	Appropriate cleaning procedures are crucial for any cGMP aseptic or sterile manufacturing process, including vial filling. In addition to having procedures, the operators on the line who are performing cleaning tasks must understand the procedures, grasp the importance of their tasks, and do their jobs well.

	Grand River Aseptic Manufacturing (GRAM), a parenteral contract manufacturer, operates cGMP aseptic and sterile vial-filling lines for both liquids and lyophilized drug products at two facilities in Grand Rapids, MI. Alex Fox, an experienced operator, and Jason Steele, operations liaison, both at GRAM, spoke to 

about the challenges and best practices in cleaning a manufacturing facility and a vial-filling line in particular.

: What are important aspects of and best practices for cleaning in a pharmaceutical manufacturing facility?

: Strict adherence to standard operating procedures (SOPs) and a training program are crucial. SOPs are in place so that different operators can complete a task in a consistent manner. FDA expects written SOPs detailing the cleaning process. GRAM's SOPs outline each step so that personnel can synchronize and work as a team. A robust training program is required so that operators understand the importance of following procedures as well as the importance of keeping the facility clean. 

	In addition, it is crucial to document all activities for cleaning. Lack of documentation or documentation errors can potentially create equipment downtime and negatively impact efficiency. 

	All personnel must understand why cleaning the facility in the correct order is a best practice. Personnel must first clean the more strictly controlled cleanrooms, which have a higher classification, before proceeding to rooms of lower classification. Cleaning in the incorrect order can be a significant risk to sterility assurance and may create cross-contamination between classified areas. 

	Attention to detail and ensuring that sufficient time is allotted for cleaning to be a priority are also important. Cleaning should never fall behind due to other tasks, and its importance in aseptic operations should never be understated. Although cleaning can be mundane, extreme focus is necessary for cleaning to be completed correctly in pharmaceutical facilities.

: What are the key steps to cleaning a vial-filling line when changing from one product to another?

: Performing a post-fill cleaning of the line immediately after a fill is completed is crucial because it ensures that the product does not become dried onto the line. It is also important to ensure that the appropriate cleaning methods and tools are used so that no product is left after cleaning is completed. Different products may require different procedures. 

	Proper disposal of any and all rejects, tailings, and any other drug product left in the room is crucial when changing from product to product. An operator must ensure that all substance is removed appropriately. Proper disposal ensures cleanliness and operator safety.

	Another tip is to begin with the cleanest equipment and move to the dirtiest area within a room. For example, begin with the fill line and, subsequently, the inside and then outside of a restricted access barrier system (RABS) if applicable, followed by the ceiling, walls, and floors.

	To have the room released for the next fill or client, an operator’s top priority must be proper line clearance by removing previous product and cleaning equipment. An operator must remember that cleaning the equipment and removing all drug substances are both equally important when preparing to switch between products.

: What are some of the challenging aspects of cleaning validation for a vial-filling line, and what are the best practices to solve these challenges? 

: A challenge is the time and resources required to perform the cleaning validation for a vial-filling line. It is important to optimize procedures and the use of resources, as well as to stay up to date with any new trends in the validation sphere. For example, GRAM is implementing disposable equipment, which can reduce cleaning and cleaning validation requirements.  

: In addition to cleaning and cleaning validation, what else is crucial to ensuring aseptic processing? 

: It is also important to have qualified sterilization methods for bringing components, materials, and equipment into the cleanroom. Autoclaving all components and equipment allowed in the cleanroom, for example, is a straightforward method.

	At GRAM, we believe that the following are crucial to ensure aseptic processing:  

		Proper training. The manufacturing crew must be trained, qualified, and most importantly, be comfortable in gowning, personnel monitoring, environmental monitoring, and aseptic interventions.

		Personnel working together. At GRAM, we make sure that our manufacturing crew and quality assurance (QA) team operate as a unit in the aseptic processing areas.

		Continuous improvement. The manufacturing and QA crew participate in 'lessons learned' sessions to review batch trending, for example; the ideas discussed in these sessions have been implemented, resulting in improvements and greater efficiency. 

Articles

Troubleshooting

Appropriate cleaning procedures are crucial for any cGMP aseptic or sterile pharmaceutical manufacturing process, including vial filling; operators share best practices for cleaning.

Best Practices for Cleaning a Filling Line

	Packaging of solid-dosage drugs generally occurs by counting rather than by weight or volume. Slat fillers remain commonplace, especially for large batches. Demand is continuing to grow, however, for electronic counters, which are now approaching slat-filler speeds and tend to be more flexible.

	“Flexibility to handle a wide range of products is critical now,” reports Darren Meister, vice-president of sales at IMA North America (Safe Division). This need for flexibility also generates demand for counters that are easier to clean and faster to change over. “Cleaning and changeover are responsible for a lot of downtime right now,” explains Meister.

