EPM October 2015

COVER STORY: SEAMLESS TRANSITIONS FROM FETTE COMPACTING GRANULATION THE FUTURE OF PHARMA PACKAGING

OCTOBER 2015

Contents October 2015 | Volume 15 Issue 7 head office Carlton House, Sandpiper Way, Chester Business Park, Chester, CH4 9QE.

Regulars 5

Features 23

COMMENT

SEEING IS BELIEVING

Is technology turning science fiction into science fact?

The importance of serialisation in pharma

7

6 NEWS ANALYSIS

28 ChargePoint’s powder handling expertise

12

WHAT LIES AHEAD

COVER STORY Fette Compacting looks at the demands on tablet presses

group editor lu rahman, lu.rahman@rapidnews.com

editorial assistant emily hughes, emily.hughes@rapidnews.com publishers mark blezard, duncan wood

production

32

20

editorial

david.g@rapidnews.com

REGULATORY AFFAIRS

OPINION

Web: www.epmmagazine.com

deputy group editor dave gray,

TAKE CHARGE

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Tel. +44 (0) 1244 680222 Fax. +44 (0) 1244 671074

The ECCPM looks at the future of continuous processing

25 39

36 EXPERT WITNESS PCI highlights its skill in the field of granulation

art robert wood

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50 CHEMICAL REACTION Marks & Clerk Solicitors in the spotlight

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PASSING THE TEST A focus on testing from Thermo Fisher Scientific and Lonzo

43 TRACK & TRACE Weber and Faubel scrutinise packaging

48 FREEZE FRAME Biopharma Technology looks at quality in the freeze-drying process

Address changes should be emailed to subscriptions@rapidnews.com.

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 15 Issue 7 © October 2015.

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. All rights for European Pharmaceutical Manufacturer are reserved and reproduction in part or whole without written permission is strictly prohibited.

ISSN No. - 2052-4811 W W W. E P M M A G A Z I N E . C O M

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from the editor The future’s so bright...

In a few years you may be forgiven for thinking that the face of healthcare – of which the pharma sector plays an increasingly significant role – has mutated into an episode of Doctor Who. It was recently reported that researchers at University College London are looking at ways of creating a ‘medical avatar’ that could be used for treatment simulations and to determine the best course of treatment for patients. Leading the study, Vanessa Diaz, the senior lecturer of bioengineering and prinicipal investigator on the DISCIPLUS project, admits that a fully realised avatar is some way off yet and is a ‘long term vision’. She has also been quoted as saying that while there is still much work to be done, the ‘future of healthcare is digital healthcare.’

Increasingly the role of digital is gaining ground in the life science sector. Within the pharmaceutical sector there have been reports of digital medicine products - one that has FDA New Drug Application status involving Proteus Digital, and another, a smart capsule that will hopefully be able to assist in the treatment of bowel conditions such as Crohn’s disease.

an integral part in the way drugs are manufactured, delivered and finally reach the patient.

There is increasing crossover from the digital health sector into the pharma world. Internet footage of biohacker Tim Cannon showed him having a Circadia computer chip implanted in his arm for three months. It communicated internal biometrics, specifically temperature, to his tablet and the aim of the project was to show that digital implants were the future of health-tracking – he says that when he implants the next version of Circadia, it will send him texts when he’s getting sick. If this is the next step in healthtracking and diagnosis then perhaps we are only a few more steps away from having our medication delivered automatically at this point of digital diagnosis. It may well seem like stuff of the Doctor and his assistant but the rate of digital development is becoming so rapid in life sciences that even time travel now seems within the realms of possibility.

Lu Rahman

What is also interesting is that the UK’s chief pharmaceutical officers (CPOs) have recently said that pharmacy’s future is ‘clinical and digital’.

Aimed more at the dispensing pharmacists, this concept is nevertheless interesting and will have impact across the wider pharmaceutical sector as the role of digital becomes

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NEWS ANALYSIS

DNA-based nanodevices developed for molecular medicine R

esearchers from Aalto University have published an article in the recent Trends in Biotechnology journal. The article discusses how DNA molecules can be assembled into tailored and complex nanostructures, and further, how these structures can find uses in therapeutics and bionanotechnological applications. In the review article, the researchers outline the superior properties of DNA nanostructures, and how these features enable the development of efficient biological DNA-nanomachines. These DNA nanostructures provide new applications in molecular medicine, such as novel approaches in tackling cancer.

Tailored DNA structures could find targeted cells and release their molecular payload (drugs or antibodies) selectively into these cells.

“Nowadays, software and techniques to design and simulate DNA nanostructures are extremely powerful and user-friendly, and thus, researchers can easily construct their own DNA-objects for various uses. The big boom in the field of structural DNA nanotechnology happened in 2006, when Paul Rothemund introduced a technique dubbed ‘DNA origami’. This method is the starting point for practically all other

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Virus-protein -coated DNA origami nanostructures.

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straightforward design approaches available today,” describes Veikko Linko, an Academy of Finland postdoctoral researcher from Biohybrid Materials Group.

Versatile DNA nanostructures The most important feature of a DNA-based nanostructure is its modularity. DNA structures can be fabricated with nanometer-precision, and most importantly, other molecules such as RNA, proteins, peptides and drugs can be anchored to them with the same resolution. Such a high accuracy can be exploited in creating nanosized optical devices as well as molecular platforms and barcodes for various imaging techniques and analytics. Furthermore, the researchers from Aalto University and University of Jyväskylä have recently shown how DNA origamis can be used in efficient fabrication of custom-shaped metal nanoparticles that could be used in various fields of material sciences.

For molecular medicine, tiny DNA-based devices could be utilised not only in detecting single molecules but also in modulating cell signalling. In the near future, highly sophisticated DNA-robots could be even used in creating artificial immune systems. A system based on tailored DNA-devices could help to avoid unnecessary drug treatments, since programmed DNA-nanorobots could detect various agents from the blood stream, and immediately start the battle against disease.

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The research group lead by Professor Mauri Kostiainen works extensively with DNA nanostructures, and the group has just recently published two research articles regarding DNA-based applications in biotechnology and molecular medicine. The researchers have coated DNA nanostructures with virus capsid proteins in order to significantly improve their transport to human cells; this could find uses for example in enhanced drug delivery.

In addition, the group has designed a modular DNA-based enzymatic nanoreactor that can be exploited in diagnostics at the molecular scale level.

Our partners: Article in Trends in Biotechnology: V. Linko, A. Ora, M. A. Kostiainen, “DNA Nanostructures as Smart DrugDelivery Vehicles and Molecular Devices.” Trends in Biotechnology 33 (10), 586, 2015.]

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NEWS ANALYSIS

Remote control device delivers drugs to brain

A

team of researchers at Washington University School of Medicine in St. Louis and the University of Illinois has developed a wireless device the width of a human hair that can be implanted in the brain and activated by remote control to deliver drugs.

On the Washington University in St Louis website, Jin Dryden writes: The research is a major step forward in pharmacology and builds on earlier work in optogenetics, a technology that makes individual brain cells sensitive to light and then activates those targeted populations of cells with flashes of light. Because it’s not yet practical to reengineer human neurons, the researchers made the tiny wireless devices capable of delivering drugs directly into the brain, with the remote push of a button.

“In the future, it should be possible to manufacture therapeutic drugs that could be activated with light,” said co-principal investigator Michael R. Bruchas, associate professor of anaesthesiology and neurobiology at Washington University. “With one of these tiny devices implanted, we could theoretically deliver a drug to a specific brain region and activate that drug with light as needed. This approach potentially could deliver therapies that are much more targeted but have fewer side effects.”

The study was published online July 16 in the journal Cell and appeared in the July 30 print issue.

Previous attempts to deliver drugs or other agents, such as enzymes or other compounds, to experimental animals have required the animals to be tethered to pumps and tubes that restricted their movement. But the new devices were built with four chambers to carry drugs directly into the brain. By activating brain cells with drugs and with light, the scientists are getting an unprecedented look at the inner workings of the brain.

“This is the kind of revolutionary tool development that neuroscientists need to map out brain circuit activity,” said James Gnadt, programme director at the National Institute of Neurological Disorders and Stroke at the National Institutes of Health (NIH). “It’s very much in line with the goals of the NIH’s BRAIN Initiative.”

The NIH BRAIN (Brain Research through Advancing Innovative Technologies) Initiative is a program designed to accelerate the

development and application of new technologies to shed light on the complex links between brain function and behaviour.

The new devices ultimately may help people with neurological disorders and other problems, according to co-first authors JaeWoong Jeong, a former postdoctoral researcher at the University of Illinois.

“Now, we literally can deliver drug therapy with the press of a button,” McCall said. “We’ve designed it to exploit infrared technology, similar to that used in a TV remote. If we want to influence an animal’s behaviour with light or with a particular drug, we can simply point the remote at the animal and press a button.”

Jeong added: “The device embeds microfluid channels and microscale pumps, but it is soft like brain tissue and can remain in the brain and function for a long time without causing inflammation or neural damage.”

As part of the study, the researchers showed that by delivering a drug to one side of an animal’s brain, they could stimulate neurons involved in movement, which caused the mouse to move in a circle.

In other mice, shining a light directly onto brain cells expressing a light-sensitive protein prompted the release of dopamine, a neurotransmitter that rewarded the mice by making them feel good.

The mice then returned to the same location in a maze to seek another reward. But the researchers were able to interfere with that light-activated pursuit by remotely controlling the release of a drug that blocks the action of dopamine on its receptors.

The researchers also believe that similar, more flexible devices could have applications in areas of the body other than the brain, including peripheral organs.

“We’ve successfully produced and demonstrated an implantable, cellular-scale microfluidic and micro-optical interface to biology, with application opportunities not only in the brain but in other parts of the nervous system and other organs as well,” said the study’s other co-principal investigator, John Rogers, professor of materials science and engineering at the University of Illinois.

For now, the devices contain only four chambers for drugs, but in the future, the researchers hope to incorporate a design much like a printer’s ink cartridge so that drugs can continue to be delivered to specific cells in the brain, or elsewhere in the body, for as long as required without the need to replace the entire device.

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NEWS ANALYSIS

Intelsius highlights industry’s fear of change at the FlyPharma conference I

ntelsius, designer, manufacturer and distributor of temperature-controlled packaging solutions based in York, called for a collaboration between key stakeholders at the recent FlyPharma conference.

Intelsius’ product manager, David Johnson joined a line-up of industry experts to highlight common pharma logistics issues across the supply chain.

Johnson highlighted the industry’s current fear of change’ in re-using passive packaging. He said: “Although active packaging is re-used daily all over the globe there is a reluctance to re-use passive packaging. This could be due to the fact that passive packaging has been single use for the majority of its history and was only qualified for this use. However, validated protocols to certify that passive packaging is

safe to re-use are now in place, despite the pharma industry being slow to adopt them.

“Stakeholders need to look at the bigger picture, including the positive impacts on product integrity and financial outlay that re-usable passive packaging can have, rather than looking for reasons to avoid change. The notion that passive means single use is now out dated and simply wrong.”

However, a change in perception will not simply be enough to ensure the success of passive packaging’s multi-use success. Johnson called for a collaboration between stakeholders and suggested packaging suppliers educate their customer base on how it can be re-cycled properly to ensure it continues to be environmentally sustainable.

Electronic smart capsule delivers drugs straight to colon

US

researchers at the Purdue University, have reportedly developed an electronic smart capsule that could deliver medication directly to the colon. This would be ideal for conditions such as Crohn’s disease and Irritable Bowel Syndrome which need medication to reach the large colon in order to work. As well as being more effective, it this development could also prove to be cheaper.

The device is made up of two sections – one carries the electronics and another carries the drug – which is released once the capsule has made its journey through stomach acid and 20 feet of small intestine.

The device also contains a magnetic switch so that when it gets close to magnetic marker that – can be worn at waist-level or implanted under the skin – triggers drug release as the capsule gets close to the right position of the large intestine. The magnetic switch has been designed so that it isn’t triggered by external signals such as those on mobile phones.

This news follows the recent announcement that the FDA has given New Drug Application status to Abilify, a combination product to treat mental illness which contains a Proteus ingestible sensor in a single tablet.

The sensor is expected to help with patient adherence because the Abilify tablet contains an ingestible sensor that communicates with a wearable sensor patch and a medical software application for measuring adherence.

