Stephanie Sutton was an assistant editor at Pharmaceutical Technology Europe.

Stephanie Sutton

The European Commission is looking to provide Sweden with EUR4.3 million to help 700 workers affected by AstraZeneca job cuts to find new work. The proposal is currently awaiting approval from the European parliament and the EU’s Council of Ministers. 

AstraZeneca announced plans earlier this year to axe approximately 7300 jobs worldwide. Almost 1000 of the job cuts will be in Sweden stemming from the closure of R&D sites in Lund and Umeå, and the limiting of operations in Mölndal and Södertälje. Of the 987 redundant workers, 700 who face the most difficulties in finding new jobs are being targeted for support.  The estimated total cost of the support package is around EUR6.6 million, EUR4.3 million of which will come from the European Globalisation Adjustment Fund (EGF), which was established in 2006 with the aim of helping workers who have lost their jobs because of changing global trade patterns or the global financial crisis. Approximately EUR500 million is available each year to aid with job-search assistance, careers advice, tailor-made training and retraining, mentoring and promoting entrepreneurship.

, the EU Commissioner for Employment, Social Affairs and Inclusion, László Andor, said, "The pharmaceutical industry is currently undergoing significant changes in order to retain its competitiveness in a tough environment, and it is therefore increasingly seeking synergies to hold down the rising costs of R&D activities. I am confident that this proposal for EUR 4.3 million from Europe's Globalisation Fund would help to make the workers' transition to new jobs easier and faster." 

Since the start of its operations in 2007, the EGF has received 101 applications, with more than EUR430 million being requested to help around 90481 workers. Applications are being received for a growing number of sectors and an increasing number of EU member states.

AstraZeneca Axe Hovers Above 7300 Workers

Articles

The European Commission is looking to provide Sweden with EUR4.3 million to help 700 workers affected by AstraZeneca job cuts to find new work.

EC Offers Aid to Former AstraZeneca Workers

Lyophilization presents challenges in defining and accurately measuring critical process and product parameters (CPPs) in laboratory and commercial scales. Pharmaceutical Technology spoke to Henning Gieseler, group leader, Freeze Drying Focus Group, in the Division of Pharmaceutics at the University of Erlangen-Nuremberg; Yves Mayeresse, director, Manufacturing Center of Excellence Filling and Freeze-Drying Operations, at GSK Biologicals; Steven Nail, principal scientist at Baxter Pharmaceutical Solutions; Trevor Page, group technical director, and Manfred Steiner, area sales manager, both at GEA Pharma Systems; and Michael J. Pikal, professor of pharmaceutics at the School of Pharmacy, University of Connecticut, to discuss analysis and scale-up methods.

 What analytical tools and techniques are essential for a quality by design (QbD) approach to a lyophilized product? Are there any gaps in current technology in this area?

Gieseler (University of Erlangen-Nuremberg):

 An innovative, process analytical technology (PAT) approach to freeze-drying requires a PAT tool that allows for the determination of CPPs, such as product interface temperature and product resistance, for the batch as a whole (i.e., batch method). Ideally, the technology should be applicable in all scales of equipment. As a compromise, two different technologies (i.e., one applied in the laboratory and one in production) can be used, but they must provide reliable and comparable measures of the same parameter without an inherent scale factor.

In addition to the batch method, it is also necessary to have a noninvasive measurement (i.e., no contact with the product) of a CPP in a single vial. The reason for such a combination is simple. A batch method gives a global, average picture of product-drying performance, while the single-vial method determines specific product-drying performance at a given spot in the freeze dryer. This would help to delineate drying heterogeneity between vials (e.g., edge effects or hot or cold spots on the freeze dryer shelf), which is always present in a freeze dryer in whatever scale and which might even change over time in a given unit.

 One of the current weak points of freeze drying is the absence of direct measurement during the process. In the past, product probes were used to monitor the freeze-drying cycle, but they were not really reliable. There are many reasons for this, but mainly they are invasive. As you modify the freezing of a vial with a metallic wire probe, it creates void around the wire that allows vapor to escape more quickly. Today, automatic loading systems mean that these probes cannot be used anymore. However, new PAT tools are appearing on the market.

 We use tuneable diode laser absorption spectroscopy (TDLAS) as the main PAT for design-space development. It isn’t essential, but it greatly decreases the time and effort required to construct a design space. We have found TDLAS to give accurate mass flow rates on laboratory-scale equipment, usually within about 6% as compared with gravimetric determination. We do this by weighing the filled vials and stoppers before and after freeze drying. However, TDLAS on production-scale equipment is considerably less accurate because of complexities in the dynamics of water-vapor flow from the chamber to the condenser in large-scale, freeze-drying equipment.