	Consistency is needed too. Programmed settings ensure a product/count runs the same way each time. Integrated quality control is another wish-list entry. There is a focus on quality assurance to ensure correct count and eliminate any broken or rogue doses.


	Today’s electronic counters share several attributes: flexibility, tool-less changeover, easy cleanability, and faster speeds. The RX-12 Enhanced solid-dose counter from BellatRx can be specified in single, twin, or quad configurations to achieve speeds up to 240 bottles/min (bpm). The flexible system handles solid doses from 2–40 mm and containers from 1–4 in. Other features include simplified product flow and tool-less changeover (1).

	The Countec DMC-60T Multi-channel electronic counter, equipped with a 12-track counting tray and twin filling nozzles, is handled in the US by Key International and counts up to 6000 tablets per minute. The DMC series of counters have programmable logic controllers, touchscreen operator interfaces, and infrared and LED optical sensors with dust-sensing windows. The sensors detect each dose on multiple planes so data can be analyzed from each object that passes. “The machine collects data about the wholeness of the tablet or capsule and checks if multiple doses are falling past at the same time,” explains Jonathan Braido, marketing manager at Key International. Dark-time adjustability helps detect broken or double tablets. “If the Countec machine identifies a broken tablet, it will trace the dose to a bottle, then reject the bottle,” reports Braido. The flexible Countec unit handles metal, glass, or plastic containers up to 120 mm in diameter. Large access areas, tool-less disassembly, quick-release connectors for product-contact parts, perforated stainless-steel product feeding trays for dust and chip collection, and dust-collection ports expedite cleaning and changeover. “It will usually take about an hour to fully clean the machine,” says Braido. Changeover to a different container (same product) involves a few minutes to change container funnels and make a few tool-less adjustments.  

IMA’s SwiftPharm 2 (SP 2) counter is a second-generation, high-speed machine (see 

). Dust-immune electrostatic field sensors replace the photoeyes or optics used by competing systems. The electrostatic field sensors not only ensure accurate counting, but also increase uptime because there’s no need to stop the line mid-run to clean the sensor when handling extremely dusty products. In operation, the falling product disturbs the field. Measuring this disturbance allows the detection of overlapping product as well as the differing mass of broken pieces so bottles containing fragments can be rejected. In addition, an optional dual-sensor configuration provides a redundant count. Both sensors must agree each dose is correct and properly counted. IMA also equips its counters with machine-vision systems built by Antares Vision. Cameras mounted over the trays detect broken and chipped doses as well as rogue product. Tool-less disassembly means one operator can remove all product-contact parts, clean the machine, and install another set of product-contact parts so the counter can run while the first set of product-contact parts is being cleaned. This changeover requires as little as 30 minutes. When changeover only involves a different container size (product remains the same), changeover time can drop to less than five minutes.

The next generation CFS-622*4 tablet counter from NJM Packaging, shown in 

, offers cleanability, quality control, and onboard inspection. The CFS-622*4 tablet counter can be equipped with a CountSafe inspection system from Optel Vision plus an automated rejection system. The system features a two-axis linear robot that can be adapted and integrated to Cremer electronic counters. The tool-less ejector rejects defects: wrong shape, wrong color, wrong size, broken product, or rogue. Different alarm levels make it possible to stop the line if a rogue product is detected, but simply reject the fragment, if a broken solid dose is located. The vacuum-reject arm captures any flawed solid dose product before it falls into a container and deposits it into a closed bin. Virtually all other inspection systems reject filled containers with a flawed solid dose, resulting in considerable rework or waste. A preseparator collector and HEPA filter prevent the escape of any substance or dust.

	The intermittent-motion Cremer CFS-622*4 tablet counter consists of four modules. It relies on a feedscrew for container transport and reaches speeds up to 200 bpm. A continuous-motion model, the Cremer CFI-622 tablet counter, can be configured with up to 10 modules, handles containers with starwheels, and reaches speeds up to 400 bpm.

	A servo-motor-driven mechanical vibration system eliminates the mechanical springs used in other vibratory systems. The result is a stable and controlled movement of the solid dose, which provides the consistent action needed for a camera inspection and efficient counting accuracy. “Proper separation and delivery of the product into the container are key to having an accurate count,” explains Mark Laroche, vice-president of sales at NJM Packaging.

In addition, a patented system, which relies on linear servo technology, feeds tablets out of the hopper. Changeover to a new bottle (same product) takes 10–15 min. Cleaning in preparation for filling another product can be accomplished in as little as 20–25 min, depending on standard operating procedures. Product-contact parts can be removed without tools, leaving a simple-to-clean frame.

