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Significance of Root Cause Analysis and Challenges in Implementing Appropriate CAPA - Dr Sivakumar, Chief Scientific Officer, Enaltec Labs
Incorporating Quality by Design in the Pharmaceutical Manufacturing Process - Lum KwongToh, Regional Marketing Manager, Asia Pacific West Pharma
Breaking the Code - Colin Morgan, Product Manager for Software Solutions Videojet Technologies
Automising Drug Discovery - Dr Shripad Joshi, Country Sales Manager - Life Sciences Agilent Technologies
How to Make Tablets from Potent APIs - Dr Harald Stahl, Senior Pharmaceutical Technologist GEA Pharma Systems
Continuous Granulation - Opportunities to Increase Efficiency in Pharmaceutical Production - Dirk Leister, Leader Technical Marketing Thermo Fisher Scientific
Challenges in the Changing Pharmaceutical Regulatory Scenario In India - Dr J Ramniwas, CEO, Sai Pharma Solutions Inc
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Significance of Root Cause Analysis and Challenges in Implementing Appropriate CAPA Identifying the root cause for market complaints, out of specifications (OOS), deviations can be challenging, but a number of tools can help to investigate the root cause so that corrective and preventive actions can be effectively implemented.
DA’s Quality System Regulation as well as the new guidelines on “Quality Systems Approach to Pharmaceutical Current Good Manufacturing Practice Regulations” requires effective corrective and preventive actions (CAPA) with root cause analysis (RCA) as reactive tool for system improvement to ensure that significant problems do not re-occur. The CAPA system is the most frequently inspected subsystem. No or inadequate procedures for corrective and preventive actions (CAPA) and missing root cause analyses are amongst the most frequently found deviations in FDA warning letters. Having compliant procedures for CAPA and compliant management is a must for any firm in the Medical Device manufacturer, Pharma Industry, regardless of marketplace. Successfully implementing and documenting corrective and preventive a c t i o n s ( C A PA ) i s o n e o f t h e c r i t i c a l processes in a medical device and pharmaceutical manufacturing company’s day-to-day quality operations. CAPAs carry significant implications for both product quality and compliance with FDA regulatory directives, and remain vital to any company’s ability to address incidents that inevitably arise in the manufacturing processes. Due to this, it is critical to take necessary steps to prevent them from re-occurring.30 per cent of the warning letters issued by FDA is due to- failure to establish and maintain procedures for implementing corrective and preventive action and root cause analysis, as required by FDA.
Dr B V Sivakumar Chief Scientific Officer Enaltec Labs 10 May 2014
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According to BRC Global Standards, root cause analysis is a problem solving process for conducting an investigation into an identified incident, problem, concern or nonconformity. Root cause analysis is a completely separate process to incident management and immediate corrective action, although they are often completed in close proximity. The individual(s) tasked with ascertaining the underlying root cause must look beyond the obvious and make a serious attempt to pinpoint root cause. The good news is that there are tools available for investigators to facilitate their quest for ascertaining root cause. Most regulatory bodies have similar requirements for CAPA and complaint management or contain pointers to a standard such as ISO 13485:2012. Table 1 depicts some of the common regulatory requirements faced by device manufacturers and Pharma Industries. Understanding Root Cause: To determine root cause, it’s essential to first understand what the term means. The best way to explain root cause analysis is to use the example of a weed. Weeds can be difficult to remove once they start to grow and spread. On the surface, the weed is easy to see; however, the underlying cause of the weed, its root, lies below the surface and is not so obvious. Conversely, the word root in root-cause analysis refers to all underlying causes and not just one. That is why it is imperative
The word root in root-cause analysis refers to all underlying causes and not just one. That is why it is imperative to be openminded and objective when performing root-cause analysis. Pharma Bio World
21 CFR 820.198
21 CFR 820.198
ISO 13485:2012, Clause 8.5.2
ISO 13485:2012, Clause 8.5.3
Ministerial Ordinance 169, Article 63
Ministerial Ordinance 169, Article 64
SOR/98-282, Section 57
ISO 13485:2012, Clause 8.5.2
ISO 13485:2012, Clause 8.5.3
Production and QC
Production and QC
Production and QC
Production and QC
Table 1: Common regulatory requirements faced by device manufacturers and Pharma Industries
to be open-minded and objective when performing root-cause analysis. Beginning an analysis with a preconceived idea of what appears to be an obvious root cause could result in the incorrect root cause being identified and the wrong correction being implemented. Effective Root Cause Analysis: There is a plethora of tools available for assisting in the identification of root cause. The underlying goal is to achieve an accurate root cause, so the appropriate corrective actions can be pursued to prevent recurrence. If the incorrect root cause is identified, it is inevitable that the incorrect solution will be implemented. Some of the tools available for quality professionals to employ in ascertaining root cause include the following: • The five whys, a simplistic approach exhausting the question “Why?” • Fishbone diagram, a causal cause and effect diagram also known as the Ishikawa diagram. • Pareto analysis, the 80/20 rule premised on a predefined database of known problems. • Fault tree analysis, a quantitative diagram used to identify possible system failures. • Failure modes and effects analysis (FMEA), which lists all potential failure modes and the potential consequences associated with each failure mode. 12 May 2014
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The fishbone diagram is prevalently used as a tool to identify defects associated with design, development, and product realisation activities. The underlying premise is that defects are typically driven by process variation. The Five ‘Why’s? The Five Whys Model: The five whys model is a root-cause analysis tool originally created by Japanese inventor and industrialist Sakichi Toyoda. The effectiveness of the model became apparent in the Japanese automotive market in the 1960s and ‘70s. Toyota became a big proponent of the five whys model, which ultimately became a critical component of the company’s problem-solving training and the foundation for its scientific approach to performing rootcause analysis. The 5 Whys is a technique used in the analyse phase of the Six Sigma DMAIC, eg, Define, Measure, Analyse, Improve, and Control methodology. It is a great Six Sigma tool that does not involve data segmentation, hypothesis testing, regression or other advanced statistical tools, and in many cases can be completed without a data collection plan. Determine the Root Cause: 5 Whys By repeatedly asking the question “Why” (five is a good rule of thumb) you can peel
away the layers of symptoms which can lead to the root cause of a problem. Very often the ostensible reason for a problem will lead you to another question. Although this technique is called “5 Whys,” you may find that you will need to ask the question fewer or more times than five before you find the issue related to a problem. How to Complete the 5 Whys: 1) W r i t e d o w n t h e s p e c i f i c p r o b l e m . Writing the issue helps you formalise the problem and describe it completely. It also helps a team focus on the same problem. 2) Ask why the problem happens and write the answer below the problem. 3) If the answer you just provided doesn’t identify the root cause of the problem that you wrote down in Step 1, ask Why again and write that answer down. 4) Loop back to step 3 until the team is in agreement that the problem’s root cause is identified. Again, this may take fewer or more times than five Whys. Pharma Bio World
The Fishbone Diagram It has been made famous by Kaoru Ishikawa and is similar to the five whys model in that it captures the causeand-effect relationship of problems. The fishbone diagram is prevalently used as a tool to identify defects associated with design, development, and product realisation activities. The underlying premise is that defects are typically driven by process variation. Sources of variation are placed into six categories to facilitate the root-cause analysis process: people, methods, machines, material, measurements, and environment. Pareto Analysis The Pareto analysis is better known as the “80/20 Rule.” The fundamental concept of Pareto analysis is the identification of the most likely sources of variation that are resulting in product defects and QMS non-
conformances. As a part of the root-cause investigative process, the investigator and/or investigative team identifies a number of potential sources causing defects and non-conformances to occur. The sources of the most prevalent causes become the focus of the investigative process. Pareto analysis is an excellent tool for supporting risk management activities because of the need to focus on big-picture product issues. Fault Tree Analysis F a u l t Tr e e A n a l y s i s i s a d e d u c t i v e investigative process in which an undesired state of a system is analysed using Boolean logic to combine a series of lower-level events. This analytical method is employed as a tool for ascertaining system failures and identifying risk removal and risk mitigation activities. For example, in system engineering the fundamental goal is assess and address
all “undesired states.” As high-level events associated with fault tree analysis, each failure condition is categorised premised on the severity of its effect. Simply stated, the more severe a condition, the more extensive the fault tree analysis. Failure Mode and Effect Analysis (FMEA) The Failure Mode and Effect Analysis method called FMEA is an established and proven method. It was developed and introduced in the sixties by the NASA and continuously expanded. Nowadays it is used routinely in many industries such as automotive, automation, chemical i n d u s t r y. T h e F M E A m e t h o d i s a l s o expanding to the pharmaceutical and medical device industry. It is the first risk analysis method mentioned in the list of Methods and Tools in the ICH Quality Risk Management Q9 guideline. Users of the method are appreciating the tool because its results are condensed in
Pictorial Depiction of Fish Bone Diagram
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a very compact central document easy to review. The FMEA helps to detect failure in a preventive way, to implement corrective action and continuously record the improvements. Moreover, the FMEA process itself triggers a great team building, training and quality awareness and spirit among the team members: a central aspect to provide excellent products and processes. Challenges Associated with CAPA One of the biggest challenges for companies is to complete investigations and actions in a timely manner. In many cases, incorrect assumptions are made that everything is an isolated incident. In other instances, problems are not corrected and everything is blamed on a single employee or a simple laboratory error or the system fails to ensure that a problem does not extend to other lots and the incident recurs. The ultimate criterion for adequate correction is to ensure that it doesn’t happen again. CAPA was adopted as a new quality management tool following the introduction of the ICH Q10 guideline. According to the ICH Q10 document, which was adopted by the FDA in April 2009 as an industry guideline, a pharmaceutical Quality Management System (QMS) consists of four central elements: 1) P r o c e s s p e r f o r m a n c e a n d p r o d u c t quality monitoring; 2) Corrective action and preventive actions; 3) Change management; 4) M a n a g e m e n t r e v i e w o f p r o c e s s performance and product quality. The guideline states that a pharmaceutical company should have a system in place to detect and evaluate non-conformances to take respective corrective and preventive actions. Among other things, the information regarding non-conformances can result from complaints, deviations, 18 May 2014
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One of the biggest challenges for companies is to complete investigations and actions in a timely manner. In many cases, incorrect assumptions are made that everything is an isolated incident. recalls, observations at audits and inspections, or from monitoring findings. The examinations within the system must have the objective of determining the actual root cause. As a result, the process and product should be better understood so that improvements can be continual. Sources that lead to Corrective and Preventive actions include, but are not necessarily limited to: Quality Audits (Internal/External); Non-Conforming Results/Products; Customer Complaints; Risk Management; Process Performance Monitoring; Management Review; Failure. One of the most fundamental steps in the CAPA process is completing an evaluation of the actions that were taken. These evaluations must not only verify the successful completion of the identified tasks, but also assess and adequately document the appropriateness and effectiveness of the actions taken. Have all of the objectives been met? Did the actions correct or prevent the problem (root cause) with adequate assurance that the same situation will not happen again? Have all the recommended changes in adequate detail been completed, verified, and fully documented? Has training and appropriate communications been implemented to assure that all relevant employees understand the situation and the changes that have been made?
and the Medical Device industries should have robust requirements for pursuing corrective action and the need for addressing Customer Complaints, OOS, and Deviations. Regardless of the industry, it is imperative that accurate root cause be ascertained. There is a plethora of tools available to support root-cause analysis. If proper training is not provided to employees and accurate root causes are not determined, chances of manufacturers from pharma and other industries implementing incorrect solutions may increase. Applying the wrong solution may potentially impact device safety and efficacy, so it is imperative that great care and attention to detail be employed as part of the root-cause investigative process. References: 1) “www.fda.gov/
2) ”Corrective and preventive action”. wikipedia. org/wiki/Corrective_and_preventive_action 3 ) “ C o m p l e t e P r o c e d u r e o f C A PA f o r Pharmaceutical Industry”, formulation.vinensia. com/2012/01/complete-procedure-of-capafor_06.html 4) Guidance for Industry, fda.gov/.../20054136b1_05_pharmaceutical%20CGMP.pdf 5) FDA-compliance-pharmaceuticali n d u s t r y, c a r a c o r p . c o m / F D A - c o m p l i a n c e pharmaceutical-industry.php 6) FDA, EU expecting manufacturers to use CAPA to halt OOS, determine ‘root cause’ Find articles.com/p/articles/mi_hb5677/is_9_5/
ai_n29033453 7) CFR code of federal Regulations Title21,
It is difficult to fathom the logic behind telling FDA that a manufacturer has no intention of complying with any aspect of the QSR. Pharma Industries
accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/ CFRSearch.cfm?CFRPart=820References 8) ISO 13485:2012 9) ICH Q9, Q10 Pharma Bio World
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Incorporating Quality by Design in the Pharmaceutical Manufacturing Process The current pharmaceutical market has faced a variety of challenges, including increasing expectations for quality from endusers and regulatory agencies driven by concern for patient safety. The pharmaceutical and biotech industry as a whole has had a series of regulatory challenges relating to issues such as lack of cGMP compliance, high end-of-line rejections and lack of best practices for compliance in general. Such incidents can cause drug shortages, which also have a direct impact on meeting patient needs. The cost for such issues to both companies and patients is significant.
ndustry suppliers play a critical role to help pharmaceutical manufacturers meet the needs of patients and regulators. As the industry evaluates the adoption of Quality by Design (QbD) techniques as a way to address these challenges, it needs to turn its focus from ascertaining drug product quality predominantly by end-product testing to achieving effective and efficient manufacturing processes by harmonising pharmaceutical development, quality risk management and pharmaceutical quality systems through science-based quality manufacturing. The goal during QbD development is to have predefined objectives with emphasis on the product and understanding the manufacturing process. An in-depth understanding of container closure components along with their manufacturing process will enable science-based decisions to support pharmaceutical manufacturing control strategies. Aspects of container closure systems critical to drug product quality can be established during the drug development cycle by identifying potential attributes of the component and applying various risk management tools. It is possible to combine and coordinate process knowledge from multiple-unit operations to achieve a holistic picture of the entire drug manufacturing process, which can incorporate the science of component manufacture. An understanding of how drug formulation and component
Regional Marketing Manager Asia Pacific, West Pharma 20 May 2014
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m a n u f a c t u r i n g p r o c e s s f a c t o r s a ff e c t quality will lead to: • Effective technology that will reduce setbacks when moving from development to commercialisation, realising time and cost savings • Data-driven knowledge to identify critical quality attributes and establish control strategies • Specifications based on how and why the rubber formulations, components and process factors impact drug product quality • Benefits throughout the lifecycle of a given product through trending of data for proactive management and effective continuous improvements Elements of the QbD Approach The importance of the container/ closure system to the efficiency of the manufacturing process and the quality of the final drug product is significant and should not be minimised. The QbD approach takes into consideration the entire supply chain from raw materials through distribution and drug packaging. Quality characteristics are engineered to meet the requirements of the pharmaceutical manufacturer and help promote protection/compatibility of drug product. There are three critical elements to a true QbD pharmaceutical product. These are: • Drug product • Drug manufacturing process • Container/closure system
As the industry evaluates the adoption of Quality by Design (QbD) techniques, it needs to turn its focus from ascertaining drug product quality predominantly by end-product testing to achieving effective and efficient manufacturing processes. Pharma Bio World
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• Develop control strategy • Ensure quality of the product throughout the product lifecycle • Increase product and process knowledge • Increase transparency and understanding for regulators and industry • Evaluate changes Consideration of all these factors during development of elastomeric components can achieve a well-understood component and robust processes that 1) deliver a component meeting the QTPP and 2) are controlled by defined steps within the manufacturing process. During commercial-scale manufacturing, the proactive trending of component performance on a continuous basis provides a major advantage through early detection of potential issues and further optimisation of the control strategy to ensure reliable level of highquality components.
