	Interphex returns to the Javits Center in New York on March 21-23, 2017. Parenteral packaging will be well-represented especially technologies associated with fill/finish of ready-to-use vials, cartridges, and syringes.

NJM Packaging, for example, plans to introduce the Dara SX-310-PP/D machine. Pairs of filling, stoppering, and capping stations precisely aseptically fill, stopper, and cap glass or plastic vials with volumes from 0.1 to 250 mL for liquids and from 2 to 1500 mg for powders. Stainless steel or ceramic rotary piston pumps achieve +/- 0.5% accuracy. Optional peristaltic pumps, which utilize single-use tubing, deliver +/- 1% accuracy.

	The compact, servo-driven machine can be programmed for full stopper insertion, followed by aluminum/flip-off cap application, or half stopper insertion, and no capping for lyophilization. A servo-driven, tangential rolling head minimizes particulate generation during closing. Inspection stations detect fill levels, missing stoppers, and raised stoppers and trigger an automatic reject to remove out-of-tolerance vials.

	The machine achieves throughputs of up to 120 units per minute and is compatible with handling suspensions, vaccines, or cellular tissue. Changeover to a new product takes 15 minutes with no tools required.

	Options include clean-in-place, sterilization-in-place, gas flushing, vacuum-assisted stopper insertion, onboard checkweigher, and ancillary equipment such as automatic or manual denesting units to adapt the machine for ready-to-fill vials.

	OPTIMA Pharma’s MultiUse Filler Series fills and closes nested or bulk syringes, vials, or cartridges. The modular design of the transport system enables a wide range of vials to be handled without installation of format change parts. Visitors to the booth will also be able to view turnkey projects in 3D, including an isolator-equipped vial processing line capable of handling 400 vials/min with 100% in-process weight control.

	Another system designed to handle nested, ready-to-use vials, cartridges, and syringes-the FlexPro 50 filling and closing machine from Groninger-now offers a single-use rotary piston pump option. The modular machine also handles vials in trays and bulk and can be integrated with an isolator and freeze dryer and supplied as a turnkey system.

	Building on last year’s debut of its Extrafill robotic monobloc, Marchesini Group, which is celebrating the 25

 anniversary of its US office in West Caldwell, New Jersey, plans to introduce the Extrafill syringe filler. Developed to meet the growing demands of packaging disposable pre-filled syringes in the North American market, the compact Extrafill machine is designed to accommodate two to five filling and stoppering stations under one isolator and can produce up to 12,000 pieces per hour. A robotic arm, which features a gripper that moves like a human hand, peels off the Tyvek protective film and pushes the tub of syringes onto a loading belt for transport to the filling and stoppering stations. Batching precision is guaranteed by systems that center the syringes and completely protect them during the filling phase to avoid contamination and to ensure a sterile process.

	Another robotic system, Steriline’s three-robot Robotic Filling Line for injectable products, is fully integrated under isolators. It handles vials sizes from 2 mL to 100 mL without change parts to minimize changeover time. “Zero-loss” inspection enables reprocessing of vials with missing stoppers or caps.  

	Rommelag now offers a Disposable Filling System (DFS) alternative for its bottelpack aseptic blow-fill-seal machines. Simple to install and compatible with in-line sterilization, the DFS consists of pre-assembled disposable components and is based on a peristaltic feed.

	On the sealing side, EMA Pharmaceuticals’ EMA Clean-Certified Caps provide “ready-to-be-sterilized” or “ready-to-be-used” overseals, processed to minimize particulate and bioburden and assembled in a cleanroom environment. Ready-to-be-used caps are packed in sealed polyethylene bags and gamma sterilized. 

Articles

Parenteral packaging will be well-represented at INTERPHEX, especially technologies associated with fill/finish of ready-to-use vials, cartridges, and syringes.

