EPM Nov/December 2017

A CRITICAL STEP NATOLI REVEALS THE CRITICAL CONSIDERATIONS REQUIRED IN TABLET DEVELOPMENT PLUS: NOV/DEC 2017

•NEW HOMES FOR OLD DRUGS •PHARMAPACK EUROPE PREVIEW

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Contents Nov/Dec 2017 | Volume 17 Issue 8

Regulars

Features

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EDITOR’S DESK

PURIFICATION & FILTRATION

A quick look at what meds should be in, or more importantly out, of your suitcase for the holiday period

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6

ANALYSIS

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Assessing financial sustainability and the cost of prescription drugs as well as some of the legal implications of the CAR-T therapy approvals.

SECTOR HIGHLIGHTS Analysing the sector highlights of 2017 as experienced by several industry experts.

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OPINION Listing five countries with healthcare sector issues and how these are getting in the way of patient access.

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LAB DIARY In the final instalment, IDBS reveals how today’s lab annoyances may be solved with tomorrow’s technologies.

group editor lu rahman, lu.rahman@rapidnews.com reporter reece armstrong reece.armstrong@rapidnews.com publisher duncan wood

advertising

Previewing some of the key aspects of next year’s Pharmapack Europe.

art robert wood

robert anderton tel: +44 (0)1244 680222, rob@rapidnews.com damien challenger tel: +44 (0)1244 680222, damien.challenger@rapidnews.com

subscriptions subscriptions@rapidnews.com

ON THE COVER

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deputy group editor dave gray david.g@rapidnews.com

GEA assesses the specific benefits of continuous manufacturing for pharma.

PHARMAPACK PREVIEW

16

editorial editor felicity thomas felicity.thomas@rapidnews.com

production

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Here, ELC Group tells us more about worksharing, leading us to a more globalised market.

Tel. +44 (0)1244 680222 Fax. +44 (0)1244 671074 Web: www.epmmagazine.com

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TABLET & TOOLING

REGULATORY AFFAIRS

Natoli discusses the three phases of the tablet development process as well as how to use the machines and tools available to provide science supported decisions.

Outlining some of the challenges associated with continuous multicolumn protein A chromatography and highlighting how the wrong seal may put your processes at risk.

head office Carlton House, Sandpiper Way, Chester Business Park, Chester, CH4 9QE.

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European Pharmaceutical Manufacturer is published by Rapid Life Sciences Ltd. European Pharmaceutical Manufacturer is distributed in electronic and print formats to a combined readership of 14,000 pharmaceutical manufacturing professionals.

Volume 17 Issue 8 © Nov/Dec 2017 While every attempt has been made to ensure that the information contained within European Pharmaceutical Manufacturer is accurate, the publisher accepts no liability for information published in error, or for views expressed.

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available at

editor’s desk

… s g a b r u o y k c Pa ! y l l u f e r ca

If you are considering a quick winter getaway or some last minute sunshine over the festive period, make sure you check your meds or you may get more than you bargain for…

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B

efore the festive season gets into full swing and intrepid holiday makers seek their last break away for the year, an update on the guidance for travel abroad has been issued by the Foreign Office on medicines.

It is always worthwhile checking with healthcare representatives and various embassies to clarify if there are any issues before you travel and if in doubt, leave it out!

”

This updated guidance has been prompted following the arrest of a UK national in Egypt for carrying the prescription painkiller Tramadol in her luggage.1 Tramadol, although available on prescription in most European countries, is illegal in Egypt and anyone taking the medication travelling to the country is required to inform the Egyptian Embassy in London or carry a note from their GP specifying the purpose of the medicine and the quantity required for personal use.

Egypt is not the only country that has strict laws governing substances, not all of which are prescription medicines, over-the-counter products can also be included in these lists. Some of the more popular holiday destinations for the festive period may have more strict laws than expected, so it is advisable to pack carefully.

The UAE, for example, is already a popular travel destination for many seeking some winter warmth.

However, the region has extremely strict laws about substances, including certain medications that are commonly prescribed or bought over the counter in European states.

There are some substances that must not be taken to the UAE and are classed as narcotics to the Ministry of Health’s Drug Control Department, such as codeine, ketamine and morphine.2 Other examples of drugs that are classed as controlled substances and should be accompanied by a prescription when travelling to or through this area include tramadol, diazepam, prostaglandins, anxiety medications (lorazepam), antidepressants (venlafaxine) and even some substances used in contraceptives and as components of hormone replacement therapy (ethinylestradiol and menotrophin).

As has been experienced within the pharma industry in relation to flavourings, Japan can apply stricter rules than other countries. This can also be true for seemingly innocuous and common substances including,

pseudoephedrine — commonly found in nasal decongestants — which is a controlled substance in Japan!

In most other countries within Asia, like China, Singapore and Thailand, prescriptions for medication are required and travellers should be careful of the amount of medication they carry with them too.3 African countries, like Zambia, may prove tricky for winter wanderers too as cough syrups may get you into trouble there.

So, despite a lot of these medications being listed on the World Health Organisation’s (WHO’s) model list of essential medicines4 (those which should be widely available to anyone who needs them) there are country specific laws of which you should be aware. And, it is important to not forget about the countries you may be traversing, prior to reaching your final destination, as your luggage may be in question even if you are simply travelling through a place.

It is always worthwhile checking with healthcare representatives and various embassies to clarify if there are any issues before you travel and if in doubt, leave it out!

Thanks for reading and hope you all enjoy the festivities… safely, of course!

Felicity

References: 1. http://www.independent.co.uk/travel/news-and-advice/foreign-office-laura-plummertramadol-drugs-advice-medication-egypt-what-can-you-take-a8041426.html 2. https://www.fairtrials.org/list-of-controlled-pharmaceutical-substances-in-uae/ 3. http://www.devonlive.com/news/devon-news/beware-taking-everyday-medicinesholiday-764177 4. http://www.who.int/medicines/publications/essentialmedicines/en/

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ANALYSIS

Opening the floodgates With the recent FDA approvals of the first CAR-T therapies, the floodgates for cellular immunotherapies seem to be opening. In this article, Frances Salisbury (partner) and Adam Gregory (associate) — European Patent Attorneys in the Life Sciences team at Mewburn Ellis — discuss innovation and IP of these therapies in more detail.

“

Owning patents around these standard techniques could be extremely lucrative, thus claims relating to improvements and refinements of the processing steps should not be overlooked.

”

W

ith the FDA approving first Kymriah and now Yescarta, the floodgates for cellular immunotherapies seem to be opening, with a lot more approvals expected in the coming years.

Understanding the intellectual property (IP) ramifications within this rising tide is vital, not least as the field becomes increasingly crowded and competitive.

Results of the treatment thus far are promising, with companies such as Kite Pharma and Juno Therapeutics reporting ~80% response rates to treatment of blood cancers with CAR-T. However, the methodologies involved in the preparation and administration of these treatments give rise to specific IP considerations that need to be understood.

The importance of method claims Each patient is treated with their own bespoke medication, which is prepared from their immune cells. Cells are taken from the patient, processed, and returned to them. The patent infringement scenarios are therefore different to those for traditional pharmaceutical products, and enforcement could be more difficult with this kind of technology, as it may be necessary to demonstrate that each batch of cells falls within the scope of the granted claims.

There could, however, be real value in method claims in this area, provided the claims are crafted carefully. In particular, the treatment may involve steps occurring in multiple countries such as through a centralised processing laboratory, whereas patent infringement will be considered within only a single country. Method claims could also be especially valuable if they cover a part of the method that becomes a de facto standard required by the FDA for approval.

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Both current approvals relate to blood cancers using CAR-T cells that target CD19, and we can expect the FDA to be cautious about step changes, looking more favourably on treatments that are based on methods and techniques that have been previously approved. Owning patents around these standard techniques could be extremely lucrative, thus claims relating to improvements and refinements of the processing steps should not be overlooked.

IP planning and prevention As may be expected the clinical and patent landscapes are crowded in certain areas, and companies should consider whether they have the freedom to operate at an early stage in development. By identifying potential patent hazards early on there is the option to take preventative action.

This can include making a change to the CAR construct to work around a patent right, taking steps to prevent a patent being granted, or forcing the claims to be amended in such a way that the risk is minimised. Procedures such as opposition at the European Patent Office can offer a potential infringer a cost-effective way to take action, although the impact of proceedings in one jurisdiction on proceedings in others must be considered.

While most current clinical trials focus on blood cancer, trials for solid cancers are in progress. Key obstacles to the use of CAR-T cells to treat solid tumours include lack of tumour penetration and the reduced survival of the CAR-T cells in the immunosuppressive tumour microenvironment.

This may necessitate developments in how CARs are designed and/or how the CAR-T cells are administered — areas that could give rise to new patent rights.

Another limitation is the per patient treatment cost. At the moment, the average cost per treatment is ~$500,000,

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although the key players are working on bringing this down so that therapy is available to more patients. While current methods use autologous T cells, taken from the patient and modified to express the CAR, many companies are generating and curating ‘banks’ of immune cells which contain cells from donors with a variety of different HLA types. These cell banks could provide ‘off-the-shelf’, allogeneic, CAR-T cells. Patents directed to methods for storing and preparing such cells could prove to be very valuable, particularly if they relate to the first allogeneic T cell treatment approved by the FDA.