QbD delivers an improved, data-driven output providing manufacturers with superior product and process understanding that minimises process risk, emphasises patient-critical quality requirements and enhances drug product effectiveness Convergence of these three operations is vital to establishing the critical quality attributes necessary for control of the drug product and the process to enable continuous improvements (See Figure 1). The following important QbD elements can be used to develop and produce components with a commitment toward enhancing drug product quality: • Quality Target Product Profile (QTPP) • Critical Quality Attribute (CQA) • Quality Risk Management (QRM) • Knowledge Management (KM) • Critical Process Parameter (CPP) • Control Strategy (CS) • Lifecycle Management (LCM) • Continuous Improvement (CI) 22 May 2014
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The QTPP forms the basis for drug product formulation and process development in a QbD framework. A series of considerations should be made for the QTPP of a sterile product. Some of these considerations include the desired product performance based on the intended clinical setting, dosage strength and delivery mode, pharmacokinetic characteristics, drug product quality criteria, sterility and the container closure system itself, just to mention a few. Scientific rationale and quality risk management are used to define CQAs and CPPs for a given product and process in support of achieving the QTPP. The information developed to determine the CQAs and CPPs will help to:
Managing Total Cost of Ownership As the industry evaluates its Total Cost of Ownership (TCO) model, it will begin to adopt QbD techniques. Such an adoption requires a significant up-front investment. However, QbD delivers an improved, data-driven output providing manufacturers with superior product and process understanding that minimises process risk, emphasises patient-critical quality requirements and enhances drug product effectiveness. A more efficient process results in a final deliverable that is a much higher quality product with well-understood and controlled sources of variation. (See Figure 2) When industry evaluates its Total Cost of Ownership model, the importance of the use of a primary package component that has been developed and produced by QbD techniques should be a significant consideration. Such a product will minimise variability downstream by pushing improved understanding and controls upstream into the supply chain. Pharma Bio World
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capital expenditures more effectively and ultimately allows more revenue to be generated for the pharmaceutical or biotech company. Regulatory expectations are that pharmaceutical and biopharmaceutical companies understand their supply chain and are accountable for assuring the inputs into the finished drug product are of highest quality.
The use of components based on a holistic QbD process assures the company it is using a well-understood product that has been developed to achieve highest patient safety and lowest risk for the pharmaceutical manufacturer. Risks such as end-of-line rejects, loss of production capacity and compliance inadequacies will be minimised, driving cost of ownership down significantly. The adoption of QbD by suppliers to the industry is the future. Although some pharmaceutical companies are still grappling with the adoption of this new model, forward-thinking suppliers have already implemented this technique. Products have been developed using the systematic, science-based approach encouraged by the regulatory agencies. Such a development process can deliver a product to the industry that provides the ultimate product and process understanding; has quality built around the patient; improves transparency; and provides improved Total Cost of Ownership to the pharmaceutical customer. Total Cost of Ownership is the analysis of price, risk, quality, service and delivery 24 ď‚ƒMay 2014
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performance in evaluating the overall cost of a product versus its benefit. If the use of a certain product solution can minimise manufacturing downtime, lower end-ofline rejections, minimise compliance and regulatory risks, and provide other related benefits, then the positives associated with this product are worth an incremental price differential. End-of-line rejections due to component d e f e c t s a r e a n e x a m p l e w h e r e To t a l Cost of Ownership benefits can be clearly recognised for the pharmaceutical customer. In a case study, a move to an improved component allowed a customer to reduce rejections from 0.75 per cent of all filled vials to 0.02 per cent . Not only is this a significant cost savings in dealing with the rejected drug product and its final disposition, it allows more product to go out to market for use. This minimises concerns with product shortages in the field, helps to manage
The use of components based on a holistic QbD process assures the company it is using a well-understood product that has been developed to achieve highest patient safety and lowest risk for the pharmaceutical manufacturer. At the c e n t e r o f a To t a l C o s t o f O w n e r s h i p analysis by the company must be hard-dollar savings coupled with the consideration of significant savings in dealing with fewer regulatory and quality challenges, potential loss of revenue and the long-term negative impact to brand equity. Additionally, if saved resources can be better applied to other areas of the business, the potential benefits are exponential. Suppliers that provide components critical to the drug manufacturing process or drug product should consider QbD as a critical input to the pharmaceutical supply chain as it directly supports a lower Total Cost of Ownership model. References: (1) ICH Quality IWG Points to Consider Guide for ICH Q8/Q9/Q10 Guidelines (2) Nasr, Implementation of Quality by Design (QbD) â€“ Current Perspectives on Opportunities and Challenges Topic Introduction and ICH Update Office of New Drug Quality Assessment www.fda.gov/downloads/AdvisoryCommittees
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Contact West today. +91 40 4940 1111 Literature.AsiaPaciﬁc@westpharma.com www.westpharma.com ® West and the diamond logo, By your side for a healthier world™ and NovaPure are registered trademarks or trademarks of West Pharmaceutical Services, Inc. in the United States and other jurisdictions. Copyright © 2014 West Pharmaceutical Services, Inc. #8258 • 0214
Breaking the Code Product coding during the packaging process is a vital part of pharmaceutical manufacturing. Perhaps to a greater degree than in any other industry, pharmaceutical packaging demands the highest quality variable coding. Legibility and contrast are a pre-requisite when it comes to regulatory and traceability codes and yet, coding solutions must also facilitate line productivity and seamless integration for today’s competitive environment.
he coding and marking of pharmaceutical products are key to reliable product identification which helps companies fight counterfeiting and most importantly help prevent errors in administering drugs to patients. As pharmaceutical product coding regulations change, so does the threat of coding errors which may necessitate costly re-work and material waste when re-work is not possible and entire batches of products must be scrapped. The reallocation of valuable time and resources to rework products directly affects the ability of a 24/7 manufacturing facility to run effectively, reducing throughput and profits. It has been reported, according to a Videojet survey, up to 70 per cent of coding errors are caused by operator error, with approximately half of these caused by mistakes during manual data entry to the coder and job selection. In addition, it was discovered that coding errors are not the deviation, but the norm. Message selection can take place centrally, at one coder or through a barcode scanner. But typically an operator has to select a job at one location unless extensive integration to manufacturing systems has occurred. While manufacturers can typically put additional checks in place during packaging to address coding errors, this does not necessarily handle the issue effectively or efficiently. By working with an experienced printing partner with extensive printing capabilities and system design know-how, they can create and implement a coding process with built-in code assurance elements that limit the potential for user error. Simplifying the process of message selection and entry through the use of automation and software tools can greatly prevent coding
Product Manager for Software Solutions Videojet Technologies 28 May 2014
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errors, increasing productivity, reducing waste, and minimising operational costs and risk management. Automated Code Assurance “Poka-yoke” is a Japanese term that can be translated as “mistake-proofing”. When applied to manufacturing operations, a poka-yoke is any measure put into place during the manufacturing process designed to prevent human errors before they occur. The right printing partner can help a pharmaceutical manufacturer design a comprehensive system that implements various poka-yoke principles through advances in printing technology, eliminating coding and marking errors. Intelligent User Interface Using an operator interface designed with existing Code Assurance tools can simplify message selection, restrict operator input and automate messages. For example, the printer’s user interface can include features such as separate user authorisation for code creation and job selection, restricted and pre-approved coding parameters, and job storage under intuitive names that speak directly to the product being coded. In addition, the user-friendly interface allows calendar selection for dates to eliminate erroneous formats due to regional or product differences, and link product dates that automatically use the “Sell By” date to determine the “Use By” date. Other simplified options can include, setting calendar rules to prevent the selection of certain dates like weekends or holidays, data selection drop down menus that eliminate incorrect key presses, confirmation of data to allow a print job to proceed, approval of data prior to every job
Up to 70 per cent of coding errors are caused by operator error, with approximately half of these caused by mistakes during manual data entry to the coder and job selection. Pharma Bio World
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change to ensure the correct job has been selected, and using calculated dates using comprehensive date rules. These design options should be an integral part of new generation thermal transfer printers, as well as ink jet coders, large character marking and thermal ink jet product lines. Software and Network Message Control Implementing windows-based software can provide additional support, isolating code design from the production floor and eliminating the need to load individual message onto each printer interface. This PC-based message creation and management tool serves to remove human error from the coding equation. In addition, network controls can further reduce or remove entirely operator input, pulling from authoritative data sources, making sure the right codes go to the right printers. These network-based coding messages can be distributed to multiple coding and labeling devices across a line, facility or even several facilities. Using automated systems to simplify message creation and management greatly reduces the potential for human error and eliminates coding mistakes. As part of a broader quality assurance system, these controls should be synched with existing Supervisory Control and Data Acquisition (SCADA), factory networks,
In addition to the costs associated with rework and scrapped printing jobs, coding mistakes can result in fines and penalties. Regulations on drug product coding are driven by security and emerging technologies Manufacturing Execution System (MES) and Enterprise Resource Planning (ERP) systems. Open data base connectivity (ODBC) allows coding messages to be created and stored in SQL, Access, Excel and generic databases. This comprehensive connectivity will allow job information access from any enabled coding or labeling system, ensuring efficiency, as well as protection against operator error. In addition, pharmaceutical manufacturers can integrate full programmatic controls from external manufacturing execution systems to ‘push’ data and command directly to coders. Regulatory Concerns In addition to the costs associated with rework and scrapped printing jobs, coding mistakes can result in fines and penalties. Regulations on drug product coding are driven by security and emerging technologies. Medication dispensing errors, the proliferation of easily available drug products via the internet and the emergence of false or incorrectly labelled products are all key concerns in the healthcare industry. The introduction of safety features (mandatory
seals and unique pack identification) on packaging for certain medicines will provide assurance to patients of the authenticity of medicines they receive through healthcare systems where these medicines are at risk of counterfeiting. There are different coding technologies suitable for packaging types for example, cartons are the most common packaging formats for the pharmaceutical industry and must be marked with the highest quality human readable and machine readable codes to ensure the product’s traceability. Bottle coding is also extremely common and they can be coded in numerous places like the bottle side, underside, label or cap. Vial marking and eye dropper bottle marking are challenging because of their small size and the complex sequence of packaging operations. Coding these packaging types is best achieved when the coder is integrated into an original equipment manufacturer (OEM) packaging specifically designed as high quality codes require precise material handling and rigid vibration-free coder mounting. Failure to comply with these standards can bring fines and even product recall – both costly and extremely damaging to any brand. While some might consider this the cost of doing business, it no longer has to be. By working with an experienced printing partner to design a coding process with built-in code assurance elements (also known as poka-yoke principles), pharmaceutical manufacturers can eliminate errors before the label or mark is even applied to the product. Utilising the latest in manufacturing automation and software tools to simplify the process of message selection and entry can prevent coding errors, enhancing productivity and increasing the bottom line.
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Pharma Bio World
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Automising Drug Discovery The imminent demand for speed to market new drugs requires that today’s drug discovery labs need to work much faster and with greater efficiency. Also, scientists today have much higher number of target molecules with potential as drugs. This in turn has slowly replaced the traditional methods with automation. The article gives an outlook of the growing trend of automation in laboratory processes.
he imminent demand for speed to market new drugs requires that today’s drug discovery labs need to work much faster and with greater efficiency. Also, scientists today have much higher number of target molecules with potential as drugs. This in turn puts enormous pressure on the scientists to screen them all with traditional methods. This is where automation has potential to play a major role and help speed up the manual processes. Automation plays a very big role in Compound Management, High Throughput screening of every drug discovery programme in Pharmaceutical and biotech companies. Agilent’s BioCel systems integrate plate management, liquid handling, barcoding and other essential functions for any efficient compound library management group. This is a big area for Automation solutions. High throughput workflows such as ADME also rely on Automation solutions for consistency and reproducibility of analyses and to make workflows involving thousands of compounds more reliable, efficient and manageable. Newer Tools and Technologies
Dr Shripad Joshi
Country Sales Manager - Life Sciences Agilent Technologies
32 May 2014
Automising Drug Discovery.indd 32
The need to automate sample preparation has played a very important role in development of automation tools over the last couple of decades. There has been significant improvement both in hardware and software. From standalone units to fully integrated systems, key sample preparation and creative walk-away automation approaches with personalised customer service are possible to provide complete solutions for your laboratory. Various novel tools available are: • Liquid Handling systems can be used to dispense with high accuracy from 100nl to 200nl in 96 and 384 well microplates with either fixed or disposable tips for specific applications. • Ve r t i c a l P i p e t t i n g S t a t i o n d e l i v e r s industry-leading speed and unparalleled performance for sample handling and liquid-transfer applications. The two-axis
positioning stage provides access to all quadrants of 96-, 384-, and 1536-well microplates. An intuitive user interface allows the operator to create and run complex pipetting protocols with ease. • Compact, high speed microplate handler for benchtop integration. Microplate Handler is a compact, microplate storage and handling system designed for integration with a variety of laboratory devices. It features a high-speed robot, and its modular design provides the flexibility and scalability required to meet the needs of the most diverse laboratory applications. It can be powered by the software or accessed through its ActiveX control for integration into any other software platform. While developing innovative solutions with increased throughput and walk-away time, Agilent Automation Solutions has partnered with various laboratory instrument providers to deliver proven, reliable integrations quickly and efficiently. BioCel System automates any microplate-based protocol providing maximum walk-away time and throughput, all in the most compact design. The new Direct Drive Robot brings speed and precision to a system that is both affordable and easily expandable. With modular cells, options for various enclosures, and environmental control, BioCel Systems are tailored to your individual needs. Operated by Agilent VWorks software, the most flexible and efficient scheduling software available, BioCel Systems will deliver the longest walk away time and throughput of any integrated system. Impacts, Advantages and Disadvantages of Automation Automation offers many benefits in the drug discovery process. With the ever spiraling costs, automation can help bring the costs down by increasing capability and capacity, improving quality by eliminating man induced errors and delivering very high precision and accuracy in results. Pharma Bio World
Automation also improves process efficiency and enhances productivity. Incorporating automation in a lab can free scientists from the hours spent manually in setting up and running complicated applications. Other big advantage is that they are customisable, scalable, and can be integrated with 3rd party instrumentation, as well as safe and reliable. However, it is also very critical to ascertain the right kind of automation need for your lab. It is important to choose a right solution based on your throughput needs, stability of reagents and samples, costs, design that facilitates integration into additional workflows in your lab etc. It is also important to note how flexible your processes in the lab are. If one has a frequently changing processes with less throughput needs, having manual processes makes lot more sense. Hence identifying the right solution and a right partner who can partner with you to clearly specify and identify both short term and long term
36 ď‚ƒMay 2014
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goals and thereby provide a solution is very critical.
Future Growth of Automation in Indian Pharmaceutical Industry
Pharmaceutical Industry accounts for about 1/3 rd of the total Automation market in India. With the increasing trend of global pharmaceutical companies outsourcing their R&D work to India, the market is expected to grow. In the last few years Indian Clinical Research Organisations (CROs) have consistently seen routine drug discovery assays and analyses outsourced by their Pharmaceutical clients and this trend is likely to continue. For CRO workflows in particular, reproducible and reliable liquid and plate handling of automation platforms along with barcode tracking capabilities will be quintessential today and going forward. Pharmaceuticals, Biotech and CROs will drive automation growth in India in the coming years.