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REGULATORY AFFAIRS

Master plan Dr Rajendra Wable, Sciformix Corporation, describes an innovative approach to repurposing a master dossier

T

he pharmaceutical industry is highly regulated, with rules enforced by the health agencies to protect the consumer. The number of regulatory requirements has grown exponentially as biopharmaceutical companies enter new and disparate markets, but efforts in global regulatory harmonisation have stalled. To support the global growth imperative, regulatory functions must meet the local needs of a greater number of countries, while supporting an expanding list of products and aggressive project timelines. Differing registration requirements across markets are a burden, however, it is possible for them to use the differences to a certain extent. This can be achieved, for example, by registering products in countries like the US or across the EU that has streamlined regulatory requirements and use these initial registrations to support registration in other countries.

Preparing one core dossier first and adapting it to the regional specificities in a second step (the ‘parallel preparation’ approach) can allow optimising resources and may lead to a faster global registration. Similarly, a sequential approach (preparation of the NDA first and then conversion to an MAA, or vice versa) can allow the applicant to obtain feedback from the first agency and make adjustments to the second dossier prior to its submission, if relevant.

For many biopharmaceuticals, the core or master dossier generally contains the most comprehensive CMC, non-clinical and clinical information available on the product from a regulatory point of view. This master dossier forms the basis of the international master dossier for non-ICH countries. Generally, the master dossier is kept up-to-date with all new information requested by health authorities from the time of initial approval and through the products life cycle.

These updated core dossiers are tailored to suit other country specific submission formats and requirements. From this core dossier, the CMC sections are shortened for confidentiality and intellectual property issues. Therefore, in the repurposed dossier, the drug substance section, Module 3, is created containing abbreviated documents. The other documents from Module 2 and the complete Modules 4 and 5 are copied from the core dossier without any redaction. Similarly, the general sections of Module 1 are only reformatted to meet the region specific requirement.

It’s not simple. If an applicant just deletes some sections of the ICH dossier and submits an ‘incomplete’ dossier, there is a risk of refusal to file. Therefore, it is strongly recommended that only the content in some sections (especially in Sections 3.2.S.2 and 3.2.S.3) should

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be reduced to fulfil the regulatory requirement. One possibility to make these changes within the dossier is the creation of master dossier with a high granularity for documents in order to be able to exchange parts quite easily for the emerging countries (eg for each section and subsection one separate document is available). This approach helps limit the highly confidential information and reduces the workload in the writing and reformatting.

Registration of generic products is similar, but simpler than, the process for new drugs. For a generic, a company develops a dossier that contains data primarily about the pharmaceutical chemistry of the product and some limited clinical data. In some instances, a product can be registered on the basis of chemical and manufacturing data only (eg an injectable formulation for which there is a recognised pharmacopoeial standard, such as the British Pharmacopoeia, or the United States Pharmacopoeia), describing the method of synthesis and quality control for the product. For oral formulations, the application needs to include dissolution testing and limited clinical data in the form of bioequivalence and/or bioavailability studies which show that the generic product is bioequivalent to the innovator. The requirements for generic product registration do vary from country to country, and there are variations in the data required depending on the type of generic product.

For any successful submission creating and managing global submission templates is of paramount importance. Selection of the correct ‘submission template’ for specific country and submission types is a critical step for successful approval. The primary purpose to develop and use the standard template is to ensure compliance with the regulatory norms of that particular region. Regulatory agencies have provided granularity guidelines and these vary based on product, agency and submission type. The template needs to be versatile such that it can be used for submissions in CTD in paper format, Non-eCTD electronic Submissions (NeeS) and for eCTD. Additionally, the template should be user friendly, and ensure that regulatory professionals can perform the reformatting with minimal training.

To achieve simultaneous global approvals, companies need focus on the strategy, capabilities, and processes. By redefining their regulatory operating models now, such companies will be better positioned to achieve near-simultaneous global market approvals and reach populations in need of their products, wherever those patients may be.

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REGULATORY AFFAIRS

In the beginning...

Capitalising pharmaceutical opportunities: why early-stage regulatory expertise is crucial

by Kushal Vyas, ELC Group

C

ompetition in the pharmaceutical business is increasing. Companies are under pressure to invent new molecules and reprogram their existing molecules owing to major patent cliff. The generics business for conventional dosage form is becoming crowded with multiple new entrants, leading to an increased focus on high technology products, biosimilars and 505b2/hybrid products.

Given these highly competitive markets, incremental innovation patents can be very helpful to brand companies by extending the product lifecycle.

Examples of key incremental innovation patents include protections of: Salts; polymorphs; crystal habit; particle size; purity/impurity; dosage forms; dosage strengths; shapes; method of treatment; dosage regimen; drug interactions; REMS issues; distribution system for controlled drug substances and so on.

There have been court proceedings for patent infringement surrounding these issues, which has affected generic entry in some cases. Involving regulatory experts – along with intellectual property agents – at an early stage and during development, can be helpful in identifying key inventive concepts and securing protection of such critical inventions.

Generics, on the other hand are typically focused on innovative design-around to overcome product lifecycle extension strategies. Major barriers to generic entry are: Regulatory exclusivities, such as

new active substance, new use, orphan drugs, pediatric studies, new combination, new dosage forms and so on; patent extensions related to delay in regulatory approval; patent linkage; patents covering basic molecule and incremental innovations and in some instances, trademarks, designs and utility models.

Among these barriers, the patents covering incremental innovation listed above are more important from a design-around perspective. Additionally, increased competition and stricter regulatory guidelines have compelled generics to perform common multicountry formulation development complying with their respective regulatory authorities. Multi-country development is also important due to the difference in expiration of critical blocking patents, so that early return-on-investment can be expected from the countries with early patent expiry. In view of these issues, understanding the viability of designaround strategies and their acceptance by regulatory authorities is of prime importance. These lucrative design-around strategies, in some cases, require expensive development and clinical studies planning.

For example, change of a patent-protected salt will allow early generic entry; however, due to relatively higher investment, its regulatory feasibility needs to be ascertained at a very early stage. Another example is related to purity patents, where a legally possible design-around strategy could be to use less pure API (compared to its claimed value in the patent),

however these impurity value are still within justifiable broadened regulatory limits. These strategies can help in early launch of design-around products versus waiting for a 20-year patent term to expire.

Related similar issues are: Feasibility/acceptance of skinny labelling by regulatory authorities; change in dosage form, its shapes, inactive ingredients etc; BA/BE queries related to morphology/PSD; interchangeability and sameness requirement related to parenteral & other dosage forms.

These issues are more complex and significant with high technology and biosimilar products due to the grant of patents on various aspects of products and relatively less advanced regulatory guidelines for such products. Therefore, anticipating and identifying a solution for these design-around queries will lead to a high probability of successful, viable products.

Both brand and generic companies can gain a competitive advantage from proactively designed strategies by involving highly skilled regulatory experts, who can visualize and resolve complex scientific and legal issues by convincing regulatory authorities beyond the general guidelines. Strategising at an early stage – and during the development stage – can deliver better product life cycle management and differentiate generic companies by early generic entry, offering increased business certainty in a fiercely competitive and crowded market.

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OPINION

Safety in numbers The task of meeting the safety features requirements of the EU Falsified Medicines Directive (EU-FMD) is daunting. Serialisation expert, Christoph Krähenbühl, 3C Integrity, deconstructs the final draft Delegated Act to summarise the key actions required by pharma manufacturers in implementing serialisation programmes

B

y early 2019, every pharma manufacturer that supplies Europe – whether originators, generics manufacturers, virtual pharma companies, parallel traders, re-packagers or CMOs – must have adapted their packs, implemented tamper evidence capability and established systems, processes and master data to be in full compliance with the EU-FMD. If they do not, they are no longer in a position to sell their products in the European market.

As practitioners, we have worked with pharma companies to implement these capabilities. The deadline for implementation is approaching, the challenges are many and the capacity to provide equipment and solutions for the hundreds of pharma manufacturers and the thousands of manufacturing lines producing for the European market are being booked as we speak.

The 10 major considerations for pharma manufacturers: 1. Timelines for EU states: The European Falsified

Medicines Directive (EU-FMD) will impact every participant in the healthcare supply chain in 32 states in Europe from late 2018 or early 2019. This includes the 28 EU member states and three non-EU European Economic Area (EEA) members Norway, Iceland and Liechtenstein, as well as Switzerland. The exceptions are Belgium, Italy and Greece, which are deemed to have preexisting features in place that will see their compliance timeline extended by a further six years.

2. Scope of products: All prescription-only medicines

supplied to the public are in the scope of this legislation and the first items on the OTC blacklist have been announced. The list of prescription medicines that are excluded contains radionuclides, medicinal gases, IV solutions in ATC therapeutic subgroup B05B ‘blood substitutes and perfusion solutions’, contrast media as well as homeopathic medicinal products. The proposed blacklist of OTC products that will be subject to the safety features requirements is even shorter and consists of two strengths of omeprazole capsules. The inclusion of this product gives a good indication of how the risk-based approach will be administered: This is a product that is OTC in some and prescription only in other markets and omeprazole was also subject to falsification alerts in April 2013.

3.

Unique

identifier and data carrier: Every manufacturer now needs to establish the capability to generate, print, capture, verify and store and manage the four- or possibly five-element Unique Identifier carried in a 2D Data Matrix printed on each and every pack. Getting the right code on the right pack sounds trivial but there are a number of practical challenges associated with this. It requires a sound understanding of product codes – in particular the GTIN/NTIN situation – a robust master data management system and process, high data quality and above all the mature understanding in the organisation that what is required is a step change from managing the product code carried on the sales pack as part of the artwork to ensure the correct code is printed alongside the other data elements.

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Christoph Krähenbühl, 3C Integrity, explains that by early 2019, every pharma manufacturer that supplies Europe must be in in full compliance with the EU-FMD

4. Pack, artwork, tamper-evidence: The key concept

that has been at the core of the EU-FMD from the outset is the systematic mandatory verification of all packs at the point-ofdispense. This verification includes both the Unique Identifier and the Tamper-Evidence device. Chapters 3 to 6 (Articles 10 to 30) describe what this means in practice for many of the alternative dispensing practices found in the rich and complex healthcare supply chain in Europe e.g. for pharmacists and people operating within healthcare institutions.

5. Item-level but also ‘aggregation ready’: While

the European approach focuses on the pack/item-level for the major use case envisioned (point-of-dispense verification), there are a number of situations where operating at a higher level of aggregation will make a lot of sense - and has been deemed acceptable by the law-maker. It makes sense that even if manufacturers limit their implementation initially to item-level, their requirements should specify the aspiration to provide at least ‘aggregation ready’ equipment.

6.

Europe-wide

‘repositories’

infrastructure:

The responsibility to upload the data to the repositories has now been clearly assigned to the Marketing Authorisation Holders supplying pharmaceutical products into the European Market. This obliges every MAH to establish a secure and capable company repository to fulfil their data reporting, data management and record-keeping obligations.

7.

Obligations on parallel distributors/ repackagers: Article 40 sets out the obligation on all brand

owners and repackagers, to ensure the decommissioning of the unique identifier of a medicinal product in every national or supranational repository for products that have been recalled, (temporarily) withdrawn or – and that is new in this version of the Delegated Act – have been stolen or will be provided as free samples (Article 41). This means that brand owners and parallel distributors will require the system capability to upload additional ‘status changes’ of the serial numbers and – as an additional obligation on repackagers – to capture and upload the serial numbers of the packs that have been ‘consumed’ when creating the new packs that will be parallel distributed.

8. Challenges for contract manufacturers: Contract

manufacturers (CMOs) may not fall under the direct data upload obligation but it is difficult to see how they would be in a position to control the supply of the appropriate information to their customers without establishing a CMO company repository. Given the typical CMO’s position of supplying multiple customers and possibly managing a complex mix of prescription and OTC products for a range of markets, the size of the challenge facing them may dwarf the challenges faced by other pharma manufacturers.

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9.

Cost implications: Pharma manufacturers are required to fund the establishment and ongoing operation of the Europe-wide repositories system infrastructure. This will add to the cost though the good news is that through the organisations representing their interests at the European level, work has already been done to establish a capable but cost-effective approach via the European Stakeholder Model.