 The most important aspects of understanding the lyophilization process are those that provide insight into the individual vial rather than simply measuring the integrated effect on the headspace. Simple aggregated measurements, such as chamber pressure, or more complex measurements, like the application of mass spectrometers to the chamber gas, all have value for overall process control.

To understand the range of process conditions caused by both forced and natural variation within the overall system (i.e., equipment, vials, and product), it is important to be able to characterize the range of experiences of individual vials. However, the problem is that techniques examining the individual vial that can be used during development and validation are frequently difficult to deploy in a large-production dryer.

 The key properties to measure are product temperature and primary drying time. Unfortunately, product temperature in given vials cannot be measured in a representative way. Inserting temperature probes reduces the degree of super-cooling, making the measured temperatures nonrepresentative of the batch as a whole. This problem can be circumvented by using controlled ice nucleation. However, although this technique is available in both laboratory and production equipment, it is not routinely used in manufacturing. Hopefully, this will change in the near future. There are also indirect ways to measure batch average temperature, such as manometric temperature measurement or, particularly, TDLAS, that could be used in manufacturing, but so far, this is not common practice.

Experts share insights into analytical tools and techniques.

Analytical Tools for a Quality-by-Design Approach to Lyophilization

GlaxoSmithKline has announced that it will acquire Human Genome Sciences (HGS) for $14.25 per share in cash, or approximately $3.6 billion on an equity basis. The offer has been approved by HGS, and the definitive agreement between the companies signals the end of negotiations that have been taking place since April 2012. 

The transaction will provide GSK will complete ownership of Benlysta, which was approved by FDA in March 2011 to treat lupus. In addition, GSK will receive full ownership of two experimental drugs, albiglutide and darapladib, which are being investigated as possible treatments for diabetes and atherosclerosis, respectively. GSK has said it will see regulatory approval on albiglutide next year. Darapladib is still in trials, but has shown promising results so far according to press statements. All three drugs were developed as part of the collaboration between GSK and HGS. 

“We are pleased to have reached a mutually beneficial agreement with HGS on friendly terms and believe the combination of GSK and HGS represents clear financial and strategic logic for both companies and our respective shareholders,” Sir Andrew Witty, chief executive officer of GSK, said in a 

. “This is a natural next step in our nearly 20-year relationship with HGS.” 

GSK first publicly offered to acquire HGS in April for $13 per share, but the price was condemned by HGS who strongly felt that the price did not reflect the company’s inherent value. The new tender offer will be open until July 27, 2012.

In a statement, H. Thomas Watkins, president and chief executive officer of HGS, said, “After a thorough analysis of strategic alternatives, HGS has determined that a combination with GSK is the best course of action for our company and the best way to maximize value for our stockholders.” 

GSK added that it expects $200 million in cost synergies to be fully realized by 2015, subject to appropriate consultation. The transaction is expected to be accretive to core earnings beginning in 2013, and GSK is also assessing the potential returns of the acquisition relative to its long-term share buyback program. In a statement, GSK explained that it expects to repurchase £2–2.5 billion ($3.1–3.9 billion) in shares in 2012.

Human Genome Sciences Rejects GlaxoSmithKline's $2.6 Billion Offer

GlaxoSmithKline: A Rebuffed Suitor for the Moment

GlaxoSmithKline Moves Forward with $2.6 Billion Offer for Human Genome Sciences

GlaxoSmithKline has announced that it will acquire Human Genome Sciences (HGS) for $14.25 per share in cash, or approximately $3.6 billion on an equity basis.

GSK to Acquire Human Genome Sciences for $3.6 Billion

There are many ways in which pharmaceutical companies can make a contribution to society beyond developing and manufacturing medicines. GlaxoSmithKline, based in the UK, has always been keen to position itself as a supporter of the British economy so it’s no surprise to see the pharma giant being patriotic once again as it touts its involvement in the Olympic Games, which will start in London in just under two-weeks time.

		As well as being a sponsor of the games, GSK is also the Official Laboratory Services Provider for the 2012 Olympic and Paralympic Games and will be working closely with King’s College London to provide facilities and equipment that will be used to identify athletes that use doping. In other words, GSK will be testing for cheats during the games. Every medalist and 50% of all athletes will be tested in this year’s games.

