Since 2003, there has been a growing level of interaction between the European Medicines Agency (EMA) and the FDA.

  With Europe and the US representing the two largest pharmaceutical markets in the world, cooperation between the agencies has several potential benefits. In particular, the increased sharing of information and opinions regarding medicines will result in better and faster information exchange regarding the safety of products being used in the US and vice versa. If unnecessary differences in regulations (with their associated costs) can be avoided, this would also offer huge benefits to industry. For instance, it may be possible to use similar documentation for submissions to both agencies; indeed, the EMA and the FDA already offer a common application for Orphan Drug Status. There are also practical steps that have been taken; for example, previously European phone numbers could not be entered electronically into the editable fields on the US form! More harmonisation among global regulatory requirements would also help encourage more innovative medicines to be brought to market because sponsors feel that meeting regulatory standards in one region will help them develop their products in another.  

Regulatory cooperation also benefits the agencies themselves because they can share experiences and learn more about one another's internal workings. This may also help to avoid duplication of work; for example, the FDA's oncology review team already holds monthly teleconferences with their EMA counterparts to discuss a range of ongoing activities, such as meetings with sponsors, regulatory decisions and even staff exchanges.

  These forums involve the exchange of documents such as minutes from internal agency meetings and important regulatory letters.  

In 2007, the two agencies also chaired a Transatlantic Administrative Simplification Workshop, which featured participation from the heads of individual EU member state regulatory bodies and the US.

  The objective was to simplify regulations wherever possible, provided that they did not involve any changes to existing legislation and as long as they maintained (or increased) public safety standards. Given the wide range of activities carried out by the agencies, it was necessary to classify the areas to be targeted under four general themes: quality and inspections; pharmacovigilance; scientific collaboration; and guidelines, format harmonisation and electronic submission. Following the 2007 meeting, a formal Coordination Committee has been established, which consists of a representative from the EC, the EMA and the FDA. They hold regular teleconferences and carry out yearly reviews of the confidentiality exchange agreements. A follow-up meeting was held in September 2009 when the agencies formalised formats, scales and time periods for information exchange. 

Other cooperative initiatives between the agencies are also underway. In September 2010, the EMA and FDA announced that an existing programme to allow both agencies to exchange confidential information as part of their regulatory and scientific processes was to be extended indefinitely.

  The new arrangement encompasses areas such as scientific advice to sponsors, orphan drug designation, paediatric drug development, and GMP and GCP inspection planning and reports. Marketing authorisation procedures are also covered, as well as any changes to marketing authorisations and postmarketing surveillance.  

Although the two agencies have upped their level of cooperation and share many similar roles, it is important to remember that they remain very different organisations. Whereas the FDA is a unified regulatory agency, the EMA is an administrative organisation that relies on the agencies in individual member states to carry out the functions required. Consequently, whereas the FDA has its own staff for certain roles (site inspections, etc.), the EMA will turn to the agencies in individual member states for such support, which means that EMA decision-making can be influenced by the working culture of the personnel being used from the supporting agencies.

  It is also quite possible that the same data package can generate different opinions from the EMA and the FDA; indeed, a frequent complaint of companies is this perceived divergence in scientific opinions, which makes the process of putting together a development programme that will generate data to satisfy both agencies difficult (and costly).  

As part of their cooperative agreement, the agencies now offer voluntary parallel scientific advice, whereby FDA and EMA assessors provide their views on scientific issues during the development phase of new products. However, this move has not fully satisfied companies. Following the advice procedure, both the EMA and the FDA retain their individual regulatory decision-making authority regarding drug development issues, which means that the advice of each agency may still differ after the joint discussion.  

In the US, there has been criticism from the pharma industry that the FDA is more conservative than the EMA when it comes to approvals. The FDA has flatly denied this accusation, despite a recent slowdown in product approvals, with some FDA officials adding that the analysis of their decision-making is flawed because it places too much emphasis on the absolute numbers of approvals in the US compared with previous years. In contrast, they believe greater attention should be paid to the quality of the applications themselves.

The pharma industry's criticism of the FDA is ironic because the agency frequently finds itself under fire from the US media and the public for being too "industry-friendly". For example, the agency has recently been criticised for having approved Pfizer's Mylotarg (gemtuzumab) for acute myeloid leukaemia (AML) based on preliminary data.

  Mylotarg had been approved under the FDA's accelerated approval regulations, but was withdrawn from the market by Pfizer earlier this year following disappointing results from ongoing trials, as well as safety concerns. This type of criticism is a worry for the FDA, which has been trying to rebuild its reputation with the US public following the scandal surrounding Vioxx (rofecoxib) in 2004.

Meanwhile in Europe, the EMA also faces much criticism and is often touted as not being as efficient and as transparent as its US counterpart. According to a report issued in 2007, over the period 2000 to 2005, of the 71 drugs approved by both agencies, 47 were approved more quickly by the FDA than by the EMA.

As with the FDA, the EMA has also received criticism over the way it has handled product approvals. In May 2010, a 

editorial attacked the EMA for not releasing additional safety information on Roche's acne drug Accutane (isotretinoin).

  The EMA initially responded by stating that it was under no obligation to release serious adverse reaction reports; however, following intervention from the European Ombudsman, the EMA decided to comply.

Moving forward, both the EMA and the FDA will have their work cut out for them regarding their intent to provide parallel scientific advice to companies. Because of limitations in resources, both agencies say they intend to concentrate on breakthrough drugs or important safety issues in areas that have been identified as "clusters of interest".

  The process will be voluntary and is generally expected to be initiated at the request of a sponsor. However, with the decision-making processes of both agencies having been called into question on occasions, finding a balance between the two systems may be problematic for the agencies. For compounds at an early stage of development, companies also worry whether the advice will still be valid by the time the product is ready for a formal regulatory application. A separate issue is how the cooperative efforts of the EMA and the FDA will be perceived by the public. Industry critics — already unconvinced by the rigour of the approval processes currently in existence — may feel that companies are being given an easier ride through joint regulatory measures. 

At present, both agencies are under fire regarding the approval of GlaxoSmithKline's Avandia (rosiglitazone).

  While the FDA has been criticised for not having enough resources to have conducted a thorough evaluation of the trial results, the EMA has been described as being too reliant on data summaries provided by the companies marketing the products. In September 2010, the EMA recommended suspension of Avandia's marketing authorisation in the EU, whereas in the US, the FDA decided to significantly restrict the drug's use. 

