Compressed air is used throughout the pharmaceutical manufacturing facility to actuate valves, manipulate products, or pressurize vessels in processes from API production to secondary packaging equipment and at every process in between. Proper monitoring of compressed airflow and consumption can tell operations personnel much about the health of the system and provide specific and critical diagnostic information before larger problems occur. Monitoring also provides necessary data to ensure that long-term energy costs in the plant do not mysteriously increase. 

Most applications or skids used in pharmaceutical production and packaging have an air preparation assembly on the front end to regulate pressure, filter the air to cleanliness levels required by FDA, provide a manual on/off valve, and monitor the system pressure. The pressure sensor in this assembly will alert the control system if there is a pressure drop that will cause actuation components to not perform properly or a pressure spike that can result in component or instrument damage. 

Flow is related to but independent of the principles of air pressure. Although air pressure determines the amount of force or torque at the field device, the proper volume of air must be supplied to reach and maintain the pressure. Volumetric flow, however, is seldom measured in pharmaceutical plants today. 

A leaking seal inside an actuator or a broken tube might not be enough to cause a pressure drop and can easily go undetected. Without a flow sensor, the problem may not be realized until there is a further or complete failure of the component and a downstream process fails. A pharmaceutical plant can have as many as 5000 pneumatic solenoid valves controlling processes and more than 5 miles of tubing, so there is a lot of opportunity to improve this analysis.  


In its simplest use, a flow sensor, similarly to a pressure sensor, will provide a digital signal to the controller when its limits are exceeded. The flow sensor complements the pressure sensor well in this basic capacity because it ensures the equipment has the required airflow to function as designed. 

Analog data provides an important tool for improving the heath of a system. It is possible to monitor the flow rate of a given process or timeframe and do comparative analysis.  This information is available to the controller, where it can be locally analyzed, displayed, maintained in a data log, used to create an alert, or passed on through the supervisory-control and data-acquisition system for further analysis.   

An increase in compressed air consumption can be an early indication of: 

Leaking seals at a quarter-turn actuator or pneumatic-linear actuator 

Investigating the source of this consumption increase early on and correcting the problem will improve the performance and uptime of all automated plant equipment. 

For further information, read the full article, 

Using Flow Sensors to Monitor Process System Health, 

Craig Correia is head of Process Automation at Festo USA, 

Articles

Troubleshooting

Changes in compressed air consumption are an early indicator of problems that need correction.

Using Flow Sensors as Diagnostic Tools

Serialization involves the application of a unique code to a package to help track, trace, and authenticate a product. Although it may sound simple, implementing serialization on a packaging line requires a complex integration of hardware and software and often involves a combination of new and existing systems, which must work together. 

“Hardware includes the printers, cameras, and material-handling machinery,” explains Chris Siegele, serialization specialist at Omega Design, a provider of coders/printers, manual and semiautomatic case-packing stations, label synchronization modules, and controls integration, in an interview with 

. He notes that the serialization-ready hardware needs to function at line speeds and adds, “Software that manages the serialization data needs to be tied to the hardware operation through controls integration and function as a seamless unit.” Software also must be capable of handling large volumes of data in real time to supply the codes to be applied, confirm correctness, and link the product to historical data, such as sources of ingredients, as well as to each packaging level from primary container to pallet load.

In-house implementation of serialization is an option. But Siegele says, “It is a disadvantage….The in-house team is just learning as they go along. To implement, you have to stop the line and now you’re not producing product. With an outside provider, you can prove the serialization operation and ultimately have less machine downtime.”

Fortunately, a number of hardware and software providers and third-party integrators have developed the expertise needed to make packaging machines, coding equipment, inspection and data capture systems, material handling, controls, and software work together to create a complete serialization system. “There are a couple of advantages to working with a single supplier when implementing a serialization solution,” said John DiPalo, chief strategy officer for Acsis Inc., a supplier of supply network visibility, brand protection, and serialization software, in an interview with 

. He explains: “There are a lot of moving parts in a serialization implementation that must all come together at the same time in order for the solution to work. One supplier managing the process has the insight to understand the complexities and the ability to coordinate all the tasks, making sure nothing is overlooked. Another big benefit is that a single supplier can help the customer see the value that serialization can bring to their business by looking at the implementation in a more holistic way.”

Schubert-Pharma, a cooperative venture formed in January 2014 by Gerhard Schubert and IPS International Packaging Systems, provides that type of holistic approach. It not only supplies integration services, but also hardware and software under its TLM brand name. TLM standard components include Schubert’s VMS Packaging Machine Controller, robotic and vision systems, and electronics, which can be customized for the application. 

