Stephanie Sutton was an assistant editor at Pharmaceutical Technology Europe.

Stephanie Sutton

	For some time, the European Federation of Pharmaceutical Industries and Associations (EFPIA) has been working on developing a European verification system to help combat falsified medicines. The system, the European Medicines Verification System (EMVS), now seems close to implementation as EFPIA has launched a tendering process to select potential vendors for the technology.

	The EMVS involves individually marking medicine packs with a unique code at the point of manufacture. The code is then verified in the pharmacy prior to release of the pack to the patient. According to EFPIA, the solution will provide end users with more confidence in the pharmaceutical supply chain and its products. In addition, the system establishes the routine activities of using serial numbers and verification, which are required by the EU 

. Member states will have to apply the measures outlines in the directive from January next year.

	The EMVS was piloted in Sweden between 2009 and 2010, and was shown to be effective in identifying fake medicines. In addition, the system’s availability and performance seemed good: pharmacists could work at a normal pace without significant extra effort and the system provided a response in less than half a second for 95% of transactions. According to a document published on EFPIA’s website, pharmacists and wholesalers found that having the expiry date and batch number in a machine-readable format particularly valuable.

	One issue that was flagged, however, was that it was essential that each pack only have one code because the presence of more than one caused confusion to the user.

	The EMVS will build on the learnings from the pilot phase and EFPIA is looking to demonstrate the system’s efficiency and viability through real-life implementation before the European Commission publishes its Delegated Act on Safety Features in connection with the Falsified Medicines Directive, which is expected in 2014. According to a statement, EFPIA believes that the EMVS is “likely to constitute the key solution for future implementation of the Falsified Medicines Directive”.

	The tender process for vendors will comprise several steps and decisions will be based on the fact that the implementation phase and future roll-out phases of the full EMVS will be commercially completely independent.

	The shortlist of candidate vendors will be issued on 15 June.

Articles

For some time, the European Federation of Pharmaceutical Industries and Associations (EFPIA) has been working on developing a European verification system to help combat falsified medicines.

EFPIA Moves Forward With Verification system

Illumina has sent a fourth letter to shareholders urging them to reject Roche’s offer of $51 per share, which Illumina claims is opportunistic and undervaluing the company. In addition, the letter urges shareholders to vote against the candidates that Roche has nominated for election to Illumina’s board of directors. The election will take place at the board’s general meeting on Apr. 18, 2012.

According to the letter, Illumina’s revenue streams are being increasingly driven by nonresearch uses that have the potential to more than double the size of the company’s addressable market from $4 billion to over $8 billion. The company has also received the backing of Institutional Shareholder Services (ISS), Egan-Jones Ratings Company and Glass, Lewis & Co., which provide independent proxy voting advice to institutional investors. All three firms have advised shareholders to support the re-election of Illumina’s slate of directors and vote against all Roche proposals. 

“We are very pleased that all three of the leading proxy advisors... have now recommended that their clients support the re-election of Illumina’s slate of directors and vote against all of Roche’s proposals at Illumina’s upcoming Annual Meeting,” said Jay T. Flatley, president and CEO of Illumina, in a 

. “The simple fact remains that Roche’s unsolicited offer clearly undervalues Illumina and that our highly qualified and experienced directors are best positioned to create value for Illumina’s stockholders.”

Roche has also been sending letters to shareholders urging them to see the merits of the transaction. In 

 to the recommendation from the ISS, Severin Schwan, CEO of Roche Group, noted, “While we are disappointed that ISS has recommended that Illumina shareholders vote against our director nominees at the Illumina annual meeting, we are pleased that ISS noted that ‘Roche would seem to be an excellent partner for Illumina as the sequencing industry grows more intertwined with new drug development.’ ISS also noted that the key to Illumina’s valuation falls in its commercialization strategy – a strategy that has not been tested but is an area in which we believe Roche could provide significant expertise.” 

Roche made its first offer to acquire all outstanding shares of Illumina in February for $44.50 per share. However, the offer was increased to $51 per share at the end of March.

Illumina has sent a fourth letter to shareholders urging them to reject Roche's offer of $51 per share, which Illumina claims is opportunistic and undervaluing the company.

