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Contents June 2016 | Volume 16 Issue 4

Regulars 5

25

Features 18

COMMENT

A FINE ART

6

How much of the fine chemicals market can pharma lay claim to?

Jan Ramakers explores

NEWS FOCUS

21

8

31

REGULATORY AFFAIRS

10 NEWS ANALYSIS

ON THE SURFACE…

OPINION

Copley Scientific, outlines testing strategies for topical semi-solids

COPA-DATA and GSK look at regulatory compliance and the importance of transparency

25 GO IT ALONE

16

Expertise in the benefits of singleuse from Quattroflow and Merck

COVER STORY Jörg Gierds, Fette Compacting, looks at effective protection against cross contamination in tabletting

PHARMA AT THE FLICKS

Ashfield Healthcare Communications, examines the role of digital health in the pharma sector

23

13

34

TWO BECOMES ONE

29 COVER DRIVE

32

Hermes Pharma is offering hot melt coatings for the pharmaceutical sector

31 PURE AND SIMPLE Bosch Packaging Technology explains how its latest development is helping the production of pure media in the pharma sector

32 THIS IS THE REAL THING… Mettler-Toledo explains how new product inspection technology can help prevent pharmaceutical product counterfeiting

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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 16 Issue 4 © June 2016 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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BPA Worldwide Membership ISSN No - 2052-4811

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Better medicines through science and engineering.

from the editor

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5

NEWS FOCUS

Designing better drugs – new strategy for more potent class of protein drugs A team at the Wyss Institute for Biologically Inspired Engineering has developed a drug engineering approach could breathe new life into drug development

A

new strategy for engineering protein fusions – to make specific cell-targeted drugs without side effects – could enable a safer, more potent class of protein drugs. A team at the Wyss Institute for Biologically Inspired Engineering has designed a better variant of the widely-used drug erythropoietin (EPO), showing how rational design can improve in vivo efficacy and safety of protein therapeutics, reduce potential side effects, and also accelerate new drug development. The findings were published online April 25 in the Proceedings of the National Academy of Sciences journal.

"Our concept is completely general," said Pamela Silver, PhD, the study's corresponding author and Onie Adams professor of biochemistry and systems biology at Harvard Medical School (HMS).

"We can reduce the toxicity of approved protein drugs, and may also be able to rehabilitate protein fusion drugs that have so far failed in clinical trials due to unacceptable side effects."

Like many drugs, protein therapeutics can cause unwanted side effects. Such has been the case for erythropoietin (EPO), a natural hormone secreted by the kidneys to increase red blood cell production, of which laboratory-synthesised variants have been widely used to treat anaemia stemming from kidney disease or chemotherapy.

However, EPO not only activates red blood cell production but can also cause dangerous complications, such as blood clotting and boosted blood vessel growth.

As a result, patients treated with EPO often suffer from higher rates of heart attack, stroke, and accelerated tumour growth. Therefore, the FDA has issued its strictest warning – a black box label advising of serious hazards associated with the drug – for the use of EPO drugs. To combat this problem, the Wyss team rationally designed a more effective, multi-part drug molecule.

"Compared to currently available EPO drugs, our molecule is engineered to prevent EPO from binding to and activating cells that promote side effects such as blood clotting or tumour growth," said Jeffrey Way, Wyss Institute senior staff scientist and the senior author on the study. "This cell-targeted EPO approach demonstrates a new theoretical basis for the rational design of engineered protein fusion drugs."

6

The team genetically mutated EPO protein, reducing its ability to bind to cell receptors. Using a chain of amino acids as a flexible linker, they attached mutated EPO to a specific antibody fragment. The antibody fragment was selected because it uniquely binds to the cell membranes of red blood cell precursors while avoiding other types of blood cells that control clotting and vessel growth.

When the team's fusion protein molecules were delivered to mice, the antibody fragments piloted toward and bound to the membranes of red blood cell precursors, towing along EPO molecules on the other end of their linkers. In such close proximity to the surface of the cells, a high concentration of tethered EPO bounced around until they ultimately toggled into place on the cell's receptors. In this way, side effects were avoided and only red blood cell production was increased.

"Our rational design strategy is unique compared to current industry approaches," said the study's first author Devin Burrill, PhD. "Our goal is to use our method to advance predictive drug design and minimise the time between drug concept and commercialisation."

"The principles of synthetic biology influenced our efforts," said Wyss core faculty member James Collins, PhD., coauthor on the study. "In drug development, the focus is typically on increasing the strength of interaction with a drug target, but here we found that weakening an interaction was useful. This illustrates how we need to adopt alternative, non-traditional approaches if we want to build complex, multi-part therapeutics."

The specific, cell-targeted approach could be applied quite broadly. The Wyss team has unveiled not only a novel design of its ‘targeted EPO’, but also ‘targeted interferon alfa’, a cancer drug that can otherwise cause side effects including flu-like symptoms, mood fluctuations, and depression.

"This is another great example of how using a synthetic 'bottom-up' engineering approach and leveraging the power of biological design – this time at the scale of individual molecules interacting on cell membranes – can lead to breakthrough technologies for medicine that overcome limitations that hold back more conventional approaches," said Wyss Institute founding director Donald Ingber.

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Image credit: Wyss Institute at Harvard University.

NEWS FOCUS

UK pharma ranks highly when it comes to reputation

Abbvie, Sanofi and Novo Nordisk seens as most reputable pharma companies in the UK and industry as a whole ranked third most reputable by general public

AbbVie, Sanofi and Novo Nordisk topped the RepTrak ranking of the most reputable pharmaceutical companies in the UK, This was based on findings collected from 1,600 members of the UK general public.

The survey also found that feelings towards the pharmaceutical industry are significantly more favourable in the UK compared with many other global markets, including key European countries. It was found to be the third most reputable industry in the UK. The top ten companies in the 2016 UK Pharma RepTrak, with strong reputations, are: 1.

AbbVie

2.

Sanofi

3.

Novo Nordisk

4.

Merck Sharp & Dohme (MSD)

5.

Abbott Laboratories

6.

Allergan

7.

Bayer

8.

Astellas

9.

Bristol-Myers Squibb

10.

Shire

The RepTrak study reveals that corporate narrative is more important than products for a pharma company’s reputation. The UK general public’s willingness to recommend a pharma company, speak about it positively and buy its products is predominantly driven by perceptions of the company (61%), vs. the products themselves (39%). Despite the importance the UK general public places on pharma companies’ governance, citizenship and leadership, only 50% are actually aware of what businesses are doing in these areas.

Kasper Ulf Nielsen, executive partner at Reputation Institute which carried out the survey, commented: “With perceptions of who you are as a company being such a huge driver of reputation, and the lack of understanding in the general public about what the individual companies stand for, the message is clear. The pharmaceutical companies should focus on engaging and telling their corporate story to put a human face on the companies behind the drugs.”

“The results in the UK demonstrate that pharmaceutical companies should not be afraid to tell their story. The levels of trust, admiration, and respect for who they are is strong among the general public, and they want to know more.”

Novo Nordisk, which came third in the UK Pharma RepTrak rankings, with a score of 77.6 has the best corporate social responsibility (CSR) score in the UK and has benefitted from sticking to its Triple Bottom Line business principle.

Giants Roche, GlaxoSmithKline and Pfizer are sitting at the bottom of the pack this year, with perceptions of GSK declining from ‘strong’ to ‘average’ over the last three years.

GlaxoSmithKline, has also invested heavily in a CSR campaign but is sitting down in fifteenth position with an ‘average’ score of 66.8. The GSK program has been focused around 23 forward-looking commitments across four areas of their responsible business approach, including health for all, behaviour in terms of improving access to healthcare for all, and providing a positive workplace. Nielsen commented: “The focus GSK has placed on improving its CSR perception is clearly yet to resonate with UK consumers. We see that more than 50% of the UK general public is uncertain as to whether they believe that GSK is as a good corporate citizen, that treats its employees well, and who is open and transparent about the way it does business.”

Interestingly, companies within the pharmaceutical industry have a better reputation in the UK than elsewhere in the world. Pharmaceutical companies in the UK have an average score of 72.8, while the average score globally is only 67.6; the US comes in at a close second with a score of 72.7.

Reputation Institute’s research reveals that reputation drives business results. For pharmaceutical companies with an average reputation, only 20% would definitely recommend the company; this climbs to 31% if the reputation is strong, but increases to 79% if the reputation is excellent.

The sector also ranks favourably as a whole in the UK. The sector has the third best reputation, beating eight others, due to strength across all seven rational dimensions of reputation.

“The impact of reputation on the business is massive, which is why the leading companies in the world are managing this asset in a systematic way,” said Nielsen.

The RepTrak system measures a company’s ability to deliver on products and services, innovation, workplace, governance, citizenship, leadership, and performance.

