	Drug packaging plays a crucial role in protecting patients. At INTERPHEX 2017, companies highlighted stringent quality systems, solutions for complying with the Falsified Medicines Directive, and improved blister packaging.

	Italy-based Capsulit, a first-time exhibitor at INTERPHEX, imprints all standard sizes of flip-off caps, 13-, 20-, 28-, and 32-mm diameters (see Figure 1). Potential messages include safety alerts and product information.

	Datwyler, a Switzerland-based supplier of elastomer components, introduced a product-centric, three-category business structure at INTERPHEX 2017: Bio Care (large molecule drugs), Pharma Care (small molecule drugs), and Med Care (medical products). The company also is expanding its position in the US market with construction of a plant in Middletown, DE, not far from its existing plant in Pennsauken, NJ. The Delaware facility, which represents an investment of more than $100 million, will run in accordance to the company’s First Line production standard, which exceeds the most stringent quality standards of European and US regulatory authorities and is certified to ISO 15378. Already in place at its plant in Belgium, Datwyler’s First Line standard relies on ultra-modern cleanroom technology, automated production cells, 100% camera inspection, and a validated washing process to produce products with extremely low levels of particulates, bioburden, and endotoxins. Production is scheduled to begin in 2018. 


	The StellaGUARD security label from Covectra embeds holographic stars in the substrate to deter counterfeiting and diversion and meet requirements of the European Union’s 2019 Falsified Medicines Directive, which requires tamper-evident seals on all primary packages for pharmaceutical products. The random pattern of stars and a serialized GS1 2D barcode enable real-time authentication and serialized pedigree tracking through the use of a mobile app developed by Covectra. On the packaging line, an image of the 2D barcode and StellaGuard pattern on each label is captured and stored in the Cloud. To authenticate product, the label is scanned with an iPhone and an image is captured and compared with the production line image. No special scanner is needed, and results are returned in a couple seconds. Scans also can generate marketing messages, coupons, and other interactions with the consumer. Scan reports show expiration date, number of scans, and GPS data and can provide alerts if one code is scanned too often, indicating possible duplication by a counterfeiter. An Android version of the mobile app will be available before the end of 2017.

	Another option that provides compliance with the Falsified Medicines Directive, a security booklet label from Schreiner MediPharm, combines a seal with security features such as a unique 15-digit KeySecure code in 2D barcode or human-readable format, a BitSecure pattern, which won’t scan if copied, and a radio frequency identification chip. Authentication can be accomplished by entering the code on the manufacturer’s website, a mobile query of the 2D code via SmartPhone, calling a hotline, or by scanning the RFID chip with an Android-based NFC-equipped SmartPhone. The phone’s contact-less scan of the chip also could take the user to a website or provide other information such as usage instructions. “There’s interest for biologics, especially self-administered products, because the information is always available [on the phone],” Glen Dul, president, Schreiner Medipharm, told 

	A specialized feeder, pick-and-place action, thermoformed web, and Scanware inspection system on the FA1 machine from Pharmaworks streamline bulk tablet inspection. The clear web allows the top and bottom of each tablet to be inspected. Configured with up to nine lanes, the unit can check up to one million tablets per hour (see Figure 2).

	To make it harder to overlook and accidentally ingest desiccant canisters, Clariant Healthcare Packaging has developed red, custom-printed labels (see Figure 3). The colorful labels not only differentiate the canisters, but also enhance brand identity. Labels feature an easy-to-understand pictogram and the words “Do Not Eat” in multiple languages. An outer varnish coating ensures ink is not in direct contact with the drug. The highly visible canisters serve as a drop-in replacement for traditional desiccant canisters.


	For blister packaging, the serialization-ready Digiline Blister printer from Atlantic Zeiser prints variable information on blister foil (see Figure 4). Clear, crisp alphanumerics can be reproduced in font sizes as small as 4-point. UV curing protects print from scuffing and other damage.

	RBP Bauer, which is represented in the United States by Prodieco, has designed the CP50 deblistering machine for the US market. Designed for paper-backed blisters, the system diecuts each blister to recover the solid dose at a rate of 50 blisters per minute. Push-through lidstock (without a paper layer) can be handled even faster at 60 blisters per minute.  

Articles

Feature

At INTERPHEX 2017, exhibitors displayed packaging innovations designed to improve quality, security, and patient protection.