Illumina Urges Shareholders to Reject Roche Offer

 that Roche could be in for a lengthy battle if it wants to acquire the gene-sequencing specialist Illumina. And indeed, the battle is still raging on. Here’s an update on some of the latest developments.

	At the end of March, Roche increased its bid from $44.50 to $51 per share, but Illumina remains dissatisfied and continues to dub the bid as opportunistic and undervaluing the company. Throughout April, Illumina has continued to send letters to shareholders (the most recent being sent on 

)  urging them to reject the offer. According to Illumina, the company’s revenue streams are being increasingly driven by non-research uses that have the potential to more than double the size of Illumina’s addressable market from $4 billion to over $8 billion

	In Illumina’s latest letter to shareholders, the Institutional Shareholder Services is also quoted as saying, “With the lack of serious competition in the near future, and the vast potential for sequencing that is already starting to appear, the board should rightfully be concerned about unnecessary truncation of value by selling the company at too low a valuation of its future.”

	On the other side of the fence, however, Roche has spent the first part of April making its own case to Illumina’s shareholders to convince them of the benefits of the acquisition. In particular, Roche has questioned Illumina’s aforementioned growth prospects.

	“Illumina has continually made a number of qualitative statements regarding the potentially large market for its products in emerging markets and industrial end-markets. However, the company has yet to produce any quantifiable evidence or projections to reassure shareholders when or how this growth will be realized,” explained Roche’s CEO, Severin Schwan, in a 

, Scwan also added, “Roche’s increased offer is highly attractive. By not engaging with Roche, Illumina reinforces the notion that its Board and management are determined to preserve their positions rather than maximize shareholder value.

	Although the situation appears to be stale mate, a turning point could be just around the corner. On 18 April, Illumina’s board of directors will hold their annual meeting. As a current shareholder of Illumina, Roche has nominated several candidates for election to the board, which, if successful, would result in Roche-nominated directors comprising a majority of the Illumina board.

	Understandably, the most recent letters from both companies have focused on persuading shareholders to vote in their favour. Which will the voting go? We’ll have to wait and see. In an article by 

,  shareholders have said that they do not expect Roche to get enough votes to appoint six new board members. However, they may receive enough votes to nominate four board members, which would force Illumina to “come to the negotiating table”.

In February, I wrote that Roche could be in for a lengthy battle if it wants to acquire the gene-sequencing specialist Illumina.

Illumina Continues to Reject Roche

As part of an ongoing collaboration into tabletting science, I Holland and the UK’s University of Nottingham have launched a two-year programme to investigate the cause of tabletting sticking. According to a 

, tablet sticking is one of the biggest problems facing tablet manufacturers today.

The project, titled the Tabletting Science Anti-stick Research (TSAR) project, will use advanced technology, such as scanning electron microscopy, laser profilometry, atomic force microscopy, X-ray photoelectron spectroscopy, Raman spectroscopy, time flight secondary-ion mass spectrometry and adhesion mapping. One particular issue that will be investigated is what makes formulations stick to tablet tooling surfaces, including why certain coatings resist sticking, whereas others do not. Currently, a number of interactions are believed to influence tablet sticking including Van der Waals forces, capillary action, deformation mechanics and static electricity.

The project will be led by Professor Clive Roberts, whose previous research into the quantitative measurements of the surface properties of pharmaceutical materials, using a range of nanoscale techniques, earned him a Queens Award for Industry in 2011.

As part of an ongoing collaboration into tabletting science, I Holland and the UK's University of Nottingham have launched a two-year programme to investigate the cause of tabletting sticking.

Research Project Targets Tablet Sticking

An initiative in the UK will invest £75 million ($120.2 million) into translational science, with the aim of transforming biological understanding into clinical impacts that will benefit patients and the UK economy. The strategy will assess current medical capabilities and outline knowledge gaps and translational barriers that must be overcome. 

The UK’s Medical Research Council (MRC), Engineering and Physical Sciences Research Council, Biotechnology and Biological Sciences Research Council, Economic and Social Research Council, and the Technology Strategy Board are all involved in the project. Together, the partners have developed the Strategy for UK Regenerative Medicine, which outlines objectives and a delivery plan. 

