EPM August 2015 by EPM Magazine

By Kraemer & Ischi

COVER STORY: FUTURE PROOF KRAEMER & ISCHI ON TABLET QUALITY CONTROL

AUGUST 2015

Contents August 2015 | Volume 15 Issue 5

Regulars 6

Features 21

NEWS ANALYSIS

NETWORK CONNECTION

Crowdfunding website supports rare diseases research

West Pharmaceutical Services on expanding into new markets

OPINION

Professor Colin Garner, Antibiotic Research UK, and Andrew Newland, Angle

DUAL APPROACH WHP looks at integrating process plant in cleanrooms

REGULATORY AFFAIRS

FORWARD PLANNING

Solving the global benefit-risk assessment dilemma

Start thinking now about the changes to impurities testing, says Butterworth Labs

IT’S GOOD TO TALK

FIT FOR PURPOSE

Tips for avoiding tablet design issues

Wickham Labs performs bacterial endotoxin testing for a big client

34 CHEMICAL REACTION

Featuring Sygnature Discovery

CHAIN REACTION

Planning is crucial for the optimal storage of IMPs, says Biotech Services

COVER STORY: FUTURE PROOF Kraemer & Ischi on tablet quality control

31 COVER STAR Colorcon compares continuous and traditional batch coating

32 TRAIN TO GAIN Fette stresses the need for tablet press operator training

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from the editor Needle-free hope: Scientists have been hard at work developing alternative delivery methods

Delivering the goods T he hypodermic needle established its stronghold during the latter 1800s and today remains the only reliable method of delivery for many large-molecule drugs such as insulin as well as vaccines. Despite its widespread use however, the traditional needle is hugely unpopular with patients as it is often painful and puts many off self-administering.

Decades of research has so far concluded that delivering large-molecule drugs orally is not feasible; any efforts to make them orally bioavailable have failed, they simply break down in the gut and become ineffective. But, as always in our industrious life sciences sector, scientists have persevered in their exploration of promising alternatives. One such popular alternative is the microneedle patch. A quick Google search brings up a number of universities and companies involved in developing these miraculous patches that promise to bring an end to the conventional injection. Penny-sized and covered in 100 plus microneedles, the patch is painlessly applied, like a plaster, by the press of a thumb. The microneedle patch has of course been in the pipeline for a number of years. A main reason for its limited success thus far has been the use of silicon and metal in the microneedles’ makeup, materials deemed unsafe as they can break off and leave fragments behind. This has seen scientists adopt an altogether ‘closer to nature’ approach. The Osaka University of Japan last month announced the development of a dissolvable microneedle patch for the delivery of

vaccines. Made of hyaluronic acid, a naturally occurring substance in the body, the scores of microneedles dissolve on application, releasing the vaccine.

The university’s researchers have successfully trialled the MicroHyala alongside the injection in two patient groups for three strains of influenza. None of the MicroHyala patients had an adverse reaction and their immune reaction proved equal to and in some cases stronger than that of those given the injection. The results of the trials are published in Elsevier’s journal Biomaterials. University of North Carolina and North Carolina State University researchers recently designed a microneedle patch that mimics the body’s natural insulin generators, beta cells, by responding directly to a diabetes patient’s glucose levels and delivering the required amount of insulin. Referred to as the ‘smart insulin patch’, its microneedles — again made from hyaluronic acid — contain insulin and the enzyme glucose oxidase. The glucose oxidase reacts biochemically to increased glucose levels, cleverly triggering the insulin’s release. In a study published by PNAS (Proceedings of the National Academy of Sciences), the smart insulin patch has been shown to normalise blood sugar levels in type 1 diabetic mice for up to nine hours. It is still early days, but the research team’s next step is to test the patch on pigs as their skin is similar to ours and they should give a better indication as to its effectiveness for patients. WWW.EPMMAGAZINE.COM

Before signing off, it should be pointed out that researchers have by no means lost faith in the oral delivery route. Only a couple of months ago, Novartis announced its backing of Rani Therapeutics in the development of a robotic pill that is swallowed just like a conventional pill. The product, dubbed the ‘Rani pill’, is a capsule of two compartments, one containing citric acid and the other sodium bicarbonate. The two chemicals mix and react as the capsule dissolves, pushing micro-sugar needles into the intestine wall to deliver the drug. Rani and Novartis will be conducting feasibility studies using Novartis’ line of biologics over the next two years. It is hoped that the Rani pill might be used to treat diabetes, rheumatoid arthritis, psoriasis and multiple sclerosis. The aforementioned stories do not even scratch the surface of the pioneering attempts being made to deliver on the needle-free promise, but there is still some way to go in convincing vaccine and drug manufacturers, as well as patients themselves, of their viability.

Ellie Valero 5

NEWS ANALYSIS

Crowdfunding platform launches for new and rare disease research A wholly new way to fund life science research, complementing more traditional funding, has launched. FutSci is the first crowdfunding platform run by scientists and dedicated to funding research, innovation and technology in life sciences. FutSci was co-founded by Dr. Deepika Kassen, a molecular biologist, and Dr. Gayathri Perera, a dermatologist and immunologist, the idea having evolved during years of experience at the sharp end of life science research and funding. It will provide a platform where accredited researchers and scientists can post any project in need of funding, at any stage, and donors worldwide can select the individual projects they wish to support, with donations in multiple currencies starting as low as £1 and no upper limit. All projects will be vetted prior to going live on the platform and all scientists will be affiliated with recognised institutes.

Dr. Perera added: “With FutSci, we engage the public in helping to fund basic research projects, such as pilots that could then go on to receive grants and research into rare diseases that may have affected them or their friends and family, and we give them a say in choosing the research that’s important to them. FutSci enables donors to choose the specific projects they wish to fund and to engage directly in dialogue with the scientists and researchers they’re supporting via the platform. “A donor feels a strong connection to a researcher who’s investigating a disease so close to the donor’s heart. And scientists clearly and transparently keep the public informed about what they’re doing and how their donors’ money is being spent.”

Dr. Kassen said: “There’s a major funding gap for life sciences in the UK. It isn’t just that there’s been no life sciences crowdfunding platform before FutSci; it’s also an absence of grants and funds for research into less well-known diseases and conditions, and a dearth of small-scale grants and funds for early stage projects.

Further benefits of FutSci are its engagement with schools and encouragement of young people to develop their interests in science, coupled with a news and views section to provide up-todate reviews of current trends in life science research and scientific advancements, providing information on the typical process, costs and people involved.

“Particularly, there’s almost no funding for blue-sky thinking and very little support for researchers in the early stages of their careers. It’s little wonder the majority of scientists who cannot access funding leave science altogether, as they cannot sustain themselves and or their research. Every year in the UK there’s a huge loss of scientific knowledge and expertise — it’s a silent brain-drain.”

Dr. Kassen concluded: “We want to foster public engagement in bioscience and biomedical research and to encourage young people to consider a science career. Scientists can be approached by schools to get a true picture of what it’s like to study for a science degree, what happens in a lab, the different kinds of science available and also what doors can be opened by having a science degree.”

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Breast cancer study raises hope of therapy to stop tumour spread

NEWS ANALYSIS

Scientists at Edinburgh University have discovered a trigger that allows breast cancer cells to spread to the lungs. They say that the findings could lead to new therapies that stop the progression of breast cancer. The majority of breast cancer deaths are as a result of the tumours spreading to other parts of the body. The lung is often one of the first organs to be affected. Researchers at the University’s MRC Centre for Reproductive Health have found that blocking the signals in mice with breast cancer greatly reduces the number of secondary tumours found in the lungs. The team investigated the role that immune cells called macrophages play in helping cells from the original tumour to spread. Their previous research had shown that breast cancer cells need the support of macrophages to invade the lungs and set up secondary tumours. They have now discovered that macrophages require signalling molecules called chemokines to communicate with breast cancer cells.

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When they blocked these signals in mice, they found that the number of secondary tumours in the lungs was reduced by up to two thirds. Blocking the signals helped to stop the cancer cells from getting into the lungs from the blood stream. It also hindered those that did get into the lungs from establishing themselves and forming new tumours.

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Human cells appear to use the same chemokine signals to communicate with each other and the researchers hope their findings may one day translate into new treatments to stop breast cancer from spreading. The results suggest that targeting a chemokine receptor signalling molecule called CCR1 may result in fewer unwanted side effects for patients while stopping the spread of breast cancer cells. The study has been published in the Journal of Experimental Medicine. It was funded by the United States Department of Defence, National Institutes of Health (US), Medical Research Council (UK) and the Wellcome Trust. Professor Jeffrey Pollard, director of the MRC Centre for Reproductive Health at the University of Edinburgh, said: “Our findings open the door to the development of treatments that target the tumour microenvironment, which may stop the deadly progression of breast cancer in its tracks.”

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NEWS PROFILE

Pharma waste disposal – are you in the know?

he pharmaceutical sector is required to dispose of waste medicines and its associated packaging for various reasons such as patient returns, out of date stock, incorrectly printed blister packs, patient leaflets, change of specification/ brand name/license number, incorrect formulations and damaged products. The reasons vary, but the disposal route must completely conform to compliance requirements. Guidance from the World Health Organisation (WHO) titled Safe Management of Wastes from HealthCare Activities (Second edition, 2014, p.129) states that for “large quantities of pharmaceutical waste, the options available include encapsulation and burial in a sanitary landfill or incineration in kilns equipped with pollution-control devices designed for industrial waste and that operate at high temperatures”. The document also states “several options exist for small quantities of pharmaceutical waste, including the return of expired pharmaceuticals to the donor or manufacturer or encapsulation and burial in a sanitary landfill.” In developed nations with modern infrastructure, such as the UK and others in the EU, high-temperature incineration is considered to be the accepted standard of destruction required for pharmaceutical waste. In the UK, the landfill of pharmaceutical waste is specifically prohibited, being listed as a ‘banned waste’ on the waste acceptance criteria for landfill [1].

