Amber Lowry is an associate editor at UBM plc.

Amber Lowry

Being knowledgeable of the most advanced equipment and technologies available for manufacturing is essential for tackling and preventing production issues.

	Over the past several months, equipment innovations have been introduced and updated to enhance pharmaceutical manufacturing operations. The following is a sampling of such products and equipment options.

	New single-use technologies for biopharmaceuticals

	Sartorius Stedim Biotech’s new automated parallel bioreactor system, ambr250, is a high-throughput bioreactor system suited for rapid cell-culture perfusion culture process development to increase therapeutic antibodies production (1). The system combines 12 or 24 single-use perfusion mini bioreactors with associated single-use perfusion components, all controlled by one automated workstation, as stated by the company. The mini bioreactors have a working volume range of 100-250 mL.

	According to Sartorius Stedim, the combination of this multi-parallel processing capacity and fully single-use perfusion vessel allows for more perfusion culture experiments in less time and cost compared to traditional perfusion-enabled benchtop bioreactors. The system is suitable for a range of hollow fiber perfusion applications, which allows for design-of-experiments studies for high cell density process development in a quality-by-design approach.

	The system, which is a collaborative effort between Sartorius Stedim and other biopharma companies, uses a perfusion bioreactor assembly based on the company’s branded bioreactor design.

	Components such as high efficiency spargers, perfusion pump chambers, and an industry-standard hollow fibre for cell retention filter enable intensified cell culture processing. The system’s fully assembled and irradiated perfusion bioreactors come with all necessary components, including single-use sensors to continuously monitor pressure at both the culture fluid inlet and permeate outlet, which enables online monitoring of transmembrane pressure and standard parameters such as pH and dissolved oxygen.

	“Transitioning from fed-batch to perfusion culture offers the potential to reduce capital intensive risk by using 1-2000-L single-use bioreactors instead of 10,000-L production volumes in stainless steel,” said Dr. Barney Zoro, ambr product manager at Sartorius Stedim Biotech, in a company press release.“[A]mbr 250ht perfusion is a predictive process development tool that could lower the cost of goods of antibody production, as well as significantly shortening development timelines.”

	Watson-Marlow Fluid Technology Group (WMFTG) has added Q Clamp, a new sanitary tri-clamp connection for single-use fluid path applications, to its BioPure brand (2). The clamp can provide a secure connection in less than 12 seconds, according to the company.

	The clamp does not require any tools for application or removal and can be closed using one hand. The company reports that a double-sided ratchet ensures that the lightweight clamp remains shut in the event that one side should fail.

	The clamp comes with a tamper-evident identification technology solution for tri-clamp connections, which can also be used for identification through eight color options, allowing procedures to specify relevant areas of the process, according to WMFTG. Application of this solution is possible either before or after the clamp is assembled.

	The connection tri-clamp, which is backed by a validation pack for non-wetted components, is manufactured and packed in an International Organization for Standardization (ISO), Class-7 cleanroom and meets current ISO and 

 <87> and <88> industry requirements. The company also confirms that the clamp has been evaluated for extractables using a single solvent approach.

	The MagMixer MBE Series from SPX Flow is a hygienic magnetic mixer that meets current operational standards and regulatory compliance and is suitable for low-viscosity blending, dissolving solids, and solid suspension in sterile applications (3). 

	The mixer has bottom-mounted magnetic agitators, is engineered using computational fluid dynamics, and uses Lightnin A281 3-blade hybrid axial/radial impellers in an open construction that facilitates improved cleaning and sterilization. Magnetic impellers remove the need for shaft and seals, which significantly reduces the risk of leakage or microbial contamination, according to the company. SPX Flow reports that in addition to optimizing product flow, the impellers also produce high levels of torque capacity in a compact form.

	Robust ceramic bearings reduce the risk of breakage, are product-lubricated, and enhance mixer stability, reliability, and performance, as stated by the company. The bearings can be easily replaced on-site with no need for a spare impeller.

	The unit is controlled by a variable frequency drive and covers a power range from 0.09 to 7.5 kW (0.12-10Hp) with operating speeds between 200-1000 rpm.According to SPX Flow, “magnetic lifting of the impeller reduces the load on the surface of the bearings and enables the mixer to continue to run until the mixing vessel is completely empty, improving formulation mixing.” Unit range options include a variety of bearings, O-rings, drive, and body materials.