AbbVie, Sanofi and Novo Nordisk lead the pharmaceutical category, with MSD and Sanofi showing major improvements on last year, and AbbVie taking the lead in its first year of measurement.

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7

REGULATORY AFFAIRS

Guiding hand Kaat Bracquiné, quality and regulatory affairs, Capsugel explains how to achieve compliance with the new EU guidelines for excipient GMPs Photo: Advice line - Kaat Bracquiné, Capsugel offers expert advice on how to achieve compliance with the new EU guidelines for excipient GMPs

L

ast year, the European Union published new guidelines (2015/C 95/02) that require the pharmaceutical industry to demonstrate appropriate excipient Good Manufacturing Practices (GMPs) through a formalised risk assessment. As of the implementation deadline in March 2016, pharmaceutical companies should have conducted these formalised risk assessments and have them available to EU regulatory inspectors.

Excipient GMPs provide assurance that excipients are consistently produced and controlled to the quality standards appropriate to their intended use and as required by product specification. The EU guidelines require all manufacturing authorization holders to: • Determine the risk profile of each excipient, taking into account the excipient source (animal, mineral, synthetic, etc.) and its use and function in the medical product;

• Determine the appropriate GMP, associated with the risk of the excipient; • Perform a gap analysis of the activities and capabilities of each excipient manufacturer used; • Establish an appropriate control strategy; and • Ensure ongoing risk review.

While international regulatory authorities have long published mandatory GMP standards for medical products, they haven’t always done so for excipients. As a result for many pharmaceutical companies, this might be new territory. Moreover, since the industry uses a wide variety of excipients – comprised from various origins, sourced for numerous applications and manufactured under different quality standards – compliance with the guidelines can prove a real challenge.

Given these obstacles, some pharmaceutical companies may not yet be prepared for the new EU guidelines. Now that the deadline has passed, companies that have not completed their formalised risk assessments face the potential of EU regulatory warnings and other actions. With that in mind, what steps can these companies take to more quickly achieve compliance with the EU guidelines?

First, pharmaceutical companies can reference recommendations from their industry peers. For example, the International Pharmaceutical Excipients Council Europe (IPEC Europe), the industry association for producers, distributors and users of pharmaceutical excipients, recently published a comprehensive ‘how-to’ document to help pharmaceutical companies comply with the new EU guidelines. The document, released in March,

8

includes practical and technical approaches for companies to implement the steps necessary to achieve compliance. Additionally, the IPEC ‘how-to’ document contains several useful annexes, with a.o. legislative tools for risk mitigation and an overview of available GMP/quality standards facilitating gap analysis with the expected GMP principles.

Second, pharmaceutical companies can seek out specialised excipient manufacturers – some of which, like Capsugel, participated on IPEC Europe’s risk-assessment task force to develop the ‘how-to’ document – which have long invested in excipient GMPs and other quality initiatives to meet and exceed regulatory requirements. Among the key offerings to look for: 1. Independent GMP Certification: Specialized excipient manufacturers with EXCiPACT-certified facilities can help pharmaceutical customers to significantly reduce their efforts needed to prove compliance with the new EU guidelines. EXCiPACT certification provides credible, independent validation that the excipient manufacturer maintains excipient GMPs and complies with current EU regulations. This certification may replace the on-site audit of excipient manufacturers by pharmaceutical companies, saving timing and resources. In 2014, Capsugel became the first hard capsule manufacturer to receive independent EXCiPACT certification for excipient GMPs at our facilities in Bornem, Belgium and Colmar, France. To date, Capsugel remains the only capsule manufacturer to receive this certification.

2. Useful Regulatory Compliance Support Packages: Specialised excipient manufacturers that offer compliance support packages for their products can help pharmaceutical companies with compliance efforts. These packages assist customers in completing their risk assessment by providing current technical information on the starting materials of their products to help facilitate required riskscoring. They can replace the resource-intense process of collecting excipient product information linked to source and origin, which is required by the EU guidelines.

3. Ongoing Regulatory Expertise: Specialised excipient manufacturers that are involved and active in IPEC Europe, and thoroughly adhere to IPEC standards, offer pharmaceutical customers with useful experience and understanding of the changing excipient requirements in Europe. These manufacturers can advise companies on ways to achieve and maintain compliance in today’s fastchanging regulatory environment, and are committed to transparent communication and change notification.

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NEWS ANALYSIS

PASS the test The importance of post-authorisation safety studies (PASS) is becoming increasingly significant, as recently highlighted by Magdalena Matusiak, KCR

T

he increasing significance of post-authorisation safety studies (PASS) was one of the topics at the DIA EuroMeeting 2016, Hamburg. Magdalena Matusiak, pharmacovigilance team lead at contract research organisation KCR, highlighted the direction of recent changes in the PASS concept during the presentation, which was a part of a session entitled, Assessing the benefits and risks as the basis of the benefit-risk management.

“

PASS is becoming an integral part of the development of medicines. Planning the design of PASS in the early phases of a clinical trial will translate into time and cost-efficiency of pre-approval research. Supporting this trend, recent regulatory requirements and recommendations help assure a high level of quality, transparency and credibility of real-life data collected.

The significant value of real-world evidences has recently been recognised and well understood by regulatory authorities and manufacturers

”

“PAS studies are becoming a vital part in drug development, especially for biological medicinal products,” said Matusiak. “Currently, biological drug development is the fastest growing segment in the healthcare industry. For the vast majority of biopharmaceuticals the long-term observation of postauthorisation is the essential condition for marketing approval.”

A post-authorisation safety study is conducted after the drug marketing authorisation to collect further information on the medicine's safety and to assure that benefits of the therapy outweigh the risks. Each marketing authorisation holder (MAH) is obliged to set up and maintain the safety management system for the purpose of monitoring, collection and assessment of adverse events reported during the clinical development of the medicinal product as well as during the post-authorisation studies.

“The significant value of real-world evidences has recently been recognised and well understood by regulatory authorities and manufacturers,” added Matusiak. “Only additional monitoring in real-life cycles allows for observation of the long-term safety and immunogenicity, interactions between products, effects of switching between similar therapies, as well as safety and efficacy assessment in other types of population not observed during clinical research.”

Current flexible regulatory approach facilitates fast and effective marketing approval. The tendency to streamline and shorten the time of the pre-approval development phase for the benefit of postapproval observation is becoming more and more prevalent. Decreased time and lower costs of the pre-approval research allow for accelerated and wider patients’ access to advanced therapies.

“

PASS is becoming an integral part of the development of medicines

PASS should be considered an integral part of the medicinal product development, not only for biopharmaceuticals.

“There is a growing role for scientific consulting services to provide creative and smart design of pre- and postauthorisation studies and this discussion starts at the beginning of the cooperation with a client,” added Matusiak.

“The process of collecting and assessing real-world evidences remains a broad area for innovative solutions, however advanced ideas are of great value only when translated into successful outcome.”

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OPINION

A smart move Martyn Williams, COPA-DATA UK describes how the pharmaceutical sector can take smarter steps to regulatory compliance

T

he pharmaceutical industry operates in one of the world’s most heavily regulated environments. Over the past few years the industry has experienced significant regulatory change. The repercussions of failing to comply with industry standards can be detrimental for pharmaceutical manufacturers. It’s no secret that the integrity and reputation of pharmaceutical brands is integral to their success. As a result, even the smallest failure can be irreversibly damaging.

With industry standards surrounding elements including product integrity, energy efficiency, health and safety and product testing, there is more pressure than ever to ensure manufacturers take steps towards compliance.

In this elaborate regulations landscape, how do manufacturers ensure production operates in an efficient and effective way?

Validation-friendly technology Digitisation of processes and the emergence of Industrial Internet of Things (IIoT) has transformed the entire manufacturing industry.

However, for pharmaceutical manufacturers the benefits of IIoT have surpassed an increase in automated productivity.

The introduction of smart devices enables real-time data reporting to central control systems – naturally reducing manual intervention and minimising adverse events during production. Paired with validation friendly software, an IIoT-enabled factory provides live monitoring of regulatory reporting, potentially reducing the validation efforts many manufacturers face with a risk-based approach. This can greatly help maximise production agility, allowing manufactures to respond to change and ultimately increase profitably.

For example, with batch control being a key step of the validation process, the combination of a smart factory and intelligent SCADA software couldn’t be more valuable. Automatically generating a trail of reliable audits, electronic signatures and real-time reporting, complicated pharmaceutical standards like FDA 21 CFR Part 11 are not so difficult to obtain.

The cloud and compliance As manufacturers embrace IIoT, migrating to the cloud is the obvious solution to house and manage the growing expanse of production data.

However, the cloud does more than just collect and store data, it allows manufacturers to gain actionable insights, directly from it.