Landfilling pharmaceutical waste is also environmentally unsustainable, as there is a lack of landfill site capacity on a national scale [2]. Implications of the incorrect disposal of pharmaceutical waste also extend to counterfeiting should any of these products fall into the wrong hands. This very real issue saw Interpol and 29 of the world’s largest pharmaceutical companies create Interpol’s Pharmaceutical Crime Programme to further build on the work of its Medical Product Counterfeiting and Pharmaceutical Crime (MPCPC) unit. The illegal manufacture, trade and distribution of fake, stolen or illicit medicines and medical devices also includes the counterfeiting and falsification of medical products, packaging and associated documentation. A media release that announced this landmark agreement in March 2013 [3] included the comment from Interpol’s secretary general Ronald K. Noble: “With no country, no drug, no medical product immune from counterfeiting, a global effort is needed to combat this threat which puts the lives of millions of people at risk every single day.” The secure destruction of pharmaceutical waste is the only fail-safe method of ensuring all products have been completely destroyed. Depending on the waste stream, secure destruction of waste can range from shredding (for items such as waste pharmaceutical packaging)

to high-temperature incineration with energy recovery (for items such as unused medicines). Surjit Bains at waste management company Avanti Environmental explained: “This secure destruction method sees the waste collected, logged and the customer receive a consignment note to show the waste has been collected and left their premises. This waste is then taken to one of our fully licenced, secure sites, with 24-hour CCTV coverage, ready for processing. Once the waste is destroyed, customers are issued with a certificate of destruction within 24 hours.” Avanti Environmental’s Dr. Chris French added: “We see varying volumes that can range from a small one-off consignment to larger pallets and can process in excess of 50,000 tonnes per annum.” This best practice of secure destruction has a clearly defined audit trail — vital when it comes to manufacturers seeking or maintaining ISO 9001 and OHSAS 18001 certifications. Where the incineration process incorporates energy recovery, this brings additional benefits to the manufactures’ operations that can be useful for demonstrating ISO 14001 environmental performance criteria. “We’ve seen pharmaceutical manufacturers ask for more sustainable solutions over the last few years,” continued Bains. “They’re not only looking for a secure destruction service, but also one that demonstrates sustainability.

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“As more sector members are adopting the waste hierarchy as a way of being sustainable, they’re looking for suppliers to meet similar sustainability standards. For the pharmaceutical waste that we collect and assign for incineration, the energy recovered is put to good use in the form of electricity for the grid or steam for heating and hot water.” However, as outlined by Bains, the industry has differing approaches to waste disposal depending on whether the product is over the counter (OTC) or prescription only. “There seems to be more caution applied to prescription only products, whereas waste OTC products are not always treated with the same diligence,” he said. “In reality, all products containing active pharmaceutical compounds, both OTC and prescription, require secure destruction via hightemperature incineration.” To conclude, an undeviating, secure destruction process that deals with all and not selective pharmaceutical waste is the only way to safeguard against the dangerous pitfalls of counterfeiting. REFERENCES: [1] Waste acceptance at landfills, Guidance on waste acceptance procedures and criteria, Environment Agency, November 2010. [2] UK warned it will run out of landfill sites in eight years, Andrew Grice, political editor, The Independent, 8 July 2010. [3] INTERPOL and pharmaceutical industry launch global initiative to combat fake medicines, INTERPOL, 12 March 2013.

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OPINION

Positive thinking Discussing the potential doomsday scenario of a world without antibiotics, Professor Colin Garner, chief executive of Antibiotic Research UK (ANTRUK), says not all is…bleak as efforts are being made to remedy the situation

he serendipitous discovery by Sir Alexander Fleming in 1928 that mould which had accidentally contaminated a bacterial plate of Staphylococcus caused the bacteria to be killed led to a new world of infectious agent treatment. As Fleming himself later said: "When I woke up just after dawn on September 28, 1928, I certainly didn't plan to revolutionise all medicine by discovering the world's first antibiotic, or bacteria killer, but I suppose that was exactly what I did." Who knows what might have happened if this accidental discovery had not been made. Fleming, together with Florey and Chain, received the Nobel Prize for Medicine in 1945 in recognition of their work in discovering penicillin, characterising it chemically and developing manufacturing processes. In Fleming’s Nobel acceptance lecture, he said: “There may be a danger, though, in underdosage. It is not difficult to make microbes resistant to penicillin in the laboratory by exposing them to concentrations not sufficient to kill them, and the same thing has occasionally happened in the body. “The time may come when penicillin can be bought by anyone in the shops. Then there is the danger that the ignorant man may easily underdose himself and by exposing his microbes to non-lethal quantities of the drug make them resistant.” It is remarkable that the world has taken little notice of Fleming’s warnings issued 70 years ago! Since the discovery of penicillin, some 200 further antibiotics have been discovered and marketed. The golden age of antibiotic development however is behind us. No new antibiotics with a novel mechanism of action have been found in the last 20 or 30 years. The antibiotic void has been compounded by many of the big pharmaceutical companies closing down their bacterial anti-infective programmes citing the lack of return on investment.

The lack of new antibiotics however is not solely down to a lack of investment. Billions of pounds have been spent by pharma on attempting to discover new antibiotics without success. Bacteria are very smart at adapting to antibiotic exposure and will inevitably develop resistance mechanisms. Resistance frequency to penicillin for example is as high a 1 per 108. Also, most antibiotics will work only on growing bacteria and yet in any infection there is a sub-group of bacteria called persisters, which are resistant to antibiotics’ killing effects. Undoubtedly there is still a huge knowledge gap of bacterial metabolic pathways and how these can be up- or down-regulated to lead to bacterial cell death. It is estimated that 700,000 people die each year from antibiotic resistant infections. There is a direct correlation between antibiotic misuse and antibiotic resistant morbidity or mortality. In Europe, 25,000 people die each year from antibiotic resistant infections, with a similar number in the US. It was reported recently that in any one year, five out of six Americans are prescribed a course of antibiotics, roughly double the frequency of the Swedes. The problem of antibiotic resistance has now started to permeate the highest levels of government. The WHO, the US president, the UK Prime Minister and the European Union have all highlighted the problem. David Cameron has asked well-known economist Jim O’Neill to chair The Antimicrobial Review Commission and come up with recommendations by 2016 of how the antibiotic discovery gap might be tackled. As of June 2015, O’Neill’s Commission have published three interim reports exploring different aspects of the antibiotic resistance problem. Some of the statistics they have come up with are truly frightening. Terms such as Doomsday scenario, preantibiotic era, death of medicine as currently practiced are just some of the terms being used to describe the current situation.

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However, not all is as bleak as the situation described. Many small pharma and biotech companies are actively researching to find new antibiotics. The US FDA approved four new systemic antibiotics in 2015, the highest number in the last 10 years. One of these drugs, Zerbaxa (ceftolozane and tazobactam), is a cephalosporin together with a -lactamase inhibitor for the treatment of systemic Gram-ve bacterial infections.

“

The time may come when penicillin can be bought by anyone in the shops.

This is where ANTRUK comes into the picture. ANTRUK was formed in 2014 by an expert group of scientists and clinicians, all with a research interest in antibiotic resistance and all frustrated at the low profile and lack of funding for antibiotic resistance research in academia and the pharmaceutical sector. The charity’s goal is to bring one new antibiotic therapy to market by 2020, with subsequent introductions in the following decades. To achieve this, the Charity needs to raise up to £30 million over the next five years. In the context of drug development, this is a very small sum — typical drug development costs are in the £100s millions and take 10–15 years. ANTRUK hopes to achieve its goal by finding antibiotic resistance breakers (ARBs) from existing therapies drawn from any drug currently used to treat any disease. It is estimated that there are between 1,000–4,000 drugs in the pharmacopoeia library and all these will need to be screened.

”

Gram-ve bacteria are the Charity’s target since 1) these account for around 50% of hospital acquired infections 2) owing to their cell wall, these bacteria are the most intractable to antibiotic treatment and 3) antibiotic resistance in Gram-ve is increasing at an alarming rate. One attraction of a not-for-profit such as ANTRUK is that it can carry out research that may not be undertaken by the pharma sector since it is not essential to make a return on investment nor is it necessary to patent any discoveries. In addition, as ARBs will be found from currently marketed drugs, pre-clinical and clinical safety testing should be much reduced as for some of these drugs there will have been millions of patients exposed to therapeutic doses over many years. To meet ANTRUK’s goals, we require funds. The Charity is currently conducting a fund-raising drive to raise £100,000 to start its scientific programmes. Anyone who wishes to assist us can donate through our website www.antibioticresearch.org.uk. We need your help to raise the profile of antibiotic resistance and to ensure our children and grandchildren can have the same medical treatments that we enjoy today.

“

It is estimated that 700,000 people die each year from antibiotic resistant infections. There is a direct correlation between antibiotic misuse and antibiotic resistant morbidity or mortality.

”

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Reaping the benefits Several major cancer centres have endorsed the Parsortix machine

ANGLE’s Andrew Newland talks to EPM about the high level of interest from across the globe in the company’s cell separation technology, which captures cancer cells circulating in the blood — even if they are as few as one in one billion — and harvests those cells for analysis. Q: How does your CTCs (circulating tumour cells) system differ from those offered by competitors?

OPINION

A: The Parsortix system harvests CTCs from patient blood without the use of antibodybased capture processes. As a result, it captures all types of CTCs including the mesenchymal CTCs involved in metastasis that are missed by traditional systems. The Parsortix system provides high purity CTCs with low levels of residual white blood cells and the target cells can be easily harvested for analysis using existing analytical techniques.