		To achieve this, GSK will be making use of King’s College London’s expertise in doping and the college’s Drug Control Centre, which has an international reputation for its work in anti-doping control. The centre is one of only 35 accredited anti-doping laboratories in the world.

		Building on this expertise, GSK has created a specifically equipped antidoping, laboratory based its R&D site in Harlow, which will operate 24 hours a day, seven days a week through the Games to test for more than 240 prohibited substances. The laboratory will measure around 4400 square meters, which is about the size of seven tennis courts, and will be operated by experts from King’s College London, with support from other scientists worldwide, and in co-ordination with the Olympic Committee and International Paralympic Committee. More than 1000 staff will be involved in the process, including collection at Games venues, and 150 antidoping experts will be carrying out testing within the laboratory.

		Overall, GSK expects that more than 6250 blood samples will be tested, more than in any other Olympic or Paralympic Games. At peak times, more than 400 tests may be carried out in one day and results will typically be turned around in 24 hours. Tracking technology will also be employed to identify and track samples using bar codes.

		According to GSK, this is the first time a pharmaceutical company has been involved in providing laboratory services to any Olympic or Paralympic Games. If the process runs smoothly, it may be that other pharmaceutical companies begin offering their services to future Olympic Games. It’s definitely a great way to garner some positive media attention and raise brand awareness.

There are many ways in which pharmaceutical companies can make a contribution to society beyond developing and manufacturing medicines.

GSK’s Olympic Role

Lyophilization presents challenges in defining and accurately measuring critical process and product parameters (CPPs) in laboratory and commercial scales. 

 spoke to Henning Gieseler, group leader, Freeze Drying Focus Group, in the Division of Pharmaceutics at the University of Erlangen-Nuremberg; Yves Mayeresse, director, Manufacturing Center of Excellence Filling and Freeze-Drying Operations, at GSK Biologicals; Steven Nail, principal scientist at Baxter Pharmaceutical Solutions; Trevor Page, group technical director, and Manfred Steiner, area sales manager, both at GEA Pharma Systems; and Michael J. Pikal, professor of pharmaceutics at the School of Pharmacy, University of Connecticut, to discuss analysis and scale-up methods. 

What analytical tools and techniques are essential for a quality by design (QbD) approach to a lyophilized product? Are there any gaps in current technology in this area? 

Gieseler (University of ErlangenNuremberg): 

An innovative, process analytical technology (PAT) approach to freeze-drying requires a PAT tool that allows for the determination of CPPs, such as product interface temperature and product resistance, for the batch as a whole (i.e., batch method). Ideally, the technology should be applicable in all scales of equipment. As a compromise, two different technologies (i.e., one applied in the laboratory and one in production) can be used, but they must provide reliable and comparable measures of the same parameter without an inherent scale factor.  

In addition to the batch method, it is also necessary to have a noninvasive measurement (i.e., no contact with the product) of a CPP in a single vial. The reason for such a combination is simple. A batch method gives a global, average picture of productdrying performance, while the single-vial method determines specific productdrying performance at a given spot in the freeze dryer. This would help to delineate drying heterogeneity between vials (e.g., edge effects or hot or cold spots on the freeze dryer shelf), which is always present in a freeze dryer in whatever scale and which might even change over time in a given unit.  

 One of the current weak points of freeze drying is the absence of direct measurement during the process. In the past, product probes were used to monitor the freeze-drying cycle, but they were not really reliable. There are many reasons for this, but mainly they are invasive. As you modify the freezing of a vial with a metallic wire probe, it creates void around the wire that allows vapor to escape more quickly. Today, automatic loading systems mean that these probes cannot be used anymore. However, new PAT tools are appearing on the market.  

We use tuneable diode laser absorption spectroscopy (TDLAS) as the main PAT for design-space development. It isn't essential, but it greatly decreases the time and effort required to construct a design space. We have found TDLAS to give accurate mass flow rates on laboratory-scale equipment, usually within about 6% as compared with gravimetric determination. We do this by weighing the filled vials and stoppers before and after freeze drying. However, TDLAS on production-scale equipment is considerably less accurate because of complexities in the dynamics of watervapor flow from the chamber to the condenser in large-scale, freeze-drying equipment.  

The most important aspects of understanding the lyophilization process are those that provide insight into the individual vial rather than simply measuring the integrated effect on the headspace. Simple aggregated measurements, such as chamber pressure, or more complex measurements, like the application of mass spectrometers to the chamber gas, all have value for overall process control. 