Predictive analysis, for example, produces an intelligent forecast of when and where industrial equipment is most likely to fail. Using this data, contingency plans can be made to ensure, regardless of equipment failure, pharmaceutical production will continue to meet regulatory standards.

In addition, cloud computing enables simplified regulatory submissions.

Using data stored in the cloud, manufacturers can directly feed digitised production information to regulatory bodies. This feature can be particularly helpful speeding up the lengthy process of clinical trials as well as post drug launch.

With the ever-increasing risks concerning drug counterfeiting, efficiency challenges, adaptations to modern day agile processes and the industry-wide efforts to implement serialisation, it will be interesting to witness how IIoT can continue to solve these challenges moving forward.

Getting the green light Over the past decade, the global focus on environmental sustainability has been hard to ignore. In industry, initiatives such as the European Union’s Energy Savings Opportunity Scheme (ESOS) and the voluntary certification ISO 50001, have put pressure on manufacturers to jump on the efficiency bandwagon. Using the same IIoT and smart software combination, organisations can gather comprehensive data from the entire factory and subsequently meet these efficiency requirements.

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14:2

OPINION

I can see clearly…

Dr Stephen McDonough, UK medical director at GSK, looks at the changing relationship between industry and health professionals and how the company is adapting to society’s growing demand for greater transparency

T

he eyes of our industry are looking ahead to new rules that will come into effect this year which will influence how healthcare companies work with the medical professions.

These new rules will affect every pharmaceutical company that is a member of its national business association.

customer engagement and business planning – and no longer on individual sales targets.

Furthermore, rather than asking doctors to speak about our medicines in return for payment, as has often been the historic industry model, GSK also now makes greater use of internal medical expertise to spotlight the benefits of our medicines, by boosting the number of medics in its workforce and through digital channels to make this expertise available to healthcare professionals .

Overseen by the Association of the British Pharmaceutical Industry (ABPI) in the UK, all members of the European Federation of Pharmaceutical Industries and Associations (EFPIA) will be required to disclose certain payments to individually-named healthcare professionals. This includes speaker fees, consultancy services, advisory boards and sponsorship to attend medical education meetings. Payments to healthcare organisations, such as donations and grants, will also have to be disclosed.

We will remain committed as our business adapts and we evolve our relationships with health professionals and ultimately GSK will be in a better position for the long-term.

Current plans indicate that first disclosures are required by 30 June 2016 but at GSK UK we are pragmatically embracing these changes and aim to go one step further.

GSK recognises the need for healthcare companies to be a trusted source for high-quality, balanced information available to healthcare professionals when they need it, in the way they want it. For this reason, we are redefining the way we work and the way we educate healthcare professionals about our medicines and vaccines.

No more sales targets As we mark the 300th anniversary of its UK origins, GSK once again aims to lead the way in how the sector works with the healthcare community. This commitment was underlined three years ago when we announced our intention to stop direct payments to healthcare professionals in return for speaking engagements for our prescription medicines and attending medical conferences.

We want to ensure all interactions with healthcare professionals are governed by our values of transparency, respect, integrity and patient focus. Many companies in our industry use words such as these, but fewer are fundamentally fracturing established ways of working and actively behaving differently, as GSK has done.

This includes changes to how we incentivise our sales force, so that sales team members are measured and rewarded on applying key competencies – including technical skills, knowledge, elements of

Steps to put this into practice have seen a range of face-to-face training sessions for colleagues on how this affects them, as well as a UK project team setting out what the global frameworks mean for UK pharma in a world of changing expectations among customers, patients and society.

Making changes to the way GSK interacts with healthcare professionals was never going to be a one-way conversation and continuing to engage with customers as well as colleagues will be crucial.

We place huge importance internally in communication and education, and our leadership has underlined the need for GSK to adapt. This is an ongoing process, but the feedback from our sales force so far has so far been positive, as has the reaction from our customers. Some are more willing to work with us now than ever before.

Conversation starters As we move forward to embed these changes and with the new rules coming into effect, it is vital that across the industry we continue talking to professional bodies, government and the NHS. Maintaining this dialogue, listening to the feedback from colleagues and health professionals, and ensuring all those involved understand this is the direction industry needs to take will be key to success. It is what patients and politicians have come to expect and GSK is committed to taking people with us on this journey.

We have already made significant progress but there is still more to do.

These issues continue to be a focus for substantial public scrutiny and it is right that we continue to shape a GSK for the long-term that meets the expectations of patients, customers, stakeholders and investors.

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COVER STORY

Guard of honour The demands on containment in the pharmaceutical sector continue to grow.

Jörg Gierds, Fette Compacting, looks at effective protection against cross contamination in tabletting

Sage guards: A high-containment plant with integrated process equipment offers effective protection against crosscontamination to OEB Level 5

P

harmaceutical production increasingly involves the use of potent to highly-potent ingredients.

This is accompanied by increased demands on containment. In the future, manufacturers will be required to an even greater extent to safeguard production processes using appropriate containment technologies. Cross-contamination in particular represents a risk for patient safety and product quality. New developments in tabletting reveal the applicable requirements and technologies offering effective protection.

HPAPIs (High Potency Active Pharmaceutical Ingredients) remain a growth driver for the pharmaceutical industry. By 2022, the HPAPI market is likely to grow from 11 billion euro (2014) to 24 billion euro, according to a forecast by Grand View Research. This will mainly be attributable to advances in tumour therapy and hormone treatment. Another study – by Transparency Market Research – projects that the global market for HPAPIs will grow by an average of 10% by 2018 (Compound Annual Growth Rate, CAGR). In contrast, the pharmaceutical market is likely to grow by a mere 6%.

Furthermore, numerous patents for pharma products containing high-potency ingredients will be expiring in the years to come with the result that manufacturers of generic products will continue to increase their investments in HPAPIs. This development will also be accompanied by increased requirements for manufacturing processes.

Pharmaceutical manufacturers will be obliged to adjust to more frequent product changes involving highly-potent substances, which will be accompanied by a general risk that potent substance residue in the plant can be transferred to other products. However, the tolerances for such cases of crosscontamination are practically zero in the case of HPAPIs.

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Keep it clean: Comprehensive containment with Wash-in-Place facilities is the best protection against cross-contamination, says Jörg Gierds, Fette Compacting

Authorities focus on cross-contamination The regulatory authorities have also set their sights on the issue of crosscontamination which subsequently appears several times in chapters 3 and 5 of the EU GMP Guidelines revised in 2015. These chapters emphasise the responsibility of companies when it comes In the future, to undertaking toxicological analyses and introducing comprehensive risk manufacturers will be required to an even greater management.

“

extent to safeguard production processes using appropriate containment technologies

However, toxicological analysis represents a major challenge for many companies.

To date, for example, standard practice has involved specifying one-thousandth of the therapeutic dose as the maximum value for tolerable residue. The general rule that a maximum ten PPM (parts per million) of another product could be contained in a medicinal product still applies. In the case of HPAPIs, however, new approaches are required which consider the individual active agents. An alternative approach which would gradually replace the current official acceptance criteria is represented by the PDE value (Permitted Daily Exposure) or the ADE value (Acceptable Daily Exposure), which defines the dose least likely to display adverse effects when someone is continually exposed to it. Users can derive information on how to calculate such limit values from Annex 1 of the EU GMP Guidelines, for example. In many companies however, expertise in terms of this validation method still needs to be developed.

”

components need to be coordinated precisely and their transfer points to be continuous. These requirements can be satisfied using doubleflap valves and hollow-profile seals, for example. A WiP centre ensures optimal hygienic results for washable systems by Fette Compacting – product residue is practically eliminated thanks to a combination of diaphragm valves and orbital welded pipes.

Automated washing and easy handling Where encapsulated plants are involved, individual components must be recorded and washed by a single program. The washing programmes for the Fette Compacting WiP and containment tablet presses, for example, can be configured and programmed depending on the respective product in order to achieve optimal results. For example, the washing system is comprised of six separate circuits through which the product and dust residue is fully bound during the washing cycle. A special rotation and spray jet design ensures that the cleaning agent reaches every inch of the process Pharmaceutical area. Tight spaces which are particularly manufacturers will be difficult to access can be rinsed using a obliged to adjust to more manual spray gun or WiP gun. The rotor, pressing tools and add-on parts can be frequent product changes easily dismantled after washing and, involving highly-potent depending on requirements, subject to substances final cleaning and conservation in a separate cleaning area. This automated washing process and simplified handling of the machine components also enables manufacturers to enjoy significant savings in time.

Comprehensive containment in tableting

“

”

In order to satisfy the requirements of contamination protection in production, suitable technological concepts are vital. I believe that comprehensive containment with Wash-in-Place (WiP) facilities is the best protection against cross-contamination. As a machine manufacturer, we work intensively on such systems which can be fully integrated in the process flow, where contamination risks lurk in every pipe and seal. For this reason, all machine components must be designed so as to prevent residue from arising in the first place as well as being fully washable.