Q: This year alone, the Parsortix has been granted Chinese and Australian patents, as well as received endorsement from several major cancer centres, what does this mean for the company and product moving forward? A: We already have two granted US patents and we have patent applications pending worldwide. The grant of these patents in China and Australia extends our protection over the Parsortix separation technology into major new markets. There is strong and growing interest in both China and Australia for liquid biopsies, and we anticipate that following Europe and the US, these will be important markets for Parsortix.

Q: A key application is personalised cancer care, would you explain how the system will assist pharmaceutical companies in delivering medicines that deviate from the ‘one size fits all’ approach? A: In order to deliver on personalised medicine, having access to patient material such as CTCs that is relatively easy to collect and analyse is critical. The beauty of the Parsortix system is that we provide pharmaceutical companies and physicians’ access to these cells from a simple blood test. The liquid biopsy is non-invasive and may be easily repeated throughout the patient’s treatment, enabling targeted therapy.

Q: Clinical trials is the next hurdle, are there collaborations in the pipeline? A: Yes, as an example we are collaborating with the Medical University of Vienna on a clinical study to use the Parsortix System to triage women having surgery to remove abnormal pelvic masses into those with a high risk of ovarian cancer and those with benign growths. There are 200,000 women a year in the US alone having such operations. Knowing in advance which ones are at risk from ovarian cancer will dramatically improve the results of their treatment whilst at the same time reducing healthcare costs by targeting specialist resources only where they are needed.

Q: When do you anticipate the Parsortix will be commercially available? A: The Parsortix system is already commercially available for research use. It is CE Marked for clinical use in Europe and we are in the process with the FDA in the US. The ﬁrst clinical applications are expected in about 18 months.

Q: ANGLE has stated that the Parsortix may potentially be used for the detection of other cell types besides cancer, can you elaborate? A: The Parsortix system has the potential to harvest a range of clinically relevant cells from patient blood. As well as cancer patient care, another opportunity is in noninvasive prenatal diagnosis through the analysis of foetal cells harvested from the mother’s blood.

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2015

NEC, Birmingham 4 & 5 November 2015 Discovering innovation at the heart of the laboratory industries

NOW

Lab Innovations 2015 offers you the chance to keep up-to-date with the industry and provides the perfect opportunity to source the latest innovative products and services in the market today. Combined with free to attend seminars and excellent networking opportunities â&#x20AC;&#x201C; this must attend event should be in your calendar. FREE registration now open at www.lab-innovations.com

Organised by

10/07/2015 16:15:59

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REGULATORY AFFAIRS

Benefit-risk Professor Sam Salek, School of Medical and Life Sciences, University of Hertfordshire, calls for a universal framework to speed up the disjointed decision-making process around the commissioning of new drugs

The regulation of medicines is essentially conducted to fulfil the criteria of quality, safety and efficacy. As patients are not equipped to make a scientific assessment, regulators play a crucial role in controlling access to safe and effective medicines. Key elements highlighted by the World Health Organisation (WHO) for effective regulation of medicines include strong cooperation and collaboration between stakeholders, transparency and accountability. The latter is deemed critical for communication of the basis of decisions and building public confidence. Despite this, there are many problems with the current regulatory system, meaning that a huge gap exists between countries when it comes to patients accessing new, potentially life-saving medicines. The review of medicines by regulatory agencies is largely based on the submission of clinical data collected from clinical trials phases I to IV. Assessment of the clinical efficacy of a medicine is supported by studies designed to provide a reliable conclusion through the scientific investigation of suitable endpoints, which it is expected would be translated to meaningful benefits to the patients. However, owing to practical reasons â&#x20AC;&#x201D; namely time restrictions â&#x20AC;&#x201D; these measured endpoints are often surrogates of the actual clinical benefits. For example, parameters like blood pressure, cholesterol levels or microbial eradication may not actually translate to reduced cardiovascular events or a faster recovery from an infection. To establish the utility of a medicine, trials are required to produce clinical endpoints that could directly benefit a patient, such as overall survival, reduction in hospital stay or an improved quality of life from a chronic debilitating disease. Indeed, the definition of a benefit may differ among physicians, patients and between diseases. This may be owing to differences in severity of the disease itself and the subjective perception of the expectations arising from the treatment. Moreover, a benefit should also take into account the trade-off incurred from the potential adverse effects of the treatment.

As a result, a proven clinical efficacy in a study may not always translate into a benefit for the patient. In the assessment of risk or harm, safety data is collected alongside clinical studies that are primarily designed for the purpose of proving clinical efficacy. Given the limitations and uncertainties in confirming the individual benefits and risks to patients, it is challenging to prove the likely safety outcomes for a patient. The traditional method of assessing efficacy and safety separately cannot be logically collated to provide a balanced view. It can be assumed that agencies go through much deliberation on the trade-offs between the benefits and risks, but these are generally not documented or made known to the public. It has therefore been emphasised by the major regulatory agencies that qualitative evaluation and expert judgment should not be replaced by quantitative benefit-risk assessment. Instead they recommended that a model for benefit-risk assessment should be structured, of a qualitative approach and be able to describe explicitly the importance of benefits and risks in the context of the decision. Though stakeholders acknowledge that a universal framework would provide a structure and consistency in decision-making, their efforts in achieving this have largely been independent. There is no common framework, which as a result compromises the consistency of the assessment of benefits and risks and decision-making. The lack of such a system could in turn result in inconsistency in approval of new medicines, making them available to patients in some parts of the worlds and denying them in others. There is now a need to identify a common framework that can be used by both regulatory agencies and pharmaceutical companies to improve communication to stakeholders and overcome the difficulty faced by agencies and companies when it comes to explaining the outcomes of the assessment.

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OPINION

Itâ&#x20AC;&#x2122;s good to talk What are your words of wisdom for overcoming tablet design issues? Steve Osborn, I Holland A high-quality tablet tooling manufacturer will always involve their expert tablet designers as early in the process as possible. These specialists will ensure that tablet designs are not only unique and visually appealing, but are also robust and easily produced in a highly demanding tablet manufacturing environment. Making just a few simple changes to a tablet can stop future problems from picking and sticking to counterfeit issues, and your brand and productivity can be enhanced through professional tablet design. It is important to remember that punches and dies are the most critical interface with your end product, the tablet.

Rich Kirk, Elizabeth Carbide Die Co. Recently a customer complained that powder was adhering to upper and lower punch faces, even though their tooling was coated on both cups. There were no visible signs of abrasion or corrosion, and the formulation properties were good. I find customers and tooling suppliers often add coatings prior to considering all the relevant factors. The problem was primarily related to compression dynamics across the punch faces, which could be solved by reconsidering the tablet geometry. Formulations vary in their ability to be compressed. When compression limits as related to cup height are exceeded, it may cause low surface density at the tabletâ&#x20AC;&#x2122;s cup apex. In this case, the cup geometry had too much volume and consequently tablet band thickness was too narrow. A narrow band can slow air dissipation during compression. After making the desired tablet geometry adjustments, a better balance between cup height and band thickness resulted in no more powder sticking, increased cup force rating and lower cost tooling than the original coated solution. Customer productivity is much greater than before.

Dale Natoli, Natoli Engineering Company When a tablet is well designed, it can be easily produced; reducing operating costs and eliminating wasted troubleshooting time. This is best achieved through communication early in the product development process, which allows the tablet design to be modified for success in the marketplace as well as in production. Consider designing your tablet to complement the characteristics of the powder. Key departments that should be included in the development of a new product: marketing, packaging, product development, research development, tablet compression and technical support. With good communication regarding tablet design, you eliminate many possibilities of failure and ensure an ontime launch.

Fabriano Ferrini, IMA Active Capping and picking are just two of the major problems associated with tablet design. Capping often happens when the tablet is deep concave and the air cannot escape from the granules. The design of the tablet should be reviewed making the tablet normal concave. Picking is a phenomenon where product sticks in the embossing of the punch tip due to the sharp corners on engraving and powder builds up. The design of the embossing should be reviewed to foresee engraving blended land.

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COVER STORY

Future proofing What requirements need to be met by a tablet testing system to guarantee a successful product release? Is it dependable upon the testing system’s quality, speed, technology, flexibility or safety? Kraemer and Ischi explain…

n truth, it comes down to a combination of all of these aspects. Today there are more challenges than ever before as the pharmaceutical industry endeavours to make products safer by guaranteeing that they are of the highest quality, protect operators by ensuring safety in the production environment and save time and money through the use of flexible systems that speed up release times.

The current industry buzzwords are ‘continuous production’. Sure, it sounds promising and somehow infinite, but what does the industry need to make it happen? Kraemer Elektronik and Charles Ischi are complementing the whole pharmaceutical development and manufacturing process with a small but very important contribution — quality control of tablets and capsules.

Modularity and flexibility There is an approach to design that divides a particular system into smaller parts, so-called modules that can be used in various systems but also made independently. This specific approach is called modular design or modularity in design. A standard modular system can be identified by the following characteristics: functional sub-division into separate, scalable and reusable parts; well-defined modular interfaces; and usage of industry standards for interfaces. Modular design offers exclusion and augmentation (meaning that a new solution is added by simply plugging in a new module), along with flexibility in design and tangible cost reduction owing to shorter learning times and less customisation. Numerous examples of modular systems surround us in our everyday life. This modularity is an attempt to combine the benefits of customisation with those of standardisation. The laboratory testing devices in the P-Series are designed to offer the latest technology, space-saving design and maximum flexibility. The basic devices, models P2-P5, can be tailored to the operators needs at any time thanks to the 'Plug and Play' extension module. This also allows for the upgrading of the semi-automatic basic devices to a fully-automatic testing system at any time. The P5 version tests all five parameters: hardness, weight, thickness, length and width.