	Munson Machinery’s rotary batch mixer with a integral lump breaker provides inline de-agglomeration of compacted bulk materials before gently blending batches uniformly in one to three minutes regardless of disparities in the bulk densities, particle sizes, or flow characteristics of batch ingredients, according to the company (4).Material entering the new De-Clumper model RDC-1515-SS is de-lumped by dual rotors with three-point, single-piece, stainless steel breaking heads rotating with minimum clearance inside a curved, perforated bed screen. On-size material passes through bed screen apertures, which range from 1/16 to 2½ in. (25-64 mm) in diameter, immediately before entering the stationary inlet of the mixer.

	The mixer has a useable batch capacity of 50 cu ft (1.42 m³) and weight capacity of 4000 lbs (1814 kg) and is equally effective in blending of batches from 100% to as low as 5% of rated capacity, as stated by Munson. As the mixer’s horizontal drum rotates, proprietary mixing flights tumble, turn, cut, and fold the material, imparting minimal energy to the batch, minimizing or eliminating degradation.

	Munson states that inline stacking of the system, when above the stationary inlet of the model 700-TH-50-SS mixer, minimizes headroom requirements while eliminating the need for flexible connections or hard piping between the units. Synchronized shafts rotate at 120 rpm to prevent heating and degrading of the product.

	The internal flights lift and direct the entire batch into the stationary discharge spout for evacuation without leaving residue of material behind, eliminating waste and improving product quality while facilitating rapid, thorough cleaning.

	A heating, ventilation, and air conditioning (HVAC) control system from Telstar automatically controls the particle concentration level in cleanroom air to maintain the required environment, depending on the cleanroom grade classification and activity (5).

	The HVAC control system is connected to a particle counter and air-handling unit, and it adjusts the number of air changes to reach the maximum level of particles permitted in the room according to its GMP classification, following the regulations stated in European Union GMP Annex 1 and ISO Standard 16644-1.

	Depending on the room, the system can reduce energy consumption by more than 40%, according to the company. The system maintains pressure, temperature, and humidity variables under stable conditions, and provides steady air changes, without oscillations. 

	1. Sartorius Stedim Biotech, “Sartorius Stedim Biotech Launches New Ambr 250 High Throughput Bioreactor System for Perfusion Culture,” Press Release, March 14, 2018.
	2. Watson-Marlow Fluid Technology Group, “Biopure Q-Clamp is Compatible with a Wide Range of Connector Geometries,” Press Release, Feb. 8, 2018.
	3. SPX Flow, “New Hygienic Magnetic Mixer Designed for Exceptional Performance and Reliability,” Press Release, March 5, 2018.
	4. Munson Machinery, “Rotary Batch Mixer with Integral Lump Breaker,” Press Release, Dec. 22, 2017.
	5. Telsar, “Telstar Designs an Innovative HVAC Control System that Provides Automatic Regulation in Clean Rooms,” Press Release, Jan. 25, 2018. 


	Vol. 42, No. 4
	April 2018
	Pages: 48–50

	When referring to this article, please cite it as A. Lowry, “New and Updated Equipment Streamline Manufacturing Operations,” 

Articles

Equipment and product innovations improve pharmaceutical manufacturing tasks.

New and Updated Equipment Streamline Manufacturing Operations

Staying up to date on the most advanced technologies is important for improving operational tasks, especially in the laboratory. The following is a sampling of the latest products available to optimize laboratory operations for biological products.

	The NGC Fraction Collector from Bio-Rad Laboratories provides flexibility and collection capacity for analytical or preparative chromatography applications when used with the company’s NGC Chromatography System (1). Features include a benchtop Peltier cooling module for temperature-sensitive biomolecules and an optional enclosure to protect samples from environmental conditions while allowing full access during a run. Because the enclosure is optional, the same fraction collector can also be used for reverse-phase chromatography applications.