Further developments expected In the coming years, we can expect to see therapies using CARs that allow for a greater control of the quality and kind of signal induced by target binding, rather than the relatively simple structures used in the first CAR-T approvals.

Modifications to CAR constructs will be designed to enhance the treatment’s impact and reduce side effects such as cytokine release syndrome. Process innovations could include improvement of methods for generating and expanding CAR-T cells, and optimisation of dosage regimes. Both aspects could yield patentable subject-matter.

The recent FDA approvals are an important landmark in cellular immunotherapy. Investment and research in this area is growing, and with the numerous technical challenges there are huge opportunities for innovation.

With so many patents and applications in this space, we can expect a large amount of patent litigation, and identifying whether there is the freedom to operate at an early stage will be a very important commercial consideration for parties looking to bring CAR-T therapies to market.

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ANALYSIS

New homes for old drugs

Health systems are facing the biggest challenge in their existence: financial sustainability fuelled by the costs of prescription drugs. Here, Marisa Miraldo, associate professor in health economics at Imperial College Business School, goes into more detail…

D

eveloping a new drug can cost up to $2.558 billion.1 The rising and unsustainable costs in drug development and the consequent drug cost inflation have been a contentious item in most political agendas and a concern for the industry that claims to have Drug repurposing experienced an annual decrease in return on investment in the past six consecutive years.2 brings forth

drug development, cost inflation and helping to tackle the burden of disease for individuals and societies.

the benefit of quickening patient access to innovative and effective treatment at lower risk and development cost for the industry.

If existing drugs that have been shown to be safe for patients could be found to work for other diseases, this can substantially decrease drug development times, decrease its associated cost and risk, enabling a greater return-on-investment and improved access to new therapeutic solutions in key areas of need. With an estimated cost of repurposing of $8.4 million,5 a fraction of the R&D costs for a new therapy, drug repurposing can translate into revenues either through increased sales or new IP, which is sometimes gained through repositioning.6

“

”

It is therefore essential for health systems to find ways of promoting innovation and maximising its value in disease areas of substantial public health importance, but for which there is either under-investment by the industry or where innovation is difficult. Policies must strike the right balance between promoting innovation of drugs with substantial health improvement that are affordable for health systems, and allowing sufficient rents to the industry to incentivise further R&D investment.

In this context, drug repurposing (redeveloping existing treatments for new therapeutic uses or indications) emerges as a new value proposition for the industry, patients and payers.

The policy and economic significance of repurposing drugs is considerable. It is predicted that by 2020 $1.4 trillion will be spent globally on prescription drugs.3 The drug bill across OECD countries in 2013 account for approximately 17% of total healthcare spending.4 Healthcare payers are, therefore, seeking to curb expenditure while safeguarding access to high quality care, including interventions that can improve value for money from drugs. Thus, there is a growing interest in repurposing as an efficient avenue to deal with attrition in

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Drug repurposing brings forth the benefit of quickening patient access to innovative and effective treatment at lower risk and development cost for the industry.

• Celgene achieved a global revenue stream of $2.8 billion by repurposing Thalomid and Revlimid.5 • Aspirin initially developed by Bayer for the treatment of inflammation and pain, is now commonly used as an antiplatelet drug in myocardial infarction and stroke patients7 as well as fertility treatments.

• Metformin (Merck & Co.) was initially launched to manage diabetes has been found to improve survival outcomes in cancer such as breast cancer8 as well as lung cancer.9 Venture capitalists have a preference for drugs that are closer to being launched on the market and are, therefore, more likely to bring a higher return-on-investment improving the prospects of raising capital for pharmaceutical firms with track record in drug repurposing.

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Even if a drug can be successfully repurposed and approved, it must still undergo the same pricing and reimbursement assessment, as a novel drug and price differentiation across different indications for the same drug might prove difficult.

Enablers

Data analytics & AI

“

Discovering new homes for old drugs requires large volumes of prescription data linked with clinical and outcomes data across individuals with different comorbidities routinely collected in many health systems.

…recent technological developments on data mining, machine learning and artificial intelligence open new avenues for the development of targeted approaches to drug repositioning.

”

The successful cases of drug repositioning have occurred through the observation of improvement of clinical outcomes of patients with comorbidities not officially targeted by the prescribed drugs.

However, recent technological developments on data mining, machine learning and artificial intelligence open new avenues for the development of targeted approaches to drug repositioning.

Building on the knowledge that drugs with similar chemical and molecular profiles can potentially have similar targets; and diseases with similar pathways and gene activity can be targeted by the same compound ‘repurposing analytics’ emerges as a powerful tool to optimise the identification of suitable drug candidates as well as predicting drugdisease interactions.10

• Example: Novartis’s Ilaris drug targeting a rare inflammatory disorder, has been found to reduce the risk reduction of complications following myocardial infarction.13 Originally priced at $16,000 per dose, this price would not be competitive in the cardiovascular disease market.13,14

Other facts • The repurposed drug market, which was valued at $24.4 billion in 2015, is expected to be worth $31.3 billion in 2020.15 • Financial potential of drug repurposing with a five-year compound annual growth rate (CAGR) of 5.1%.15 Currently 10–50% of R&D spending is on drug repurposing.16

• Examples - NuMedii has invested in ‘mapping gene activity patterns from a database of 300 diseases’ to identify genetic similarities across diseases that can potentially be targeted by the same compound;11 - Biovista building on data for 23,000 diseases, 6000 adverse events, 20,000 drug targets and 95,000 drugs is deploying technology to identify patterns and make predictions on drug-disease associations that can potentiate drug repurposing;11 - Pfizer, Bayer and Novartis: have set up standalone units to develop repositioning opportunities.5 References: 1. DiMasi, J.A., et al.,. Journal of Health Economics, 2016;47:20–33.

Collaboration While there are 4,000 API’s approved globally many of these molecules have been strategically shelved.12 These molecules can potentially be made available to other companies of research institutes to be further investigated for their potential use in alternative indications.

Secondly, with more than 80% of the 30,000 available drugs being expatent,7 there are substantial drug repurposing market opportunities for drug companies, university research groups and new start-ups.

New business models for innovation and intellectual property rights are required to enable collaboration of this sort that can potentiate value of therapeutic innovations.

2. The Pharmaceutical Journal (2017). Return on investment falls for pharmaceutical industry.

DOI: 10.1211/PJ.2017.20202146 3. Aitken, M., and Kleinrock, M., Global medicines use in 2020: outlook and implications. IMS Institute for healthcare informatics, 2015;1–43.

4. OECD (2015), Health at a Glance 2015: OECD Indicators, OECD Publishing, Paris.

5. Persidis, A. (2011), The benefits of drug repositioning. Available at: http://www.ddw-online. com/business/p142737-the-benefits-of-drug-repositioning-spring-11.html 6. Ashburn, T., and Thor, K., Nature Reviews Drug Discovery, 2004;3:673–683.

7. Kollewe, J. (2012). Why finding new uses for old drugs is a growing business. [online] the Guardian. Available at: https://www.theguardian.com/business/2012/nov/27/new-usesold-drugs-business 8. Wan, G., et al., Oncotarget, 2016;7(23):35437–35445.

9. Xu, H., et al., The Oncologist, 2015;20(11):1236–1244. doi:10.1634/ theoncologist.2015-0096.

10. Li, J., et al., Briefings in Bioinformatics, 2016;17(1):2–12.

Challenges

11. Scudellari, M., (2011) Teaching an old drug new tricks, The Scientist, 25(4).

12. Shim, J., and Liu, J., International Journal of Biological Sciences, 2014;10(7):654–663.

The regulatory landscape & incentives The regulatory landscape is becoming more complex and stringent in public and private healthcare systems.

However, the current value assessment frameworks reimbursement schemes do not contemplate the possibility of maximising value through finding ‘new homes’ for existing drugs and as such there are currently no streamlined processes to assess the value of repurposed drugs nor to adopt them to scale in healthcare systems.

13. Roland, D. (2017). The price dilemma over a $16,000 drug. [online] Fox Business. Available at: http://www.foxbusiness.com/features/2017/07/12/price-dilemma-over-16000-drug. html 14. Herper, M. (2017). Forbes Welcome. [online] Forbes.com. Available at: https://www.forbes. com/sites/matthewherper/2017/06/22/novartis-drug-becomes-first-to-prevent-heartattacks-and-strokes-by-targeting-inflammation/#79bf6c4c2b1a 15. Arnum, P., (2016). Drug Repurposing and Repositioning: Making New Out of Old - DCAT Connect. [online] Connect.dcat.org. Available at: http://connect.dcat.org/blogs/patriciavan-arnum/2016/07/05/drug-repurposing-and-repositioning-making-new-out-of-old 16. Novac, N., Trends in Pharmacological Sciences, 2013;34(5):267–272. Available from: doi:10.1016/j.tips.2013.03.004.

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OPINION

Here, Maria Yasko, PR manager at phamax, lists five countries with limited access to healthcare, going into detail about how these countries are suffering from healthcare sector problems and how these are getting in the way of patient access.

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e live in a modern age with incredible medical advances that hit our headlines on a daily basis.1 As the years go by, we find quicker and more efficient ways to operate, diagnose and treat patients.

Diseases are becoming more manageable and people are living longer than ever before.2 Despite this, there are countries with serious pharmaceutical market access issues,3 which we should really address.

Liberians are suffering in the face of malaria, the second leading cause of death in the country,7 which kills thousands of pregnant women and children each year. unfortunately, hospitals don’t always have access to antimalarials.8 The Ebola outbreak in 2014 also hit the country hard.