To understand the range of process conditions caused by both forced and natural variation within the overall system (i.e., equipment, vials, and product), it is important to be able to characterize the range of experiences of individual vials. However, the problem is that techniques examining the individual vial that can be used during development and validation are frequently difficult to deploy in a largeproduction dryer.  

The key properties to measure are product temperature and primary drying time. Unfortunately, product temperature in given vials cannot be measured in a representative way. Inserting temperature probes reduces the degree of supercooling, making the measured temperatures nonrepresentative of the batch as a whole. This problem can be circumvented by using controlled ice nucleation. However, although this technique is available in both laboratory and production equipment, it is not routinely used in manufacturing. Hopefully, this will change in the near future. There are also indirect ways to measure batch average temperature, such as manometric temperature measurement or, particularly, TDLAS, that could be used in manufacturing, but so far, this is not common practice.  

What are the key challenges and potential factors to consider when planning to scale up a lyophilization process? 

Examples of challenges include differences in environmental factors (e.g., non-cGMP 

 sterile environment) and the different freezing behavior of the product solution in manufacturing. Other challenges are differences in equipment design and performance, such as emissivity of the surfaces, condenser performance, shelf cooling/control performance, vacuum control capabilities and choked-flow conditions, and a lack of appropriate tools to monitor the freeze-drying cycle. 

However, the above-mentioned challenges can be overcome if operational qualification testing is performed on pilot–production equipment during a factory test or installation at the customer site. Performance testing can be conducted using a predefined freeze-dryer load (i.e., water or excipient solution) at various shelf temperature and pressureovertime profiles.  

 During the early development of a new product, the final facility is not necessarily defined and a product may also be transferred to another factory or CMO. For good scale up, it's important to know the final freeze dryers in which the product will be lyophilized. However, as this is not always possible, the best method is to define a design space that is large enough to transfer towards in the worst-case scenario, such as an in-house industrial freeze-dryer. 

Perhaps the biggest mistake development scientists make when developing freeze-drying cycle conditions is to conduct trial cycles using too few vials, in which most, or all, of the vials are in the "edge effect," where vials close to the edge dry at a faster rate than vials in the center of the array. We always use at least one full shelf of product for trial cycles. If there is not enough drug available for this, we use placebo for most of the vials, and put the vials containing active in the center of the vial array. 

In addition to this, we consider differences in equipment capability between laboratory- and production-scale equipment, such as lowest attainable shelf temperature, fastest attainable shelf temperature, ramp rate under load, lowest attainable vacuum, and so forth.  

Science and risk management must form the basis of the scale-up process. The impact of changes in heat and mass transfer with scale and equipment design can be measured and predicted by applying basic process engineering techniques. If the process equipment is not properly characterized and understood, then scale-up will be a trial and error process. Where the equipment has been properly characterized, however, there is no reason why the scale effects should not be reasonably estimated and validated. 

There are differences in heat and mass transfer that may constitute scale-up problems. These issues need to be addressed by doing operational qualification testing under conditions of defined thermal and masstransfer load, perhaps using TDLAS, so that the capabilities of each dryer are known. Thus, a process can be designed with this constraint in mind. However, the major scale-up issue is the bias in ice nucleation temperature between freezing in a standard laboratory or pilot laboratory, and that characteristic of the Class 100 environment of a production facility. An easy way to circumvent this issue is to use controlled ice nucleation. In fact, even with the extensive knowledge we have now, good freeze-drying practice must include controlled ice nucleation. 

What recent advances are being made in heat and mass transfer theory? How might breakthroughs in this area be applied to more effective scale-up using a QbD approach? 

 There are several good mathematical models that can be used, and some have been applied to freeze dryers to facilitate cycle development. One of the benefits of mathematical models is that they can support the thinking behind the physical aspect of the freeze-drying process. These models are a simplification of the reality and allow for better understanding of the underlying rules. In the future, more specific models based on other mathematical theories may arise that will offer more accurate insight into process development. Such models will surely improve the scale-up process in freeze drying. 

I don't think any real advances are being made in heat and mass transfer theory, because both disciplines are already very mature, but there are advances being made in application of this theory to freeze drying. In particular, the industry has realized the relative importance of thermal radiation as a heattransfer mechanism. This understanding could result in changes in equipment design and construction that take better advantage of thermal radiation, resulting in a more efficient process. 