Many customers across the world have b e n e f i t t e d i m m e n s e l y f r o m A g i l e n t â€™s Automation solutions. One example is that of Rigel Pharmaceuticals, San Francisco, USA. It is a clinical-stage drug development company that discovers and develops novel, small-molecule drugs for the treatment of inflammatory and autoimmune diseases, as well as muscle disorders. Rigel uses functional genomics to discover small-molecule drugs for the treatment of inflammatory and/or autoimmune and metabolic diseases. The company uses a custom built Agilent Biocel 1200 platform as a complete solution for large-scale functional genomics screening from experiment start to finish. The platform covers DNA preparation, transfection, viral production, and analysis of the effects of the DNA on cells.
(Article reprinted from Pharma Bio WorldJune 2012 edition)
Pharma Bio World
How to Make Tablets from Potent APIs With regards to production of solid dosage forms, often containment becomes one of the issues with Active Pharmaceutical Ingredients (APIs) becoming more and more potent along with stressing more on health and safety of the operator. The article deals with the introduction and details of the containment technology for potent APIs.
hen talking today about solid dosage form production, often containment becomes one of the issues. The first is that Active Pharmaceutical Ingredients (APIs) are becoming more and more potent - meanwhile more than 50 per cent of all New Chemical Entities (NCE) are classified potent [Occupational Exposure Limit (OEL) < 10 μg/m 3]. Secondly, health and safety authorities all around the world are putting more focus on the protection of operators dealing with these substances. The third reason is that suppliers of various hardware components have developed a huge variety of containment solutions, making it difficult to decide which is best, even for experienced people. Regulatory Situation It is the first duty of the employer to protect (the health) of its employees. The Control of Substances Hazardous to Health (COSHH) rules provide the following hierarchy of controls: 1) Elimination at the source; 2) Substitution with a less hazardous material or form; 3) R e d u c t i o n o f t h e q u a n t i t y b e l o w critical limits; 4) E n g i n e e r i n g c o n t r o l s t o p r e v e n t intolerable operating staff exposure (contained handling); 5) Administrative controls 6) Use of Personal Protection Equipment (PPE). In many other countries, no legislation enforces this hierarchy. Most of the western countries will monitor the conditions under which operators have to work in the countries from which they import as it is seen as highly unethical to support practices that create health and safety risks in other areas of the world.
Dr Harald Stahl
Senior Pharmaceutical Technologist EA Pharma Systems Pharma Bio World
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There are good reasons for this order of preference; especially that PPE should only be used as a last resort (for maintenance; for necessary, but unforeseen interactions; or if any other method further up in the hierarchy has been considered without success). Why is this? Firstly, PPE only protects the operator. The hazardous substance is not contained, which means that the associated problems are increased: changing of filters, cleaning of rooms and equipment, inside and outside, become major containment issues. It is also important to notice the hidden c os ts as s oc iated with th o s e s y s te ms such as: • Large number of systems required; • Lifetime of suits and filters is limited; • Cost for clean air supply; • Requirement for extra changing and storage areas. These areas are most critical for the performance of the systems. After working in the contaminated area, the outside of the suit is contaminated with API. This contamination needs to be removed, which can be done either by air or wet showers. Whichever method is chosen, the remaining residuals, especially for very potent substances such as hormones or oncology products, can still be critical. The effectiveness of air suits needs to be understood. It is a common misconception they provide total protection, but in reality typical Nominal Protection Factor (NPF) and Applied Protection Factors (APF) are as per Table 1. APFs represent the reality of daily operation. Using the same example as above, this means that if the dust concentration in a room is 3 mg/m³, at best the exposure level for an operator wearing a full air-fed suit will be 15 μg/m³.
When highly potent substances are handled, strict containment is the only way to protect both the operators’ health and the other products. May 2014 37
Air-Fed Half Suit
Filter Air Hood
Table 1: NPF and APF of Equipment Items
Cross Contamination How much cross contamination can be allowed is mainly dictated by the potency of the products handled. The most common definition of an acceptable level is: In the maximum daily dose of product 2 only 1/1000 of the minimal daily dose of the active of product 1 should be found. If we compare now Paracetamol tablets (4000 mg max daily dose) with typical oral contraceptives (containing 0,02 mg as a maximum daily dose) we see that the acceptable level of cross contamination in case 2 is by a factor of 200.000 higher than in case 1. Common ways to reduce the level of cross contamination in multi product facilities include separate production rooms, air looks and pressure cascades. These are fine for less critical products but when highly potent substances are handled, strict containment is the only way to protect both the operators’ health and the other products. How Much Containment is Required? Three main factors dictate how much containment is required and, therefore, which method of containment is best: the nature, especially the potency, of the API handled is of paramount importance; the type of process to be executed; and lastly the working regime of the operators. The Product The potency of a substance is, in most cases, characterised either by the Occupational Exposure Limit (OEL) or by the Acceptable Daily Intake (ADI). The ADI describes the absolute amount of a specific drug substance that an operator can absorb without any negative effect on health. The OEL describes the maximum concentration 38 May 2014
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of a drug substance, which can be tolerated in the air of the production room, without any negative effect to the health of the operators. For established substances, these values are listed in textbooks such as ISBN 07176 2083 2 EH40/2002 OEL 2002 & ISBN 07176 2172 3 EH 40/2002 Supplements 2003. According to those, the OEL for Paracetamol is 10 mg/m³, while the OEL for Ethinyl estradiol is 35ng/m³. It is important to understand that these values are based on certain assumptions. Also, the values might change during the lifecycle of a substance especially after more toxicological data is generated. If an OEL for a substance cannot be obtained from the literature, the value can be determined as follows: OEL = NOEL [mg/(kg x day)] x BW [kg]/V [m³/time] x SF1 x SF2 x... with: • OEL :- Occupational Exposure Limit • NOEL :- No Observable Effect Level • BW :- Body Weight • V :- Breathing Volume • SF :- Safety Factor ADI and OEL are interconnected by the typical breathing volume of an operator (normally estimated as 10 m³/shift). Therefore; ADI = OEL [mcg/m 3] x V[m 3/day] ADI = 10 x OEL [mcg/day] ADI = NOEL [mg/(kg x day)] x BW [kg] Additionally, it is common practice to describe the potency of a drug substance by an easy categorisation system classifying all potent substances from 1 (less potent) to 5 (most potent). This allows production equipment to be classified as suitable for the production of a class X compound, plus it easily shows to operators the potency of the substance. However, when talking
about this simple classification system, two important facts need to be considered: it is not universal, and nearly every company has its own classification system. It also does not take into account the dilution of the API by excipients. The handling of a mixture containing 80 per cent of a ‘class 3 API’ can demand higher containment levels than the handling of a mixture containing 5 per cent of a ’class 5 API’. The Equipment Suppliers not specialists in the field often try to promote ’their containment equipment’ with claims such as ‘3 μg/m³’, ‘better than 1μg’ or even worse ‘OEL 2 μg/m³’. While the last claim obviously is wrong (OEL is a product-related number, it only has the same unit as the containment performance of a piece of equipment), the problem of the other claims is that the test conditions are not defined. This makes it extremely difficult to compare figures obtained by using different test materials, different samplers, different sampler positions or different analytical procedures. After inventing the split valve technology, GEA Buck Valve again took the lead to form [under the umbrella of International Society for Pharmaceutical Engineering (ISPE)] an expert working group, consisting of experts from pharmaceutical companies, engineering companies and containment equipment suppliers. This group developed a guideline in which all of the variants discussed above are defined. The accepted test procedure uses Lactose of a defined grade (other substances are possible), uses the equipment in a defined environment (humidity, temperature, number of air changes), and places the defined samplers in specific positions. The test includes performing the intended task, and collecting air (via the filters of the samplers) for 15 minutes. Analysing the filters gives the quantity of lactose in a measured amount of air, which is the containment performance of the equipment. As the average of 15 minutes is taken, this performance is called Short Term Time Weighted Average (STTWA). It is important to note that the total Pharma Bio World
Figure 1: Intermittent and Permanent Exposure
amount of powder escaping is measured. If dealing with potent APIs, often only a small percentage of a powder mixture is active, while the rest is excipient. The Long Term Weighted Average (LTTWA) is defined as the containment performance over a longer period of time, for example one shift of 8h. Figure 1 shows two different scenarios. It is important to distinguish if there is an intermittent exposure as shown on the left side of Figure 1 generated, eg, by the docking of a container with raw materials to a fluid bed with subsequent operation of the fluid bed, or a permanent exposure as shown on the right side eg, by a tablet press which is not totally tight.
Figure 2: Operator Intake Diagram
Pharma Bio World
How to Make Tablets.indd 39
The Operator Operator exposure is described by Real Operator Intake (ROI) and Real Daily Intake (RDI). These describe the amount of API that gets into the body of the operator while being for a certain period of time in an area with a certain airborne drug concentration. I f we k now the breathing rate of the operator, and the dust concentration in the room, then the drug uptake can be calculated (eg: Figure 2). If the actual RDI is less than the drug specific ADI, the situation is fine. If the RDI exceeds the ADI, measures must be taken to improve the situation. In our example the
most effective way would be to upgrade the granulator by a loading/unloading system with a better containment performance. This visualisation helps the concept to be easily understood. For real situations of course, a detailed risk analysis needs to be done in order to judge the containment performance of an existing installation, or to select the appropriate equipment for an upgrade of an existing facility, or the design of a new facility. Selection of Appropriate Production Technology A typical tablet production consists of thefollowing steps: • Dispensing of API and Excipients; • Milling of Raw materials in order to destroy lumps; • (Wet) Granulation with subsequent Drying; • Dry Milling; • Addition of Lubricants; • Tablet Compression; • Coating; • Primary and secondary packing; The s elec tion of the o v e r a ll ma te r ia l handling system for potent APIs is of paramount importance as it determines more than any other aspects the containment performance of the entire installation. There are fundamentally two choices: systems based on stainless steel or disposable systems. May 2014 39
The selection of the overall material handling system for potent APIs is of paramount importance as it determines more than any other aspects the containment performance of the entire installation. Intermediate Bulk Containers (IBCs) with split butterfly valves are the most commonly used material handling systems for dealing with potent APIs: the entire material required for a batch is loaded, eg, under a laminar flow booth, into the IBC in the dispensing area. This IBC is then moved into the granulation area where it is docked using a split butterfly valve connection to e.g. a discharge station. The raw material is loaded either by gravity (if the room height allows) or via vacuum conveying into the granulator. A mill for breaking lumps should be integrated in between. Granulator For granulation, various options exist. Typically these low dose recipes are best suited to wet granulation. Here there are four main options: 1) Integrated line consisting of a high shear granulator and a fluid bed; 2) Fluid bed spray granulator; 3) Continuous granulation and drying; 4) Single pot processing. The advantage of option 1 is to combine the most efficient granulator with the most efficient dryer to achieve high throughput can be realised. Additionally the high shear granulation process avoids any issues with material separation. The process also creates material with high inter-granular porosity that demonstrates excellent compression behavior. Using the FlexStream™ system developed by GEA Pharma Systems, granules also show excellent flow properties that are most important for a homogenious filling of the dies during compression. Continuous lines such as GEA’s Consigma™ offer a good alternative to conventional batch systems. The ideal solution for the granulation of 40 May 2014
How to Make Tablets.indd 40
potent API is offered by the Single Pot. It combines the process advantages of a high-shear granulator with a minimal surface area and the built-in possibility of cleaning in place to offer an extremely fast changeover. For compression of potent materials GEA’s MODUL™ offers an unbeaten solution. Case Stories Over recent years several companies in India have used the experience and technical excellence of GEA Pharma Systems when installing containment systems for highly potent compounds. These include: Zydus Cadila - Oncology solid dosage formulations • Single Pot Processor - UP 75 & UP 10 (for R&D); • Material Handling Solution: includes IBCs with Buck® MC 100 valve, Vibroflow™ & blending prism, Hicoflex®for discharging API from Isolator & charging into Single Pot Processor, IBC filling station at discharge of Single Pot Processor, Post Hoist Blender and Buck® MC Valve on Courtoy Tablet compression, IBC wash station, WIP drain frame; • Tablet compression machine MODUL™P with HC ECM. Cosmas - Oncology Solid dosage formulations • Flexstream™ size 3 in 10 bar execution; • Material Handling system consisting of 100 L IBCs with Buck® MC 100 Valve, Vibroflow™ & blending pris m, IBC filling station at discharge of Fluid bed processor, Post Hoist Blender, Buck® MC Valve on Courtoy Tablet compression, IBC wash station, WIP drain frame; • Tablet compression machine MODUL™P with C-ECM.
Natco Pharma - Oncology Solid dosage formulations • Integrated line comprising of PMA 150, integrated wet mill, wet product transfer line from High Shear Mixer to FBD, Fluid bed processor Flexstream™ size 3, Integrated Dry mill & Vacuum transfer system for dried granules from FBP to IBC; • Material Handling Solution: IBCs with Buck ® MC 100 valve, Vibroflow™ & blending prism, Hicoflex® for discharging API from Isolator & charging into PMA 150, IBC filling station at discharge of FBP, Post Hoist, Buck Valve on Courtoy Tablet compression, IBC wash station, WIP drain frame; • Tablet compression machine MODUL™P with HC ECM. Project: Ranbaxy - Oncology Solid Dosage Formulations • Single Pot Processor - UP 75 & UP 10; • Handling Solution: IBC with Buck valve, Hicoflex ® for discharging API from Isolator & charging into Single Pot Processor, IBC filling station at discharge of Single Pot Processor, Post Hoist Blender, Post Hoist, Buck ® Valve on Courtoy Tablet compression m/c, IBC wash station, WIP drain frame; • G P S C o u r t o y : Ta b l e t c o m p r e s s i o n machine MODUL™P with wash off line ECM. Conclusion The design of a line able to handle potent APIs in a save way requires an in depth understanding of the required level of protection. Here, the specifics of the API, the dilution with excipients, the containment performance of the equipment and the frequency of operation are the key parameters, which are linked by complex interrelations. Contact: email@example.com (Article reprinted from Pharma Bio WorldJune 2012 edition) Pharma Bio World
Continuous Granulation - Opportunities to Increase Efficiency in Pharmaceutical Production The process step of particle size enlargement by granulation is often used in the manufacturing of tablets and capsules. This is the most widely-used formulation of current drugs. The efficiency of a traditional batch process can improve considerably if the whole process of tablet manufacturing is converted into a continuous process. Granulation is important here, as this influences the compressibility and the release profile of the drug, as well as the quality of the final product. A method for the continuous granulation can be introduced to allow the user to adapt its existing processes while simultaneously designing new developments that utilise sustainable and robust production technologies.