In the future regulatory environment, there will be increased cooperation between the EMA and the FDA, and this is set to provide numerous benefits. At present, various projects focusing on different areas of drug regulation are underway to generate specific recommendations on how the cooperative measures will work in practice. A further development has been an exchange staff programme — the FDA has had a permanent representative in the EMA office in London (UK) since 2009 and the EMA adopted a similar approach earlier this year by placing a representative at the FDA headquarters in Maryland (USA).  

Despite the progress being made, however, the agencies will need to ensure that they gain the support of both the pharma industry and the public. Only in this way will the true benefits of collaborative regulatory measures be realised. 

1. European Medicines Agency, "European Medicines Agency and U.S. Food and Drug Administration extend confidentiality arrangements indefinitely" (2010). 

2. European Medicines Agency, "Statement of authority and confidentiality commitment from the European Medicines Agency not to publicly disclose non-public information shared by the United States Food and Drug Administration" (2010). 

3. European Medicines Agency, "Partners & networks: Regulators outside the EU: United States of America" (2010). 

4. EuroPharma Today, "FDA and EMEA: Minding the Gap" (2009). 

5. European Medicines Agency, "Transatlantic Administrative Simplification Action Plan Implementation report — 2009" (2009). 

6. R. Lane, "Similarities and Differences between CMC Information required for EU IMPD CTA and US IND" (2008). 

7. Biopharma Today, "Is FDA More Conservative Than EMEA? FDA Says No; Investors Weigh In" (2009). 

8. Europharma Today, "FDA Not More Conservative Than EU, Jenkins Says; Investors Not Convinced" (2009). 

9. Business Week, "Pfizer Withdraws Drug After Deaths, No Proven Benefit (Update1)" (2010). 

10. New York Times, "FDA Official Admits 'Lapses' on Vioxx" (2005). 

11. Eye on FDA, "The EMEA and the FDA" (2009). 

12. The Lancet, "European Medicines Agency — more transparency needed" (May 2010). 

13. European Ombudsman, "Ombudsman welcomes release of adverse reaction reports by the European Medicines Agency " (2010). 

14. European Medicines Agency, "General principles EMEA — FDA Parallel scientific advice" 

15. Financial Times, Pharmaceuticals: Perils for pill pushers (2010). 

Articles

Industry Insider

There has been increasing cooperation between the EMA and the FDA in recent years, and this looks set to continue in the future.

Will Transatlantic Regulatory Cooperation Meet Expectations?

This article is part of a special feature on packaging that was published in the November issue of PTE Digital, available at http://www.pharmtech.com/ptedigital1110.

Q Which geographical markets are stagnating/declining in terms of sales?

: The economic crisis of 2009 has deeply affected investment in Europe and the US, but not in the markets of Asia, the Middle East and South America, which are showing good growth prospects. For our company, the percentage of business in the emerging markets is considerable and we foresee it growing in the next few years. 

: We serve both the traditional pharmaceutical markets, such as North America, Europe and Japan, as well as emerging markets, such as the BRIC countries. Currently we do not see a decline/stagnation in any of these; the pharma industry has not been as badly affected by the financial crisis compared with other industries and we see continuing strong investments. In the emerging markets, we've seen strong dynamics and this trend is clearly continuing. Machine requirements in emerging markets are constantly increasing, with regards to automation, performance and flexibility amongst others. Already, these markets contribute strongly to our overall sales and this is set to continue within the coming years. 

: North America is generally considered to be a stagnating market for the pharma industry at the moment. However, it may be that the current healthcare reform will generate new impulses. In emerging countries on the other hand, such as Russia and Turkey, market conditions are showing promise. Once a market shows enough potential we tend to start growing our acquisition force in these markets. Currently, about 5% of our business comes from emerging markets and per annum we estimate that the percentage growth is about 5–10%. 

: In general, we've been able to expand our sales even in the difficult years of 2008 and 2009, although the growth rate differs in certain regions. Our traditional markets of Western Europe and the US have grown slower than Asia recently, but it's only in Eastern Europe where we've seen a decline in the past few years — and this represents only a small share of overall sales. In the future, however, we expect further growth in all regions. In particular, we expect to see good growth from the emerging markets. From a mere 5% a few years ago, we can see this number going up to 30% in the next 5 years. 

: A certain degree of sluggishness has been noticed in countries of Western Europe, which has always represented a reference market for us. This is due to a number of contingent reasons; for example, some countries such as Spain are still heavily affected by the consequences of the economic crisis, while in Germany local companies are safeguarded by a recent policy of protectionism. To fight against this, we focus strongly on innovation and the efficiency of our machines. Additionally, we've responded to the economic climate by offering increasingly advantageous maintenance and service contracts, as well as a wide array of accessory services.  

In 2010, roughly 30% of our sales have come from up and coming countries, such as Eastern Europe (14.3%), Latin America (11.5%) and the Far East (4.1%). These markets usually require simpler, but extremely flexible machines as batch and size changeovers are everyday occurrences. These markets also appreciate ruggedness, ergonomics and ease of use over absolute performance. We are very interested in these markets and we expect to grow by roughly 5% over the next 3 years. 

Q What are the key hurdles to servicing the emerging markets?

: There are no huge differences between regulatory requirements in the emerging markets and those in the West for packaging. The most important requirement to effectively service these markets is the need for a very efficient local structure to be able to promptly respond to market requirements. 

: A major hurdle in emerging markets is overcoming the high initial investment costs compared with the cheap labour costs. This hurdle will decrease with time and the need for automated solutions will continue to increase. Concerning regulatory requirements, standards are constantly increasing, with emerging markets following industry standards, such as FDA regulations.  

: There are many territorial-specific factors in the emerging markets. In particular, however, there is a big difference between primary packaging requirements and secondary packaging requirements. As a general rule, the demand regarding fraudresistant packaging is first seen in the primary packaging sector (e.g., filling of syringes or vials). In the secondary packaging sector (e.g., cardboard packaging, blister etc.) these demands are implemented with a time delay, partly because secondary packaging is often still processed manually. However, the investments for this implementation are also lower.  

