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Carina Geiger R&D Production Engineering MAQUET Cardiopulmonary AG a member of the Getinge Group, Specialist supplier to the Life Science industry
R Rely ely on automation automation solutions from from Mitsubishi Mitsubishi Electric Electric When a key manufacturer of advanced oxygenerators wanted to reduce their production costs, they turned to Mitsubishi Electric for a robot-assisted production system. Key requirements fo or the system were flexible deployment, easy alteration of the control programs and constant maintenance of clean room conditions. This meant that the programmes and mechanical engineers could easily understand each other and their requirements. Mitsubishi Electric’s range of SCARA, articulated-arm robots and controller components fulfilled MAQUET ’s Per fusion Systems division requirements exactlyy, especially as all the Mitsubishi Electric robot arms are clean room ready and can, thereffo ore, (almost) be used straight out of the box. For the full facts on our Liffe Science Solutions visit eu3a.mitsubishielectric.com
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A round-up of some of the sector’s breaking news and news in brief
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P8 NEWS PROFILE Rhenovia’s SMARTT e-patch — what does it mean for the pharma sector? What’s the thinking behind Kline’s Polymers For Solubility Study?
P10 OPINION Want to increase productivity? Improve the coding process, says Colin Morgan, Videojet Think it’s all over? Brian Williamson says that while Pfizer has been fighting it out in the UK, US lawmakers are making their move in the long game Regulatory Affairs
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COMMENT
Waiting game As we waited to see whether or not Pfizer would be successful in its takeover of AstraZeneca, the approach has raised several issues for the pharmaceutical sector. While the attraction of the profit to be made from the sale could not be under-estimated, the reputation of Pfizer, renowned for its continual acquisitions and what this would mean for AstraZeneca employees, the UK economy and the UK life science sector as a whole, came under scrutiny. What would become of the centre of excellence created by AstraZeneca? And also importantly, what would this mean for drug discovery and development? As we have seen with the recent launch of MedCity — the £4 million medical initiative linking London, Oxford and Cambridge — politicians are keen to push the UK’s position in global life science rankings, creating a hub and network that will rival Britain’s financial services sector. This drive to cement growth and development through investment and advancement in the life sciences sector is clear and offers long term economic gain for the UK which has so long relied upon consumption, property and the financial service sector. It highlights the true value that life sciences hold within the economy and why many of those who opposed the takeover have a valid point to want to hold tight to the assets companies such
as AstraZeneca create. As Pfizer continued its quest to takeover this flagship of the UK pharmaceutical sector, the concerns of the sector and government became increasingly relevant as the extent to which the industry could be negatively affected, became apparent. Of course, there were those that pushed the benefits of the sale, looking back at AstraZeneca’s floundering R&D department of recent years. Today the company has 19 products that are or will be in late stage trials by next year, showing the potential of the company and the value it holds for the UK pharmaceutical sector, not just in terms of product development but also ensuring security of skilled jobs and manufacturing within the UK. It will of course, be interesting to see what happens over coming months. There is talk of increased pressure on shareholders going forward as Pfizer makes a return bid and that now is the time for the UK government to intervene and put in place a public interest test for proposed takeovers of this size, similar to that which exists in France. When we consider the implications the takeover may have for the UK life sciences, perhaps we really do need to consider this to ensure the UK retains sector excellence and the considerable contribution to the economy that a company such as AstraZeneca possesses. Lu Rahman
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NEWS
We are living in an incredibly exciting age, where the human genome is being decoded and scientists are examining how we can cure diseases rather than just offer symptomatic relief.
Future medicines need new thinking, says RPS harmaceutical scientists are calling for a new covenant to be developed between the pharmaceutical industry and wider society, including government, to accelerate and incentivise the development of new types of tailored medicines and treatments. Long term conditions such as heart disease, which are currently managed through the provision of effective but non-curative treatments, are in the sights of scientists who are developing treatments which aim to eradicate, rather than just manage, symptoms in specific groups of patients. A report published by the Royal Pharmaceutical Society (RPS), New Medicines, Better Medicines, Better Use of Medicines, spells out both the advances ahead as well as the limitations of current business and funding models to deal with a future where pharmaceutical companies will no longer be able to rely on ‘one-size fits all’ blockbuster medicines for patients. Professor Jayne Lawrence RPS chief scientist said: “We are living in an incredibly exciting age, where the human genome is being decoded and scientists are examining how we can cure diseases rather than just offer symptomatic relief. “However, the market is not set up to incentivise the production of new types of medicines. The current
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n a global scale, the oral solid dosage form (OSDF) excipients market is growing significantly. This market is valued at nearly $2.3 billion in the United States, Europe, India, and China, according to recently published Specialty Excipients for Oral Solid Dosage Form Pharmaceuticals Global Series: Business Analysis and Opportunities by research firm Kline & Company. In the emerging Indian and Chinese markets, growth in consumption of excipients is driven by rising incomes and willingness to spend more on healthcare. Key factors driving growth in major markets like the United States and Europe include the aging populations and high demand for pharmaceuticals. Nikola Matic, industry manager
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crisis in antimicrobial resistance is in part due to the lack of new classes of antibiotics coming on the market. “Antibiotics can cure infections in weeks, so the volume of sales of drugs is low. This doesn’t allow the tens or even hundreds of millions required for research and development to be recouped. “We need the NHS to be able to cope with funding treatments which have a high initial cost but may not require a lifetime of use by patients. Unless we find a way to develop treatments that cure illnesses in months, rather than treat symptoms for years, we will not see the breakthroughs that both scientists and patients want.” Kevin Shakesheff, professor of advanced drug delivery and tissue engineering, University of Nottingham said: “Future medicines will be highly personalised, for example using stem cells and regenerative drugs to treat patients after a stroke, heart attack or spinal cord injury. “These treatments will transform medicine but we face major hurdles getting them into widespread clinical use. They present new problems in manufacturing, safety and economics and require new ways of working across disciplines in order to accelerate commercial and clinical success.” Richard Bergström, director
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general, European Federation of Pharmaceutical Industries and Associations, said: “There is a lot of excitement in my industry about all the targeted medicines that are in the pipeline. “However, there is also concern that the regulatory requirements and way forward for developing new drugs are not clear. We need the
Report shows OSDF market growth at Kline’s Chemicals & Materials practice, said: “Due to this growing demand, the major markets will continue to flourish; however, it is worth noting that emerging markets will outpace major markets. Driven by the Indian and Chinese markets, the consumption of OSDF excipients is expected to grow at a healthy pace of 7.4% per year until 2018.” Although the major markets of Europe and the United States have similar volume to the emerging markets of India and China, which currently stand at approximately 100,000 tons per region, the market
values are very different from one region to another. This is due to the different types of excipients used based on the geography. While mature markets are dominated by functional and usually more expensive excipients, emerging markets are looking to use cheaper alternatives, such as native starches. “The added properties of some excipients allow more functional finished products, for instance, offering sustained-release of the active ingredient. Excipients vary greatly in price from $1.00 to $40.00 per kilo, and emerging markets are
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regulators to move with the science and update their guidelines as our understanding of disease changes. “We have a duty to deliver the new science to patients as quickly as possible. Both regulators and organisations that pay for drugs need to come together and jointly consider what evidence should be developed.”
dominated by cheaper alternatives. However, prices are not the only factor affecting the excipients market, as the consumption of OSDF excipients is driven by three different levels of drivers and restraints,” explains Matic. The consumption of excipients is primarily driven by the global growth of the pharmaceutical industry itself. Its key drivers include aging populations in mature markets and economic growth in emerging markets. The second driver consists of the factors affecting OSDFs in particular. For their easy use and manufacturing, OSDFs are the trends shaping the OSDF excipients market internally. This includes the larger growth of excipients used in tablets due to the increased instances where tablets are preferred to capsules.
News in brief Novozymes Biopharma has entered a collaboration with UK-based biotechnology company ThioLogics. The collaboration brings together Novozymes’ modified recombinant human albumin (rAlbumin) Veltis technology, with ThioLogics’ sitespecific next generation maleimide conjugation platform. This allows Novozymes to offer the pharma industry serum stable albumin drug conjugates with enhanced pharmacokinetic and/or targeting capabilities.
Triple attack on cancer
HCL Technologies, IT services provider, has been selected by Novartis, to provide global infrastructure management services, covering more than 70 countries across six continents. Domain Therapeutics, a biopharmaceutical company specialising in the research and development of new drug candidates targeting G protein-coupled receptors (GPCRs), has appointed Dr Youssef Bennani to the board of directors. Bennani takes over from Sam Eletr who held the position from November 2008 to April 2014. German oligonucleotide manufacturer BioSpring has selected and installed GE Healthcare Life Sciences’ OligoProcess, a fully automated oligonucleotide synthesizer, as a core element of its production facility in Frankfurt. The technology will allow BioSpring to improve output and flexibility in its manufacturing capabilitites. Parexel International, biopharmaceutical services organisation, has appointed Dr Sy Pretorius as chief scientific officer. Pretorius currently serves as the company’s corporate vice president. Sanner, manufacturer of plastic packaging and components for pharmaceutical, medical and healthcare products, topped the €55 million mark and set a new sales record in 2013.
Finox Biotech has appointed three executives to help strengthen its leadership team. Luigi Marro has been appointed to the position of chief financial officer; Ken Shields joins as executive vice-president, head of European commercial operations and Nicole Stigemar has been appointed executive vicepresident, head of marketing & business development. H3 Biomedicine, a biopharmaceutical company specialising in the discovery and development of precision oncology treatments, and Selvita drug discovery firm have validated the importance of a kinase target in a specific genetic context and have generated multiple novel chemical series against this target. The companies expect the first candidate molecule originating from the collaboration to move to IND-enabling studies in 2015.
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Delivering chemotherapy drugs in nanoparticle form could help reduce side effects by targeting the drugs directly to the tumours. In recent years, scientists have developed nanoparticles that deliver one or two chemotherapy drugs, but it has been difficult to design particles that can carry any more than that in a precise ratio.
Triple whammy: The new MIT nanoparticles consist of polymer chains (blue) and three different drug molecules — doxorubicin is red, the small green particles are camptothecin, and the larger green core contains cisplatin. Image courtesy of Jeremiah Johnson
Merck Millipore, the life science division of Merck has named Bonnie Bassler, Squibb professor and chair of the department of molecular biology, Princeton University, as winner of the 2014 Merck Millipore Alice C Evans Award for Leadership in Clinical Microbiology. The award recognises individuals who have made significant contributions toward the advancement of women in microbiology. Dr Bassler is a Howard Hughes Medical Institute Investigator and is best known for her work on quorum sensing, the molecular mechanisms that bacteria use for intercellular communication. For this work and her dedication to teaching, she has been given numerous honours, including a nomination by president Barack Obama for membership on the National Science Board. “I am honoured, surprised and delighted to receive the Alice C Evans Award and to be counted among many of my science heroes,” said Dr. Bassler. “This award validates the work of many labs to decipher how bacteria communicate using the process called ‘quorum sensing’ . . . The importance of prizes like this one — awarded for helping women to participate in science — is the evidence.”