But since this time, thanks to the government working on strategies to improve patient care and international aid, healthcare services have started to improve.

No two countries are alike and each country with limited access to healthcare will be experiencing unique and pressing issues. Below are five countries which suffer from healthcare sector problems. I’ll cover what these problems are and how they are getting in the way of patient access.

The healthcare system is now more decentralised, there are more medical supplies for health workers and extra training is being provided in infection prevention control. Healthcare in Liberia is also free,8 which helps struggling patients who would otherwise have no means of obtaining treatment.

Liberia’s struggles with civil war, malaria and Ebola One of the world’s poorest nations, Liberia is a country that is struggling to achieve better access to healthcare after years of civil war and prolonged regional instability.4 A great deal of clinics, hospitals and equipment were destroyed during Liberia’s 14-year civil conflict,5 and attempting to rectify the situation is wrought with financial roadblocks. On top of this, Liberia is suffering from a lack of qualified doctors.

Figures suggest that there are only 14 physicians per million people in Liberia.6

There are also other exciting technological advances that could facilitate access to healthcare. Increasingly, mobile devices are being used for this purpose, and Julius SM Gilayeneh, a Liberian medical doctor, has said that he hopes investments in modern mobile technology could change the lives of those who live in rural areas. 9 Where medical access is concerned, travelling is always an issue, but Gilayeneh believes that long trips to the hospital could be eliminated if individuals were able to call or text doctors for advice.

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Malawi has to cope with regular ‘stock-outs’ Healthcare in Malawi faces a lot of problems, notably that of infant mortality, tuberculosis, HIV/AIDS and malaria. As with Liberia, Malawi has a dearth of physicians; there are only 19 doctors per million people and the World Health Organisation’s (WHO) report ranks Malawi’s health system as number 185 out of 190 due to lack of manpower, lack of skills and scarcity of appropriate equipment and technology.6 Only 46% of Malawi citizens live within 5 km of a health facility and, although most public health services are free, patients can rarely afford the associated costs that are involved when it comes to travelling to and from a facility.10 This means that despite how much they might need care, some patients refuse to, or are unable to, get the attention they deserve.

As we mentioned above, scarcity of equipment and drugs are an issue in Malawi — so much so that a phrase has been coined (stock-outs) to describe empty hospital and pharmacy shelves,11 so even if patients manage to travel to the appropriate facility, they might not be able to receive the necessary drugs. The government acknowledges these problems and is making efforts to resolve the issues, but as it stands, the people of Malawi, especially in rural areas, are having to deal with long periods of drug shortages.

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Somalia’s healthcare concerns are linked with political and environmental complications Access to basic and essential healthcare services remains a challenge in Somalia. WHO argues that the reasons behind Somalia’s struggles with access to healthcare are numerous and complex, including environmental stress, ongoing armed conflict, political instability, recurring drought conditions, overcrowding and forced evictions.12 The lack of access to clean drinking water and malnutrition cause disease outbreaks, but with such limited healthcare and with only 35 doctors per million citizens,6 patients struggle and very often die without medical care. It is likely that with added investment in healthcare, along with improved water and hygiene practices, disease outbreaks will lessen and more patients will get appropriate care.

In many ways, Indian healthcare is globally acclaimed and provides a wide quality of care.16 In other areas, however, Indian hospitals and healthcare research are suffering, particularly due to the lack of reliable data with relation to certain diseases. On top of this, access to healthcare tends to depend very much on where you live. For example, it has been shown that 80% of doctors in India only serve 28% of the nation’s population.17 This could be explained by the fact that 70% of the Indian population lives rurally, in areas that have no or limited access to hospitals.

Research into healthcare issues in India shows that the country spends only 4.2% of its national GDP on healthcare goods and services,17 which can be compared to the USA, which spends 18% of its GDP on this area.

Despite the fact that Nigeria has ‘one of the largest stocks of human resources for health’,13 this African country still struggles with a deficit of midwives, nurses and doctors, meaning that delivering appropriate patient care is a challenge. On top of this, the healthcare providers tend to be concentrated in urban areas, causing rural areas to suffer. The country also deals with medical supply shortages.14

One area that is rarely discussed, but which causes a problem for Indian citizens, is the question of haemophilia. There are approximately 16,000 registered haemophiliacs in India,18 according to the Hemophilia Federation of India, but the actual estimated haemophiliac population is actually 54,000.

This shows that not all Indians who suffer symptoms of haemophilia are seeking help, which might be because The Insurance Act in India doesn’t accommodate individuals with pre-existing genetic disorders. So, these sufferers never seek treatment.

One of the biggest worries for Nigeria, however, is the issue of health insurance. According to one source, only approximately 3% of Nigerians have access to healthcare coverage under the National Health Insurance Scheme (NHIS).15 Professor Usman Yusef, executive secretary of NHIS, has expressed his sadness at this statistic and has said that they are determined to do better, with the aim of improving access to quality health care for all Nigerians.

This is a serious market access concern, as the only way we, as a modern society, will adequately address and treat rare bleeding disorders is if we get a full and accurate picture of how many sufferers there are in the world while collecting data on their symptoms and bleeds. Some sources suggest that the Indian government should implement an ‘Orphan disease’ policy to create drugs for diseases that don’t receive a lot of attention.19

Nigeria has issues with health insurance

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India has great healthcare, but only some individuals can benefit

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NO SIMPLE SOLUTION All the countries above have their own unique sets of problems with relation to healthcare and, as such, the answer to improving access to healthcare will be different in each case. There is no simple way to resolve such complex issues, but with governmental support, technological evolution and a dedication to medical advancements, it’s likely that all the countries above will thrive long-term and provide patients with the support and care they need.

References: 1. http://www.huffingtonpost.com/entry/7-amazingmedical-breakthroughs-that-will-wow-the-world-in-2017_ us_5852c870e4b012849c05d133 2. http://www.bbc.co.uk/news/health-35550407 3. http://phamax.ch/blog/?p=800?utm_ source=enoutreach&utm_medium=article 4. http://allafrica.com/stories/201705240964.html 5. http://who.int/hac/donorinfo/cap/Liberia_compendium_ Jan06.pdf 6. http://www.worldatlas.com/articles/the-countries-withthe-fewest-doctors-in-the-world.html 7. http://www.healthdata.org/liberia 8. https://kristof.blogs.nytimes.com/2017/06/23/in-liberiamore-drugs-in-my-suitcase-than-in-the-hospital/ 9. http://ghi.wisc.edu/ghi-in-action/mobile-technologyimproves-health-in-rural-africa/ 10. http://joshuainmalawi.org.uk/what-we-do/health/ 11. http://policy-practice.oxfam.org.uk/blog/2012/06/ access-to-medicines-in-malawi 12. http://www.who.int/emergencies/response-plans/2017/ somalia/en/ 13. http://www.who.int/workforcealliance/countries/nga/ en/ 14. https://www.internations.org/nigeria-expats/guide/ moving-to-nigeria-15540/healthcare-in-nigeria-3 15. https://www.dailytrust.com.ng/news/health/only3-percent-of-nigerians-have-healthcare-coveragenhis/172812.html 16. http://content.healthaffairs.org/content/35/10/1753. full 17. http://www.hindustantimes.com/health-and-fitness/80of-doctors-in-india-serve-only-28-of-the-nation-spopulation-report/story-hxfxTu1jiYoplroBrD0vyL.html 18. http://phamax.ch/blog/?p=772?utm_ source=enoutreach&utm_medium=article 19. http://www.thehindubusinessline.com/companies/ hemophilia-patients-concerned-over-medicine-pricesshort-supply-as-customs-waiver-goes/article8214172. ece

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Y L L UA

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T U M

One of the potential pitfalls when preparing a product launch is planning for GMP inspections.

An upside of recent events, the FDA confirming that eight EU member states have at least equivalent capabilities as the FDA in performing GMP inspections, is worksharing, leading towards a more globalised market. In this article Vikash Patel, senior regulatory specialist for ELC Group, tells us more…

O

ne of the potential pitfalls when preparing a product launch is planning for GMP inspections. An upside of recent events, the FDA confirming that eight EU member states have at least equivalent capabilities as the FDA in performing GMP inspections, is worksharing, leading towards a more globalised market. In this article Vikash Patel, senior regulatory specialist for ELC Group, tells us more…

Most drug development teams know that apart from the various internal mechanisms that need to be navigated before product launch, there are obviously many external regulatorydriven mechanisms to steer through. One of these potential pitfalls is planning for GMP inspections, so as to ensure that the majority of markets are covered in the first wave of submissions, as well as subsequent markets that accept mutual recognition, normally wave two and three markets covering ROW territories.

The good news is that, as of 1 November 2017, the FDA has confirmed that eight EU member states have at least equivalent capabilities as the FDA in performing GMP inspections. This is a historic first, since to date all companies wishing to launch products in the US and EU needed to plan separate inspections from both the FDA and an EU member state.

The EMA had already confirmed back in June 2017 that the FDA had the equivalent capabilities with regards to GMP inspection, so this recent reciprocation from the FDA

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is a welcome move and allows much closer cooperation and worksharing between the bodies.

There are many upsides to this latest move by the regulatory bodies to improve on working collaborations, one of which is a consistent view of GMP, enabling a much more streamlined approach by companies to plan for their inspections. It has been well documented that, hitherto, many manufacturing plants have had to run two separate programmes to cater for EU and FDA inspections.

