	Primary packaging sealing integrity is crucial in ensuring product viability and shelf life. The days of sampling as the primary means of inspection and analysis for the quality control of pharmaceutical packaging may be nearing an end. One method for non-destructive, 100% inspection of packages is using dynamic thermal imaging to inspect the integrity of induction-sealed bottles. Inspection is performed through closed bottle caps without damaging or degrading the product and without reducing line speeds. Precise data can also be collected to increase understanding of the process, improve quality, and allow operators to detect and amend issues in real-time.

	This solution goes beyond the level of accept/reject analysis to also indicate the source in the process that may have caused the faulty seals, including problems related to the raw material, the capper, or the sealer. Incorrect settings can be quickly detected, allowing the immediate removal of defective bottles from the production line and adjustment of the source of the problem. Problems can be corrected in real time, before an entire batch is completed. This process analytical technology (PAT) for the induction-sealing process allows the input and output to be tracked, enabling continuous process verification.


	All objects have a certain temperature and emit waves of energy, called infrared radiation (IR), invisible to the naked eye. In general, hot objects emit more energy than cold objects. A thermal imager creates a viewable image from the IR waves, showing a "heat picture" of a scene.

	Thermal imaging was originally developed for the defense industry and is regularly used for military and security applications, as well as non-intrusive inspection of plumbing, electrical systems, and insulation. Combined with high-speed image analysis, this technology provides unique monitoring and detection capabilities that can be used to inspect pharmaceutical primary packaging, specifically, induction sealing.


	In the induction sealing process, as shown in 

, a bottle is filled, and a closure with a composite liner inside is screwed onto the filled container. The container then travels by conveyor under an induction sealer, which uses an electromagnetic field to heat the aluminum foil layer of the liner. The heated foil, in turn, causes the heat-seal layer to melt. When cooled, the polymer creates a bond with the container, resulting in a hermetically sealed product. When the cap is removed, the foil remains, providing an airtight seal and preventing any tampering or contamination of the bottle's contents until the customer pierces the foil. A good induction seal prevents product leakage, is tamper-evident, maintains product quality, and fosters consumer confidence.

Maximizing the efficacy and efficiency of an induction sealer requires a holistic, carefully coordinated approach that incorporates machine, materials, quality control, and operator education. The container, closure seal liner, and induction sealer must be compatible, and an operating window that allows the sealer to be successful within a range of predetermined operating tolerances must be established. Defects can originate at various steps along a packaging line, including the capper, induction machine, conveyor and, of course, the raw material itself. Potential problem areas are described as follows:

		Material related problems include bent or damaged foil; missing foil; damaged edge or edges; or an upside-down liner (

		Problems related to the capping equipment include untorqued or crooked caps (

		Problems tied directly to the sealer itself usually involve overheating or under-heating (

Underheating the foil can result in the familiar ‘potato-chip’ effect, as shown in 

. Overheating the foil can cause damage to the seal layer and to any protective barriers, which could result in faulty seals, even weeks after the initial sealing process. Other sealing problems do not typically originate with the induction sealer but, rather, are associated with a fault earlier in the process that made it impossible for the sealer to perform properly.


	In a classic torquer problem, an incorrectly calibrated torquer does not correctly close the cap, and as a result, the induction sealer can not create a proper seal. 

 shows thermal imaging results used to track the process. In the first batch of 2000 bottles, a significant number of rejections (shown as red dots) is seen. This deviation from the defined process window indicates that there is a faulty process that should be stopped and the source of the problem checked before more bottles are incorrectly sealed. The rejections in this case were discovered to be associated with the tightness of the cap. Based on this information, the line operator stopped the line and adjusted the torquer. The batch was then continued and rejections return to an acceptable number, as shown in 


	Given the myriad potential problem areas, the need for a troubleshooting process that assures the highest possible level of quality control is clear. In each of these cases, use of dynamic thermal imaging allows the operator to identify the problem early, stop the line, immediately remove any defective bottles, and make necessary corrections to the production line process. Preventing issues before they become significant problems minimizes the cost of wasted time, work-backs, materials, and labor. This real-time, non-intrusive monitoring of package integrity is currently in use on packaging lines at several leading pharmaceutical packaging companies.