	To further reduce line clearance time, NJM Packaging offers the TFE (tablet-free entrapment) conveyor (see 

). Generally installed after the counter, it eliminates the time-consuming task of disassembling or removing the conveyor chain between runs to check for trapped products. The TFE conveyor chain drops down for tablet recovery, and integral windows and lights help operators see any trapped tablets inside the conveyor.

	Monoblock systems also are available and offer a high level of flexibility. IMA’s four-in-one Uniline machine integrates desiccant dispensing, solid-dose counting, cottoning, and capping on a single base (see 

). Changeover occurs with the push of a button.

	Uhlmann’s Integrated Bottle Center can integrate counting and capping with desiccant feeding, cottoning, and induction sealing, plus inspection systems such as cameras and metal detectors. Options include the IBC 120 model, capable of speeds of 150 bpm, and the faster IBC 240 machine (240 bpm). The IBC 120 model handles a slightly broader container range with volumes from 30–1500 cc, diameters from 25–125 mm, and heights from 45–200 mm (2). 

	Romaco also supplies integrated systems with Romaco Bosspak RTC Series or VTC Series counters as the centerpiece (3). The RTC counters feature rotary continuous-motion container filling and tool-less changeover. Positive tablet/capsule separation and vibration-free stream filling help ensure products enter the container singly and maximize count accuracy. A range of models offer one, two, four, or 12 counting stations and speeds from 15–200 bpm (4).

At the opposite end of the solid-dose counting spectrum, there are smaller units for quality control (QC) counts, stock checks, and short runs. Kirby Lester’s latest standalone tablet counter, the KL1 model, features a reduced footprint, fast counting speed, and interchangeable product-contact parts (see 

). Sharp Packaging Solutions purchased seven units plus product-contact parts for each product it runs to perform hourly QC checks on all bottling lines and small quantity bottle filling. Return on investment is expected within 10 months (5). Patented optic sensing technology “sees” doses falling past the batch sensors to count up to 15 doses/sec. After completing the count, the tablets/capsules are emptied from the KL1’s clear tray into a waiting bottle or vial. Cleaning takes approximately 60 seconds. The entire pill path is removable for cleaning with soap and water or alcohol and a lint-free cloth.

	Another small unit designed to confirm counts, the Countec DMC-CQ2 tablet verification counting machine from Key International, “can replace a visual count inspection and ensure quality of the tablets or capsules,” reports Braido. Suitable for quality checks on the packing line or in the lab, the counter handles tablets or capsules of any shape or size and counts up to 9999. An easy-to-use touch screen with a built-in printer supports QC and data management. An adjustable container platform accommodates different bottle heights and diameters.


	Selecting the best counter for an application involves many considerations. First and foremost, “Understand what you want to accomplish,” advises Laroche of NJM Packaging.

	Braido notes that other questions to be asked include: What products are to be handled (e.g., tablets or capsules)? Is the product coated or uncoated? Dusty or not dusty? How big are the batches to be handled? How many counted tablets and/or bottles/minute are needed for your production line?

	“If the machine is changing over three times a day, an electronic counter is better suited,” says Meister of IMA Pharma. “If one product runs all day, a slat counter might make the most sense.”

	“Machines also should be user-friendly for operating, cleaning, and changeover,” says Braido. Other considerations include bottle sizes, cost and labor requirements, room size, and changeover complexity and related downtime. Many pharmaceutical manufacturers and contract packagers specify a counter with dedicated product-contact parts. “They need a solution where they can swap out the entire ‘pill path’ to eliminate any chance of cross-contamination between counting runs of different medications,” explains Mike Stotz, senior marketing manager at Kirby Lester. “They want to change these parts out quickly, clean them easily, and store them for specific 

	Specifications also must consider integration with upstream and downstream equipment and communication between machines so stop and restart signals can be sent when problems arise and are cleared. It’s also important to plan sufficient accumulation between machines to prevent downtime for minor faults. “You don’t want the counter to stop because it’s waiting for bottles, nor do you want containers backing up into the filler due to a downstream slowdown or stoppage,” says Meister.

	Finally, is onboard inspection needed? “Inspection of tablets has been a number one wish-list item for a long time,” reports Laroche. However, onboard inspection can slow production speeds, and small, acceptable variations have been known to cause false rejects.


	New technologies will be able to count and fill even faster and more efficiently. “Future counting machines will be easier to operate, which leads to less user error and will provide better data management capabilities,” says Braido.

	Meister predicts we’ll see more counters equipped with inspection systems. “There’s always the push for more quality,” he explains.

	Laroche agrees. “Inspection is what customers are requesting. It will take a while, but once we start seeing integrated inspection systems, it will become a requirement.”