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assachusetts Institute of Technology (MIT) designs nanoparticles that can deliver three cancer drugs at once. Delivering chemotherapy drugs in nanoparticle form could help reduce side effects by targeting the drugs directly to the tumours. In recent years, scientists have developed nanoparticles that deliver one or two chemotherapy drugs, but it has been difficult to design particles that can carry any more than that in a precise ratio. Now MIT chemists have devised a new way to build such nanoparticles, making it much easier to include three or more different drugs. In a paper published in the Journal of the American Chemical Society (JACS), the researchers showed that they could load their particles with three drugs commonly used to treat ovarian cancer. “We think it’s the first example of a nanoparticle that carries a precise ratio of three drugs and can release those drugs in response to three distinct triggering mechanisms,” says Jeremiah Johnson, an assistant professor of chemistry at MIT and the senior author of the new paper. Such particles could be designed to carry even more drugs, allowing researchers to develop new treatment regimens that could better kill cancer cells while avoiding the side effects of traditional chemotherapy. In the JACS paper, Johnson and colleagues demonstrated that the triple-threat nanoparticles could kill ovarian cancer cells more effectively than particles carrying only one or two drugs, and they have begun testing the particles against tumours in animals.
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NEWS PROFILE Rhenovia Pharma’s, SMARTT e-Patch project recently won an award at the World Innovation Challenge, founded to identify future champions in the French economy. Michel Faupel, Rhenovia Pharma, VP, reveals the science behind the company’s innovation and what it means for pharmaceutical manufacturing
henovia Pharma offers expertise in wireless healthcare technology with intelligent drug delivery design and new smart device concepts. Its SMARTT e-Patch device, allows controlled administration of medicinal products in treating chronic conditions such as Alzheimer’s. Wireless technology has huge potential in the healthcare sector and its drug delivery systems offer individual therapeutic applications through smart devices that anticipate therapeutic needs. These are particularly relevant to elderly medical care.
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EPM: What could this patch mean for the pharma manufacturing industry? MF: Rhenovia’s new SMARTT e-Patch device uses wireless technology to enable the pharmaceutical industry to develop and produce tailor-made therapies. In addition to customisation opportunities, the SMARTT e-Patch offers enhanced efficacy and safety benefits. It can enable dosage reduction and will adapt to assigned pharmacokinetic profiles. This helps reduce potential side effects, while still maintaining the desired levels of efficacy. Personalised drug delivery combined with a trans-dermal approach provides new solutions and choices in the treatment of poly-pathologies, which are ideally suited to individual polymedications. And the wireless technology allows instructions to reach the device remotely. The patch consists of the immobilisation of the active ingredient on nano biovectors, and a physical stimulus (photonics) to release the required amount of active nano biovectors. Once the active ingredient is released, the drug delivery takes place by diffusion through the skin. In the absence of the correct stimulus, further administration of the compound is completely interrupted.
The SMARTT approach In general, a physical stimuli (which could be heat, electricity or electromagnetism) will release the active principle from its support. A thermal stimulus permits the modification of the properties of the skin. However, such change is effective only with the application of a sufficiently large temperature gradient. This carries the risk of degradation of the active ingredient and is unsuitable for the patient. This method also carries the risk of not being reversible if the substrate is degraded. The literature has reported an electric potential to stimulate diffusion of charged molecules and/or to improve skin porosity. However, some limitations are still present: it is not possible to use such patches for uncharged molecules and it is difficult to completely terminate active ingredient release. Rhenovia has a three-pronged approach with the SMARTT e-Patch. Firstly, there is an electronic support comprising a power source and a programmable memory — with which the physician can adjust the dosage for the patient — and at least one light source. The software determines light emission which controls the amount of drug to be released. Secondly, there is a drug carrier (Rhenovia nano biovectors), which is immobilised through a chemical bond sensitive to a light pulse (this support should allow free diffusion of the active ingredient). Thirdly, the whole system is assembled with an adhesive backing to maintain the drug carrier contact with the skin, without interfering with the electronic control module. In my opinion, the patch innovates with the option to apply poly-pharmacy for a poly-therapy within a single support, together with fine and specific adjustments for each patient. It is possible to control the quantity and time of release of several active ingredients. Furthermore, the potential synergism of the active principles is evaluated by our Neuronal Biosimulation platform, which allows the development of a number of bespoke combinations. These elements guarantee considerable flexibility within individual treatment programmes.
EPM: Is it something that manufacturers would be able to replicate and if so, for what diseases? MF: The next step for manufacturers is to address the scope of targeted markets. These include prolonged, often lifetime therapies for diverse diseases such as cardiovascular, diabetes and neuro-degenerative disorders.
EPM: What’s the long-term future for the patch? MF: In the long term this new category of medical device for trans-dermal administration has the potential to capture a large part of the overall market in medical product manufacturing. EPM: What significance is it likely to have on pharma manufacturing? MF: It could substitute classical patches as well as oral administration to treat a high number of existing and novel therapies.
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Patch work: According to Michel Faupel, Rhenovia, the company’s SMARTT e-Patch could substitute classical patches as well as oral administration to treat a high number of existing and novel therapies.
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Michel Faupel is co-founder (2007) of Rhenovia Pharma. He is a former life sciences chemist with 38 years experience in biomedical research at the Novartis Institute for BioMedical Research, Basel (executive staff member, Systems Biology, Genomics and Proteomics). Faupel is also associate professor (biotech engineering) at the University of Haute Alsace.
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NEWS PROFILE ccording to Kline, poor solubility has been a major challenge in the formulation development for oral solid dosage form (OSDF) pharmaceuticals, a preferred route for pharmaceutical consumption. Various methods have been researched to improve solubility of poorly soluble API and among these the use of polymers for solubility enhancement in solid dispersions is among the most popular. Identifying the importance of the trend and to fulfill inadequately assessed market for polymers for solubility enhancement, global consulting and research firm Kline & Company is announcing the undertaking of a comprehensive study on Polymers for Solubility Enhancement in Pharmaceutical Oral Solid Dosage Forms: Global Market Analysis and Opportunities. The study will cover current and forecast demand by major products, supplier sales, and technical and market trends, as well as market opportunities and challenges for manufacturers of these polymers worldwide. Oral administration is a natural means of consumption and is best for chronic drug therapy. In addition, the manufacturing of OSDF can be an advantage compared to other dosage forms; positively impacting the price of pharmaceutical products. Nikola Matic, industry manager at Kline’s Chemicals & Materials practice, states: “After having pushed in the direction of OSDFs for many years, the pharmaceutical industry now faces a dilemma stemming from the poor solubility of an increasing number of new drugs. Furthermore, of about 80-90% of products in the research and development pipeline are reported to be poorly soluble in water. As a result, this triggers low oral bioavailability and could in turn jeopardize the development of new drugs.” Solubility is growing in importance and those who are able to capitalize on the potential that these enhancers bring to the table will see its inherent value. “Solubility enhancement is becoming a must for pharmaceutical companies and an area representing vast growth potential for chemical suppliers since tomorrow’s block-busters will most likely make use of one of the possible technologies to increase dissolution rate,” adds Matic. This is a complex topic and today’s reality can quickly evolve into something different tomorrow as the industry experiences trends and innovations that influence its
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Polymers for solubility enhancement will drive the oral solid dosage market course. Kline’s Polymers for Solubility Enhancement in Pharmaceutical Oral Solid Dosage Forms: Global Market Analysis and
Opportunities report will introduce all available technology and present their advantages and/ or constraints and will focus on the polymers
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available for solubility enhancement through solid dispersion. The report will provide insights into the global market and regional specificities for solubility enhancement and provide a comprehensive overview of the markets’ present undertakings, and, most importantly, shed light on what lies ahead in the unknown future.
OPINION roduct coding during the packaging process is a vital part of pharmaceutical manufacturing. Perhaps to a greater degree than in any other industries, pharmaceutical packaging demands the highest quality variable coding. Legibility and contrast are a prerequisite when it comes to regulatory and traceability codes and yet, coding solutions must also facilitate line productivity and seamless integration for today’s competitive environment. The coding and marking of pharmaceutical products are key to reliable product identification which helps companies fight counterfeiting and help prevent errors in administering drugs to patients. As pharmaceutical product coding regulations change, so does the threat of coding errors which may necessitate costly re-work and material waste. The reallocation of valuable time and resources to rework products directly affects the ability of a 24/7 manufacturing facility to run effectively, reducing throughput and profits. According to a Videojet survey, up to 70% of coding errors are caused by operator error, with approximately half of these caused by mistakes during manual data entry. In addition, it was discovered that coding errors are not the deviation, but the norm. Message selection can take place centrally, at one coder or through a barcode scanner. But typically an operator has to select a job at one location unless extensive integration to manufacturing systems has occurred. While manufacturers can typically put additional checks in place during packaging to address coding errors, this does not necessarily handle the issue effectively or efficiently. By working with an experienced printing partner with extensive printing capabilities and system design know-how, they can create and implement a coding process with built-in code assurance elements that limit the potential for user error. Simplifying the process of message selection and entry through the use of automation and software tools can greatly prevent coding errors, increasing productivity, reducing waste, and minimising operational costs and risk management.
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Code breaker According to Colin Morgan, Videojet Technologies, improving the coding process can increase productivity for pharmaceutical manufacturers during the manufacturing process designed to prevent human errors before they occur. The right printing partner can help a pharmaceutical manufacturer design a comprehensive system that implements various poka-yoke principles through advances in printing technology, eliminating coding and marking errors. Intelligent user interface Using an operator interface designed with existing code assurance tools can simplify message selection, restrict operator input and automate messages. For example, the printer’s user interface can include features such as separate user authorisation for code creation and job selection, restricted and pre-approved coding parameters, and job storage under intuitive names that speak directly to the product being coded. Software and network message control Implementing Windows-based software can provide additional support, isolating code design from the production floor and eliminating the need to load individual message onto each printer interface. This PC-
based message creation and management tool serves to remove human error from the coding equation. Regulatory Concerns In addition to the costs associated with rework and scrapped printing jobs, coding mistakes can result in fines and penalties. Regulations on drug product coding are driven by security and emerging technologies. Medication dispensing errors, the proliferation of easily available drug products via the internet and the emergence of false or incorrectly labelled products are all key concerns in the healthcare industry. In the United States, manufacturers are legally required to correctly display product information, such as ingredient or nutritional data mandated by the Nutrition Labelling and Education act and the Federal Food, Drugs and Cosmetics. The introduction of safety features (mandatory seals and unique pack identification) on packaging for certain medicines will provide assurance to patients of the authenticity of medicines they receive through healthcare systems where these medicines are at risk of counterfeiting.
Automated code assurance “Poka-yoke” is a Japanese term that can be translated as “mistakeproofing”. When applied to manufacturing operations, a pokayoke is any measure put into place
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There are different coding technologies suitable for packaging types for example, cartons are the most common packaging formats for the pharmaceutical industry and must be marked with the highest quality human readable and machine readable codes to ensure the product’s traceability. Bottle coding is also extremely common and they can be coded in numerous places like the bottle side, underside, label or cap. Vial marking and eye dropper bottle marking are challenging because of their small size and the complex sequence of packaging operations. Coding these packaging types is best achieved when the coder is integrated into an original equipment manufacturer (OEM) packaging specifically designed as high quality codes require precise material handling and rigid vibrationfree coder mounting. Failure to comply with these standards can bring fines and even product recall – both costly and extremely damaging to any brand. By working with an experienced printing partner to design a coding process with built-in code assurance elements (also known as poka-yoke principles), pharmaceutical manufacturers can eliminate errors before the label is even applied to the product. Utilising the latest in manufacturing automation and software tools can prevent coding errors, enhancing productivity and increasing the bottom line.
