	Blister packaging, a common format for solid dosage forms, continues to evolve. Equipment advances were discussed in the January 2017 

. Alternative packages, improved quality control equipment, and new materials also help improve product quality.

	Cartons are the traditional secondary package for blisters, but CR pouches provide a lightweight, flexible packaging option. To simplify adoption of a CR pouch, the Child-Guard CR track and slider from Presto Products has a Drug Master File listing. In use, the caregiver moves the Child-Guard slider over a notch, pushes down on a tab and pulls back the slider to open the pouch (1). CR pouches from Impak meet ASTM (American Society for Testing and Materials) D3475 CR standards. Sliding tab or press-to-close CR designs require two-handed dexterity to open, making access difficult for toddlers but not for seniors (2).

	Quality control systems confirm blister packaging equipment is working properly. Systems, such as the camera-based IBIS inline blister inspection system from Pharmaworks (3), check product and print on sealed blisters. Installed inline or offline, the vision system identifies flaws such as mis-shaped, damaged, missing, or rogue product, as well as incorrect color and foreign objects.

Seal integrity is checked on units such as the AMI 120 leak detector from Pfeiffer Vacuum (see 

). The leak detector requires no tracer gas to nondestructively detect holes as small as five microns, a sensitivity up to 1000 times better than the traditional destructive blue dye dunk test. “Using helium as a tracer gas boosts sensitivity even more,” says Dennis Seibert, head of business development, Leak Detection, at Pfeiffer Vacuum. Time spans for the offline test range from 10–60 seconds. Calibrated orifices quantify the leak rate and provide an alert if seal quality is deteriorating. Compatible with thermoformed or cold-formed blisters, testing a different blister only involves a simple fixture change.

	The VeriPac UBV leak detection system from PTI Packaging Technologies and Inspection combines vacuum with volumetric imaging to detect leaks in multi-cavity blister packs. The nondestructive test involves three steps: input the number of blister cavities; place the blister pack on the inspection plate; press start. In seconds, the display shows pass or fail, the volumetric measurement reading, and the location of any defective cavity. The technology provides rapid detection of defects as small as 10 microns in a test cycle that lasts less than 15 seconds (4).

	Activ-Blister material from CSP Technologies heat-stakes absorbent material to the interior of blister cavities. Silica gel and molecular sieve technology absorb tailored amounts of water vapor, oxygen, or a combination of the two to control the internal atmosphere of each cavity and protect product shelf life. The active feature can be adopted without changing the footprint of the packaging line (5).  

	Another option for sensitive products, Pentapharm LiquiGuard films from Klöckner Pentaplast offer protection from package leaching and moisture gain or loss. The crystal-clear, autoclavable laminate accommodates hot-fill liquids, gummies, and other emerging dosage forms. Features include a customizable moisture barrier, excellent deep-draw properties for complex blister geometries, high heat stability (the glass transition temperature of the contact layer is 120 ºC), high slip for quick release and increased productivity, and low leachability and extractability, with excellent odor and flavor retention. Applications include chewables, formulations sensitive to flavor or odor loss, nutraceuticals, pharmaceuticals, unit-dose liquids, and veterinary products (6).

		Presto Products, “Slide-Rite Child-Guard Track & Slider,” http://fresh-lock.com/product-list/slide-rite-child-guard-slider-zippers/, accessed Nov. 27, 2016.	

		Impak, “Impak Offers the Largest Selection of Child Resistant Pouches, Plus the Option for Labeling and Custom Print,” www.impakcorporation.com/flexible_packaging/child-resistant-pouch, accessed Nov. 27, 2016.

		Pharmaworks, “IBIS Inline Inspection,” www.pharmaworks.com/index.php?id=271, accessed Nov. 23, 2016.  	

		PTI Packaging Technologies and Inspection, “Introducing New Non-Destructive Technology for Blister Package Testing at PACK EXPO International,” Press Release, Nov. 2, 2016.	

		CSP Technologies, “CSP Technologies, Inc. Introduces Activ-Blister Solutions for Customizable Product Protection at INTERPHEX NYC,” Press Release, April 28, 2016.	

		Klöckner Pentaplast, “Pentapharm LiquiGuard Films from Klöckner Pentaplast,” Press Release, Oct. 26, 2016. 

 Packaging Forum editor, 4708 Morningside Drive, Cleveland, OH 44109, Tel. 216.351.5824, Fax 216.351.5684, editorhal@cs.com.

Articles

New materials, packaging types, and quality control systems enhance product quality.

Blister Packaging Innovations

	Process analytical technology (PAT) is becoming more widely used in solid-dosage drug manufacturing. PAT’s use is primarily in batch manufacturing, which still makes up the majority of processes, but also in continuous manufacturing. On-line near infrared (NIR) spectroscopy, for example, is being used to measure critical quality attributes (CQAs) such as blend uniformity and moisture content of tablets.