,” accessed May 5, 2015.
	2. Uhlmann, “

,” Machine Product Information, accessed May 19, 2015.
	3. Romaco, “

Romaco Tablet and Capsule Counting Machines – Suited for All Requirement

s,” accessed May 21, 2015.
	4. Romaco, “

,” accessed May 21, 2015.
	5. Kirby Lester, “


	This article initially appeared in the July issue of 

 
	When referring to this article, please cite it as H. Forcinio, “Ensuring Correct Tablet Count,” 

Packaging

Electronic pharmaceutical tablet counters meet demands for accuracy, flexibility, speed, compact size, easy cleanability, and quick changeover.

Electronic Tablet Counters Improve Efficiency

	The Benjamin Franklin axiom, “An ounce of prevention is worth a pound of cure,” holds true for cleaning of pharmaceutical manufacturing lines and is one of the ways to build quality into drug products. Not enough companies focus on preventive measures, however, as evidenced by the high number of FDA 483 observations related to cleaning, sterilization, or a lack of appropriate procedures, noted Shabana Chaudhry, an aseptic trainer at Allergan, in a presentation at the CBI Institute of Validation Technology Network’s conference on Cleaning Validation and Critical Cleaning Processes (Aug. 18–20, 2015).

	Also at the conference, Jeanne Moldenhauer, president of Excellent Pharma Consulting, discussed the need for a paradigm change to preventing contamination problems rather than merely reacting to them. "A 2011 study (1) indicated that the cost for the pharma industry to do reactionary control mechanisms is 10 times higher than if the company prevented the contamination from happening," Moldenhauer told 

. "Unfortunately, few companies have widely implemented preventative measures." 

	Prevention, said Moldenhauer, includes actions such as routine cleaning and disinfection, but can go beyond that using technology available today, such as a mold barrier to prevent mold growth. As another example, she explained, "A gowning room used a paint that prevented microbial growth and resulted in extremely low counts even though there would be a high number of bacteria present during the initial gowning process (coming in from outside in street clothes)."

Cleaning and cleaning validation best practices


	Having a robust cleaning validation program is another key to preventing contamination problems. Beth Kroeger, technical services manager at STERIS Life Sciences, spoke at the conference about how to ensure a successful validation. “When you make a validation plan, it is crucial to understand the manufacturing process and the manufacturing and cleaning equipment, as well as the role of the equipment in the process,” Kroeger explained to 

. "The process lifecycle approach calls for having this understanding up-front."

	She explained the importance of having all the involved departments-including quality, process engineering, and manufacturing-work together to identify and prevent potential problems even before making the validation plan. For example, a piece of equipment may have a difficult-to-clean section, such as an air-liquid interface, baffles, or vortex breakers. "You need to be aware of this equipment design so you can have the correct cleaning procedures in place," said Kroeger.

	Although in many cases, process engineers must work with existing equipment (whether or not it is easily cleaned), it is ideal to involve all departments when initially specifying equipment and to consider the cleaning processes as part of this specification, added Kroeger.

	Periodic maintenance of tanks and clean-in-place equipment is a crucial preventive measure to ensure that tanks are passive and reduce risk for rouge buildup. "Rings in buffer tanks is a hot-button issue that has recently been noted by FDA," said Kroeger. "Although these tanks are typically cleaned with water, a best practice is to implement a periodic cleaning (once a month or once a quarter) with alkaline detergent."

	Another best practice is designing a cleaning process by using coupon studies to look at residues and do a risk analysis for soils. "What you think is the hardest to clean residue may not be, but a coupon study may help identify this," noted Kroeger.


	Preventing contamination requires quality systems to be in place and functioning properly, noted Chaudhry. These include proper facility design, a cleaning and disinfection program, clear and detailed standard operating procedures, and personnel training. At the conference, Chaudhry described common sources of contamination, which are predominantly human-borne but include some that are routinely overlooked, such as the water system, parts washer, new equipment, cleaning equipment, incubators, and others. In addition to controls and cleaning-and not missing these overlooked areas-maintenance, validation, environmental monitoring, and quality unit oversight are crucial, said Chaudhry. "If any part of the quality system is not in control, the facility is not in control and the risk for contamination increases," she explained. With effort and attention, however, it is possible to have control over processes and thus better prevent contamination.


	1. J. Macher, “Business Case for Quality,” presentation at the Pharmaceutical Quality Systems (ICH Q10) Conference (Arlington, VA, Oct. 2011). 

Production Trends

Preventing contamination requires quality systems to be in place, including routine cleaning, a robust cleaning validation program, and preventive maintenance.

Equipment and Processing Report-09-16-2015

Best Practices for Cleaning a Filling Line

Electronic Tablet Counters Improve Efficiency

An Ounce of Prevention: Cleaning and Preventive Measures Deter Contamination Events