Pall
     A single-use system provides flexible automation for biopharmaceutical manufacturing.

I Holland
   Tablet-tooling coating improves punch and die performance

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November 2013 Editor's Picks: Products from Pall and I Holland

Life-sciences companies face more pressure than ever to reduce costs and increase efficiency. In response, many companies have embarked on operational excellence programs. When these programs are carefully planned and executed, they can significantly improve how companies work by reducing waste, streamlining processes, increasing productivity, and assuring an uninterrupted supply of products to customers. In addition to increased efficiency and cost reduction, there is a third leg to the stool: quality and compliance benefits. With carefully designed, executed, and sustainable operational excellence programs—and with improved quality and compliance targeted as one of the goals from the outset—companies can ensure they reap the full benefits of operational excellence.

 Operational excellence programs may be narrowly focused on specific processes and functions or broader in scope to encompass an entire site or multiple sites. Consider a vaccine manufacturer that faced recurring compliance problems in two key manufacturing operations. To address the problems, the organization undertook an operational excellence initiative focused on reducing human-error-caused deviations and increasing right-first-time performance in batch records. The ultimate goal was not simply to make the processes compliant, but to create sustainable improvement by training all stakeholders, not just a targeted few; increasing collaboration and partnership between operations and quality; and creating a continuing quality assurance (QA) presence on the shop floor. The absence of a QA presence coupled with the perception by shop floor personnel that QA auditors were adversaries who simply policed production were principal underlying causes of the compliance problems faced by the company. Through an extensive coaching and mentoring effort, QA personnel came to see themselves not solely as auditors (which they have to be), but as partners with the operations staff, there to help assure quality and compliance, but also to help address issues and provide guidance to help up-skill shop floor personnel in their understanding and performance of cGMP/compliance.

To tackle human-error-caused deviations, the deviation management process was redesigned to bring it into line with current FDA expectations and industry best practices, and to assure that the people closest to the observation of issues were involved in the process. Instead of handing off deviation management to another department, as was done previously, the operations group took over responsibility for managing alerts and deviations in real time on the shop floor while the trail was still warm. Deviations could then be investigated in a matter of hours-not weeks-and closed faster in a scientifically sound and compliant manner. Deviation reports were made the responsibility of a single investigator with specific analytical and investigation reporting skills. The reports were then designed to connect the event and its root cause to the corrective and preventive action, helping make recurring deviations rare.

 In a parallel effort, batch records were simplified and optimized, as were a number of critical standard operating procedures, which were so difficult to follow that they each generated errors, deviations, and waste. Working together, the quality and operations groups were then able to dramatically improve the rate of right-first-time documentation. The quality function created new roles designed to partner with operations and deliver quality and compliance in real time, in-process, on the shop floor. A quality coordinator was assigned to the area with sole responsibility for compliance. Compliance specialists were created to rotate through the operations area and to spend 80% of their time on the shop floor to provide real-time, in-process batch record documentation review and mentor operations personnel on compliance issues and decision-making when deviations occurred.

, PhD, is a managing consultant at Tunnell Consulting, and 

Operational Excellence: More Than Just Process Improvement

," published in the October 2013 issue of 

Troubleshooting

An operational-excellence initiative increased collaboration between operations and quality personnel to address human-error-caused deviations.

Operational Excellence Improves Quality and Compliance

Change is coming to the way biopharmaceutical products are manufactured, said industry thought leaders at the ISPE national meeting in Washington, DC in November 2013. Although how quickly change will occur is uncertain, the manufacturing paradigm is shifting from large, single-product facilities to smaller-scale, flexible, multiproduct facilities that may even be moved to different locations as the need arises. New facility designs that enable flexible, multiproduct production include single-use technologies, the use of controlled nonclassified (CNC) spaces with closed systems, modularization, and continuous processing.

Single-use systems face hurdles, such as a conservative industry mindset and existing investments in stainless-steel facilities, but some companies are moving ahead with increasingly complex systems, such as single-use bioreactors and other single-use unit operations, said Joshua Hays, associate director for upstream sales development at EMD Millipore, in a presentation. Single-use components are an enabling technology for smaller-scale production of biopharmaceuticals as well as cell therapies, such as stem cells, which would otherwise be much more difficult to produce. Because revalidation is costly, the majority of single-use systems are being employed for new products, and many companies choose hybrid facilities with both stainless-steel and single-use components. Hays predicted a big move to single-use components, estimating that as much change would occur in the next three to five years as it has in the past 15 years.  