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OPINION hile British attention in the Pfizer-AstraZeneca takeover battle has been focused on clashes between MPs and Pfizer chief executive Ian Read, events have been unfolding across the Atlantic which could have an infinitely greater bearing on where the pharma giant eventually conducts its business. As UK representatives fret over the implications for AstraZeneca jobs and R&D, their US counterparts appear to have woken up to a fundamental threat to their economy and started taking positive steps to fix it - with a piece of fancy legislative footwork which could have a longterm impact on US investment around the world. The fact is that Scots-born Read has been eyeing AstraZeneca for some time and for a variety of reasons - not just the tax benefits which would accrue from removing £63 billion of its current cash pile from US jurisdiction. Pfizer will almost certainly also have been attracted by the UK government’s positive attitude towards encouraging innovation and technological expertise through the judicious use of research and development (R&D) tax relief. This scheme, which has pumped billions of pounds into British companies since it was introduced, has been enhanced at almost every Budget, and has created a regime based on security and permanency to foster long-term investment. In America, by contrast, the tax credit for business R&D is one of dozens of tax laws which are temporary and have to be continually extended. It has been renewed 15 times since 1981 and, in fact, technically expired at the end of last year. Clearly this fosters an environment of uncertainty and instability, and it is hardly surprising that research-heavy multinational enterprises such as pharmaceutical companies seek calmer waters in which to fish. However, as part of a drive towards comprehensive tax reform, Republicans want to make R&D tax credit permanent and, on 9 May, the House of Representatives voted to enshrine a 20% tax break in the federal tax code. The cost is enormous — some $150 billion over 10 years, and Democrats are insisting on new tax rises to offset it, so the proposal faces prolonged legislative infighting before it ever lands on President Obama’s desk. But it is indicative of US thinking on the necessity of encouraging
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Tough pill to swallow? As Pfizer has been fighting it out in Britain, US lawmakers are making their move in the long game, says Brian Williamson, Jumpstart domestic innovation as an integral part of the economic recovery and establishing research as one of the most important catalysts for growth. If Pfizer’s bid had succeeded, the maker of Viagra had committed to locating 20% of the company’s global R&D workers in the UK and it has been open about the substantial tax saving which would accrue from re-domiciling in the UK. Read has pointed out that there is a 20% corporation tax rate in the UK while, because of dividend requirements, it would probably be a 38% in the US. If he had to do the deal in the US, negative synergies would kill it, so he has to domicile in Britain. He has told MPs that “some” R&D jobs would be cut in AstraZeneca and confirmed that the company would be split up, making its constituent parts more attractive to potential buyers. The bottom line in this dramatic bid is that Pfizer’s move is a significant vote of confidence in the UK economy and it illustrates that, in a fluid and interconnected world, enterprises will go where the conditions which allow them to flourish are most favourable.
But as the vote by US Representatives also shows, conditions can quickly and unexpectedly change and, though there is no reason to doubt Mr Read’s five-year commitment to
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the UK, that is a very short time in macro-economic terms. If the US does work towards a more favourable climate for domestically-located research and development, it may not just affect the enlarged Pfizer’s long-term strategic thinking - it could sway the decision-making of multinationals across the board. Brian Williamson is managing director (Scotland) at R&D tax relief specialist Jumpstart.
REGULATORY AFFAIRS orea’s Ministry of Food and Drug Safety (MFDS-former KFDA) has moved quickly to develop its biosimilar product guideline. Due to the targeted nature of treatment, biological products are well known to have low adverse events and high efficacy. However their cost is often excessive, limiting their availability to patients. To resolve these issues, the MFDS is encouraging the development of inexpensive biosimilar products as a publishing guideline. After consulting numerous scientific advisory boards, as well as reviewing guidelines and literature from overseas authorities, scientific experts and WHO, the MFDS published its biosimilar product guideline in 2009. Since then, a range of clinical trials for biosimilar products, including Phase I/Ib, IIb and III, have taken place and continue to do so. In July 2012 the guideline was granted first approval for monoclonal antibody biosimilar products. Among the guideline’s sponsors are some of Korea’s largest pharmaceutical and biological companies, including Celltrion, Samsung Biologics, Daewoong, LG Life Science, Hanwha Chemical, Dong-A Pharma and CKD. It is no doubt that Korea is one of the leading countries for introducing biosimilar products into the global market. Like other biological products, a biosimilar product is evaluated in terms of quality, safety and efficacy. When compared with a new drug, less information is submitted for marketing authorisation. However this practice is only acceptable when the comprehensive physicochemical and biological study results demonstrate its comparability to the innovator product. To develop extensive characterisation studies, a preconsultation meeting with the MFDS is strongly recommended. Quality and S&E technical officers will provide full advice and consultation. Indication extrapolation is accepted if it demonstrates similar levels of efficacy and safety to the preexisting innovator product, even if all the clinical studies are not performed, although post-marketing surveillance will be required. The MFDS is also highlighting the importance of immunogenicity in line with the EMA. It is required to obtain and provide immunogenicity data until the efficacy studies are completed and if necessary, followup data should be submitted. Since it is limited to submit accumulated immunogenicity data at preauthorisation stage, further characterization of the
K
Biosimilar evaluation in Korea
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By JinHee Kang, senior regulatory expert, biosimilars immunogenicity profile is recommended. If immunogenicity is likely to be rare, additional postmarketing analysis is called for. The major difference from the EU biosimilar product guideline is that the Korean MFDS will accept the purchase of reference products from overseas market. However it will only do so under certain conditions; if the reference product authourized in Korea is not commercially available, or if there are other justifiable reasons, such as showing the same biological product as the one authorized in Korea, including the manufacturing site and the manufacturing process. The US FDA accepts the usage of data derived from animal or clinical studies that compares a proposed product with a non-US license product, under certain circumstances. In such a
case, the adequate data or information to justify the relevance of the comparative data to an assessment orf biosimilarity, and to establish an acceptable bridge to the US-license reference product, must be provided. The EMA is also considering revising the guideline in step with the FDA. It may be possible to compare the biosimilarity in certain clinical studies and in vivo nonclinical studies with a non-EEA authorised comparator and by establishing an acceptable bridge to the EEA-authorized reference product. The revision is still in its infancy but it will help avoid the unnecessary repetition of clinical trials and in vivo non-clinical studies and facilitate the global development of biosimilar products.
Guiding light: JinHee Kang discusses the way in which Korea’s Ministry of Food and Drug Safety (MFDSformer KFDA) has moved quickly to develop its biosimilar product guideline.
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THE TECHNOLOGICAL FUTURE HAS STARTED:
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s Drying, granulation and coating can now be done in one bowl without any modification s Simple operation with tangentially mounted nozzles s Innovative process analytical technology (PAT) methods monitoring particle size and humidity, optimizing your process
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Conventional Wurster process
Groundbreaking Bohle Uni Cone BUC®-Technology
BLOW-FILL-SEAL
The French connection Incorporated in France in 1993 as a Contract Development and Manufacturing Organization (CDMO), Unither offers expertise in high-tech blow-fill-seal bottelpack technology with 2 billion doses manufactured per year
nither uses blow-fill-seal (BFS) technology to produce small, (0.3mL) to medium volume (20 mL) liquid-filled sterile unit-doses. Over the last 20 years this manufacturing technique has become more prevalent within the pharmaceutical industry, and Unither points out that it is now widely considered to be one of the top forms of aseptic processing by various medicine regulatory agencies including the US Food and Drug Administration (FDA) in the packaging of pharmaceutical and healthcare products.
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Unither uses blow-fill-seal (BFS) technology to produce small, (0.3mL) to medium volume (20 mL) liquid-filled sterile unitdoses
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The main advantage of this type of manufacturing is to produce preservative-free formulations. Because each individual dose is for single use and must be discarded after one administration, there is no microbiological contamination of the contents. This preservative-free formulation is of essence when one considers the sterile content is to be generally administered on inflamed or injured mucosas (eyes, nose, ears, and lungs). However, the mucosal application is not exclusive as Unither also produces spore probiotics in suspension for oral administration.
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The second advantage of BFS technology is to avoid misuse of the drug product by delivering the right dose. In the case of inhalation products for asthma (nebules), the full volume of the BFS unit-dose is the exact dose for one use. Regarding eye-drops, the BFS unitdose usually contains no more than four to six drops (two to three for each eye). With one R&D dedicated facility and three industrial plants — two in France and one in the USA — inspected by a number of Health Authorities (European, US FDA, ANVISA – Brazil, Turkish, South Korean, Middle-East), Unither provides full-development services, clinical batches and commercial products manufacturing. Unither is the only CDMO in the world able to
Team talk: The R&D team at Unither boasts 25 years of experience in handling NCEs (New Chemical Entities)
facilities in Europe, the USA, with sales offices in Brazil, and tomorrow facilities on other continents to serve local markets and end-users. With an overall capacity of 2.5 billion doses produced by 18 Rommelag 4010 rotative and three alternative Bottelpack machines, Unither continues bringing more BFS opportunities every year to provide such an internal network to optimise and secure the development and the manufacturing of its customers’ products. One of the most critical services Unither provides to customers is formulation and analytical development. Unither employs pharmacists, scientists and engineers with extensive BFS development know-how to offer the best formula adapted to the ocular, nasal, pulmonary, buccal or topical delivery. The R&D team at Unither boasts 25 years of experience in handling NCEs (New Chemical Entities) and generic drug substances, and performs early-stage pharmaceutical development for Phase I clinical trials. After a thorough understanding of the physicochemical characteristics of the API and the consideration of the biological targets, the formulation works results in a number of formulas for screening. Several formulas are provided together with the analytical methods and prestability studies results. The pharmaceutical development process continues, including analytical methods validation and QC of the batches produced, until the tech-transfer to a Unither industrial site in charge of Phase I clinical batches manufacturing (active and placebo). The R&D team supports all the development process, including changes in formulation, exploration of Impurities, stability stress-tests, up to the manufacturing of registration batches, ICH regulatory stability studies and over. The close relationship with the regulatory affairs allows a rapid compiling of IMPD/NDA/ANDA or CTD dossiers and delivery to the customer. Over the 20 past years, Unither teams have developed a wide knowledge in simple solutions, and above all, a specific expertise in more complex formulations: suspensions which exclude endfiltration sterilisation and emulsions where one of the two media cannot be heat sterilised. In response to an increasing customer demand for aseptic processing, Unither continues its growth on several continents with
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customers worldwide with the highest-quality support systems. Because of its high expertise in the BFS industry, Unither is able to provide cost-effective, customised manufacturing options for the most complex treatments, ensuring what it describes as a reliable global supply and an uncompromising commitment to quality.
BLOW-FILL-SEAL o provide enhanced process safety, a new true gas decontamination process is available for aseptic filling lines using nitrogen dioxide (NO2) as the sterilant. Weiler Engineering has pioneered a patent-pending application using this NO2 technology in its ASEP-TECH blowfill-seal (BFS) systems to offer enhanced sterility assurance for production of pharmaceutical products. The NO2 technology, developed by Noxilizer, is a roomtemperature process that combines decontamination of exposed critical zone surfaces with the potential for depyrogenation of these surfaces. Providing an automated gas decontamination process that also offers the potential of endotoxin reduction increases the safety of the pharmaceutical products produced in the ASEP-TECH BFS systems. In the BFS system, a container is moulded from plastic resin, aseptically filled and hermetically sealed in one continuous, integrated and automated process. The BFS process provides flexibility in container design, high volume product output, low operational costs and a high assurance of product sterility. Packaging liquid pharmaceuticals with BFS technology provides the highest level of sterility assurance available for aseptic filling. As such, the BFS technology is characterised as an “advanced aseptic process” by the FDA and the USP.