“

There are many upsides to this latest move by the regulatory bodies to improve on working collaborations, one of which is a consistent view of GMP, enabling a much more streamlined approach by companies to plan for their inspections.

”

Additionally, technical and quality teams from individual companies can now start working towards a better harmonisation of systems and resource planning, as well as dialogues with the inspectorate. The EMA has issued a press

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release to give further background to this latest development,1 and it is clear to see from this that regulatory bodies are increasingly working towards a more globalised market.

Inspection planning can be all too often rushed and left to the last minute; however, with these changes being brought about by the competent authorities, there has never been a better time for companies to become more proactive with their strategies with regards to site of manufacture as well as inspection preparation.

The expectation is that there will be further expansion of such worksharing between authorities, including GMP guidelines and directives. As this worksharing is just in its initial official phase, there will naturally be more questions than answers regarding already planned and agreed inspections as well as supporting documentation changes to support FDA and EU submissions.

It is imperative for regulatory divisions to maintain a watchful eye on these developments and contact the competent authorities to ensure correct procedural understanding if intending to take advantage of this new worksharing agreement.

Reference: 1. http://www.ema.europa.eu/docs/en_GB/document_ library/Press_release/2017/10/WC500237909.pdf

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15

COVER STORY

A critical step Tablet manufacturing poses many challenges and the development process of a tablet form is a critical step that requires the correct tools and equipment. In this article, Robert Sedlock, director of Technical Training and Development for Natoli Engineering Company, will discuss the three phases of the tablet development process: Pre-formulation, formulation, and scale-up, as well as how to use the machines and tools available to provide science supported decisions.

T

ablet manufacturing poses many challenges but is still the preferred pharmaceutical dosage form.

Compressing a block of particles into a single compact is a science that must be understood to ensure a successful manufacturing process.

For consumers, tablets are a simple and convenient dosage form and if developed properly tablet manufacturing With the many rates are higher than any other challenges found dosage form available.

“

in the tabletting process a clear understanding of your materials and processes is vital.

The tablet development process is a critical step that requires the correct tools and equipment to minimise the challenges through scale up and in the manufacturing environment.

A quality by design (QbD) approach requires careful characterisation and an understanding of the properties and limitations of the product and process.

”

From a tabletting standpoint, it is important to complete the material science work upfront.

This applies to API’s, excipients, diluents, binders and formulation mixtures. Among the most significant challenges in early tablet development are the high costs and limited amounts of material available for laboratory experiments and process scale up. Material sparing tools for powder characterisation such as single-station tablet presses, compaction simulators and emulators are essential to cost effective tablet development.

Pre-formulation At this stage, the mechanical properties of the API are characterised. Commonly, API’s do not have sufficient bonding properties to

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form a robust compact, requiring appropriate excipients during the formulation process. Some properties of note include the deformation characteristics, compactibility, ejection force levels and sticking potential.

Single-station tablet presses, compaction simulators and compaction emulators are all very effective tools to help characterise mechanical properties of your API. These machines can provide compression data from one single tablet and only require milligrams of material. Additionally, a linear displacement sensor can be easily installed allowing real time in-die thickness measurements — enabling recording of the punch displacement along with the compression force profile associated with the compaction event. This can provide an understanding of: • The consolidation of the particles during compression.

• When plasticity occurs.

• Inter-particulate bonding.

• The elastic energy or work put into the tablet and remaining work after the decompression event.

Other valuable measurements include the upper and lower compression force, ejection force, residual and peak radial die wall force and take off/punch adherence force.

Single-station tablet presses (figure 1) are a cost-effective way of recording the above measurements but they do not simulate the compression event of a high-speed production tablet press. Materials that undergo compression at slow rates have more time for the particle consolidation process, increased dwell time or the time under maximum force and relaxation time during the decompression event. This may result in a stronger compact as compared to the

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manufacturing process where the tablet presses are running at high velocities and have low dwell times, which can result in insufficient tablet strength, capping or lamination.

Figure 1) NP-RD10A single-station tablet press.

Furthermore, most single-station tablet presses are designed for singled ended compression — the upper punch applies and the lower punch receives the force through the powder bed.

A typical manufacturing tablet press is designed with an upper and lower compression roller and both punches travel in the die to compress the tablet. Despite this limitation, a single ended compression cycle can provide useful information if both the upper and lower punch forces are recorded.

A compaction simulator is a sophisticated singlestation tablet press designed to mimic a double ended compression cycle of a rotary press at high velocities. These machines are typically hydraulically or electrically driven and fully instrumented including punch displacement profiles.

A compaction emulator is also a highly technological press designed to mimic a double ended compression cycle of a rotary press at high velocities. A compaction emulator

is mechanically driven and leverages the design of a traditional rotary press where the upper and lower punches are forced between a set of compression rollers (figure 2).

The slope of the linear regression is the Heckel constant — the minimum compaction pressure required to cause deformation of the material under compression. In this example, the yield pressure or the Heckel constant is 28 MPa, which is a third of the inverse of the slope, where the slope is 0.0118x.

Formulation

Fig. 2) Presster compaction emulator.

The punch type, head profile and compression rollers are easily replaced to replicate the production tablet machine that will potentially be used during the manufacturing process.

Furthermore, a compaction emulator is designed with a linear track allowing the punches and die to travel through a fill track, dosing stage, compression rollers and a user set ejection angle.

Based on the API properties the excipients can be chosen to provide the necessary deformation properties to provide a robust tablet. At this stage compaction studies can be performed with formulation variants while simulating production tablet press rates and dwell times.

From a mechanical standpoint the excipient choices should be made to aid in the powder flow, provide sufficient tablet strength, provide a smooth ejection and take off process with minimal forces. Instrumented benchtop rotary tablet presses are common machines used at this stage. But when bulk quantities of materials are limited single-station tablet presses are still a valuable tool for screening and evaluating formulation compositions. Figures 5, 6 & 7 are examples of compaction studies performed during the formulation process.

Figure 5) Tensile strength versus compaction pressure.

Figure 3) Single-station data — work curve

A work curve or force displacement curve measures the real-time tablet thickness during a single compression event (figure 3).

As the compression force increases the tablet thickness decreases and the area under the curve represents the amount of work/energy remaining in the tablet. This information also provides the elastic recovery of the material.

In the example given, the elastic recovery is 20.5%.

The Heckel plot provides a linear relationship between the relative porosity of a powder and the applied compaction pressure (figure 4).

Figure 4) Single-station data — Heckel plot.

Figure 6) Solid fraction versus compaction pressure.

Figure 7) Tensile strength versus solid fraction.

The tabletability profile depicts the tablet tensile strength as a function of the applied compaction pressure. This profile is normalised for the punch tip face area and tablet geometry allowing for a true comparison of the formulation robustness independent of tablet size. The example above compares ratios of lactose and microcrystalline cellulose with added acetaminophen (APAP).

The added APAP decreases the tablet strength and requires a higher compaction pressure to achieve a desired tablet tensile strength.

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This study can be performed on a singlestation press but more valuable if performed on a compaction simulator/emulator at the velocities and dwell times of a production tablet press speed.

The compressibility profile depicts the tablet solid fraction as a function of the compaction pressure. The solid fraction is a ratio of the tablet density over the powder true density where the true density can be measured from a helium pycnometer. The tablet porosity is one — solid fraction and this provides valuable data that will influence the disintegration.

The compactibility profile depicts the tablet tensile strength as a function of the tablet solid fraction. This allows the scientist to evaluate the tablet strength as related to the solid fraction and disintegration potential. The tabletability and compressibility profiles are influenced by the speed of the compaction event where the compactibility profile is not speed dependent and can be generated on a slow singlestation tablet press while generating valuable information that will transfer to larger scale.

Scale up At this stage, manufacturing variables can be evaluated on a small scale. Longer production runs can be tested to address any issues found at this level. The effects of processing variables, excipient suppliers, changes in particle size and manufacturing conditions can be evaluated.

During this process a pilot scale rotary tablet press is suitable to provide the longer tabletting runs where friction and heat play a role and allows the scientist to identify any tablet quality issues. A compaction simulator or emulator is designed to mimic a high speed rotary tablet press and this tool can provide insight in what to expect but it doesn’t simulate the continuous movement of multiple punches throughout a series of cam tracks on a rotary turret.

Load cell transducer design, data acquisition performance and calibration techniques are critical aspects that make up a quality instrumentation software system. Load cells can measure compression, tension and shear with a typical error of less than 0.1%. The data acquisition system must be designed to handle data capture rates up to 100 kHz in order to measure data at high tableting speeds typically occurring in 1 to 100milliseconds. Calibration techniques are also very important to ensure the accuracy of your data. When measuring in-die thickness during the compaction event the linear displacement sensors need to compensate for the machine compliance or deformation. Since tableting machines are not perfectly rigid a calibration should be performed to correct this error.

With the many challenges found in the tabletting process a clear understanding of your materials and processes is vital. Material science is of fundamental importance in formulating a robust tablet that is scalable to the manufacturing environment. With the high costs of API’s and bulk powders, material sparing systems such as singlestation tablet presses, compaction simulators and emulators are of great value.

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PURIFICATION & FILTRATION

Continuous

“

…there remain a number of challenges and barriers to implementing continuous downstream processes and consequently overall integrated continuous processes for the production of biopharmaceuticals.