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Flexible gains: Semi-automatic basic devices in the P-Series can be upgraded to a fully-automatic testing system

PAT testing and uniformity checking Nowadays, batches easily reach sizes of >1,000,000 tablets. However, only 30 tablets are used for content uniformity (CU) release testing. This same assay of samples is typically checked for other parameters such as weight, hardness, thickness and diameter. These huge batch sizes and the trend for the change to continuous production require rapid and accurate analysis methods such as the well-known parameter tester Universal Test System (UTS) from Kraemer Elektronik and the rapid NIR measurement device VisioNIR LS for CU from visiotec. The UTS-Extended with integrated VisioNIR LS technology can check for these physical-chemical characteristics. In some cases, the thickness or the bizarre shape of the tablets does not allow the transmission measurement. The solution is the possibility to switch via a multiplexer from transmission to reflection mode to enable the user to measure each available tablet on the market. For detailed homogeneity inspection requirements, the tablet can be area-scanned in reflection mode. The resulting plot is an image of the tablet showing the active pharmaceutical ingredient (API) content distribution in the tablet. On the other hand, the mean content of this multi-spot measurement can be used for an overall statement of the API content of the tablet. From a quality point of view, the RAS measurement provides more solid results. As opposed to the required 30 samples, the UTS-Extended can increase the sampling size up to 240 samples per hour. The system can be run at-line configuration for automated tablet feeding from a connected tablet press or as a standalone system in production or the laboratory. The reliable trend monitoring visualises the CU prediction value of each sampled tablet. Outliers can be safely identified. The UTS-Extended is dedicated to real time release (RTR).

hazardous

moderately hazardous

low hazard

OEB Occupational Exposure Band

The pharmaceutical industry is still the driver of new and improved containment solutions that provide better protection of operators and better cleaning to avoid cross contamination of different products and because of these requirements, we had various requests from customers to find a more cost-efficient solution.

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re Lim

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P AD DE E Per

Operator and environment protection

Containment Classification

Keeping up: The UTS-Extended can check the CU of 240 sample tablets per hour, a much needed capability as batch sizes typically reach >1,000,000

Containment manufacturing operating costs can approach hundreds of thousands to millions of euros and a major contributing factor is the time taken to change between products and cleaning. The most up-to-date containment strategies merge the production process equipment with containment to keep the contaminated space as small as possible. The UTS IP65i system is an addition to washable tablet presses for wash-in-place (WIP) or wash-off-line (WOL) applications for processing medium and highly potent products up to OEB (occupational exposure band) level 5. As an addition to the existing dust-proof and easy-to-clean testing systems UTS4.1-S10 and UTS IP LR, the UTS IP65i is claimed to be the first fully washable, universal testing system. The UTS IP65i tests the physical parameters of tablets; their weight, thickness, hardness and diameter.

Process integration: The UTS IP65i is a hermetically sealed and fully washable automatic testing system

10-year forecast According to Richard Denk, chair of the ISPE Containment Group, containment in 2025 will see a lot of changes in the design and implementation as well as better integration of current process technologies. The three focal areas for containment over the next 10 years will be process integrated containment, disposables and cleaning. Process integrated containment calls for a better understanding between the process expert and containment expert. Containment implemented in the process instead of adapted to the process will be one of the biggest changes the pharmaceutical industry has had to accommodate. The aforementioned UTS IP65i is a good example of a step in this direction. A number of other containment integration solutions can already be found in the packaging industry.

Cleaning is an equally important consideration. It is currently a huge challenge in multi-purpose facilities and the situation is unfortunately predicted to worsen with the EMA (European Medicines Agency) having published new regulations. Containment is a very complex interaction between process, room, containment technologies, validation, cleaning, waste and operators, so much so that it called for the ISPE Containment Expert Group’s formation in 2010. The group has just announced the impending launch of its Containment Manual, scheduled for November this year, offering comprehensive guidance on the containment lifecycle, from start to finish.

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EMERGING MARKETS

Quality first Capsugel’s Steven Facer says prioritisation of quality and regulatory compliance from the start is key to achieving long-term gains for emerging markets

All-rounders: Empty, two-piece hard capsules are suitable for a wide range of pharmaceutical and health and nutrition product formulations

etween 2014 and 2018, pharmaceutical sales in EMEA emerging markets, including Africa, Eastern Europe, the Middle East and Russia, are projected to increase by more than 35 per cent, representing $29 billion in new sales[1]. While this explosive growth represents a significant opportunity for pharmaceutical companies based in these markets, it also presents new challenges. After years of importing medicines, the local pharmaceutical industry is growing in many emerging markets, fueled by local entrepreneurs and the opportunity to develop an independent and local drug supply. As the nascent industry develops, it is confronted with an evolving regulatory environment that is quickly adopting stricter and more stringent criteria. International developers and manufacturers of dosage forms such as capsules, with established roots in Western Europe and the US, are well positioned to help pharmaceutical companies in emerging markets with their local business needs. First, international dosage form developers and manufacturers have a business model that prioritises quality and regulatory compliance. These companies allocate resources to quality management that are integral to their offering and cannot be minimised or reallocated. The investment in developing and manufacturing quality dosage forms is a baseline for doing business in the pharmaceutical industry. This is an approach that the industry in emerging markets is striving to embrace more and more. This commitment to maintaining the highest quality standard requires recognition that investing in quality can have a much more positive impact on margins, reputation and other factors than the short-term gains achieved by offering lesser quality products at lower costs.

By investing in quality from the start, these manufacturers are able to more often avoid costly recalls or regulatory fines, among other issues. Second, dosage form developers and manufacturers based in developed markets maintain the highest level of quality manufacturing processes and standards. These companies place quality at the core of all of their management and operational processes. They also pour significant resources into product quality systems, from the earliest stages of product development through the manufacturing process. This includes the creation and implementation of quality by design (QbD) processes and good manufacturing practices (GMPs) to help maintain quality and realise efficiencies throughout product development. At Capsugel, we have adopted a quality risk management approach, centred on traceability, safety and integrity throughout the supply chain, which helps to ensure compliancy with industry standards in all markets. Our European sites have received EXCiPACT certification, an independent validation that Capsugel maintains excipient GMPs and complies with European regulations in manufacturing empty two-piece hard capsules. Third, international dosage form developers and manufacturers have decades of experience collaborating with large pharmaceutical organisations in the development of their products. Based on this expertise, these companies can assist organisations in emerging markets throughout the product lifecycle, from fast track development support through to a customised supply chain programme for commercial drugs. Also, these companies can support innovation with customised capsule design or formulation using, for example, bioenhancement technologies.

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The dosage form specialist of choice should be able to provide: • Commercial team support that understands local business practices, so that business is conducted efficiently and seamlessly. • Scientific and product development support that address questions related to dosage form development and scale up. • A full array of supply chain programme services to ensure optimal delivery times. • A readily available technical service team that helps customers develop and implement a flawless manufacturing process. • Regulatory support that tracks and analyses the latest global and local regulations and stays in close contact with authorities across markets, so customers can anticipate and adapt to any regulatory change with minimal impact to their business. • Market development specialists who build and leverage their relationships with local players for insight on global industry trends and best practices, which can translate into new business for customers. As both business opportunities and regulatory regulations in emerging markets continue to evolve, local pharmaceutical companies need global dosage form solution providers as partners with the commitment, locally accessible knowledge and experience to put quality and compliance first and fully optimise their growth opportunities to compete within the local and global pharmaceutical market.

Reference: [1] IMS Market Prognosis 2013–2018.

EMERGING MARKETS

Network connection Dr. Mike Schäfers, West Pharmaceutical Services, stresses the importance of local insight when establishing a presence in new growth markets Emerging markets have played an increasingly important role in global pharmaceutical business strategies for the past decade. For many leading companies in the industry — ranging from drug manufacturers to packaging and administration systems providers — these markets have already proven to be an important area of growth. Market forecasts predict rapid growth rates for these regions for the coming years, providing significant sales opportunities for the predominantly Western-based pharmaceutical industry. Drug manufacturers’ plans to expand into emerging markets — such as China, India, Brazil, MENA and Eastern Europe — have been executed upon to varying degrees of success. While many pharmaceutical companies have already established sales and manufacturing subsidiaries in these regions of growth, others are less determined and shy away from the immediately apparent hurdles. However, with the global scope of today’s pharmaceutical companies, expansion into newer economies seems almost inevitable. While economies in North America and Europe show moderate demand increases, there is tremendous growth potential in pharmaceutical packaging from emerging markets across the globe. Beyond the sales potential, emerging markets are also experiencing an increase in highly educated talent, which will become an asset to pharmaceutical companies’ research and development strategies in the near future. Furthermore, chronic diseases like diabetes are on the rise across the world and are creating demand for new, innovative therapeutic treatment options. This need is especially prevalent in India and China, which have the highest number of people with diabetes in the world. With greater numbers of patients affected by chronic diseases, pharmaceutical sales for those treatments (and

their corresponding packaging and delivery systems) are expected to rise even further. In order to benefit from the increased demand, it is important for companies to carefully plan and execute their global expansion strategies, otherwise cultural and administrative challenges can potentially lead to frustrating drawbacks. Every emerging market has unique characteristics to be managed — including product and quality requirements, product registration requirements and local competition —among others. Additionally, regulations in emerging markets are changing faster and more unpredictably than in North America and Europe, requiring a high level of specialised experts to ensure compliance. Most emerging markets have, however, one thing in common: the demand for good product quality at an affordable price. With improved patient health and better access in mind, governments are working to make it easier for Western companies to establish a presence in their countries.

decades, we established sales offices in Australia, China and India, created two manufacturing plants in China and, most recently, opened a manufacturing facility in Sri City, India. The key to our successful expansion was the composition of the project teams, which were tasked with locating and establishing our new facilities in Asia. The team for the Sri City plant, for instance, consisted of West’s subject matter experts from India, Singapore, Germany and the US, reflecting the global strength and knowledge of our business. In a global world it is important to transfer knowledge and competence across borders and learn to adapt to local circumstances. The knowledge transfer should not be a one-way street, but instead a two-way dialogue. Now, and in the decades to come, there will be a great deal for Western companies to learn and gain from working both in and with emerging markets.