In order to minimise the risk of cross-contamination, Fette Compacting has realised special design concepts which start as soon as the plant is set up. For example, we have designed the pipe system to be very transparent in washable tablet presses. As a general rule, pipes are difficult to examine for residue on the inside which is why we use a single-pipe piping system, which directs the water via a single, easyto-control line through the plant.

Clean and clear: During automated washing of the process area, all parts coming into contact with the product are cleaned in an encapsulated area

Inside the tablet press, product loss can be particularly prevalent where machine components intersect, eg valves, seals and welded connections. In its capacity as a process part, a tablet press is subject to the corresponding pressure. This means that powder can even reach places you would never imagine it to be. Consequently, all

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17

FINE CHEMICALS

A fine art How much of the fine chemicals market can pharma lay claim to today – and in the future?

Jan Ramakers, Jan Ramakers Fine Chemical Consulting Group writes

F

ine chemicals, speciality chemicals, and performance chemicals are some of the various names used to describe products in the high-value end of the chemical market. In order to avoid any confusion, it is good to keep in mind that fine chemicals are defined as (high value) chemical products that are sold for what they are, ie for their precise chemical structure. Speciality chemicals, often also referred to as performance chemicals, are (high value) chemical products that are sold for what they do. So an intermediate used in the manufacture of a specific API is a fine chemical as it needs to have a very specific chemical structure; a different chemical structure cannot be used. Fine chemicals are used across a wide range of market segments, and it is easy enough to make a list that features 40-50 different application areas.

The products end up in speciality chemicals markets, for instance as active ingredients in biocide formulations, as additives for plastics and coatings, or as active ingredients in cosmetics and toiletries. Some are used as intermediates in the manufacture of liquid crystal displays, and so on. Many of those end markets are quite large, but most of them are fairly small as an outlet for fine chemicals.

Larger markets for fine chemicals include agrochemicals, flavours & fragrances, and dyes. Together, agrochemicals and flavours and fragrances represent some 17% of the value of the total fine chemicals market. The pharmaceutical industry has been the largest market for fine chemicals for a long time. In the late 1990s the pharmaceutical industry was responsible for just over half of the fine chemicals market.

As a result of the fact that the pharma market has enjoyed significantly higher annual growth rates than the other segments of the fine chemical market for many years, the market share of the pharmaceutical industry increased to 69% in 2014 (figure 1).

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Figure 1.

Fine chemical market split. Source: Jan Ramakers Fine Chemical Consulting Group

In view of the anticipated market developments of the various segments in the coming years, it is likely that the pharma market will account for some 73% of the fine chemical market by 2020. By that time the life science sector – human and veterinary pharma and agrochemicals – will use more than 80% of all fine chemicals (by value).

The massive market share of pharma means that the trends and developments in the pharma market largely determine what is happening in the fine chemical industry. In the remainder of this article we will look at the main trends in pharma and what they could mean for fine chemicals.

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In the nineties the annual growth of the pharma market was often in the double digit figures. Gradually however the overall growth figures came down to the current level of about 6% per year (figure 2).

Together the markets for high potency drugs and biotechnology drugs are set to grow to just over one third of the pharma market value in 2020.

Generics is the third segment of the pharma market that has shown above average recently, due to the large number of blockbuster drugs that lost patent protection in recent years (the patent cliff). The peak of the patent cliff is well behind us. In spite of that the share of generics will continue to grow, fuelled by regulations in countries around the world that promote the use of generics instead of originator drugs where possible, as part of the effort to keep the cost of health care under control.

Figure 2.

Growth of the pharma market. Source: Jan Ramakers Fine Chemical Consulting Group

It is interesting to note that the effects of the credit crunch on the global pharma market appear to have been limited, as the overall market growth did not drop off. It is fair to say however, that there have been some effects of the credit crunch on the R&D side of the pharma market.

Some segments of the pharmaceutical market are showing annual growth rates that are well above the average for the whole market.

One of those segments is high potency drugs. Currently drugs with a high potency API are estimated to represent more than 14% of the total market value. During the next few years the annual growth of this segment is estimated to be well above overall market growth.

The manufacture of high potency compounds requires specialised production equipment and because of the very low exposure limits of the compounds manufactured the barrier requirements to prevent anybody from coming into contact with the products are very strict.

Needless to say that the right equipment and physical barriers alone are not enough; training and attitude of the people running and operating the plant are even more important here than in other areas. So far the number of fine chemical companies involved in the manufacture of high potency products is limited. Because of the higher growth rates the segment does attract a lot of interest from companies that consider entering this market.

Another segment with a significantly higher growth than average is biopharmaceuticals, where the manufacture of the APIs requires at least one biotechnological step. That can be anything between a fermentation and mammalian cell technology. Currently the market for biotechnology drugs is estimated to be similar in size to the market for high potency drugs. The growth of this segment The massive market share is estimated to be in the 10-12% range for of pharma means that the the coming years, giving a market value of around $260-280 billion in 2020. A trends and developments lot of these biologicals are developed in the pharma market by specialist biotech companies. After largely determine what initial development, such companies is happening in the fine often license out their new products to the big pharma companies for chemical industry. further development, making use of the economies of scale that their partners can offer. Many of the larger fine chemical companies have invested in biotechnology (mostly fermentation), either through acquisitions or self-funded R&D and commercial plants. The relatively high investment needed to be able to use mammalian cell technology has kept all but a very few of them away from that technology.

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During the past decades an increasing number of large pharma companies have chosen to outsource more of their manufacturing to the fine chemical industry. With the increasing complexity of the chemistry and technology involved in the manufacture of the newest generations of APIs it makes sense to source those products from the specialists: the fine chemical industry. The increased outsourcing obviously creates opportunities for the fine chemical industry because it increases the merchant market The fine chemical industry for pharmaceutical fine chemicals. This remains as fragmented should not be confused with additional overall market growth however. The as it has always been, additional products that are going to and even the leading fine be outsourced because of the increased chemical producers have outsourcing level of the pharma industry a market share of only used to be made in-house by them. about 3%.

Therefore, the increase of the merchant market is compensated by an equal decrease in the captive market. Because of the increased outsourcing, in-house fine chemical equipment will be freed up and often the pharma companies will try and divest the plants to the fine chemical industry too. In that case both the merchant market and the merchant capacity will grow at the same time and overall capacity utilisation across the industry will remain more or less unchanged. Looking at the overall picture, certainly in the mid-term future more outsourcing should benefit the fine chemical industry.

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The fine chemical industry remains as fragmented as it has always been, and even the leading fine chemical producers have a market share of only about 3%. M&A activity has been low during the economic downturn but during the last few years the number of fine chemical businesses (companies or parts of larger companies) involved in M&A has increased significantly. It is interesting to note that the interest of private equity companies in acquiring businesses in the fine chemical segment is growing.

As always there are threats for the industry, such as the growing number of new fine chemical suppliers from non-traditional areas like India and China. More recently, however an increasing number of Chinese and Indian producers of pharma intermediates, drug substances, and drug products have been facing significant quality and compliance issues. As a result of that some have been (temporarily) banned from supplying their products to Western markets. At the same time their domestic markets are growing rapidly, which means ever larger quantities of drug products can be sold locally. As a result of those developments a new trend emerged, called ‘re-shoring’. Western pharma companies are increasingly bringing (custom) manufacturing back to Europe and North America.

Going forward the fine chemical industry should be able to benefit from the developments in the pharma industry, especially those fine chemical companies that are working in close partnerships with their customers, to provide high quality products as well as high quality service. That is what the pharma industry is looking for, now more than ever.

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DIGITAL HEALTH

Two becomes one Andrew Binns, strategy and planning at Ashfield Healthcare Communications, part of UDG Healthcare, examines the role of digital health in the pharma sector and the benefits it can bring

D

igital is finally making a big push into the pharma market. But can the two come together to truly create digital health and provide benefits for the end user?

A recent report from PushDoctor, a UK telemedicine company, shows that 58% of the 1,013 UK citizens surveyed have used some kind of health or wellness technology.

Another report from healthcare marketing group Ipsos Health shows that 72% of the 131 primary care doctors interviewed in the UK, Germany and France have already used or recommended at least one form of digital health technology with their patients1.

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Of the countless benefits that digital health provides, it is important to focus on the following two areas; the ever-improving ability to track and manage the impact that treatments have on a person’s life and the advancement in communication efficiency for these individuals. By digging deeper into these aspects it becomes clear as to why digital is now intrinsically linked to today’s pharma world in the form of digital health.