”

s e g n e l l cha

Dr Hani El-Sabbahy, a biopharmaceutical application engineering specialist at science-based technology company 3M, outlines some of the challenges associated with continuous multicolumn protein A chromatography.

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he advantages of continuous bioprocessing have been well covered in the literature. They include reduced equipment footprint, reduced capital cost, higher productivity, greater flexibility to increase capacity by operating parallel production lines, and, in some respects, enable a steady state operation. There is, therefore, significant interest in continuous processing in the biopharmaceutical industry.1 Whilst a number of companies currently use continuous upstream processes, there remain a number of challenges and barriers to implementing continuous downstream processes and consequently overall integrated continuous processes for the production of biopharmaceuticals. These challenges include less flexibility of each production line and greater risk of contamination, both of which result from long run times. Additionally, process understanding remains relatively poor due to the complex nature of biological systems and, at times, the empirical approach to process development that is still prevalent today.

Furthermore, the industry is only really at the beginning of addressing the need for robust online measurement of key parameters required to enable effective process control.2 With these in mind, one of the key barriers is system complexity or perceived complexity.3 Of course, the more complex the system, the more difficult it is to understand, model and control.

The cost of protein A is one of the most significant costs in a mAb process. Decreasing the cost of protein A should have a significant impact on the overall cost of the downstream process. Continuous multicolumn chromatography is able to achieve this by using more of the capacity of the resin, and for clinical manufacture, more of the resin lifetime.4

Work specifically on the impact of multicolumn continuous protein A mAb capture chromatography on cost of goods has shown the biggest impact is at clinical, rather than commercial, scale due to the greater resin reuse at commercial scale.4,5 However, there was a key difference between these two studies, namely, the residence times investigated. The Xenopoulos’ study conducted the continuous multicolumn protein A chromatography using incompressible beads at 0.5 min residence times showed savings of 16% to 24% at commercial scale. In contrast, 18

Pollock’s study was conducted at residence times more characteristic of batch operations (greater than or equal to three minutes) and showed only a five percent reduction in cost of goods at commercial scale. Therefore, it appears that selecting most productive conditions can make the difference between modest and significant cost savings at commercial scale.

Loading and regeneration are necessary steps for each of the columns in a continuous multicolumn chromatography unit operation. The regeneration, as in a batch system, consists of the equilibration, wash, elution and cleaning steps. Matching the loading and regeneration steps as closely as possible is necessary to achieve maximum productivity.4 Optimisation of the column regeneration steps is required to ensure they are as short as possible without impacting product purity and quality. Once this has been achieved, the regeneration time can effectively limit the maximum achievable productivity unless more columns are introduced.

of columns to maintain the balance between loading and regeneration. This increases system complexity which, as discussed above, makes it more difficult to control and model.

Alternatively, it is hypothesised that feeding the continuous multicolumn protein A chromatography unit operation with cleaner feed material may allow these regeneration steps to be further shortened, thereby allowing shorter residence times or higher titre feed material to be used whilst minimising system complexity.

To explore some of these issues, 3M has commissioned experts at UCL (University College London) to conduct in-depth research into the performance of the Emphaze AEX Hybrid Purifier. The goal of the project is to quantify the value of purifying the cell culture fluid with the purifier before the continuous chromatography operation. This product may potentially reduce the time required for nonloading steps by reducing soluble impurities upstream of capture chromatography. The results are expected to be published in a scientific journal next year.

References: 1. Konstantinov, K.B., and Cooney, C.L., ‘White Paper on Continuous Bioprocessing. May 20–21, 2014 Continuous Manufacturing Symposium’, J. Pharm. Sci., 2015;104(3):813–820.

Another important point to consider is the length of the load step which is a function of the loading residence time and the product titre. Higher product titres will give rise to shorter load times whilst lower product titres will give rise to longer load times at constant residence time.

2. Schmidt, S.R., ‘Drivers, Opportunities, and Limits of Continuous Processing’, BioProcess International, 20 Mar 2017. [Online].

Available: http://www.bioprocessintl.com/manufacturing/continuousbioprocessing/drivers-opportunities-limits-continuous-processing/

It has been proposed that residence time is the most important parameter affecting the productivity of a periodic countercurrent chromatography protein A capture step.6 However, particularly at higher feed stream product titres, shorter residence times can be impractical due to the length of the regeneration time.

5. Xenopoulos, A., J. Biotechnol., 2015;213, no. Supplement C:42–53.

In the literature, some have suggested that this can be mitigated by running those steps faster than loading or for a shorter time or by compromising on residence time.5 The other approach to deal with this, is to increase the number

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3. Munk, M., and Langer, E.S., ‘What is holding Industry back from Implementing Continuous Processing: Can Asia Adopt More Quickly? — Biopharma Asia’, Biopharma Asia, 28 Feb 2017.

4. Pollock, J., et al., J. Chromatogr. A, 2013;1284:17–27.

6. El-Sabbahy, H., et al., ‘Factors affecting the productivity of 4-Column Periodic Counter Current Chromatography (4C-PCC)’, Integr. Contin.

Biomanufacturing II, Nov 2015.

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17.11.17 09:53

PURIFICATION & FILTRATION

Mechanical seal of approval Pharmaceutical companies are unwittingly putting production processes at risk of contamination by fitting mechanical seals which fail to comply with EU regulations, says John Smiddy, European Sales and Technical Support Director for AESSEAL. Here he explains how non-compliant seals might slip through the net and suggests how the issue can be resolved.

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he regulations relating to mechanical seals in pharmaceutical production processes couldn’t be simpler: every component in contact with an active pharmaceutical ingredient (API) must be 100% traceable and a statement of compliancy must be clearly marked on the packaging pay equal it comes in.

The need to attention to spare parts when considering quality compliance is often overlooked.

Crossover between the pharmaceutical, biopharmaceutical and food and beverage sectors is routine — the use of the dairy by-product β-lactose as an excipient is a typical example. So, it stands to reason that both pharmaceutical current good manufacturing practice (cGMP) and regulations governing food contact materials (FCMs) must apply with equal weight in both sectors.

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Regulation (EC) 1935/2004 on FCMs is unequivocal: “A name, reference number and batch or delivery number should identify each raw material, so that it can be traced, if necessary. The traceability of raw materials is achieved throughout the production chain and in-house by the delivery and/or batch reference numbers. It is a legal requirement that traceability exists at least to the level of one stage back and one stage forward.”

So, why is there a proliferation of mechanical seals in pharmaceutical processing plants whose components cannot be traced — and what are the potential operational implications of installing them?

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Understanding supply chains First it helps to understand the often complex supply chains involved in the production of component seals currently being imported into Europe from Asia.

An engineer or purchasing department tasked with buying in spare parts for repairs might take it for granted that the original equipment manufacturer (OEM) has sometimes bought the product from the source offering the lowest cost. What they might not be aware of is that to achieve this low cost the product has often been through so many links in the supply chain that by the time it arrives at the end user all traceability has been lost. And if you have no traceability you have zero knowledge of the material the seal is produced from.

Let me give you just one example of the importance of knowing the source material of a seal.

Many mechanical seal faces are made from carbon. However, there are around 15 grades of carbon commonly used. Of these there may be only three that are compliant with Food and Drug Administration (FDA) standards. Of the remaining carbons around 10 are suited to chemical applications and don’t require FDA compliance so, fine for chemical, nuclear or power generation industries but not for food or pharmaceutical.

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Finally, there are antimony carbons, which are used in the oil and gas industry and, put simply, these are poisonous. It seems blindingly obvious that these should never be used anywhere near the food or pharmaceutical supply chain but incredibly we have seen this type of carbon on sites where the implications of them being misapplied could be disastrous.

The problem with all these materials is that they all look exactly the same as a seal that is 100% traceable and compliant. You simply cannot differentiate between a compliant and non-compliant seal — unless you have its traceability clearly stated on the box it comes in.

The potential risk implications of installing untraceable mechanical seals can’t be overstated. A pharmaceutical company that carries out stringent checks at every step along the production might be blissfully unaware that there are in fact a number of points of heightened contamination risk along that line — one for every seal.

The standard for compliance on site is often focused on the end-product yet a non-compliant mechanical seal can create a risk at every stage of the production process, from beginning to end.

If we take the example of pharmaceutical plant producing an active pharmaceutical ingredient (API), involving lots of different rotating equipment, that could mean as many as 15 to 20 mechanical seals and 60 to 100 static sealing joints across the whole production line. The more complex the process, the greater number of seals and the greater the risk of product contamination and, in the worst-case scenario, product recall.

There is a simple solution to what effectively amounts to building risk in to production processes at the same time as breaking the law. Look at the label. And if the seal comes in packaging that doesn’t clearly state its source, don’t use it.

Less scrupulous companies might claim to have traceability and as FDA auditing fails to cover the supply chain of the materials there are no proper checks and balances to demand proof.

Lack of awareness Lack of awareness is the overwhelming issue, as well as lack of communication between quality assurance and others responsible for compliance with FDA and EU regulations and operatives and at the lower ‘repair and replace’ end of the production line.

The need to pay equal attention to spare parts when considering quality compliance is often overlooked. This is compounded by the need for expediency when repairs are required. Getting a production line back up and running means engineers may be less focused on regulations in the effort to avoid costly downtime.