T
Process control As Weiler Engineering and Noxilizer announce an exclusive global supply agreement, Chuck Reed and David Opie reveal how ASEP-TECH blow-fill-seal systems have introduced a new decontamination and depyrogenation process for the critical fill zone using nitrogen dioxide Aseptic processing requires rigorous and careful manufacturing practices due to the potential adverse effect on the health care consumer. Regulatory agencies are placing greater focus on improved patient safety, developing standards to ensure sterile, contamination-free products. In particular, regulatory standards increasingly state that pharmaceutical manufacturers should be aware of new procedures designed to improve product safety through the use of enhanced technology. One such procedure is the reduction of pyrogens during the decontamination process. Pyrogenic contamination comes from endotoxins, which are mainly lipopolysaccharide components of Gram-negative bacterial cell walls, which can cause acute febrile reactions. These endotoxins are heat stable and may be present even when viable organisms are no longer detectable. Endotoxins are impossible to eliminate from filled containers; thus, procedures are
generally directed at eliminating endotoxins during the preparation process. The NO2 process offers a new procedure for depyrogenation, efficiently completing the decontamination and depyrogenation in a single, rapid process. Study results from the first demonstrated decontamination and depyrogenation of the critical zone of an aseptic filling system using NO2 were presented at the 2014 PDA Annual Meeting in San Antonio, Texas. The study was conducted at the Weiler Engineering facility. Weiler worked with Noxilizer, to apply the room temperature, NO2based technology to the ASEPTECH system. Weiler utilised a patent-pending design of the ASEPTECH system with integration of Noxilizer’s NOX FLEX rapid biodecontamination system. The Noxilizer process is a fast (less than one hour), automated process that yields more than a six log reduction in biological
indicator organisms and more than a three log endotoxin reduction. Another feature of the NOX FLEX system verified in this study was the remote operation of the decontamination process with up to 50 metres of conduit between the NOX FLEX unit and the ASEP-TECH system. This capability permits the location of the Noxilizer equipment outside of the cleanroom in which the BFS machine is installed. The ASEP-TECH BFS System offers advantages for manufacturers with biologic, protein-based and heat-sensitive products. NO2, a rapid and effective sterilant, has been commercialized for decontamination and sterilisation. As a result of the successful collaboration with Noxilizer, Weiler Engineering is now able to offer the NO2 process with NOX FLEX rapid biodecontamination units for its ASEP-TECH blow/fill/seal systems through an exclusive global supply agreement. Noxilizer’s NOX FLEX provides a single-step decontamination and depyrogenation process in a patentpending application that is expected to broaden the use of ASEP-TECH BFS systems world-wide. About the authors: Chuck Reed is director of sales & marketing, Weiler Engineering and David Opie is senior vice president, research & development Noxilizer.
Leading the way: Weiler Engineering has pioneered a patent-pending application using NO2 technology in its ASEP-TECH blow-fill-seal (BFS) systems
Single issue: In the BFS system, a container is moulded from plastic resin, aseptically filled and hermetically sealed in one continuous, integrated and automated process
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BLOW-FILL-SEAL
Golden glow Fifty years ago, Rommelag believes it revolutionised plastic packaging technology with blow-fill-seal. This success story is of great importance to the pharmaceutical, food and chemical industries, as well as to the lives of many people
n 1963 Rommelag founder Gerhard Hansen invented and built his first blow-fill-seal machine. The technology was an immediate success. Only a short time later, in May 1964, he founded the Rommelag sales and marketing company in Aarau, Switzerland, in order to sell his products on the international market. Today Rommelag is a member of the Hansen Group headed by ceo Bernd Hansen, with sales companies in Switzerland, Germany, the USA and China. It is a leading supplier of blow-fill-seal machinery, Bottelpack.
I
Three steps It’s a matter of three steps. All Bottelpack machines operate according to the blow-fill-seal principle (BFS). In a single automatic process they create containers from thermoplastic granules (blow), insert the contents (fill) and close them (seal). The technology has numerous advantages: the products contain no preservatives or contaminants; the process is fully automatic, which saves time, space and labour; the containers are sealed, unbreakable and collapsible; and maximum product safety is ensured at all times (the containers are aseptic and tamper-proof). Today these machines are used throughout the world in the pharmaceutical industry for aseptic packaging of sterile liquids, creams and ointments (including vaccines). New containers and closures are being created in a process of continuous innovation and optimisation. Examples are ready-to-use products like syringes with integrated injection needles, ampoules with a Luer fitting that does not require a harvesting needle, and unit-dose ampoules for eye drops, nose drops and ear drops with integrated dispensing chambers that eliminate the need for preservatives. BFS technology does not require the cleaning and sterilisation processes that are essential in other kinds of container production.
However, to ensure maximum safety in aseptic production, Bottelpack machines can be equipped with a range of safety, quality assurance and monitoring modules. In this way they comply with government standards such as those of the US Food and Drug Administration (FDA). The modules include aseptic systems for automatic cleaning and sterilisation of lines that come into contact with products. Other modules test containers for leaks, inspect them for particle contamination and automatically eject defective items. In addition, there are devices for testing ampoules during production, monitoring cleanroom air, etc. In spite of all these safety mechanisms, BFS systems can produce more than 34,000 containers per hour in sizes from 0.1 ml to more than 1,000 ml – impressive proof of their technological maturity and efficiency. Customer contract Rommelag says close contacts with customers are a key to its success. The company coordinates the planning, commissioning and maintenance of its systems with each customer individually. Its worldwide services include deployment of specially trained service personnel, provision of remote diagnostics systems and customer training at the Bottelpack training centre. Glass is a key material. But customers throughout the world have recognised the advantages of plastic containers. Aseptic packaging by means of Bottelpac blow-fill-seal systems is gaining increasing dominance, says Rommelag. Modern plastics are strong enough to be made very thin without risk of breaking and they are easily collapsible so that ventilation is not necessary. They are chemically inert, free of additives and highly impervious to water vapour. Handling is easy and safe, not only in hospitals but also in mobile operations. This is why
Bottelpack systems are coming into increasing use in countries where the healthcare system is still in development. Not surprisingly, China and India have become important markets for Rommelag. Thanks to subcontracting by its sister companies Holopack in Germany and Maropack in Switzerland, Rommelag offers a range of products and services for packaging of liquids, including vaccines. It provides support to its customers in manufacturing trials, contract manufacturing, process development, qualification and validation. Customers can also move their Bottelpack machines to Holopack Pharma 2020 for production.
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Change for the better: Fifty years ago, Rommelag believes it revolutionised plastic packaging technology with blow-fill-seal
LABWARE
Making a splash Purite’s Select Fusion water purification unit, has been developed specifically for costeffective, long-term use in a range of laboratory and small-scale pharmaceutical applications. The Select Fusion, which produces two grades of purified water, forms part of Purite’s range of modular, standalone water purification units. The Select Fusion is capable of producing up to 50 l per day of laboratory grade purified water and ultrapure water up to 18.2 MΩ.cm that exceeds current British, European and US pharmacopoeia water quality specifications, making it ideal for laboratory users operating in the highly regulated pharmaceutical industry. The Select Fusion, designed to produce consistently high quality purified water that meets pharmacopoeia and laboratory standards and at a competitive cost, incorporates pre-treatment filtration, reverse osmosis, UV irradiation, ion exchange and sub-micron filtration technology in a single, robust enclosure. The unit can be wall- or bench-mounted and includes an integral 20 l purified water storage tank, thus minimising use of valuable workbench space. The use of low-energy, reverse osmosis semi-permeable membranes, combined with the use of the automatic recirculation pump, help to maintain water quality and minimise power consumption, especially during periods of low demand. In addition, all of the consumables have been developed to be easy to change and to give a long and consistent operating life.
Measure for measure
Balancing act
The useable shelf life of medical and pharmaceutical products is limited by the rate of decline of drug potency and sterility. Both are controlled by the speed at which contaminants can permeate through the packaging. The sterility of dressings and syringes, etc, is controlled by the same effect, though in this case the packaging needs to be permeable to water vapour and oxygen, non-permeable to bacteria. To develop and quality control the processes and materials used in these products, Versaperm’s latest single and multi-chamber instruments are designed to measure permeability with respect to virtually any vapour, including water vapour, which is by far the world’s most common contaminant. The equipment can characterise the permeability of a wide range of products including unitary dose blister capsules, sachets, syringes, inhalers and wound dressing packaging, etc. It can produce results quickly and has a typical accuracy to a few parts per million (ppm) or better. The equipment can determine the vapour permeability of almost any material against any gas/vapour and, unlike conventional gravimetric measurements, which take days or even weeks, it can produce results in as little as 30 minutes for some materials. This speeds the neverending quest for effective packaging with new marketing and technical features.
Sartorius has introduced the Entris, a balance that the company says focuses on the most commonly used weighing applications and dispenses with costly additional functions. The Entris analytical and precision balance is available in 15 models, covering a weighing capacity from 60 to 8,200 g, with a readability of 0.1 mg to 0.1 g. Most models of the new Entris family are equipped with a monolithic weighing system, featuring external adjustment or an internal, motorised adjustment function. This is how the balance is said to deliver consistently accurate weighing results, which should also be easy to read on the backlit, high-contrast display. The logical key assignment on the Entris and its clearly structured user interface both make daily routine weighing much easier. The Sartorius balance is equipped with applications for density determination, animal weighing, counting, conversion and weighing in per cent, and it is supplied in the languages German, English, French, Italian, Spanish, Russian and Polish.
Cost analysis Laboratories operating on a limited budget can now obtain high-quality spectroscopic data and perform complete mixture analyses using a new attenuated total reflectance (ATR) accessory and accompanying FT-IR spectrometer, says Thermo Scientific. Combining the new Thermo Scientific iD7 ATR accessory with the Thermo Scientific Nicolet iS5 FT-IR spectrometer and Thermo Scientific OMNIC Specta software, users can analyse complex samples easily with a rapid ROI. Using a high-performance monolithic diamond, the iD7 ATR provides the robustness necessary to analyse hard solid samples as well as liquids and powders. The optional zinc selenide or germanium crystals, in easily swappable plates, provide users with flexibility in terms of price and applications. OMNIC Specta software moves users from sample to final report efficiently, and its multi-component and contaminant analysis tools complete the package.
Touch of class The L-series of ploughshare laboratory mixers from Gebr. Lödige Maschinenbau now come with a touchscreen panel. The thinking behind this was to improve the handling of the mixers providing user-friendly visuals of the controls by offering a clear and uniformly designed screen display. Basic functions are performed using easyto-understand icons to enable intuitive operation of the mixer and
EPM 18
features include the fact that mixer shaft speed is infinitely more variable via the touchscreen panel. With the replacement of pushbuttons in the L-series of laboratory mixers, Lödige has expanded its portfolio of mixers with a touchscreen panel for product and process development or pilot operation. The basic version of the MGTL laboratory mixing granulator is also available with this equipment feature.
Raw Materials ID THROUGH THE CONTAINER 10x increase in testing throughput
Container
Handheld Raman
RapID
Paper or plastic sacks Plastic bottles and tubs Thick amber glass FIBCs
Benefits ...
Savings ...