In order to avoid some of the pitfalls often related to emerging markets, it is essential to establish a network that helps you gain local insights. If possible, work with a local partner that can navigate the business culture of a given country. Also, rather than trying to ramp up business in different countries simultaneously, choose one subsidiary with a short-term plan for further presence in neighbouring countries. The learning curve can be steep, but with the right planning and a willingness to learn, an incremental approach is usually the most beneficial. West established its first Asian manufacturing plant in 1983 in Singapore. From there, we gradually, step-bystep, expanded our network throughout the Asia-Pacific region with the help of local teams. Over the past three

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A perfect world According to Clean Room Construction (CRC), when designing and building cleanrooms for pharmaceutical and other scientific and technological applications, there should be absolutely no room for error

Standout design: Huge cellular graphics fit with the centre’s cell therapy focus

Fast work: The ‘world-beating’ facility was completed within 22 weeks

Introduction Cleanrooms are controlled environments where provisions are made to reduce particulate contamination and control other parameters including temperature, humidity and pressure. This is vital in fields such as pharmaceuticals, biotechnology, aerospace and the life sciences, which involve critical processes in environments that are very sensitive to contamination. Innovative cleanroom solutions play a crucial role in the manufacture and manipulation of pharmaceutical products. The tiniest particles can adversely affect manufacturing processes so even the equipment and furniture inside cleanrooms is designed to generate minimal air contamination.

Challenge Clean Room Construction (CRC) was given the job of principal contractor with responsibility for designing, installing and commissioning a state-of-the-art cleanroom laboratory suite in the new Cell Therapy Catapult centre within Guy’s Hospital in London. The world-famous teaching hospital is part of the Guy’s and St Thomas’ NHS Foundation Trust, which has an annual turnover of £1.2 billion and two million patient contacts. Guy’s is also an acclaimed centre of pioneering medical research and innovation. The Cell Therapy Catapult, which was officially opened last year, is a centre of translational excellence for cell therapy and regenerative medicine. The centre takes products into early clinical trials, providing clinical, technical, manufacturing and regulatory expertise and access to the NHS. It will help develop potentially lifesaving new drugs, taking them through clinical trials and reducing the risk involved, both nationally and globally.

CRC’s project director, Richard Rowe, said the fasttrack project presented a major challenge for everyone involved: “Firstly it was to take place within a live hospital environment on the 12th floor of the 30-storey Tower Wing building at London’s Guy’s Hospital. The whole project had to be planned and executed with minimal disruption to the hospital’s operational capacity. ISG plc was the main contractor for the project, with eXmoor pharma concepts creating the concept in conjunction with the Cell Therapy Catapult and Guy’s and St Thomas’ NHS Foundation Trust.”

Results The Cell Therapy Catapult wanted a facility that connected scientists with the operational staff in a bid to encourage collaboration. The approx. 2,323 m2 area therefore incorporates well-equipped and modular laboratories with open plan office space, breakout areas and meeting rooms. The laboratories are designed to mimic manufacturing suites, enabling the progress of cell therapies from the laboratory scale to commercial scaleready using the pilot process development expertise at the Cell Therapy Catapult. A key design feature is a viewing area between the laboratories and office space, encouraging interaction and visits. The facility comprises entry/exit change rooms, assay development laboratory, large-scale and smallscale process development laboratories, a good manufacturing practice-proving room, cold store and equipment room. A new HVAC system was installed to serve the laboratories and to provide an integrated air conditioning filtration and process extract system to maintain the specified conditions of temperature, pressure, cleanliness, noise, humidity and air change rates.

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Turnkey security and access control and fire detection systems, as well as an environmental monitoring system to monitor, record and display the environmental parameters within the rooms and the Cell Therapy Catapult suite, have been integrated into the cleanroom solution. CRC installed bespoke M&E service pods to service mobile benching, and corridors were also prepared in order to accommodate an eye-catching mural design. The finished facility was completed within 22 weeks and has been described by global companies as ‘world-beating’. Rowe added: “Through science and industry, the Cell Therapy Catapult’s expertise in cell and gene therapies will one day provide better treatments that will ease suffering and improve quality of life while helping to build a global industry that the UK can be proud to be leading.”

Conclusion One year since the facility was officially opened, the Cell Therapy Catapult is in the running for a prestigious S Lab Award. These annual awards recognise excellence in the design, operation and management of laboratories that create improved performance while maintaining and enhancing safety and sustainability. Rowe concluded: “CRC is very proud to have been involved with such a nationally and globally groundbreaking project. The facility is recognised as ‘world-beating’ and will enable science and commerce to collaborate to showcase the face of future medicine. The design and installation of quality cleanrooms as part of such a facility will remain a critical component of converting great science into market-ready products.”

CASE STUDY

CLEANROOMS

Meeting expectations: It pays to inform the client of any shortcomings at the tender stage

Dual approach John Challenger, WH Partnership, emphasises the importance of integrating process plant and cleanrooms for successful pharmaceutical production

The devil is in the detail One of the deeply worrying aspects of modern design for the pharmaceutical industry is how far designers are becoming removed from the reality of construction. As a design and build contractor that employs its own construction teams for both process plant and cleanrooms installation, WH Partnership is often required to tender for the detailed design, supply and construction of facilities based on designs and specifications developed by third parties. We are seeing an increasing number of enquiry documents, which include preliminary design information that is either incorrect or not practical from a constructability point of view. Designs can often include plant and services that cannot physically be installed in the space available, have not been thoroughly planned or ignore the requirements of installation, commissioning, validation and maintenance activities. The causes of such errors include poor quality of training, lack of spatial awareness, inadequate design time, inappropriate experience and poor checking procedures. It is likely that many modern designers have only limited exposure to and experience of practical aspects of manufacturing or 24

construction and therefore, unlike designers of the past, do not bring to the process that essential understanding of how a complex facility is built or operated. Considerable pressure is placed on companies bidding for pharmaceutical projects as they often have incredibly short tender periods. As a result, the contractor then has a choice to make, he either tenders for what is issued to him or he takes the view that he has a duty of care to inform the client of the shortcomings of the information provided. The former approach is a gamble and could well lead to high numbers of variations, claims and potentially costly disputes. Opting for the latter approach and informing clients of any potential issues with the data they provide and then trying to adopt practical and cost-effective solutions makes far more sense, since the time taken to resolve such matters at the early project stages pays massive dividends in the end.

obvious. From small startup enterprises to major international pharmaceutical companies, researchers and manufacturers alike require facilities that will meet the expectations of the regulatory bodies, yet are value for money. Clients also expect facilities to be designed and built in extremely short timescales. Integrating the operation plant, utilities and equipment into a cleanroom is key to meeting client expectations regarding capital and operating costs as well as timescales. This calls for an inside-out approach, starting with the process and treating cleanrooms and any associated building as part of the production plant.

An inside-out design

Few companies combine the full design and construction capabilities for both process plant and cleanrooms in a single organisation. This is surprising since integration of the two essential facets of pharmaceutical production is paramount in the successful outcome of projects for the clean industry sector as a whole.

When the issues of clean or aseptic standards are added to the design mix, the need for thoroughly integrated design and construction becomes

The development of a process-led user requirement brief or specification that fully covers the manufacturing plant and the building is essential to achieving a

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successful project. So often, building designs are developed separately from process plant and often by companies with little true understanding of the operations that are to take place within, which inevitably leads to failures in quality, purchaser disappointment and sometimes dispute.

Design and construction â&#x20AC;&#x201D; an integrated approach It is for the reasons stated above that WH Partnership seeks to persuade clients of the need to fully integrate the design, procurement and construction process as a combined activity. Generally speaking, clients and their operating staff working in manufacturing facilities know what they need but often do not have the time to establish a reliable brief or consider how that brief is to be achieved. The contractorâ&#x20AC;&#x2122;s job is to listen to and interpret what is required, then advise on a range of possible technical and commercial solutions. This proactive approach, when linked to a stage gate project management approach, provides the purchaser with access to, and control of, both design and commercial information at appropriate times throughout the project.

FINAL PRODUCT TESTING

Big investment: An ICP-MS costs around £125,000

Forward planning John Welch, Butterworth Laboratories, urges pharmaceutical manufacturers to prepare sooner rather than later for the impending changes to elemental impurities requirements

Harmonisation of pharmacopoeia methods has a history of making slow progress and it is not surprising that the new instrumental based elemental impurities test has taken time to be implemented. However, the US Pharmacopeia (USP) and European Pharmacopeia (EP) have now set dates for implementation of new monographs of 1st January 2018 and 1st January 2017 respectively. In total, there are 28 elements listed in the various publications. However, companies are required to comply from next for new products. So what do pharmaceutical manufacturers do until then? Put their heads in the sand and wait for their implementation? Or do they take action and try to find ways they can prepare for what’s to come? A key point that many in the industry have overlooked is the fact that the USP implementation will only apply to finished products with monographs. So that means manufacturers of products like toothpaste and talcum powder do not have to take any action, whereas those of prescription and over-the-counter medications need to be prepared for the changes. How have these manufacturers been preparing? Pharmaceutical manufacturers are applying the principles of quality risk management, with the risk assessment being based on scientific knowledge and principles as set out in the ICH Q9 guidance document. This process can be described in four steps: • Identify: Identify known and potential sources of elemental impurities that may be present in the product. • Analyse: Determine the probability of observance of a particular elemental impurity in the product. • Evaluate: Compare the observed or predicted levels of elemental impurities with the established permitted daily exposure (PDE) limits.

can then be used for risk assessment and shared across product ranges.