10. Technology and support: Serialisation

technology stack is only part of the work that needs to be undertaken. Against the background of tight timelines, companies setting off now on their implementation journey cannot afford to risk getting things wrong at this late stage. The budget for every EU-FMD readiness programme therefore needs to make provision for the technology and expert help and support that will more than pay for itself in the long run.

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The unique design of AseptiSafe valve technology ensures a closed, contamination free operation before, during and after each transfer. Additional techniques can be adopted to suit existing or new process configurations and enhance the sterility assurance of the transfer process. Introducing an optional ISO5 HEPA air flow provides a Grade A environment around or inside the valve transfer interface, ideal for installation in Grade B cleanrooms. Alternatively small space H2O2 gas decontamination in the AspetiSafe ® bio eliminates the ‘area’ of concern with a validated 6 log reduction of the enclosed area, ideal for installation in lower grade rooms eliminating the need for larger high air class control areas.

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OPINION

Building regs Farzad Henareh, Stericycle ExpertSolutions, discusses taking responsibility for product safety, regulation and classification

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are prompting increased traceability programmes to try and curb the hazards they present.

n today’s complex regulatory environment, product classification, particularly in the medical and health sectors, is an important component of product safety. Varying regulations govern different product categories, whether they are pharmaceutical, medical devices and instruments or even health applications on mobile and tablet devices.

One of the difficulties is ensuring that all parts of the supply chain, from manufacturers and developers to distributors and retailers understand and comply with regulations; another is how regulations differ from country to country, not just in Europe but across the world. All stakeholders, including regulators, must take ownership of product safety. To shirk this responsibility leads to confusion at best and a dangerous threat to consumer’s health at worst.

It is not unusual to see pharmaceutical or medical device companies recalling products for a range of reasons. Recently the Medicines and Healthcare products Regulatory Agency (MHRA) initiated the use of unique device identifiers based on GS1 standards to improve traceability, efficiency and the onerous financial impact on the NHS in the event of a healthcare recall. However, collectively the aim should be to prevent recalls and to do this we need to more carefully scrutinise and police regulations and combat the discrepancies in product classification.

At Stericycle ExpertSolutions we publish a quarterly European Recall and Notification Index which for Q2 2015 shows that there has been a 7% drop in the number of recalls in all sectors by comparison with Q1. This suggests that manufacturers are increasingly taking responsibility for ensuring and improving safety standards. However, in the broader context it is apparent that since 2003 safety notifications and recalls have actually been on an upward trend, and 88% of them have been classified in the most ‘serious threat’ category.

The pharmaceutical picture The global pharmaceutical industry could be worth nearly $1.6 trillion by 2020 says PriceWaterhouseCoopers, but it has warned that new entrants to the market and new technology are beginning to disrupt the status quo. Amongs the threats are counterfeit medicines which

Like in so many sectors, the challenge for pharma companies is that the industry has no single regulatory enforcement agency, which means that organisations are battling not only to implement traceability procedures, but also to meet the standard product safety rules. One light on the horizon is a willingness in Europe by central governments to work together to adopt traceability regulations and implement legislation.

Health apps Away from pharmaceuticals – but still in the wellness sphere – another example of regulatory confusion can be found in the smartphone health and medical applications sector. According to a recent report from the Deloitte Centre for Health Solutions, there are currently over 100,000 medical apps available in the UK app store. Where these remind consumers to take critical medication or monitor life-threatening conditions, they can revolutionise people’s approach to health and wellness. However, developers must be aware of the regulations governing them. Once again, the MHRA, together with the European Commission, have issued guidance on whether a healthcare app can be considered a medical device based on a list of keywords. Apps that are intended to ‘diagnose’ or ‘monitor’ fall under the medical device category and all the safety implications that it carries, while those that remind patients of medical appointments are considered to be consumer applications.

Imagine the potential for confusion and the health safety issues, if apps don’t fit neatly into these two categories. Inevitably, the impact of incorrect classification will have an effect on the notification and recall landscape. For example, the industry may start to see programme errors in a health and wellness app being classified as a medical device recall event.

The government is currently reviewing the UK’s system for the recall of unsafe products under consumer champion, Lynn Faulds Wood, and the classification and regulation issues are sure to be high on the agenda. In the meantime our evolving pharma and medical device environments with their complexity of regulations demands that all of us have to remain vigilant in order remain safe.

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“Mitsubishi Electric’s MELFA robot

range provided simple programming and uniform data output” Carina Geiger

Library image for iLLustrative purposes onLy

R&D Production Engineering MAQUET Cardiopulmonary AG a member of the Getinge Group, Specialist supplier to the Life Science industry

Rely on automation solutions from Mitsubishi Electric When a key manufacturer of advanced oxygenerators wanted to reduce their production costs, they turned to Mitsubishi Electric for a robot-assisted production system. Key requirements for the system were flexible deployment, easy alteration of the control programs and constant maintenance of clean room conditions. This meant that the programmes and mechanical engineers could easily understand each other and their requirements.

Mitsubishi Electric’s range of SCARA, articulated-arm robots and controller components fulfilled MAQUET’s Perfusion Systems division requirements exactly, especially as all the Mitsubishi Electric robot arms are clean room ready and can, therefore, (almost) be used straight out of the box.

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OPINION

Talent show According to Farida Gibbs, Gibbs S3, hybrid workforce solutions specialist, tech expertise is key for pharma firms to maintain global momentum

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hile most sectors are still recovering from the 2008 economic crash, the global pharmaceutical industry has emerged as a powerhouse of consistent growth. PwC’s Pharma 2020 report predicts that the international industry will be worth a staggering 1.6 trillion by 2020, commenting “in some respects, pharma’s never had it so good”.

Such growth is always driven by a skilled and experienced workforce, yet this is becoming one of the biggest challenges the industry. This is especially relevant as companies are increasingly forced to rethink their entire business model to incorporate technology and meet new challenges in productivity and quality assurance. For example, product serialisation and traceability have become increasingly important as the industry seeks to combat the prevalence of dangerous counterfeits and grey market trading. Legislation such as the Drug Supply Chain Act coming into effect in the US this year and the Falsified Medicine Directive in the EU placed an even greater pressure on companies to track their products.

The roots of the STEM shortage Meeting the stringent requirements of these new regulations requires the latest in data management technology and the integration of enterprise resource planning (ERP) software across all operations.

Aside from meeting regulations, having a single, unified view of all data - from raw materials and production capacity to market demands – through implementing ERP and other data processes is now essential for the successful completion of many projects. Strong data management enables pharmaceuticals to power growth by greatly enhancing their productivity, decreasing costs and improving market agility. Achieving this requires the work of skilled experts, while on-going maintenance requires superbly talented technical staff across the board. Unfortunately world-class employees are rarely available for long so companies need to make sure they are embedded in the candidate market to avoid missing top talent.

Working with some of the world’s biggest companies, we have found that those set on growth are encountering more difficulty accessing the staff they need to implement these changes and successfully expand. A pervasive lack of interest in STEM (science, technology, engineering and maths) subjects has led to a growing global shortage of the experienced, qualified technical workers pharma firms now desperately need.

The situation has intensified because the popularity of disciplines such as cyber-security, cloud and big data means technical specialists are in demand across the board. Pharma firms aren’t only competing against each other for the most skilled workers but against insurers, retailers and utility companies. These sectors are all desperate for qualified data analysts and are now looking to poach qualified workers from other disciplines.

Research from the Confederation of British Industry (CBI) found that nearly 40% of firms looking for STEM-based staff encountered problems when recruiting – and roughly half thought the situation was getting worse. Meanwhile, the Change the Equation survey of the CEOs of 126 major corporations in America found that almost 98% believed the current skills gap threatens their business.

Negotiating a scarce market One impact of the shortfall is that wages for the most in-demand technical roles have increased as companies fight to attract the best talent from a dwindling pool. This increases the already-significant risks of making a bad hire – something which can have negative ripple effects across an organisation.

The result is that more companies are looking to try and develop talent internally, an important and valuable trend. However, while this new workforce gets up to speed, the answer to the skills deficit may lay abroad in the meantime. Hiring within a country is generally the best option, but many markets have burgeoning skilled workforces that can be drawn upon when needed, particularly in the digital space. Eastern Europe for example has become an increasingly valuable area, aided by the ease of migration within the EU. For this reason, we recently established an offshore/onshore development centre in Lithuania to help meet the high demand.

The war for talent shows no sign of abating but leading companies are constantly innovating to try and offer the most attractive incentives, work cultures and growth prospects to retain the very best.

Moving beyond this, the most forward-looking firms are making sure they are constantly engaged in the market, understanding the shifts and trends in order to adjust and capitalise. If the pharmaceutical industry is to maintain its position as one of the leaders in global growth, firms must think outside the box to secure a skilled technical workforce against fierce competition around the world.

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OPINION

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artnerships, drug development, open platforms, clinical trials: collaborating is key to success in the pharmaceutical industry.

Team Spirit Collaboration is difficult and involves conflict and debate, but the potential rewards for the pharmaceutical sector are worth the effort says Mike Straw, Achieve Breakthrough.

But while pharma companies appreciate the need to work together, in my experience many of them are misdirecting their efforts into co-operation and co-ordination.

These concepts, although often interchangeable, are quite different things when applied to an organisation. Collaboration can lead to real innovation and change; co-ordination and co-operation just lead to more of the same thing, only done more efficiently.

It’s well known that collaboration is key to new drug development and successful clinical trials. Eli Lilly, Proctor and Gamble and others, for instance, have made a great success of using the Innocentive website over the last decade to ‘crowdsource’ solutions – putting ego aside to collaborate with others – while AstraZeneca is successfully collaborating with Cancer Research UK and finding real breakthroughs, to name just a few.

Also, in a sector that has seen a proliferation of M&A activity, large players acquiring smaller ones are having to learn how to collaborate with their new offshoots in order to make the deal deliver on its promises. And, with cost pressures greater than ever before on public services around the world, pharma companies are having to collaborate with health services and research associations to find new ways of delivering within the market constraints.

What’s the difference?

Collaboration is about working towards an agreed objective in a way that produces more than could have been produced individually. Whereas co-operation is about co-ordinating processes, collaboration is about reaching a goal through dialogue, openmindedness and interaction. It’s about having a common vision not just a common process.

Co-ordination and co-operation are still useful – but they are not revolutionary. Hierarchies often still exist and egos prevent people from fully embracing the partnership. At the same time, opinions are watered down in order to avoid conflict. It’s a negotiation and a suppression of tensions.

Alternatively, collaboration is not about always about just agreeing with each other. There is a place for conflict and contention. However, things must not be taken personally. It’s about having strong opinions, lightly held. Being prepared to argue a point and then accept whatever the outcome of the debate is, without resenting or brooding on it.

So collaboration is definitely not a ‘soft’ option for those that can’t hack it by themselves. It’s actually the harder thing to do – to set ego aside and bring many minds together, working for a mutually beneficial outcome. That’s why it’s hard for companies to do. The old hierarchies and pecking orders are deeply ingrained. To let go of that and open up to others and their ideas doesn’t come naturally.

A changing world It needs to, though. The world has changed. Technology and social media have revolutionised how we act and behave. Ideas are crowdsourced, projects are crowdfunded – it’s all about people connecting and sharing in an ‘open source’ environment.

The traditional culture in pharma is that you keep your research and challenges to yourself, hoping to make the next big breakthrough.

Although this is opening up in some areas, the desire to stay in control still remains. Organisations are fiercely protective of their own science. When they do co-operate, it is often still at arm’s length.

Your organisation may be co-operating and co-ordinating with others – but are you going to be able to create something new? In an industry facing multiple challenges, everyone is desperate for that leap that will deliver the next big thing. But in our rapidly-evolving modern world with its new technologies and economic uncertainties, no organisation can do everything on its own anymore. Looking at the tech sector, for example, even the mighty – and hugely profitable – Apple is entering into collaborations with others such as IBM. When two giants of the tech sector (and deep historical rivals) start to collaborate, you know that it’s worth adopting more widely in other industries too.

Collaboration may not be easy or always come naturally, but I believe that it’s the pharma’s with the courage to collaborate who will be the most successful in the future. Others may struggle to survive.