Enables 100% ID
10x faster workflow
Wide materials compatibility
Reduce sampling costs
Differentiates growth media
Reduce staff costs
Avoid contamination Regulatorily compliant
Tel: +44 1235 856555 to arrange a full product demonstration
Cobalt Light Systems Limited 174 Brook Drive. Milton Park, Abingdon, Oxfordshire OX14 4SD United Kingdom T: +44 1235 856555 F: +44 1235 856556
email: info@cobaltlight.com
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RAW MATERIALS INSPECTION apID is a new tool for raw materials ID that works through unopened packaging, such as sacks. “It can reduce the total analysis time for incoming goods significantly over handheld Raman instruments, and because of that capability, it has grown more quickly than we expected. The most obvious benefit is in removing the sampling step in the testing process; avoiding opening the containers to take a measurement or taking a physical sample saves cost. Since sampling of containers is expensive and time consuming RapID makes 100% testing an easier option for pharma companies,” reveals Andrews. RapID uses a patented technology called SORS. According to Andrews, this offers a range of advantages compared with handheld spectroscopy devices. “Handheld instruments operate on a line-of-sight principle. If you can see the contents by eye then you can usually ID it, although exceptions include large amber bottles or thick plastic containers,” he says. RapID can work with those containers as well but also paper sacks, plastic sacks, tubs, bottles and super-sacks, regardless of whether they are transparent, opaque or coloured. “SORS basically removes the signal from the container to leave a Raman spectrum of the contents. SORS doesn’t require a more powerful laser (in fact, it
R
RapID results EPM talks to Cobalt’s Darren Andrews about the company’s new tool for raw material inspection — its key features, benefits and applications — and what the company has up its sleeve for the future operates at significantly lower power densities than handhelds); it works by taking multiple measurements.” One of Cobalt’s customer uses a lot of benzene-derivatives for sterile product manufacture. It receives thousands of amber bottles per year. “Since they are sterile, opening and sampling the bottles requires a sterile booth and many slow steps
In the bag: Lactose and other sugar products typically arrive in large batches of multi-layer paper sacks, and cutting open each one in a dedicated sampling booth creates a testing bottleneck
to keep the contents from being contaminated. This significantly impacted their testing resource, which at 100% of containers created significant cost. With RapID they ID the contents in little more than five
seconds per container in a normal non-sterile room or open warehouse floor,” adds Andrews. “One of our most common application areas is identifying excipients for manufacture of tablets and capsules. Lactose and other sugar products typically arrive in large batches of multi-layer paper sacks, and cutting open each one in a dedicated sampling booth creates a testing bottleneck. RapID can remove that bottleneck. We have been increasing our presence in the parenteral and biopharma industries since not opening sterile or chilled/frozen containers is a big advantage,” says Andrews. The technology is also suited to any material which is easily contaminated (hygroscopic, for example) or dangerous to humans (hormones, for example) and is best tested through sealed containers. So, what next for Cobalt? According to Andrews, the company is expanding across the globe. He adds: “The next big news will be about our TRS100 instrument; it uses transmission Raman technology to perform content uniformity testing, replacing many HPLC instruments and their operators for every Cobalt instrument. A TRS100 can complete a uniformity of dosing units test on multiple tablets or capsules in a few seconds per tablet, with no solvents or consumables. What is exciting news is that pharma companies are deploying our technology for regulated batch release of their products.”
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Plus points: According to Darren Andrews, Cobalt, the SORS technology in use in its RapID tools offers a range of advantages compared with handheld spectroscopy devices
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Variety show: RapID can work with a range of containers including paper sacks, plastic sacks, tubs, bottles and supersacks, regardless of whether they are transparent, opaque or coloured EPM 21
RAW MATERIALS INSPECTION EPM: What do you see as the main challenges faced by the pharmaceutical industry when it comes to raw material identification? FI: Raw material identification (RMID) is a crucial part in the pharmaceutical manufacturing process and is essential to ensuring quality control and compliance with industry regulations. Materials can be ‘out of specification’ due to a variety of factors, including incorrect formulation, contamination, counterfeiting or even the mislabeling of their containers. If out-of-spec materials are not promptly identified and rejected they can lead to additional costs as a result of material waste, reprocessed work, time delays – or ultimately, product recalls. While protecting patients from being exposed to below standard products, recalls always have an implication on a company’s brand. The Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-Operation Scheme now requires 100% inspection of incoming raw materials (in most countries) which means every container must be analysed. The traditional RMID workflow includes material sampling for laboratory testing purposes. This can lead to bottlenecks since the lab testing process is rarely real-time and quality control laboratories are often located off-site. This also means that material needs to be held in a quarantine area before confirmation of the results and that valuable space is taken up by materials waiting for clearance.
Material world Federico Izzia, VP sales & marketing at Rigaku Raman Technologies, provides an insight into the raw material identification sector substances through bags and other types of packaging, eliminating the risk of compromising the integrity of the contained materials. All of these factors result in an improved workflow, reduction in space and inventory, as well as time and cost savings.
EPM: What does Rigaku offer customers in the pharmaceutical industry? FI: Before we launched Progeny, users of handheld Raman devices with 785nm or 532nm visible range extraction lasers were not able to identify coloured substances,
EPM: What do you believe the future holds for raw material identification technology? FI: There is currently a cultural preference in the pharmaceutical industry towards laboratory benchtop equipment, but as more handheld devices become available and the level of confidence and efficiency they deliver is proven, I believe we will see a dramatic shift in a move towards the use of handheld devices for RMID. At that point, laboratory personnel could focus on higher valued tasks, including root cause analysis of failed material.
materials through coloured containers or samples with high fluorescence interference, such as sodium carboxy methoycellulose, xantum gum, or gelatin. Progeny’s 1064nm excitation laser enables users to broaden their analysis range thanks to minimal fluorescence. Ease of use is a key consideration and Progeny has been engineered to be quickly and easily implemented into customised RMID workflows with features such as a touchscreen user interface inspired by modern smartphones. Users also benefit from Progeny’s single hand operation and angled display meaning that the device can quite literally ‘point and shoot’ at the container being analysed while the user simultaneously checks the measurements on screen. In order to ensure accurate data entry tracking and compliance, Progeny has an integrated digital camera and 21 CFR Part 11 compliant electronic signature capabilities.
In hand: Federico Izzia, Rigaku Raman Technologies, says we will see a dramatic shift in a move towards the use of handheld devices for RMID
EPM: How can handheld Raman spectroscopy technology help meet these challenges? FI: Raman spectroscopy is a recognised technique in the US Pharmacopoeia (USP), and the European Pharmacopoeia (EP) and, for RMID purposes handheld Raman devices are as analytically effective as conventional lab-based methods. With the push towards 100% inspection and lean manufacturing, handheld Raman optimises the RMID process in a number of ways. Handheld Raman devices provide the ability to analyse, identify and qualify materials against specific criteria on the spot. This removes the delay in waiting for lab results, improving cycle time, optimising material movement, and the need for quarantine. Handheld Raman instruments can also identify
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FREEZE DRYING: Case study Who: SP Scientific What: Retrofit of a production freeze dryer How: Using ControLyo Nucleation On-Demand Technology
ny new production freeze dryer can be manufactured to allow control of nucleation using ControLyo On-Demand Nucleation Technology, a process by which product nucleates at the same time and temperature. If the dryer is steam sterilisable (SIP), the chamber is generally rated to withstand pressures greater than 20psig. The components necessary for ControLyo Technology can be incorporated into the dryer design relatively easily and cost effectively. However, given the cost of a new production dryer and the large installed base of existing dryers, we believe that widespread adoption of the technology necessitates a retrofit approach strategy. Fortunately, most SIP production dryers can be retrofitted for controlled nucleation. We have demonstrated that this retrofit can be done quickly to minimise downtime (less than one day), and without having to compromise the integrity of the dryer (eg. no new holes put in the chamber). Retrofit is also quite cost-effective. A schematic of a dryer retrofit is shown in figure 1.
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Figure 1 - ControlLyo retrofit of a production dryer image
Controlling factor Mark Shown, VP technology development, SP Scientific, outlines ControLyo Nucleation On-Demand technology – moving from the lab to production Key requirements are as follows: A. The chamber can withstand the pressurisation required for the ControLyo technology. Most SIP freeze dryers meet this criteria. B. The freeze dryer has available or unused ports of sufficient diameter to mount the depressurisation manifolds and inert gas fill manifold. These could be condenser bypass ports, site glass ports, validation ports or spare ports. In our experience, most dryers have the required spare ports available. C. If the dryer has an isolation valve, it must be capable of withstanding the chamber pressure during pressurisation. If not, the condenser can be pressurised to equalise the differential. D. The process needs to be controlled. This can easily be achieved by using a stand-alone control box to actuate the pressurisation and depressurisation manifolds, or it can be integrated into the software of the dryer by modifying the dryers PLC and HMI code.
Scale-up case study of controlled nucleation While the results and benefits demonstrated in development freeze dryers are encouraging, from a commercial standpoint, they are only interesting research projects if the financial benefits cannot be achieved by scale-up to production freeze dryers. Prior to the study described below, controlled nucleation using the ControLyo technology had been demonstrated in freeze dryers with shelf areas of 6, 10, 48, 54, 98 and 277 square feet. The purpose of this study was to show that a 300-square-foot production dryer could be retrofitted with the ControLyo technology and that 100% nucleation of a fully loaded dryer could be demonstrated with a variety of vial sizes and fill volumes. This study was done in conjunction with Fresenius-Kabi and the results were jointly presented at the 2013 PEP Talk Conference in Palm Springs, CA. A 300 sq-ft (27.8m2) Hull production dryer at the Grand Island, NY Fresenius-Kabi production site was retrofitted as follows: A. An available 6” condenser bypass port was used to mount the main depressurisation manifold.
Double benefit: ControLyo OnDemand Nucleation Technology is a process by which product nucleates at the same time and temperature EPM 24
B. A spare 2” port was used to mount the manifold used for the low pressure purges. C. A capacitance manometer port was used to mount the pressure transducer, which provides the pressure readings to control the system. D. Control of the system (pressurisation and depressurisation) was done using a stand-alone control module E. Pressurisation of the system with the inert gas (nitrogen) was done using the gas bleed system of the dryer. Figure 2 shows a schematic of the vial loading of the dryer. Nine shelves were loaded with trays, each containing different size vials with 5% mannitol. A total of 8701 vials were loaded including 100ml, 50ml, 30ml and 20ml vials. Vials were either 1/2 full or 1/4 full (in different runs). The dryer was pressurised to 18.5psig with nitrogen and the shelves were cooled to -6.5°C (the selected nucleation temperature). After sufficient time to allow equilibration of all vials to -6.5°C, the system was rapidly depressurised by opening the main depressurisation manifold. Following this, the dryer was opened, trays were removed and all vials were manually inspected by operators in the clean area for evidence of nucleation. Nucleation was observed in all 8701 vials.