	Fabian Schapiro is the VP Marketing and Sales of DIR Technologies, 

:
	When referring to this article, please cite it as F. Schapiro, "Using Dynamic Thermal Imaging to Correct Sealing Problems," 

Articles

Packaging

Problems in an induction-sealing process, such as untorqued or crooked caps, can be identified and corrected in real time using dynamic thermal imaging.

Identifying Problems in Induction Sealing

	The advantages of single use systems (SUS), including lower capital cost and increased flexibility, are well understood. Some disadvantages, however, have grown larger than life due to a lack of understanding and a low level of comfort with something new, says Chris Smalley, director of engineering in the Sterile & Validation Center of Excellence, Global Technical Operations at Merck. "Stainless steel and glass don't have to prove themselves, but single-use plastic is the 'new kid on the block'." Issues that are seen as obstacles include extractables and leachables, container integrity (i.e., leaks), and waste disposal. Various industry groups have been working to increase understanding of how to get past these obstacles and to develop standards to drive acceptance of SUS. For example, an updated version of the American Society of Mechanical Engineers (ASME) Bioprocessing Equipment Standard includes a section on shelf life and storage of SUS (1). The Bio-Process Systems Alliance (BPSA) published an update to its 

Single-Use Manufacturing Component Quality Test Matrices Guide

 in November 2015 (2). In addition, the International Society for Pharmaceutical Engineering (ISPE) is authoring a 

	The industry has been talking about standardization since 2009, and, although all the issues have not yet been resolved, knowledge has been developed and significant progress has been made, says Smalley. Collaboration between users and suppliers has been one of the keys to this progress, as users have more fully delineated their requirements and communicated with suppliers about how to meet these needs. 

	Clear user-requirement specifications are needed to mitigate the risk of technology selection and qualification, and a partnership between users and suppliers is needed to minimize risks throughout the lifecycle and to have better change control, said Sabrina Restrepo, associate director of component engineering in the Sterile & Validation Center of Excellence, Global Technical Operations at Merck, in a presentation at the ISPE annual meeting (3). "If you have a design space and clearly understand risk, you can better deal with changes because you can see how they might affect the process," she explained. 

	"Users should implement SUS with the same validation procedures they would use with a stainless steel system," added Smalley in a presentation (4). "First, define the user requirements, and identify specifications, such as processing temperature. Have a knowledge repository and a system for handling documentation." One small difference in SUS documentation is that some items in a data-set about the part might come from the supplier of the plastic tubing, for example, and other information might come from the supplier of the plastic material used to make the tubing. Users should also note that the same component may have different requirements depending on where in the process it is used, and any inventoried part should be identified as to where it is approved for use. For example, a bag used in buffer storage may have less stringent requirements for particulates, extractables, and leachables than the same bag used in fill/finish.

	Understanding the risk of extractables, which depend on the component material, and leachables, which depend on the actual use of the SUS in the pharmaceutical process, is crucial and requires collaboration between users and suppliers, explained Malik Belattar, deputy director of the nonprofit organization, the Single-Use Technology Assessment Program (SUTAP), based in Switzerland (5). SUTAP was founded in December 2014 for the purpose of facilitating single-use standards development.

	Users and suppliers are now cooperating on both the individual company level and the industry level. The BioPhorum Operations Group (BPOG), which is primarily an end-user group, and the BPSA, which is primarily a supplier group, are now doing some projects together. For example, in two ongoing BPOG-BPSA collaboration efforts regarding 

 and user requirements, data from surveys taken by participants have been leveraged to better understand the opportunities. These efforts should drive increased use of SUS by creating a more robust understanding of its capabilities. "Presenting a unified message to regulators will help to show that industry has gained understanding of SUS and will alleviate some of the fear of the newness of SUS," suggests Restrepo. The high level strategy was published last October (6), and authors are encouraging readers to provide feedback via 

		ASME, Bioprocessing Equipment Standard (New York, NY, 2014). 	