: Language and local support are paramount to success. Also, a low price strategy is required because most of the companies in these regions are startups and cannot spend a lot on equipment upfront. At the moment, there are still differences in the packaging and regulatory requirements of emerging markets compared with the West; for instance, in emerging markets there are not as many regulations to follow, but this will change. Also, if you want to export the product then you still have to follow the rules at the receiving end.  

: There are mainly two obstacles to servicing the emerging markets. First and foremost, there is the cultural gap that separates us from these markets, but this can be resolved (at least partially) through onsite agents backed by constant and proficient technical assistance. We have recently opened branches in India and China to cut the physical and cultural gap between these markets. The second obstacle for us is down to production costs, since our production is fulfilled mainly in Italy. 

Q How do you overcome the hurdles to expansion in the emerging markets?

: To overcome the hurdles to expansion in emerging markets it is very important to have a strong and stable local presence in charge of sales and service in these markets. It is beneficial to have highly skilled people who know the relevant market well and the products that are commercialised within it. 

: The hurdles to expansions in emerging markets can be overcome by strong local sales and service organisation, in cooperation with manufacturing operations. For us, the emerging markets are of highest priority, and we foresee strong future growth potential driven by factors such as wealth, the increase of a strong middle class, better health insurance and increasing living standards. Consequently, we continue to build our local expertise in these markets. This includes production according to market requirements and strong support from our European competence centres for high-end applications. This strategy allows us to understand market requirements, react quickly to changing demands and secure responsiveness. 

: We develop packaging machine concepts with high flexibility specifically focused on these markets in order to package the wide variety of package styles on one and the same machine. The manufacturers in these markets can use the technology platform for different kinds of packaging applications and still only have one base machine investment to make. 

: Our strategy is low technology and low price equipment, as well as our own subsidiaries in those countries. It's important to get in front of the customer and speak his language. Having local support and testing facilities also helps. 

Q With increasing focus being placed by governments and regulators on improving the security of genuine pharmaceutical products, what measures are you putting in place to help ensure the security of your packaging?

: The use of tamperevident solutions varies worldwide as there are no standardised regulations. The simplest packaging integrity solution involves using glue sealing, which can be performed directly by the cartoner to speed-up production and reduce potential errors. However, the system is not flawless because all it takes is a heated blade to melt the glue. Another simple solution is to use a tamperevident labeller. This is more reliable because it is difficult to tamper with an adhesive label without damaging the material. The label can also have logos and holograms.  

Traceability technologies have also been developed that can help battle counterfeits. These are extremely reliable, especially when combined with a tamperevident system. Track and trace (T&T) systems were first developed 5 or 6 years ago, but are becoming more and more important nowadays in view of regulatory enforcements. 

: Our customers have asked us to adapt several of our systems to prevent the counterfeiting of pharmaceutical products packaged on our machines. Some of the measures adopted are the use of film for blisters, boxes with hologram images, the printing of bi-dimensional codes and the application of labels with magnetic codes. The two last technologies can also be used for cartons containing blisters and bottles. 

: T&T has been established as a particular growth field in anti-counterfeit solutions. We've been applying T&T systems in production processes for 8 years for controlling and documentation purposes, as well as for product liability reasons. A number of companies have also requested that packaging systems are able to apply 2D matrix codes and mass serialisation, including value stream mapping. 

: Securing the product in the package is typically a joint development between the manufacturer and the machine builder. In order to meet changing market requirements for secure package development, we establish a close collaboration between the supplier of the packaging materials, the machine manufacturer and the manufacturer of the products. Ideally, this approach leads to safe, cost-effective and marketconforming packaging design. 

: We are often asked to implement T&T devices in our lines to allow pharma companies to track their products throughout the supply chain, right down to the pharmacist. Implementing these isn't a challenge; it's just a question of what kind of codes have to be detected and how the information needs to be transferred to the IT department. 

Q Which anti-counterfeit technologies are showing most promise?

: There are a number of labelling systems showing promise for fighting counterfeits. The topoftherange models are equipped with vision systems, onboard printer and sensors for detecting rejects and the position of the carton, which can in turn be installed in line with the casepacker. One of the complications of these technologies, however, is the disposal of rejects. If the vision system records a product that is to be rejected, the latter is entered in the database whatever the case and the decommissioning process is consequently triggered, which wastes operator time and slows down production. This problem can be partly solved by fulfilling all the control functions upstream from the chain and by positioning the cameras at the end. The challenge for the future is improving integration between sensors, vision systems and printers, which will also become faster and more efficient.  

Another possible solution is serialising and mapping tamper-evident labels; however, this would involve the implementation and management of complex databases. Looking further into the future, we are studying applications of RFID technology, which seem to be rather promising. 

: The anticounterfeit technology that is showing most promise is 2D data matrix code because it is able to maintain a great deal of information at a lower cost. This technology will be become more and more widespread, especially in markets where pharmaceutical products are largely commercialised. 

: There are many anticounterfeit technologies on the market, but there is no silver bullet; rather an effective solution is to use a combination of different technologies, such as mass serialisation and tamper-evident packaging combined with holograms. Recent government regulations to curtail counterfeits are making these measures ever more crucial for manufacturers. Fortunately, many manufacturers now offer T&T and mass serialisation on a machine level in production lines and at plant level for overall production from a single source. 

: When it comes to anticounterfeit technologies, the easier the better. This means designing a packaging principle that is easy to process in the machine, but complex to remanufacture. If a packaging concept requires specific machine functional principles, for instance, this necessitates higher investments and raises the barrier against plagiarists. In the future, I think widespread adoption of anti-counterfeit technologies is possible, but only if processible safety features for packaging can be achieved. 

: There are a few interesting ideas talked about such as RFID, but nobody has decided yet which route will be the main one for pharma. For producers of packaging machinery, the chosen option won't really make much difference as our systems will still have to be able to adapt to all available anti-counterfeit technologies. 

Q In general, are pharma packaging companies doing enough to curb the threat of counterfeiting? 

: Anti-counterfeit technologies are common in many Western countries where there is a culture of safeguarding the origin of the product both for the pharma and the food markets. In some countries, our clients need to implement certain anticounterfeit technologies to ensure they follow packaging rules and regulations. In general, however, I believe that pharma companies could still do more to curb counterfeits. 