, Rob Buckle, head of regenerative medicine at the MRC, said, “The Strategy for UK Regenerative Medicine provides a coherent framework for research and development activity in this area over the next five years to ensure that we build upon our existing strengths to deliver the regenerative therapies of the future.”

Part of the strategy will be a £25-million ($40.1 million) investment in a Regenerative Medicine Platform, which will work closely with the 

Technology Strategy Board Cell Therapy Catapult Center

, established last year to bridge the gap between business, academia, research, and government in the area of cell therapies.

The strategy will build on existing investments in centers of excellence in stem-cell biology, medical imaging, tissue engineering, and manufacturing science. In particular, there will be a focus on early-stage translation. Buckle added, “Regenerative medicine has the potential to revolutionize patient care in years to come and UK scientists are at the forefront of this rapidly evolving field. But without continued investment and careful planning, this privileged position could be at risk.”

An initiative in the UK will pump £75 million ($120.2 million) into translational science, with the aim of transforming biological understanding into clinical impacts that will benefit patients and the UK economy.

UK Invests in Regenerative Medicine

PharmTech: What types of unique approaches and product knowledge are required when using a QbD approach for lyophilization?

Gieseler (University of Erlangen-Nuremberg):

  We need to find a more profound translation for experiments conducted in different scales of equipment. Successful freeze drying requires a sound understanding of both product and process related attributes, as well as the corresponding analytical tools used during product and process development to representatively measure them. When we look at the desired final quality characteristics of a freeze-dried product, the term 'quality' is, in the first instance, unrelated to the stability of an API, but targets other characteristics, such as cake elegancy, reconstitution time, moisture content and other parameters. A vial with a collapsed cake is routinely rejected from the batch during optical inspection, even though API stability may be perfectly acceptable from a pharmaceutical point of view. Optical inspection is one of the first tests to be performed on a freeze-dried product, not API stability.  

(IMAGE: DIAMOND SKY IMAGES/DIGITAL VISION/GETTY IMAGES)			

The connecting link between 'quality attributes' and 'product/process attributes' is often grounded in the physicochemical behavior of the formulation, which is a function of temperature and time. Physicochemical properties, such as the critical formulation temperature (the glass transition temperature of the freeze concentrated solute [Tg'] for amorphous products or the eutectic temperature [Teu] for crystalline materials) are important parameters that must be determined prior to cycle development. Then, the goal is to control product temperature at the ice sublimation interface below this critical temperature during the cycle to avoid elevated mobility in the system and morphological changes, such as shrinkage, collapse and melt. In industry, differential scanning calorimetry (DSC) has been used for decades to assess the thermal fingerprint of a material. DSC is a powerful tool, but not perfectly representative for the real freeze-drying situation of a product. A more representative procedure is the determination of the collapse temperature (Tc) by freeze-dry microscopy (FDM). The technical set-up of an FDM experiment is currently the best way to simulate freeze-drying in microscale, but still presents obstacles in data interpretation. 

Bearing these critical temperatures in mind, freeze-drying demands reliable and representative control of the product temperatures at the ice sublimation interface during primary drying to obtain a high-quality product. Many commercially available PAT tools (e.g., manometric temperature measurement, TDLAS and others) help during the developmental stage to determine product interface temperatures, but such tools often cannot be used in a production environment. As a result, the biggest obstacle and challenge for the future when establishing a reliable QbD concept for freeze drying is to determine (relevant) critical product and process parameters that are also scaleable.  

  Lyophilization has evolved a lot during the past 20 years. Years ago, lyophilization development mainly relied on the skills of scientists who learned through trial-and-error. Today, analytical tools exist to assist the development of the freeze-drying process. For instance, apparatus such as a cryomicroscope enable the determination of the glass transition temperature, which is used to set up the temperature and pressure during the primary drying phase of a freeze-drying cycle. For a QbD approach, it is quite easy to define at which step each tool will apply and what will its output will be on the process. 

Today, the development of a new process is more systematic, which gives developers more time to concentrate on the product's specificity.  

