David M. Marks

	Facility modernization can be a complex and difficult process even under the best of circumstances, but when one factors in the global regulatory hurdles in pharmaceutical manufacturing, the challenges are significantly greater. However, the reality of aging facilities that must be maintained in a state that is reliable, efficient, and compliant with current good manufacturing practice cannot be avoided. Successful implementation of change must be executed with a good understanding of the challenges associated with introducing new technology and an execution strategy that proactively achieves strategic outcomes.

	Obstacles to new technology implementation

	In an industry-wide survey of the lifesciences sector conducted by DME in partnership with INTERPHEX, DME Facility Focus (1), industry insiders-those in engineering and operations roles-were asked what they believed was the biggest obstacle to the adoption of new technologies for facility modernization.  As shown in 

, the majority (62% of respondents) indicated that regulatory challenges (process validation or regulatory acceptance) were their biggest concerns. The remaining survey participants cited the biggest obstacle as process development requirements (18%), lack of industry standards (12%), and insecure vendor supply chain (5%).  Those with “other” responses (4%) most frequently indicated their belief that general industry conservatism is the biggest obstacle.
	
	

This finding is consistent with a recent survey by the Parenteral Drug Association (PDA), which reportedly suggested, among other things, “that product-related post-approval changes (PACs), and the time and investment that they require, are stifling conversion to new technologies or methods” (2). In response, PDA established a task force (PAC iAM) to seek comprehensive post-approval change reform, focusing on the global regulatory challenges. As group members noted in an op-ed published in the August 2016 edition of 

, these challenges “create a disincentive-albeit unintentional-for manufacturers to integrate growing product and process knowledge, continually improve, or innovate technologies” (3).  In their public call to action, the taskforce went on to link the current post-approval change environment to drug shortages and deferred process improvement, writing, “In order to avoid the burden of implementing changes in such a complex environment, many [manufacturers] find it easier to postpone improvements to facilities, processes, and analytics, or simply refrain from planning advancements at all.”

	While PDA focuses on systemic change through a global forum and their regulatory harmonization efforts, manufacturers still need to deal with aging facilities in the here and now. The DME Facility Focus survey provided further insights into how manufacturers are coping with these challenges.

	When asked what new technologies they have introduced as part of a facility modernization project, ranked from most common to least common technology, participants responded as follows:

, these trends generally held true even when broken down by industry cohort.  The lone exception is single-use technology, which is far more commonly implemented in biologics manufacturing than chemical synthesis.
	The most common technologies implemented likely correspond to post-approval changes that yield the greatest advantage and are easiest to implement. There is a strong case to be made that the most frequent type of change, process automation upgrades, will improve product quality, particularly when the operations being automated were originally manual. In many instances, it’s relatively easy to demonstrate that process automation changes will not adversely affect the manufacturing process. In addition, the DME survey found that aging automation drives 11% of equipment obsolescence issues in legacy equipment (1). Automation can also be a key component in the corrective action addressing manufacturing deviations.  
	The second most common technology, single-use, has garnered a lot of attention in recent years as manufacturers explore the potential for bioprocessing with a completely disposable wetted path.  Such facilities could potentially do away with expensive utility systems associated with cleaning, and they promise less reliance on cleanroom environments for process segregation. These initiatives, however, require a purpose-built facility and a significant commitment to process development within the single-use framework and are, therefore, more useful as a platform for new products in the pipeline. The prevalence of single-use technology in facility modernization projects is most likely limited to the replacement of specific unit operations and procedures within traditional facilities with predominately stainless-steel equipment. The replacement of a sampling system on a stainless-steel process vessel with a disposable sample assembly is a good example of the kind of process change that can yield a significant improvement with a reasonable post-approval change effort. Similarly, manufacturers have adopted single-use bag systems for supporting operations such as buffer preparation and hold vessels without disrupting the primary unit operations that are processing product.

The survey findings suggest that manufacturers choose to selectively introduce new technology in aging facilities where the potential benefits significantly outweigh the pain points (e.g., total cost and risk due to many aspects of implementing a change). In legacy facilities, a new technology is strategically adopted in areas that yield the greatest benefit and where it is relatively easy to demonstrate that the change will not adversely affect product quality.

	Considering the PAC iAM task group’s conclusion that the complexity of post-approval changes discourages facility improvements, it is instructive to examine the most common drivers for the introduction of new technology within legacy pharmaceutical facilities. When asked to rank the frequency of risk-based drivers for GMP facility renovations, respondents clearly identified product quality and regulatory compliance as dominant concerns. The survey also found that internal assessments of facility and equipment compliance are most frequently triggered by manufacturing deviations (58%) (1). These responses suggest that a reactive approach to modernization is typical in the pharmaceutical industry. The ensuing corrective action and preventive action (CAPA) process after manufacturing deviations requires the implementation of corrective action, which presumably mandates facility improvements in some circumstances. CAPA is clearly the worst possible driver for facility improvement because changes are forced irrespective of the disruption to scheduled manufacturing, and a failure to follow through in a timely manner can result in regulatory action.

	The second most common driver for GMP assessments is opportunistic (55%), executed as part of planning for a GMP renovation driven by other factors, which suggests a path forward to a more proactive approach to facility improvements. Given the high pain threshold required to implement post-approval changes, there are many factors that must accumulate before improvements can be justified. These include both risk-based factors (e.g., compliance, safety, obsolescence, reliability) and opportunity-based factors (e.g., new products, increasing throughput, improved flexibility, reduced costs, better sustainability). When product quality and patient safety are at stake, manufacturers are required to take action immediately. But manufacturers can introduce new technology in a more controlled and comprehensive way if they piggyback risk-reduction and GMP improvements on projects that are primarily driven by opportunity-based factors.  

		DME Facility Focus Survey, www.dmeforlife.com/about-us/facility-focus (2016).	

Pharm. Tech., Quality Throughout the Supply Chain

		“PDA Program to Address Post-Approval Hurdles,” 

, August 24, 2016, pda.org, www.pda.org/pda-letter-portal/archives/full-article/pda-program-to-address-post-approval-hurdles.

	David M. Marks, P.E. is the president of DME, an engineering design and consulting firm that specializes in solutions for advanced technology facilities in the life-sciences industry, www.DMEforLife.com. 

	DME will be presenting the results of this year’s survey and hosting a panel discussion on 

cGMP Facility Modernization: New Solutions for Aging Facilities 

Articles

The DME Facility Focus survey revealed best practices for coping with the challenges of aging facilities and implementing facility modernization.

GMP Facility Modernization: Opportunities for Successful Implementation

Facility modernization can be a complex and difficult process even under the best of circumstances, but when one factors in the global regulatory hurdles in pharmaceutical manufacturing, the challenges are significantly greater. However, the reality of aging facilities that must be maintained in a state that is reliable, efficient, and compliant with current good manufacturing practice cannot be avoided. Successful implementation of change must be executed with a good understanding of the challenges associated with introducing new technology and an execution strategy that proactively achieves strategic outcomes.

:
	When referring to this article, please cite it as D. Marks, "GMP Facility Modernization: Opportunities for Successful Implementation," 


	David M. Marks, P.E. is the president of DME, an engineering design and consulting firm that specializes in solutions for advanced technology facilities in the life-sciences industry, www.DMEforLife.com.