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Volume 14 | Issue 05

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Life begins at 40: Merck Millipore goes from strength to strength Thinking clearly: Noxilizer explains why its nitrogen dioxide technology supports biopharma changes

NEWS

NEWS PROFILE The expertise on offer from Gerresheimer as the company continues to expand

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STERILISATION

contributing editor aleksandra jones,

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How a certain kind of molecule with concentric layers of membranes offers new possibilities for drug release

Maintaining the edge: I Holland in the spotlight The secret to a long life: Natoli reveals all...

Omron, Prisym and Purite makes their voices heard

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CLEANROOMS High fibre: The importance of wipes in a cleanroom environment Cleaning up: Expertise from Parker Hannifin The immaculate collection: What’s on offer from Pharma Hygiene Products

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POWTECH PREVIEW A selection of what to see at this key industry event

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INSPECTION & TESTING In the mix: Quantitative analysis of APIs in blending mixtures and tablets GSK – a case study Put to the test: Validity of traditional destructive test methods for sachet and flexible container packaging

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production

NEWS ANALYSIS

OPINION

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Time trials: Parexel discusses cutting clinical trial start-up time Critical thinking: Techorizon, looks at technology in clinical research and asks if it’s time way a new way of thinking

EXCIPIENTS The perfect formula: Avantor helps manufacturers meet the challenges of impurities in drugs

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CHEMICAL REACTION Looking good: When it comes to x-ray inspection, Metrix NDT says you need look no further than what it has on offer

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“

COMMENT

It’s interesting, although of course to be expected that despite persistant warnings from medical experts, it takes a few words from David Cameron to make the media take note of the issues we all face regarding antibiotics.

In recent weeks the press has highlighted the increasing issues of antibiotic resistance and the fact that we have failed to develop replacement drugs to act against the infections and illnesses we have become so used to using antibiotics against as cures.

Earlier this year, the World Health Organisation (WHO) issued a warning that we could be on the verge of seeing common infections and minor injuries kill – illnesses we have been treating until recently, successfully with antibiotics. WHO called for urgent action and the UK’s chief medical officer, Professor Dame Sally Davies, agreed, warning that the era of modern medicine is coming to an end unless we do something about antibiotic drugs. Alarmingly, the European Centre for Disease Prevention and Control estimates that antimicrobial resistance results in 25,000 deaths a year.

With terms such as ‘catastrophic effect’, ‘the implications will be devastating’ and talk of going back to the ‘dark ages of medicine’ being used, it’s hard for us all not to sit up and take notice. And of course, having the prime minister enter into the debate does help to bring the gravity of the situation to the fore.

Whether or not we should be surprised that we have reached this point with antibiotics is one issue. For years, we have come to expect doctors to hand out these drugs for a whole host of complaints, without really thinking about it. Indeed, as a parent I regularly hear others bemoaning their GP as they have been sent away empty-handed to fight an infection naturally. Antibiotics have also managed to enter the food chain in a bid to keep animals healthy. These actions clearly have consequences – ones which we are now having to address.

Channel Four recently reported that back in 1928 when Alexander Fleming invented penicillin, he warned that bacteria would grow resistant. When this happened, synthetic penicillins were created which again, faced the same problem. The next generation was

modified further – the carbapenems – but once again, these began to face problems against certain microbes. Increasing numbers of doctors cut down on the number of antibiotics they prescribed but, reported the news programme, this ‘backfired’ as pharmaceutical companies, realising they wouldn’t make any money developing new antibiotics, stopped doing so.

Laura Piddock, professor of microbiology at the University of Birmingham and chair of Antibiotic Action, told Channel 4 News: “The main concern is we keep talking and talking - but we have to start implementing the recommendations made by doctors and scientists,” describing the situation as a ‘market failure’ and that action is needed.

So where do we go from here and what role do pharmaceutical companies have to play in developing drugs which future-proof us against illness we have thought of as so easy to treat?

Cameron is pushing forward an initiative which will examine the development of antibiotics and regulatory issues. It will discuss drug-resistant strains as well as the issues we have with overuse of these medicines.

Of course, this is a way forward but I would be keen to know how the pharmaceutical companies view this initiative – is it too little too late? Where is your role and indeed your voice in this matter? Is it unfair to expect the sector to develop drugs which might not be prescribed – after all drug manufacture has to be profitable?

And what would the industry like to see happen to encourage the development of antibiotics whilst protecting the business interests of drug manufacturers? Get in touch.

Lu Rahman

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”

NEWS University of Sheffield welcomes PM’s review of antibiotics As prime minister David Cameron warned that the world could soon be ‘cast back into the dark ages of medicine’ the University of Sheffield is leading international work to tackle the growing threat of resistance to antibiotics.

Researchers at Sheffield’s Florey and Imagine projects are addressing resistance to antibiotics, one of the biggest biomedical problems of our age. New treatments will be essential as resistant strains proliferate and will help save countless lives.

Commenting on the prime minister’s announcement of the forthcoming review of the development of antimicrobial drugs, Sir Keith Burnett, vice-chancellor of the University of Sheffield said: “We were delighted to see that the prime minister has asked our Sheffield graduate Jim O’Neill to lead vital international work on this crucial area. The development of antibiotics means that many have lost sight of what it was like to be under constant threat from infectious diseases.