  At Baxter, the QbD approach to freeze-dry cycle development and optimization relies heavily on a process analytical technology called tunable diode laser absorption spectroscopy (TDLAS). This is a near-infrared technology that measures the instantaneous mass flow rate of water vapor from the chamber of the freeze-dryer to the condenser. We also use fairly standard methods for characterizing the formulation, such as low temperature thermal analysis and freeze-dry microscopy, to determine the upper product temperature limit during primary drying. We use a graphical approach to the design space that incorporates limitations placed on the process that are based on both the characteristics of the product and the capability of the freeze-drying equipment. TDLAS facilitates measurement of the vial heat transfer coefficient as a function of the pressure, measurement of the resistance of the dried product layer to flow of water vapor, and the maximum sublimation rate supported by the equipment as a function of pressure. All of these are needed to construct the design space. 

  In any QbD process, it is important to first define the required performance of the finished product. In other words, what are the critical quality attributes of the product? For a freeze-dried product these are typically things like reconstitution time, appearance, shrinkage, collapse, viability of product, and shelf life. 

The next step is to use analytical methods to determine the behavior of the product during the freezing and drying process. A risk-assessment technique, such as failure modes and effects analysis, can determine which factors in the process may impact the  final-product quality.  

The basis of QBD is to make sure the level of knowledge regarding product and how product quality varies with changes in raw materials or variability in process conditions ensures that the process is fully capable of producing a product that meets specification. 

  Nearly all lyophilized products must be sterile, which imposes a critical quality attribute that is not relevant to oral products. Also, while stability is often an issue with oral products, it is nearly always an issue with a lyophilized product; otherwise, why lyophilize? In addition, Design of Experiments (DOE) is often a critical part of QbD. Although QbD can be useful for the design of formulations and processes for lyophilized products, it is not useful in the design of the primary drying stage of lyophilization. This is a result of the fact that the physics of primary drying are well understood. Designing processes based on physics is better and more efficient than designing them based on statistics. 

PharmTech: What key factors must be considered when determining a design space for a lyophilized product?

   Design space should be defined for critical formulation and process factors. Considering formulation, such factors could include the critical formulation temperature (i.e., the collapse temperature), moisture content, API stability parameters, appearance, and morphological parameters (e.g., specific surface of the cake inner structure that influences, among other things, reconstitution time). Most scientists, however, focus on the process design space, or more precisely the primary drying design space. Here, the most important factor is the product interface temperature, which, in turn, is a result of the applied shelf temperature, chamber pressure, and heat and mass transfer characteristics of the applied container system.  

Recent studies have suggested that determination of the primary drying design space alone seems insufficient to draw a representative picture of product behavior during the process. At the very least, the freezing step must be considered as well because it determines the pore size distribution and, therefore, affects mass flow resistance during primary drying. Moreover, the freezing step may cause API instability due to occurring freeze concentration or ice/water induced surface denaturation (proteins). A product morphology that has formed at different nucleation temperatures during the freezing step might also provide a different degree of stability to the cake structure during primary drying. For example, warmer nucleation temperatures form bigger pores. Some product cakes have shown a higher structural firmness during the sublimation phase when bigger pores were present. The product morphology formed during the freezing phase even influences the secondary drying performance of the drug product. 

The biggest obstacle is to representatively determine the formulation and process design space. While the process design space is typically defined in laboratory-scale equipment, such information must then be scaled to manufacturing. The challenge is that the originally defined process design space might not perfectly match the process design space in manufacturing. 

  The key factors to determine a freeze-drying process are temperature of the shelves, pressure in the chamber, and time. The value of these parameters is influenced by the equipment, which means the design space should be as large as possible. For the output parameters of the process, the key factors are cake elegance, moisture content and potency. Depending on the product, some specific parameters can be added. For example, if the active ingredient is prone to oxidation, a specific test can be developed.  

   The key factors are the upper product temperature limit during primary drying (either a collapse temperature or a eutectic melting temperature) and the capability of the equipment. In addition to this, we need to know the relationship between the variables we control, such as shelf temperature and chamber pressure, and the variable we are most interested in, which is the product temperature. This is done using well-established equations for heat and mass transfer in conjunction with the vial heat transfer coefficient and the resistance of the dried product layer to flow of water vapor. 