Packaging Innovations Protect Pharma Products

	Through its continued effort to harmonize and update pharmaceutical standards, the 

 (USP) is revising and modernizing its chapters on elemental and organic impurities in pharmaceutical development and manufacturing.  To gain some insight on these changes and how they may affect the industry, 

 spoke with Kahkashan Zaidi, principal scientific liaison, USP, and Antonio Hernandez-Cardoso, senior scientific liaison, USP, about these updated 

	To hear more about elemental impurities standards, attend USP’s upcoming presentation, “

,” to be held on Thursday, May 18, 2017 at 10:30 am to 12 pm, as part of the Drug Manufacturing track at 

 What prompted the updates to the elemental impurities chapters?

 No specific event triggered the revision of the 

 standards. USP engages in continuous evaluation and revision of all its standards in order to maintain scientific and public health relevance.

	In addition to coordinating efforts in this area with FDA and the industry, USP worked closely with the 

 (ICH) to ensure alignment of its standards for elemental impurities with the ICH Q3D 

 <232> and <233> that drug manufacturers should be aware of?

 There are some key considerations for manufacturers regarding compliance with General Chapters <232> and <233>. 

 chapter <232> requirements are for drug products. This chapter is aligned with ICH Q3D in all respects but one: total parenteral nutrition products. Those are within scope for Q3D, but out of the scope of General Chapter <232>.  

	One thing for manufacturers to keep in mind is that General Chapter <233> does not restrict them to use only the ICP technique (Inductive Coupled Plasma). This chapter is very flexible and offers guidance on validation requirements for several alternative procedures to test for elemental impurities.

 <232> and <233> harmonized with ICH requirements and FDA expectations?

 USP’s toxicology experts worked closely with the ICH Q3D toxicologists to achieve a consistent outcome. USP revised the content in General Chapter <232> after this collaboration to ensure alignment across both documents.  USP’s Elemental Impurities Expert Panel and Chemical Analysis Expert Committee added additional elements and corresponding limits in General Chapter <232> based on the collaboration with the ICH Q3D. 

 In addition to the chapters on elemental impurities, USP updated chapters on organic impurities. Why does USP feel it is necessary to modernize organic impurities testing?

 USP continuously reviews and modernizes its quality standards to incorporate new technologies, testing methods, and procedures, as well as to reflect the best practices in industry and to keep the standards in the 

	In 2013, USP’s Expert Panel on Modernization of Organic Impurities Testing in Drug Substances and Drug Products decided to revise 

 General Chapter <1086> to be in line with current regulatory thinking on over-the-counter (OTC) and generic products regarding organic impurities testing. Also, recommendations from a stakeholder survey indicated that the use of terminology and principles established in ICH Q3A and Q3B guidelines should be reflected in any effort to modernize chapters.

	The Expert Panel was also tasked with evaluating the advantages and disadvantages of moving relevant text from the current General Chapter <1086> to a new General Chapter below <1000>. General Chapters numbered above <1000> are informative while General Chapters below <1000> contain mandatory requirements.  

<1086> and what should drug manufacturers know about the upcoming <476> chapter?

 Based on the input received from the stakeholder survey and from a workshop co-sponsored with FDA on organic impurities in OTC products, the Expert Panel decided to update <1086> to reflect the terminology and principles of ICH Q3A and Q3B. The intention is to add some statements and applicable information to keep them aligned for existing and legacy products.

	Regarding <476>, the Expert Panel decided to create a companion mandatory chapter including acceptance criteria aligned with the organic impurities thresholds established in the ICH guidelines. The proposal (similar to the current approach in the 

) is to incorporate cross references in monographs to address unspecified and total impurities, on a case-by-case basis, based on maximum daily doses (MDD), as outlined in ICH Q3A and Q3B.

	The final piece of information to be synchronized will be the General Notices. Once the final text in <1086> and <476> is approved, the current text in General Notices will be revised accordingly.

 When will these changes to impurities testing and requirements be implemented?

 The work on revising these General Chapters is ongoing. The first step was to address the comments received when the chapters were open for public comments and to make the relevant changes.