I would maintain that the physics of heat and mass transfer, which is quite relevant to the design and control of primary drying, is relatively well understood. There may well be advances in applications, including using heat and mass transfer theory to assess in a quantitative fashion the impact of natural variation in key freeze-drying parameters (i.e., heat transfer coefficient, ice nucleation temperature, fill volume, and shelf temperature variation) on product quality (i.e., thermal history, collapse, and degradation). Indeed, some efforts in this area have started. Use of theory in scale-up is also underutilized, and application guidelines are needed. 

Experts share how to choose analytical tools and techniques when scaling up a lyophilization process.

Lyophilization: How to Meet Scale-Up Challenges Using QbD

To gain a perspective on what have been the most significant changes affecting pharmaceutical development and manufacturing, 

 conducted a series of reader polls between December 2011 and May 2012 that asked our readers what they regarded as the most important changes affecting drug-substance and drug-product development and manufacturing during the past 10 years. The polls were directed in five main areas: small-molecule API manufacturing, biologic-based API manufacturing, solid dosage/oral drug delivery, sterile manufacturing, and analytical methods development and instrumentation (see Figures 1–5). Although individual technological advances were cited, an important theme throughout all the polls was the importance of quality by design (QbD).  

QbD came into prominence a decade ago when FDA announced a significant new initiative in August 2002, 

Pharmaceutical Current Good Manufacturing Practices (CGMPs) for the 21st Century

 (1). The initiative was intended to modernize FDA's regulation of pharmaceutical quality for drugs and select human biological products such as vaccines. The initiative evaluated the pharmaceutical as well as the chemistry, manufacturing, and controls (CMC) regulatory programs with the following specific goals: 					

Encourage adoption of new technological advances

Facilitate application of modern quality management techniques, including quality systems, to pharmaceutical production and quality assurance

Encourage implementation of risk-based approaches

Ensure that regulatory review, compliance, and inspection policies are based on modern pharmaceutical science

Enhance the consistency and coordination of FDA's drug-quality regulatory programs, in part, by further integrating enhanced quality-systems approaches (1).

The science- and risk-based approach to pharmaceutical manufacturing that underpins quality by design has been furthered by subsequent guidance from FDA, EMA, and the International Conference on Harmonization. It is not surprising, therefore, that QbD was cited as a significant factor in reader polls.  

When asked what was the most important change that has influenced chemical API development and manufacturing during the past 10 years, 61% of respondents cited QbD (see Figure 1). The significance of QbD far exceeded any single technological advancement in chemical API manufacturing, including microreactors, chemocatalysis, and biocatalysis.  

Figure 1: What is the most important change that has influenced chemical API manufacturing during the past 10 years? 			

Readers also cited QbD as the most important change in biologic-based API manufacturing (see Figure 2) although its importance was more evenly matched with specific technology gains. Thirty percent cited QbD as the most significant change in biologic-based API manufacturing. Advancement of single-use technologies closely followed at 28%, and then improvements in upstream and downstream processing, each cited by 21% of readers polled.  

Figure 2: What has been the most significant development in biologics-based drug development over the past 10 years? 			

Dosage form development, manufacturing, and analytical technology

We also asked readers to evaluate which technology has contributed the most to advancing oral product forms or oral drug delivery (see Figure 3). The two areas that received the highest responses were orally disintegrating tablet technology (24%) and nanotechnology-based applications (21%). 

Figure 3: Which of the following breakthroughs has contributed the most to advancing oral drug delivery or oral product forms? 			

Advances in isolator technology and systems was cited as the most significant gain in sterile manufacturing, being cited by 36% of respondents, making it the highest ranked change in this area (see Figure 4). QbD followed at 23%.  

Figure 4: During the past decade, what has been the most significant advance in sterile manufacturing? 			

Reflecting again the importance of QbD, 30% of respondents identified process analytical technology (PAT) as the most significant development in analytical methods development and instrumentation (see Figure 5). PAT tied with greater throughout in chromatographic methods as the most importance advance. 

Figure 5: What would you identify as the most significant advance in analytical instrumentation and methods development during the past 5â10 years? 			

We also asked readers to identify what they think will be the most significant change influencing the future of drug development and manufacturing (see Figure 6). More than one-third (36%) of respondents said the move to personalized medicine through the increased use of diagnostics with traditional pharmaceuticals. More than one-quarter (29%) said the rise of biologic-based drugs in drug pipelines and commercial product portfolios followed by fuller adoption of QbD (22%).  

Figure 6: Looking forward 10 years from now, what do you think will be the most significant change in drug development and manufacturing?			

Pharmaceutical CGMPs for the 21st Century—A Risk-Based Approach, Final Report (

Readers point to quality by design as having a significant influence on manufacturing and drug development during the past decade.