Figure 2 – schematic of vial loading
LIMS
Master plan
Task manager
Core Informatics has introduced a master data management software system to accelerate scientific and laboratory processes and collaboration across multiple industries. The Core LIMS is a flexible database and also includes an electronic laboratory notebook (ELN), scientific data management system (SDMS), workflow, dashboards and data analysis, designed to allow customers to design applications and integrations that meet their specific needs with minimal long-term cost of ownership. Core Informatics’ data management solution is 100% web-based and can be configured to suit the majority of user requirements for laboratory workflow. The rapid configuration of the LIMS database remove the need for highly customised, traditional LIMS software. It is claimed to reduce time and resources associated with configuring and deploying LIMS software and help ensure a rapid ROI. The Core LIMS offers an array of functionality. For instance, the integrated laboratory inventory and storage management tool informs customers where everything has been located and for how long, with location audit logs and sample and container tracking. The system can be deployed in a manner consistent for meeting regulations such as CFR 21 Part 11. To enable customers to easily design applications and integrations that meet their specific needs with minimal long-term total cost of ownership, the Core foundation is supported by the Core software development kit (SDK), including the Core application programming interface (API). The Core SDK makes the Core LIMS extendable, presenting customers with the opportunity to add components to the system as and when necessary.
Autoscribe has unveiled a revised version of the scheduler module for the Matrix Gemini LIMS. The versatile Matrix scheduler runs as a service so that even if a user logs off their PC, the schedule is still executed. It allows the scheduling of userdefined tasks based on specific dates or dates built from the classifiers of years, months, weeks, days and times. One example might be: 14.30 on the third Thursday of January, March, and September. The module also allows non-working dates (ie. weekends and public holidays) to be programmed in with the option to include or exclude tasks that would be scheduled to occur during these periods. Where a user task is not allowed to be launched on either a weekend or a public holiday and an actual scheduled date falls at that time, the scheduled date can be rescheduled forwards or backwards. The scheduler comprises three parts: new workflow screens to manage the scheduling of user tasks and holidays from within Matrix Gemini itself, a separate task launcher that is a Windows service and the actual task libraries that contain the specific tasks. The task launcher not only performs Matrix operations but is also capable of running any appropriate Windows executable files.
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Two predefined task libraries are installed with the scheduler: sample registration using a bulk sample registration template and printing or exporting of predefined reports using Crystal Reports. Both these task libraries automate the corresponding manual action from within Matrix Gemini. Other task libraries can be developed and added. User task management allows the management and scheduling of user tasks. It has all the usual management screens as well as screens for viewing user task launches and for the scheduling of user tasks.
LIMS afe pharmaceuticals may be the end goal of pharmaceutical QA/QC laboratories, but reliable, accurate and accessible data is what makes that goal possible. When data isn’t collected and organised well, labs become inaccurate and inefficient, which can result in delays – and even product recalls. These errors quickly become lost revenue through reduced productivity and time-consuming rework. Errors in laboratory data fall into two categories: the first, data collection, encompasses all errors made at the instrument level. This includes improperly calibrated or misused instruments, user error and problems with sample collection or preparation. The second category is information management, which includes how the collected data is transmitted, stored, accessed and analysed. Ensuring data integrity by reducing the potential for error in both these categories is one of the most critical challenges that QA/QC laboratories face. Successfully meeting this challenge requires two things: smart instruments and a smart laboratory infrastructure. The cornerstone of a smart lab infrastructure is a laboratory information management system (LIMS), which can collect and manage raw instrument data from a series of integrated smart instruments in the lab. Every lab instrument – from simple scales to complex spectroscopic and chromatographic instruments – can be integrated into the LIMS (also known as a scientific data management system, or SDMS), ensuring that data is easily, reliably and efficiently collected. Just as business innovation is facilitated by a well-organized, collaborative team, reliable QA/QC is the product of seamless integration between laboratory instruments and software. The end result is a highly-automated paperless laboratory where all instrument data is accessible enterprise-wide in real-time, increasing efficiency and ensuring reliable QA/QC data. To create this environment, QA/QC lab managers need to focus on two things: data collection and information management.
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Data Collection The first step in creating the paperless lab is to select the right instruments – not only do they have to be appropriate for the application, but they also must be able to interface with a LIMS. Most common instruments for pharmaceutical
Smart moves Nicole Keppy and David Joyce, Thermo Fisher Scientific, explain how information management can transform pharmaceutical QA/QC laboratory productivity, reliability and connectivity QA/QC labs, such as UV-visible spectrophotometer have many different variants that are each appropriate for a different application. For at-line measurements using a UV-visible spectrophotometer, an instrument equipped with a sipper module is the best choice. Biopharmaceutical samples, however, are best analysed using a double-beam instrument equipped with a thermal accessory and xenon lamp. Regardless of the application, it’s critical that the instrument has the capability to interface with a LIMS. Laboratory managers must also decide the appropriate time interval for performance verifications of smart instruments – their smart technology does not exempt them from the need for maintenance to ensure that they remain on specification. Lab administrators must make this judgment based on the level of risk acceptable for the lab. The cost and frequency of maintenance is indirectly proportional to the possibility for instrument error, and each lab must decide the appropriate balance of these two factors. Many laboratory instruments and accessories also require periodic alignment or calibration to perform accurate analysis. This can be made more efficient using a LIMS – automating these vital procedures and executing them on a predefined schedule saves time, keeps labs up to specification and helps ensure regulatory compliance. Additionally, processes defined for one smart instrument, such as a spectroscopy system, can be easily applied to other instruments in the lab via the LIMS.
process but reduces human error by eliminating manual data collection. Many software suites are instrument agnostic, which minimises training expenses as technicians only need to learn one software package. Despite their high level of automation, many of today’s software-enabled instruments still require human operation – and are therefore still subject to human error. Fortunately, software solutions exist to help lab managers reduce the possibility of user error. Some pieces of instrument-level software, for example, allow the user to custom configure their spectrophotometers to better serve the specific applications of their instruments. Used in conjunction with customised user environment software, the spectrophotometer can then guide the user through a step-by-step process to ensure proper operation. All data collected
Information Management In addition to being properly collected, the data from laboratory instruments and systems must also be properly analysed and managed. This is best done using a combination of software that starts at the instrument level. The GRAMS Suite of software, for example, is used by many QA/QC labs to automate and integrate data collection from multiple spectroscopy systems and other lab instruments. Automating this data integration not only speeds up the EPM 26
can be easily audited by an administrator, as well as formatted for use by customers and/or other systems further downstream. When smart instruments and smart infrastructure work together, laboratories can reach an unprecedented level of connectivity, reliability and efficiency. Labs that integrate their instruments with LIMS, GRAMS and SDMS software also benefit from a data “safety-net” that reaches from loading bay to final shipment and ensures the reliability of accessibility of their data – not only across labs, but across continents. Critical lab data can be easily accessed by anyone within the enterprise using desktop, mobile and web applications. Perhaps most importantly, automated smart laboratories reduce the time employees waste on routine tasks, freeing up human capital for more valuable and productive work. About the authors: Nicole Keppy is senior product specialist, UV-visible spectroscopy, Thermo Fisher Scientific and David Joyce is senior product manager, laboratory informatics, Thermo Fisher Scientific
Data crunch: Nicole Keppy, Thermo Fisher Scientific. She explains how safe pharmaceuticals may be the end goal of pharmaceutical QA/QC laboratories, but reliable, accurate and accessible data is what makes that goal possible
Specially selected: David Joyce, Thermo Fisher Scientific. The first step in creating the paperless lab is to select the right instruments
FORMULATION odern medicines have had a dramatic effect on human health. Quality of life has been greatly improved by drugs to treat chronic conditions with painful or debilitating symptoms. While new molecular entity (NME) approvals are increasing in the US and EU, the chorus of investors demanding predictable and sustainable R&D productivity continues to grow louder. Innovation in our business requires safe, efficacious molecules delivered to the right place in the body, at the right time. But if a product does not improve patient outcomes compared with other treatments, reimbursement will be elusive, or non-existent. Industry is increasingly concerned with rising development costs and stagnant R&D productivity. Formulation technologies and enabling drug delivery platforms are increasingly important for clinical development success. It’s estimated that more than 90% of drugs in development have poor bioavailability – they are insoluble in water, have very low permeability, or both. The drug may also require delivery at a controlled rate or to a specific location to improve safety and efficacy. Clever formulation can also offer commercial advantages by extending the duration of patent protection, thus delaying the onset of generic competition. Clinical development teams focus on demonstrating differentiated patient outcomes for the NMEs. Often, it’s a balance between perfection and ‘good enough’ in clinical development, with sub-optimal bioavailability or delivery properties tolerated to reduce clinical complexity and increase speed to market. Many small-to-mid-sized pharma companies rely on collaboration networks to access expertise, development resources and drug delivery technologies. Specialist drug delivery solutions companies are often employed to create formulations that overcome delivery problems, by applying existing technologies to new applications, or creating novel delivery platforms and dosage forms. Many already-marketed products can also be improved. As an example, a self-emulsifying drug delivery system was applied to the immunosuppressant drug Cyclosporin, improving its pharmacokinetic properties. Initially launched under the brand name Sandimmune as a lipid-based formulation in a softgel capsule, its poor solubility resulted in highly variable drug levels, impacting
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The drugs do work More products and better treatments — the role of drug development and drug delivery technologies by Kurt Nielsen, senior vice president, innovation & growth, Catalent Pharma Solutions
Team effort: Catalent Soft gels. The company believes that collaboration between industry and academia remains vital
patient tolerability and outcomes. A reformulation as a microemulsion preconcentrate in a softgel capsule resulted in rapid gastric dispersion, vwith the drug maintained in solution with a solvent system that prevents precipitation. The result was Neoral, whose enhanced bioavailability and pharmacokinetic properties have transformed life for transplant patients. Challenges such as the creation of drug products from molecules that prove difficult to formulate often require the invention of new delivery technologies. Collaboration between industry and academia remains vital. Academic research groups can run the kind of speculative, creative projects that are much more difficult for industrial companies to support directly. Pharma and drug delivery companies contribute by sharing the very real problems they need to solve, alongside expertise in “realworld” drug formulation and process
development so drugs are formulated for rapid onward development, scalability and commercial success. By working together to leverage the skills and expertise of all parties, identifying these solutions becomes more likely. This was the thinking behind the establishment of the Catalent Applied Drug Delivery Institute in 2012. The institute has academic partnerships with the New Jersey Technical Institute, Purdue University, Rutgers University, St. Johns University, the University of Mississippi, and the University of North Carolina at Chapel Hill. Now in its second year, it also has
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confirmed student participation from the University of Bristol in the UK, and Heinrich Heine University in Düsseldorf, Germany. As part of this programme, the second Global Academic Competition was launched in January for students enrolled in graduate programmes related to pharmaceutical science, industrial pharmacy, drug delivery, and drug development. These partnerships are working to develop new, innovative technologies in the fields of taste masking, bioavailability enhancement via particle engineering, hot melt extrusion, oral vaccines and oral macromolecules. Other drug discovery challenges could also benefit from the collaborative approach in future, from injected biologics to inhaled medicines. The institute will promote open innovation through knowledge sharing and collaboration between industry leaders, academic experts, customers and regulators to advance the best available and emerging drug delivery technologies and, most importantly, improving patient care. It is pursuing a multitiered approach of seed funding, strategic advice and educational programmes. The institute and the academic competition are practical ways in which Catalent is looking to promote these important links between industry and academia. Only by working together will the development and formulation challenges that arise from the nature of modern APIs be readily solved. Collaboration facilitates the application of knowledge from the world’s leading experts in drug development, delivery and formulation to improving drug delivery, and, ultimately, creating better treatments for patients.