At my company, we have directed most of our attention to design space development for primary drying, because it is generally the most time-consuming part of the process, and is generally associated with the highest risk to product quality. We also need to direct our attention to the freezing and the secondary drying phases of the cycle. 

  The design space defines the acceptable processing conditions that have been shown to result in an on-spec product. Frequently, the concept is considered in terms of the allowable range of setting of the critical process parameters. However, it is also useful to use it to consider the range of process conditions that naturally occur inside a freeze dryer.  

The main paradigm shift that occurs currently within the lyophilization world is to admit that each container has its own individual process, which is determined by influencing factors such as the position on the shelf or nucleation sources. This applies for all kinds of containers, including vials, syringes, or trays. 

  Normally there are three types of constraints. First, you want to restrict the temperature of the product during primary drying to a value less than some maximum allowable temperature, which is frequently (but not always) the collapse temperature. Selecting the proper combination of shelf temperature and chamber pressure will ensure that this goal is met, but the process should also at least close to the minimum time as possible to achieve the best process efficiency. Second, the time spent in primary drying needs to be sufficiently long enough such that all of the product will be devoid of ice before the shelf temperature is increased for secondary drying. Premature increase of shelf temperature may cause product collapse.  

Finally, the process needs to be run at a sublimation rate that is within the capabilities of mass and heat transfer for the system. Running under conditions that are excessively aggressive may, for example, result in choked flow, meaning loss of chamber pressure control and perhaps leading to loss of the entire batch. 

PharmTech: According to ICH guidelines, determining the "edge of failure" is nonessential when establishing design space but can is onbe informative. How much consideration should be given to determining the edge of failure in lyophilization process development and why?

   In my opinion, the 'edge of failure' is important to both know and understand in freeze-drying science. Although processes or formulations should not be designed at the 'edge,' you can't estimate an appropriate 'safety margin' that is required. In cases where the 'edge of failure' has not been investigated, a safety margin might be too conservative, or defined on a trial-and-error basis. More importantly, for some critical process or product parameters, "edge of failure" conditions do not exist, which is then quite relevant. For example, a product that can be processed in primary drying at shelf temperatures well above ambient, the limiting parameter is not the product anymore, but the design of the equipment. Again, we should work with a safety margin in the established design space, but we need to rationally set the safety margin, based on the knowledge of the 'edge of failure.' 

   It's interesting to know where the edge of failure is, even if it's nonessential data because it provides knowledge about the total robustness of the formulation. In a QbD approach, the extent of your design space comes from the risk analysis you used to determine the necessary margin. Let's imagine that for shelf temperature we define a 5 °C range around the target. For some formulation, 5 °C is near the edge of failure, but for others we have five more degrees. From this value, different formulation can be ranked in term of robustness against collapse.  

   We give this a great deal of consideration for the development of freeze-dried products. Our understanding of the idea of a design space is to know all of the combinations of, for example shelf temperature and chamber pressure, that result in a pharmaceutically acceptable product. We like for this design space to be as large as possible, so the boundaries of the design space are the upper product temperature limit during primary drying (i.e., the edge of failure of the product) and the equipment capability, which is the edge of failure of the equipment. Therefore, we think the 'edge of failure' is a key component in design space development. 

  The value of knowing where the process may fail is important. Determining the design space depends on the level of confidence in the rate of change of the relevant parameters in the region between the limit of the design space and the edge of failure. If a process is very predictable and linear, then risk of failure can be reasonably predicted. However, in a freeze-drying process the impact of the process condition on the product quality may be non-linear and prediction of the proximity to the failure edge less easily defined. In this case, it may be better to explore the edge of failure explicitly. 