: Many pharma companies are now adopting anti-counterfeit measures for their products. Counterfeit APIs and medicines pose a growing threat to patients worldwide, and are becoming increasingly prevalent in Europe and the US. In particular, seizures of counterfeit medicines at European borders have risen explosively in the last 5 years. In addition, more medicines are being sold 

 the internet, which makes it much easier to put counterfeit products into circulation.  

: A number of efforts have been taken by the pharma industry to ensure the integrity of their products. With regard to the packaging concepts, however, more innovation and progress could be achieved, but the amount of time and effort required to reregister authorised packaging materials is extensive and many companies try to avoid this. 

: Companies could do more, but this would incur additional costs in an already competitive marketplace. If it is a voluntary option then many companies choose not to incorporate additional security features.  

: No, they don't do enough. Many manufacturers, especially smaller ones, consider the implementation of anti-counterfeit technologies as a cost accessory and hold out. Because of this, anti-counterfeit technologies tend to only be used where standards mandate them. 

Q What strategies has your company put in place to improve the environmental impact of its packaging processes? 

: We are constantly testing and trialling plastic films designed to reduce the environmental impact of our packaging processes. The results of these tests and trials have been promising. Also, the machines and complete lines that we design and manufacture have reduced energy consumption. 

: There are a number of ways that environmental issues can be addressed in pharmaceutical technologies. For instance, for pharma equipment with high energy consumption, environmental benefits can be achieved by reducing water and energy usage. Often, modules or transport conveyors of a packaging line continue to run during operator breaks or equipment failures. Energy consumption can be reduced dramatically by having the machine recognise the situation and cease operation to reduce energy consumption. This can be aided by softwarebased assisting systems. 

In the sealing process, ultrasonic sealing technology can also help reduce energy consumption by 30% compared with heat seal applications. The seal quality of ultrasonic sealing allows savings of up to 10% in flexible packaging material, and also provides the ability to control the sealing process based on the monitoring of parameters to reduce rejects, waste and rework. 

Environmental benefits can also be gained by eliminating complex interfaces between functional modules, which reduces failures leading to rejects of packaging materials. This substantially decreases the waste of packaging material and consumption of energy for the rework.  

To really address environmental impact, it is vital to look at the whole production, packaging, distribution and sales processes. A prerequisite for this integrated view is close cooperation between a company's marketing and production departments and packaging systems suppliers. 

Special Feature

Leading European experts from the pharmaceutical packaging industry explain how they are coping with industry trends.

Packaging: The Experts' View

What do regulators talk about behind closed doors? Just about everything! The good news, however, is that one area getting a lot of attention behind the closed doors of the European Medicines Agency (EMA) and the FDA is regulatory harmonisation. At the 2010 symposium of The Organisation for Professionals in Regulatory Affairs (TOPRA), held in London (UK) in October, regulatory international cooperation and communication emerged as a key theme. 

Hilde Boon, the EMA's liason official at the FDA, described a number of ways in which the EMA and FDA are collaborating. "Many of our exchanges concern changing draft review reports and assessment reports," she explained. "We also share pharmacovigilance information and we have ongoing pilots in GMP/GCP that allow us to exchange inspections information and start planning for possible joint inspections." 

One of the most interesting developments is the growing number of joint API inspections 

 a pilot programme being conducted by the EMA, the FDA and Australia's Therapeutic Goods Administration (TGA). The benefits? Less duplicate routine inspections — a benefit to both manufacturers and the workloads of regulators — and an increase in the overall number of API manufacturing sites inspected. 

"We've heard from sponsors and manufacturers of APIs that they sometimes suffer from inspection fatigue," explained Janice M. Soreth, Deputy Director of the FDA's Europe office and liason to the EMA. "One way to alleviate this is for us to partner and do inspections together." 

As of Q1 2010, seven joint inspections have been conducted; one involving the EMA and the FDA, five involving the EMA and the TGA, and one involving the FDA and the TGA. Several other joint inspections are also currently in the process of being concluded. 

"In addition to joint inspections or observing one another in inspections, there are also frequent requests from one or the other authority for reports of API inspections that we think may have been conducted by one of our partners," said Soreth.  

Unfortunately, perfect harmonisation between the agencies is still a long way off and the issue of duplicate inspections still hasn't been nailed. Soreth admits that the reasons for these duplicate inspections still needs to undergo further analysis and that they may stem from lack of communication. In some instances, however, it may be that it was an inspection for cause rather than a simple routine inspection.  

"No matter what level of confidence we may have in one another, our laws and our need to defend any enforcement actions we take will probably always leave us in a position, at least for inspections for cause, where we have to do our own inspections," said Soreth.  

Another area that the EMA and FDA are working closer together on is GCP. In September 2009, another pilot was initiated whereby the agencies will exchange GCP-related information and conduct collaborative GCP inspections, in light of the fact that more and more data from foreign facilities and clinical trial sites are making up applications to the EMA and FDA.  

"This can sometimes present an opportunity for less attention to detail and, in the worst cases, economically motivated deviations from GMP and GCP," said Soreth. "With our GCP pilot, we get our arms around the global conduct of clinical trials to assure ourselves that they're ethically conducted and to assure the integrity of the data that makes up a marketing authorisation application."  

There will always be differences between the agencies; however, where possible, efforts to harmonisation are being made. "Whether we're talking about the pilots or our other collaborations, these exchanges drive us to harmonisation where that's possible," said Soreth. "At the same time, it also helps us to identify areas where we diverge or where we look at the same body of data and take a different decision." 

IMS Health's new report predicts that the industry will rebound somewhat in 2011, growing at a rate of 5–7%, compared with only 4–5% in 2010, to reach $880 billion. However, it's not all good news as the underlying constraints to growth will be stronger than ever in 2011. 

Sanofi-aventis has initiated a hostile tender offer of $69 per share for all outstanding shares of Genzyme. The latest offer is similar to previous public and nonpublic offers, which Henri Termeer, Genzyme's CEO had rejected as "opportunistic." The offer is scheduled to expire on 10 December. 

Pharma companies must ensure that patients have access to "objective, unbiased information" about medicines, according to the European Parliament's Health Committee — this should be a patient right rather than an option for pharma companies. 

The EMA has adopted new policies on access to documents and the handling of conflicts of interest. In particular, the new policy on access to documents takes into account recommendations made by the European Ombudsman, which earlier this year criticised the EMA for its transparency when the agency refused to grant public access to reports on adverse drug reactions. 