The VMS Packaging Machine Controller integrates all functions of the packaging process to enable serialization from filling to pallet of finished product. All automation components, such as robots, scanners, cameras, and printers communicate with the VMS.

The TLM Transmodul, a single-axis rail-based robot system, conveys product and provides 100% position control. Because the Transmodul continuously defines the status of products being conveyed, it always knows what code belongs to what package. So, when cartons are loaded into a shipper, code information is recorded automatically. No camera system is needed to record and communicate code data. As a result, aggregation occurs in real time in one system. Interface issues are minimized because components receive data directly from the line management or VMS system. Fewer individual components for tracking mean simplified qualification. Other benefits include consistent documentation and a single user interface. 

Regardless of whether integration is done by an original equipment manufacturer, software provider, third-party integrator, or in-house, DiPalo says pharmaceutical manufacturers, “need to look at serialization from a few different angles. First you need to understand that adding serialization to a line will change your work processes, so change management and training are essential to a successful rollout. Second, the process of serialization does not end once product leaves the packaging line. You need to understand the downstream implications of adding serialization to your supply chain and how you are going to handle the processing of this serialized data in your downstream activities. From a tactical perspective, it is important to fully map out all of the touch points on the line where you will need to manage serialized data, not only how you are going to get serial numbers on items and cases. Other activities like rework of rejected product and managing of aggregation data become very important in making sure that your overall productivity is not impacted by the implementation of serialization,” he concludes. 

Hallie Forcinio is Pharmaceutical Technology's packaging editor, 

Packaging

Packaging machines, coding equipment, inspection and data capture systems, material handling, controls, and software must work together in a serialization system.

Integrated Systems Hold the Key to Successful Serialization

Pharma Technology Inc. (PTI) introduced the PharmaSpray external lubrication system that sprays dry lubricant continuously onto tablet press punch tips and die walls. The system delivers a consistent, validatable amount of dry lubricant to enhance tablet press performance. 

Excess lubricant is eliminated by vacuum suction on the side of the spray nozzle and collected in a double bag discharge system. This system allows consistent amounts of lubricant to be applied to tablets throughout a batch and from one batch to another. It also allows the amount applied to be accurately validated. 

For existing hygroscopic or effervescent formulations, external lubricant helps reduce die wall friction at the ejection stage and lower punch-face friction at the take-off stage and also helps prevent logo picking or stickiness issues. Lubrication provides the added benefit of reducing wear on tooling and ejection cams.

For new formulations, the system helps eliminate the need for dry lubricant in the blend, which enhances the solubility of the tablet because blended magnesium stearate tends to create hydrophobic bridges in compressed tablets. This solubility enhancement has been in demand for new drugs that often have poorly soluble APIs. The minimal quantity of lubricant sprayed externally onto the tablets can be accurately measured and validated, allowing manufacturers to remain below the threshold for listing this lubricant as an ingredient under US Pharmacopeia requirements.

PharmaSpray delivers a consistent, validatable amount of dry lubricant.

External Lubrication System Enhances Tablet Press Performance

Highly potent APIs present several challenges for finished-dosage drug manufacturing because they must be handled in a manner that both protects the drug product from cross-contamination and protects manufacturing personnel. Automation, process analytical technology that allows monitoring without operator contact, and disposable equipment are technologies that offer potential solutions to some of these challenges (1). No matter what equipment is used, however, manufacturers must first assess the risk of cross contamination and exposure. 


A significant issue has been whether manufacturers can use shared facilities for manufacturing highly potent drugs. FDA regulations say that penicillins must be processed in dedicated, segregated facilities, and a 2013 FDA guidance added that beta lactams should also be segregated (2). Other products may be manufactured in shared facilities if precautions are taken to prevent cross contamination or mixups, noted Stephanie Wilkins, president of PharmaConsult US, in a presentation at Interphex 2014 (3). 

The European Medicines Agency (EMA) has updated their GMP regulations, and the final version of Chapters 3 and 5 will come into effect March 1, 2015 (4, 5). The new regulations say that the outcome of a quality risk management process should determine the need for segregated facilities. The risk assessments should address modes of cross-contamination that could occur to be sure that certain thresholds are not exceeded. Dedicated facilities must be used if scientific data from the toxicological evaluation does not support a controllable risk (e.g., for penicillins or beta lactams), cannot control the risks to acceptable levels, or do not have an analytical method that is more sensitive than the relevant residue limits derived from the toxicological evaluation, noted Wilkins.