Parenteral Packaging Equipment On Display at INTERPHEX

	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 

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

	Process analytical technology (PAT) is helping process engineers to better understand and control their processes by measuring the critical process parameters (CPPs) that affect critical quality attributes (CQAs) of the product. PAT is particularly important for implementing continuous solid-dosage manufacturing, in which material must be measured and tracked as it continuously flows through connected equipment. Spectroscopic PAT is useful, but has some limitations (1). Industry experts say that PAT can be more than spectroscopy; PAT can also include “soft” (i.e., software or virtual) sensors that correlate easily measured process conditions (e.g., temperature, feedrate) to CPPs using first-principle models. 

 spoke with Dr. Jim Holman, process development manager, APC Pharma Solids, GEA UK, about the role of PAT in solid-dosage manufacturing and in the GEA ConsiGma continuous manufacturing platform, for which the company won the “Best manufacturing technology and equipment” award at the 2016 CPhI Pharma Awards (2). The ConsiGma platform can produce blends, granules, or coated tablets continuously using either wet granulation or direct compression. 

	PAT in continuous solid-dosage manufacturing

What role does PAT play in continuous solid-dosage manufacturing?

 PAT plays a crucial part in continuous dose manufacture and is already successfully utilized on a number of GEA continuous solid oral dose manufacturing platforms. The mistake that is often made is to automatically assume that PAT refers only to spectroscopy or other added instruments, such as laser diffraction. In theory, a displacement sensor could be called PAT if after data analysis, it allows one to analyze and control the process, and therefore product quality, through the (indirect) measurement of a CQA.

	However it’s defined, the real benefit of any PAT system is that it can enable real-time monitoring of the drug product quality attributes that would normally be measured by other methods, usually off-line laboratory testing.  PAT often also ensures that a far higher percentage of the material is measured, thereby increasing the ‘data points per kg’ in comparison to traditional off-line or at-line methods.

	Blend uniformity prior to compression, particle size 

 laser diffraction, moisture content post drying, tablet assay, and tablet coating film thickness are all examples of measurements that have been successfully enabled on GEA continuous lines in the past. The use of PAT enables the rapid development of the process design space without the need for extensive off-line testing, and it allows the development cycle to fully utilize structured scientific methods to assess products in a much shorter timeframe. 

	For example, on a GEA ConSigma granulation, drying, blending, and compression line, 105 separate design of experiment points have been conducted in one eight-hour working day. By comparison, the feedback from the project industrial partners at the time was that 3–5 points would be managed, at best, using traditional manufacturing methods. PAT enabled the real-time measurement of granule loss on drying and blend particle size distribution (PSD), while at-line PAT enabled the measurement of tablet assay and other key properties. This testing would have taken weeks to yield the same level of data using off-line systems. 

	Spectroscopy, however, is not a golden bullet that will solve this matter for all cases. Not all products can be tracked using near infrared (NIR) spectroscopy.  Secondly, if there is significant change to raw materials/API lots, then models built and verified for one supply may no longer be valid for another. Changes to the process can also cause the model to be invalidated, for example ramping the throughput of a line from 10 kg/hr to 50 kg/hr.  NIR models will be required to cover specific API concentrations, so for multi-dose strength formulations, a number of PAT models will need to be built and maintained.

	The key to PAT is consistent sample presentation, and while continuous processing makes it easier to control this, the shifts naturally seen in development programs as the design space is explored can cause issues with some PAT applications.

What are some examples of what is measured by online spectroscopy for continuous tablet production?

 Currently spectroscopy based-PAT is employed in a number of locations on GEA continuous platforms:

  NIR spectroscopy focusing on the specific water wavelengths has been integrated into the GEA continuous tableting line for some time now, and is routinely used to give a real-time prediction of the loss on drying of exiting granules. These data can be fed back into the control system of the fluid bed dryer, altering the release criteria and actively controlling the drying process to ensure the correct product quality of the dried granules.

Particle Size Distribution (Laser diffraction):

 Instruments aimed at measuring the PSD of the milled granules has been proven on ConSigma granulation lines.