	New versions of <476> and <1086> will be published in 

for another round of public comments. Some of the changes being considered are the inclusion of cross references in monographs, better coordination with the Expert Committee on OTCs to synchronize implementation activities, incorporating decisions taken with FDA on terms used (“Disregard Limits” 

 “Reporting Thresholds”, for example), and the possibility of a delayed implementation date for compliance.

 What will participants learn at your CPhI North America session?

 Participants will learn about the work being conducted at USP through Expert Committees and Expert Panels to modernize General Chapters <486> and <1086> (related to organic impurities). They will also learn of any updates to General Chapters <232> and <233> (elemental impurities), particularly as related to the upcoming official date for compliance (January 2018).

At CPhI North America 2017, the US Pharmacopeial Convention will be discussing its upcoming revision and modernization of the standards for elemental and organic impurities.

Modernizing Organic and Elemental Impurities Standards

	Finding an ideal balance between high speed and precision on a modern tablet press-to optimize the ratio between bulk product introduced into the feed hopper and the acceptable tablets that exit the discharge chute (i.e., yield)-is likely to rank number one on any end user’s priority list. Paradoxically, the attainment of idealized yields often remains the most elusive goal in the compression suite. This article  sheds light on factors that affect yield and how to improve them.

	Reaching an optimal yield state is predicated on getting the most bulk powder into the die cavities between punches and, ultimately, into finished tablets. It is not just about making the press look clean, with minimal dust and mess. One can easily reduce the mess made on a press by simply using maximum vacuum, running the press slowly, or indiscriminately scraping excess powder away from the die cavities. These examples, however, will not improve final yields, as the goal is to put the maximum (but desired) amount of powder 

 the cavities, rather than directing it elsewhere.

	Most modern pharmaceutical manufacturers using state-of-the-art tablet presses will look to achieve final yields as high as 99% for single-layer tablets. Multi-layer yields are more challenging, given the number of different variables involved, with realistic figures often dipping closer to 85%. Multi-layer yields can be as high as 92%, however,  on a press with excellent first-layer sampling features; sampling frequency, and the time it takes to cycle through a sample, can be precisely adjusted on select presses, resulting in significantly improved yields.

	The best first step in attaining optimal, repeatable results is systematic training. Operators and set-up technicians should, ideally, participate in and successfully complete a formal, comprehensive training program, which are offered by equipment vendors.  The best programs will teach about all of the contributing factors discussed in the following section, all of which have a strong influence on product yields.

 Perhaps somewhat obvious, but often overlooked, poor hopper seals can cause a surprising amount of product loss, especially over the course of an entire batch. Product can escape either from the top seal, where the hopper is connected to an overhead feed system, and/or from the bottom, where it connects to the feeder assembly. The following are some recommendations for hopper seals:

		Consider the use of tri-clamp fittings, which provide more robust connections between components.

		If silicon (or similar) caps are used, ensure they are checked regularly for wear; replace as necessary as part of a systematic preventive maintenance program.

		Periodically observe both upper and lower connections over the course of a run.

 The correct positioning of an induced feeder can prove a fickle undertaking, which is probably why it is so often a major cause of product loss. Some degree of space must exist between the base of the feeder and the die table surface passing beneath it, but the optimal setting of this gap will vary across products. Leveling the feeder is also a significant concern, as an uneven feeder will invariably lead to premature wearing of other components. The following are recommendations for feeder positioning:

		Make certain that operators have been trained by the tablet press manufacturer. The procedures for properly setting a feeder often include nuances not obvious to the end user. Make it a point during the initial commissioning of a new press to request that this topic is one of those prioritized by the vendor’s representative technician.

		Invest in supplementary training materials and software that specifically cover the setting and adjustment of a feeder assembly.

		Request written feeder set-up procedures from the vendor.

 Just as important as a feeder’s positioning is the installation, condition, and efficacy of the seals used beneath the feeder, in its base, to ensure that product is effectively contained and that only the desired amount reaches the die cavities. Worn seals lead to measurable product loss. There are many types of seals in use, but the best mitigate the effects of heat while also offering easy installation and removal. The following are recommendations for feeder seals:

		Ensure that operators are systematically examining feeder seals each time the feeder is removed from the tablet press, searching for signs of wear or excessive abrasion.

		Make the replacement of worn seals part of a comprehensive, regular preventive maintenance schedule.