Leader Technical Marketing Thermo Fisher Scientific Pharma Bio World
continuous granulation.indd 41
he mixture includes active ingredients and excipients (fine powders). These ingredients undergo granulation and agglomeration, while keeping a homogeneous particle size distribution. The changes in physical properties, such as better flow behavior, compressibility, low dust formation and, possibly, optimised release profile of active ingredients, favor the subsequent tableting. The changes also render the tableting possible.
bed system. Since the entire process is modular, the critical process steps are relatively easily scaled-up and, one can set up facilities for development (approx. 1 kg/h) to the production scale (approx. 300 kg/h). [Figure 1]
In pharmaceutical production, individual process steps are traditionally executed in subsequent batches. This is also true of granulation. Large vertical mixers are often used and agglomeration takes place inside the vessel by adding the granulating liquid and using fast-rotating agitators and choppers. For a required throughput, these devices have a narrow optimal working point. Thus, for process development, all the way from research and development to production scale, a significant number of scale-up steps have to be performed. These are often considered difficult and risky [Serno, Continuous Granulation - Opportunities to Increase Efficiency in Pharmaceutical Production Kleinebudde, Knop 2007]. Moreover, the yield of pharmaceutical batch production often lies in the vicinity of about 30 per cent OEE [Overall Equipment Effectiveness, Vervaet 2005]. This could be increased through the application of continuous production technologies that have already been established in other industries such as, fine chemicals and food. The process described here can be continuously operated, from mixing of the starting powders to the packaging of the final tablets. The process focuses on the continuous granulation of powder mixtures by using a twin-screw extruder and subsequent drying in a fluidised
Figure 1: Continuous granulation process
Granulation Using a Twin-Screw Extruder In this process, a Thermo Scientific Pharma 16 TSG, with two co-rotating, parallel and partially overlapping screws of 16mm diameter (D) and length (L) to diameter ratio of L/D = 40/1 is being used. [Figure 2]
Figure 2: Thermo Scientific Pharma 16 TSG
May 2014ď‚„ 41
• • • • •
efficient process development and small-scale production. Ve r y s h o r t r e s i d e n c e t i m e s ( 8 - 1 5 sec), thus very low drug demand (cost savings) Tr u e , c o n t i n u o u s p r o c e s s , w h i c h enables rapid process development and precise control. Low space requirements both for development and production machines With a few scale-up steps production rates increase up to 300 kg/h per machine Use of robust PAT instrumentation for process control possible
Drying in the Fluidised Bed – Continuously
Figure 3: Flexibility of Screw Element Design
By using an extruder for the granulation process, several steps of a classical batch granulation can be carried out in a single device. The screw shafts can be equipped with differently-shaped screw elements, which are able to meter, mix or granulate the powder mixture. [Figure 3]. The feeding of the individual powder components, as well as the granulation liquid, is carried out with dedicated, gravimetric feeders. This allows omitting an upstream (batch) mixing process and reduces the possible loss of expensive active ingredients. In addition, the segregation of a premix by storage or transport is also excluded. After introducing the granulation liquid, agglomeration of particles takes place by shear forces between the screw and the extruder barrel. By utilising a suitable screw design and precise control, the process parameters of the extruder granules are produced. These have a defined particle size distribution (small content on under- and oversized particles) and are ideal for further processing in a tablet press. To avoid unnecessary compacting of the material, the extruder 42 May 2014
continuous granulation.indd 42
is operated without nozzle or die at the end of the barrel. The advantages of using an extruder for granulation are: • Large adjusting range of the throughput, eg, 1 to 15 kg/h with the same extruder possible. Allows
The material exiting the extruder is dried in a ProCell LabSystem with GF5 insert (Glatt GmbH) to the required residual moisture. Due to its special design, a plug flow is created in the GF5 insert, which moves in a circular manner through the system. Through adjustable weirs and preciselycontrolled process air, the residence-time can be adjusted precisely, ensuring that uniformly-dried granules with suitable residual moisture are available at the outlet of the dryer.
Pharma 16 TSG
Pharma 24 TSG
Pharma 36 TSG
Screw Diameter (mm) Throughput (kg/h)
Rotation Speed (rpm)
Thermo Scientific Pharma Twin-screw Granulator
Glatt Continous Fluid Bed Dryer GF 5
Bottom Screen Area (m2)
Table 1: Scale-Up of Continuous Granulation Process
Pharma Bio World
Ideally, the combination of the extruder and fluid bed dryer can be operated in the throughput range of 1 to 15 kg/h. Thus, on this system, a process development is possible, as well as a small production of up to 360 kg per day. For productions with higher throughput needs, both technologies, extrusion and dryer, can be adapted by using machines with higher performance. [Table 1] Tableting Some formulations need the addition of other excipients and lubricants (eg, magnesium stearate) before being compressed into a tablet. These are metered gravimetrically into the continuous granulation process after a dry-milling step and homogenized with the granules by means of a continuous paddle mixer. The tableting step concludes the process, but it is possible to directly connect the final packaging in blisters, bottles or boxes. PAT In contrast to the final batch analysis for the product release, the continuous process has to be monitored in real-time, in order to guarantee operation in steady-state.
In pharmaceutical production, individual process steps are traditionally executed in subsequent batches. This is also true of granulation. Here, the process analytical technology (PAT) plays a major role. As described in the FDA guidance [www.fda.gov], the use of PAT serves the immediate release of the product. This enables faster timeto-market, as final and time-consuming inspection and evaluation of the respective analysis can be dispensed. The process of continuous granulation, as described above, provides the opportunity for robust process on-line analytical technologies to be used at various critical process points. For example, a NIR probe can be used directly in the extruder barrel [Figure 4] to monitor the homogeneity, residual moisture and particle properties of the resulting granules. In the fluidised bed microwave and laser diffraction, sensors have proven to be a reliable way to determine the particle size distribution the residual moisture. All gravimetric feeders used in the process
constantly monitor the signal of the highprecision load cells for controlling the dosing and as an overarching parameter of the entire process. In the tablet press, coupled measurements of compaction pressure and NIR signal are established technologies to ensure the quality of each tablet. If a defective tablet is identified, it can blown-out by a directed air stream, thus 100 per cent control is realised. The Know-how Makes the Difference The continuous granulation process can be used for the production of tablets from mixing of the raw materials all the way to the packing of the final drug. It is important to meet the respective process requirements by utilising modular and coordinated components. This enables the yield of classical batch production to increase significantly. Established PAT instrumentation helps in the development and operation of the process. Moreover, it can reduce “time-to-market” for a product significantly. Important for the successful implementation of such a project is the know-how of the involved parties. Thermo Fisher Scientific and Glatt GmbH are offering the ideal prerequisite to achieve the specific customer requirements. Reference 1) P Serno, P Kleinebudde, K Knop, “Granulierung”, Editio Cantor Verlag (2007) 2 ) C Ve r v a e t , J P R e m o n , “ C o n t i n u o u s granulation in the pharmaceutical industry”, Chem Eng Sci 60 (2005)
Figure 4: NIR measurement directly inside the Extruder barrel
Pharma Bio World
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(Article reprinted from Pharma Bio WorldJuly 2011 edition) May 2014 43
Challenges in the Changing Pharmaceutical Regulatory Scenario in India Keeping in pace with the international regulatory scenario, the Indian pharmaceutical regulatory bodies have come out with major changes, which will play a pivotal role to put India on the top of the pharmaceutical map of the world. In pursuance of the same, the article describes the guidelines, implementation and revolutionary changes bring by the Indian Regulatory in the domestic Pharmaceutical Industry.
ndian Pharmaceutical Industry is one of the largest and most advanced among the developing countries. It has over the years made significant progress in infrastructure development, technological capability and hence produced a wide range of products. Understanding the regulatory scenario in this sector is extremely crucial not only due to the rapid and ongoing changes at the global level, largely with reference to Good Manufacturing Practices (GMP), Good Clinical Practices (GCP) and Good Laboratory Practices (GLP) but also due to the onus on the regulatory bodies to ensure a healthy supply of quality drugs at affordable prices to the Indian masses. The Industry today is in the front rank of Indiaâ€™s science-based industries with wide ranging capabilities in the complex field of drug manufacture and technology. It ranks very high in the third world, in terms of technology, quality and range of medicines manufactured. From simple headache pills to sophisticated antibiotics and complex cardiac compounds, almost every type of medicine is now made indigenously. Playing a key role in promoting and sustaining development in the vital field of medicines, Indian Pharmaceutical Industry boasts of quality producers and many units approved have been by regulatory authorities in USA, Japan, EU, Canada, Australia and UK. Now there is no such country in the world where Indian manufactured pharmaceutical products are not available. Keeping in pace with the international regulatory scenario, the Indian
Dr J Ramniwas
CEO, Sai Pharma Solutions Inc Vadodara 44 ď‚ƒMay 2014
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pharmaceutical regulatory bodies have also come out with major changes. This initiative by the Indian regulatory bodies will play a pivotal role to put India on the top of the pharmaceutical map of the world. In pursuance of the same, they have published guidelines on the following topics and now they are in the implementation stage and they are going to bring about revolutionary changes in the Indian Pharmaceutical Industry. Good Manufacturing Practices (Current Schedule M) GMP aims to ensure that drugs and other pharmaceutical products are safe and effective. Since then, Good Manufacturing Practices (GMP) has been considered a seal of quality for pharmaceutical products. GMP has been adopted by many countries worldwide and that includes India which is now the second largest producer of pharmaceutical products in the world. The revised Schedule M advises proper pressure differentials in the areas of operation, which can be achieved through dedicated air handling units with adequate number of air changes. These pressure differentials will help to eliminate/reduce the chances of cross contamination between the products. In addition to these, revised schedule M emphasises proper cleaning validation of the equipment and the processing areas whenever there is product change over. It is also mandatory to display status boards of each equipment material to avoid mixups, which leads to
The current GCP guidelines of India are at par with ICH guidelines of GCP and these guidelines would open new vistas to companies who want to locate their clinical programme in this country. Pharma Bio World
cross contamination. Current Schedule M also gives importance to the stability study of drug substances and drug products to claim the re-test date and expiry date. The Government of India has recognised Pharmaceutical Industry as a technologydriven industry and is focusing on the growth of the industry both for domestic as well as for the expanding global markets. To create a confidence about the quality of drug manufactured in this country, it is essential that the regulators of the country define standard, which are on par with global standards through proper legislation. The Indian Pharmaceutical Industry will have to go a long way for the successful compliance of current schedule M but once compliance is achieved, the Indian pharmaceutical industry will be able to beat any GMP global standard. Change can be good or difficult at times; this largely depends on how prepared a person or an organisation is to adapt and survive with the new set up. Apparently, the small players in India’s pharmaceutical companies have to buckle down to be more equipped with the changes that GMP brings into their businesses. Good Laboratory Practices (Schedule L1) The Drugs & Cosmetics Rules were amended to incorporate Schedule L1 on Good Laboratory Practices and Requirements of premises and Equipments published under notification GSR 780 (E) dated 10th November 2010; a period of two years was granted for t h e P ha rm a c eu t ica l in d u st ry t o m a ke necessary arrangement to comply with the requirement of Schedule L1 before these are made mandatory. Rules laid by Schedule L1 are terse and minimum with an objective to improve the reliability of data without much a d d i n g t o t h e c o s t t o t h e c o m p a n y, particularly for the small to medium scale pharmaceutical industries in India. On the other hand, WHO eyes towards every small aspects of and related to the Pharma Bio World
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laboratory procedure with a view to assure the output scientifically proof. Schedule L1 Good Laboratory Practices (GLP) requirements are applicable to laboratories attached to all manufacturers covered under rules 74 and 78 of Drugs & Cosmetics Rules, which include manufacture of ‘medical devices’, ‘diagnostic reagents’, ‘surgical dressings such as gauges and bandages’, ‘disinfectant fluids’ and ‘sanitising fluids’, etc and hold licenses in forms 25 and 28. These laboratories even though tiny sized, shall be in conformity with all GLP requirements even laboratories attached to the manufacturing units too. This will be particularly useful to the laboratories that already comply with the requirements of Schedule L1 and want to move ahead towards WHO compliance. Good Clinical Practices (GCP) Clinical research is the key to the discovery of latest diagnostic methods and to develop modern drugs for treatment of diseases. Good Clinical Practices (GCP) is an ethical and scientific quality standard for designing, conducting and recording trials that involve the participation of human subjects. Compliance with this standard provides assurance to public that the rights, safety and well being of trial subjects are protected, consistent with the principles enshrined in the Declaration of Helsinki and ensures that clinical trial data is credible. It has been widely recognised that I n d i a o ff e r s u n i q u e o p p o r t u n i t i e s f o r conducting clinical trials in view of the large patient pool, well-trained and enthusiastic investigators and premiere medical institutes available in the country along with considerable low per patient trial cost, as compared to developed countries. The current GCP guidelines of India are at par with ICH guidelines of GCP and these guidelines would open new vistas to companies who want to locate their clinical programme in this country.