CNC multiproduct ballroom facilities, which have most unit operations in one room, are not monitored to a specific environmental classification, but are GMP facilities that must use demonstrably closed systems and have other appropriate controls (e.g., quality systems), noted Paul Smock, senior director of quality assurance at AstraZeneca's MedImmune, speaking as a member of the Area Classification team of the Biophorum Operations Group, which is a collaborative community of biopharmaceutical industry experts who meet to establish best practices. Other important considerations for a successful multiproduct manufacturing facility, said Smock, are understanding the process, using advanced controls and testing, and having a flexible organization with good communication.

Modular manufacturing designs, which add flexibility by using prefabricated modules that can be arranged as needed and in the location where they are needed, continue to grow in use in biomanufacturing. Modularization reduces capital cost compared to conventional construction and is also advantageous for construction in developing countries. 

The rate of change in biomanufacturing is increasing, and the new value driver is flexibility, said Parrish Galliher, founder and CTO of Xcellerex, a GE Healthcare Life Sciences company, in a presentation at the meeting. Blockbuster-drug facilities are not flexible enough for the future, which is moving to smaller, multiproduct facilities made "in market, for market". Future technologies, such as cell and organ therapy and personalized medicine, will require even smaller-scale manufacturing, predicts Galliher. These facilities would need to be located "at clinic, for clinic" to have the proximity needed to deliver live products with short shelf-lives. Such technologies have high treatment costs and it is uncertain if they will make a viable business, but the technology is in development. Peering even further into the future, Galliher painted a vision of "on patient, for patient" manufacturing that could include noninvasive real-time diagnostics and real-time, microfluidic laboratory-chip drug synthesis. 

Continuous biomanufacturing is a game-changing technology for smaller-scale, flexible, multiproduct production that is emerging even now. Sanofi's Genzyme is developing a closed, continuous manufacturing process with the vision of a universal platform for all its protein biologics, said Robert Snow, senior project engineer in Sanofi’s Biologics Development Group, in a presentation at the meeting. The continuous process integrates upstream and downstream unit operations into one process train. Similar to its solid-dosage counterpart, continuous biomanufacturing offers a smaller footprint when compared to traditional perfusion or batch-type systems, and capacity is increased by increasing the number of process trains rather than their scale. The combination of closed, continuous processing and platform approach will result in smaller and more flexible multiproduct manufacturing facilities that can take full advantage of CNC ballroom-type facilities. The concept is being developed using mainly single-use components, but would also work with more traditional stainless steel process equipment, commented Snow.

Facility Trends: Modularization and Single Use

, insights from presenters at INTERPHEX 2013 in the May 2013 issue of  

Flexibility in Biopharmaceutical Manufacturing

, by Simon Chalk of the Biophorum Group in the June 2013 issue of 

Production Trends

New facility designs enable flexible, multiproduct production.

Tracking Biopharmaceutical Manufacturing Facility Trends

With the Jan. 1, 2015, California e-pedigree deadline less than 14 months away and federal traceability legislation likely to take effect, pharmaceutical manufacturers are focused on writing specifications, conducting pilot tests, and implementing full-scale serialization solutions on one or more packaging lines. 

The California deadline is likely moot. The US House of Representatives passed the Drug Quality and Security Act (H.R. 3204) on Sept. 28, 2013, and sent it to the US Senate on Sept. 30, 2013 (1). The Senate passed it on Nov. 18, 2013. (See PharmTech's blog "

Senate Finalizes Drug Compounding, Tracking Legislation

.") The bill, which was not amended by the Senate and has widespread support from industry, now awaits President Obama’s signature. 

Title I of H.R. 3204 clarifies FDA’s authority over compounding of human drugs and requires the agency to collaborate with state authorities to ensure the safety of compounded drugs. Title II of the bill would create a uniform national standard for drug supply-chain security to protect against counterfeit drugs. This standard would involve establishing a framework for supply-chain security and provide a 10-year transition to a unit-level tracking system (2).  

If signed by the President, as expected, H.R. 3204 “will preempt the current California regulations,” says John DiPalo, COO of Acsis, a provider of turnkey serialization solutions and software, in an interview with 

. “Companies that were developing a strategy just for California will now need to incorporate all operations across the entire supply chain. For example, if a company was looking to initially outfit a West-coast distribution center…to serve California, that will no longer be an option. In addition, it appears that the phased approach is no longer available and 100% of product moving through the supply chain will need to be serialized,” he explains. 