	The unit, which runs on ChromLab 5.0 Software, allows researchers to choose how to collect and when to access their fractions. The system can be activated to collect based on slope, percent of buffer from pump B, pH, and detector signals. According to the company, front-to-back dispensing provides access to fractions before method completion for improved speed of downstream analysis. Researchers can also choose the type of collection vessel they prefer for each phase in a method, including deep-well plates, tubes, bottles, and carboys (with prep-rack adaptors for large-scale purification). Adding two new fraction collectors to each NGC System can further expand capacity, according to a company press release.

	Automated Control Concepts’ (ACC) Lab Owl is a bioreactor control and information system that integrates laboratory instrumentation for data collection and analysis for labs using cell culture and fermentation applications (2). Its user-friendly interface can be used with bench-top bioreactors in development labs, in pilot plants, and in manufacturing, according to company. The system is available in flexible and scalable form factors to meet the needs of labs dependent on bioreactors for cell culture and fermentation experiments.

	“We’ve discovered that most scientists felt that there had to be a better way to control their experiments and collect and analyze their data,” said ACC CEO Michael Blechman, in a press release. “Lab Owl provides that better way. Developed in collaboration with scientists from several major biotechnology companies, Lab Owl is easy to configure, flexible in control, and integrated with analytical instruments--allowing scientists to focus on innovation.”

	Corning and CytoSMART Technologies, a company spin-off from The Netherlands’ Eindhoven University of Technology that manufacturers ultra-compact, live-imaging systems and cell counters for biological laboratories, have partnered to simplify mammalian cell counting in laboratories (3). The new Corning Cell Counter uses technology developed by CytoSMART and offers enhanced speed for automated cell counting. The device, which is exclusively supplied by Corning, will be available through Corning´s global sales team and worldwide distribution network.

	Cell counting is a crucial subcultivation step in the cell-culture workflow, according to the companies. Many laboratories still perform manual cell counting using a hemocytometer or a counting slide viewed under a microscope. In comparison, the Corning Cell Counter returns an accurate and precise digital cell count in a few seconds. The device can accommodate the standard reusable hemocytometer or disposable slides, but microscopic viewing in order to perform the cell count will no longer be needed, as stated by Corning.

	The Freezemobile freeze dryer from SP Scientific is suited for high-quality preparation of peptides, proteins, plant materials, and organic tissue (4). Unlike many traditional freeze dryers that employ coil condensers, these freeze dryers use a smooth-walled condenser that enables fast defrost and removal of ice for faster turn-around time and also alleviates vapor port ice blockages other systems are prone to, according to the company.

	The freeze dryer is offered in 25- and 35-liter condenser sizes and is suitable for labs with multiple users, as well as labs with high quantity of product through-put. The device has a -85 °C condenser to enable the removal of a variety of solvents and can be configured for exact user processing requirements.

	Individual samples can be added or removed without interrupting the instrument, thereby enabling users to continue their experimental process without having to wait for another freeze dryer to become available. 

	The freeze dryer also includes a range of single- and multi-tiered horizontal “T” type manifolds, which can be used to dry multiple flasks simultaneously, and provides an optimized platform for drying large quantities of samples in bulk flask format. To improve the laboratory operating environment, the freeze dryer can also be supplied with a low noise, oil-free vacuum pump, as stated by SP Scientific.

	Additionally, the company offers a control system that offers a range of control features to meet the demands of various applications. Vacuum levels, condenser temperature, ambient room temperature, and component status are all displayed on a clear LCD display, while alarms warn of any unwanted process deviations. 

	The company’s Freezemobile Shell Bath helps to decrease manifold freeze-drying time. The tool rotates sample flask on its axis, thereby coating the interior surface of the flask with frozen product. According to the company, this increases the surface area of the product-to-energy input, as well as vapor removal, helping to reduce the freeze-drying process to the shortest time possible when utilizing flasks and a manifold system.

	1. Bio-Rad Laboratories, “Bio-Rad Launches NGC Fraction Collector for NGC Chromatography Systems,” Press Release, Jan. 8, 2018.
	2. Automated Control Concepts, “New Bioreactor Control System Integrates Lab Instrumentation for Optimal Data Collection and Analysis, and Aims to Liberate Labs From Routine Processes,” Press Release, Jan. 16, 2018. 
	3. Corning, “Corning and CytoSMART Announce Agreement for Cell Counting Device,” Press Release, Feb. 2, 2018.
	4. SP Scientific, “Flexible Freeze Drying for Life Science Labs,” Press Release, Feb. 8, 2018.