		Consider the use of feeders that offer sealing options for different fill channel widths. Some vendors offer styles that can be tailored to the specific size of different tablets: wider widths for larger tablets, narrower widths for smaller tablets. The closer that one can match the width of the fill channel to the actual size of the tablet, the smaller the product losses incurred.

 Fill cams play an integral role in making tablets. The filling process is similar from one press to the next, in that the fill cam allows the lower punches to be pulled down farther than they really need to go, thereby ensuring enough powder is in the die cavity to start (i.e., over-filling). A dosing cam will then “dose out” (i.e., push) a quantity from the die, such that the amount of product left in the cavity just prior to the upper punch making its entry is exactly how much is necessary for reaching target tablet weights. It is important that set-up technicians do not default to choosing fill cams with a filling range larger than necessary for a particular tablet weight. The following are recommendations for fill cam sizing:

		Stick to the “80%” rule; using 80% of a fill cam’s nominal range for achieving target weights is the best prevention for cam-related product loss.

		Ensure that operators are systematically examining fill cams each time tooling is removed from the tablet press, searching for signs of wear or excessive abrasion.

		Make the replacement of worn fill cams part of a comprehensive, regular preventive maintenance schedule; use of cams that have worn outside of their original, intended range will result not only in product loss, but also erratic tablet weights.

		Use original equipment manufacturer (OEM) fill cams, whenever possible. Fill cams have a direct and incontrovertible effect on final tablet quality, as they are tolerance-specific; the use of non-OEM supply for such parts often proves a risky proposition.

		Consider the use of a fill cam wear tool; some press manufacturers make their own.             

 The use of new, or at least well-maintained, tooling should be a cornerstone guideline. Sloppy tolerances on inferior or worn tools will contribute to product loss, sometimes in a fashion that is hard to detect. The following are recommendations for tooling tolerances:

		Invest in quality tooling in the first place.

		Use “matched” tools, where particular punches and dies are paired.

		Implement and adhere to a regimented preventive maintenance program, as recommended by any of the leading tooling manufacturers.

		Use quality measuring equipment for in-house maintenance.

		Ensure dies are seated properly; their tops should not rise above or sit below the surface of the die table.

		If using tapered dies, endeavor to keep the tapering to a minimum.

Condition and positioning of product scrapers.

 Modifying the position of scrapers can certainly affect product yields. The scrapers that follow the feeder, just prior to upper punch penetration of the die, are there to ensure product stays in the cavity where it belongs. Other scrapers are intended to direct any excess powder into a recirculation channel (if the press in question is so equipped), such that it can ultimately be returned to the entry side of the induced feeder. The following are recommendations for condition and positioning of product scrapers:

		Review the operating and cleaning manuals as provided by the tablet press vendor and adhere to the standard operating procedures (SOPs) for set-up.

		Ensure that operators are systematically examining all scrapers each time the tablet press is serviced and/or when a product change occurs.

		Make the replacement of worn or suspect scrapers part of a comprehensive, regular preventive maintenance schedule.

 The depth to which the upper punch penetrates a die presents opportunities for effectively containing product (thereby improving yields), but it’s another case of finding the “sweet spot.” Generally, if penetration depth is too shallow, it is likely powder will be blown out of the dies as the punch penetrates. If the penetration is too deep, the risk of entrapping too much air increases, resulting in another undesirable compression phenomenon known as “capping” (in which the finished tablets split into two pieces). The following are recommendations for upper punch penetration depth:

		Methods for finding optimal penetration depths should be discussed during a machine’s initial commissioning, while the vendor’s representative technician is on-site; make it a point to ensure this specific topic is covered during the installation and training period.

		For existing presses, contact the vendor and request guidance and reference materials for setting the penetration depth.

		If working with placebo, experiment with various penetration depths, ideally with the use of a high-speed camera to observe exactly what happens as the upper punch enters the die.

		Exercise caution when adjusting the penetration depth on presses that do not synchronously adjust the lower stations while the uppers are in motion; there is a risk of the upper and lower punch tips colliding if the upper punch penetration is too deep.

 Most modern tablet presses offer some form of recirculation features, which are specifically intended to guide any excess powder around the inner circumference of the turret and ultimately return it to the induced feeder. This end goal is accomplished through the use of strategically placed scrapers, a channel and, in many cases, a “plough.” It is common, however, for the adjustment of these parts to be off by just enough to negatively affect final yields. The following are recommendations for using recirculation features::

		The methods for properly positioning recirculation components should be discussed during a machine’s initial commissioning, while the vendor’s representative technician is on-site; make it a point to ensure this specific topic is covered at that time.