 In general, I agree with this philosophy. However, I maintain that with regards to the impact of collapse, it is advisable to freeze dry a product well above the collapse temperature to observe the impact on product quality. The reason is that collapse temperatures are determined using techniques that do not always quantitatively predict collapse in a product that is being freeze dried in a vial. Sometimes you can freeze dry 5 °C or more above the collapse temperature measured by freeze-drying microscopy without observable collapse in the vial. There are theoretical reasons and several observations that provide documentation for this statement. Second, even if collapse does occur in the vial, there is a question on whether or not any critical quality attribute is compromised. Often, the answer is no, and sometimes product quality (stability) is better in a collapsed product. The application of this information is the knowledge on assessing the risk of collapse. The measure of risk is really the product of the probability of the event and the severity of the occurrence of the event. Running above the collapse temperature addresses the 'severity' of the occurrence of the event. 

 guideline states, "Changes in formulation and manufacturing processes during development and life-cycle management should be looked upon as opportunities to gain additional knowledge and further support establishment of the design space."How can this principle be applied to development of a lyophilization process?

  One of the best methods of gaining additional knowledge about the product and process is to implement robustness testing protocols during cycle development in the laboratory. Here, one would use the desired final formulation composition and desired (optimized) freeze-drying recipe and then develop protocols that challenge the cycle and the formulation. The shelf temperature is elevated in predefined steps to obtain higher product temperatures during primary drying. The same principle can be applied to the chamber pressure set point. After the cycle, the product-quality attributes are inspected and correlated to the observed process-performance attributes, such as mass flow rates, product temperature profiles and product resistance. This way, it is possible to simulate, for example, the impact of a loss of pressure control situation in the drying chamber and its impact on product appearance, moisture content, and other relevant factors. A loss of pressure control in the chamber will result in increasing product temperatures that, in turn, can cause cosmetic or other defects.  

The same robustness testing concept may be applied to the formulation stage. A change in excipient concentration or even exchange of single excipients typically results in a significant change of the formulation performance, and thus design space. The use of statistical methods, such as DoE, helps during formulation development to identify relevant factors. In general, DoEs are much more helpful during the formulation stage than during process development because of the number of experiments required. Overall, a gain of additional knowledge is certainly a desire for most formulation scientists or process engineers, but stringent timelines in the routine day-to-day work don't usually provide enough time to look deeper into the science.  

 The role of stabilizers such as sugar, buffer, polymers and surfactant are now better understood. Nevertheless, depending on the complexity of the molecules, some surprises can occur during development that will need to be corrected. The knowledge gleamed from this will be remembered when developing new molecules. It is necessary to detect all the specificities of the molecule during the early stage of the development because at this stage it can easily be corrected without impacting results of clinical studies. Formulation changes in the late stage of a project can be a major concern.  

 We don't consider changes in the formulation in the context of life-cycle management; that is, once the formulation is established, we don't make changes. However, during product development, making systematic changes in composition is part of the development of the formulation design space. This might be a plot of Tg' versus pH, for example. The idea is to get a good sense of how changes in composition affect the behaviour of the product. For examining stability, we generally rely on shortterm testing under stressed conditions. 

  In the past, quality control techniques have tended to consider and record only binary attribute data such as pass or fail/good or bad. This approach is often rooted in old-fashioned concepts of quality control by inspection of the final product. But if only pass/fail attributes are recorded, a lot of useful information about the parameter being measured is lost. By determining and recording actual measurements it is possible to apply simple statistical process control techniques that can characterise the capability of the process and give warnings of unpredicted variability long before the process reaches a specification limit. For example, measurement of shrinkage within an acceptable range may be a useful indicator that the process is moving closer to a point where an unacceptable level of collapse may occur. 

  I would like to think there are actual examples of industry implementing this advice and finding enthusiastic endorsement from FDA. However, I have no direct knowledge of such examples. I do know, however, that many processes are run far from the optimal. If these were optimized, or at least improved using existing good freeze-drying practice, it would result in shorter processes with absolutely no increase in the risk of loss of product quality attributes. Indeed, in some cases, risk of loss of product quality attributes would be less in the redesigned process.  

In the formulation area, we know now how to formulate at least some proteins in such a way as to obtain far superior stability, with the amount of aggregation developing at room temperature storage for two years being far less than the aggregation that develops during two years at refrigerated storage. However, I have not seen any examples of a company reformulating to reduce the level of aggregates, as long as the 'current formulation' meets the minimum product requirements. 

Experts discuss the best practices for developing a QbD-based lyophilization process.