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COVER STORY

Seamless transitions Jörg Gierds, Fette Compacting looks at the rising demands on tablet presses for highly potent agents and explains how efficiency can be achieved through seamless containment

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ore and more tablets contain potent and highly potent substances (High Potency Active Pharmaceutical Ingredients, HPAPIs) which can be bound to powders and granulates through methods such as hot melt extrusion. After consumption, these formulations release precise doses of the active ingredients – painkillers, hormones or cytostatic drugs – into the body. Medications of this sort offer new hope to many therapies, since their action in the body is both accurately targeted and low in dosage.

A study by the trend researchers at Transparency Market Research predicts a global growth of about 10% annually until 2018 for high potency substances. By comparison, it is predicted that the pharmaceutical market as a whole will only grow by about 6% over this period. On top of this, manufacturers of generic medicines are increasingly entering this market as many patents for medication with high potency substances will expire in the next few years.

Growth creates standards Pharmaceutical manufacturers will not, however, be able to obtain a share of this growth without adjusting their production processes. The regulating authorities have laid down clear requirements in order to assure working safety, product safety, and environmental protection for processing high potency substances. On 1 March 2015, for example, supplements to the EU-GMP guidelines came into force. These relate primarily to the question of cross-contamination, referring to the unintentional transfer of active ingredients to other products. With active or toxic substances this involves high levels of risk.

Companies often find it hard to assess what is involved in the evaluation of such contamination risks. It is even more difficult to implement the guidelines into a practice that is both effective and efficient. The latest example of this is the “Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients” (ICH Q7), which has been incorporated into the GMP guideline. This resulted

in a number of uncertainties, with the result that the authorities arranged for the publication of a comprehensive Q&A, containing the most important answers, in June 2015. One of the topics highlighted is the relevance of technical and process-oriented measures to effective contamination protection.

Requirements of the tableting process The active and toxic ingredients present in the tableting process necessitate strict requirements if the associated powders and granulates are to be compressed safely and efficiently.

This presents a particular challenge to the makers of tablet presses, since it is their job to ensure that pharmaceutical manufacturers are supplied with GMP-conforming technology. They must also demonstrate pharmacological competence, so that directives – such as the European Pharmacopoeia, or “Pharmacopoea Europaea” – can reliably illuminate production planning. One important criterion for tableting technology here is the integration of a containment solution into the full processing sequence. If the focus is only placed on individual machines the likelihood of faults will rise and efficiency will fall.

Fette Compacting has defined binding containment targets which not only satisfy the official guidelines but also the commercial requirements the manufacturer has of the production process. In this context, the features of containment components must be such that the release of dust during the production process cannot occur, and also that the cleaning process cannot result in contact with toxic substances. On top of this, the compression chamber must be waterproof and dustproof and must offer a maximum of safety to the equipment operators. Due to the rising number of active and toxic ingredients, in the future a dustproof machine will be looked on as the minimum standard for pharmaceutical production.

Interaction of containment components Integrating the containment solutions seamlessly into the production process also presents new challenges to the makers of tableting machines. The fundamental principle is that all the technical interfaces must be conceived and designed in such a way that their connections are sealed without any gaps. The FE55 highperformance rotary press from Fette Compacting, which is available with an optional containment package, illustrates how this can be achieved. In its standard form, this high-performance rotary press can manufacture about 90% of all products. Since 2015, this has now also been true for toxic or potent ingredients, with dust contamination outside the machine measuring between 10 and 100 micrograms per cubic metre.

A number of special components have proven themselves for ensuring tight sealing of the connections. From OEB Level 3 upwards, tablet presses must be totally sealed. For this purpose, Fette Compacting has developed a lockable, encapsulated compression chamber with double-lip seals which prevents the release of even extremely small dust particles. The locking is monitored automatically to ensure maximum safety for the operators.

High praise: An example of a high containment plant from Fette Compacting

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The window flaps of the FE55 are in turn provided with Rapid Transfer Ports (RTP). This quick-transport connection system provides

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hardness, diameter and thickness of the tablets. The parameters for all the components of the FE55 can be adjusted centrally via the HMI terminal. Operators can conveniently monitor the individual steps of the compression cycle and the in-process control through the terminal.

Through an analysis of the production process in respect to possible sources of contamination, followed by optimisation of the system for maximum dust proofing, the FE55 aims to ensure that both the maximum permitted dust contamination of up to 100 micrograms is maintained and that the product quality needed for medications with active substances is achieved.

The future of containment Pharmaceutical technologists predicted some two decades ago that the importance of containment would grow. Numerous components and methods that have made pharmaceutical production safer and more efficient have been developed since then. This process is still a long way from coming to an end, and trends can even now be detected which will improve containment even further. As one example, the production process will become even more closely assimilated to containment, allowing containment production to be performed in a very small space. This promises advantages for both cleaning and refitting. There will also be an increased emphasis on continuous manufacturing. One effect of this is to link the process steps together, thereby requiring fewer potential containment interfaces.

The FE55 from Fette Compacting already implements some of the central aspects required for dustproof pharmaceutical production.

As a high-performance rotary press, the system, together with the optional containment package, unites the aspects of compliance with operations and high-efficiency that are crucial to the pharmaceutical sector.

Fette Compacting also offers reliably compliant solutions for the higher toxicity of OEB Level 4 and Level 5. WiP/Containment tablet presses are available with standard process equipment for OEB 4.

For highly toxic substances up to OEB 5, users can take advantage of tablet presses with complete containment and integrated process equipment. Pharmaceutical manufacturers can participate in the growth of the active substances sector by using machines of this sort.

Clean billing: Dustproof as the new standard in pharmaceutical production. The FE55 rotary press has an optional containment package

the basis for fast, repeated transfers. Operators can, for example, safely introduce tableting tools into the tablet press and replace them through an RTP. A hollow-section seal between the RTP and the window flap ensures that containment is maintained.

As far as possible, the tableting process should continue automatically. Ideally, there should be no intermediate manual steps that might risk contamination from the filling of the machine until the tablets are transported away. If, however, manual intervention is unavoidable, gloveports in the window flaps are essential in order not to break the containment. An automatic monitoring system ensures that the operator is protected, and stops the tablet press in the event of any interventions. Thanks to double seals, it is also possible to replace the gloves without contamination. The OEB-3 concept of the FE55 also provides for a split valve for secure product supply, a HEPA H13 filter with a real-time display of the vacuum, and a dustproof tablet outlet integrated into the pillar. There are three more components that can be integrated into the process with dust proofing: an upwards tablet deduster, a metal detector and an IPC unit for in-process monitoring of the weight,

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Show and tell: The FE55 with containment equipment was launched at Achema 2015

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Fast. Simple. Precise.

The new MultiTest 50 tablet hardness tester The new generation MultiTest 50 sets new standards in testing up to 5 physical parameters of virtually all tablet shapes with one single unit. In full compliance with current Pharmacopeia requirements, the system offers highest precision, flexibility and exceptional user-friendliness. Next to fast and efficient operation, the MultiTest 50 provides accurate and highly reliable test data, resulting in increased productivity and ease of regulatory compliance. www.pharmatron.com/MT50 Dr. Schleuniger ÂŽ Pharmatron is a brand of

Quality matters.

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SERIALISATION Serialisation is the system of tracking, tracing and verifying pharmaceutical products, with the goal of ensuring patients are taking reliable medicine.

Seeing is believing Ian Lemon, Essentra, looks at the issues the pharmaceutiucal sector faces with counterfeiting and where the future of packaging is heading

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he World Health Organisation estimates that up to 15% of all pharmaceutical drugs globally are counterfeited. This translates to around 1% of drugs in Europe and the USA with the issue is particularly severe in the developing world. As the supply chains for pharmaceuticals are now global and increasingly complex, the opportunity for illegal activity will continue to grow. This must be countered with a focus on monitoring and maintaining the integrity of the supply chain by paying more attention to detail and having proper protocols in place.

In 2011, the European Parliament and Council of the European Union formally recognised the public health threat posed by counterfeit pharmaceutical products and agreed upon a definition for a ‘falsified medicinal product’ as well as actions that should be put into place to combat the threat. Today, the implications of the directive are more broadly known, as is the 2018 deadline for implementation. The directive has served an important purpose in highlighting the growing issue of counterfeiting in pharmaceuticals as well as some solutions including serialisation and tamper evident packaging.

Serialisation Serialisation is the system of tracking, tracing and verifying pharmaceutical products, with the goal of ensuring patients are taking reliable medicine. A unique identification can reveal the transactional history of the drug, from supply chain to patient distribution. Serialisation can take many different visual forms, for example as a linear barcode, 2D barcode or a combination of numbers. Technologies for more advanced solutions are being developed, but the format of the unique code differs from country to country.

The advantages of drug serialisation are widely known. Serialisation can confirm the integrity of the medicine. A serial code reveals key information about the drug, such as its name, quantity, expiration date and can allow capture of key events in the process from manufacture to patient. In some cases, each serial number connects

to a larger network of numbers which identify the medication within a bulk container, case or carton.

Authentication of pharmaceutical drugs is of critical importance, as counterfeiting poses a high level of risk to the industry and to the consumer.

Tamper evidence Tamper evident features provide a clear physical indication to the consumer regarding the integrity of an individual pack. As the final line of defence against counterfeiters, it provides an important layer of protection and allows consumers to make a judgement about the authenticity of their pharmaceutical product.

Indeed, while serialisation provides unit-level track and trace, counterfeiters could easily collect used packaging (such as cartons) and refill these with fake product, reclosing the original packaging and passing the product off as genuine. Tamper evidence solutions help to prevent this by leaving a visible mark on the original packaging, so the end user knows it has been opened.

Tamper evidence solutions are available in many forms, such as labels, overwraps, and glued cartons, each having their own benefits and considerations for pharmaceutical manufacturers.

In the case of labels, these are available with varying levels of security.

For example, high-adhesion labels with a tear feature ensure that if attempts are made to remove the whole label, the carton below will be visibly compromised. Void release labels ensure that when the label is removed, aspects of the label are left behind permanently on the packaging. Hidden holograms work in much the same way as void release but provide additional security verification through being bespoke.

Only by layering attributes will the industry be able to deliver enhanced protection. That is why companies such as packaging specialist Essentra have developed technologies to integrate security within product packaging supporting industry needs from serialisation to tamper evident features.

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code carrier for a wide range of regional ounterfeit products entering the How manufacturers can meet and country-specific serialisation supply chain is a serious problem consumer safety regulations, requirements â&#x20AC;&#x201C; onto packaging that has long affected the protect their brand and maintain commonly found in pharmaceutical pharmaceutical industry. These drugs operations. The printer fires tiny ink can contain ineffective or even harmful profits by Richard Nemesi, drops through fine-gauge nozzles onto ingredients posing a threat to consumer Videojet Technologies packaging as it passes the printhead. safety. Additionally, counterfeit drugs Traditionally, TIJ was well-suited to cost the pharmaceutical industry printing high-quality text and bar code billions of dollars each year and can erode priceless commodities â&#x20AC;&#x201C; brand reputation and consumer trust. and marking labels on porous substrates. However, recent innovation in TIJ technology has made it possible to code on a range of nonThese safety concerns have given rise to regional and global porous substrates including blister lidding foils, pouches and other regulations requiring strict product serialisation that allow products flexible materials. TIJ is also ideal for carton coding, offering high to be quickly and accurately traced throughout the supply chain. throughput for the dense coding applications typical of on saleable With that in mind, now is the time for pharmaceutical manufacturers unit. Additionally, printheads can be stacked to create large images to leverage the coding and marking solutions within their packaging suitable for the sides of cases and other porous substrates. operations to help prevent counterfeiting.

Laser marking can also be used to create high resolution 2D bar codes In order to make the best choices, there are key factors to consider as well as human legible codes. Laser is an ideal choice for creating such as optimal technology and line integration. High-quality, permanent coding on a variety of pharmaceutical packaging. Laser permanent coding will allow pharmaceutical manufacturers to marking uses a beam of infrared light focused and steered with a ensure regulatory compliance and consumer safety, while also series of carefully controlled small mirrors to create marks where the heat of the beam interacts with the packaging surface. A variety maintaining operational efficiency and protecting brand integrity. of laser sources such as CO2, fiber and UV, enable laser coding to be effective on an array of pharmaceutical packaging like cartons, Coding & marking solutions bottles, vials and labels.