Delivery charge: Catalent Opti Dose. According to Kurt Nielsen challenges such as the creation of drug products from molecules that prove difficult to formulate often require the invention of new delivery technologies
EXTRACTABLES & LEACHABLES
Testing testing: Understanding a material’s chemical profile is necessary to detect of leachables, says West. Many analytical technologies can be employed for extractable and leachable testing
aterials that have direct or indirect contact with a drug or biologic product can leach harmful substances into the final pharmaceutical product. Substances that leach can originate from various materials, at any point in the supply chain and throughout the product’s lifecycle. Constituents that migrate from primary packaging into the final product when manufactured and stored under its normal conditions are referred as leachables. Typically, leachable compounds are found in trace amounts yet can have a negative impact on pharmaceutical quality with potential to compromise patient safety. Any component used during manufacture, storage, shipping and administration to the patient can be implicated as a source of leachables.
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Compatibility issues There are multiple types of components to be considered throughout the manufacture, storage and delivery to patients. Primary classes of materials used to manufacture and store drugs and biologics include elastomers, plastics, glass, metal and paper board components. These components must be compatible
Quality first Diane Paskiet, director, scientific affairs, West Pharmaceutical Services explains how to understand risk from extractables and leachables (E&L) and the key quality considerations when designing E&L studies with the final product and function properly for intended use as well as provide protection over the drug’s shelf life. A pharmaceutical product can be affected by chemical substances migrating from material into final product with distinct outcomes. The leached substance can be toxic, affect the product stability or react with active pharmaceutical ingredients or excipients to form a new chemical entity. Patient risk needs to be assessed and mitigated based on understanding potential for leaching. This is accomplished by designing systematic studies to identify and quantitate extractable substances. Component profiles have many levels of complexity, which may become more varied once the component is formed, washed,
sterilised and assembled. Common sources of extractables include residuals and by-products from the material. Processing aids and additives such as stabilisers, antioxidants, lubricants, curatives and their breakdown products are all examples of species contributing to the chemical profile. An extractable study will establish the chemical profile, which reflects risks relative to potential toxicity and incompatibility. Toxicity will depend on the leachable concentration in the final product and patient total daily intake; incompatibility is fundamentally dependent upon the pharmaceutical matrix and conditions of use. Often compatibility issues are manifested by different end points such as pH shift, degradation, oxidation, aggregation, foreign particles and
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other impurities that can become evident over a period of time. All materials will leach to some degree under certain conditions. The goal of an extractable study is to provide evidence that materials are suitable for intended use by understanding how risk for leaching correlates to patient harm and eliminating or mitigating that risk. Key considerations for E&L studies An extractable and leachable strategy consists of multiple steps in which voluminous information is acquired and builds until final drug product stability studies are completed. This can span a period of five years or more from discovery to confirmation. The objective of an E&L study is to identify and communicate risks by conducting controlled extractable studies, which can be correlated to drug/biologic safety and quality. Formal risk assessment tools such as flow diagrams, control charts, risk ranking/filtering or hazard analysis, and critical control points can add value in assessing components for intended use, although these tools are not required. The studies should be designed so the various components are evaluated
Point of concern: Any component used during manufacture, storage, shipping and administration to the patient can be implicated as a source of leachables commensurate with the level of risk to final product quality and safety. Criticality should be justified based on the likelihood of component interaction with the drug or biologic product during manufacture, storage or when in contact with a patient. Once the components are deemed critical for evaluation, the chemical make-up of each material should be understood. This will feed into the component sampling, preparation of extracts and analysis techniques. Multiple solvents that encompass organic as well as aqueous solutions should be employed to explore a comprehensive chemical profile. Multiple analytical techniques and those that are orthogonal should detect a wide range of extractable species with various sensitivities. Analytical methods should be robust and fit for purpose; that is, having a system capable of detecting certain predetermined targets at specified levels as well as detecting unexpected extractables. Understanding a material’s chemical profile is necessary to enable detection of leachables. The chemical characterisation of a component should include extraction solvents and conditions that are aggressive enough to indicate the basic chemical ingredients and by-products of the material; however, this is not often indicative of actual leachables. In certain applications, it can be an advantage to simulate or mimic final product under exaggerated conditions to define targets better. The purpose of an extractable study is to provide comprehensive data to indicate risk for leaching and guide a leachables assessment. Methods need to be optimized to measure trace leachables which are easily masked and difficult to detect in a complex matrix. Spiking and recovery studies are necessary to confirm the presence or absence of target compounds. Correlation of the component extractables with confirmed leachables under worstcase conditions will lead to the necessary control strategy. Setting acceptance limits There are limits in various compendia for certain materials used in pharmaceutical and medical device industries; however, these limits are considered a starting point to identify materials that might be acceptable. The final drug or biologic product will influence appropriate specifications and acceptance criteria. Acceptance criteria should be set based on the
observed range of variation according to ICH guidance Specifications: Test Procedures and Acceptance Criteria for New Drug Substances, New Drug Products (Q6A); Biological Products (Q6B). The guidance establishes the criteria to which a drug and biologic product should conform to be considered acceptable for its intended use. There is a provision for control of extractables from container/closure systems in which parenteral products are considered significantly important. The guidance indicates that where development and stability data show evidence that extractables are consistently below levels demonstrated to be acceptable and safe, the elimination of this test can be accepted but should be reinvestigated if the container/closure system or formulation changes. The guidance also recommends collecting data for components as early in the development process as possible. This is consistent with quality guidelines on Pharmaceutical Development (ICHQ8 (r2), Risk Management (ICHQ9) and Pharmaceutical Quality Systems (ICH Q10). Acquiring appropriate evidence to demonstrate suitability of materials is necessary for each pharmaceutical product. Extractables are a function of the material chemical make-up, physicochemical properties, configuration of the delivery systems, various environments and length of exposure. Risk variables include component proximity to the
final product, area of direct contact, dosage form and conditions of use throughout material processing, manufacturing, filling and storing. Risk for leachables can be indicated based on identifying those extractable compounds with the highest propensity to leach into final product. The extraction and analysis methods should be tailored to substantiate that leachable levels are below quality and safety concerns. This allows risk of toxicity or poor quality needs to be identified and mitigated. It is not practical to assume a standard method or even suite of methods can provide all the essential evidence. Nonetheless, a standard strategy has been conceived by the Product Quality Research Institute (PQRI). In 2006, Recommendations for Safety Thresholds and Best Demonstrated Practices for Leachables and Extractables in Orally Inhaled and Nasal Drug Products (OINDP) was published (www.pqri.org). This is currently being extrapolated for parenteral and ophthalmic drug products (PODP). Recent USP guidelines <1663> Assessment of Extractables Associated with Pharmaceutical Packaging and Delivery Systems; and <1664> Assessment of Leachables Associated with Pharmaceutical Packaging and Delivery Systems were also published in USP PF 39 in September 2013 and are consistent with PQRI approaches. To set acceptance criteria for extractables and/or leachables, relevant data must be collected and assessed. It is important to justify
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specifications based on impact to final product and patient. Control points can be considered early on, but the nature of leaching often occurs over time. Variability will exist from component to component as well as the extractablesâ&#x20AC;&#x2122; propensity to leach. Control points are not easily derived until there are multiple lots of components representing full shelf-life stability studies. Once an analytical target profile (ATP) is established for leachables methods should be optimised and measurements fully validated. Statistically relevant data is necessary to establish acceptance criteria. A range of sophisticated analytical technologies can be employed for extractable and leachable testing. While all-purpose methods can be a starting point, these will not address distinct applications. Pertinent information is acquired by understanding the materials and intended use to enable specific extraction and analytical methodology to be justified. Upcoming advances may be a combination of improving technologies for identifying/qualifying leachables along with development of new materials that are engineered to fit a purpose in a quality by design (QbD) paradigm. Accurate and precise analytical measurements will be the means to enable the future of applying the right knowledge at the right time to materials used in the manufacture, containment and delivery of high-quality pharmaceutical products.
INGREDIENTS: EXCIPIENTS he European Commission Guidelines on the formalised risk assessment for ascertaining the appropriate good manufacturing practice (GMP) for excipients of medicinal products for human use, explicitly state that certification held by the excipient manufacturer and the standards against which this has been
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Quality assured How can qualified persons be assured the quality of the pharmaceutical excipients used in their medicinal products meets the requirements Falsified Medicines Directive and changes to EU Part 1 GMP Section 5 without incurring a huge audit burden? Iain Moore, president, EXCiPACT, explains
The Smart Bulk Excipient
The new platform excipient for tablets, sachets and more • first rate filler-binder properties due to excellent compressibility • fast and slow disintegrating tablets (chewables, effervescents, suckables, FDDTs…) • ideal in sachets for direct oral application or dry suspensions • outstanding flow and mixing properties • high dilution potential and high content uniformity • very low hygroscopicity and excellent stability • GMO-free and non-animal origin BENEO-Palatinit GmbH · Phone: +49 621 421-150 · galenIQ@beneo.com · www.galenIQ.com
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granted, can be used to demonstrate that the supplier meets the determined GMPs. So what would define a suitable GMP certification of the excipient supplier? One such certification scheme, which has been specially designed for this purpose is now available from EXCiPACT-registered third party certifying bodies and their EXCiPACT-registered auditors. Suppliers holding EXCiPACT certificates will allow QPs to simplify their responsibilities in the release process of batches of drug products and related activities without any loss of quality assurance or compliance to GMPs. Not only does the EXCiPACT certification scheme include GMP requirements but it can also include good distribution practices (GDP) if these are applicable to the supplier’s business activities. EXCiPACT-certified suppliers will provide QPs with an EXCiPACT certificate and the audit report(s) plus any corrective and preventive action plans. Audits will occur at least annually and so over a short period of time a comprehensive picture of the supplier’s compliance to the EXCiPACT GMP and or GDP standards can be built up. This auditing frequency is greater than most excipient users could perform, even for their critical excipients. The scheme’s development took the existing IPEC-PQG GMP and IPEC GDP guides and converted them into auditable standards as annexes to ISO 9001, making the adoption and assessment more consistent and simpler for all concerned. For organisations without ISO 9001, the audit can be performed by the same certifying body and auditors to the forthcoming ANSI NSF 363 US national standard which is expected to be equivalent to the EXCiPACT standard. To maintain the scheme’s high quality and service provision and to be formally approved and publically listed, all registered third party certifying body auditors must undergo a rigorous and formal twoday training course and exam, and be witnessed during a live audit to verify their competence and understanding of the scheme’s requirements. Before certifying bodies are approved, registered and listed on our website, EXCiPACT checks they have a quality management system in place to deliver an audit that meets the requirements set out in the annex to ISO 17021 in the EXCiPACT standards book. This requires that the certification
INGREDIENTS: EXCIPIENTS Sorbitol excipient performance in ascorbic acid tablets Tereos Syral has conducted a formulation study to assess the tabletting performance of sorbitol powder against lactose when associated with a poorly compressible active: ascorbic acid. By Marjorie Lejeune, application engineer
Iain Moore, explains what’s behind the EXCiPACT certification scheme decision is NOT made by the auditor but by an independent review board. The website lists those registered certifying bodies who have used registered auditors to audit excipient suppliers who have received an EXCiPACT certificate. Anyone who has an EXCiPACT certificate and audit report from an excipient supplier, can verify them on the website to see if that supplier, the certifying body and the auditor(s) are listed. The US FDA and the European Medicines Agency continue to press for site audits of excipient suppliers with the attendant increase in the audit burden. The EXCiPACT certification scheme can help to significantly reduce the audit burden for both excipient suppliers and users. The scheme has received excellent support from the regulatory authorities. Only last month at ExcipientFest Americas, Steve Wolfgang of the FDA stated that excipient users should be “looking at third party certification” as an effective means of managing their audit burden. To know more about the EXCiPACT certification scheme, those interested can refer to the website for full details and to download a copy of the scheme’s standards. Approved third party certifying bodies, registered auditors and the EXCiPACT certified excipient suppliers are all listed (www.excipact.org). Alternatively, those interested can register for an EXCiPACT two-day training course listed on the website.