However, this is very challenging but helps making a niche in the clinical trial business with global acceptance. Drug Registration and Regulatory Submission Guidelines Drugs defined as New Drugs under the Drugs and Cosmetics Act are subjected to bioavailability/bioequivalence (BA/BE) evaluations through clinical trials, which are reviewed by the Drugs Controller General (India). A drug has a New Drug status for four years from the date of first permission. After four years, the State Licensing Authority grants license but they do not insists for BA/BE and clinical trial studies which are essential to establish the efficacy of the drugs. Central Drugs Standard Control Organisation (CDSCO) has come out with new draft guidelines on the approval of clinical trials and new drugs. CDSCO has decided to adopt Common Technical Document (CTD) format for technical requirements for registration of pharmaceutical products for human use. The same is in use for biological products since 2009 and now this guidance document describes the format for preparation of CTD for marking approval of pharmaceuticals for human use other than biological products. It is apparent that Indian Pharmaceutical Regulatory bodies will be able to expedite the review process of new drug application marketing approval. These guidelines are applicable to for import, manufacture and marketing approval of new drug applications. The adoption of Drug Master File (DMF) and drug product dossier concepts CTD format in tune with the global requirements will help the Indian pharmaceutical Industry to contribute production and speedy entry to the global markets and simultaneously Indian patients would also receive quality and safe medicines. The Indian Regulatory Agencies and Regulatory Affairs professionals will be of immense importance to address these challenges in the right perspective to make May 2014 47
Indian Pharmaceutical Manufacturers competent and regulatory savvy. Pharmacovigilance Programme of India (PvPI) for Assuring Drug Safety The CDSCO, Directorate General of Health Services, under the aegis of M i n i s t ry o f H e a lt h & Fa m ily We lf a re , Government of India, in collaboration with Indian Pharmacopeia commission (IPC), Ghaziabad is initiating a nationwide Pharmacovigilance programme for protecting the health of the patients by assuring drug safety. The programme shall be coordinated by the IPC, Ghaziabad as a National Coordinating Centre (NCC). The centre will operate under the supervision of a Steering Committee. Since, there are considerable social and economic consequences of Adverse Drug Reactions (ADRs) there is a need t o e n g a g e h e alt h -ca re p ro f e ssio n a ls, in a well structured programme to build synergies for monitoring ADRs. The purpose of the Pharmacovigilance Programme of India is to collect, collate and analyse data to arrive at an inference to recommend regulatory interventions, besides communicating risks to healthcare professionals and the public. IPR Issues Concerning Global Pharma Market As per World Trade Organization (WTO), from the year 2005, India granted product patent recognition to all New Chemical Entities (NCEs) i.e., bulk drugs developed then onwards. This introduction of product patent regime from January 2005 is leading into long-term growth for the future, which mandated patent protection on both products and processes for a period of 20 years. Under this new law, India will be forced to recognise not only new patents but also any patents filed after January 1, 1995. Under changed environment, the industry is being forced to adapt its business model to recent changes in the operating environment. India’s Patents Act should ensure that it does not exceed the requirements of 48 May 2014
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Trade-Related Aspects Of Intellectual Property Rights (TRIPS), and that prioritizes access to medicines and public health, while retaining the right to participate in the compulsory license scenario. India should lead a movement of developing nations and create a TradeRelated Aspects Of Intellectual Property Rights (TRIPS) south and G-20 alliance is a step in that direction. Price Control The Pharmaceutical Price Control Policy carried forward earlier governmental initiatives in terms of ensuring quality drugs at reasonable prices, strengthening of indigenous capability for cost-effective production, reducing trade barriers and providing active encouragement to inhouse R&D efforts of domestic firms. The objective is to increase revenue and lower prices of medicines by using fiscal deterrent on Maximum Retail Price (MRP). This change may have had some impact in terms of magnifying the advantage to industries located in the excise free zones. This also succeeded in attracting some small pharmaceutical firms to these zones. This development indicates the heightened sensitivity of the government towards consumer access to medicines at reasonable prices and keeping a check on profit mongering by the industry. In addition to the Quality (GMP, GLP, GCP), Intellectual Property Rights (IPR) and drug price control change initiative by the Indian Pharmaceutical Regulatory Agencies, the Indian Pharmaceutical manufacturers will have to face the challenges in the subsequent areas to remain in completion in to the global market, which are listed below: Quality by Design New Perspective to Product Development With the advent of ICH-Q8 and ICH-Q11, guidelines have revolutionised the product development concept and Quality design has become the buzzword in the
pharmaceutical world and to that India is no exception. The US Food and Drug Administration (FDA) is planning to make the submission of Quality by Design (QbD) document mandatory for all the New Drug Application (NDA) applicants from January 2013. All the manufacturers exporting to the US, will now have to submit an entire set of documents supporting their product, right from its inception stage to the US regulatory authority while filing for approval. The documents submitted should support the companies claim on how effective and efficacious their product is from the design stage itself. Failing which there are chances of their application being rejected by the FDA officials. QbD is a concept that is introduced by the US FDA with an aim to understand the design and development of the pharmaceutical formulations and manufacturing processes to help ensure quality of the end product. On this occasion, the International Pharmaceutical Excipients Council (IPEC) has urged all the Indian manufacturers exporting to the US to update and prepare themselves on the procedural requirements so that they will not be taken by surprise while filing any NDA applications. Design of Experiments (DOE) is the most effective method to achieve product and pro¬cess efficiency and optimisation. Design of Experiment (DOE) studies can help develop process development knowledge by revealing relationships, including multifactorial interactions, between the variable inputs (e.g., component characteristics or processing parameters) and the resulting outputs (e.g., in-process material, intermediates, or the final product). The application of Quality by Design principles is beginning to be well established in the pharmaceutical industry. In particular, the demonstration of the science and risk-based approaches being applied to specific subsets of the drug Pharma Bio World
product design or processing has been discussed intensively during the past several years. Therefore, it is now time to widen the scope of QbD across multiple unit operations, including important aspects of the drug substance. Model development and implementation is a core principle to employing a QbD approach in drug product design and process scale-up. The advantages in taking this approach are realised through the ease of visualisation or mathematical expression of data sets for greater process understanding, which leads to clear decision making and results in superior product quality. There are several model types that can be developed and used at every stage in the QbD process. A favored approach is to begin with the end in mind by outlining up front a clear plan toward model design and development for the drug product process, considering how each model will be used, limitations, assumptions, qualification, and maintenance. The experimental approach to the development of each model should consider the type of model (mechanistic or empirical), selected variables, scale dependency and relationship to the overall drug product process. Once a model has been developed, steps are needed toward implementation through qualification of the model and evaluating uncertainty in predictions. Finally, for models selected for use in commercial manufacture, a maintenance plan is needed to support product life cycle. New Concept in Facility Design Manufacturing plants will increasingly utilise modular building strategies. Facilities will include disposable process equipment, enclosed clean rooms around process equipment, and lean design concepts. This approach provides significant cost savings and reduces start-up time frames for new facilities. Designing outcomes into manufacturing processes via quality-by-design concepts Pharma Bio World
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will be critical to reducing costs, in cr eas ing effic ienc ies , and as s uring regulatory compliance. Flexible facility design will contribute to reduced financial risk as products progress from Phase 1 to Phase 3. Traditional approaches require investment of millions of dollars into a facility for a product to be manufactured in the hope that the candidate will succeed in Phase 3 testing. While agile and adaptable facility designs will become more widespread, dedicated manufacturing facilities will still be required under certain conditions, in cluding large-v olume produc ts with high API and/ or drug product demands, manufacture of highly potent or toxic drug substances, and the need for specialised processes. The Indian pharmaceutical industry shall ensure that essential drugs at affordable prices are available to the vast population of this sub-continent and also continue providing employment for millions. India shall implement all the rules and regulations, which guide, monitor and control the activities of the providers of the healthcare system in the country and shall examine the way to bring them up to international standards. The government should implement the recommendations of Mashelkar committee and constitute the Central Drug Authority at the earliest. The basic course of education should be designed to ensure that the newly qualifi ed pharmacist has the necessary knowledge and skills to commence practicing competently in a variety of settings including community and hospital pharmacy and the pharmaceutical industry. Continuing professional development must then be a lifelong commitment for every practicing pharmacist. Concept of National schools of pharmacy should be established to develop and introduce model curriculum. Pharmacists should become knowledgeable to
participate in medication management and outcome monitoring. Pharmacy profession should orient concept of pharmacy practice at community and hospital pharmacies through appropriate training and compensation. The pharmacy profession will make the clinical trial industry in India to grow to over a billion dollars in the next fi ve years and position itself as a destination of choice for CRO services by way of strict implementation of patent laws, single window clearance of clinical trial protocols by regulatory clearances and shall accord industry status to this sector. India will emerge as a major global player in the fi eld of pharmaceuticals exports and as a provider of quality medicines at low costs. It shall also emerge as a major player in the generic drugs market in USA and Europe. India shall attain new heights in herbal drugs research in shaping Indian Systems of Medicine into a popular system of medic ine of the fut u r e fo r h o lis tic health care and ensuring health care for all - especially for the welfare of the poor. The focus of Indian Pharmaceutical Regulatory bodies is now shifting towards the risk management and science based GMP regulations with the affordability of quality medicines. The need of the hour is to change the attitude by the Indian Pharmaceutical Manufactures from ‘What will happen to others, will also happen to me’ to ‘We resolve to make our industries compliant to regulatory requirements by converting industries research and innovation driven’. This too is true that when our intentions are clear and our efforts are consistent in the right direction, nothing is impossible. All changes and challenges are always tough but facing them with determination yields a long lasting success! Contact: firstname.lastname@example.org (Article reprinted from Pharma Bio WorldJune 2012 edition) May 2014 49
pharma news Novartis’ Zykadia Gets US FDA Nod US Food and Drug Administration (FDA) has approved Novartis’ Zykadia (ceritinib, previously known as LDK378) for the treatment of patients with anaplastic lymphoma kinase-positive (ALK+) metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib. The approval of Zykadia addresses an unmet medical need for patients with this type of lung cancer who have progressed on prior therapy. The approval of Zykadia is based on a pivotal trial that included 163 patients with metastatic ALK+ NSCLC who progressed on or were intolerant to treatment with crizotinib. The most common sites of metastases in the patient population studied were brain (60%), liver (42%) and bone (42%). Zykadia is an oral, selective inhibitor of ALK, an important therapeutic target in lung cancer. ALK is a gene that can fuse with other genes to form an aberrant “fusion protein” that promotes the development and growth of cancer cells. Zykadia is one of the first medicines to be approved following FDA Breakthrough Therapy designation, which was received in March 2013 due to the significance of results observed in the pivotal trial and the serious and life-threatening nature of ALK+ NSCLC. Additional regulatory submissions for Zykadia are underway worldwide, with an application currently filed in the European Union.
Cipla’s UK Arm Invests in US Based Chase Pharma Cipla Limited, a global healthcare company which uses cutting edge technology and innovation to meet the everyday needs of all patients, has announced its investment in Chase Pharmaceuticals Corporation Inc, US, through its wholly owned subsidiary, Cipla (EU) Limited, UK. Chase is an early stage drug development company, based Subhanu Saxena in Washington DC. Chase is focused on MD & Global CEO Cipla Ltd developing novel approaches to improve treatments for Alzheimer’s disease. It has a unique patented approach and is focused on improving the efficacy, safety and tolerability of existing Alzheimer medications. Cipla – through its impact investment unit Cipla New Ventures – is investing in the Series B round of financing as part of a syndicate, which also consists of Edmond de Rothschild Investment Partners and New Rhein Healthcare LLC. Cipla New Ventures was set up to chart a trajectory in innovation around biologicals, repurposing existing safe drugs and leveraging 50 May 2014
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Cipla’s enviable suite of delivery technologies through disruptive innovation around access and affordability. It is managed by Chandru Chawla. The USD 21 million two-phase financing will support Phase 2a and Phase 2b clinical trials for Chase’s lead drug CPC 201. The original venture funding for Chase was provided by the Brain Trust Accelerator Fund in 2010. Commenting on the investment, Subhanu Saxena, MD & Global CEO, Cipla Ltd said: “This investment is consistent with Cipla New Ventures’ mission to build more innovation-led business streams for Cipla in the future. We want to bring affordable medicines, where we identify an unmet patient need, in a way that leverages Cipla’s formidable technology, device and development capabilities.”
ScinoPharm, Lee’s Pharma Sign Collaboration Agreement ScinoPharm Taiwan, Ltd, a specialty Active Pharmaceutical ingredient (API) company, and Lee’s Pharmaceutical Holdings Limited (950. HK) announced the execution of two collaboration agreements. The two parties will jointly develop and produce Fondaparinux, an anti-thrombotic agent and Travoprost and Bimatoprost, two prostaglandin derivative drugs for treating glaucoma. Capitalising on the strengths and expertise of the two companies, the products are expected to offer competitive advantages upon entering into the Chinese high-end generic drug market. These drugs have extremely high technical entry barriers in process development and manufacturing. This collaboration takes the advantages of the two sides, ie, the R&D strengths of ScinoPharm in the development and manufacturing of highly potent APIs, coupled with Lee’s wealth of experience in developing and manufacturing ophthalmic products plus its outstanding marketing channels in China. Dr Jo Shen, President and CEO of ScinoPharm said, “It is our privilege to work with Lee’s Pharmaceutical to penetrate into the Chinese market actively for niche drugs. This collaboration signifies ScinoPharm’s strategic growth strategies in China by aggressively expanding our “Double A Strategy”, ie, developing ANDA (Abbreviated New Drug Applications) for in-house developed APIs. It will be also helpful in triggering a formal on-site inspection by the China Food and Drug Administration (CFDA) of ScinoPharm’s new manufacturing and R&D Center in Changshu, Jiangsu. This will allow products produced at ScinoPharm Changshu plant to enter the Chinese market thus opening up a wide range of business opportunities related to high-end generic drugs.” Pharma Bio World
pharma news Ve r a c y t e , F l e u r y J o i n H a n d s t o Market Afirma GEC in Brazil Veracyte Inc and Fleury Medicine and Health announced a new partnership that will make Veracyte’s Afirma Gene Expression Classifier (GEC) available to patients in Brazil, helping to reduce unnecessary surgeries and potentially lower costs there as part of thyroid cancer diagnosis. Financial terms of the agreement were not disclosed. Through the agreement, Fleury, which has diagnostics centers across Brazil, will exclusively offer the Afirma GEC when patients’ thyroid nodule fine needle aspiration (FNA) results are indeterminate – not clearly benign or malignant – following cytopathology review. Genzyme, Veracyte’s global co-promotion partner, will promote the Afirma GEC to physicians throughout Brazil, who will order the test through Fleury. FNA samples for the Afirma GEC will be sent to Veracyte’s CLIA-certified laboratory in South San Francisco, Calif., for analysis. Veracyte’s genomic test is used to identify patients whose thyroid nodules are benign following an indeterminate cytopathology result and who can thus potentially avoid unnecessary diagnostic surgery. Based on 2014 Brazilian National Cancer Institute (INCA) estimates of 9,050 newly diagnosed thyroid cancers per year, Veracyte and Fleury estimate that nearly 100,000 thyroid nodule FNAs are performed each year on patients in Brazil, with 15 to 30 per cent of such FNAs assumed to be inconclusive. Traditionally, these patients have been directed to surgery, with most of such thyroid nodules ultimately proving to be benign.
based on the initial discovery of a highly potent, highly selective, locally active P-glycoprotein inhibitor of the gastro-intestinal tract, HM30181. Potent and selective suppression of the PGP pump allows certain clinically important compounds (such as paclitaxel, irinotecan, and others), which would normally be effluxed back into the gastrointestinal tract and excreted, to enter the bloodstream and become bioavailable through oral administration. Through this collaboration, Kinex has global development and commercialisation rights for Oratecan, excluding Korea, Japan and India that are owned by Hanmi. With its attractive preclinical profile, additional Orascovery partnerships have been established with Zenith Technology Corporation for the New Zealand and Australia Territory, and with PharmaEssentia for the Taiwan and Singapore Territory. Through these partnerships and collaborations, a global drug development alliance has been established, with all partners involved in the clinical development of the drug candidates in a coordinated fashion for the overall global registration strategy.
Pacira Submits sNDA for Exparel Pacira Pharmaceuticals, Inc has announced the submission of a supplemental New Drug Application (sNDA) to the US Food and Drug Administration (FDA) for a nerve block indication for Exparel (bupivacaine liposome injectable suspension). The sNDA is based on positive data from a Phase 3 study assessing the safety and efficacy of EXPAREL in femoral nerve block for total knee arthroplasty, and will also include additional safety data from a Phase 3 study of Exparel used to perform an intercostal nerve block for thoracotomy.
Kinex Pharma’s Oratecan Gets US FDA Allowance
The timeline for review of the sNDA, under the Prescription Drug User Fee Act (PDUFA), is 10 months. If the FDA accepts the sNDA filing, a PDUFA target date of March 5, 2015 is expected.
Kinex Pharmaceuticals, Inc announced that the United States Food and Drug Administration (FDA) has allowed its Investigational New Drug (IND) application for Oratecan, an oral form of an approved anti-cancer drug irinotecan with enhanced oral absorption.
Gen-next Re-Usable Insulin Pen from Lilly and Boehringer Ingelheim
This is the Company’s second IND to be allowed in the past 10 months that uses the Orascovery technology platform for oral delivery of anti-cancer drugs. In July 2013, the US FDA allowed the IND for Oraxol, an oral formulation of paclitaxel, which is currently in phase I clinical studies in the United States and New Zealand, and Phase 2 studies in Korea with encouraging preliminary clinical data. Both Oraxol and Oratecan are orally administrated anticancer drugs.
Eli Lilly and Company India (Lilly) and Boehringer Ingelheim India, announce the launch of HumaPen SAVVIO, an innovative insulin delivery pen that meets the diabetics’ individual need. Engineered to resemble a small personal accessory rather than a medical device, this latest innovation was designed following feedback from people with diabetes who shared their aspiration to manage diabetes discreetly. HumaPen SAVVIO, an invention by Lilly, offers an extended shelf life of up to 6 years after first use.
The Orascovery programme represents a successful partnership between Kinex Pharmaceuticals and Hanmi Pharmaceuticals
HumaPen SAVVIO, an original research product of Lilly will be co-promoted by the Lilly-Boehringer Ingelheim alliance in India.
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pharma news US FDA Approves GSK’s Incruse Ellipta Sun Pharma Mulls to Close Detroit Facility US Food and Drug Administration
Darrell Baker SVP & Head, GSK Global Respiratory Franchise
(FDA) has approved GlaxoSmithKline plc’s Incruse Ellipta (umeclidinium) as an anticholinergic indicated for the long-term, once-daily, maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.
Umeclidinium is GSK’s first once-daily anticholinergic, a type of bronchodilator also known as a longacting muscarinic antagonist (LAMA), and is contained in the Ellipta inhaler. The FDA-approved strength is 62.5 mcg. Darrell Baker, SVP & Head, GSK Global Respiratory Franchise, said: “We believe Incruse Ellipta, our first monotherapy in the anticholinergic class, will be an important once-daily treatment option for appropriate patients with COPD. GSK has a long-standing commitment to the development of respiratory medicines in order to offer physicians a choice of treatment options for their patients. We are delighted by this approval, and are looking forward to making Incruse Ellipta available for appropriate patients with COPD in the US.”