News

Joint regulatory API inspections on the rise.

What are the key challenges that face cell-based bioprocess manufacturers today? 

Several issues present challenges for manufacturers today, including purification and stabilisation, delivery, yields, contamination, process development and scaleup.  

Harvest of product cells from adherent cell bioreactors is one of the critical bottlenecks in the cell therapy manufacturing process.

Many processes utilise trypsin or other enzymatic digest methods to remove cells from cultivation surfaces, but the cells must be neutralised, washed, analysed for purity and formulated within a narrow window of time — as short a timeframe as possible and typically in less than 1 hour — to produce a reliable product. Many cell production processes are patched together from singleuse bioprocessing containers designed for supernatant rather than cell harvest. Factors such as particle loads from singleuse bags, smaller process volumes and lack of terminal sterilisation of the product all impact on process design, as these factors are not a concern for supernatant processing. There is limited equipment available that has been purpose-designed for sterile, scalable cell harvest, washing and concentration, although this situation is changing.  

Products can currently be formulated and filled into storage or delivery bags or vials for fresh or frozen inventory. Particularly if products are shipped fresh, the product should be quantified for stability, viability and preferably dose-response.  

The factors mentioned above all contribute to delivery concerns with both fresh and frozen product. In addition, the manufacturing model should be considered — whether the product is allogeneic or autologous, and manufactured in small batches close to the site of delivery or at scale at a central manufacturing location. Although fixed costs may be lower, operators may be better trained and have greater process experience, and the product quality and consistency may be easier to control at centralised sites, none of this matters if the product degrades unacceptably during transport. Each product needs to be assessed separately due to varying inherent cell lineage characteristics to determine whether fresh or frozen is acceptable and to determine parameters, that can even possibly be monitored throughout transport, which indicate the cell population viability. 

One of the more troubling cell therapy process development issues is trying to develop a consistent, safe and efficacious autologous stem cell therapy when inherent genetic, and perhaps epigenetic factors, cause cells from different donor/patients to grow and differentiate at different rates. This means that multiple batches cannot all be maintained by the same protocol on the same time schedule, which currently precludes automation of that process. Relevant process variables will need to be defined and measured to take the 'art' out of producing such cultures before this system can become amenable to automation; therefore being safer and, over time, more efficient and cost effective. The development and integration of additional PAT into bioreactors will enable automation in the future. At the moment, many assays indicating the culture's growth and differentiation status are done manually. Development of online, singleuse sensors with feedback loops will permit automation. Additionally, the FDA guidance on manufacturing autologous somatic cell therapies indicates that acceptable ranges for operating and control parameters be defined for a cell growth process — typically these would include cell doubling time, cell purity, viability and culture time. These native differences in the donor cell populations may necessitate the use of alternative parameters or validation of a wider acceptable range than the manufacturer would prefer.  

Scaleup of adherent cell culture has always been a difficult challenge in biological manufacturing. Some manufacturers of laboratoryscale tissue culture plasticware make 'larger scale' units. While these ideally mimic the smallscale cultivation situation, which facilitates development of the growth process, they do become unwieldy on a larger scale and still have an upper limit on surface area. Therefore, manufacturers are forced to multiply the numbers of bioreactors they run, which mitigates risk and also creates more labour and batch size limitations, limiting economies of scale and increasing the quantity of testing, verification and documentation.

Limited purposedesigned, singleuse equipment is available for the cell harvest, wash and concentration part of the process. This is one part of the process where adaptation from a supernatantfocused process is of limited utility; those processes often use continuous (reusable) stackeddisc centrifuges that are efficient for processing volumes over several hundred litres and which pellet and discharge cells. For maintenance and recovery of a viable cell population, however, lower shear methods that don't deprive cells of oxygen and nutrients would be more ideal. 

Already, new embryonic stem (ES) cell line derivations can be made much more stable and robust than earlier derivations; various 'adult' stem cells can be grown reliably and defined, whilst animal-free media have been developed for cultivating such cells. This evolution mirrors that of the development of Chinese hamster ovary (CHO) and similar cell lines and their media for monoclonal antibody production more than 20 years ago. The sheer volume of current research detailing biochemical pathway inhibitors, surfaces for preferential growth or directed differentiation of many different stem cell lines and moves from 2D adherent culture to 3D culture (whether on microcarriers or using other suspension techniques) is indicative that production of sufficient cell numbers for allogeneic therapy will quickly become more easily achievable. 

For autologous therapies where the donation of cells is small, this may be more difficult. Yield needs to be sufficient for both the therapy and safety/efficacy release testing. In this situation, guidelines may need to be more flexible for testing as there are relatively few tools available to increase yield for lowdividing cell types.  

Relatively few biological processes have absolutely required top-to-tail sterility assurance, even if that situation has been ideal. Most processes have had some option for terminal sterilisation whether by heat or filtration — a situation that can't work with cells. Most largescale cell manufacturing processes use singleuse bags, tubing, aseptic connectors or tubing welders and sealers in a clean room to create a continuous aseptic process. For smaller scale processes — particularly patient-specific autologous therapies — this becomes problematic and the costs rise. Some of these therapies are made using multiple open manipulations in a laminar flow hood; robotics and new equipment development from manufacturers with a cell therapy focus are targeting this area. 

Of those challenges discussed above, could you please explain how they can be overcome?

Vendors will need to overcome shortcomings in their equipment and disposables that limit their use in this nascent bioprocessing market. These may be 'small' issues (such as temperature limitations on transfusion bag film or having bioprocessing singleuse disposables in the right size) or larger issues (such as the lack of critical harvesting equipment or small-batch final bag fill equipment). Establishing cooperations and information sharing between researchers, manufacturers and vendors will assist the rapid development of appropriate processing equipment. Likewise, involving the regulators in this process will optimise the concurrent workup of manufacturing and compliance with existing regulations, as well as those that will inevitably be added as this field matures.  

Manufacturing models will need to be assessed on a productbyproduct basis. For example, having small scale manufacturing close to the point of harvest and use makes sense for most autologous therapies; indeed, several vendors have been developing selfcontained, easily transportable 'manufacturing suites' to serve this model. Allogeneic therapies that can be manufactured on a large scale will most likely utilise centralised facilities and have to put more effort into validating the transport and storage chain. This is something that will have to be assessed on a perproduct basis. 