Regulations introduced over the past several years significantly increase the amount of information required on pharmaceutical TTO is best-suited for marking flexible packaging such as pouches products. Additionally, it is important to consider that the information and barrier materials, offering high quality codes from date, lot, must be presented in both human and machine readable formats. and time stamps to more complex codes such as bar codes, use The good news is that recent advances have yielded solutions across warnings, and ingredients lists. TTO systems use a digitally controlled a variety of coding technologies to meet the challenges of the printhead to precisely melt ink from a ribbon directly onto flexible pharmaceutical industry, including Thermal Inkjet (TIJ), Laser, Print films, providing high-resolution, real-time prints. Marking directly & Apply Labeling (LPA), Thermal Transfer Overprinter (TTO), and on labels frequently requires integration with labelling equipment, which yields high quality, precisely positioned codes. TTO offers a Continuous Inkjet (CIJ). simple method of direct contact coding on labels before application TIJ is generally used to print high resolution traceability information to the bottle or packaging. including 2D DataMatrix codes â&#x20AC;&#x201C; the standard machine readable

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The next step is knowing where and how to best implement serialisation solutions. Coding solutions can be acquired as components of broader packaging solutions such as cartoners, starwheels, bottlers, and thermoformers, or they can be retrofitted into existing equipment. Incorporating coding solutions properly along the packaging line can go a long way in increasing the overall efficiency of a manufacturing operation.

A starwheel is ideal for ensuring accurate placement on small packaging, due to the improved product control of the equipment.

Cartoner CIJ systems can be used to print on a wide variety of packaging. CIJ technology is a fluid-based, noncontact printing method, capable of up to five lines of text, linear and 2D barcodes. Fast print speeds and a range of application-specific make CIJ a strong option for challenging pharmaceutical packaging applications. CIJ can also be used in bottle and vial applications, printing in a range of visible inks, UV and other invisible inks for covert coding.

To meet increased demand for high grade coding downstream on packaging lines, such as bundles and corrugate cases, Print and Apply Labelers (LPA) automatically prints and places labels of various sizes onto packaging. LPA can help pharmaceutical manufacturers ensure accurate label placement and high resolution coding. This enables supply chain partners to easily identify products through highly accurate, clearly readable information on shipping cases, contributing to effective supply chain management.

Coding can take place in several locations within the equipment, integrated into the cartoner, itself, or on the outfeed conveyor. Integrating the printer into a cartoner provides great product control and the additional benefit of applying the code after the product has been inserted into the carton.

Sidegrip conveyor The sidegrip conveyor can be used to mark visible and covert codes on the top or bottom of bottles, as well as carrying out code verification immediately downstream. Printing on the bottom of the bottle can help protect the code and minimise its impact on the aesthetics of the pack.

Bottle labeller Many coding technologies can be utilised for contact or non-contact marking of the label before application, ensuring high-quality alphanumeric and bar code printing.

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Checkweigher The checkweigherâ&#x20AC;&#x2122;s performance properties, such as precise material handling at high production speeds can be used to improve overall print and DataMatrix quality.

Thermoformer Coders can be integrated with thermoformer equipment, allowing high quality marking on webbased materials, including blister lidding foils and other barrier films.

As counterfeit drugs continue to pose a problem for the pharmaceutical industry and serialisation regulations are growing more widespread. As such, companies throughout the supply chain are under pressure to comply with traceability requirements in order to protect consumer safety and uphold brand reputation, while ensuring operational efficiency to maintain their bottom line.

To achieve high coding and marking standards, manufacturers need to understand the wide range of technologies available for their needs, as well as packaging types and substrates. While it might seem like a daunting task, experienced providers are prepared to support manufacturers with guidance, ensuring product authenticity, regulatory compliance, and overall operational efficiency.

27

POWDER HANDLING

Take charge ChargePoint’s microbiological study of aseptic transfer of vial stoppers using its split butterfly valve

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he test was carried out by Skan. The AseptiSafe spilt butterfly valve is said to have a number of practical advantages over existing transfer techniques although for years lacked the microbiological data to support its use. This study aims to gather this data by means of qualifying the technology.

The ChargePoint butterfly valve consists of half ports – an active and a passive. During the operation, the passive is docked to the active port in such a manner that the previously exposed surfaces of both ports are locked against each other. In this way, two different controlled environments (class C and class A, for example) should be kept separated, and an aseptic transfer of material should be assured through the valve.

This study investigates its suitability to achieve an aseptic transfer of material, in this case vial stoppers, through the valve keeping controlled environments separate and free form migration of microbiological contamination.

Test protocol The practical qualification involved challenging the split butterfly valve with class C bioburden (20-25 spores per 2826 mm2, i.e. area of a standard contact agar plate), using Geobacillus stearothermophilus spores, and transfer vial stoppers through the valve.

The transferred stoppers where then incubated in a growth medium to detect any bacterial growth. The microbial study was further divided into two test parts (A and B).

In the test (B), class-C bioburden exposed surfaces of the valve (valve plates) was disinfected with 6% H2O2 prior to the assembly of the valve. Whereas, in test (A), no prior decontamination of class-C exposed surfaces was carried out. For each test, the experiment was conducted in triplicates using three valves with multiple make and breaks under identical experimental conditions in a pharmaceutical sterility isolator (PSI).

Results • Bacterial growth was observed in positive controls for both parts of the test (A and B) • Negative controls remained clear.

• No turbidity (implying no bacterial growth) was observed in any of the test containers.

This means that non of the contamination inoculated onto the faces of the discs had managed to migrate onto the stoppers during the transfer.

Discussion With the results of this study it could be clearly demonstrated that aseptic transfer of stoppers through the valve assembly can be achieved in routine pharmaceutical processes wherever required.

Loaded isolator chamber and airlock

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POWDER HANDLING

Ready for the decontamination cycle

Wiping with 6% H2O2 after inoculation (and image below)

Aseptisafe benefits • Ergonomically, docking and actuation is unhindered by gloveport or gloves. (operated from outside the enclosure) • No intervention into the line and less operations to perform the transfer.

• No intervention means less risk (particle generation and damage) • No intervention means no additional gloveports to access the device internally.

• No intervention means no additional cost from the RABs / isolator supplier (glass /port/glove).

Transferring stoppers through the valve

• No opening parts inside the line means no disturbance to the laminar flow inside the aseptic core and no particle generation over the stopper bowl.

• Passive can be reused after transfer.

Autoclaved or SIP if mounted to a stopper transfer vessel.

• Contamination free transfer.

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29

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QUALITY MANAGEMENT

The IT crowd Robert Gaertner, Veeva Vault QualityDocs, looks at the way that digitisation has changed life sciences and what the future holds, including technology development and upcoming regulatory requirements

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oday’s pharmaceutical companies are moving away from the ‘one-size-fits-all’ approach, recognising the need to develop more personalised treatments. However, traditional manufacturing and quality functions will struggle to keep pace with this necessary innovation in personalised therapies unless there is a change.

This is where ‘Industry 4.0’ as the next big trend has potential to revolutionise pharmaceutical operations from the inside.

Increased cost pressure and greater global competition require a different approach. Companies are starting to combine drugs, advanced application devices, and medical apps to be more patient-centric.

However, previous product launch approaches, process technologies, and proven validation concepts are no longer sufficient, as they have an increasing number of product variants and smaller batch sizes.

Enabling personalisation of medicines requires more than putting a nice wrapper around the same processes and systems that have been in place for decades.

Digitalisation will play a strategic role in all aspects of the new value chain, from R&D to manufacturing to patient-centric information exchange. Industry 4.0, therefore, is not only about new technology, but also domain-specific concepts and standards that transform supply chains, manufacturing facilities, and processes.

This technology leap will lead to disruption, which brings with it a level of uncertainty. But this uncertainty cannot be an excuse to halt progress. And no other industry is more prepared than the pharmaceutical industry to analyse critical processes, assess risks, and define controls. This is where the quality organisation is critical to a digital revolution. As a result, it is essential that quality professionals gain a deep understanding of information technologies so they can advise on how to best implement them in a timely and compliant manner.

From Industry 4.0 to Pharma 4.0 The vision for Industry 4.0 is to connect all resources – human, data, and physical machines – in one virtual network. This connectivity is both within and beyond company walls; the most benefit will be achieved by going beyond plant walls.

Industry 4.0 combines diverse technologies, including big data analytics and cloud computing. The ability to analyse enormous data volumes and share insight across the virtual value chain will be important to delivering new innovation and responding to changing market dynamics. Content and data are stored in a regulated cloud repository so information can be accessed in real time from anywhere.

By applying the concepts of Industry 4.0 to the pharmaceutical industry, “Pharma 4.0” is both revolutionary and transformational from the outbound flow of goods to the information flowback of real-time patient data.

Impact on quality organisations The trend towards more individualised therapies means more quality data to review and more releases to support. With this comes more pressure on quality to avoid being the bottleneck in a make-to-order world.

Realisation of Pharma 4.0, however, requires a shift in how GxP content and data are managed. Today’s approach is still greatly based on paper and a traditional definition of documentation needs. This slows down processes and is limited when it comes to efficient knowledge sharing and collaboration across multiple parties.

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Transformation needs to start with changing the mindset and perception of GxP content: • Electronic content is not just “paper under glass” – Many enterprises think they have state-of-the-art execution systems, but those systems still support paper-based processing for GxP record-keeping. Looking ahead, GxPcompliant documentation will arise in new electronic formats, which cannot be properly managed with legacy paper-based processes.

• GxP and non-GxP data management will merge – GxP relevance to records and systems will be defined by usage, not physical separation (e.g. multiple paper/file copies).

This means classification as GxP or non-GxP will not be feasible anymore, and this requires security mechanisms and controls for nonGxP areas.

• Global collaboration and content exchange are musts – The goal is no longer to isolate content and data behind company walls, but rather to facilitate a secure exchange among a virtual team. Team set-up can change quickly, and processes may need to be reconfigured.

Therefore, it is important to not only grant access to external parties on a granular level, but also to revoke access in a flexible, secure fashion.

The trend towards personalised therapies requires a transformation – one that supports the shift from inflexible mass production to manufacturing individually tailored products with the expected quality, safety, and efficacy. A Pharma 4.0 approach is needed to support this shift. Quality needs to mandate the assessment of risks and the implementation of effective controls to open the doors to Pharma 4.0.

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THE FUTURE OF PHARMA

What lies ahead...

The European Consortium on Continuous Pharmaceutical Manufacturing (ECCPM), looks at issues surrounding continuous processing

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ecently the FDA has endorsed the transition towards continuous manufacturing (CM) as a way to shorten the supply chain, increase agility and flexibility of development and manufacturing and to improve product quality through real time process control.

Significant resources and capital investment are required by industry, according to CDER director Janet Woodcock.

Several large pharmaceutical companies have been earlier adopters of CM. Vertex, J&J, GSK and Novartis are all working on continuous manufacturing facilities. Along with Pfizer, they already have secondary process equipment installed or under development. Novartis and GSK have been reported to be investing significant resources in continuous primary production and crystallization. On the academic side, several universities are researching continuous production technology, including the ERC on Structured Organic Materials led by Rutgers University, the MIT-Novartis Center for Continuous Manufacturing, and the Center for Continuous Manufacturing and Crystallisation at Strathclyde University and our multi-centre initiative the European Consortium of Continuous Pharmaceutical Manufacturing (ECCPM).

processing equipment is relatively small in the pharmaceutical industry (compared with the oil, food or plastics industries) it should be modular, portable, and transferrable, ie, skid-mounted to facilitate a ‘plug and play’ approach. CM plants should also be interchangeable with respect to coupling of different continuous processing unit operations for better process and formulation flexibility. In terms of process monitoring, the process should be adaptive and amenable to continuous quality verification of key process intermediates and the end product. Most importantly, the continuous process should afford a product with improved specific product quality.

Challenges of continuous processing

With so many perceived advantages, why has continuous processing not been adopted more quickly by the pharmaceutical industry?

For new products, the financial justification is clear in terms of significant API and resources saved in R&D. Equally significant are the savings in direct and indirect labour in commercial plants.