A report from PushDoctor shows that 58% of the 1,013 UK citizens surveyed have used some kind of health or wellness technology

Overcoming the persona

Of crucial importance is the way that a patient is tracked systematically throughout the lifecycle of their treatment. This is a huge step forward from the previous approach of simply measuring data at two points: the beginning and the end. By understanding the patient at various stages it becomes possible to deliver a more personalised and contextualised treatment offering. As a result, a patient takes the form of an ‘individual’ rather than just another ‘persona’ generated from archetypes. By using digital health to segment patients at a granular level, we can ensure any deviances or niche behavioural changes are understood and taken into account prior to and during treatment.

Personalisation helps efficiency By developing a more personalised understanding of the patient, it also becomes easier to offer relevant and appropriate treatments. The more customised the treatment, the greater the impact.

Digital health allows the metric and measurement approach to be detailed and based on data, ensuring assumptions and presumptions are removed and insight-led decisions are made.

Big data is not the answer, it is the tool

Understanding the impact that a treatment or drug has on a patient is essential to the future of efficient healthcare. Digitising the sphere does exactly that by allowing us to define, track and manage the impact in a variety of different ways. Some current options already include wearable technology, cloud-based data collection and simply self-reporting.

However, while data collection and analysis is important, it is not the full answer. The collected data should be utilised to create stories that resonate with the patient in a real-world scenario. Big data is simply an abundance of information that needs skill and human integration to make it relevant.

Paul Sonnier, Digital Health Strategist describes digital health as “The underlying lexicon of digital health is extensive and includes all or elements of mHealth, Wireless Health, Health 2.0, eHealth, Health IT, Big Data, Health Data, Cloud Computing, e-Patients, Quantified Self and Self-tracking, Wearable Computing, Gamification, Telehealth & Telemedicine, Precision and Personalised Medicine, plus Connected Health...”

The pharmaceutical industry is only linked to today’s pharma beginning to realise the value of digital world in the form of health. It provides information that digital health marketers, communicators, healthcare professionals, patient advocacy groups and pharma can evaluate and use to engage with patients more effectively. The results will garner more effective patient treatments that will result in overall better patient outcomes across the board.

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Digital is now intrinsically

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http://mobihealthnews.com/45646/surveys-58-percent-of-uk-patients-72-percent-of-uk-frenchor-german-docs-have-used-digital-health-tech

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TOPICAL SEMI-SOLIDS

On the surface…

Model answer: Vertical diffusion cell test system model HDT 1000 from Copley Scientific

Tony Copley, Copley Scientific, outlines testing strategies for topical semi-solids The skin is an important and commonly used route of administration for pharmaceutical products, for both topical and systemic action. Associated test methods are defined on the basis of the intended action, with new specifications being released for topical products as recently as 2013, in the form of United States Pharmacopeia (USP) Chapter <1724>. This article provides a brief introduction to transdermal and topical drug product testing and the associated regulatory landscape, focusing on methods for semisolids.

Using the skin for drug delivery For certain drugs for systemic action, such as nicotine and hormones, the skin offers a delivery route with high patient acceptability that avoids first pass metabolism. The resulting transdermal systems or transdermal drug products are typically patches, of varying design, that release an active ingredient into the blood stream, over time.

Topical drug products are, in contrast, designed to treat a localised skin condition, and may be foams, sprays or aerosols, or semisolids; the focus of this article. Semisolids include creams, gels, ointments, pastes, suspensions and lotions. These topical drugs enable the delivery of high loadings of active ingredients, directly to the site of action, with a significantly reduced risk of any systemic impact.

The testing applied to transdermal and topical products reflects their different modes of action, and includes both product quality and product performance tests. Product quality tests assess general quality attributes, while product performance tests focus specifically on drug substance release, from the formulation matrix.

Regulatory guidance and compendial methods for semisolids Until relatively recently there were no compendial methods specifically for semisolid testing but chapters are now in place for both product quality and product performance testing, USP Chapter <3> and USP Chapter <1724> respectively1,2. Product quality tests for semisolids include the measurement of apparent viscosity and product uniformity over the assigned shelf life. Performance testing involves the measurement of drug release rate, and three different apparatuses are specified: Vertical Diffusion (or Franz) Cell (VDC); Immersion Cell; and Flow-Through Cell (USP Apparatus 4).

Food and Drug Administration (FDA) Guidance for “Non-sterile Semisolid Dosage Forms SUPAC-SS CMC 7”3, which provides guidance for scale-up and post-approval changes, similarly references the Franz cell.

Although better suited to automation, the double port arrangement employed on the Cell Type A design is widely acknowledged to be less than ideal from a practical perspective because of its propensity to cell leakage and/or back diffusion. The simpler design of Cell Types B and C, which have a single arm for sample withdrawal and media replacement largely eliminates these problems. These latter two cells differ only in terms of size, with Cell Type – C enabling higher volume testing.

All three cells essentially comprise of two main parts: the donor chamber which contains the sample, and the receptor chamber. These two parts are separated by a membrane which holds the sample in contact with the receptor medium. Testing is typically conducted over a period of six hours with samples taken at regular intervals and media levels subsequently topped up to maintain a full cell. Holding the receptor medium at 32°C mimics normal skin conditions.

The introduction of USP <1724> has focused attention on semisolids testing and equipment manufacturers have, in response, refreshed their offering to meet evolving needs. For example, the latest cells are designed for use with heating blocks, as oppose to being water-jacketed. This saves bench space and also eliminates the “spaghetti” of pipework associated with jacketed systems. Accessories such as the Vacuum Deaerating Apparatus Model VDA, from Copley Scientific, can also be helpful in routine testing, which requires a degassed receptor medium to avoid bubble collection beneath the membrane and a consequent reduction in diffusion rate.

In conclusion The testing procedures and regulatory framework for drug products applied to the skin differs depending on whether they deliver topical or systemic treatments. The latest revisions to the USP provide welcome specifications for topical semisolid testing, to complement methods already in place for transdermal delivery systems. Associated equipment developments make it easier for drug developers to test semisolids efficiently, in line with the new specifications, supporting faster progress towards a successful submission.

At the time of writing, the European Medicines Agency (EMA) does not offer specific guidance for semisolids and though transdermal products are covered in the European Pharmacopoeia (EP Chapter 2.9.4)4, there is, as yet no equivalent chapter to USP <1724>.

The practicalities of drug release testing

Figure 1: Line Drawings showing the construction of the VDCs described in USP <1724> as Model A (left) and Models B and C (right)

As stated in USP <1724> semisolids performance testing is “conducted to assess drug release from manufactured pharmaceutical dosage forms.” This includes measurement of the total amount of drug released as well as release rate. In practice drug release testing is achieved by placing a sample in contact with a reservoir of receptor medium and measuring the changing concentration of drug substance in the receptor medium, as a function of time.

The VDC is rapidly emerging as the apparatus of choice for this application, with three different cell designs referenced in USP <1724> (see figure 1).

References: 1 USP37-NF32 Chapter <3> Topical and transdermal drug products – product quality tests.

2 USP38-NF33 Chapter <1724> Semisolid drug products – performance tests 3 FDA Guidance for Industry. Nonsterile Semisolid Dosage Forms. Scale-up and Postapproval Changes: Chemistry, Manufacturing, and Controls; In Vitro Release Testing and In Vivo Bioequivalence Documentation.

4 Ph. Eur. 8th Edition, Chapter 2.9.4, Dissolution Test for Transdermal Patches.

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SINGLE-USE

Go it alone Jennifer Campbell and Sebastian Ribault, Merck discuss the use of single-use technology for flexibility, contamination reduction and automation in biopharm manufacturing

T

he market for biosimilars is rapidly evolving, with over 450 molecules in development worldwide. The value of the global biosimilars market is expected to climb from USD 2.29 billion in 2015 to over USD 6 billion in 2020 (1). This growth is being driven by multiple factors, including pressure to cut healthcare costs, the rise of diseases treatable with biologics and the number of biologics coming off patent in 2020 (2). Drawn by the promise of profit, many geographies are entering as new players, creating the conditions for high market saturation and cost competitiveness.

Despite their promise to provide low-cost, life-changing therapies to patients around the world, biosimilars still require significant manufacturing and development investments. For example, while a reference biologic is estimated to cost US $800 million to develop, biosimilars may still require an investment of US $100-150 million(3). This difference is due in part to reduced costs for research and development and for clinical trials. However, biosimilars do not earn the same profit margins as biologics.

As a result of these conditions, cost is a critical factor in biosimilar manufacturing. Given this sensitivity – and the need for flexibility and accelerated speed to market – biosimilar molecules are ideal candidates to be manufactured with flexible factory concepts.

Advantages of single-use Flexible factories can help keep process costs at a minimum while maximising adaptability. This concept implements single-use equipment in modular or classic facilities designed for flexible processing, reduced risk of contamination, automation and overall ease-of-use.

Increased flexibility Flexibility is embedded in the equipment design of single-use technology.