What are the main obstacles to implementing QbD principles to cell-based bioprocessing? 

One of most conducive factors for implementation of QbD in cell therapy processes is that much cell bioprocessing is new, i.e., without legacy plants and protocols. With cell therapies arising from basic biological research, however, early development work may have been done in a laboratory without an understanding of GMP and with insufficient process or development documentation. Many cell biologists have a 'feel' for growing cells, but this doesn't translate into a reproducible, documented process. The aim is to design the process, rather than the personnel, to be reproducible and, depending on the origin and training of the personnel who invented or developed the therapy, the culture of the workplace may need to shift to embrace the principles of QbD. 

Improvements in purification techniques — their specificity, scalability and options for single-use —will help the industry progress to make a more reproducible, safer cell product. 

The innate variability of a cell type derived from different sources is also a factor for autologous therapies. If a process is workedup on mesenchymal stem cells (MSCs) from a selection of sources; the parameters for growth, viability, etc. could vary depending on the site the MSCs were harvested from, the age of the donor if the patients to be treated are dissimilar from those donors used for the process validation, genetics and general health. It is unlikely that it will be possible to validate a process with just one cell source or to draw from master or working cell banks that can be used for allogeneic therapy production.  

The cell processing industry has learned lessons from the existing bioprocess industry, from where many key personnel have transferred, and this manufacturing experience is essential to balance out the basic R&D origin of many therapies currently in development. 

What equipment types are most widely in use in the bioprocessing of cell-based therapies today? Where is there room for improvement in current practices?

Adoption of singleuse processing tools is almost at saturation level within cellbased bioprocessing. While singleuse bioreactors and fluid handling systems are still on the upswing within traditional bioprocessing, they've proven to be absolutely essential for cell production due to the sterility assurance, elimination of crosscontamination risk and negligible contamination risk from environmental toxins (residues, endotoxin etc). Cell processing does not allow for the removal of such incidentals, so manufacturers have adopted this equipment to prevent risk of introduction during processing. 

We have already discussed challenges in scaleup of product filling and cell harvesting equipment/techniques, but bioreactor design is another area where some improvements will be made over time. Various groups are working on stem cell cultivation techniques to enable less spaceintensive scaleup, an issue that other bioprocessing industries haven't faced directly; CHO and other cell lines used for protein production are typically adapted for suspension culture. Most stem cell types are unconditionally adherent. Cultivation as aggregates, in alginate encapsulation, on 3D matrices of various sorts and on microcarriers are all works in progress. Improvements in design, handling and automation of adherent cell bioreactors is possible within a limited scope, but overall the industry may move to using adherent surfaces in suspension reactors (e.g., Cultibag RM; Sartorius Stedim/wave reactors or stirred tanks) if technical problems with adapting to microcarriers or suspended 3D matrices can be solved. This would also enable further process automation, including use of singleuse pH and dissolved oxygen sensors to monitor and control cultivation parameters, reducing handson time. 

What are your predictions for the future of cell-based bioprocessing? 

Cell purity and sorting requires innovation in techniques and equipment from industry. Stem cell populations are rarely, if ever homogeneous, and most therapies require expansion of the cells and differentiation. Currently, this is not an 'allornothing' phenomenon — some cells will differentiate down other lineages than desired. For safety and efficacy reasons, cell products will need to be defined as part of their release testing. Depending on the derivation of the product, some contaminating cell types may be dangerous to the patient (e.g., undifferentiated ES cells) or simply have an unknown effect on the 

 culture. Sorting techniques, such as fluorescenceactivated cell sorting, can produce a pure population, but most (with the exception of the BD Influx single-use fluidics option; BD Sciences) have reusable product contact components that are difficult to sanitise confidently. Positive and negative bead selection and centrifugal elutriation provide some selection, but only by a limited number of parameters. The remaining cell populations and any carryover from the purification process needs to be tested for nontoxicity and stability. Improvements in purification techniques — their specificity, scalability and options for single-use —will help the industry progress to make a more reproducible, safer cell product.

 Product Manager, Laboratory Technologies, Stem Cells & Tissue Engineering at Sartorius Stedim Biotech

Interview

Discussing the key challenges that face cell-based bioprocess manufacturers today, how these challenges might be addressed and the innovations that could facilitate the process in the future.

Overcoming The Challenges Of Cell-Based BioProcessing

Although there are no regulatory requirements or established pharmacopoeial techniques for the dissolution testing of inhaled drugs, such testing can potentially open up the opportunity to tailor formulation properties. The authors explain how a new technique using standard dissolution test equipment in combination with US Pharmacopeia methods for the dissolution testing of solid dosage forms can be used to differentiate the solubility of orally inhaled products. 

Dissolution testing of inhaled drugs is of significant interest to the developers of orally inhaled products (OIPs) that deposit solid particles in the lung. As yet, there is no regulatory requirement or established pharmacopoeial technique for such testing, but its relevance is clear; understanding and, in the longer term, learning to control the dissolution rate of an active (particularly one for systemic therapy) opens up the possibility of tailoring formulation properties, as well as dosing levels and frequencies, for improved drug efficacy and patient compliance. 

Against this background, research has been conducted to establish a suitable method for dissolution testing of inhaled products. This paper considers the need for this and describes a technique developed at the University of Texas at Austin (TX, USA). Based on using standard USP dissolution test equipment for solid dosage forms, this new technique differentiates the solubility of OIPs. 

Assessing the need for dissolution testing for inhaled drugs

For solid oral dosage forms, such as tablets and capsules, dissolution testing is standardised and routine. The dissolution profile of a product guides formulation and development, and is a widelyused QC tool. Dissolution data may also be used to support claims of parity in a generic product and/or to demonstrate equivalence following a formulation change since it is sufficiently sensitive to identify outofspecification manufactured batches. 

With orally inhaled products (OIPs), the efficiency of drug delivery is linked with the extent of deposition in the respiratory tract. A particle size of less than 5 µm is usually regarded as optimal for penetration to the deep lung, so the focus is to develop device/formulation combinations that deliver a high proportion of the dose in this size range: a high fine particle dose (FPD).