Sun Pharmaceutical Industries Ltd has announced that, as a part of its manufacturing consolidation in the US, it has notified the Workforce Development Agency for the State of Michigan regarding its decision to cease manufacturing operations and close the Detroit (Caraco Pharmaceutical Laboratories, Ltd.) facility located at Elijah McCoy Detroit, Ml, USA. The Company has provided the requisite advance written notice of the facility closure to the employee union and all affected employees. The company has ensured that the impacted employees get compensated with more than their regular entitlement under the severance package. They will also receive other support services including out-placement assistance. The rest of the employees are continuing through mutually consented arrangements. The company has undertaken necessary measures to ensure business continuity of the products being manufactured at this facility. The manufacturing of these products is being transferred to other units and all necessary steps have been taken to avoid market shortage. Sun Pharma expects a negligible impact of this development on its FY15 consolidated revenues.
AbbVie Seeks EU Marketing Nod for Cardiome, UDG Healthcare Sign its HCV Therapy Distribution Deal AbbVie has submitted marketing authorisation applications (MAAs) to the European Medicines Agency (EMA) seeking approval for the company’s investigational, all-oral, interferonfree regimen for the treatment of adult patients with chronic genotype 1 (GT1) hepatitis C virus (HCV) infection. The Scott Brun, MD MAAs are supported by data from the VP-Pharmaceutical largest all-oral, interferon-free clinical Development, AbbVie program in GT1 patients conducted to date, which consists of six Phase III studies that include more than 2,300 patients in over 25 countries. “These regulatory submissions bring us closer to offering adult genotype 1 chronic hepatitis C patients an all-oral, interferonfree regimen which has the potential to provide a promising advancement for the hepatitis C community in the European Union,” said Scott Brun, MD, vice president, Pharmaceutical Development, AbbVie. 52 May 2014
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Karim Lalji Chief Commercial Officer Cardiome
An affiliate of Cardiome Pharma Corp has entered into a distribution agreement with UDG Healthcare plc, headquartered in Dublin, to fulfill orders and distribute BRINAVESS (vernakalant intravenous) in Ireland. The initial term of the agreement is for three years effective as of April 1, 2014. Financial details have not been disclosed.
“We are pleased to have entered into this agreement with UDG Healthcare that will maintain BRINAVESS availability to our customers in Ireland,” said Karim Lalji, Cardiome’s Chief Commercial Officer. “This agreement continues the previously established BRINAVESS distribution partnership, thereby minimising distribution interruptions to our customers,” he added. Pharma Bio World
pharma news ICON Buys Aptiv Solutions ICON plc, a global provider of outsourced development services to the pharmaceutical, biotechnology and medical device industries, has completed the previously announced acquisition of Aptiv Solutions. Aptiv Solutions is a recognised leader in the design and execution of adaptive clinical trials for pharmaceutical and biotech customers. The company also has in-depth experience in the management of medical device trials and its Japanese subsidiary, Niphix, is a full-service, oncology-focused CRO serving both Japanese and international customers.
Dr Nuala Murphy President, ICON Clinical Research Services
“Aptiv’s adaptive trial capabilities, combined with our existing technology platforms, such as ICONIK and Firecrest, will further differentiate our services and help our customers take time and cost out of the development process,” commented Dr Nuala Murphy, President, ICON Clinical Research Services. “Their presence in Japan and medical device capabilities will also broaden our offerings in these markets.”
Valeant, Actavis End Acanya Gel Patent Litigation Valeant Pharmaceuticals International, Inc has announced that it’s subsidiaries, Dow Pharmaceuticals Sciences, Inc and Valeant Pharmaceuticals North America LLC, and Actavis’ subsidiary, Watson Laboratories, Inc, entered into an agreement to settle all outstanding patent litigation related to Actavis’ generic version of Acanya (clindamycin phosphate and benzoyl peroxide) Gel, 1.2%/2.5%. Acanya Gel is a lincosamide antibiotic and benzoyl peroxide indicated for the topical treatment of acne vulgaris. Under the terms of the agreement, Valeant will grant Actavis a license to market its generic Acanya Gel beginning July 1, 2018 or earlier under certain circumstances. Launch of Actavis’ generic product is contingent upon Actavis receiving final approval from the US Food and Drug Administration (FDA) on its Abbreviated New Drug Application (ANDA) for generic Acanya Gel. Additionally, Valeant’s subsidiaries, Valeant Canada LP and Valeant International Bermuda, and Actavis Pharma Company have entered into an agreement to settle outstanding patent litigation related to Actavis’ generic version of Tiazac XC (diltiazem hydrochloride) 180 mg/240mg/300mg/360 mg capsules. Tiazac XC is a calcium cellular influx inhibitor (slow channel blocker) indicated for treatment of hypertension.
Fresenius Kabi Acquires Novafarma Fresenius Kabi has entered into an agreement to acquire the privately held Brazilian pharmaceutical company Novafarma Indústria Farmacêutica Ltda. This transaction is part of Fresenius Kabi’s strategy to expand its market presence and product portfolio in emerging markets. Novafarma offers a comprehensive range of generic IV drugs, including antibiotics, analgesics and anesthetics, for the Brazilian hospital market. Fresenius Kabi entered the Brazilian market in 1977, and is one of the country’s leading suppliers of clinical nutrition, infusion therapy and medical devices/transfusion technology. The acquisition significantly broadens Fresenius Kabi’s generic IV drugs portfolio for the region, and creates an excellent platform for further growth in this product segment in other Latin American countries. Financial terms were not disclosed. The transaction is subject to antitrust approval in Brazil, and is expected to close in the second quarter of 2014. Pharma Bio World
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Agilent, SNU Team up on New Drug Development Centre Agilent Technologies Inc has announced a collaboration with Seoul National University (SNU), one of the world’s leading universities and Korea’s top research university, on a new research center that will support the College of Pharmacy’s New Drug Development Centre. As stated in a memorandum of understanding signed by Seoul National University’s College of Pharmacy and Agilent, the collaboration aims to conduct drug metabolism studies; research, evaluate and develop new compounds; understand the remedial effects and toxicity; assess pharmacokinetics; and conduct clinical tests for drugs. “We have been leading Korea’s pharmaceutical industry through the strategic use of technology and driving the development of new drugs. As we prepare students for the future, we will push the frontiers of drug development by expanding our research facilities, producing outstanding research, and leading the development of technology,” said professor Bong-Jin Lee, dean of the college. May 2014 53
biotech news Connexios, Boehringer Ingelheim Sign Research Collaboration Deal
Suri Venkatachalam CEO and Founder Connexios
Connexios Life Sciences, a Bangalore based biotechnology company, and Boehringer Ingelheim, one of the world’s leading pharmaceutical companies, announced an exclusive global research collaboration agreement for AMPK agonists for the treatment of patients with Type 2 Diabetes.
As part of the agreement, Boehringer Ingelheim obtains global rights to CNX012, Connexios Life Sciences’ programme on AMPK activators. The programme includes CNX-570 and other compounds in early pre-clinical development. Boehringer Ingelheim will be responsible for all further development and commercialisation of the candidates from the AMPK programme. Further terms and financial details were not disclosed. “As a pure research-driven organisation from India, we believe that the agreement with Boehringer Ingelheim is a big validation of both our scientific approach and capabilities as well as of our business model,” commented Suri Venkatachalam, CEO and Founder of Connexios. “CNX-012 is one of our flagship programs which leverages our Network Biology approach and platform and we are extremely pleased to be working with Boehringer Ingelheim to advance candidates from this programme. We strongly believe that the collaboration will yield best-in-class activators of this exciting but challenging target and ultimately result in better therapies for patients of Type 2 Diabetes who also suffer from the burden of several other cardiometabolic co-morbidities.”
CMC Biologics & MacroGenics to Develop Oncology Product Candidate CMC Biologics, Inc, a global leader in process development and contract manufacturing, and MacroGenics, Inc, a clinicalstage biopharmaceutical company focused on discovering and developing innovative monoclonal antibody-based therapeutics for the treatment of cancer and autoimmune diseases, have entered into an agreement to further develop the production process for transfer and clinical manufacturing of one of MacroGenics’ product candidates. “We look forward to working with MacroGenics to further develop and advance this immuno-oncology programme. This contract highlights CMC Biologics’ focus on working with our customers 54 May 2014
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as partners and our capabilities in the development and clinical manufacturing of monoclonal antibodies,” said Gustavo Mahler, PhD, Global Chief Operations Officer of CMC Biologics. “We are impressed with CMC Biologics’ experience and technical competency in biopharmaceutical development and cGMP manufacturing,” said MacroGenics President and Chief Executive Officer, Scott Koenig, MD, PhD. “Choosing a contract manufacturing partner with quality facilities that is able to provide flexible solutions and meet our clinical timelines is critical to realising the potential of life-saving medicines, he added”
Idera Inks Pact with Abbott to Develop In Vitro Companion Diagnostic Test Idera Pharmaceuticals, Inc, a clinical-stage biotechnology company developing novel therapeutics for orphan patient populations with B-cell lymphomas and autoimmune diseases, has entered into an agreement with Abbott, the global healthcare company, for the development of an in vitro companion diagnostic test for use in Idera’s clinical development programs to treat certain genetically defined forms of B-cell lymphoma with IMO-8400. Under the agreement, Abbott will develop a test utilising polymerase chain reaction (PCR) technology to identify the presence of the MYD88 L265P oncogenic mutation in tumor biopsy samples with high sensitivity and specificity. This mutation, which can be identified in approximately 90 per cent of patients with Waldenström’s macroglobulinemia and approximately 30 per cent of patients with the ABC sub-type of diffuse large B-cell lymphoma, plays a key role in activating theToll-like receptor (TLR) pathways targeted by Idera’s lead drug candidate, IMO-8400. “Research by Idera and by independent investigators has established TLR antagonism as a potentially promising and novel therapeutic approach for patients with B-cell malignancies harboring the MYD88 L265P mutation,” said Lou Brenner, M D, Senior Vice President and Chief Medical Officer of Idera Pharmaceuticals. “This companion diagnostic will be an important tool for the clinical community in evaluating whether their patients are potential candidates for IMO-8400 therapy for the treatment of these genetically defined forms of B-cell lymphoma. We are excited about the opportunity to partner with Abbott, a leader in companion diagnostics, as part of Idera’s mutation- targeted development programme for IMO-8400 in B-celllymphomas.” Pharma Bio World
biotech news AtheroNova Gets Notice of Issuance of its 2 nd US Patent 8,697,633 AtheroNova Inc, a biotech company focused on the research and development of compounds to safely regress atherosclerotic plaque and improve lipid profiles in humans, has received a Notice of Issuance for an additional compound for cardiovascular treatments. This patent Thomas W Gardner, CEO issuance further exemplifies the AtheroNova Company’s plan to develop a broad platform of intellectual property involving atheroma stabilisation and reduction, lipid modulation and other metabolic diseases. This issuance continues efforts by the Company and its patent counsel in pursuit of numerous patents covering the systemic delivery of naturally occurring bile acids, bile acid synthetics, analogs and conjugates. “This latest patent issuance expands our patent portfolio to now include multiple compounds for addressing atherosclerotic plaque and stands as an important continuation of our goal of being the clear leader in the systemic delivery of bile acids, bile acid synthetics, analogs and conjugates to dramatically enhance cardiovascular and metabolic health,” said AtheroNova CEO Thomas W Gardner. “As our drug development efforts accelerate, the company will continue to pursue additional pending patent applications for systemic delivery of our family of bile acids and bile acid derivatives. The development of our platform is significantly advanced by this achievement.”
Regeneron, Avalanche to Develop Gen-Next Gene Therapy Products Regeneron Pharmaceuticals, Inc and Avalanche Biotechnologies, Inc have announced the formation of a broad collaboration to discover, develop and commercialise novel gene therapy products for the treatment of ophthalmologic diseases. The collaboration covers novel gene therapy George D. Yancopoulos, vectors and proprietary molecules, Chief Scientific Officer, discovered jointly by Avalanche and Regeneron and President Regeneron Laboratories Regeneron, and developed using the Avalanche Ocular BioFactory, an adeno-associated virus (AAV)-based, proprietary, next-generation platform for the discovery and development of gene therapy vectors for ophthalmology. Pharma Bio World
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Under the terms of the agreement, Avalanche will receive an upfront cash payment, contingent payments of up to USD 640 million upon achievement of certain development and regulatory milestones, plus a royalty on worldwide net sales of collaboration products. The collaboration covers up to eight distinct therapeutic targets, and Regeneron will have exclusive worldwide rights for each product it moves forward in clinical development. In addition, Avalanche has the option to share in development costs and profits for products directed toward two collaboration therapeutic targets selected by Avalanche. As part of the agreement, Regeneron has a time-limited right of first negotiation for certain rights to AVA-101, Avalanche’s gene therapy product targeting vascular endothelial growth factor (VEGF) currently under development for the treatment of wet age-related macular degeneration (AMD), upon completion of the ongoing Phase 2a trial. “We look forward to the opportunity to collaborate with Avalanche, a leader in the field of next-generation gene therapy technologies,” said George D. Yancopoulos, MD, PhD, Chief Scientific Officer of Regeneron and President of Regeneron Laboratories. “This collaboration highlights the commitment by Regeneron to invest in potentially breakthrough therapies that could benefit patients with sight-threatening diseases.”
Verastem Expands COMMAND Study in Japan Verastem, Inc, focused on discovering and developing drugs to treat cancer by the targeted killing of cancer stem cells, has announced the expansion of its ongoing COMMAND study to include clinical trial sites in Japan. COMMAND is a registrationdirected trial evaluating the Company’s lead candidate targeting cancer stem cells, VS-6063 (defactinib) a potent inhibitor of focal adhesion kinase (FAK), in patients with malignant pleural mesothelioma. Mesothelioma is a highly aggressive form of lung cancer and a high percentage of cases contain cancer stem cells. With the inclusion of Japan, COMMAND is now accruing patients and pursuing parallel clinical development in the major markets worldwide. “Typically the Japanese development of novel oncology agents is delayed compared to the rest of the world,” said Professor Kazuhiko Nakagawa, MD, PhD, Professor, Department of Medical Oncology, Kinki University Faculty of Medicine. “We were able to initiate and complete the Phase 1 assessment of VS-6063 in less than a year. By completing the trial so quickly, the ongoing COMMAND study can now include Japanese clinical sites in parallel with the other major countries participating in the trial.” May 2014 55
press release CAT Rules in Favour of Schott The Competition Appellate Tribunal (CAT) has cleared SCHOTT India from all penalties and charges made under an Order of the Competition Commission of India (CCI) that had been initiated by Kapoor Glass Pvt. Limited. SCHOTT India was falsely accused of abusing its strong position in the glass tubes market and granting discriminatory pricing and other favorable terms to its affiliated entity, SCHOTT KAISHA as compared to other converters in the market. In July 2010, Kapoor Glass Pvt Limited (Kapoor), a converter and former manufacturer of Glass Tubes, filed information with the CCI in which it complained of alleged anti-competitive practices of SCHOTT India which affected the competition in the market for Neutral USP Type I Borosilicate Glass Tubes as well as in the downstream market for the Containers. After the CCI initially decided against SCHOTT India, the case was referred to CAT. In the CAT judgment, it was pointed out that SCHOTT KAISHA was a vertically integrated subsidiary of the SCHOTT Group and that the quantity purchased by SCHOTT KAISHA by far exceeded the purchases of any other converter company. Better terms for SCHOTT KAISHA were therefore justified. The tribunal also clarified that there was no negative impact on the downstream market for glass tube containers and that the ultimate consumer did not suffer any damage as alleged in Kapoor’s appeal.