	With increased use, however, some of the limitations of current technology are becoming evident. “The industry is starting to take a serious look at where current PAT is reaching its limit and what the alternatives are,” notes Doug Hausner, Associate Director for Industrial Relations and Business Development at the Engineering Research Center for Structured Organic Particulate Systems (C-SOPS), an academic–industry consortium based at Rutgers University. One of the challenges is that using PAT commercially, over a long time period, requires a significant amount of personnel hours for maintenance-checking equipment and keeping calibrations up to date, notes Hausner.

	One reason why existing calibration curves are a burden to maintain is that they lack robustness, says Hausner. “A solution is to build better calibration curves using more datapoints and using design of experiments to identify the edges of failure,” he explains. Hausner notes that continuous manufacturing allows process engineers to run experiments more quickly, with less material compared to batch, so that collecting more data is not as costly. Another benefit of continuous manufacturing is that, unlike batch processes where laboratory equipment is smaller than commercial equipment, the continuous manufacturing process is already at scale, so the data collected in development experiments are relevant to commercial manufacturing conditions.

	Another solution seeks to use “soft” (i.e., software or virtual) sensors, which use existing, direct process measurements (e.g., temperature, pressure, feed rate) to calculate the desired CQA or critical process parameter, instead of using on-line spectroscopic PAT. Measurements from these sensors do not need complex multivariate models that require developing, validating, and maintaining, explains Jim Holman, process development manager, APC Pharma Solids, at GEA UK. “The methods are robust to potential variation in incoming raw materials and scalable over throughput ranges.” 

	Another problem is that some PAT techniques may be too slow for some processes. For potent drugs, for example, the amount of API in the blend is typically low, so there can be a lot of “noise” in spectroscopy and a longer sample time is required. Light-induced fluorescence (LIF) spectroscopy is one of the solutions being considered to evaluate API concentrations that are too low to be measured with NIR or Raman spectroscopy, although it also has limitations.

	PAT enables real-time release and closed-loop control

	Real-time release (RTR) is often discussed as a goal for more efficient manufacturing that applies to both batch and CM processes. Regulators have not yet signalled acceptance of soft sensors for product release, and spectroscopic PAT would likely still be needed, notes Hausner.  RTR for drug tablets, for example, would need PAT to confirm the chemical identity of the API at the correct concentration in finished tablets exiting the tablet press, as well as to predict hardness and weight or thickness.

	Communication between PAT sensors and systems enables visibility of information about a reaction in real time and can eventually allow movement to automated, closed-loop control of a small or large-molecule reaction using PAT, says Ernie Hillier, principal systems manager at Waters Corporation. Hillier will discuss the lessons learned from ongoing industry collaborations in sampling and sensing in a presentation at the IFPAC conference (Feb. 28, 2017).  Waters’ PATROL ultraperformance liquid chromatography (UPLC) process analysis system allows nearly real-time chemical analysis so that scientists can know in greater detail what is happening in a reactor at a given point of time. Data from UPLC is used in R&D, process development, and manufacturing, notes Hillier.

	Eli Lilly and Company’s continuous direct compression process for oral solid dosage drug manufacturing won the International Society for Pharmaceutical Engineering (ISPE) Facility of the Year Awards category award for Process Innovation, in part, for a control scheme anchored by advanced automation and PAT (1). The process uses soft sensors to estimate CQAs, and NIR integrated with a real-time residence distribution time model to allow real-time release. Spectroscopic PAT combined with automation logic can be used to reject portions of the batch suspected as being out of limits, explained the company (1).

	The upcoming IFPAC conference (Feb. 27–Mar. 2, 2017, Washington DC) is dedicated to advances in PAT, quality by design, and process control for the pharmaceutical, biotechnology, and other industries. Topics will include RTR and soft sensors in continuous manufacturing and advances in PAT technologies such as LIF.

		ISPE, “Category Winner for Process Innovation,” 

www.facilityoftheyear.org/winners/2017-process-innovation

Improved process analytical technology and new ways of thinking seek to enhance measurement and control for next-generation pharmaceutical manufacturing.

Overcoming Obstacles in Process Analytical Technology

	
	Stainless steel is usually the preferred substrate for good manufacturing practice (GMP) applications, and it constitutes the majority of GMP product-contact surface areas. The austenitic stainless-steel series (e.g., 304L and 316L) has been popular in pharmaceutical applications because of its high stain and corrosion resistance and affordability. Although stainless steel is named “stainless

, it is really “stain resistant”. This property comes from its ability to naturally form an oxide-rich, passive layer on the surface.

	Passivation is a process in which a passive layer forms on the stainless-steel surface; this layer occurs naturally in the presence of oxygen when the surface has been cleaned of exogenous matter (1–3). The passive layer on the stainless-steel surface becomes the primary means of protection to prevent corrosion. Stainless steel can corrode, however, when the chromium-to-iron ratio has been significantly reduced, resulting in the oxidation and subsequent release of iron oxides that form deposits on surfaces.