As with solid dosage forms, the therapeutic effect of an inhaled powder is realised 

 dissolution and subsequent absorption. Powders delivered to the lung are, of necessity, extremely fine, so there may be an assumption that dissolution rates are rapid enough to have little impact on the overall process of drug delivery. Within a recent USP Pharmacopeial Forum review,

  however, it was recognised that dissolution testing may expand our understanding of inhaled drug delivery and support the development of new OIPs. This view is reinforced by industrial interest in the topic, as exemplified by recent work presented by GlaxoSmithKline contrasting the dissolution profile of a longacting beta agonist with that of an inhaled corticosteroid.

  If inhalation technologies follow the same development trajectory as tablets, there is no reason why the modification of particle properties, such as size, shape or crystal habit, to control 

 release rate should not become routine. Formulations based on liposome, micelle and microsphere technologies also provide for more closely tailored delivery profiles.

  The trend towards the pulmonary route for the delivery of systemic drugs strengthens the impetus for refining OIP performance in this way.  

Understanding the requirements for OIP dissolution testing

 dissolution testing for inhalable products should be able to distinguish between samples in a way that replicates trends found 

. This suggests that test conditions should reflect the pulmonary environment. Perfectly designed for absorption, the lungs are not ideal from the point of view of dissolution, with fluid levels in the region of 10 to 20 mL/100 m

  of surface. Such small amounts of liquid are likely to be stagnant, inhibiting dissolution. Also, the exact composition of the aqueous fluids and surfactants lining the respiratory tract is not accurately known,

  which complicates the selection of a test medium. 

Equally importantly, testing must also consider the delivery characteristics of OIPs. Just a portion of the emitted dose, the FPD, enters the lung so dissolution testing of the whole dose is inappropriate. A better aim is to access the dissolution profile of only those particles that will deposit in the lung.  

Developing a dissolution testing technique for inhalable formulations

In 2003, Feddah and Davies introduced a dissolution testing technique for inhalable formulations based on a flow through apparatus.

  This technique involves the use of an Andersen cascade impactor (ACI) to capture the emitted dose from the DPI. A glass fibre filter mounted at the base of a USP induction port, of the type routinely used with multistage cascade impactors, captures the dose during otherwise standard operation of the ACI. Once captured, the dose is held in a dissolution cell through which solvent is pumped at a known flow rate. 

This method was used to differentiate the solubility of glucocorticoids employed in the treatment of pulmonary disease, but it has a number of disadvantages. Firstly, although an ACI was used to capture the dose for testing, the size fractionation capabilities of the impactor were not exploited — the entire emitted dose was captured. Therefore, the recorded dissolution behaviour does not relate to just those particles fine enough to deposit in the lung. An additional problem is the amount of solvent used in flow through testing, which is significant; no attempt is made to simulate the sparing presence of lung surfactant 

. Furthermore, recorded solubility is dependent on the flow rate of solvent selected, making it too easy to achieve noncomparable results for "zero order" drug solubility. 

To address these issues and improve test sensitivity, researchers at the University of Texas have developed a dissolution test for OIP formulations based on the standard "Paddle over Disc" method described in US Pharmacopeia Method 5 and European Pharmacopoeia 2.9.4.

  A modified version of this solution is now commercially available (

). To ensure analysis only of the portion of interest in the emitted dose, the apparatus enables preseparation and sample collection using a Next Generation Impactor (NGI), one of the systems of choice for routine aerodynamic particle size distribution (APSD) measurement. 

Figure 1: NGI dissolution cup and membrane holder (Copley Scientific, UK). 

Multistage cascade impactors, such as the NGI and ACI, separate the emitted dose from an OIP into fractions on the basis of aerodynamic particle size. Using the NGI, these fractions are captured in collection cups. The NGI dissolution cup (Copley Scientific, UK) is almost identical to a standard NGI cup except that it has a 50 mm removable insert in the impaction area where separated sample collects. It fits directly into positions 2 through 7 in a standard NGI cup tray.  

To collect a dose for dissolution testing the NGI is operated exactly as for routine APSD measurement, but with the dissolution cup installed at the stage of interest to allow capture of only the size fraction of interest rather than the entire emitted dose. Once collection is complete, the insert is simply removed from the cup and covered with a pre-punched 55 mm diameter polycarbonate membrane. Securing this in place with the supplied membrane holder forms a sealed disc or sandwich that can be placed in a vessel of a conventional dissolution tester (

). Dissolution testing can then be conducted in an exactly analogous way as for other solid dosage forms, using appropriate operating conditions. 

Figure 2: NGI membrane holder in position in the vessel of a standard USP Method 2 test apparatus. 

Selection of an appropriate diffusion barrier for testing was crucial to the success of this solution. Although relatively thin (approximately 6 µm), the polycarbonate membrane is robust with properties superior to those of a cellulose acetate alternative used in prototype studies. The chosen membrane neither swells nor creates air bubbles, and has non-tortuous cylindrical pores of well-defined size. These allow free diffusion of both the dissolved drug and dissolution media, enabling dissolution testing under relevant hydrodynamic conditions.  

Optimising a dissolution test method for inhalation formulations

Through a series of experiments, factors associated with each step of the test process — from dose collection through to solution sampling method — were investigated to develop an optimal test procedure for use with this new apparatus.

  The following discussion tracks the experiment path taken and its outcome. 

Tests to establish optimal conditions were carried out using budesonide (BD) and albuterol sulphate (AS), which are routinely used to treat asthma. BD and AS were fired into the NGI with a Pulmicort Flexhale DPI (AstraZeneca) and Ventolin HFA MDI (GlaxoSmithKline), respectively. Multiple actuations ensured the presence of sufficient sample on the collection surface in initial tests; however, the actuation number was one of the variables investigated as part of the experimental programme.  

The test flow rate through the NGI was set at 30 L/min for the Ventolin HFA and 60 L/min for the Pulmicort Flexhaler. These air flow rates were established with reference to pharmacopeial monographs for the testing of MDIs and DPIs.

  The monographs stipulate that the flow rate should be set to 30 L/min when testing an MDI (using the NGI) and at a flow rate to give a pressure drop across the device of 4 kPa when testing a DPI. Calibration data for the NGI allows the accurate determination of stage cutoff diameters at both of these flow rates.

Following size fractionation of the sample in the NGI, the removable impaction surface from the dissolution cup was covered with a polycarbonate membrane (pre-soaked in dissolution fluid) and secured in the membrane holder. This entire assembly was then placed at the bottom of a vessel of a standard USP Method 2 apparatus containing 300 mL of dissolution fluid. 