Oviya MedSafe Ally with Assured Information Systems Indian pharmacovigilance consulting and drug safety services company Oviya MedSafe Pvt Ltd has signed an agreement with British software development company Assured Information Systems Ltd to combine the former’s drug safety services with Dr J Vijay Venkatraman Managing Director & CEO the latter’s hosted pharmacovigilance Oviya MedSafe database product PV247, to offer intuitive end-to-end pharmacovigilance support to the global pharmaceutical industry. This strategic alliance aspires to promote the adoption of drug safety systems, especially among small and mid-sized pharmaceutical companies throughout the world, by delivering comprehensive pharmacovigilance solutions in a cost-effective and user-friendly manner. Dr J Vijay Venkatraman, Managing Director & CEO of Oviya MedSafe indicated that the alliance has happened at the right time. 56 May 2014
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“As drug safety regulations begin to tighten globally, investing in pharmacovigilance becomes inevitable for all pharmaceutical companies”, he said. “With Oviya MedSafe’s increasing recognition as a quality-conscious yet cost-effective pharmacovigilance service provider in the market since the past two years, our strategic partnership with Assured Information Systems, an established company with similar values, will help in achieving our shared goal of providing affordable, simplified yet reliable drug safety support.” Dr Alan K Rawling, Managing Director of Assured Information Systems said “This partnership with Oviya MedSafe recognises the need to provide a total pharmacovigilance solution that addresses the challenges of regulatory compliance, electronic reporting and signal detection. Combining our software and services expertise offers a unique proposition to pharmaceutical companies of all sizes within the Asian continent and globally to companies wishing to outsource to India”.
Lonza Bags cGMP Certification from HSA Lonza Bioscience Singapore Pte Ltd has received cGMP certification from the Singapore Health Sciences Authority (HSA). The audit/conformity assessment, performed by the HSA, confirmed that Michael Cicio Lonza Singapore has maintained an overall Vice President acceptable level of compliance with the Operations Pharmaceutical Inspection Convention/CoOperation Scheme (PIC/S) Guide to Good Manufacturing Practice (GMP) for Medicinal Products (Part I) relating to finished products. This encompasses all the recommendations of the World Health Organization (WHO) in relation to GMP. PIC/S guidelines to GMP for Medicinal Products (Part I) require that the company is compliant with the standards required for the following: quality management, personnel, premises and equipment, documentation, production, quality control, contract manufacturing and analysis, complaints and product recall, and self-inspection. “We are proud to be one of the first Cell Therapy contract manufacturers in Singapore to have received this certification,” said Michael Cicio, Vice President of Operations. “This certification will allow Lonza to contract manufacture investigational medicinal products for aseptically prepared cell-therapy products and will facilitate the use of these products in both the United States and Europe.” Pharma Bio World
press release Sanner Surpasses 55 million Euro Mark Sanner GmbH, a manufacturer of high quality plastic packaging and components for pharmaceutical, medical and healthcare products, topped the 55 million Euro mark and set a new sales record in 2013 (2012: 50.6 million Euro). This Holger Frank, CEO development was supported by a Sanner clear brand positioning with the new slogan “Sanner. Protecting Health” and substantial national and international investments. “The year 2013 was full of positive changes for our company,” explains Sanner CEO Holger Frank. “Our business continued to grow with a 10 percent increase in sales to 55.5 million Euro. We also managed to further strengthen our market leadership position.” The focus here is on market segments that require the use of desiccants. “Sanner. Protecting Health”, the company’s new slogan introduced to the public in 2013, signified a clear brand positioning for Sanner. The new product divisions Pharma Desiccant, Teststrip, Effervescent and Pharma & Medical Packaging, as well as Eye Care and Ready-to-Fill Syringes underline the strategic orientation. The packaging specialist is also setting new standards in the development of new packaging concepts. Sanner was awarded a number of new patents in the past year.
Biocon Appoints Dr Arun Chandavarkar as CEO and Joint Managing Director Biocon Ltd, Asia’s premier biotechnology company, announced that the Board of Directors of the Company, have approved the induction of Dr Arun Chandavarkar, on to the board of Biocon Limited. Dr Arun Chandavarkar CEO & Joint MD, Biocon
He has also been appointed as Chief Executive Officer and Joint Managing Director.
Welcoming Arun on the Board, Kiran Mazumdar-Shaw, CMD, Biocon, said, “I am extremely happy to have Arun join the Board of Directors and take on the mantle of CEO & Joint MD. Arun has been a core member of the leadership team at Biocon and has worked very closely with me over the last 24 years. He Pharma Bio World
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has played a pivotal role in the evolution of Biocon and I am confident that, in his new role, he will build immense value for Biocon and its stakeholders.” Dr Arun Chandavarkar, CEO & Joint MD, Biocon, said, “I am delighted and honoured to join the Board of Biocon. These are exciting times and I look forward to steering the Company to the next level.” Dr Arun Chandavarkar has a B. Tech from IIT, Bombay and earned his Ph.D. in Biochemical Engineering from the Massachusetts Institute of Technology, Cambridge, USA.
Study Forecasts Sustainable Growth in OSDF Excipients Market On a global scale, the oral solid dosage form (OSDF) excipients market is growing sustainably, historically exhibiting a robust increase. This market is valued at nearly USD 2.3 billion in the United States, Europe, India, and China, according to recently published Specialty Excipients for Oral Solid Dosage Form Pharmaceuticals Global Series: Business Analysis and Opportunities by worldwide consulting and research firm Kline & Company. In the emerging Indian and Chinese markets, growth in consumption of excipients is driven by rising incomes and willingness to spend more on healthcare. Key factors driving growth in major markets like the United States and Europe include the aging populations and high demand for pharmaceuticals. Nikola Matic, Industry Manager at Kline’s Chemicals & Materials practice, states, “Due to this growing demand, the major markets will continue to flourish; however, it is worth noting that emerging markets will outpace major markets. Driven by the Indian and Chinese markets, the consumption of OSDF excipients is expected to grow at a healthy pace of 7.4 per cent per year until 2018.” Although the major markets of Europe and the United States have similar volume to the emerging markets of India and China, which currently stand at approximately 100,000 tons per region, the market values are very different from one region to another. This is due to the different types of excipients used based on the geography. While mature markets are dominated by functional and usually more expensive excipients, emerging markets are looking to use cheaper alternatives, such as native starches. May 2014 57
press release ISPE Introduces New Plan to Avert New Trends in Vaccine Development Drug Shortage Following the successful development of vaccinations against ISPE, the International Society for Pharmaceutical Engineering, has announced that it will work with stakeholders worldwide to produce a Drug Shortages Prevention Plan to guide the Drug Shortage Prevention Plan pharmaceutical and biopharmaceutical industry in establishing reliable, robust and resilient supply chains that provide quality medicines to patients without interruption. The Plan, which will be based on ISPE research with the input of its membership, company leaders and regulators, will serve as a roadmap that when implemented, can significantly reduce drug shortages. The Plan will address optimal organisational strategies, such as aligned governance and communication practices, effective manufacturing and quality systems, and appropriate measures of supply chain robustness and quality. This effort addresses rising concerns around drug shortages within companies, among global health authorities, and for patients who depend on a reliable and available supply of quality medicines. The ISPE Drug Shortages Prevention Plan will be the Society’s second major output on this topic since launching its Drug Shortages Initiative in 2012. This second phase of the Initiative is aimed at addressing the root causes of drug shortages to prevent delay of supply. The 2013 survey provided clear evidence that mitigating shortages requires a holistic approach that encompasses both the organisational and technical issues affecting drug manufacturing and quality. “How much of the increasing number and severity of incidents of drug shortages within our industry are fundamentally tied to a lack of understanding, or even concern for, the risk profiles of our current supply chain structure?” commented Andy Skibo, Regional VP, Biologics Supply, AstraZeneca/MedImmune. “I therefore welcome ISPE’s initiative to tackle the root causes of shortages for the benefit of all stakeholders—ISPE Members, industry companies, regulators and health authorities, thirdparty providers and patients.” The ISPE Drug Shortages Prevention Plan will provide a key component of the Society’s input to a European multi-association task force, moderated by ISPE, which intends to provide EMA a proposal and plan that address the prevention of drug shortages due to manufacturing quality issues. 58 May 2014
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numerous viral and bacterial diseases, vaccine research and development (R&D) is now targeting areas of high unmet need, and a number of promising strategies are being investigated for novel preventative and therapeutic vaccinations, according to a new report from business intelligence provider CBR Pharma Insights. The company’s latest report states that due to existing vaccines already providing effective protection against some of the most serious diseases, including pneumococcal disease, flu, measles, diphtheria and polio, there is now an increased focus on developing preventative vaccinations for adults and against pathogens that affect the developing world. However, the development of preventative vaccines, particularly in vulnerable populations, generates a number of practical and ethical issues, including the possibility of infecting otherwise healthy individuals with a disease and disallowing concomitant treatment. Moreover, despite preventative vaccinations being the mainstay of vaccine development and commercialisation in previous years, more attention from big pharma and biotechs alike has recently been placed on therapeutic vaccines. However, obstacles surrounding the development of therapeutic vaccinations, including the fact that some of these vaccines need to be tailored to the individual, also make this a challenging area, despite its promising commercial potential.
Indonesian Pharma Market to Thrive Driven by increased government healthcare spending and growing life expectancy, the Indonesian pharmaceutical market value will climb from approximately USD 5 billion in 2013 to USD 9.9 billion by 2020, at a Compound Annual Growth Rate (CAGR) of 10.2 per cent, forecasts research and consulting firm GlobalData. According to the company’s latest report, this growth is due to the introduction of government healthcare reimbursement programmes, such as Jamkesmas and the Family Hope Programme. Their aim is to provide health insurance to all Indonesians by 2019. However, the increasing use of generics, coupled with counterfeit medicines, could slow down the Indonesian pharmaceutical industry expansion. Pharma Bio World
press release STA to Market Iluvien in Australia and New Zealand
project, which has been initiated, will be undertaken primarily at state-of-the-art R&D labs of Jubilant Biosys (India) and some parts at Jubilant Discovery Center, USA.
Australian and New Zealand patients suffering from vision impairment due to a type of diabetes-induced eye disease will have access to a new treatment, following a license deal between Australian biopharmaceutical company Specialised Therapeutics Australia (STA) and Alimera Sciences.
Dr Subir Kumar Basak, President of Jubilant Biosys Ltd, said: “We are excited to partner with Orion to offer integrated drug discovery services. Over the past few years, we have been strengthening our therapeutic area focused discovery platform, and this partnership serves as a validation of our efforts. We are confident of offering successful results to Orion at various stages of research.”
The exclusive agreement enables STA to distribute Iluvien (190 micrograms fluocinolone acetonide intravitreal implant in applicator) – a sustained release intravitreal implant used to treat vision impairment associated with chronic diabetic macular oedema (DMO), when the condition is deemed insufficiently responsive to current available therapies. Under the terms of the license arrangement, STA will be responsible for all regulatory and commercial activities for Iluvien in Australia and New Zealand. The agreement includes a milestone payment to Alimera Sciences on achievement of a Pharmaceutical Benefits Scheme (PBS) listing, as well as an increasing royalty payment based upon a specific sales target. Australian Ophthalmologist Professor Mark Gillies from the Department of Clinical Ophthalmology and Eye Health, University of Sydney, said ILUVIEN was a welcome treatment option for patients with DMO who no longer respond to conventional therapies and who face progression to loss of vision.
Jubilant Sign Drug Discovery Deal with Orion Jubilant Biosys, a Bengaluru-based subsidiary of Jubilant Life Sciences, and Orion Corporation (Orion), the largest pharmaceutical company in Finland, has announced a path breaking drug discovery collaboration to discover small molecule inhibitors Dr Subir Kumar Basak in neuroscience therapeutic area. The President research deal is aimed at developing Jubilant Biosys Ltd drug that can benefit large population of people with unmet needs in the pain management area. As per the terms of agreement, Jubilant’s extensive experience in drug discovery and pre-clinical development will be utilised by Orion to address pain management needs of Central Nervous System (CNS). Jubilant will offer integrated drug discovery services across early discovery, synthetic and medicinal chemistry including scale up and pre-clinical services. The research for the Pharma Bio World
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ACG Gets LEED-India Gold Rating Award ACG’s continued commitment towards sustainability and efforts in building sustainable sites, reducing water and energy consumption, recycling building material and improving indoor environmental quality has now been recognised. Indian Green Building Council (IGBC) LEED-India has awarded its prestigious Gold rating to ACG’s new state-of-the-art capsule manufacturing plant in Pithampur, making it the first factory in Indian pharmaceutical industry to receive this rating. In another development, ACG Worldwide’s UK subsidiary ACG Europe Ltd is listed in the UK’s ‘Top 41 Fastest-Growing Indian Companies.’ ACG Europe features within the top 25 fast-growing Indian-owned companies. The list, developed by the UK’s leading auditing and management consultancy firm Grant Thornton LLP in conjunction with Confederation of Indian Industry (CII), identifies fast-growing Indian companies in the UK by turnover, sector and employee strength.
MS Prevalent Cases to Witness Highest Growth by 2023 The number of multiple sclerosis (MS) prevalent cases across the ten major markets (10MM) will increase from 904,908 in 2013 to 940,413 by 2023, at an Annual Growth Rate (AGR) of 0.39 per cent, says research and consulting firm GlobalData. The company’s latest report states that among the 10MM (the US, Canada, France, Germany, Italy, Spain, the UK, Japan, China and India), India will have the highest increase in prevalent cases, with an AGR of almost 2 per cent, followed by Spain and China, with AGRs of 1.05 and 0.93 per cent, respectively. Despite having lower AGRs, GlobalData epidemiologists forecast that the US will have the highest number of prevalent cases of MS by 2023, with 303,343. May 2014 59
Continuous Nitration System KEC specialises in stainless steel fabrication of pressure vessels including reactors, columns, condensers, heat exchangers and storage tanks. GMP and nonGMP equipment for chemical and pharma sectors are manufactured in accordance with international standards: ASME, TEMA, DIN and BS. KEC has ample expertise to manufacture various tailormade equipment for mixing of highly viscous materials, especially for paint industries, operating at high RMP. KEC have fabricated and delivered equipment under all the major third party inspection agencies like BVIS, TUV, SGS, Chempro Mott Macdonald, Joshi & Associates, etc. Nitration system operate continuously for 24x7. The entire set of equipment consist of 12 equipment (7 are for rotating equipment for mixing and 5 are separation vessels). All 12 equipment are interconnected and mounted on skid frame.
Chromatography Data System Software Agilent Technologies Inc offers the latest revision of its Chromatography Data System (CDS) software, OpenLAB CDS A.02.01. The enhanced software features exclusive benefits for chemical, petrochemical, high-throughput and regulated laboratories. It provides new data acquisition, data analysis, reporting, secure storage and e-Familiarization capabilities that increase laboratory productivity and lower costs in all chromatography laboratories. A software maintenance agreement entitles all customers to these enhancements at no additional cost. The new release of OpenLAB CDS dramatically reduces the time needed to capture, analyze and share chromatography and mass spectrometry data. The new features include flexible data capture; reliable automation; fast data analysis; powerful reporting; secure content management; simple upgrade path; etc.