• Control: Document and implement a control strategy to limit elemental impurities in the product. The data on elemental impurity content for the components of a drug product can be derived from a number of sources. These include data provided by reagent and/or excipient manufacturers or data previously generated by the manufacturer themselves. However, manufacturers have been finding that there is little or no substantive information on the levels of elemental impurities available for making this risk assessment. There are also materials where it will be difficult to obtain consistent data, e.g., plant derived materials or natural products and inorganic minerals, which may be grown or mined in differing parts of the world, where it may not be possible to set a reliable baseline of typical elemental impurities content. Whilst pharmaceutical manufacturers may push excipient suppliers to provide the data, most excipient manufacturers are not manufacturing materials primarily for the pharmaceutical industry and hence there is little incentive for this information to be generated. With this lack of reliable data, some pharmaceutical manufacturers have decided to generate the data themselves for their current product ranges. To assess if any particular product or dosage form gives rise to significant levels of elemental impurities, they are using inductively couples plasma (ICP) generic quantitative screening methods for 30 or so common elements. In other cases, where manufacturers use a limited range of excipients, the approach has been to assess multiple batches of raw materials in the same way. This data

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The three major pharmacopoeias — US, European and Japanese — describe procedures based on analysis by ICP. Whilst they do not rule out alternative techniques such as atomic absorption spectroscopy (AAS), X-ray fluorescence (XRF), ultraviolet spectroscopy (UV) and ion chromatography (IC), the standard method of reference will be ICP. Although there are obvious benefits from the use of modern instrumentation in replacing the wellestablished wet chemistry limit test, manufacturers are faced with a number of considerations before investing in the new technology required. • The capital expenditure; an ICP-OES costing in the region of £50k, plus an ICP-MS at £125k, together with a closed vessel microwave digestion system for £35k. • The cost of installation of the equipment, services and ongoing running costs. • The cost of training of staff in the new technique or, in some instances, the employment of another analyst with the relevant experience to operate the equipment and interpret the data. These costs then have to be weighed against the level of ongoing testing requirements once the risk assessments of each product have been concluded. This has led to many manufacturers looking to outsource this risk assessment work, rather than investing in new equipment. Once the risk assessment has been performed, manufacturers are then faced with the decision of what ongoing testing will be required. Whether this is on the finished products or specific raw material components, specific validated methods will need to be produced for the elements of concern. 25

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Fit for purpose The market release of a pharmaceutical product is achieved by ensuring it has met its product specification, which varies dependent on the type and use of the product, says Wickham Laboratoriesâ&#x20AC;&#x2122; Louise Rigden

Return to nature: The Limulus Amebocyte Lysate test is derived from the blood cells of the horseshoe crab

Expert hands: Louise Rigden heads up the Bacterial Endotoxin & Cytotoxicity section at Wickham Laboratories

Introduction Microbiological testing for most products requires non-sterile specification or total aerobic microbial count (TAMC) and absence of specific pathogens such as Escherichia coli and Salmonella. Parenteral (injectable) products have more stringent testing and are required to be both sterile and bacterial endotoxin free. In this case study, Wickham Laboratories focuses on endotoxin testing. Endotoxins are constituents of the bacterial cell wall of Gramnegative bacteria and are released during the break down of Gramnegative bacterial cell membranes. Quality control measures for parenteral drugs require testing for endotoxins as they can illicit an immune response, resulting in a pyrogenic reaction when they enter the bloodstream. Each drug or medical device has a limit specifying the amount of endotoxin that can be safely present. Endotoxin levels that are higher than that limit are dangerous owing to their pyrogenic response and at higher doses, toxic effects, so it is vital that all drug compounds and medical devices undergo this safety screening.

Wickham Laboratories then proceeded with the gel clot method, which is an endpoint assay giving a positive or negative result at the sensitivity of the lysate used. While this is the most time-consuming method of bacterial endotoxin detection, it is both efficient and extremely sensitive, detecting very low levels of endotoxin with fewer interactions inhibiting the reaction. This method remains the reference method as it produces fewer false-positive and false-negative results.

Results Upon completion of the testing, Wickham Laboratories was pleased to report to the client that bacterial endotoxin levels were well within specification. If endotoxin levels higher than the limit had been found, the standard procedure would be to initiate an investigation to determine whether there were any laboratory errors on Wickham Laboratoriesâ&#x20AC;&#x2122; part that may have contributed to the out of specification result. This investigation would include a review of the entire process, including environmental monitoring, operator interview, testing procedures and materials.

Wickham Laboratories utilises the internationally established pharmacopeial method Limulus Amebocyte Lysate (LAL) test to assess products for bacterial endotoxins. This test is based on an extract from the blood of the horseshoe crab (Limulus polyphemus), which has a primitive immune response clotting mechanism triggered by bacterial endotoxin, which will be present following the break down of the Gramnegative bacterial cell wall.

The most likely cause of a product failure from the presence of bacterial endotoxins is a contamination event during the manufacturing process. Focus on the investigation should start with a close examination of any aqueous processes within production where the Gram-negative bacteria may proliferate. While Wickham Laboratories cannot retest a sample that has failed, the client may choose to send additional samples for testing to determine whether the manufacturing issue is widespread or an isolated incident.

Challenge

Conclusion

Wickham Laboratories was recently approached by a leading pharmaceutical company to carry out endotoxin testing on its product, the finished dose of which was in powdered form. Bacterial endotoxin testing is one of Wickham Laboratoriesâ&#x20AC;&#x2122; specialities and the company was able to quickly allocate personnel to the project.

In order to comply with regulatory requirements and maintain an efficient manufacturing environment, it is important to identify any manufacturing issues at an early stage. Process validation is one way in which companies address the need for a sterile environment, however batch quality control testing such as the type performed on this occasion may still be required.

As this sample was cytotoxic, its preparation required a slightly different handling process and the use of a safety cabinet to ensure the safety of technicians. Usually, a powdered product would be weighed during the preparation stage, but in this instance, the powder was reconstituted within its vial using endotoxin-free LAL reagent water and then diluted down to the 0.5 mg/ml validated concentration. At this time, a method suitability test was conducted to ensure there was no inhibition or enhancement of the test system by the product.

It is also important to note that there are some chemical pyrogens that cannot be detected by the LAL test and some molecules that are incompatible with the test system, thus alternative methods of testing may still be required depending on the product or device. Any uncertainties regarding process validation or testing requirements should be directed to an organisation or consultant with regulatory expertise to ensure that all products and devices are safe and fit for their intended purposes.

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CASE STUDY

FINAL PRODUCT TESTING

CLINICAL TRIALS

Feasibility study Muriel Berthier and Denis McMillan, PAREXEL, discuss the key factors for achieving more reliable feasibility in clinical trials

linical trial complexity is placing a greater emphasis on — and creating a critical need for — study feasibility. A key success factor is ensuring the planning and design is correct from the beginning to avoid re-work and delays, which requires moving away from opinion-based decisions and adopting a more sophisticated data-driven approach. Whilst there is more and more data available to support this approach, the challenge remains in selecting and analysing the right data that can help select the right countries, sites and patients. Feasibility refers to the identification and quantification of risks in clinical trial planning, including: protocol (regulatory, scientific, medical, statistical), country and site, patient, resourcing, quality, financial or contractual. It also involves the assessment of drug supply risk, a critical evaluation factor for investigators. Feasibility is a complex team activity requiring high levels of open collaboration between sponsor, CRO, investigator and patient. As a discipline, it sits within risk management and plays an integral role in the planning and design process, as well as in ensuring reliable delivery. It is a continuum — programme, protocol, country, site and patient recruitment — with a feedback loop to the start of the next project. To be effective, it requires large volumes of data from a wide variety of sources, as well as feasibility-orientated technology platforms.

Data-driven country and site selection Technology platforms combine dynamic and sophisticated analysis of data with best-in-class visualisations to generate key insights to optimise protocols, country placement, site selection and proactive recruitment and contingency plans. Aggregating and mastering data across both in-house and third-party databases produces a more comprehensive and therefore clearer picture of prior performance, current variables and future trends. Informed country placement evaluates a full range of factors, including medical, clinical, financial, regulatory and operations/logistics, which helps reduce risk to acceptable levels. Looking at only one or two factors would create a bias; therefore, technology is required to efficiently analyse and score country suitability and create insightful visualisations. Country-allocation technology enables CROs to be more influential and transparent with recommendations, in turn driving more efficient and effective conversations with the sponsor. 28

Site selection remains an important part of the successful delivery of trials. But just how much do we know about primary investigators (PIs) and investigative sites? With too much siloed data for clinical decision makers to analyse, they end up relying on survey data and an impression of past performance. Technology can help consolidate the information from CTMS, IVR, labs, QA, imaging and thirdparty databases. Automatic analysis and insightful visualisations are essential; however, the lack of unique investigator identifiers makes this a difficult task.