For mechanical seal suppliers like AESSEAL compliance is an issue of integrity as well as law. The number of times we’ve encountered noncompliant seals makes it clear that their proliferation is an issue that must be addressed.

My message to company boards and CEOs is: don’t assume that because you’re aware of the EU regulations that everybody across your company is too. Check that your quality assurance manager is aware of the need for clearly labelled traceability. Then make sure that they trickle that information all the way down the production line team so every member knows what constitutes compliance and how to carry out the simplest checks on packing and labels to ensure that products adhere to it.

The pharmaceutical industry can rightly pride itself on its high levels of quality assurance and self-regulation, but the failure to understand or act on the laws and regulations around traceability and labelling is a serious chink in its armour.

With a solution so blindingly obvious there should be no excuses for installing non-compliant mechanical seals in any pharmaceutical production plants.

But Regulation EC1935/2004 is clear — if that traceability is not visibly evidenced on the packaging those claims carry no validity and the mechanical seal should not be installed on a pharmaceutical production line.

That rule of thumb might sound not just simple but blindingly obvious, but that doesn’t mean all pharmaceutical companies apply it. Why not?

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21

CASE STUDY: PURIFICATION & FILTRATION Who:

BHS-Sonthofen

What:

Continuous filtration to increase efficiency in antibiotics production

How:

Using a rotary pressure filter

Continuous improvement The company BHS-Sonthofen is an owner-operated group of companies in the field of machinery and plant engineering based in Sonthofen, Germany.

The company offers technical solutions for mechanical process technology, concentrating primarily on mixing, crushing, recycling and filtration. BHS-Sonthofen has a global presence, with more than 350 employees and several subsidiaries.

The production scenario A global pharmaceutical company, producing a highly efficient new drug based on the traditional batch process method, encounters rapid success that exceeds internal sales forecasts after market introduction. The company launches a project to increase production and the drug rapidly develops into a blockbuster, calling for a production increase that more than doubles previous capacity.

An analysis of the entire production process is performed to streamline and increase efficiencies in production as quickly as possible.

Typical rotary pressure filter of type RPF A09 with an active filter surface of 2.16 m² for use in pharmaceutical applications.

The review The project team detected several critical process steps after analysing the existing production process:

The reaction batch is always prepared at the start of the late shift, as the reaction can take place without the need for major manual intervention overnight. However, the subsequent separation and cleaning in the Nutsche filter requires several manual actions that must take place during daytime. This means that despite an actual processing time of approx. 10 hours, a single batch alone can be produced in a 24-hour period unless major additional investments are made to upgrade the existing infrastructure.

Previous process The previous production process adheres to the traditional ‘reaction — separation & washing — crystallisation — drying — packaging’ process chain. Each of these steps involves an autonomous batch process, so the overall production batch is produced in independent steps and in sequence.

The daily active ingredient (solid) production yield of approx. 120 kg is manufactured in a 4,000 L reactor over the course of 8–10 hours.

The yield is then transferred to a single-plate Nutsche filter that can accommodate the entire batch.

This filter separates the reaction residue from the mother liquor that contains the active ingredient and rinses it with a solvent to increase the final yield. The solvent is then flushed out with water to allow for proper disposal of the residue. This process step takes between 10–14 hours.

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Filtrate samples taken throughout the process ensure the required product quality. However, this measure also introduces some uncertainty regarding the duration of the individual processing steps.

The time to complete each process step can vary depending on the cake structure, washing agent distribution, crack formation etc. Also, changing from turbid to clear flow at the beginning of the process, as well as mixing in washing agents, can lead to a significant loss of the active ingredient. In the following process step, there must be no solids in the active ingredient solution. This reduces the final utility of the original reaction batch to the so-called ‘mean production’, which constitutes roughly 75% of the active ingredient generated in the reactor.

Finally, the active ingredient is precipitated from the cleansed solution in a crystallisation step and then dried in a spray dryer.

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Also, the amount of active ingredient produced in the reactor exceeds the actual yield after drying. Most of the loss occurs in the Nutsche filter. The turbid flow stage at the beginning of filtration causes the loss of a large amount of the active ingredient. Further loss takes place due to limited carry-over of solvent into the crystallisation process.

An insufficient load alters the crystallisation behaviour, thus resulting in a grain distribution outside the specified range.

The crystallisation and drying facility is used for just a few hours each day. Yet, due to the long batch filtration cycle time, multiple runs cannot be performed with certainty. Valuable potential is thus wasted.

A second reactor for alternating production could theoretically double the output if the downstream process allowed for such a setup.

Looking for a way to significantly increase the production capacity, the project team determines that greater output can be achieved either by installing a second production line or by leveraging the unused potential, ideally in combination with improving the yield.

Based on these insights, the separation stage is found to be the production bottleneck. The project team consequently analyses what causes problems at this stage and works out possible solutions. Extensive lab and pilot tests are executed to gauge various versions and configurations to modify the existing Nutsche filter. This includes ‘disruptive solutions’ that challenge the entire batch-based production concept.

In the end, the advantages of continuous production convince the project team to change the underlying concept of the existing line. Therefore, project management recommends modifying the introduction of a continuously operating BHS Rotary Pressure Filter (RPF) and addition of new reactors.

The solution

A fully continuous separator such as the BHS RPF can process the resulting 8,000 L of solution produced daily to filter out 240 kg of the active ingredient (in a continuous product flow of approx. 340 L/h). A filter surface of just 0.5 m² is fully sufficient for production. The previous 4,000L batch system formed a 30- to 50-cm-high filter cake from all solids contained in the batch. In contrast, the BHS Rotary Pressure Filter of type RPF P02 reduces the cake thickness to about 10 mm, which results in lower cake resistance.

With a thinner filter cake, the filtration pressure can be lower. This enables the use of a dense filter medium, which results in clear flow, removing the need for the turbid flow stage. By removing this stage, loss of the active ingredient is reduced from approx. 25% to less than 5%.

Moreover, the compact structure of the filter cake facilitates solid washing.

Additional online monitoring of the washing filtrates allows the operator to quickly optimise the quantity of the washing agent. Therefore, the pharmaceutical company is consequently able to reduce the amount of solvents by roughly 20%.

Optimised piston flow cake washing also means that now the entire washing filtrate is usable. Here, too, continuous processing in connection with process-analytical technologies (PAT) leads to a more efficient use of consumables and thus higher yields.

The conclusion Batch-based operation with a complex process flow, high consumable requirements and mediocre yield was improved by putting a continuous process in place. The success of this production redesign is in large part owing to the rotary pressure filter of type RPF P02 with an active filter surface of 0.5 m².

A continuous solution increases production to the order of 150%, while incurring only a fraction of the investment costs of the previous manufacturing process. Additionally, changing to continuous filtration increases the yield by nearly a third. The key to achieving these benefits is the ability to monitor the continuous filtration and cleaning process online.

The first challenge relating to this concept is to generate a continuous production flow from the batch reactor. As it is not possible to change the reaction itself, either buffer containers need to be introduced to stretch batch production for downstream processes, or a second reactor needs to be installed to enable alternating operation.

The table below shows the individual process stages performed in the rotary pressure filter of type RPF during continuous operation.

Starting with (a) suspension feeding and filtration to (b) cake washing and (c) cake drying all the way to (d) discharging the cake.

STAGE 1

STAGE 2

STAGE 3

STAGE 4

Suspension feeding and filtration

Cake washing

Cake drying

Cake discharge

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23

SECTOR HIGHLIGHTS

Inflection point With the industry experiencing dramatic change, from regulatory changes to investments in capacity and the uncertainty of the political landscape, we asked several industry heads to review the opportunities, challenges and trends of 2017.

M

uch has happened over the course of the year for the pharma industry, there have been a slew of opportunities through advancements, investments and expansions. Yet, the industry has also experienced challenges and is currently riding the tide of The new political uncertainty. serialisation

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requirements in the US and Europe are the biggest regulatory change currently affecting our industry – Quick

”

Despite these challenges, however, the European Federation of Pharmaceutical Industries and Associations (EFPIA) reported that the pharma industry represents a key asset to the European economy.1 Contributing both directly and indirectly to global economies, there can be no doubt pharma health is a matter of great importance.

Investments, expansions and acquisitions Throughout the year, we have witnessed a lot of news on expansions, investments and acquisitions. Companies have been looking to improve operations to meet growing demand in various therapeutic areas.

As such, expansions were highlighted as a big opportunity for some of our invited experts. Cambrex, for example, fully integrated PharmaCore over the past year to enhance and complement its portfolio and manufacturing facilities in the US and Europe.

“Companies are facing a choice of whether to expand organically or strengthen through M&A activity,” said Simon Edwards, VP, Global Sales and Business Development, Cambrex. “We have moved past the stage where projects are judged solely on cost and price, but the whole value proposal, and one where quality is back again at the top of the list.”

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Expanding into the emerging markets represented a significant win for Recipharm with the strategic acquisition of Kemwell’s pharmaceutical business in India. “The addition of Kemwell has hugely increased our development operation both in terms of scale and breadth of capabilities,” stated Mark Quick, executive vice president of corporate development, Recipharm. “Our Bengaluru facility is now our centre of excellence for stability studies, as well as adding US FDA and EU approved efficient manufacturing options to our business.”

Investing and expanding manufacturing capabilities ranked highly for both ChargePoint and Idifarma — the former investing in new manufacturing machinery to meet increasing containment demand, driven by growth within therapeutic areas, and the latter expanding its GMP manufacturing offering.