		For existing presses, contact the vendor and request guidance and reference materials for setting recirculation components.

		Reference the operating manuals and SOPs as provided by the tablet press vendor, and adhere to procedures as outlined therein.

 Virtually all tablet presses make use of some system for vacuuming excess powder from the die table surface. Excessive vacuum, however, can actually pull good product away from the die cavities, or elsewhere, resulting in unwanted losses. The following are recommendations for vacuum settings:

		Follow the vendor-supplied SOPs for guidelines on optimal vacuum settings.

		Make a measured assessment of the vacuum in the compression suite and compare it to the press vendor’s recommended specifications.

		Consider presses that have automatic “damping” valves in their extraction system, which allow for the modulation of how much vacuum is applied at the turret-mounted extraction ports.

 Computer-controlled presses generally allow the user to configure a parameter for rejecting a certain number of tablets every time the machine is started, in certain modes. These features are offered due to the risk of producing out-of-specification, “transitional” tablets as the machine ramps up to operating speed and to help mitigate the risk of those tablets finding their way into the good tablet channel. The following are recommendations for start-up reject settings:

		Pay close attention to the vendor-supplied operating manuals, as most will provide detailed explanations for all possible parameter settings.

		Consult onboard help functions, if available.

		For new press installations, encourage operators to request specific guidance for parameter set-up from the vendor’s representative technician.

	Many tablet manufacturers are compressing products that contain increasingly expensive active ingredients or, at a minimum, are implementing overall efficiency programs. It is thus of paramount importance to embrace good manufacturing practices, with an eye towards maximizing product yields.

	Newer presses generally have features that will help prevent product loss, but this fact should never absolve the end user from maintaining a press to the highest standards and regularly implementing good usage habits to fully understand what impact those features have on final tablet quality and overall efficiency.

	Take advantage of the resources available from a tablet press vendor and regularly request new or revised SOPs for operation, cleaning, and maintenance. Participate in training seminars whenever possible. Your yields may depend on it.

:
	When referring to this article, please cite it as M. Bundenthal, " Optimizing Yields on Modern Tablet Presses," 


	Matt Bundenthal is direct sales and communications manager at Fette Compacting America, www.fetteamerica.com.

Learn how to prevent common causes of product loss.

Optimizing Yields on Modern Tablet Presses

	In implementing quality by design for drug formulation, it is crucial to identify the critical properties of excipients and understand how their variation affects the final drug product. Yihong Qiu, senior research fellow for Oral Drug Products, Manufacturing Science & Technology, AbbVie, Inc., is giving a presentation at CPhI North America titled, “

Understanding Critical Excipient Properties to Ensure Consistent Quality of Amorphous Solid Dispersion and Extended-Release Products

.” The presentation is scheduled for Wednesday, May 17, at 4 pm. 

 spoke with Dr. Qiu, who shared some of his insights on the topic.

 What are the critical excipient properties that can have a “natural variability” in what is supplied for pharma processing?

 Physicochemical and mechanical properties of an excipient are known to impact quality, performance, or processing of the final drug product. Properties of excipients generally show different degrees of inherent or ‘natural’ variability due to variations of the starting materials and manufacture of the excipients. Criticality of certain properties is usually determined by its essentiality to the function of a particular excipient. Criticality of a specific excipient property is also often defined by its possible influence on drug product quality, which is controlled by the characteristics of API, formulation, and process. Therefore, assessing critical properties of an excipient needs to be based on understanding of the excipient as well as the API, product, and process.