Single-use bioreactors can be moved from one suite to another depending on manufacturer needs. Carts containing chromatography or other equipment can also be placed in optimal locations in suites when in use or stored in a corner, enabling more effective use of valuable suite space. This flexibility to move equipment from one suite to another allows for quick changes in production plans.

Similarly, buffers can be prepared in one location and rolled into another suite for use, or removed without impacting the other processes in a suite. Mobile equipment means hard piping is no longer necessary and maximum flexibility is possible.

Reduced risk of contamination With single-use technologies, the risk of contamination is greatly reduced at every step. Single-use systems arrive at manufacturing facilities fully gamma-irradiated and immediately ready for processing runs. Bioreactor bags are connected to media bags through sterile connectors, removing the open phase of processing. Harvests are also completed in a sterile, closed process.

Disposable, single-use technology also virtually eliminates the risk of cross contamination. Rather than completing validated clean-in-place processes after each run, single-use equipment is discarded after each use, effectively keeping proteins and other drug products from being introduced in new runs.

Increased automation Finally, single-use technologies allow for higher levels of automation. In general, single-use equipment is easier to use. Setup for a variety of processes is fast and requires less operator training.

Changeovers between batches can also be done quickly, increasing capacity.

New generations of technology further automate processes by enabling several process operations with one piece of single-use equipment. For example, Merck’s Smart Flexware system integrates both chromatography and tangential flow filtration (TFF), reducing capital expenditures and operator training.

Lower mAb production costs with single-use To demonstrate the quantitative advantages of single-use systems, Merck compared single-use with glass or stainless steel in monoclonal antibody (mAb) development labs and production suites. The evaluation was based on a standard process development, including three consecutive runs and associated analytics, followed by tech transfer to production with cell expansion and manufacturing of one preclinical and three GMP runs. The study found a 15% savings in time when using single-use technologies.

The same study found that transitioning to single-use systems doubled production at medium scale (50-200 litres) and increased the number of large-scale runs (1,000-2,000 litres) by 42% per year. A significant cost savings was also observed: 42% savings at the 200-litre scale and a 23% savings at the 2,000-litre scale. These cost savings were due to decreased utilities costs (electricity and water) and personnel costs (to operate equipment).

Conclusion Many biotech processes and facilities still contain a number of stainless steel and multi-use equipment. However, under the pressures of speed and cost efficiencies, biosimilar manufacturers should consider singleuse and flexible facility concepts a fundamental part of their strategy for success. Single-use processing will provide increased flexibility and automation and reduce contamination to minimise the risk of failure during tech transfers, to support accelerated timelines and – most importantly – keep the cost of manufacturing competitive.

References: 1. http://www.marketsandmarkets.com/PressReleases/global-biosimilars-product-market-worth19.4-billion-by-2014.asp 2. http://www.digdeepsolutions.com/2015/04/15/biologics-biosimilars-the-current-opportunitypipeline-part-1/ 3. http://www.biotechnoblog.net/techno-blasts/TB0715/BioPlan.pdf

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How to achieve supply chain traceability in the life science sector

WEBINAR Date: 21/07/2016 Time: 14:00 Europe/London Price: Free Accomplishing full traceability to safeguard compliance across the enterprise and throughout life science supply chains As if compliance is not difficult enough in the enterprise, the pressures to manage quality across all suppliers are a huge challenge.

While your own operations may be of a high standard and under constant supervision, suppliers are inevitably less transparent, and this can pose a threat to your organisation both financially and in terms of reputation, if something should go wrong.

Supply chain compliance is now a leading priority for quality managers operating within the life sciences sector. From the silos that block chain visibility and the ever-present threat of counterfeiting to the growing regulatory burden – factors such as these represent formidable compliance challenges.

Join us for this essential webinar to discover how new technologies draw on the power of the cloud and the latest integration capabilities. Find out: • • •

How to identify the challenges of supply chain traceability How new technologies, including cloud-based platforms, can finally give quality managers full visibility How to deal with crises when they do occur

SPEAKER: ALEXANDRE ALAINE, Life Science Product Manager, EtQ HOST: DAVID GRAY, Deputy Group Editor, Rapid Life Sciences

Register Now www.epmmagazine.com/webinars Can’t make the date? Sign up anyway and we will send you an on demand copy after the event.

At EtQ, we focus on products that provide visibility and control into compliance. We want to make sure you have a solution that will enable you to not only manage the processes related to compliance, but be able to report and improve, based on the data.

European Pharmaceutical Manufacturer is a highly regarded brand covering the pharmaceutical manufacturing supply chain from conception to production, keeping readers informed of the latest news, opinions, developments and breakthroughs in this innovative and technologically advanced sector.

SINGLE USE

Mix and match The QuattroMix single-use mixing system unites expertise from QuattroMix and JM Separations.

Dr Andreas Frerix, Quattroflow outlines its benefits and how the human heart provided inspiration for part of the technology

B

iopharmaceutical manufacturers face a significant number operational challenges in bringing products to consumers. These include maintaining a high level of purity and sterility; achieving low levels of leachables and extractables; minimising particle shedding impact from contact materials contaminating the product stream; utilising shear-sensitive product handling and producing a controlled, constant product flow with low pulsation.

moving forward. Its pump chambers contain no rotating parts subject to friction for no operational heat build-up. In addition, the pumps can run dry, are self-priming and produce little or no shear because of low slip. They also offer low-pulsation and leak-free operation with some of the highest turndown capabilities in the industry for repeatable and consistent production rates.

In the mix

The JM Separations and Quattroflow partnership resulted in the QuattroMix single-use mixing system that utilises a single-use mixing bag filled via a Quattroflow pump through a 16-hole mixing plate built into the bag. After the mixing bag is filled, the Quattroflow’s pumping action through the mixing plate forces the liquid from the bottom of the bag, up around the outer walls and back down through the mixing plate in the center, where it is Quattroflow pump recirculated through the pump.

Two decades ago, Mark van Trier and John van der Veeken formed JM Separations in The Netherlands. The company now specialises in biopharmaceutical industry engineering and design.

This successful system prompted JM Separations to create a new division named JM Bioconnect.

Other considerations include minimising the addition of heat to the production process; achieving a high level of volumetric consistency; optimising equipment and maintenance costs as well as increasing speed-to-market capabilities and maximising the earning potential of the biopharmaceutical’s patent window.

Van Trier and van der Veeken focused on ways to help biopharmaceutical companies improve hygienic product integrity, time-sensitive processing and cost-effective performance. They identified a key opportunity in batch mixing of liquid/liquid and liquid/ solid solutions, concluding that singleuse equipment could offer better batch Biopharmaceutical mixing because of its low cost compared manufacturers face to permanent stainless-steel pumping systems and its ability to ensure higha significant number purity production. operational challenges

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in bringing products to consumers.

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For a solution, they enlisted former colleague Frank Glabiszewski, who, with Josef Zitron, invented the positive displacement quaternary (four-piston) diaphragm pumping principle and founded Quattroflow Fluid System.

Ideal for biopharmaceutical-mixing applications, Quattroflow pump technology was modelled on human heart operation with its four pumping chambers and check valves keeping product flow constantly

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technology was modelled on human heart operation with its four pumping chambers

The mixer with more Quattroflow pumps’ high capacity allows the QuattroMix to run up to 1,200 litres an hour (317 gph) of liquid/liquid or liquid/powder solutions. The non-magnetic, impeller-free operation of Quattroflow pumps also gives them distinct operational advantages over competitive mixing systems.

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“Some mixing solutions have magnetic beads so a magnetic part will not work,” said van Trier. “A mixer inside the bag creates the chance for impeller contamination since the impeller has to go through the bag.

The QuattroMix is a pre-packed complete unit with the pumphead next to it to eliminate this possibility, basically a complete plug-and-play unit.

It also allows solution transfer from the mixing bag to a storage unit without utilising another pump to further decrease chances of product contamination.”

Current customers includes global pharmaceutical giants such as Johnson & Johnson, Pfizer and Novartis.

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HOT MELT COATING

Cover drive Hermes Pharma is now offering hot melt coatings for the pharmaceutical sector

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ermes Pharma, an expert in user-friendly solid oral dosage forms, has announced the commercial implementation of hot melt coating (HMC) in its production facility. The implementation of this technology is the result of a research project aimed at developing new pharmaceutical formulations that are stable, effective and user-friendly.

Acetylcysteine (NAC), a thermosensitive mucolytic compound exhibiting an unpleasant sour and metallic taste, was selected as the model active pharmaceutical ingredient (API) for this research project. The dosage form designated was orally disintegrating granules (ODGs), which consist of small granules that are applied directly into the mouth. ODGs do not require any water and are easy to swallow – even for people with difficulties swallowing tablets. As they do not have to be swallowed whole and spend more time in the mouth than conventional tablets, they are more thoroughly tasted, making taste-masking crucially important.