EMA does not yet have a final guidance for the toxicological evaluation. An EMA draft guidance on manufacturing in shared facilities (6), however, outlines how to determine threshold values or permissible daily exposures (PDEs) that can be used to set limits for unacceptable cross-contamination. Alternatively, the International Society of Pharmaceutical Engineering (ISPE) 

 provides guidance on how to determine acceptable daily exposures (ADEs) that can also be used to set the limits (7). These limits are more appropriate than previous limits, which may not be stringent enough to protect workers or product quality for highly potent compounds, said Wilkins. 


  In a risk assessment, companies must examine various routes of cross-contamination. These routes include mixups, carryover, and mechanical or airborne transfer, Wilkins explained in her presentation. 

An example of a mixup is a wrong label on a product. Mislabeling does occur. In September, 2014, for example, Baxter initiated a voluntary recall of one lot of injectable product due to a labeling error on a shipping carton (8).  

With shared equipment that is cleaned between different materials, material retained in equipment could be carried over into the next product, resulting in cross-contamination. The big change in regulations here, explained Wilkins, is using health-based limits based on ADE, acceptable daily intake (ADI), or PDE thresholds to determine what the limits should be for confirming that cleaning processes are effective to prevent retention and carryover. ISPE’s Risk-MaPP Baseline Guide offers a scientific, risk-based approach to determining and managing cross-contamination using ADE, which is similar to PDE (7). 

Mechanical transfer can occur if residue escapes the process (e.g., a spill onto the floor), where it could be transferred, for example, by operators’ shoes or gloves. Airborne transfer can occur if residue escapes the process and is in the air, where it could be transferred through the air-handling system. Controls must be set to prevent cross-contamination through any of these routes, noted Wilkins in the presentation. In addition, the new EU GMPs now require a risk assessment of these controls to be able to confirm that these products can be safely manufactured in shared facilities.

C. Challener, "Technology Choices in Highly Potent Solid Dosage Manufacturing," Jul. 2, 2013, 

www.pharmtech.com/pharmtech/article/articleDetail.jsp?id=817278

Guidance for Industry: Non-Penicillin Beta-Lactam Drugs: A CGMP Framework for Preventing Cross-Contamination

S. Wilkins, "Using Shared Facilities for Manufacturing High Potency Finished Drugs," Presentation at Interphex (New York City, 2014).  

EudraLex Volume 4, Chapter 3: Premises and Equipment

Draft Guideline On Setting Health Based Exposure Limits For Use In Risk Identification In The Manufacture Of Different Medicinal Products In Shared Facilities

Baseline Guide: Risk-Based Manufacture of Pharmaceutical Products (Risk-MaPP)

, "Baxter Initiates Voluntary Recall of Potassium Chloride Injection,"  

http://www.pharmtech.com/pharmtech/article/articleDetail.jsp?id=854254

To hear a recorded interview with Stephanie Wilkins on this subject, watch 

Production Trends

Manufacturers using highly potent APIs must examine cross-contamination routes and determine acceptable limits.

Evaluating Cross-Contamination Risk of Highly Potent APIs

The CUT 1405 horizontal cartoning machine from Bosch Packaging Technology offers a flexible choice of in-feed systems, package formats, and closure options. The machine can handle different carton sizes and packages for a wide variety of primary packaging, such as bottles, vials, syringes, ampoules, tubes, blisters, trays, bags, stick packs, and sachets in folding cartons. Inserts to single and combination products such as spoons or outserts can also be integrated into the modular in-feed system. 

The conveyor technology of the carton magazine (in-feed device) has been optimized. To prevent the cartons from getting caught, they are transported into the magazine by a lifting motion of the rake. The patented folding carton carrier enables the individual cartons to maintain their shape as the intermittent transport system moves them through the machine, which prevents damage to the product.

The new servo technology reduces the need for maintenance, and the human-machine interface allows easy handling. The operator can quickly localize machine disorders via error messages and resolve them using the automatic troubleshooting guide. Optional serialization, aggregation, and tamper-evident modules take into account current guidelines and safety standards.

The intermittent cartoner can be equipped with a variety of in-feed systems and can handle different package formats and closure options.

Equipment and Processing Report-10-15-2014

Using Flow Sensors as Diagnostic Tools

Integrated Systems Hold the Key to Successful Serialization

External Lubrication System Enhances Tablet Press Performance

Evaluating Cross-Contamination Risk of Highly Potent APIs

Horizontal Cartoning Machine Increases Flexibility