Materials and methods The following excipients have been evaluated: Spray-dried sorbitol, Merisorb SD 250 Pharma, Ph. Eur. – USP-NF, Tereos Syral Crystalline sorbitol, Merisorb 200 Pharma, Ph. Eur. – USP-NF, Tereos Syral Direct compressible (DC) spraydried lactose, commercially available on the market
10 Crystalline ascorbic acid
9
Crystalline sorbitol, Tereos Syral
8
Spray-dried sorbitol, Tereos Syral
7
Spray-dried lactose
6 % (vol.)
Lactose is widely used as a filler or diluent in tablets. Among the various commercial grades available, spraydried lactose, which was developed 30 years ago, is specifically designed for direct compression. Today, galenic formulators have a wider range of choices. Among them polyols, such as sorbitol and maltitol are sugar-free excipients with a low glycaemic index. They are white, crystalline and odourless powders with a pleasant sweet taste and more or less intense cooling effect. They have an extremely low content of reducing sugars, thus unwanted browning reaction with the amino-groups of the actives can be dramatically reduced. Generally compatible with active pharmaceutical ingredients (API), polyols’ functionalities in tablets formulation is of utmost importance. Tereos Syral has an expertise in the production of dry products. Its sorbitol powders display high performance in tabletting; they are produced either by crystallisation or spray- drying, providing specific particle structures and crystalline states to fit different needs in solid dosage forms. The company has conducted a formulation study to assess the tabletting performance of sorbitol powder against lactose when associated with a poorly compressible active. Crystalline ascorbic acid (vitamin C) was used as a model drug in the study. Ascorbic acid is usually present at a high content in tablets, up to 1000 mg. It is soluble, hygroscopic and poorly compressible. In Tereos Syral study, it was blended at a ratio of 25% w/w with various sorbitol or lactose powders.
5 4 3 2 1 0 1
10
100 Size (μm)
1000
10000
Figure 1: Particle size distribution of the tested excipients and ascorbic acid METHODS Powder properties Particle size distribution was determined by laser light scattering (Mastersizer 2000, Malvern), water content by the Karl Fischer method (848 Titrino Plus, Metrohm) and loose and packed density by a volumetric method. Tabletting process Each formulation consisted in 74% w/w of excipient, 25% w/w of crystalline ascorbic acid and 1% w/w of magnesium stearate as a lubricant (Ligamed MF-2-V, Peter Greven). Batches of 500 g were blended with a 3-dimensional blender (Turbula T2F, Willy Bachofen). The excipient and crystalline ascorbic acid were first blended for 5 minutes. After adding magnesium stearate, the batch was further blended for two minutes. Tablets of 500 mg were compressed on an instrumented table top eccentric single punch press (Minipress, Riva), using a standard round flat punch, with a surface of 1cm2 and applied forces ranging from 5 to 20 kN. Tablets testing Analysis of the tablets was done according to the methods prescribed by the European Pharmacopoeia current edition. From each batch, tablets of each compression force were selected
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and tested on weight, diameter, hardness (8M, Schleuniger), friability (TAP, Erweka). Average and standard deviations were calculated for hardness, friability and diameter values. Disintegration tests were conducted (DT2, Sotax) without disks in a water bath at 37°C on 6 tablets. Dissolution profile (AT7, Sotax) of tablets compressed at 10 kN was determined in a dissolution medium at 37°C consisting in hydrochloric acid at 0.01 N mimicking the stomach conditions. Aliquots were sampled at different times and measured in an UVspectrophotometer (UV-1800, Shimadzu) at 243 nm wavelength. The tablets were stored for two months in polyethylene bags sealed under slight vacuum and placed in a climatic chamber (Binder) at 30°C and 70% relative humidity. The colour of tablets compressed at 10 kN was assessed after this storage with a spectro-colorimeter (Ultrascan Pro, HunterLab) in the L*a*b* space. Results and discussion Powders characterisation The median particle size diameter of the excipients was around 250 µm for spray-dried sorbitol, 225 µm for crystalline sorbitol and 130 µm for lactose, whereas it is of 250 µm for ascorbic acid (Figure 1).
INGREDIENTS: EXCIPIENTS
Tablets testing Compression behaviour and dilution potential Sorbitol powders enable to obtain tablets with hardness higher than with lactose (Figure 2). Maximum hardness of sorbitol is twice that of lactose at 15 kN. Tereos Syral crystalline and spray-dried sorbitols exhibit quite similar compression profiles, although the crystalline grade reaches higher hardness at slightly lower compression forces. Dilution potential is calculated by dividing the area under the compression curve (AUC) of the excipient blended with ascorbic acid by the AUC of the excipient alone. It gives an indication of the ability of an excipient to maintain its tabletting performance when associated with other material even if poorly compressible. Lactose has the lowest dilution potential, losing half of tablet hardness when incorporating 25 % of ascorbic acid. Crystalline sorbitol has the highest dilution potential. Spray-dried sorbitol ranks in-between lactose and crystalline sorbitol. Sorbitol could thus enable to incorporate higher amount of poorly
Loose density (g/L)
Loose density (g/L)
Ascorbic acid
890
1090
Spray-dried sorbitol, Tereos Syral
640
750
Crystalline sorbitol, Tereos Syral
630
710
Spray-dried lactose
630
670
Table 1: Loose and packed densities of tested excipients
compressible material compared to lactose when applying direct compression.
They perform well for higher compression forces. Sorbitol tablets show nice sharp edges compared to lactose tablets, which have irregular edges.
Friability At all the applied forces, lactose tablets display the highest friability above the 1% limit set up in the European Pharmacopoeia. As the tablets compressed at 20kN were capped, they broke during the test and failed (figure 3). Friability of sorbitol-based tablets is below the 1% acceptance criteria except when compressed at 5kN.
Disintegration time Disintegration time increases with the compression force in relation with the increase in hardness (Figure 4). Lactose tablets have a short disintegration time when compressed at 5 or 10 kN, but their behaviour is similar to sorbitol at 15 kN. When compressed at 20 kN, the
300
Dissolution profile at 10 kN Lactose tablets dissolve the fastest: 80 % of ascorbic acid is released after 8 minutes (Figure 5). Sorbitol tablets dissolve in a longer time but remain under the 30 minutes limit defined by European
Crystalline sorbitol, Tereos Syral Dilution potentials
Spray-dried sorbitol, Tereos Syral Spray-dried lactose
250
58 54
200 150
50
100 50 0 0
5
10
15
20
25
Compression force (kN)
eos Syral
Crystalline sorbitol, Ter
5.0
Spray-dried sorbitol,
4.5 4.0
Tereos Syral
Spray-dried lactose
3.5
ABOVE Figure 2: Compression profile of the tested excipients with 25% of ascorbic acid and 1% magnesium stearate
Friability (%)
Ph. Eur. limit
3.0
LEFT Figure 3: Friability of tablets produced at different compression forces.
2.5 2.0 1.5 1.0 0.5 0.0
lactose tablets exhibit a higher disintegration time than sorbitol tablets, which is even above the acceptable limit of 900 seconds (i.e. 15 minutes) defined by European Pharmacopoeia. Sorbitol tablets remain well under this limit whatever the compression force applied.
Hardness (N)
Spray-dried sorbitol has a slightly higher loose density than the crystalline one because of a higher content of fine particles between 50 and 80 Âľm. Lactose has a loose density close to crystalline sorbitol. With a higher difference between loose and packed density, sorbitol powders have a higher tendency to compaction. Ascorbic acid has a quite high density in relation with its compact structure (Table 1). Sorbitol moisture was comprised between 0.5 and 0.6 %. Lactose moisture content was at 4.9 % and ascorbic acid at 0.3 %.
5
10
20
15 ) (kN ce for n sio res Comp
EPM 32
Crystalline sorbitol, Tereos Syral Spray-dried sorbitol, Tereos Syrall Spray-dried lactose
1200
LEFT Figure 4: Disintegration time of the tablets produced at different compression forces.
Ph. Eur. limit Disintegration time (s)
1000 800
BELOW Figure 5: Dissolution profiles of tablets compressed at 10 kN
600 400 200 0 5
10
15 Compression force (kN)
20
120
Colour evolution After two months storage in tough conditions, a global decrease in lightness (L*) and an increase in yellowness (b*) is observed in tablets containing ascorbic acid (Table 2). Nevertheless, Tereos Syral sorbitols are more stable than lactose towards colour evolution. Lactose tablets are far more unstable, with a brownish fade appearing over time. Sugar-free excipients such as polyols are commonly more stable towards browning with regards to their extremely low reducing sugars content.
Conclusions The study conducted by Tereos Syral to assess the tabletting performance of sorbitol powders (Merisorb SD 250 Pharma and Merisorb 200 Pharma) against lactose when associated with ascorbic acid at 25%, shows that these excipients ensure high quality tablets and provide competitive advantages. Tablets formulated with ascorbic acid and sorbitol excipient demonstrate higher hardness and better dilution potential compared to tablets made with lactose. Sorbitol opens
imiitt Ph. Eur. llim 100 ased (%) release Drug rele Dru
Pharmacopoeia. Spray-dried sorbitol tablets dissolve after 24 minutes, crystalline sorbitol tablets dissolve after 26 minutes. Therefore, spray-dried or crystalline sorbitol excipients have a clear advantage on lactose when a sustained release is required.
80 60 all os Syra eos ere Ter l, T itol, bito sorb lline sor talline sta Crys Cry
40
all os Syra eos ere Ter l, T itol, bito sorb ried sor drie y-d aySpra Spr
20
e ose lacttos ried lac drie y-d aySpr Spra
0 0
5
20
15
10
25
45
40
35
30
50
in) e (min) Time Tim
Placebo tablet (Excipient alone)
Ascorbic acid tablet
L*
a*
b*
L*
a*
b*
Spray-dried sorbitol, Tereos Syral
98.6 ± 0.1
-0.0 ± 0.0
0.05 ± 0.03
96.6 ± 0.3
0.23 ± 0.1
5,28 ± 0.7
Crystalline sorbitol, Tereos Syral
99.4 ± 0.0
0.0 ± 0.0
0.24 ± 0.0
96.0 ± 0.2
0.12 ± 0.1
7.05 ± 0.4
Spray-dried lactose
99.1 ± 0.1
-0.02 ± 0.0
1.65 ± 0.1
96.0 ± 0.5
-0.70 ± 0.2
9.34 ± 0.7
perspectives in the production of high quality tablets incorporating high load of poorly compressible active substance. Sorbitol-based tablets demonstrate exceptionally low friability compared with the tablets formulated with lactose, thus limiting tablets damaging upon packing, transport and ageing. Tablets with spray-dried and
crystalline sorbitols exhibit a more sustained release of the active substance compared with lactose tablets, while staying under the acceptable limit of dissolution time defined by European Pharmacopoeia. Sorbitol excipient in direct compressible tablets preserves colour stability by maintaining whiteness upon storage.
EPM 33
ABOVE Table 2: Colour measurement of the tablets after two months storage (average value ± standard deviation)
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