	Vol. 42, No. 3
	March 2018
	Pages: 58, 69

	When referring to this article, please cite it as A. Lowry, " Improving Operations in the Lab," 

New and emerging products advance bio/pharma laboratory operations.

Improving Operations in the Lab

Improve operational tasks in the laboratory with the latest product offerings.

New Products Optimize Lab Operations

	Understanding the role of both people and technology in the maintenance of data integrity in the analytical laboratory is crucial as companies move toward predominately electronic systems. While technology has helped make the preservation of data easier, it is just as important that the people operating these systems are aware of the relevance of each step involved in the process, says Steve Hayward, product marketing manager at BIOVIA, Dassault Systèmes. Hayward spoke with 

 about what it takes to successfully maintain the integrity of data in the modern laboratory.

: What is most important to consider for lab data integrity?

: The people in the lab and the digital solutions they use play an equal role to ensure data integrity. Technology helps to make it easy to execute, as well as to proof integration. The technology of the past decade has allowed for better preservation of data, from the time of capture in electronic format through to its analysis and use in reports. 

	This digital thread of information can now be preserved throughout an organization, but it is critical that the people who use the technology are aware of why each process step is relevant, and adhere to them at all times.  Automation is also a key factor. The best way to ensure this consistency is by making it easier and less time-consuming to perform each routine activity, while passively recording each action for regulatory compliance. This can be achieved by automation-enabling technology.

: How can data integrity in the lab be improved by the use of electronic systems?

: Electronic data systems that automate data transfer allow for the reduction or even elimination of human intervention, and therefore, the reduction of errors. Audit trails will prove the integrity of the data or show the details of the change. This means any data alteration--voluntary or involuntary--will be either not possible, or any changes will be recorded so it will be obvious that data have been modified. 

: What are the data integrity risks associated with computerized systems and how can they be diminished?

: In the modern lab, it is a fact of life that there will be multiple electronic informatics systems, where the landscape’s complexity has usually scaled with the size and age of the company.  Data are constantly passed back and forth amongst these systems, and may be transformed during the process.  At each step along the way, the process must be validated to ensure that the integrity of the data, and the digital thread of information, is preserved. Recently, the trend has been toward consolidation of these disparate systems into more comprehensive solutions, where the data are stored in a single, centralized system and accessed as needed, without the need for constant transformation and transposition. While validation is still necessary, this removes both the day-to-day complexity in the lab and much of the risk of compromised data integrity.

: How can manipulation of electronic records be identified and prevented?

: In the lab, all data files should only be accessible through a software system which requires secure user login, and tracks all modifications as part of the audit trail. A computer’s operating system-level login is not sufficient for this purpose.  Although many solutions exist to enforce audit trails, in many cases, a user must log in to multiple different systems, sometimes more than once, just to complete a single task.  With ever-increasing regulatory requirements, routine tasks can take longer. A goal in the modern digital lab is to minimize the number of systems a scientist must use for any given tasks, which increases efficiency, centralizes the management of audit trails, and minimizes the potential for data corruption or manipulation.

: What can companies do to improve lab data integrity when using electronic systems?

: Many paper-based processes have already been eliminated from the lab during the first wave of digital lab solutions. However, the multitude of different electronic systems in place, often from many different vendors, means that data still must be transposed and often transformed as it moves from one system to the next. Each of these steps must be configured and validated to ensure both regulatory compliance and the preservation of the data’s integrity.  Where possible, systems should be consolidated to remove the multiple different data file types and connections between software from different vendors.  It is also of the utmost importance that users are appropriately trained on the systems, and that their qualifications kept up-to-date.


	Vol. 42, No. 2
	February 2018
	Page: 30

	When referring to this article, please cite it as A. Lowry, " Navigating Data Integrity in the Modern Lab," Pharmaceutical Technology 42 (2) 2018.

Steve Hayward, product marketing manager at BIOVIA, Dassault Systèmes, discusses the importance of both technology and people in the modern laboratory.