Broader than the California regulations, H.R. 3204 “…affects all of the stakeholders in the process, including manufacturers, distributors and retailers,” notes DiPalo. Manufacturers would be required (by Jan. 1, 2015) to capture and provide transaction history, transaction information including a lot number, and a transaction statement. Four years after enactment, manufacturers would be required to affix a product identifier (e.g.,  two-dimensional barcode) to a package and homogeneous case. Manufacturers would also be required to have a serialized numeric identifier (SNI), lot, and expiration date. The regulation also spells out requirements for distributors, dispensers, and repackagers regarding information they must have to accept a product and information they must provide to the subsequent owner.

Even as federal regulations were being hammered out in Washington DC, work has been continuing on serialization implementations. One company with a serialization pilot in progress, Daiichi Sankyo, is installing a turnkey solution from Acsis on a line at its packaging plant in Pennsylvania. The Acsis Serialization Management Suite includes line management, site management, and serial aggregation management software and is integrated with vision inspection from Cognex, printing equipment from Domino, material handling technology from Omega Design, and labeling technology from Weiler Labeling Systems. In addition to managing all aspects of implementation and support, Acsis prebuilt integration with Daiichi Sankyo’s SAP Auto-ID Infrastructure and Object Event Repository so product data can be shared and tracked in real-time throughout the supply chain.  

Automates and      manages application of serialized codes on the packaging line

Tracks and      controls all parent-to-child relationships

Provides real-time      access to current and historical posting reports, reconciliation reports,      and serial-number status reports

Supports commissioning,      decommissioning, aggregation, and deaggregated events, as required,      regardless of component hierarchy. 

Acsis also works with Kodak to deliver integrated, end-to-end solutions that securely, cost-effectively, and reliably authenticate, track, and trace product. The collaborative effort, announced on Sept. 4, 2013, integrates Acsis Serialization Management software with the Kodak Traceless System and its viewers and Smartphone apps to create dual serialization marking and coding on the packaging line via a visible code for aggregation and distribution processes and an invisible covert code for investigation and enforcement. “[Acsis software]…has the level of granularity needed for item-level serialization that addresses both the packaging line requirements and tracking throughout the entire distribution chain,” says Randy Young, global director, Kodak Brand Protection Solutions (3).  

The solution integrates to enterprise systems and can be implemented with minimum downtime, and without a major retooling of manufacturing or packaging processes. If needed, Acsis can provide its turnkey Serialization in a Box system, which integrates its Enterprise Serialization track-and-trace software with smart vision cameras and handheld barcode readers. 

Whatever serialization solution is chosen, DiPalo advises allowing extra time for implementation. “Everything takes a little longer than you think, and you need to allocate adequate time and resources for validation,” he explains. He also recommends dedicating resources to the project instead of adding serialization responsibilities to existing duties. “Serialization affects many different areas of an operation, and it is a big job to keep track of all the moving parts. You are introducing new technology into the packaging world as well as additional information-technology requirements that typically the team members haven’t had to deal with in the past,” he notes. 

Despite the rigors of implementation, serialization can achieve true supply-chain visibility and offer benefits beyond regulatory compliance. “There is some immediate payback in the areas of returns management and recall management that can provide some immediate, tangible benefits,” concludes DiPalo.  

H.R. 3204, US House of Representatives, 113th Congress, 1st Session (Washington, DC), Sept. 30, 2013.   

US House of Representatives, Energy & Commerce Committee, “Backgrounder-H.R. 3204, The Drug Quality and Security Act,” 

energycommerce.house.gov/fact-sheet/hr-3204-drug-quality-and-security-act

Kodak, “Kodak Names Acsis, Inc. as Serialization Software Partner of Choice,” Press Release, Sept. 4, 2013. 

Hallie Forcinio is Pharmaceutical Technology's packaging editor, 

Packaging

The Drug Quality and Security Act creates national standards for serialization of drug products to protect against counterfeiting.

Equipment and Processing Report-11-20-2013

November 2013 Editor's Picks: Products from Pall and I Holland

Operational Excellence Improves Quality and Compliance

Tracking Biopharmaceutical Manufacturing Facility Trends

Serialization Efforts Move Forward