Increased accuracy of recruitment forecasts Self-estimated recruitment numbers have traditionally driven most investigators’ planning decisions while set-up and recruitment timelines are missed more often than not, causing the majority to miss their recruitment target. Access to electronic medical record (EMR) data can help increase the accuracy of investigator estimates. In addition to quantifying the impact of individual inclusion and exclusion criteria on the general population, combining all criteria can create a more comprehensive understanding of the pool of eligible patients for a specific trial. The often-missed consideration, however, is the opinion of the patients. How do they feel about their current treatment? How is their disease impacting their everyday life? How willing are they to participate in a clinical trial and accept all the requirements of the protocol with its advantages and constraints? Whilst information is more widely available to patients, the industry still relies on investigators to comment on patient opinion. Patient feasibility surveys introduce the patient voice and are becoming instrumental in accurately forecasting recruitment rates, as well as in developing the right patient material to drive successful recruitment. As important as it is to identify the risks involved, decision makers need to be appraised of the size of the problem (likelihood of occurrence and the size of the impact). The subsequent operational strategy must then help mitigate the risk and provide prudent contingency to ensure delivery. Industry-leading feasibility is only possible when expertise, experience and technology are closely aligned. Feasibility is, however, part of a continuous risk management process and should not sit in isolation. The combination of scientific and clinical knowledge, along with advanced technological capabilities, all within a single point of accountability is the path towards more reliable feasibility.

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CLINICAL TRIALS

Ultra cool: Biologics usually require cold chain storage, and some require ULT storage

Chain reaction Rachel Griffiths, Biotec Services International, a PCI company, advises on maximising clinical supply chain efficiency for biologics

he supply chain requirements of a biological product are not significantly different to those of a non-biological product; deliver the drug safely and on time, to the right location, at the right temperature and at the lowest cost. Expertise is essential in achieving these requirements.

trial, those responsible obtain all the details of the IMP to import into all countries where the trial is taking place and establish timelines for obtaining import licenses. This information may influence the decision to perform the trial in a country and should be considered alongside the regulatory authority requirements.

Biologics are a preparation, such as a drug, a vaccine or an antitoxin, which is synthesised from living organisms or their products and used as a diagnostic, preventive or therapeutic agent. These products usually require cold chain storage, packing and distribution; some may require ultra low temperature (ULT) storage and logistics. Maintenance of the product at the correct temperature is critical and must be managed throughout the supply chain.

The transportation method is also important when shipping biological products. Most require cold chain and are shipped by air, as the time product temperature can be maintained during transit is limited. The shipping systems must maintain the required temperature for the expected duration of the flight, customs clearance and delivery. In most cases, specialist couriers are used and have the capability to hold the material at 2â&#x20AC;&#x201C;8Â°C or top up dry ice at the airports. These specialist shipments can be costly; however, the risk of losing a shipment owing to a temperature excursion far outweighs these costs, as most biologics are far more expensive than conventional drugs.

The supply chain for low-temperature biological investigational medicinal products (IMPs) can be considered in three phases.

The importance of forward planning In the EU, IMPs for use in clinical trials must be stored and distributed from a licensed facility in compliance with good manufacturing practice (GMP) and good distribution practice (GDP). In the majority of clinical trials, the IMP is not manufactured in the same country as the qualified person (QP) certification and requires importation. For biological products, the information required to obtain import licenses can be lengthy. In the UK, the Department for Food, Environment and Rural Affairs (DEFRA) issues licences for the import of any animal or human derived product. Issues occur if the product contains materials not covered under general licences, as individual product applications must be made. It is vital at the initial set up of a clinical

Mapping shipping routes and storage depots When shipping to countries outside of the EU, several factors may require the use of an incountry depot. These factors include import license requirements (an import license is required for each shipment) and transportation time. Additionally, for some trials, the time between patients being screened to receiving their first dose can be short, customs processes make it impossible to meet these timelines and depots are essential. The supply route should be considered on an individual product and country basis. The product, cost and availability as well as site storage capacity and recruitment rates must be

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addressed to ensure a secure and cost-effective route that meets the trial demands. Cold chain packaging for trial material logistics The selection and preparation of shippers is critical for temperature-controlled products. The shipper must be qualified to last the duration of the shipment and the courier should have the facilities to top up dry ice or hold refrigerated product. Even when shippers are qualified, a temperature monitor must be included to ensure the product remains within temperature. Temperature monitors are available with a USB connection, allowing immediate review of the data. These monitors are usually single use, which also reduces cost. Whilst high-quality shippers and monitors may add additional cost, using them reduces the risk of temperature excursion. These phases look at the supply chain for a product where final packaging is already defined. Greater efficiencies could be made if an integrated design process is introduced in conjunction with the supply chain. By setting up an integrated design process in which the whole supply chain is considered at the design or proposal stage, a streamlined, well-documented and efficient strategy for each trial and product can be developed that is capable of delivering product on time, at temperature and cost effectively. Selecting an experienced service provider to work with early in the study development phase ensures frustrations common to shipping cold and ultra-cold chain products can be avoided. This allows clients to focus their energies on the successful delivery of their lifesaving therapies.

ORAL SOLID DOSAGE

Cover star Charlie Cunningham, Colorcon, says continuous coating by far outperforms traditional batch coating and is fast catching on with pharmaceutical customers

ontinuous coating is rapidly becoming more than a niche technology for high volume products. In March 2015, at the 50th American Association of Pharmaceutical Scientists (AAPS) Arden Conference, focus was set on the continuous manufacture of tablets, capsules and other oral solid dosage (OSD) forms. Speakers from many of the largest global pharmaceutical companies as well as the US Food and Drug Administration discussed the benefits and challenges of continuous manufacturing and initiatives supporting this bold shift in the manufacture of OSD forms. Aligned with this trend, Colorcon has seen a dramatic increase in customer requests for film coating support in continuous coating technologies. Historically, a handful of dietary supplement (DS) and over-the-counter (OTC) manufacturers in the US have utilised continuous coating. We are now helping customers develop, optimise and implement continuous coating processes not only for DS but also for pharmaceutical applications in the US, Europe and Asia. There is rapid advancement in the equipment used for continuous film coating, with technology employing new mechanisms to eliminate start-up and shut-down product losses. The scale of equipment to meet product capacity demands is variable, and some manufacturers have developed novel approaches to coating in both continuous and semi-continuous modes.

Proven results: Superior uniformity and higher throughput were achieved using the Thomas Engineering FLEX CTC continuous tablet coater

provide significantly improved process efficiency and enhanced moisture protection compared with traditional hypromellose-based coating systems. A benefit of new low viscosity coating formulations is the ability to apply at significantly higher solids concentrations compared with traditional coatings, resulting in shorter process times. Other benefits resulting from low viscosity film coating systems may include more efficient droplet atomisation, a smoother finish to coated tablet surfaces and fewer process related issues such as spray gun nozzle blockages. In order to realise the full advantages of these low viscosity coating formulations, the limitations of traditional batch-oriented coating pans must be addressed.

Less is more: Increasing tablet bed depth with pan diameter decreases turnover of tablets through the spray zone and may induce tablet defects

While there is plenty of information on traditional batch coating technology, published over the past decades, new information and understanding is needed to support this evolution in continuous coating technology. Colorcon continues to work with several leading equipment manufacturers, including Thomas Engineering, Oâ&#x20AC;&#x2122;Hara Technologies, DRIAM and GEA, to progress a deeper understanding of the processes and how optimisation can provide the highest product quality and efficiency.

In traditional batch coating, pilot-scale batches regularly run in a coating pan of 15 to 24 inches in diameter, and production-scale pans often extend to 60 inches in diameter or more. This increase in pan diameter greatly affects the tablet bed depth and the difference is significant. By increasing tablet bed depth in scale-up, the turnover of tablets through the spray zone is dramatically decreased, and the weight of the bed increases to a point that may induce tablet defects not previously seen in smaller scale trials.

Film coating formulation technology is also advancing with the utilisation of lower viscosity polymers that

On the other hand, rather than increasing pan diameter, continuous coaters have maintained the diameter

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of a typical pilot-scale coating pan and elongated it to a length as long as 15 ft. This produces a tablet bed depth that is more consistent with laboratory or pilot scale batch coating pans. A 24-inch continuous coater is able to produce up to 1,000 kg/hr of coated tablets compared with 300 kg of tablets over two hours in a 60inch batch coater. The elongated spray zone and shallow bed depth of the continuous coater ensure that the tablets are presented with high frequency to the spray zone. This results in the faster development of colour uniformity, reduced process times and shorter exposure of the tablets to the adverse thermal and mechanical stresses of the coating process. However, individual tablet movement and transit times through these elongated pans is less understood, as well as coating variability related to any potential variation in forward movement. At the aforementioned AAPS Arden Conference, Colorcon presented a study focused on the effect of tablet residence time and uniformity of tablet progression on coated tablet weight variation in a Thomas Engineering FLEX CTC continuous tablet coater. The coating uniformity of a typical production scale batch coating process was also evaluated for comparison with the continuous coating process. Quantification of coating variability and tablet movement were studied to gain further understanding of this type of coating equipment. Tablets progressed through the continuous process with relatively small variability in transit times and exhibited superior uniformity compared with tablets coated in a traditional batch coater. Higher tablet throughput rates were also achieved utilising low viscosity coating systems, enabling application at >20% solids concentration. Colorcon continues to work with the industry evaluating a variety of continuous and semi-continuous coating machines, and further developing coating formulations to provide greater productivity benefits, specifically suited for these applications. 31

ORAL SOLID DOSAGE

Train to Gain Jörg Gierds, Fette Compacting, says that training of tablet press operators will help manufacturers stay on the right side of the US Food and Drug Administration (FDA)

he number of warning letters sent by the FDA increased from around 500 in 2009 to more than 8,500 in 2014. According to the organisation, the companies’ processes and manufacturing environments were not complying with good manufacturing practices (GMPs). According to an assessment conducted in 2012 (published in International Pharmaceutical Quality (IPQ) magazine, March 2012; Fred Rowley), there are two reasons why out-ofspecification tablets are placed on the market: 1/the machine operator and 2/ the tablet press. To understand the causes, manufacturers need to focus on answers to problems that can be avoided by means of good operator guidance and the technologies used in tablet machinery. To offer a couple of examples, even the best machine will fail if the operator does not regularly calibrate his scales in the external test station (one reason indicated in the assessment), and it will also fail if the operator sets the cycle rates higher than the SOP guidelines in order to increase tablet output.