  By locating a NIR system on the powder inlet to the tablet press, the blend uniformity of a system can be measured in real time just prior to tablet compression. This system is employed on both the continuous direct compression system and the continuous wet granulation line. The measurement of blend uniformity is used for two key purposes:

		For APIs where an accurate and precise NIR model can be validated, the system can be used to track the actual blend concentration in real time in place of off-line high-performance liquid chromatography (HPLC) testing. 

		If models can only be used to give indications of the API percentage, NIR can still be a powerful tool in assessing the process design and operating space. Measuring the residence time distribution (RTD) of systems enables the direct modeling of systems using fundamental understand of the process. GEA continuous blending and compression systems have been accurately modelled using RTDs to the point that the blend potency can be predicted using the measured input feed variability and the system RTD, which can be fully aligned with measured blend potency from the online NIR system.

 On the GEA continuous coater, the thickness of coating layers can be measured as the layer is applied in real time. The measurement is performed by monitoring the drop in the API signal as the tablet is coated and the inherent rise in the coating material signal.

How can ‘soft’ sensors be used as PAT tools and what information can they provide?

 Some of the most powerful tools often overlooked as PAT on any continuous solids line start in the basic process data taken from current unit operations, specifically loss-in-weight feeders and the tablet compression systems. The development of virtual (soft) sensors that use robust direct measurements (e.g., temperature, pressure, displacement, force) and turn these data into product quality information is of significant interest at this time and has already been shown to give insight that can potentially replace the function of some spectroscopy-based PAT. 

	Data generated from the unique, air-compensated compression stations in a GEA tablet press are shown to track RTD disturbances through the system (to the actual point of compression as opposed to close to point of compression as with NIR). In one case study, a valid NIR model could not be built, so this alternate PAT method was used to quantify the mixing capability of the entire GEA CDC-50 direct compression system. The design space was mapped using the GEA RTD model of continuous blending built on the data from the tablet press only. This method eliminated the need for NIR and allowed for the development to continue without the need for time-intensive HPLC testing.

	The advantage of such an analysis is that unlike NIR, the measurement signals from displacement sensors do not need complex multivariate models that required developing, validating, and maintaining. The methods are robust to potential variation in incoming raw materials and scalable over throughput ranges. 

	Previous studies have shown that by tracking changes in the filling of individual dies in the tablet press, changes in granule properties out of the granulation and drying system can be directly tracked by comparing the apparent powder bulk density in the press. This method has been shown to have a greater accuracy than continuous PSD measurements via laser diffraction. 

	Changes in powder characteristics (e.g., lot-to-lot density or flowability changes) can be directly measured going into a continuous process using the data from the GEA compact feeder, potentially opening the possibility of feed-forward quality control where systems are prepared for product changes.  

What do you foresee as trends in the use of PAT in continuous solid-dosage manufacturing as this type of process begins to be more widely used?

 The benefits of spectroscopic PAT instruments are well known, as are the limitations. The technology is shown to yield significant benefits into the development system of a product, enabling faster analysis of products. The exponential growth area, however, will be in other virtual sensors that can be considered PAT. Continuous systems generate a significant amount of data, and at this time only basic data are routinely used. Using soft sensors to analysis these data, yielding more insight into the actual product quality, will generate significant interest in the coming years.

	We are already seeing a trend of using spectroscopy-based PAT during development to verify fundamental models such as RTD models, but this spectroscopic PAT is excluded for commercial production platforms in favor of soft sensors and mathematical models that are more robust.

		J. Markarian, “Overcoming Obstacles in Process Analytical Technology,” Equipment & Processing Report, Feb. 15, 2017.	

		PharmTech, “Manufacturing Technology and Equipment Prize Goes to GEA Group,” (Oct. 5, 2016), 

www.pharmtech.com/manufacturing-technology-and-equipment-prize-goes-gea-group

Soft sensors are powerful tools that can be used along with spectroscopic instruments in on-line measurement.

Equipment and Processing Report-03-08-2017

Parenteral Packaging Equipment On Display at INTERPHEX

GMP Facility Modernization: Opportunities for Successful Implementation

Using Spectroscopic and Virtual Sensor PAT in Continuous Solid-Dosage Manufacturing