and the launch facility returned to developing new processes and products. 

Multi-product Biopharmaceutical Manufacturing Facilities-Part I:  Product Pipeline Manufacturing