	High excipient variability can become detrimental when certain excipient properties have been shown to affect potency, purity, or even processing of a particular product (e.g., pH, moisture, residual metals, or peroxides). This variability may also become detrimental when consistent properties of functional excipients are crucial to achieving reproducible product performance and quality, especially for more sophisticated delivery systems, such as modified release (MR) or amorphous solid dispersion (ASD) products. The extent of supplier-to-supplier and/or batch-to-batch inherent variability of an excipient often depends on the variations in the starting raw materials (e.g., source, specifications), manufacturing technology (e.g., batch vs. continuous processing), process parameters and controls, scale, equipment, systems, operators, environmental conditions, and even characterization tests (e.g., sensitivity, selectivity). The source of an excipient (i.e., natural, naturally derived, synthetic, or semi-synthetic) typically plays a key role in its inherent variability. For example, feedstock for naturally derived polymeric excipients often varies with species of crop, growing conditions, and/or harvesting location. Due to a broader natural variation, batch blending is sometimes required to meet product specifications, resulting in greater composition variations. In contrast, synthetic excipients are manufactured from purer starting chemicals and thus generally exhibit lower variability when manufacturing is well controlled. Its variability is more often manifested by variations in residual starting materials, byproducts, or synthetic impurities, for example, though excipient properties can still fluctuate. Lastly, impact of excipient properties can also be related to sensitivity (robustness) of formulation, process, and even test methods of a product to excipient variability.

 Which critical quality attributes of a drug product are affected by these excipient properties (as well as by other raw materials and processing conditions)?

 How properties of an excipient may affect drug product performance and critical quality attributes (CQAs) depends highly on the function of the excipient in the formulation and the relationship between excipient quality and the drug product. For example, variability in the rate-controlling polymers for MR products can significantly influence drug-release performance and reproducibility, but dissolution performance of an immediate-release product containing soluble API is often capable of tolerating greater variability of an excipient used as processing aid or diluent. Impact of chemical properties (e.g., substitution, trace impurities) and physical properties (e.g., particle size, flowability) of an excipient on product CQAs may also differ depending on API, product design, and process. For instance, stability of a drug that is prone to hydrolysis could be sensitive to variability in pH and moisture content, but not variation in residual peroxides whereas the opposite can be true for a different drug that primarily undergoes oxidative degradation. Drug release of an extended release product may exhibit high variability between the rate-controlling polymer batches or suppliers even though variations of the apparent viscosity and/or substitutions of the polymer remain within specifications. This variability could be a result of variation in excipient properties that can affect drug-release performance but are not controlled by the specifications, such as polydispersity or homogeneity of the substitution. Excipient properties and its interplays with certain processes or unit operations can also impact processability or quality of the drug product. For example, variability in glass transition temperature of a polymer used to form ASD using a hot-melt extrusion process may affect reproducibility of the extrusion process and residual crystallinity. However, the spray-drying process would be more forgiving to this type of variability.  

 What are some of the solutions for handling this variability?

 Not all excipients or all properties are critical to product quality and performance. Each drug product and associated manufacturing process is unique and influenced by individual excipients to a different extent. Therefore, a risk- and science-based approach is required to manage and address excipient variability. For many excipients, appropriate tests and specifications are in place to ensure consistent quality and reliable performance at an acceptable risk level associated with the general end-use applications. For excipient properties that are critical to critical quality attributes of drug products, especially more sophisticated products (e.g., MR and ASD) with higher level of risk and impact, a more in-depth understanding is required by closely linking excipient attributes to the intended function and by determining how excipient functionality can be controlled and whether additional product-specific specifications should be added based on formulation and process understanding. For example, understanding excipient’s critical role in a product or reactivity between the trace impurities with a specific API can help provide a solution tailored for a particularly sensitive API or formulation. To develop a robust formulation and/or process that is capable of tolerating excipient variability, pharma companies and excipient suppliers need to closely collaborate and exchange information. Pharma companies need to share details on the end-use application of the excipient, required functionality and attributes, and problems encountered or anticipated at the early stage of development. The excipient manufacturers need to share their knowledge and expertise to help evaluate excipient properties critical to the drug product by providing in-depth characterization and historical data and identifying raw material and manufacturing variables or changes that can potentially affect these properties and functionality. This type of cooperation can help develop an effective and practical approach to predict and control future batch-to-batch variability within acceptable ranges. In short, to control, reduce or minimize possible negative impact of excipient variability on products and processing, a collaborative effort among pharma companies, excipient suppliers, the US Pharmacopeial Convention, and regulators is essential.

In implementing quality by design for drug formulation, it is crucial to identify the critical properties of excipients and understand how their variation affects the final drug product.

Equipment and Processing Report-05-10-2017

Packaging Innovations Protect Pharma Products

Modernizing Organic and Elemental Impurities Standards

Optimizing Yields on Modern Tablet Presses

Understanding How Excipients Affect Drug Quality