CM can reduce frequently occurring However, financial justification for Several advantages are associated with CM scale-up problems, since the investment in continuous processing – flexibility possibly being the most important involves a well-planned and expansive development can be performed using one [1], [2]. For example, CM can contribute transition from existing batch capacity. the manufacturing equipment. to the industry’s response capacity in case of Here an important consideration is that changing market demands or emergencies batch capacity is probably in excess on by reducing the development and an international level, given declining manufacturing time. Another advantage is production volumes in the industry. speeding up the supply chain, which is critical being able to react to changing market demands. CM can reduce frequently occurring The regulatory framework means it can be expensive to switch existing scale-up problems, since the development can be performed using products from batch to continuous production, requiring significant the manufacturing equipment. Moreover, critical quality attributes resources for post-approval changes. It requires development of a (CQAs) are monitored in real time, improving the product quality. process design space, a control strategy, generation of stability data Since CM plants have a small footprint, they can be setup in flexible and possibly a bioequivalence study. For some products the business and portable environments, eg, containers allowing deployment case might not be sufficiently strong. Geographical diversity can also around the world. be a factor. In some cases, pharmaceutical companies are required to produce in the country where the product is distributed or sold.

Several requirements are expected from a CM plant: Floor space CM plants may not be approvable by local authorities. should be small and the equipment should be easy to clean.

Moreover, it should allow for rapid changeover for multiple-product manufacturing. CM systems must provide a reasonable range of throughputs, either to meet different product-volume requirements, or to enable coupling of other unit operations. Because continuous

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Year Post Launch Figure 1: Product lifecycle sales of a typical product

Technically there are some challenges. First is the issue of feeding and processing, as some APIs and excipients are difficult to handle due to their cohesive nature and low bulk density. Second are the numerous issues with process monitoring and control. To assure product quality, all of the Critical Process Parameters (CPPs) and Critical Quality Attributes (CQAs) must be identified then measured and controlled within acceptable limits, preferably directly and not by surrogate means. Consider the projected lifecycle sales of a typical product (see Figure 1). The demand is not consistent, it rises then falls. A product dedicated line, sized to manufacture a peak demand of 250M tablets per annum, would operate well below full capacity for much of the product lifecycle.

An alternative approach would be to deploy multiple continuous units to meet total demand across a portfolio of products. A key advantage of this approach is that the production scale is the same as the late phase development scale, eliminating technology transfer issues.

Other considerations

Issues needing attention are the financial environment, manufacturing strategies and various technical gaps, including PAT tools. Moreover, a change towards well-engineered API would enable simpler secondary process streams to be deployed.

The ECCPM Though there are significant benefits of CM, implementation in the industry is just beginning. Beside technological issues, the regulatory perspective has to be considered, with the FDA encouraging continuous manufacturing submissions and the EMA beginning to embrace CM as well [3]. The ECCPM (www.eccpm.com) has been founded to facilitate the transfer of continuous manufacturing from R&D to production scale. This consortium focuses on the investigation, development and implementation of continuous manufacturing approaches for solid oral dosage forms. The need for better manufacturing brings together several companies and universities along the value chain to work on a collective vision on continuous manufacturing (see Figure 2).

The product dose must be factored into calculations as seen in Table 1. It illustrates the number of weeksâ&#x20AC;&#x2122; production required for different strength tablets, assuming 120 hours output per week. The two lower dose products could be manufactured in 50 weeks on one small machine if the product changeovers were efficient.

Commercial Volume (m units pa)

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Granulator Weeks @ 25kg/h

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Table 1: Number of weeks required for different tablets

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Figure 2: ECCPMâ&#x20AC;&#x2122;s vision on continuous manufacturing

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THE FUTURE OF PHARMA

Figure 3: Organisational structure of the ECCPM

The objective and scope of the ECCPM are: i) focusing on the development and implementation of CM strategies for solid oral dosage forms, ii) several vertical (company specific) streams the socalled â&#x20AC;&#x2DC;use casesâ&#x20AC;&#x2122;, which represent the company-related work on a specific product sponsored by a pharmaceutical company partner, iii) one main horizontal (shared) stream, iv) two additional horizontal streams dealing with process simulation and process analytical technologies (see figure 3). Due to the open access strategy, additional partners with specific use cases can join at any time, if agreed by all the existing and already active partners.

The expected benefits for participating companies are: i) use of existing platform technologies ie, wet, dry granulation and HME) for the development of a continuous process for their specific drug products, ii) the economic evaluation in terms of costs (production, materials, footprint, etc.), efficiency and yield, iii) implementation of concepts for integrated quality control strategies, iv) access to consolidated scientific expertise (eg, simulation, material science, PAT), equipment and instrumentation suppliers without exposure to CAPEX and v) co-authorship of scientific publications and relevant conference presentation.

The pre-competetive platform is the workshop series, in which all industrial and scientific partners are involved to an equal extent and share data, experience and information related to continuous manufacturing science. Topics of common interest for all project partners are addressed and discussed within biannual workshops.

In this context, the common platform works together on subsequent, exemplary mentioned topics:

References Implementing Continuous Manufacturing to Streamline and 1.

Accelerate Drug Development; Hurter, Thomas, Nadig, EmiabataSmith and Paone; AAPS Newsmagazine, August 2013.

- What is necessary and missing for RTRT and how can it be implemented in the virtual process supported by the recent developments in the field of PAT, process monitoring, and visualisation (see Figure 4).

- Developing of DEM Models for the simulation of particle related interactions (segregation, aggregation) within continuous processes (eg, mixing and transport) and units (eg, hopper, pipes).

- Pelletising of thermoplastic formulations with the target of narrow RSD micro pellets

2. Rantanen J. and J.G. Khinast, The Future of Pharmaceutical Manufacturing Sciences, J. Pharm Sci. (2015) in press 3. Gretchen Allison, Yanxi Tan Cain, Charles Cooney, Tom Garcia, Tara Gooen, Oyvind Holt, Nirdosh Jagota, Bekki Komas, Evdokia Korakianiti, Dora Kourti, Rapti Madurawe, Elaine Morefield, Frank Montgomery, Moheb Nasr, William Randolph, Jean-Louis Robert, Dave Rudd, Diane Zezza, Regulatory and quality considerations for continuous manufacturing, ISCMP White paper 3 (2014) Authors Dave Doughty, Johannes Khinast, Massimo Bresciani, StephanLaske, Research Center Pharmaceutical Engineering, Graz, Austria Jarkko Ketolainen, University of Eastern Finland, School of Pharmacy Thomas De Beer, University of Ghent, Laboratory of Pharmaceutical Process Analytical Technology

Figure 4: Exemplary process line including material properties automatically and potentially monitored via PAT tools

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Expert witness David O’Connell, PCI highlights the company’s expertise via an overview of its granulation service

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harmaceutical granulation is a common technique for solid oral drug production, whether as tablets, capsules or granules for use in bottles or sachets. PCI offers multiple granulation methodologies addressing requirements of a range of Active Pharmaceutical Ingredients (API), irrespective of potency.

Granulation combines individual formulation components (API, diluents, binders, disintegrants) into a single uniform particle. The various techniques include wet granulation; dry granulation; fluid bed granulation and hot melt granulation.

Granulation is of benefit in overcoming challenges such as active content uniformity; densification of formulation; powder flow properties; compression properties; controlled API release profiles and API bioavailability.

PCI’s granulation is performed by aqueous-based solutions with investment in granulation equipment including high shear mixers, one pot processors, roller compactors and fluid bed processors.

PCI has the additional capability to produce high potent products (OEL down to 0.01 µg/m3) utilising high shear granulation and fluid bed processing. Containment performance is proven using

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Standardised Measurement of Equipment Particulate Airborne Concentration (SMEPAC) testing. PCI’s granulation suites include totally contained engineering systems with no open powder handling.

The suites include small-scale (1-5 kg) (Figure 1) and large-scale (20 – 120 kg) equipment. Traditional physical assessment of the granule from the operator is not required as end-point of granulation is determined reliably from data obtained. Data is converted into user-friendly batch reports (Figure 2): the figure graphically indicates the power and torque of the impeller blades which, with relevant training, can determine the end-point of granulation prior to product over massing. The figure also demonstrates the granulation fluid addition rate.

The granulation bowls are geometrically similar with similar design of impeller blades meaning products developed at small-scale can be scaled up to large-scale. PCI uses precise mathematical scale-up modelling to ensure successful larger batches. Modelling includes the scale-up of the speed of the impeller blade, the granulation fluid addition, mixing times and bowl volumes. The impeller blade speed can be altered by choosing the most appropriate model to obtain a similar physical granule (tip speed, Froude number or constant shear stress).

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GRANULATION

Similar models can be performed for fluid bed granulation assessing the required air flows and spray rate calculations. This can be used to deliver a low API concentration within the formulation via the granulation fluid. Other elements of fluid bed granulation include low porosity density (particles remain more spherical) and end product bulk density that is similar to the starting material. This process is also utilised for pellet and tablet film or modified release coating.

One pot processing is another granulation technique where product drying is performed using a jacketed bowl. The bowlâ&#x20AC;&#x2122;s insulated water jacket is used to raise the temperature, evaporating the aqueous media drawing moist air away using a vacuum system with a condenser. During the drying phase, the impeller blade is rotated incrementally moving the colder material to closer proximity of the heated jacket wall. The Collette U600, PCIâ&#x20AC;&#x2122;s newest and largest one pot processor, also includes a heated bowl lid to aid drying, an inbowl camera and a sample chute which prevents heat loss when taking samples or visualising the product.

PCI has a range of one pot processors; from small laboratory to large-scale equipment. Scale-up models can provide a faster path to large-scale manufacturing with the similar physical and chemical properties as the developed granules.

Both the high shear granulators and one pot processors can be used to perform hot melt granulations. This type of granulation introduces a waxy bioavailability enhancing excipient to poorly soluble APIs. This granulation assists in the dispersion of the granules into a fine particulate suspension aiding absorption within the patient.

Roller compaction is a process that provides a granulation method for materials that are heat and moisture sensitive by compressing powder blends between two rollers under pressure with the resulting material sized by dry mill. The granule produced is densified with a larger particle size and better powder flow in relation to the starting material.

Figure 1: Small-scale granulation suite

PCIâ&#x20AC;&#x2122;s latest investment in a Gerteis Mini-Pactor provides fully contained roller compaction for the processing of highly potent APIs with the ability to perform small development batches at 10g/hour and scale-up to 100 kg/hour. This provides a distinct advantage in executing scale-up activities from development through clinical trial manufacture and subsequent commercial production. In line with the other state-of-the-art equipment, the PLC systems perform feedback loops for optimal control of ribbon thickness produced from the rollers.

PCI will continue to invest in granulation methods offering clients maximum flexibility in drug development and manufacturing.

Figure 2. Example of wet granulation report from high potent HSM

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PRODUCT FOCUS

Passing the test Thermo Fisher Scientific explains how its TruScan analyser helps to meet the challenge of 100 percent ID

Many pharmaceutical manufacturers are turning to Raman spectroscopy to enable 100% inspection

Direct line: Using handheld instruments like Thermo Fisher Scientific TruScan analysers brings analysis directly to the warehouse

The trend toward 100% material ID continues to gather momentum, with both the European Pharmacopeia and Pharmaceutical Inspection Co-operation Scheme (PIC/S) mandating 100% inspection of raw materials.

This demand forces manufacturers to re-evaluate their quality control procedures, and challenges them to exponentially increase inspection without dramatically increasing staff – and cost.

Many pharmaceutical manufacturers are turning to Raman spectroscopy to enable 100% inspection, leveraging handheld instruments like Thermo Scientific TruScan analysers to bring the analysis directly to the warehouse. But not all handheld Raman analysers are created equal, and it’s critical that users consider several factors as they evaluate potential solutions.

Is the instrument fit for purpose? How difficult is validation and deployment? Who is the trusted partner with proven industry leadership?

Fast validation Deploying Raman as a replacement for the compendia ID that complies with USP/EP/PIC’s guidelines requires validation of a spectral library method while ensuring specificity. With the aid of ‘one-button validation,’ TruScan analysers achieve these requirements by directly testing a sample scan against methods for the material of interest as well as the entire user or factory library on the device (factory library includes 4,300+ common pharmaceutical materials). This eliminates the need to test each material one by one versus every material in the user library, greatly reducing the time required for validation.