Navigating Data Integrity in the Modern Lab

In recent years, data integrity in analytical laboratories has become a major concern for both pharma companies and regulators. Common violations detailed in recent FDA warning letters (1-5) include incomplete or inaccurate data from various laboratory tests. More specifically, factors such as inconsistent audit trails, disconnect between various electronical data management systems, quality inadequacy, as well as human error and manipulation have led many companies down a path of noncompliance. The prevalence of such violations emphasizes the growing focus on data integrity from regulators.
	
	Companies are now faced with the challenge of streamlining digitized data integrity methods in the lab by understanding both the level of accountability necessary from personnel who use these systems in addition to recent technological advances, according to Steve Hayward, product marketing manager at BIOVIA, Dassault Systèmes  (see 

	To address current lab data integrity violations and prevent new ones, it is important to stay up-to-date not only on regulatory standards, but on the latest technologies available to help companies meet these requirements. Below is a sampling of products to help maintain data integrity in the lab.

 states that it is unacceptable to store data electronically in temporary memory, and advises companies to design a laboratory information management system (LIMS) or an electric batch record system to automatically save each separate entry (6).
	
	LabVantage 8.3 from LabVantage Solutions is the latest version of the company’s LIMS (7). The system features a dynamic auditing function to aid in the GxP-compliant management of data in temporary memory. The function also helps to maintain a complete audit trial based on a full history of analytical testing, including temporary and permanent data, changes between temporary and permanent data entries and the reason for the change, identity of the user entering the data, date and time of data entry, as well as electronic signatures and mandatory reason for changes.

	Other system features include improved reagent integration within the advanced batch control module; additional improvements to array and plate handling, specifically with persistent auditing on reasons, activity, and electronic signatures; and better storage explorer capabilities to search for open and empty spaces for new samples.

	Additionally, the company has expanded its inventory of Laboratory Execution System (LES) Worksheets, which can help streamline electronic record-keeping. In addition to the existing LES worksheets based on test methods, the new worksheets are available for quality control (QC) batch testing, instrument certification, and finished product sample testing, which can facilitate the review of multiple analytical tests on a single sample, according to the company.

	Another applicable tool is LabVantage’s Chemical Viewer, which has been added to the company’s electronic laboratory notebook (ELN) and LES. Users can upload a chemical file to a chosen location or copy it into the control system. The viewer offers a modifiable graphic rendering of the chemical structure defined in the file. 

	ACD/Labs has added new updates to its ACD/Spectrus Platform, the company’s suite of informatics software products (8). Version 2017.1 provides improved functionality to a range of solutions, including MetaSense, the company’s metabolite identification software. It also introduces Luminata, a new solution for the management of impurity data, according to ACD/Labs.

	The updated software includes expansions and improvements for the ACD/Spectrus, an instrument format support across analytical techniques. A new liquid chromatography/mass spectrometry deconvolution algorithm for high-resolution mass spectrometry data also includes usability-improvements. Additionally, tools for analyzing samples by nuclear magnetic resonance and mass spectrometry have been enhanced.

	According to ACD/Labs, the company’s metabolite identification software has been updated to bring new metabolic pathways into the prediction algorithm and provides easier navigation of data in ways that are better aligned to scientists’ workflows.

	The new Luminata solution enables organizations to establish effective impurity control strategies through the assembly of analytical, chemical, and process information in a single enterprise informatics environment, following quality-by-design principles, as stated by the company.

Software supports regulatory compliance for microbiology QC labs

	The latest version of Lonza’s MODA-EM software enables microbiology QC laboratories to comply with the latest regulatory guidelines (9). Version 3.3 of the software meets daily challenges faced by QC laboratories with additional features focusing on data integrity, data visibility, and data review, creating an improved workflow experience with enhancements in analytics and reporting, according to Lonza.
	
	Including a streamlined application and a risk-based validation solution, the paperless software has a fully searchable audit trail that allows scientists to track changes made through a sample’s lifecycle and saves time on routine activities such as settling plate exposure times, organism identification, and master data management and review, according to a press release statement by Sinéad Cowman, European Union business development manager for Lonza Informatics.