	Rouge is the commonly used term for the visible corrosion product of stainless steel; it can be composed of several forms of iron oxides, with ferric oxide being the predominant form (4–7). Rouging is typically found in water generation systems, process tanks, and pipeline systems that are routinely exposed to corrosive solutions. Rouge seems to be a common problem. Regulatory agencies such as FDA have cited in at least one warning letter that corrosion is unacceptable in direct-contact pharmaceutical systems (8). The reasoning is that rouge on product-contact surfaces can create an environment for process residues and microbes to tenaciously adhere to the rouged area and become more difficult to clean and sanitize (9-11). Residues and microbes might also reside within the rouge layers, where the routine cleaner and sanitizer may not be able to penetrate.

	Considering the risk associated with rouged surfaces, manufacturers would benefit from focusing more attention on treatments that prevent rouge from happening. Some companies take a reactive approach and wait until rouge has been detected or has impacted production before taking corrective action. Process attributes such as elevated temperature, extreme pH solutions, or surface damage (e.g., from poor quality welding) can corrode stainless-steel surfaces (4-7). If a process or surface condition is expected to lead to corrosion at some point during the life of the equipment, then an effort should be made to investigate and prevent that corrosion from occurring.

	Unlike preventive maintenance, which is done to mitigate the cause of the potential problem or undesirable situation, corrective maintenance is done to correct a problem or fault once it has been detected. With a stainless-steel preventive maintenance procedure, for example, an operator knows exactly what needs to be done at a predefined schedule. On the contrary, in the case of a corrective maintenance, the critical parameters and overall procedure would depend on what is found. Corrective maintenance often requires evaluation of the severity of the rouge problem before any treatment can be recommended. This evaluation is referred to as a risk assessment, and includes a review of the potential impact to the patient, product, personnel, and equipment (12). Once the rouge is formed, there may be unknown variables associated with it and correcting the problem typically takes much longer than a preventive task. Many published references about stainless-steel corrosion are focused on corrective maintenance (3–11, 13–15).

	When assessing the risk of the corrosion or rouge to the quality of the next product or batch, one should ask the questions about risk and mitigation actions summarized in 

	For more information about passivation treatments, laboratory tests to evaluate the effectiveness of passivation treatments, and tests to determine critical cleaning parameters for passivation, read the complete article by E. Rivera, P. Lopolito, and D. Hadziselimovic, 

"A Risk-Based Approach to Stainless Steel Equipment Maintenance," 

A967–13,Standard Specification for Chemical Treatments for Stainless Steel Parts 

Standard Practice for Cleaning, Descaling, and Passivation of Stainless Steel Parts, Equipment, and Systems 

		ASME, “Nonmandatory Appendix E: Passivation Procedure Qualification,” in 

		M.M. Gonzales, “Stainless Steel Tubing in the Biotechnology Industry, Biotechnology/Pharmaceutical Facilities Design,” (April 30, 2001) 

www.ispe.org/san-francisco/stainless-steel-tubing-biotechnology-industry.pdf

		J.C. Tverberg and J.A. Ledden, “Rouging of Stainless Steel in WFI and High Purity Water Systems,” Proceedings of Tube 2000, (Dusseldorf, 2000).	

		P. Lopolito, “Addressing Rouge in Biopharmaceutical Manufacturing Equipment,” 

Pharm.Tech. Equipment and Processing Report

www.pharmtech.com/addressing-rouge-biopharmaceutical-manufacturing-systems

		GMP Trends, “GMP Trends #886,” (Dec. 15, 2013).	

Rouge & Biofilm: Compounding Cleaning Challenges

www.pharmaceuticalonline.com/doc/rouge-biofilm-compounding-cleaning-challenges-0001

		A. Deal, D. Klein, and P. Lopolito, “Strategies for biofilm remediation,” 

www.cleanroomtechnology.com/technical/article_page/Strategies_for_biofilm_remediation/110760

		A. Deal et al., “Use of the CDC Biofilm Reactor to Test Cleaning and Disinfection on Rouged Stainless Steel,” 

 (March 20, 2015) www.reinraum.de/news_en.html?id=3179.	

		International Conference on Harmonization (ICH) Q9 


	Elizabeth Rivera is a technical services manager; Paul Lopolito is a senior technical services manager; and Dijana Hadziselimovic is a senior technical services associate, all at the Life Sciences Division of STERIS Corporation in Mentor, Ohio. 

Process conditions can corrode stainless-steel surfaces, necessitating corrective and preventive maintenance.

Equipment and Processing Report-02-15-2017

Blister Packaging Innovations

Overcoming Obstacles in Process Analytical Technology

Preventive and Corrective Maintenance for Rouge in Stainless-Steel Equipment