		BPSA, "Single-Use Manufacturing Component Quality Test Matrices Guide," 

http://www.bpsalliance.org/wp-content/uploads/2015/11/BPSA_Component_Quality_Test_Matrices_FINAL_November_2015.xlsx

		S. Restrepo, "Development of Standard Tools for Risk Assessment Evaluation Related to Single-Use Technologies," presentation at the ISPE Annual Meeting (Philadelphia, PA, 2015).	

		C. Smalley, "Single Use Systems-Why the New Kids on the Block Need to Prove Themselves," presentation at the ISPE Annual Meeting (Philadelphia, PA, 2015).	

		M. Belattar, "How to Make E&L from an Unidentified Risk to a Managed Risk,” presentation at the ISPE Annual Meeting (Philadelphia, PA, 2015).	

		T. White and K. Ott, BioProcess Intl. 13 (9) 24-29 (2015).

Production Trends

Collaboration between users and suppliers to increase understanding, clearly define user requirements, and mitigate risk is facilitating acceptance by industry and regulators.

Overcoming Challenges in Implementing Single-Use Systems

	The World Health Organization (WHO) defines contamination as

the undesired introduction of impurities of a chemical or microbiological nature, or of foreign matter, into or onto a starting material or intermediate during production, sampling, packaging or repackaging, storage, or transport." WHO defines cross-contamination as "contamination of a starting material, intermediate product, or finished product with another starting material or product during production" (1).

	In 2003, WHO released their report on specifications for pharmaceutical preparations recommending that certain hazardous substances be processed and filled in segregated areas (1). FDA requires that, with few exceptions, all drugs be manufactured in compliance with CGMPs. It has become increasingly important for all pharmaceutical facilities to implement documentable precautionary measures for the prevention of both contamination and cross-contamination. Many pharmaceutical companies have implemented color-coding as one of these risk-mitigation methods. The following best practices can help make a color-coding program successful.  


	Manufacturing facilities that produce multiple drugs may already have separate buildings or strict zoning specifications in place. In this case, it is recommended that each zone or building is assigned a color. All tools used in that zone correspond to the assigned color. Best practices dictate that everything from the scoops that collect medicines and medicine ingredients to the cleaning tools, such as brushes and brooms, be color coordinated to ensure that tools stay in proper zones and only come in contact with the correct materials (see 


	Many pharmaceutical manufacturing facilities choose to color code by identifying potentially hazardous drugs and materials. Color coding is most successful when done as simply as possible. For example, if a facility identifies only one material that falls into this potentially hazardous category, it should have a two-color plan: one color for tools that come into contact with the hazardous material and one color for all other tools. If several potentially hazardous materials are identified, a few different colors could be used. If you are at the point where you can no longer easily remember the color meaning, however, you should probably reconsider your color-coding plan and aim for something simpler. 


	When building out a color-coding plan, it is important to have everyone involved in the manufacturing process voice their opinions. Everyone, from the pharmaceutical experts to the people who are responsible for cleaning the facility, should be involved in the process and should propose the plan they believe works best. The most successful plans are usually devised this way, because no possible issues are overlooked, saving time and money in the long run.


	Frequent re-evaluation is needed to ensure a long lifetime of a color-coding plan. Again, this should come from employees at all levels of the company hierarchy to gain a full picture. It is our experience that addressing problems earlier and often is key to ensuring the plan continues to meet your needs.

		WHO, “WHO Expert Committee on Specifications for Pharmaceutical Preparations, 37

 Report” WHO Technical Report Series 908 (Geneva, Switzerland, 2003).


	Bob Serfas is the founder and executive of 

Troubleshooting

Pharmaceutical manufacturing facilities can help prevent contamination and cross contamination by using color coding.

Equipment and Processing Report-12-16-2015

Identifying Problems in Induction Sealing

Overcoming Challenges in Implementing Single-Use Systems

Best Practices for Color Coding