During dissolution testing, 3 mL samples were periodically withdrawn from the vessel for analysis using a validated HPLC method. A corresponding volume of fresh dissolution medium was added after each extraction. With the BD, sample testing took place over a period of 2 h, while 1 h proved sufficient for AS. At the end of the experiment, the residual material on the membrane was recovered and quantified.  

Selecting an optimal collection surface for dose collection

Using the dissolution cup it is possible to select one fraction with which to compare one drug to another, or to assess the influence of particle size on dissolution rate by testing different fractions of the dose. With the Pulmicort Flexhaler (BD) stage 4 consistently displayed the maximum deposition while for the Ventolin HFA (AS) it was stage 5. These stages were therefore selected for dose collection for subsequent tests. Stage 4 has a cutoff diameter of 1.66 µm at 60 L/min, while stage 5 has a cut-off diameter of 1.36 µm at an air flow rate of 30 L/min. 

For the BD, dissolution profiles were determined as a function of particle size by collecting samples on stage 2 through 5 (

). Eighty percent of the samples collected on stages 2, 3 and 4 dissolved after 15 min, but there were differences in initial dissolution rates. Statistical analysis shows similarity factors* of 52.5 and 59.7 for stages 2 and 3 compared with stage 4 (the reference stage), but the dissolution profile for stage 5 is significantly different (a similarity factor of 40.6). The smaller particles on this stage, which has a cut-off diameter of 0.94 µm, have a large surface area to volume ratio and, therefore, might be expected to exhibit a faster dissolution rate in accordance with the standard NoyesWhitney model. 

Figure 3: Exploring the influence of particle size on dissolution profile for budesonide. 

Optimising the speed of rotation of the paddle

Experiments were carried out at paddle rotation speeds of 50, 75 and 100 rpm. With this dissolution apparatus 50 rpm is the norm; however, the presence of the membrane holder necessitated an increase to 75 rpm because of the 'dead' volume between the membrane holder and the base of the vessel, where stagnation could occur after volumes are withdrawn and replaced during the sampling procedure.  

Varying the number of actuations during testing permits investigation of the impact of drug loading on dissolution behaviour. For BD, increasing drug loading from 30 to 220 µg by increasing the number of actuations of the device during sample collection has a marked influence on dissolution behaviour. On the other hand, AS dissolves rapidly even at high drug loadings (

Figure 4: The impact of drug loading on dissolution profile for (a) budesonide and (b) albuterol sulphate (Dissolution media: simulated lung fluid (SLF); T= number 

Increasing the thickness of the drug layer increases the amount of diffusion/dissolution activity required to release the entire dose from beneath the membrane since the wetting and dissolution processes proceed inwards layer by layer. This has a marked effect with the hydrophobic BD increasing the obstacles to dissolution, but with the hydrophilic AS this is not the case. This suggests that powder wetting within the membrane holder may be an issue in certain circumstances, especially with hydrophobic or poorly soluble formulations.  

A simple solution to this problem is to use just a single actuation to obtain the thinnest possible layer of sample for analysis. The practicality of this approach, however, depends on the limits of detection of the HPLC method for a given solvent/drug formulation. In some cases, it will be necessary to use multiple actuations simply to obtain sufficient drug to enable detection in the extracted samples. An alternative is to consider modification of the dissolution media within the constraint of reflecting the composition of fluids present in the lung. 

In the first instance, dissolution profiles for BD were measured using three solvents: simulated lung fluid (SLF); 0.2M phosphate buffer (pH 7.4); and phosphate buffered saline (PBS) (

). There are currently no pharmacopoeial suggested components for artificial lung fluid and it is not feasible to exactly mimic conditions in the lung; rather, the aim during this phase of the study was to identify an appropriate, practical fluid that would simplify testing within the constraint of maintaining relevance. 

Figure 5: Dissolution profiles for budesonide measured using different dissolution media: phosphate buffer, simulated lung fluid (SLF) and phosphate buffered saline (PBS). 

The concept of SLF was introduced by Moss and the solution is described as being similar to actual lung fluid in terms of ionic composition and pH, the full composition can be found at the original reference.

  Unfortunately SLF has low pH buffering capacity and its pH varies significantly with time (over a 24 h period) unless carbon dioxide is continuously bubbled through. There was a possibility that a flow through system might theoretically help to alleviate the issue of low pH buffering capacity, but at the time of the experiments this speculation was wholly unproven. Therefore, the other dissolution media assessed were considered to be a more practical choice, especially for pH-sensitive or slowly dissolving formulations.  

For the assessment of different dissolution media, the DPI was fired just once during each sample collection. The similarity factors for PBS and phosphate buffer are 63.4 and 56.1, respectively, compared with SLF suggesting that either is a suitable substitute. 

To address the issue of poor wettability with the hydrophobic BD, further trials were carried out, incorporating surfactant into the dissolution media. The results for two modified PBS solutions are shown in 

: mPBS contains dipalmitoylphosphatidylcholine (DPPC), tPBS contains polysorbate 80. DPPC is one of the main components of lung surfactant and lowers surface tension at the air–water interface by forming a monolayer. Here, however, the results suggest that DPPC has little impact on dissolution behaviour, with polysorbate 80 proving much more effective. DPPC forms liposomal aggregates in aqueous media that have a larger particle size distribution than the membrane pore size.

  It is therefore likely that the DPPC has little effect because it cannot penetrate through the membrane to the sample. 

Figure 6: Dissolution profiles for budesonide measured using surfactant-modified dissolution media. (DPPC is dipalmitoylphosphatidylcholine). 

Although there are no regulatory requirements or established pharmacopoeial techniques for the dissolution testing of inhaled drugs, such testing can potentially open up the opportunity to tailor formulation properties.

Pharmaceutical Technology Europe-11-01-2010

Will Transatlantic Regulatory Cooperation Meet Expectations?

Packaging: The Experts' View

News

Overcoming The Challenges Of Cell-Based BioProcessing

Dissolution Testing For Inhaled Drugs

Lessons in efficiency

Designing An Effective PAT-Driven Scale-Up Of Lyophilization Processes

Is Pharma Doing Enough To reduce The Environmental Impact Of packaging?