Hermes Pharma successfully deployed HMC to mask the sour and metallic taste of NAC, as well as its sulfuric smell, which are specific to this API. It also achieved a stable, immediate release profile and unaltered polymorphic form of the coating during storage (Fig. 1).

friendly compared with conventional coating methods. HMC involves covering the API solid core with a molten coating material at a carefully controlled temperature. This then solidifies to create a homogenous coating (Fig. 2).

Fig. 2 The illustration below shows the HMC process, from spraying through to the finished coating. In the first step, the coating constituents are heated up and melted. Following this, the coating droplets are sprayed onto the seed particle (API) and wetting occurs on the surface. As the seed particle is colder than the melting temperature of the coating mixture, the droplets solidify and form a homogeneous layer.

Thanks to this research project, a number of technical hurdles have been overcome. By applying Quality by Design (QbD) and using Process Analytical Technology (PAT) methods the progress and endpoint of coating can now be determined in real time. Hermes Pharma uses near-infrared spectroscopy (NIR) to monitor and control the coating process inline. This saves time and improves quality.

HMC is now a proven technology to mask the unpleasant taste and smell, which patients often experience when pharmaceuticals dissolve in the mouth. The technology has been upscaled from laboratory to production, meeting the strict standards for pharmaceutical production (GMP), and can be transferred to other APIs. The coated API can be easily blended with excipients and flavours, as well as other APIs for tailor-made products to suit customer requirements and deliver further medical benefits. HMC technology could also be applied to other dosage forms, for example orally disintegrating tablets (ODTs) and multiple unit pellet system (MUPS). Two related patents have been successfully filed.

Fig. 1 The figure below shows the dissolution profiles of an acetylcysteine ODG over a storage period of 12 months. After one minute always less than 3% of acetylcysteine was dissolved, indicating effective and stable taste masking. The unaltered immediate release characteristics of the ODG are proven by the fact that more than 90% of the NAC was dissolved after 15 minutes.

HMC was originally developed in the food industry. Among other purposes, it has been used to coat seasoning mixes in convenience food in order to minimise their hygroscopicity and volatilisation of the flavour during the logistic chain and prior to consumption. Flavour is only released upon heating, but not beforehand, improving taste, smell and quality of ready-made meals. HMC is a solvent-free coating technology that offers very short processing times (depending on the API, coating thickness and scale), and lower costs. It is also more eco-

“We believe that our scientific know-how has led us to prove our technological and production leadership, resulting in being the first company to make HMC commercially available for the pharmaceutical industry,” said Dr Detlev Haack, director research & development at Hermes Pharma. “Our industrial customers will benefit from products that are truly user-friendly and deliver real value to patients and consumers.”

Patient adherence to a medication regime impacts the therapeutic outcome. Based on recent data resulting from a study commissioned

by Hermes Pharma, ODGs and other user-friendly dosage forms have been found to be a welcome alternative to conventional dosage forms.

They offer patients with swallowing difficulties, including children and the elderly, a user-friendly alternative that can lead to better compliance thus reducing healthcare costs.

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28 SEPT - 29 SEPT 2016

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MANUFACTURING

Pure and simple Bosch Packaging Technology explains how its latest development is helping the production of pure media in the pharma sector

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osch Packaging Technology has developed a new generation of pure media systems including pure steam generators and distillation units for the production of sterile, pyrogen-free pure steam or WFI (water for injection).

“We contribute to a significantly more efficient production of pure media and to more sustainability in the pharmaceutical industry,” said Dr John Medina, sales director at the Bosch subsidiary Pharmatec. For instance, the preheater reduces heating energy consumption by up to 30%.

Focus on energy efficiency and sustainability Pure steam and WFI are key components of pharmaceutical production.

While WFI is predominantly needed for the production of infusion and injection solutions, pure steam is mainly used for sterilising equipment components like preparation vessels, piping systems and filling machines. In addition, pure steam is employed for the humidification of air in cleanrooms.

Bosch delivers the new distillation units with a preheater by default.

From the second column onwards, it uses pure steam from the previous column to preheat the feed water. As a result, heating energy demand is significantly reduced. For pure steam generators, a preheater is available as an option. It is fed with condensate from the heating steam.

Using this stored energy leads to reduced heating steam consumption.

High thermal efficiency and reduced blowdown Evaporation is a basic operation in the production of pure steam and WFI. The equipment’s evaporator operates according to the proven natural circulation principle. The water, which is fed for evaporation, continually circulates between the evaporation chamber and the heat exchanger. A high thermal transfer enables the system to be heated up smoothly without causing temperature stress for the evaporator.

This process only needs electrical energy or heating steam; no further process steps or functional modules such as a compressor are required.

“The new, compact design of the evaporator contributes to optimal thermal use of heating energy, leading to high yields and low operating costs”, explains Medina.

“Since the production of pure steam and WFI is particularly energyintensive, improvements in efficiency play an important role in sustainability and climate protection.”

The geometry of both evaporators and condensers has been optimised for the new product range. For instance, Bosch adjusted the evaporator’s diameter as well as number and formation of the heating pipes.

Subsequently, the machines can achieve 20% higher performance rates compared with previous models. Bosch also succeeded in reducing the amount of water loss, which results from the disposal of endotoxins (blowdown) in the feed water, from between 5% and 8% to no more than 4%.

From 100 to 7,500 kilograms per hour With these new developments, Bosch has streamlined the product range, compiling a consistent set of machines. The number of different sizes was reduced from 11 to six pure steam generators and from 14 to 10 distillation units. “Customers profit from shorter delivery times, lower acquisition costs due to a higher degree of standardisation and modularisation,” said Medina. The series now encompasses a performance range of 100 to 7,500 kilograms per hour. In order to enable quick set-up, feed water pumps with frequency regulation are used for all sizes. The equipment can be further adapted to the respective operating conditions.

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SERIALISATION

Faking it: According to the World Health Organization (WHO), counterfeit drugs make up between 7% and 15% of all medicines circulated in developed countries

This is the real thing…

Serialisation innovation – how new product inspection technology can help prevent pharmaceutical product counterfeiting. By Reinhold Van Ackeren, Mettler-Toledo PCE

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ounterfeit medicines are a growing problem throughout many parts of the world. According to the World Health Organization (WHO), counterfeit drugs make up between seven and 15% of all medicines circulated in developed countries. The problem is worse in developing countries, with nearly 25% of all medicines likely to be counterfeit . In addition, the amount of counterfeit pharmaceutical products sold online has increased significantly, with little to no regulation. Taking advantage of available technology, counterfeiting operations are becoming increasing sophisticated. In some cases, counterfeiters are using almost identical packaging systems as original manufacturers. This presents some very serious problems, beginning with the potential impact on consumer safety due to harmful or ineffective ingredients. Counterfeit drugs can also have a significant effect on bottom lines, damaging brand reputation and decreasing pharmaceutical manufacturers’ profits.

The good news is that a number of new regulations are being implemented across Europe, Asia and North America to combat the issue of counterfeit drugs throughout the supply chain. The authorities in Europe, Asia and North America are making serialisation mandatory. These regulations will optimize the traceability of products, facilitating the identification of counterfeit products in the supply chain by retailers and the authorities, ensuring consumer safety and protecting the integrity of pharmaceutical manufacturers’ valuable brands.

The implementation of serialisation solutions on the pharmaceutical production line is no longer optional, but the question is: how do manufacturers ensure compliance with these new regulations? For starters, it is important to stay ahead of the curve on the latest serialisation requirements, either in effect or coming online across key regions, such as Europe, Asia and North America. Manufacturers must then familiarise themselves with the latest technological advances that meet their production needs while achieving global serialisation compliance.

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Regional Regulations Serialisation is becoming a strict requirement worldwide and in order to do business in key global markets, pharmaceutical manufacturers must be in compliance with legislation that differs from region to region.

Europe The European Union (EU) has approached the use of serialisation to prevent counterfeit drugs, introducing the Falsified Medicines Directive (FMD). Serialisation aimed at manufacturers of pharmaceutical products, including amended package design, will come into effect in 2018. After this, no product under the FMD can be sold in Europe without a serial number. Requirements include barcodes printed on pharmaceutical product packaging that is then checked into a database by the manufacturer.

Asia China’s Food and Drug Administration (CFDA) has mandated that all pharmaceutical products require serialisation and compliance reporting, while the South Korean Ministry of Food and Drug Safety (MFDS) requires serialisation and serialised product reporting for all pharmaceutical products, which came into effect in January 2016. In India, serialisation is only currently required for products being exported.

However, there is now a draft regulation where in the future serialisation and aggregation may be required across all packaging levels, starting from primary packaging. This means that in India, blister packs may also have to contain appropriate coding.