	Additionally, the software features improved scheduling and calendar capabilities for simplified sample management. It also offers web-based dashboards so that metrics and results can be accessed from anywhere with an Internet connection, as stated by the company. According to Lonza, scientists in QC laboratories are also supported with a validation documentation package that meets current industry standards and regulatory requirements, with execution and pre-validated service options available.

Synthetic chemistry offering to cloud-based R&D platform

	IDBS has added a synthetic chemistry offering that extends its E-WorkBook Connect cloud-based platform, part of the company’s E-WorkBook Cloud, an R&D cloud platform that supports internal, external, and hybrid data management and research needs (10).
	
	With the now-extended E-WorkBook Connect, organic chemists can share data externally and collaborate with partners using a secure work space. Additionally, chemists are provided with the ability to transfer all experimental data to an on-premise or hosted E-WorkBook environment.

	While some contract research organizations are allowed direct access to a secure corporate ELN, others are mandated to maintain a local installation of the desktop ELN. Both approaches are an additional overhead that IDBS’ platform resolves, according to the company.

	“Extending the capabilities of E-WorkBook Connect with stoichiometry, to support synthetic organic chemistry, addresses the data management challenges and costs associated with collaborative research, especially when it comes to communication,” said Ian Peirson, head of product planning at IDBS, in a company press release.

Automation workstation for clinical and regulatory compliance

	Tecan, a provider of laboratory instruments and solutions in biopharmaceuticals, forensics, and clinical diagnostics, announced in a Jan. 25, 2018 press release that it will add the Fluent Gx Automation Workstation for clinical and regulated laboratories to its range of liquid handling solutions in 2018 (11). 

	According to the company, the workstation solution will meet a host of laboratory needs, including clinical diagnostics, next-generation sequencing, and nucleic acid purification, and provide the advanced process security features required for regulated applications in clinical, GXP, and QC facilities.

	In addition to the liquid handling and workflow features available from related company products, the solution will also include a suite of software features needed to comply with rigorous regulatory requirements, including FDA 21 

) Part 11, as stated by the company (12). The Fluent Gx Assurance Software provides full sample tracking capabilities and secure electronic records, together with a LIMS interface, multi-level user management, and electronic signature options to ensure compliant and audit-ready operation.

	The solution also includes software utilities to simplify system management. The compliance checker provides rapid, fully automated verification of the integrity of all executable software components, while the data audit tool performs a similar function for electronic records, ensuring data integrity, according to the company.

	1. FDA, FDA Warning Letter 320-16-13, Mar. 19, 2016.
	2. FDA, FDA Warning Letter 320-17-15, Jan. 6, 2017.
	3. FDA, FDA Warning Letter 320-17-24, Feb. 14, 2017.
	4. FDA, FDA Warning Letter 320-18-02, Oct. 16, 2017.
	5. FDA, FDA Warning Letter 320-17-51, Sep. 12, 2017.
	6. FDA, 

Guidance for Industry, Data Integrity and Compliance With CGMP

 (April 2016).
	7. LabVantage, “LabVantage Is First to Launch Compliant-Ready LIMS Addressing FDA Draft Guidance on Data Integrity,” Press Release, Oct. 10, 2017.
	8. ACD Labs, “ACD/Labs Announces Updates to its Spectrus Informatics Platform,” Press Release, Oct. 18, 2017.
	9. Lonza, “Latest MODA Software Release from Lonza Enables Companies to Meet Updated Regulatory Guidance,” Press Release, Oct. 25, 2017.
	10. IDBS,“IDBS Adds Synthetic Chemistry to its E-WorkBook Connect Platform,” Press Release, Dec. 14, 2017.
	11. Tecan, “Tecan to Launch Fluent Gx Automation Workstation for Use in Regulated Laboratories,” Press Release, Jan. 25, 2018.  
	12. 


	Vol. 42, No. 2
	February 2018
	Pages: 28–31

	When referring to this article, please cite it as A. Lowry, "Maintaining Lab Data Integrity," 

This article explores lab data integrity violation trends, as well as a sampling of the latest technologies that can help avoid them.

Maintaining Lab Data Integrity

How can technology create a foundation for avoiding regulatory violations and preserving data integrity in the lab?