Trusted Solutions The TruScan family of products is designed to meet the stringent requirements of the pharmaceutical manufacturing environment. It is robust, chemically resistant and sealed for cleaning with solvents or bleach without complicated protocols for each surface.

The TruScan software platform is built onboard the instrument and does not require a separate computer package to manage and build libraries. This should help with rapid deployment since there is no separate computer qualification requirement. It automatically creates secure PDF reports of run data, batch reports and audit trails during synchronisation, aiding in compliance and ease of use.

All-in-one: The TruScan software platform is built onboard the instrument and does not require a separate computer package to manage and build libraries

Smart decision making The TruScan analyser belongs to the next generation of analytical instrumentation called ‘reactive analysers.’ It uses a patented probability approach

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(p-value) based on fundamental understanding of measurement uncertainty. Thus, the p-value approach provides superior specificity and sensitivity than correlation methods like HQI, Euclidean distance and empirical modeling approach such as SIMCA, PLS, etc. As the analysers acquires the Raman spectrum for a test material, they determine in real-time the uncertainty of that measurement with consideration of sample characteristics, instrument telemetry, and testing environment over a wide range of potential sampling conditions.

This makes the product portable and also adaptive to the testing environment as it exists during the actual sample measurement. This is absolutely critical for a handheld device outside the well-controlled environment of a laboratory where benchtop instruments have the benefit of highly reproducible sampling interfaces.

Embedding this probabilistic approach within the analyser required the development of robust hardware and software platforms and their full characterization to understand performance within specified operation ranges. Our technological developments were scrutinised by pharmaceutical manufacturers, and we’ve proven that our solutions provide equal or greater specificity than required by current material ID testing protocols.

Customer driven solutions To meet the challenge of 100% raw material ID, pharmaceutical manufacturers are increasingly turning to handheld Raman instruments to increase inspection intervals, improve inventory management and reduce global supply-chain risk.

39

PROCESS EFFICIENCY

Liquid assets Glycol-based heat transfer fluids

Heat transfer fluids used for heating and cooling within the pharmaceutical industry have a significant impact on the operational efficiency and lifespan of processing equipment and long-term costs.

Gary Lydiate, Kilfrost, discusses the importance of choosing the correct heat transfer fluid

The higher heat capacity and thermal conductivity of glycol-based heat transfer fluids makes them far more efficient in terms of heat transfer than non-aqueous alternatives. This reduces overall energy consumption, lowering both carbon dioxide emissions and long-term financial costs. In addition, aqueous-based heat transfer fluids have a superior environmental profile to non-aqueous-based equivalents.

It is well understood that glycol/water mixtures (commonly referred to as antifreeze) are corrosive and the use of simple commodity chemicals, like glycols, as heat transfer fluids can lead to significant issues. These include corrosion and fouling of processing equipment, leading to increased downtime and, in some cases, expensive repairs and replacements. There are, however, heat transfer fluids, with an inhibited glycol base, formulated specifically for heating or cooling processes. Inhibited glycol/water mixtures make excellent heat transfer fluids in comparison to oil and synthetic-based fluids.

Corrosion inhibition of glycol-based heat transfer fluids has advanced dramatically over the last 20 years, with the use of toxic chromates, nitrites and borates, as well as environmentally harmful phosphates and nitrates in decline. Advanced, fully inhibited glycol-based fluids will include longlasting organic corrosion inhibitors based on a combination of long and short chained carboxylic acid salts, heterocyclic compounds and polymeric materials.

A demanding international standard with respect to corrosion control is adhered to by reputable companies, although it still remains voluntary. The ASTM D1384-05 corrosion test standard is playing an increasingly important role, as the pharmaceutical industry begins to recognise the challenges that system corrosion can cause. The test immerses metals commonly used in heating and cooling systems in a heated and aerated glycol/water mixture. After two weeks the metals are analysed for signs of corrosion, assessing the impact of heat transfer fluids on a system.

It is not always easy to find a heat transfer fluid that meets businessesâ&#x20AC;&#x2122; needs.

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Inhibited glycol/water mixtures make excellent heat transfer fluids in comparison to oil and synthetic-based fluids.

Labeling by Faubel.

CONVINCING QUALITY.

Efficiency versus toxicity A variety of glycol-based fluids are used within heat transfer fluid formulations. The most commonly used glycol bases are mono ethylene glycol (MEG) and mono propylene glycol (MPG). Both of these base fluids have different thermo-physical properties and, of prime consideration for the pharmaceutical industry, very different toxicity profiles.

www.faubel.de

Inhibited MEG based fluids are an excellent choice for numerous applications, but the fluidâ&#x20AC;&#x2122;s high toxicity means it poses a health risk when used in systems where incidental contact with items intended for human consumption is possible.

MPG based fluids are commonly used in systems within the pharmaceutical industry due to their low toxicity. However MPG is far less efficient than MEG at transferring heat energy because of its higher viscosity which leads to increases in pressure drops and often

makes the attainment of efficient turbulent flow unfeasible (Figure 1).

In consequence, the use of MPG based products will lead to higher overall investment and operating costs.

As the chart shows, below 0o C the viscosity of MPG based heat transfer fluids rises sharply, making it increasingly difficult to pump efficiently. The difference in viscosity and overall system efficiency becomes even larger as the circulating temperature of the fluid decreases. To provide the industry with an advanced lower viscosity, low toxicity, ASTM-D1384-05 rated heat transfer fluid, Kilfrost ALV has been developed.

Environmental profile The environmental profile of heat transfer fluids is also very important, with more and more companies looking for sustainable options to replace petroleum-derived specialty chemical products, like heat transfer fluids.

Current bio-derived heat transfer fluids formulated with a sustainable chemical feedstock have struggled to make a significant impact in the glycol-based heat transfer fluid market as they offer no significant additional advantages aside from their green credentials. However, Kilfrost ALV offers better performance than existing products, whilst also making use of available bio-derived feedstocks.

Booklet labels for automatic application Multi-layer labels up to 9 pages Single-layer labels from small lots to high volumes Tamper-evident solutions

With the growing demand for non-toxic heat transfer fluids, alongside the ever-increasing desire for fluids that boost system efficiency, it is not always easy to find a heat transfer fluid that meets businessesâ&#x20AC;&#x2122; needs. Kilfrost ALV removes the need for compromise, providing a non-toxic heat transfer fluid which guarantees higher system efficiency than products already on the market.

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41 22.04.2015 13:26:39

TESTING

LAL

Recombinant Factor C

Endotoxin

FC

Endotoxin

Glucan

FC

FB

FC

rFC

rFC

FG

FC

Substrate Proclotting Enzyme

Clotting Enzyme

Substrate

E

ndotoxins are lipopolysaccharides found in the outer membrane of Gram-negative bacteria.

These pyrogenic components can elicit an immune response if administered via the blood stream through contaminated parenteral drugs or other medical devices. Hence, bacterial endotoxin testing (BET) needs be carried out for all such products in order to prevent any adverse effects.

In the 1950s, Fred Bang discovered that horseshoe crab (Limulus polyphemus, Tachypleus gigas and T. tridentatus) blood reacts in the presence of endotoxin.

This is due to the presence of Factor C, a component that activates the clotting cascade (Figure 1) and forms the basis of the Limulus Amebocyte Lysate (LAL) and Tachypleus Amebocyte Lysate (TAL) assays used in BET today.

The industry is heavily reliant upon the supply of LAL/ TAL for endotoxin testing. However, scientists have now developed a recombinant version of Factor C (rFC) that is comparable to the natural equivalent.

One of the reasons the industry has perhaps been reluctant to adopt this alternative is the fact that the pharmacopoeial regulations currently necessitate an additional validation procedure to be carried out.

However, this is not as complicated or time-consuming as it may appear.

The need for alternative tests The need for the widespread adoption of an alternative assay is becoming increasingly important due the fact that the demand for LAL/TAL may soon exceed the supply. This is due to an increasing number of new biologics being developed, the growing impact of personalised medicine and the maturing Asia-Pacific markets. In addition, as with any natural resource, crab populations are at risk of mismanagement and loss.

Therefore, adopting rFC-based methods would not only meet European and global initiatives to reduce animal use in testing, but would also decrease the demand made on the crabs, a finite resource.

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Detectable Signal

Detectable Signal

Figure 1: Comparing LAL turbidimetric and chromogenic assays to fluorescence-based Pyrogene recombinant Factor C assay.

Testing Times Lakiya Wimbish, Lonza, discusses the benefits of recombinant Factor C based endotoxin testing In addition to negating the need for an animal source, rFC products, such as Lonza’s fluorescence-based Pyrogene rFC assay, perform comparably or better than LAL/TAL-based methods for some applications, and offer a number of additional benefits to the user. These include improved lot-to-lot consistency, enhanced endotoxin specificity, statistically more robust spike recovery, ease-of-use and a suitable sensitivity range (0.005 EU/ml – 5 EU/ml).

Validating the alternative So what is holding back manufacturers from adopting rFC-based assays? According to the United States Pharmacopeia (USP) rFC-based assays are listed as ‘alternative methods’, and must be validated as per USP <1225> or International Conference on Harmonisation (ICH) Q2B. This means that their use requires extended validation over and above the compendial methods, to prove the alternative tests meet the intended analytical application. While these steps do require some additional effort, these can be accomplished in one to three days of following a well-structured protocol, alleviating any concerns of significantly lengthening the testing workflow.

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The procedure includes four steps. The initial qualification involves an assessment of the reagents and testing equipment to establish whether the current system is functioning properly. The second step determines the level of dilution required to overcome product inhibition or enhancement.

Thirdly, the alternative method must be validated and should show that the rFC is capable of achieving comparable results to the current method. In order for the regulators to evaluate the validity of the proposed method, submissions should contain the following: 1) a rationale for using the test, such as the fact that it reduces a reliance on animals and offers enhanced endotoxin specificity and reproducibility; 2) a complete description of the proposed analytical procedure; and 3) data elements that demonstrate the analytical performance of the procedure. The latter should include the following parameters: accuracy, precision, specificity, linearity, range, detection limit, quantitation limit, and robustness. The fourth and final step of the validation process requires a productspecific validation to ensure it is possible to generate consistent results using the chosen method.

Conclusion Clearly, there is a need for LAL/TAL assay alternatives due to the growing demand on resources. Fortunately, rFC-based methods are available that offer a number of benefits to the user. Although defined as an alternative by the pharmacopoeia, these tests are simply a fluorescence-based version of the existing LAL/TAL assay and do not require much additional effort to implement. Hence, companies should not be dissuaded from adopting these methods. To make the switch even easier, companies such as Lonza have compiled pre-developed documentation to assist with regulatory submissions and can also help users to incorporate the technology in their testing workflow.

It seems likely that rFC will become the go-to solution for BET in the future, and many forward-thinking manufacturers are already adopting it into their processes.

PACKAGING

Track & trace Weber explains how medical device manufacturers can keep on track with UDI requirements

Print works: UDI label data printed using Weber technology

T

he FDA’s ruling requiring UDI’s (Unique Device Identifiers) to be assigned to medical devices and their related packaging will undoubtedly bring many benefits. Patient safety will be greatly enhanced through increased protection from counterfeit devices and the ability to identify a device, even when it has been separated from its packaging will make it much easier to link the product to its original manufacturer in the event of problems.

The term UDI stands for Unique Device Identification.

This is a unique numeric or alphanumeric code which includes a device identifier, specific to a model and a production identifier.

For some manufacturers the ruling could have implications across a number of different aspects of their manufacturing processes, from the materials used to produce a label right through to the verification of the information printed to it. With decades of experience within the medical device and healthcare industries, Weber is able to provide the expertise, guidance and technologies needed to ensure a smooth transition to conformity.

The term UDI stands for Unique Device Identification. This is a unique numeric or alphanumeric code which includes a device identifier, specific to a model and a production identifier. Also included is the current production information for that specific device, such as the lot or batch number, the serial number and / or expiration date. The UDI must appear on every device using a label or through direct marking methods such as ink jet marking or lasers. The information

must also be both human readable, in the form of plain text and machine readable through bar code, 2D Matrix code or RFID technology.

There are a number of compliance dates identified within the FDA’s final ruling, the latest of which is that by the 24th September 2015 UDI’s must be present on labels and packaging of implantable, life supporting or life sustaining devices, multi-use devices that are life supporting or life sustaining and on stand-alone software that is life supporting or life sustaining. Further regulations will come into force periodically until September 2020.