For more information, please contact:
For more information, please contact:
Kwality Process Equipments Pvt Ltd, Plot No: 8, Laxmi Indl Estate, Nandore Road, Opp: Vinod Cookware Palghar (E ), Dist: Thane, Maharashtra 401 404 Tel: 02525-654248, Fax: 91-0250-2457710 E-mail: email@example.com
Agilent Technologies Inc 5301 Stevens Creek Blvd Santa Clara, CA 95051 U.S.A. E-mail: firstname.lastname@example.org
Gas Generators Cole-Parmer offers Paker Balston’s hydrogen gas generators. These generators are compact and reliable. Its unique display lighting, changes colour for easy status checks and water level indication. Its exclusive water management system and control circuitry maximize uptime. Parker Balston’s Proton Exchange Membrane (PEM) cell eliminates the use of liquid electrolytes with hydrogen generators. The maintenance of the equipment requires only a few moments per year at no inconvenient and extended downtime. One have to simply change the filters every six months and the desiccant cartridge whenever it turns dark brown. De-ionized water is all that is required to generate hydrogen for weeks of continuous operation. With an output capacity of up to 510 cc/minute, one generator can supply 99.9995% pure hydrogen for up to several FID’s. Based on cylinder gas savings alone, a Parker Balston® hydrogen generator pays for itself in less than a year. For more information, please contact: Cole-Parmer India 403-404, Delphi - B, Hiranandani Business Park, Powai, Mumbai - 400 0076 Tel: +91-22-67162253, 67162222, 67162229 | Fax: +91-22-67162211 E-mail: email@example.com / firstname.lastname@example.org
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Precision Instruments Cole-Parmer offers new line of test and measurement products to fill the technicianâ€™s toolbelt. The DigiSense brand offers new technologies that deliver accurate readings while withstanding rigorous use. From environmental testing meters to performance monitoring equipment, many of the items are precalibrated to save time, cost and effort. The Digi-Sense brand currently includes 25 models of thermometers, infrared devices, humidity meters, anemometers, light meters and manometers. Additional products that fill other measurement needs will soon be available. Digi-Sense also features a comprehensive line of temperature probes with customization available for unique applications. For more information, please contact: Cole-Parmer India Pvt Ltd 403-404, Delphi - BHiranandani Business Park, Powai, Mumbai 400 076 Tel: 022-67162253, 67162222 | Fax: 91-022-67162211 E-mail: email@example.com
12 Station Dissolution Testing Instrument The fully USP-711/724 and EP2.9.3/4 compliant PTWS 1210 offers a massive 12 sample throughput for busy labs and those wishing to complete Q1 and Q2 result levels in one test. This bath design offers the same physical conditions for all 12 samples inside the dissolution vessels: the same tool speed, same temperature and the same immunity to both internal and external potential vibration sources. The testing positions are arranged in two rows (6+6) and offer staggered start capability. The vessels are covered by individual lids. Each lid features openings for sample withdrawal, temperatues or pH measurements. For manual sampling we offer the PT-MDS manual sampling device. For more information, please contact: Pharma Test Instruments India Pvt Ltd No: 2, Sree Datri Niwas, 2nd Floor Nagwara Circle, Outer Ring Road Opp: Manyata Softech Park, Bengaluru,Karnataka 560 045 E-mail: firstname.lastname@example.org
Smart Camera In-Sight 7010 from COGNEX is smart camera vision system for inspection tasks where vision sensors are too limited and the solutions available in the market may not suit the entire requirements. It includes autofocus optics and integrated lighting in a compact IP67 rated industrial housing. Applications can be configured quickly using the intuitive EasyBuilder user interface software. The vision library has been simplified to focus on the tools most frequently used in straightforward vision applications. Included are tools such as Pattern Matching, Edge, Blob and Circle detection tools. Additionally, the colour vision system model includes a Color ID tool for applications that require the ability to identify different colours. It has 800 x 600 (SVGA) resolution and takes 102 frames per second. It has an external light connector providing powers and strobe (requires Cognex light cable kit). Users can also fine-tune focus levels manually with the interactive software. The In-Sight 7010 autofocus system is available with five different lens options to match the working distance and field of view requirements of each application. It also offer integrated, field-replaceable white lighting as well as four specific colour lights (red, green, blue and Infrared) to highlight particular parts or features. The compact In-Sight 7010 features integrated white lighting that is suitable for most vision applications. If a specific colour light is required to highlight particular parts or features, four optional coloured lights are available. For more information, please contact: Cognex Sensors India Pvt Ltd Regus Level 6 Pentagon Towers P2 Magarphatta City, Hadapsar Pune, Maharashtra 411 028 Tel: 020-40147840 | Fax: 91-020-66280011
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Automatic Ointment Plant Fluidyme manufacture various types of direct and gear driven agitators, agitators with single and double mechanical seal and gland packing.
Agitators are heavy-duty designed to process a wide range of fluids of varying viscosities and specific gravities in various processes like blending, dispersion, reactions in solution, elocculation, dissolution, solid suspension, gas dispersion, high viscosity mixing, heat transfer, crystallization/precipitation in the industries, viz, pharmaceutical, chemicals, paint and coatings, screen ink, adhesives, resins, sealants, plastisols, concentrates, biotech, lubricant, coolant, paper, chemicals, dye, cosmetics, food, etc. Modular design of the agitator enables various mounting arrangements, ie, from open tank to closed tank. High efficiency impellers designed for specific process applications.
The ointment units are ideal tools for the pharma and cosmetic industries for the production of ointment creams, lotions and other emulsions and homogenisations. The combined action of horizontal blade and specially designed anchor ensures most efficient mixing with shearing action of homogenizer, important when working with viscous products. The ointment plant comprises of manufacturing vessel and agitators made out of AISI SS-316 fitted with flush bottom valve; wax/water phase vessel with side-mounted fast speed stirrer, flush bottom valve and conical filter; manufacturing veseel with variable speed anchor and fast speed emulsifier fitted with mechanical seal; jacket is of AISI SS-304/mild steel with rock wool insulation and AISI SS-304 cladding; lifting hydraulic for manufacturing vessel; spray ball installed on top cover of cleaning main vessel; monitoring of the product temperature; PT 100 probe with digital indicator on panel; electric control panel board with all necessary controls; etc.
For more information, please contact:
For more information, please contact:
Fluidyme Process Flow Technologies E-2/4,Popular Prestige Off Highway Bridge Warje, Pune, Maharashtra 411 058 E-mail: email@example.com.
Brilliant Pharma Machinery Unit Nos: 1, 2 and 14 Modern Indl Estate Waliv Phata, Vasai ( E), Dist: Thane, Maharashtra 401 208 Tel: 0250-3293636, 2454015 | Fax: 91-0250-2454015 E-mail: firstname.lastname@example.org
Octagonal Blender Octagonal blender due to its octagonal shape is designed to process larger volume of material. It occupies less space compared to other similar blenders like V and double cone. Power consumption is also less. The blending takes place at low speed during operation. It is well balanced even in higher capacities. It is very useful for pharma industries wherein gentle blending of dry granules of powder is to be done. Octagonal blender due to its octagonal shape is designed to process larger volume of material. It occupies less space compared to other similar blenders like V and double cone. It is a slow speed blender and has removable type baffles mounted on the rectangular shell. The important feature of the machine is easy to clean in place. Octagonal blender is supplied with a bin charging system or can be designed for vacuum charging. Dust-free charging system is also incorporated, which is completely close system for charging and discharging of powders or granules. For more information, please contact: Tapasya Engg Works Pvt Ltd A-212, Road No: 30 Wagle Indl Estate Thane (W), Maharashtra 400 604 Tel: 022-25822287, 25823250 | Fax: 91-022-25825243 E-mail: email@example.com / firstname.lastname@example.org
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Panel PC 2100 The new Panel PC 2100 from B&R is a full-fledged PC system whose exceptional performance is concealed by its ultra-compact housing. The innovative design of this new system takes advantage of the latest Intel Atom technology and represents a decisive advancement in the performance of embedded systems. Equipped with a PC module, which has the same dimensions as a Smart Display Link or DVI receiver, any 2 nd generation Automation Panel can be turned into a full-fledged Panel PC – including completely closed panels mounted on a support arm. Available with single-, dual- or quad-core processors, the computing power of the Panel PC 2100 is fully scalable. At the high range of performance, it is even possible to exceed the performance of Core i3 chips. Regardless of the variant, no fans or other rotating components means that no maintenance whatsoever is required. Other standard features include two Gigabit Ethernet interfaces as well as one USB 2.0 and one USB 3.0 interface. Fieldbus technology such as POWERLINK or CAN can be individually configured through the use of interface modules, and compact MLC-based CFast cards up to 60 GB and more are available to meet every memory need. The graphics engine used in Intel Atom processors is derived from Core i technology and provides powerful processing all the way up to Full HD. This is also the first time that support for DirectX 11 is provided in this segment, opening up even more possibilities for enhanced graphic capabilities in SCADA and other HMI systems. For more information, please contact: B&R Industrial Automation Pvt Ltd 8 Tara Heights, Pune-Mumbai Road CTS21 (19A) Wakdewadi, Shivaji Nagar, Pune, Maharashtra 411 003 Tel: 020-4147 8999 Fax: 91-020-4147 8998
Laboratory Refrigerators Cole-Parmer offers laboratory refrigerators, your reliable storage of high value and critical samples. These refrigerators operate with stable temperatures and are developed for the consistent storage of samples. With sleek design, large storage capacity and a concealed thermostat, it is the first choice for most of the applications in pharma, laboratories and universities. Refrigerators are equipped with external digital temperature display and fully electronic temperature control that ensures a correct set temperature between +2°C to +8°C and are developed for the consistent storage of samples. The refrigerators have large control panel. Its large display provides an easy view of the current cabinet temperature. You can view temperature history with the illustrative graph chart that can be generated on the screen. Temperature data can also be downloaded with the USB data logging system. The tall and streamlined design makes the refrigerator fit easily into any room and setup. Mobility is, in addition, enhanced by the castors, which makes positioning and re-positioning effortless and is equipped with an ergonomic door handle for better grip and LED lighting for clear viewing of contents. Typical applications of these refrigerators are storage of reagents, chromatography equipment and samples, biological/BOD (biochemical oxygen demand) samples, culture media, vaccines and academic research labs/ biotech labs/pharmaceutical labs/certain clinical labs. For more information, please contact: Cole-Parmer India 403-404, Delphi - B Hiranandani Business Park, Powai, Mumbai - 400 0076 Tel: +91-22-67162253, 67162222, 67162229, Fax: +91-22-67162211 E-mail: email@example.com / firstname.lastname@example.org
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5 th Annual Clinical Trials Summit 2014 Dates: 10 th - 11 th June 2014
BIO International Convention - ABLE India Pavilion
Venue: Kohinoor Continental Hotel, Mumbai, India
Date: 23 th - 26 th June 2014
5 th Annual clinical trials Summit 2014 will examine the current issues faced in clinical trials operations, addressing the risks, timeline and budget stipulations, while effectively tackling key challenges in overcoming trials agreement and site contract arbitration problems. This summit will discuss the operational element of trial site management, strategic partnership with CROs and SMOs, patient, talent &investigators management in order to improve & optimise the overall drug development effectiveness and ROI. Discover on how to implement and benefit from electronic data management & monitoring cost effectively.
Venue: San Deigo, California, USA
Brinda Rajendran Association of Biotechnology Led Enterprises – ABLE Tel: +91-80-4163 6853 / 2563 3853 E-mail:email@example.com
Deepak Raj Virtue Insight Mobile: +91-9171350244 Email - firstname.lastname@example.org, email@example.com
Global Pharma Outsourcing & Procurement Summit Date: 11 th - 12 th June 2014 Venue: Maritim proArte Hotel, Berlin, Germany The Pharma Outsourcing & Procurement Summit addresses the growing pharmaceutical outsourcing requirements in contract manufacturing, bulk, fill finish, drug delivery and formulation, research & development API sourcing.
The BIO International Convention 2014, San Diego happening this June 23 rd - 26 th , brings together life science leaders and policy makers from around the globe covering the wide spectrum of life science innovations and application areas. Key elements of the event include education, networking, BIO Business Forum partnering and the 1,700 companies showcasing the latest technologies, products and services in the BIO Exhibition. Contact:
US-India BioPharma & Healthcare Summit Date: 27 th June 2014 Venue: Boston Marriott Cambridge, Massachusetts, USA USA India Chamber of Commerce has created a BioPharma ecosystem where all stakeholders: Industry, Academia, Investors and Policy Makers meet to learn, share, deliberate and network. This unique platform creates mutually beneficial opportunities and relationships for the global Bio Pharma industry.
This year’s summit featured case studies and interactive sessions by the world’s leading procurement professionals in risk management, low cost country sourcing, clinical outsourcing and cost reduction.
USAIC’s annual BioPharma & Healthcare Summit has become THE BioPharma event in the world for senior executives focused on Drug Discovery & Development, Partnering, Licensing, External Research, Translational Research, Medical Devices, Healthcare, Innovation and Emerging Markets.
Sema Tezel Tel: +44 (0)20 7202 7690 E-mail: firstname.lastname@example.org
USA-India Chamber of Commerce Tel: 781 586-1212 email@example.com
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Pharma Bio World
bookshelf Quality by Design for Biopharmaceuticals: Principles and Case Studies (Wiley Series in Biotechnology and Bioengineering) Authors: Anurag S Rathore (Editor), Rohin Mhatre (Editor) Price: USD 76.23 No of Pages: 328 pages About the Book: Quality by Design (QbD) is a new framework currently being implemented by the FDA, as well as EU and Japanese regulatory agencies, to ensure better understanding of the process so as to yield a consistent and high-quality pharmaceutical product. QbD breaks from past approaches in assuming that drug quality cannot be tested into products; rather, it must be built into every step of the product creation process. This book presents the first systematic approach to QbD in the biotech industry. A comprehensive resource, it combines an in-depth explanation of basic concepts with real-life case studies that illustrate the practical aspects of QbD implementation.
Quality By Design: A Clinical Microsystems Approach [Paperback] Authors: Eugene C Nelson (Editor), Paul B Batalden (Editor), Marjorie M Godfrey (Editor) Price: USD 68.05 No of Pages: 508 pages Quality by Design reflects the research and applied training conducted at Dartmouth Medical School under the leadership of Gene Nelson, Paul Batalden, and Marjorie Godfrey. ‘Quality By Design: A Clinical Microsystems Approach’ includes the research results of high-performing clinical microsystems, illustrative case studies that highlight individual clinical programmes, guiding principles that are easily applied, and tools, techniques, and methods that can be adapted by clinical practices and interdisciplinary clinical teams.
Good Design Practices for GMP Pharmaceutical Facilities (Drugs and the Pharmaceutical Sciences) [Kindle Edition] Authors: Andrew Signore (Editor), Terry Jacobs (Editor) Price: USD 53.31 No of Pages: 576 About the Book: A convenient single-source reference for anyone involved in the planning, construction, validation, and maintenance of modern pharmaceutical facilities, this guide assists project managers as they develop, diagram, and implement pharmaceutical production facility projects-demonstrating how advances in technology and external regulation can impact the production and efficacy of a pharmaceutical facility and the products it produces.
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36 Front Cover
Pharma Bio World
Who’s Who th 14 Edition
Who’s Who is an exhaustive listing & fact book on CHEMICAL PROCESS, PHARMA BIOTECH, HYDROCARBON INDUSTRY & INDUSTRIAL SAFETY
AN ISO 9001:2008 CERTIFIED COMPANY
Chemical Products Finder | November 2013 | 15
R.N.I. No.: MAHENG/2002/08502. Date of Publication: 1â€™st of every month. Postal Registration No: MH/MR/SOUTH-284/2014-16 Posted at Patrika Channel Sorting Office, Mumbai 400001, on 26th & 27th of every month. Total Pages:- 68
Back cover.indd 15
Published on Jun 2, 2014
Published on Jun 2, 2014
Pharma Bio World brings you an issue themed on Quality by Design (QbD). QbD is applied to build quality in a product based on scientific kno...