The principles and concept of tablet production

Operating the tablet press

Machine operators and those responsible for the production processes have a good understanding of the manufacturing process and its tablet presses. Nevertheless, there are indicators for some serious misunderstandings on the part of the operator.

You need a driver's licence to drive a car. Likewise, verifiable and certified qualification of operators is evidence of the quality of the manufacturing enterprise as well as the quality of the respective production process. GMP defines the personnel qualification very precisely: ‘Each person engaged in the manufacture, processing, packing or storage of a drug product shall have education, training and experience or a combination thereof to enable that person to perform assigned functions.’

Like many other machines deployed in oral solid dosage (OSD) production, tablet presses are complex machines featuring a variety of parameters, some of which are of particular relevance, such as tablet weight. Modern machines feature technologies and constructive elements that prevent heavier or lighter tablets from reaching the good-channel. An operator who understands the machine and the process is generally more confident in how he handles the machine, for example, when selecting the setting parameters. It is however recommendable that manufacturers offer their operators and process managers qualification in the form of certified training by the machine manufacturer.

Critical benefit: Modern tablet presses such as Fette Compacting’s FE55 take additional parameters into consideration before approving the good channel

Fortunately, machine manufacturers provide integrated protection features. Modern tablet presses are safeguarded against accidental or intentional maloperation. Password-protected parameter entries through to the foureyes principle ensure protection against unauthorised machinery settings or manipulation. All machine parameters, operating conditions, operator entries, modifications and statistics are saved in databases in line with GMP, are tamper-proof and can be retrieved at any time, as well as being trackable and transparent. Accordingly trained personnel will ensure that these integrated protection features will work properly.

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The role of the material to be pressed The mixing and granulation processes are followed directly by the flowing of the product into the tablet press. Millions of tablets are pressed by high-performance rotary presses during the production stage and at a speed of more than 600,000 tablets per hour or more than 180 tablets per second. Problematic product characteristics and poor flow properties can cause considerable faults. Experienced tablet press manufacturers have a technical laboratory or pilot plant for testing the tablet material at both laboratory- and production-scale. These tablet specialists possess extensive practical knowledge covering thousands of different materials and product mixtures. They are well versed with regard to interaction between the product and machine. Tests at laboratory- and production-scale are offered through to production batches involving millions of tablets. This bodes well for subsequent major series, even before investments are made in machinery, which in turn ensures that good tablets are produced, even after the validation process and the restrictions associated with it. If the material is problematic in terms of handling â&#x20AC;&#x201D; for example, with regards to its flow properties and problems relating to stickiness or compacting â&#x20AC;&#x201D; the experts are able to find a solution.

The influence of the tablet press One critical factor is the machine start-up phase after changeover, cleaning or a machine stop. Older machines only count a defined number of initial tablets before approving the good-channel. More recent machines such as Fette Compactingâ&#x20AC;&#x2122;s FE55 (Figure 1) now also take other parameters into consideration; the good-channel is not approved until the press punches have returned to their final position and the compression force levels have been re-established in the set range.

control of the following test parameters: tablet weight, tablet hardness, tablet diameter, tablet thickness and active substance analysis. At adjustable intervals, tablets are automatically fed into the external test system where they are measured in a fully automatic process. The tablet weight and other tablet parameters measured are reported back to the tablet press via data interfaces. Of course, a tablet found to be faulty must be rejected. While older machines still use mechanical sorting guides, which are susceptible to faults as well as being slow, rejection by means of compressed air nozzles has asserted itself in newer presses. A clever airflow represented by air curtains in front of and inside the ejection channels ensures that the tablets are guided accordingly. Additionally, a good software product offering comprehensible diagnoses provides operators with support via the graphic user interface during operation and in the event of a fault (Figure 2).

Summary Manufacturers and their technologies play an essential role in tablet production. The innovative technologies deployed in machinery today are milestones that continue to evolve in response to demands for improvement in tablet manufacturing. A reliable machine manufacturer will be able to provide the user with support in each of the areas highlighted above. Such support should integrate operator training together with tests with products in the manufacturer's own technical laboratory and pilot plant where experience gleaned over many decades is focused and employees are the true experts.

The filling system plays a more-or-less critical role when it comes to tablet quality depending on the product (powder) and the filling hole (tablet dimensions and shape). Modern filling systems in line with the best practice principle for correct filling and tablet weight are based on three adjustment and control options. First of all, the turret speed and filling speed (adjusting the filling wheel speed) can be optimised for a good tablet. Second, the compression force monitoring checks the correct filling during the pressing process. Deviations are detected causing the dosage (filling volume) to be adjusted. Depending on the degree of deviation or frequency established, the machine may deem that the tablet is bad and eject it and/or the machine stops. As a third option, the statistic tablet weight monitoring by the tablet test system supplies the tablet weight with a resolution of 1/1000 grams. The tablet weight established also leads to direct or indirect adjustment of the dosage (filling). Another important factor is compression force, which is applied to the punches via the compression rollers. It correlates with the tablet mass (tablet weight). State-of-the-art technology enables the monitoring of a single tablet by measuring the force in the compression stations. But only force measured in the mechanical power flow path supplies the requisite high measuring signal quality. Only high measurement resolution of this force curve and detection of the peak force in these signals represents reliable correlation to the tablet weight. Automatic tablet test systems such as Checkmaster or AutoTest 4 are usually positioned beside the machine and are designed for in-process

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In control: Good software provides invaluable support during operation and in the event of a fault

CHEMICAL REACTION It’s important to keep on top of the latest services, companies and innovations. EPM’s Chemical Reaction highlights a technology, service or business we think would be worth keeping an eye on…

Sygnature tune Dr. Paul Clewlow, Sygnature Discovery, talks to EPM about the company’s successful track record in discovering medicines for the benefit of patients with debilitating diseases such as cancer Who are you and what do you do? PC: Sygnature Discovery is the UK’s largest independent provider of integrated drug discovery expertise, offering advanced scientific research into medicinal drug discovery programmes for clients ranging from academic departments to pharmaceutical and biotechnology companies worldwide. The company’s in-house capabilities include medicinal chemistry, bioscience, computational chemistry and DMPK (the internal effects of medicines).

Q & A

Sygnature’s medicinal research is early stage, small molecule drug discovery and it often takes a further 10 years before a medicine reaches patients in the form of a new medicine. The company provides scientific expertise in terms of identifying a molecule that selectively binds to a biological target in a diseased cell. This is a notoriously complex area of research and demands that continual innovative methods are applied to enhance project success. What have you focussed on recently? PC: Sygnature has focussed on the overseas market and, as a result, international sales have increased by 58 per cent in the last two years. This was recently recognised when the company was ranked in the top 100 private small- to medium-sized enterprises (SMEs) in the UK by The Sunday Times BT Business SME Track 100 awards. What is your latest service/innovation? PC: Through significant technological and financial investment, additional capabilities have been continuously added to the already established medicinal chemistry department at Sygnature. These include biochemical testing and computational chemistry. Most recently, in January 2015, a DMPK & Physical Sciences department was established to provide support for fully integrated client projects in the hit-to-lead and lead optimisation phases and in support of other chemistry and biology only projects. With medicinal and computational chemistry, in vitro biology/screening and DMPK now all housed within Sygnature, we are able to design and synthesise novel compounds, test them in sophisticated biological assay formats and analyse the complex data more quickly and efficiently to accelerate potential drug candidates towards the clinic. How can you benefit the pharmaceutical sector? PC: Sygnature Discovery’s mission is to accelerate new medicines into development to treat patients with debilitating diseases such as cancer, respiratory disease and Alzheimer’s. To date, Sygnature scientists are named inventors on over 50 patents, with further patent applications pending. This record of success demonstrates that our scientists are experts in their field of research, with the ability to enhance the value of research projects and accelerate treatments into the clinic. So far, the company has identified 11 compounds on behalf of clients, which have progressed into development. Five are in human clinical trials, with the most advanced

being in Phase 2, meaning it is being given to a relatively large group of patients, typically 100–300. This last compound has the potential to treat chronic obstructive pulmonary disease (COPD), which is an extremely serious respiratory disease and a $billion market. There are a further 15 compounds in pre-clinical development, which could enter the clinic within the next 6–12 months. What are your future plans? PC: Sygnature has a clear, long-term vision and intends to widen its service capabilities further, giving the company an even stronger competitive edge in the field of scientific research. Headcount is projected to increase to over 200 within the next three years as part of this expansion plan, and a new purpose-built facility to house a suite of new laboratories and offices is currently under construction.

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Successful Clinical Trials Start Here. We believe our customers deserve nothing less than exceptional service, at every stage of their productâ&#x20AC;&#x2122;s development, from each phase of clinical development to successful commercialization. Our experienced team offers expertise in all aspects of clinical manufacturing, packaging, storage, and distribution services. We are with our clients every step of the way, providing scalable solutions to support the earliest Phase I studies to the largest global Phase III/IV studies. The ultimate measure of success is commercialization of your product, and PCI helps navigate the clinical phases in launching over 50 new products a year. Our expertise helps clients bring products to market efficiently and effectively, with keen insights to enable launch and commercial success. With an expert team focused on your investigational product, PCI is uniquely positioned to support your product throughout its life cycle.

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Now and for the future. At Natoli Engineering Co., weâ&#x20AC;&#x2122;re proud to engineer punches and dies of superior quality, but we also provide all the technical knowledge and support equipment that you need. We have built an outstanding reputation for quality service and support and we are driven to exceed our own high standards for performance. Find out more at natoli.com.