This system minimises the risk of product counterfeiting by laying the foundation for tracking and tracing products via serial numbers.

This enables downstream devices and systems to closely monitor a package through its custody chain, meeting regulatory track and trace requirements.

Another extension of the scalable XMV system platform that is designed especially for the pharmaceutical industry is the Mettler-Toledo Garvens’ Checkweigher Combination XS2 MV, which brings fraud prevention and quality control together by joining various production line functions, such as dynamic checkweighing, completeness check, detecting askew packages and open flaps, marking, verification, precision product handling and reliable sorting/rejecting. In addition to precisely capturing weights, this complete system prints product codes using laser marking or inkjet printing systems, that are then verified for accuracy and legibility, serving as a key part of an overall track and trace program for compliance purposes. A key driver for using tamper evident seals in the production line is the strong demand for consumer product safety. By using such a solution, pharmaceutical manufacturers are able to prove easily that their products are not counterfeit.

Solutions are now available to a high degree of operational flexibility, offering over 375 standard configurations to facilitate multiple product selection. All components have been finely tuned to work in perfect unison, even at extremely high speeds (up to 90 m/min), thereby combatting counterfeit medicine products.

North America In the United States, by November 2017 the Drug Supply Chain Security Act (DSCSA) will require that specific product information be provided on product packaging, including National Drug Code (NDC) or Global Trade Identification Number (GTIN), serial number, lot number and expiration date.

By 2023, the DSCSA will include complete interconnectivity, meaning shared ownership of data between all supply chain partners - from manufacturers, wholesale drug distributors and re-packagers, to dispensers, such as pharmacies - allowing for full real-time traceability of pharmaceutical products back to their origins. With integrated coding, serialisation and track and trace solutions across the entire supply chain, this will provide what is known as ‘cradle to grave’ traceability.

Serialisation technology As new laws are adopted throughout the world, the pharmaceutical industry must incorporate serialisation into production in order to ensure compliance. Serialisation systems typically consist of several elements, including printers and visual inspection systems. For the pharmaceutical industry, this equipment must be fine-tuned to meet specific needs such as high production line speeds and throughput. Advanced technology now allows for the integration of complex serialisation system components that can meet both the performance needs of pharmaceutical manufacturers, as well as global regulatory requirements.

Leading product inspection technology companies have developed rapid and accurate serialisation solutions designed to have minimal impact on manufacturing processes through innovative component integration. For example, Mettler-Toledo’s XMV family of solutions allows for marking and verification system components – including ink jet printing systems, high-resolution visual verification systems, mechanical transfer units and rejecting devices – to be combined into one unit that can be efficiently added to existing or new production lines.

Unifying these various elements into one solution significantly reduces costs and streamlines operations.

Need to comply:Manufacturers must familiarise themselves with the latest technology to meet their production needs while achieving global serialisation compliance, says Reinhold Van Ackeren, Mettler-Toledo PCE

Counterfeiting is one of the most serious issues facing the pharmaceutical industry today. In some countries, nearly one-quarter of all medicines may be counterfeit. Due to their very nature, these products can pose serious consumer safety issues, as well as cause irreparable damage to hard-won brand reputations. Taking this threat very seriously, nations around the world have taken active steps to protect the consumer and strengthen the pharmaceutical supply chain, making product serialisation mandatory. As a result, pharmaceutical manufacturers must gain a firm understanding of the serialisation requirements necessary to do business in various parts of the world. With that knowledge, they can then specify the best serialisation solution for their production lines. Advances in serialisation technology have yielded equipment that combine inspection, marking and vision technology into a system that can be efficiently integrated into the production process without slowing throughput. With this technology in place, pharmaceutical manufacturers can ensure regulatory compliance and prevent counterfeit product from entering the supply chain, protecting consumer safety and the integrity of their brands.

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A M R PHA THE AT CKS FLI

Big pharma goes ape Sadly, clinical trials can go badly wrong – in some cases with tragic consequences. Rise of the Planet of the Apes is a movie that uses this premise to tell an imaginative morality tale about clinical trials and animal testing.

EPM’s David Gray reviews this blockbuster return to the planet of the apes.

The film: Rise of the Planet of the Apes The year: 2011 The budget: $93 million Box office takings: $481 million Rating: 7.6/10 IMDB / 81% Rotten Tomatoes Leading lights: James Franco, Freida Pinto, John Lithgow, Brian Cox, Tom Felton, Andy Serkis Written by: Rick Jaffa and Amanda Silver Directed by: Rupert Wyatt

Synopsis Will Rodman is a scientist employed by fictional big pharma firm Gen-Sys to research a new drug designed to cure Alzheimer’s disease. The drug is tested on chimpanzees, but when one of the test subjects breaks free and embarks on a rampage of the facility, she’s killed, leaving behind a newborn infant.

The trial is aborted, but lead protagonist Will adopts the infant and brings him home, naming him Caesar. Will still believes that the drug could work, and has a vested interest, as his father is suffering from Alzheimer’s.

Time passes, and Caesar, who was exposed to the drug in utero, is developing superior cognitive abilities. Likewise, Will’s father initially responds to the drug, which Will is administering illegally as part of his own secret trial. Unfortunately however, he develops a resistance to the medication, and his condition soon worsens.

Eventually Caesar begins to display aggressive behaviour, and Will has to send him to a primate shelter, where he is treated badly by his human guardians.

Meanwhile, Gen-Sys returns its attention to the original drug, and develops a more powerful, gaseous version. Will steals the drug to try and save his father at home, but is ultimately unsuccessful.

Caesar, who has developed an awareness of the reason for his unnatural intelligence, heads to Will’s house and claims the canisters of the new gaseous drug. He returns to the primate

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shelter and opens the canisters, exposing his fellow primates.

Primate intelligence develops rapidly, and the apes make good their escape, forming a militant colony in a nearby forest (after a bloody battle up against a police blockade on the Golden Gate Bridge – one of the most memorable scenes in the film).

Pharmaceuticals There are two drugs referenced in the movie: ALZ-112 (liquid) and ALZ-113, the more potent, gaseous version of ALZ-112. Both are fictional ‘miracle drugs’ designed to cure Alzheimer’s disease. However as the narrative develops, it becomes apparent that enhanced cognitive development is an unexpected sideeffect of the drug. Therefore, not only would patients see improvements in their condition, they would actually improve on their original intelligence levels.

Portrayal of the sector As imaginative and unorthodox as the Planet of the Apes franchise has always been, the movies have all drawn heavily on ethical debates of their time. First and foremost, it has to be said that big pharma doesn’t do at all well in this installment. Wyatt’s depiction of the suffering of animals kept for clinical trials is subversed as the plot unravels, with the apes benefitting in unpredictable ways – and indeed (spoiler alert) in the sequel, they become the dominant race.

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Drug resistance is also alluded to, with Will’s father becoming immune to the drug, and ultimately losing his battle with Alzheimer’s.

Subsequently, during the closing credits, we see an indication that the release of the gaseous ALZ-113 has triggered a global health epidemic (another spoiler alert – by the time the sequel comes along, the human race has been largely eradicated by the drug).

At the same time, our protagonist is himself a member of the big pharma community, and throughout the film he gets a good treatment: his actions are motivated by the desire to help, rather than make money. He’s also shown to be a caring foster parent to Caesar.

This is a helpful reminder that big pharma, often described as faceless, is composed of thousands of individuals who are using their talents for the right causes.

Why you should see this film Rise of the Planet of the Apes, like the other films in the franchise, features a subversive plotline that preaches a thought-provoking lesson. Whilst its true that ultimately, in this one big pharma is the bad guy, my advice here is to take it with a pinch of salt. This is the first in the franchise to use full CGI effects to create the apes, and for my money, that’s a huge improvement. Parting ways with the rubbery costumes makes for a far more engrossing watch.

Bormed™ Because we care

Reliable plastic solutions for the safety of patients Borealis and Borouge are leading suppliers of innovative plastic solutions that add value for all stakeholders in the healthcare value chain – from pharmaceutical company to patient.

With more than 30 years of experience, we enable customers to meet their need for high-quality, lightweight and aesthetic products. We focus on delivering excellence by working in line with the principles of Commitment, Service and Conformance.

Our portfolio of Bormed™ products is the result of our continuing dedication to your industry.

Our Bormed™ portfolio of polyolefin solutions offers superior technical performance for medical devices, pharmaceuticals

and diagnostic packaging. We guarantee the security of our supply and provide technical support tailored to the specific and stringent requirements of the market. Our service specialists cover 55 countries worldwide, so we can offer global service, while ensuring fast and reliable delivery.

We are dedicated to the quality of your products – for the safety of patients – because we care.

For more information visit: www.borealisbecausewecare.com

Visit Borealis and Borouge at Pharmapack Europe in Paris from February 10-11, stand 2015, hall 5.2.