Serialisation — an enormous project Serialisation has been discussed extensively over the past year and with the deadline for Europe coming in 2019 and already past for the US, this compliance requirement is considered by some to be a potential headache and for others a massive opportunity!

“The new serialisation requirements in the US and Europe are the biggest regulatory change currently affecting our industry,” emphasized Quick. “As such, they have been a key focus for pharmaceutical manufacturers throughout 2017 and are shaping the sector.

It has presented a huge opportunity to us. In 2016, we committed to invest �40 million in our serialisation programme, preparing us for the European Falsified Medicines Directive (EU-FMD).”

Tjoapack have also made significant preparations for compliance through the implementation of fully aggregated serialisation in 2008.

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“ This is proving to be a huge advantage in terms of preparing us for newly introduced legislation worldwide,” added Dexter Tjoa, director of corporate strategy, Tjoapack.

“We are ready for the deadlines in both the US and Europe.”

Already, we have witnessed a delay in the enforcement of the US Drug Supply Chain Security Act (DSCSA) by a year due to a lack of readiness in the industry. This, according to Quick is leading to consolidation among contract manufacturers.

This viewpoint was shared by Jean-Marie Aulnette, vice president of EMEA Sales, TraceLink, who stated: “Lack of preparedness for serialisation requirements is already beginning to shape the pharmaceutical landscape, and the situation will heighten.

Consolidation is likely among smaller industry players who lack the available resources to invest in new technologies and processes for compliance.”

“The enormity of serialisation projects has driven a trend towards outsourcing project implementation to specialist third-party suppliers,” said David Staunton, director of global managed services at Zenith Technologies. “As the deadlines for EU and US regulatory enforcement approach, the need to become compliant is becoming more urgent.”

Consolidation and the one-stop-shop!

As we have seen in the discussions around serialisation, there is an inevitable drive towards consolidation in the contract manufacturing space. “As the industry looks not only to outsource commodity services but also highlevel expertise in R&D, the contract development and manufacturing organisation (CDMO) sector is evolving at a rapid rate,” stressed Claire Madden-Smith, SVP at Juniper Pharma Services. “Consolidation in the CDMO sector is expected to continue at around 10–20% for the next few years.”

This trend towards consolidation will also have an effect on the way that services are delivered. Quick explained: “Small, niche players are struggling to compete with larger CDMOs that can offer customers a more complete development and manufacturing service that simplifies their supply chain. CDMOs that can provide solutions across the globe, including supporting market access restrictions such as those in Russia and Turkey, are well positioned for growth.”

“The need for specialists and experts is as important now as ever — merely being a company with ‘capacity for hire’ is not an option,” continued Edwards. “The trend towards becoming a ‘one stop shop’ is still in vogue despite numerous attempts in the past to leverage value from the concept.”

Biopharma and the rise in high potency drugs Growth areas witnessed this year have included the biopharma market — which has experienced a surge in the need for the development of potent compounds and an increase in conventional drug manufacturing using high potency active pharmaceutical ingredients (HPAPIs).

“In an industry that is seeing a surge in oncology and immune-suppressant therapies, and increasing demand for HPAPIs, there is a growing need for manufacturers to look at more innovative containment strategies In the coming to meet high potency handling requirements,” stated Avraam. years, once “In this environment, ensuring security fears operator safety, alongside are eased, the protecting the drug product market for cloud to avoid cross contamination computing will (particularly in the case of aseptic processing), is a challenge that undoubtedly must be addressed.” experience

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huge growth – Covey-Crump

“Currently, approximately 25% of drugs in development worldwide are classified as highly potent,” explained Leal.

“This number continues to rise, driven in particular by growth in the oncology market and cancer-related drugs, which account for approximately 60% of all highly potent APIs.”

”

Leal added that this growth is driving the need for agile CDMOs that have the experience and expertise to handle complex, low volume projects involving highly potent drugs. “Also,” he continued, “increasing regulatory, safety and environmental requirements are driving the need for specialist providers of high potency capabilities in the pharmaceutical industry.”

“Funding in this area has remained strong, which has greatly influenced the need for outsourcing,” commented Madden-Smith. “The high level of investment in biotech companies comes with significant pressures to deliver clinical results as rapidly as possible, especially in many therapeutic areas where there is a significant unmet medical need.”

Moving to the cloud?

An increasing theme has been the management of data, particularly in preparation for the upcoming serialisation requirements.

“With new serialisation requirements, companies are being forced to handle large volumes of data, and overcome the associated challenges such as data integrity and security,” revealed Aulnette. “As a result, cloud platform adoption is increasing, as companies realise that to simplify the exchange of data with supply chain partners, they need to be part of an established network. This is a trend that will only continue as new global regulations take hold and the supply chain becomes more complex.”

“In 2017, the industry has gradually begun to embrace Software as a Service (SaaS) and the idea of using solutions hosted in the cloud,” reported Dr Liz Covey-Crump — director of Business Development at Lhasa.

“Pharmaceutical companies are beginning to realise that the scalability and agility of the cloud can support R&D, simplify clinical research and deliver significant cost savings.”

Avraam echoed this explaining that through embracing a more automated approach, the industry will be able to receive vital equipment performance data and generate audit trails faster and easier. “As a result, maintenance, health and safety and compliance teams in high potency manufacturing environments can ensure the safer and contaminationfree handling of API and other formulation ingredients,” he said.

At SGS Life Sciences — Clinical Research, Wim Verreth (head of Business Development and Support) discussed the trends in the clinical trial space. “Obviously, strong R&D trends such as eSource, more specifically immediate electronic capturing of data at the bed side or ePRO (electronic collection of patient reported outcomes), and the use of wearable devices by the subjects improve the quality and speed of the data collection, and allows us to better monitor the overall safety and efficacy of the new treatments,” he stated.

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“In the coming years, once security fears are eased, the market for cloud computing will undoubtedly experience huge growth,” summarised Covey-Crump.

Pan-Atlantic highs and European lows The pan-Atlantic landscape had a boost with the recent formation of the ‘Mutual Recognition Agreement’ by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA),2 allowing eight European drug regulatory authorities to conduct inspections of manufacturing facilities that meet FDA requirements.

“Under this agreement, US and EU regulators will be able to utilise each other’s good manufacturing practice (GMP) inspections of pharmaceutical manufacturing facilities,” said Leal. “This is a positive move and will bring greater efficiency across the industry.”

Casting a shadow over the year, however, has been Brexit and the implications this may have for the industry. We have already been informed of the relocation of the EMA to Amsterdam from London, with concerns raised over medicines safety with this upheaval and a risk of losing staff, resulting in a disruption of services.

“The biggest challenge Lhasa has faced in 2017 related to the uncertainty around Brexit – which in turn has resulted in two common challenges,” said Covey-Crump. “The first of these relates to the potential of participating in future EU funded projects; the second involves future recruitment of valuable skilled EU citizens.”

Final words…

“The pharma industry is at an exciting inflection point,” concluded Staunton. “This evolving industry focus, combined with the large-scale capital investments, is allowing clients to ‘make the most of now’ both this year and into 2018.”

References: 1. https://www.efpia.eu/media/219735/efpiapharmafigures2017_statisticbroch_v04-final.pdf 2. https://www.fda.gov/NewsEvents/Newsroom/ PressAnnouncements/ucm583057.htm Contributors • Simon Edwards — VP, Global Sales and Business Development, Cambrex • Michael Avraam, global product manager, ChargePoint Technology • Manuel Leal, business development director, Idifarma • Claire Madden-Smith, SVP at Juniper Pharma Services • Dr Liz Covey-Crump — director of Business Development, Lhasa Limited • Mark Quick, executive vice president of corporate development, Recipharm • Wim Verreth, head of Business Development and Support, SGS Life Sciences — Clinical Research • Dexter Tjoa, director of corporate strategy, Tjoapack • Jean-Marie Aulnette, vice president of EMEA Sales, TraceLink • David Staunton, director of global managed services, Zenith Technologies

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TABLET & TOOLING

Large volumes only!

Despite its popularity in the food and chemical industries, continuous manufacturing in pharmaceutical tablet production has not been well adopted. However, there are diverse advantages of this method of production, especially for large volume products. Here, GEA assess the specific benefits of continuous manufacturing for pharma.

D

espite the fact that less well-regulated food and chemical production has long been dominated by continuous manufacturing (CM), pharmaceutical tablet production — until relatively recently — was solely a batch-based process.

In terms of product volumes, as opposed to product values, the blockbuster era is over! Now, several bestselling products are priced in the $100 per tablet range. When the pharmaceutical industry started to develop these products, they identified three further CM benefits.

To add some context, the aforementioned food and chemical lines are typically used to manufacturing a single, large-volume item and, as such, require very little cleaning and rarely undergo product benefits changeovers.

Pharmaceutical development: When working with rare and/or expensive active pharmaceutical ingredients (APIs), development can be done with significantly smaller amounts of material. You don’t need to process an entire (small) batch to generate a design of experiment (DoE) data point, just run a continuous line for a short while until stable conditions have been reached (typically about two minutes). Then, the next data point can be assessed. This not only saves huge amounts of API, it speeds up development as well.

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The of continuous manufacturing are diverse and many… all of which contribute to more costeffective production — especially for large volume products.