Keeping abreast of these regulations and ensuring compliance at the different stages of implementation requires an intimate knowledge of the industry, the regulatory requirements and the materials and technologies needed to support the production processes. Many suppliers to the industry however may be small and medium size enterprises (SMEs) and for organisations such as this UDI compliance could be costly not only in terms of labelling system upgrades, but also in the management time needed to understand and administer the changes needed to comply with ever changing regulatory requirements.

Manufacturers must include at least one method of allowing Automatic Identification / Data Capture (AIDC). This can be in the form of a conventional bar code, however where space may be an issue or where

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PACKAGING

UDI Implementation Steps for Medical Device Manufacturers Identify the FDA requirements applicable to your device

Check existing quality systems against FDA requirements

Develop a quality plan for UDI requirements

Select label printing and device marking systems

Design and procurement of labelling stock

Select the barcode numbering system for device and packaging

Choose barcode style to be used on device and packaging

Update quality system documentation to reflect UDI implementation

Validate UDI application processes. Protocol, execution, report

1

2

5

6

Design artwork for labels and direct marking

Establish barcode quality verification programme

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Substantiate implementation readiness as per the quality plan

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Enter UDI data into the Global Unique Device Identification Database

3

7

11

With several decades supporting manufacturers and suppliers to the medical and healthcare sectors Weber has built up an understanding of the industry’s requirements and is able to offer expert guidance on label materials, label design & production and the selection of the most appropriate coding method. Combining this expertise with the printing and application technologies it offers means there are solutions for each stage of the manufacturing process – from the device production to pallet labeling – that can be configured to meet the individual requirements of each manufacturer.

4

8

12

Go Live

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greater amounts of data need to be made available, then the 2D Matrix or QR codes can be used. It is also possible to use RFID labeling but the additional costs incurred in using this type of label may exclude this as an option in certain cases.

End users may have a preferred technology that they wish to use to acquire the data from the device, its label or packaging and this will have a direct influence on the AIDC method to be employed at the time of manufacture.

SMEs who supply to a number of customers may need to use different methods as some customers will require bar codes and others may prefer 2D Matrix codes.

Obtain membership of FDA accredited issuing agency

Expert advice: Weber offers advice on label materials, design & production

Healthcare labels have to communicate important information to both doctors and patients. It is essential therefore that the labels are capable of withstanding the most arduous of environmental conditions.

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Healthcare labels have to communicate important information to both doctors and patients. It is essential therefore that the labels are capable of withstanding the most arduous of environmental conditions. Among other things Weber has developed creative solutions to the problems faced by healthcare companies, including custom die cuts, complex build and more. On-press, variable code-dating and messaging using laser etch or UV inkjet allows additional information to be added on the fly, with sequential back-of-liner numbering aiding inventory control. On-press and post-press video inspection is used to maintain the highest levels of quality assurance and Weber employs ISO 9001-registered label manufacturing processes that can assist cGMP compliance to 21 CFR Subpart G. Weber’s range of printers, applicators and print and apply systems are deigned to offer a solution to every application. The company also provides labeling systems for indirect product marking which can be integrated and used for downstream packaging operations. The range also includes RFID solutions, providing manufacturers with the widest choice of labeling solutions to meet UDI requirements, irrespective of the device and its packaging.

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PACKAGING

Not my type: Faubel says that when selecting a suitable sealing label, first consider the type of packaging to be protected

Easy life: The more difficult the removal of a sealing label is, the less likely it is for counterfeiters to use the original packaging for fake products

Don’t mess with me Faubel looks at tampering issues in the pharmaceutical sector

T

he online trade in medicines that are illicit are hazardous to health has been rising continuously.

This is also confirmed by the results of the Interpolcoordinated operation Pangea. While 9.8 million illicit and counterfeit drugs were seized in 2013, their number has climbed to 20.7 million in 2015. There is a pressing need for pharmaceutical manufacturers and international institutions to take action.

EU directive provides standards In mid-2011 the Council of the European Union adopted Directive 2011/62/ EU requiring that safety features be integrated into the outer packaging of prescription drugs and provide evidence of tampering, amongst other things. Counterfeiters tend to use the original packaging and replace the medicine inside by a fake replica. Such activities pose a significant health risk to consumers. Pharmaceutical manufacturers and distributors are facing financial losses, huge brand damage and a loss of confidence on the consumers’ part.

Security seals, labels and tapes Security seals, labels and tapes are one means of protecting the integrity of the packaging. When selecting a suitable sealing label, first consider the type of packaging to be protected. So-called fibrebreakage labels are a popular option. These labels are coated with a high-performance adhesive that

bonds consistently with the cardboard packaging.

When trying to detach the label, individual fibers will come off the substrate and the folding box will be irreversibly damaged.

Labels made of shrinkable materials are remarkably effective when it comes to protecting bottles, vials, pens, syringes and dose containers against tampering.

Subjected to heat shrinking, labels will wrap tightly around containers of any shape so that custom shapes can also be protected.

Highly informative Seals can be enhanced with additional functions and converted into thick booklet labels featuring many pages. To do so, it is necessary to widen the gutter or the closing part of the booklet label and enhance it with security perforations or special materials. The combination of tamper-evident closure and labeling provides enough space to accommodate legally required information in many different languages.

Moreover, label sections can be peeled off the seal and stuck into a patient record for documentation purposes. Integrated scratch-off fields where identification numbers and codes are covert is another possible option. Authentication features such as guilloche, temperature-sensitive and UV-sensitive inks as well as specialty materials with hidden markers can also complement the design of sealing labels.

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Changes in temperature and void seals If counterfeiters are skilful enough, a sophisticated seal will often not be sufficient to protect drug packaging against tampering. When they encounter self-adhesive labels or cartons sealed with hot-melt adhesive, counterfeiters may attempt to melt the glue by heating it. If it succeeds, the package can be opened and resealed without notice of initial opening.

This technique and other similar ones can be averted by using adhesives that perform well at service temperature but also in other temperature ranges.

Ultimately, the use of temperature-sensitive inks is bound to reveal changes in temperature.

Another group of seals are the so-called VOID seals.

When peeling the label off the package, there is a “void effect” which results from the combination of color, ink and adhesive layers protected by transparent cover film.

Effective solution The more time-consuming and difficult the removal of a sealing label is, the less attractive it is for counterfeiters to use the original packaging for their fake products. Thanks to this effective solution, consumers’ risk therefore becomes lower and that of pharmaceutical manufacturers, too.

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Freeze frame Biopharma Technology explains how to build quality in the lyophilisation processes

Q

bD is an FDA and EMA backed approach to ensure drug quality remains consistently high through ‘statistical, analytical and risk-management methodology in drug design, development and manufacturing’.

Lyophilisation (freeze drying) is a multi-stage process with different risks present at each stage. Using QbD methodology in product and process R&D results, generates robust processes and consistent quality but also safeguards a large amount of data is subsequently available for quality assurance and regulatory submissions.

In freeze drying, the CQAs might typically include: • • • • • •

the appearance of the final product residual moisture left in the dried product behaviour under reconstitution preservation of biological activity stability; and sterility of packaged product

QbD family for freeze drying CQAs (critical quality attributes) define the most important characteristics of the final product to ensure it is within acceptable quality levels. CQAs can be chemical, physical, biological, microbiological or any other type so long as they can be defined, measured, and continually monitored.

Lyophilisation (freeze drying) is a multi-stage process with different risks present at each stage

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FREEZE DRYING

The QTPP (Quality Target Product Profile) defines the overall product in terms of its necessary characteristics. QTPPs are product and context specific and therefore may depend on where and how the product is to be used, the container type, product type, and other variables. QTPPs for freeze drying might include porosity, storage conditions, and stability length.

The choice and balance of excipients in a formulation has a significant bearing on its freeze drying process parameters

A range of tolerance for each CQA must be established, and with it an understanding of where and how the risk of failures presents in the process. In order to ensure the productâ&#x20AC;&#x2122;s CQAs are maintained at each stage of the process, Critical Process Parameters (CPPs) translate the productâ&#x20AC;&#x2122;s requirements into process variables. In freeze drying, variables that must be controlled to mitigate risk include the choice of excipients; temperature and pressure conditions at different stages of freezing and drying; the thermal profile of the formulation; and production conditions.

Selecting your excipients The choice and balance of excipients in a formulation has a significant bearing on its freeze drying process parameters. Various additives offer protection for different processing stresses and formulation development aims to create a balance that results in the best possible final product. However, the exact constitution of a formulation is what defines the subsequent process parameters and for this reason, formulation and cycle development should ideally be conducted together.

Another point to consider is the temperature gradient through the drier.

Temperature may vary by height or across a shelf. Shelf mapping will locate any pockets of difference that may impact drying.

Establish the critical temperatures

Scientific methods of determining the critical temperatures of a formulation make it possible to design a high quality cycle. The key technologies are freeze drying microscopy (FDM), differential thermal analysis (DTA) and impedance analysis.

FDM involves the visual examination of the behaviour of a small sample of the product as it freezes. An expert operator can pinpoint the temperature of the critical events. FDM is used to determine the eutectic melt temperature and the collapse temperature.

DTA allows the determination of significant endothermic and exothermic changes such as crystallisation, eutectic melt, and glass transition events.

Impedance analysis detects changes in molecular mobility that thermal techniques may not pick up. This allows determination of events such as glass transition in more complex amorphous products, or changes in the frozen material that do not have an associated exothermic or endothermic signature.

Building a design space

Know your equipment The efficiency of your freeze drier can be maximised by following the manufacturerâ&#x20AC;&#x2122;s specifications when setting up shelf spacing, choosing vial fill depth and deciding on the product load.

Equipment limitations can be determined by carrying out ice slab tests. These can be used to determine the trapping rate and the choke flow of your machine, in other words, the maximum rate of vapour that can be efficiently extracted.

A design space is a multidimensional combination and interaction of input variables and process parameters that have been demonstrated to provide assurance of product quality. A successful and detailed study into all the product and process variables makes it possible to establish a design space that provides repeatable, consistent and provable results.

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Q & A

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

Word of the law Simon Portman, Marks & Clerk Solicitors, outlines the work the company does advising pharmaceutical companies on intellectual property issues

Who are you and what do you do?

SP: Marks & Clerk Solicitors is a leading specialist intellectual property law firm, practising exclusively in all areas of IP, including areas relevant and important to the pharma industry such as patents, supplementary protection certificates and confidential information.

I specialise in non-contentious IP and related commercial contract and regulatory matters. A big part of my work is advising pharmaceutical companies on the development and commercialisation of their IP. This entails ensuring they have the requisite access to core technology at inception, conducting IP due diligence for rounds of investment and trade sale and drafting and negotiating contracts such as licences, R&D collaborations and contract manufacturing agreements.

What have you focussed on recently?

SP: Recently, I have focussed on supplying licensing, distribution and maintenance contracts for a new diagnostics product and drafting and advising on a wide range of grant-funded R&D collaborations. Even in the improved economic climate, many companies find it difficult to secure funding from investors and, in such circumstances, “soft” money available under UK or EU grant schemes is an attractive option.

What is your latest service/ innovation?

SP: Over the last year we have been conducting free seminars on contract law and negotiation which have been very popular with contract managers in the pharma sector and university technology transfer officers. While the course is not specifically directed at the pharma sector, many of the real life examples we use are pharma related.

We made the course free to attend and, as well as supplying useful training, it affords a valuable opportunity for networking. Attendees come away from the day realising that similar issues appear again and again, no matter what industry they are from. The course trains them in how to deal with those issues, what elephant traps to look out for and when to seek specialist advice.

How can you benefit the pharmaceutical sector?

SP: Our advisors combine strong scientific backgrounds with legal expertise and commercial nous and can tailor their approach to fit any type of client in the sector, from small start up to big multinational. They also operate under the same roof, both literally and metaphorically, as patents and trade mark attorneys and IP valuation experts who complement our services, leading to the full spectrum of specialist IP input on offer.

Future plans?

SP: Targeting new clients and markets in the technology clusters where we have offices and growing the commercial team. I’m also heavily involved in rolling out internal training in legal and regulatory matters, thereby ensuring that both our trainee and qualified patent attorneys have the edge when they take their skills to the market.

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