Advantages of continuous manufacturing The benefits of continuous manufacturing are diverse and many, ranging from smaller installation footprints, greater levels of efficiency, higher quality, lower staffing requirements and shorter cycle times, all of which contribute to more cost-effective production — especially for large volume products.

So why was big pharma hesitant to adopt CM? Conventional wisdom suggested that only large volume products (more than 1 billion tablets per year) justified dedicated production lines. And, although some over-thecounter (OTC) products are manufactured in volumes of more than 10 billion tablets per year, the vast majority of pharmaceutical solid dosage forms are produced in much smaller quantities that don’t warrant a dedicated line.

”

Furthermore, the CM lines in the food industry are extremely complex. Should extensive cleaning be required during a product changeover, for example, the potential downtime could extend to several weeks, which would eliminate any cost advantages gained as a result of the increased productivity.

The right time for pharma CM? During the last decade, the pharmaceutical industry has become increasingly interested in CM for a number of reasons. In batch mode, the finished product (as well as intermediate products) is tested by quality control (QC) personnel and either the entire lot is accepted or the entire lot is rejected.

As this procedure has, in several cases, actually resulted in drug shortages, the authorities have put considerable pressure on pharmaceutical companies to implement a much higher level of process control and understanding to minimise the risk of out-of-specification (OOS) batches and consequent product losses.

By contrast, tablet compression has always been a continuous operation, including an inline weight check of every tablet. Compared with endproduct testing, only a limited number of tablets are rejected should weight variations occur.

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Eliminate scale-up: As products for clinical trials and commercial supply are made using the same line, there’s no need for scale-up. It’s simply a matter of how long you run the machinery.

Reduced losses for IPC and QC: Modern analytical techniques allow the inline determination of (nearly) all critical quality attributes (CQAs) without the need to extract material for destructive testing. This massively increases the yield, particularly when working with small volume/high value products. Real-time release (RTR) capitalises on this concept: if the in-process controls (IPCs) are within specification, no final QC testing is required. Just ask Vertex!

The direct compression trend For large-volume products, economics often dictate the use of ingredients with suboptimal physical properties (such as flowability). During wet granulation, these materials are converted to a form that’s easier to process using a high-speed tablet press. This process also reduces the risk of segregation. For small-volume products, however, the situation is different.

Here, it is more economical to use more expensive raw materials with optimised physical properties and eliminate the wet granulation step.

CM also removes the risk of segregation. In batch mode, hundreds of kilograms of granules sit above the tablet press and are exposed to all kinds of mechanical forces; during continuous processing, the formulation is blended and compressed immediately.

Conclusion Whereas the food and chemical industries are chiefly interested in the throughput benefits of using dedicated large-scale systems, the advantages of CM for big pharma manifest themselves in massively reduced OOS product, huge API savings during development and the elimination of scale-up.

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PHARMAPACK PREVIEW

À bientôt As we get set for Pharmapack Europe, taking place early next year — 7 & 8 February, we preview some of the key aspects of this event that makes it an inevitable industry favourite.

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harmapack Europe is the industry’s go-to place to kick-off the year. The next edition of the two-day exhibition and conference for Pharmaceutical packaging and drug delivery takes place on 7 and 8 February 2018, at Paris Expo, Porte de Versailles, France.

There will be an anticipated 411 exhibitors and over 5,290 attendees at the 2018 show, looking to get an update on the latest trends, developments and regulations impacting the industry.

Pharmapack exhibitors encompass the pharma packaging, medical devices, packaging materials as well as packaging machinery and equipment industries. They come from 35 countries around the world to present their innovative products and services.

The 2018 conference focus will be on subjects that are currently receiving close review within the industry: 1. Regulatory changes and impacts.

2. Challenges in packaging and devices development: biologics, material, sustainability and quality consistency.

3. How will new drug delivery revolutionize life and improve treatment adherence?

Visitors to the show will also have the opportunity to benefit from features, such as: ✪ Innovation Gallery — showcasing the latest industry innovations, ✪ Pharmapack Start-up Hub — gathering the most innovative start-ups, ✪ International Meetings Programme — facilitating pre-planned networking or ✪ Innovation Tours — hosted by industry experts.

Did you know?

Each year, the Pharmapack Awards recognise new products that are set to shape the future of the industry in two categories: Exhibitor Innovations and Health Products.

The awards are judged by a panel of independent industry experts and are a yearly returning highlight at Pharmapack Europe.

86% of visitors attended Pharmapack 2017 for the quality of the companies exhibiting.

Important companies exhibiting include Aptar Pharma, Biocorp and Cetis.

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EXHIBITION & CONFERENCE 7-8 FEBRUARY 2018 PARIS EXPO, PORTE DE VERSAILLES

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• Innovation Gallery • Pharmapack Awards • Innovation Tours • Pharmapack Start-up Hub

• Networking Areas & Events • International Meetings Programme

EDUCATION

INNOVATION

NETWORKING

Pharma’s dedicated packaging & drug delivery event

• Conference • Symposium • Workshops • Learning Lab

REGISTER NOW! #PharmapackEU

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O Diary entry #8

LAB DIARY

In the final instalment of the Lab Diary, R&D software provider, IDBS looks at today’s lab annoyances may be solved with tomorrow’s technologies.

Problems which currently plague the laboratory, from short staffing, manual processes and repetitive mundane tasks, are all in the sights of technology providers.

New technologies have the potential to reshape the way researchers collaborate, produce research and engage with their equipment, facilitating many new potential hardware and software implementations further down the line. Take repetitive strain injury (RSI) caused by pipetting, for example. This simple, unassuming task used to be a major problem for research organisations, with the potential for injuries to escalate into prolonged and expensive lawsuits.

Thankfully, an increased prevalence of new and easily accessible technologies and equipment, such as ergonomic pipettes, has effectively eliminated this particular RSI problem. While technology will not be able to solve every pet peeve — from sticky fingers to staff accountability for broken equipment — it can go a long way in freeing up time for researchers to concentrate on making new discoveries. So, if technology can solve problems like pipetting, what else could be solved in the years ahead?

No more handwriting or keyboard nightmares Despite the technology already available, many laboratories still rely on paper notebooks for record keeping, and that can be bad news if you’re working with colleagues whose handwriting is a bit ‘suspect’.

Replicating experiments with illegible writing can be impossible, and manual transcriptions can lead to compounded errors, costing businesses thousands upon thousands.

An electronic laboratory notebook (ELN) can solve the handwriting problem — but using an ELN still means you might need to stop mid-experiment to record valuable information. Fortunately, there is a solution on the horizon: voice recognition. In just a few short years, voice recognition technology has improved considerably. It’s likely we’ve all used an ‘assistant’ like Siri, Alexa or Cortana, and it’s only a matter of time before similar technologies in the lab are capable of understanding and transcribing scientific terms and vocabularies.

Just imagine, no more illegible handwriting and no more keyboards!

Radio-frequency identification (RFID) tags are a good example.

They allow for the automated reading of data, meaning test tubes won’t need to be scanned or have their information manually inputted, because storage spaces — like fridges — can automatically detect what is being kept, and where. In the long-term, this technology could even see laboratories ordering or re-ordering items that are running low, without the need for human intervention.

End the goose chase with external partners Working with external partners or collaborators can be very beneficial for laboratories, giving them access to expertise and resources when they’re needed most. But, despite the rise of CROs and CMOs in recent years, managing collaboration partners can still be painfully difficult. It’s easy to see why — with teams based in different locations, time zones, and using different technologies, transferring and managing data effectively is a tough ask.

When you’re paying for data, you shouldn’t compromise on data quality — and cloud technology will be able to help you manage all your external partnerships from one platform. No more password protected emails, or internet transfers for data files. Instead, your partner’s results can be passed back directly into your ELN and even automatically checked for accuracy. Going one step further, it’s even conceivable that your platform could soon be able to choose a suitable collaboration team for you, based on your project type and budget.

Looking to the future We all have our own grievances in the lab, so it’s unlikely that technology will be able to solve everything within the next few years.

That said, with the rate at which technology is already evolving, the new advanced systems already in development could find their way into your laboratory sooner than you might expect. The cloud is more accessible than ever before, and organisations are already looking at the automation and machine learning industries with keen interest. Anything is possible, so watch this space.

Make stock-taking and book-keeping a thing of the past So, hands up, who really enjoys admin? Stock-taking and bookkeeping are some of the most time-consuming and mundane tasks to undertake in the lab. In future though, it’s likely we’ll see technology taking on some of the lab’s more repetitive tasks, freeing up time for scientists to spend on more valuable activities.

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@makingpharma

13-14 March 2018 Exhibition & Conference Brussels Expo, Place de Belgique 1, 1020 Bruxelles, Belgium

The Exhibition:

The Conference:

Forge new business partnerships

Comprehensive and FREE to attend

Meet face to face with new and existing clients

Processing Regulations Serialisation Excipients Active Ingredients Medical Devices Microbiology and Pharma Pharmaceutical Engineering GMP Packaging New Technologies

Learn about the latest innovations and developments in your industry Network with other key industry professionals Showcase your products, services and expertise to the market place Launch new products and services Focus on future investment & business strategies

To secure your stand and all the latest event updates Tel: 01892 518877 or email Marie-CharlotteGrene@stepex.com

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GDP Biosimilars Clinical Testing Research and Development CDMO Data Management Pharmaceutical Quality Operational Excellence Pharmaceutical Laboratories Clean Room Technology Excipients

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