Speaking at Fortune Most Powerful Women, London, Sandra Peterson, group worldwide chairman of Johnson & Johnson said: “One of the great exciting things that is happening is the understanding of biology and genomics and all the other omics, which are many of them, is really changing the way we understand how diseases develop, the progressions of disease, the disease pathways.

“Ten years ago, when people talked about, we’re going to sequence the genome and we’re going to have personalised medicine, I think most people had a perspective of what

“Today we are seeing the emergence of increased numbers of antibiotic-resistant pathogens.

This is a pressing issue for global healthcare as the prime minister has explained. Essential work of the kind carried out by the Florey Institute at the University of Sheffield, is needed to reinvent our understanding of pathogens and develop new treatments that will help save millions of lives across the world.”

Simon Foster, professor of molecular microbiology and Imagine project director, said: “We have forgotten what it is like to be under the constant threat of infectious disease, but this is something we are seeing more and more of as pathogens become resistant to antibiotics.”

“One of our failings is that we see the world from the perspective

of a human timeframe. Diseases, of course, can adapt at dizzying speed, and our challenge is to wrong-foot them with innovative new treatments.

“Antibiotic resistance is a pressing issue for human healthcare as highlighted today by the prime minister. The University of Sheffield has recognised the potentially dire situation in which we find ourselves and has launched our flagship Florey Institute specifically to tackle important antibiotic resistant organisms.

“The Florey Institute will take an approach that spans the fundamental life of pathogens, how they interact with us and how we develop new treatment and prophylactic regimes. This learning could help save countless lives across the world.”

We are witnessing pharma renaissance, says industry expert that was going to mean for what the pharmaceutical industry does and how it works. And the reality is what we’re seeing now is quite different than what we thought but it’s even much more exciting, which is that we now understand how diseases can develop and migrate

in pathways through your body in a way – using deep data.

“And this is where big data and analytics is important because you need a lot of data to figure out what’s really going on here.

But it helps us have a much

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The University of Sheffield has made a multi-million pound investment in two strategic and complementary projects - Florey and Imagine.

Together they will establish Sheffield as a centre for biological imaging and understanding of infectious disease associated with important antibiotic resistant pathogens.

“

We have forgotten what it is like to be under the constant threat of infectious disease, but this is something we are seeing more and more of as pathogens become resistant to antibiotics.

”

better understanding of how these diseases develop, how they transmit, what kind of treatments and what kind of drug development you need to have to make this become a reality. And we’re seeing a renaissance in the pharmaceutical industry as a result of this.

“The medicines are much more specialised. They’re addressing diseases that people thought were not curable in lots of different ways and the old methods of finding ways to cure them were not working. So it’s a very exciting time, but what it requires is a very different view of how you manage R&D.”

Clinical development of inhaled products – is it really tough?

By Dr Siddharth Chachad

I

n the EU, guidelines for the clinical development of inhaled products first came into existence in 1999, wherein the document was made available by the agency for the authorisation of drugs used to treat chronic obstructive pulmonary diseases. In 2002, a guidance document for the development of asthma products was made available. In 2004, a detailed document CPMP/EWP/4151/00 was released by the EU agency highlighting points to be considered on the Requirements for Clinical Documentation for Orally Inhaled Products. Especially directed at the replacement of chlorofluorocarbons (CFCs) with the hydofluoroalkanes (HFAs), this guidance described how to demonstrate therapeutic equivalence for the inhaled products.

This guidance advised that potential marketing authorisation applicants also refer to the guideline on clinical requirements for locally acting products (CPMP/EWP/239/95) which mentions that the demonstration of therapeutic equivalence in clinical trials is, in principle, necessary.

So while the abridged application for known active was possible with demonstration of in vitro equivalence, it did, on the other hand, indicate the need for a clinical programme with minimal role of bioequivalence studies.

In 2009, the revised guidance CPMP/EWP/4151/00 Rev. 1 came into effect for clinical documentation of orally inhaled products. It clarifies the requirements for clinical documentation for abridged applications for orally inhaled formulations and variations/ extensions to a marketing authorisation, including both single active substance products and combination products, in respect of the demonstration of therapeutic equivalence between two inhaled products for use in the management and treatment of asthma and chronic obstructive

pulmonary disease in adults, and the management and treatment of asthma in children and adolescents.

Products containing a new active substance are required to undergo a full clinical programme regardless of the type of inhalation device.

However, in case of a known active substance, this guidance describes a three step approach: in vitro comparability, pharmacokinetic study with and without charcoal blockade, and therapeutic equivalence study.

If the product does not satisfy all of the pharmaceutical criteria for equivalence, in vivo studies should be performed to substantiate equivalence. Whilst for abridged applications, satisfying the 9-point criteria to meet in vitro comparability with the innovator drug product is a real tough challenge; it is equally or even more difficult to match drug pharmacokinetics with the reference products, with variability in the inhalation technique playing a key role.

claim, all making this project a hard nut to crack. However, a face-to-face dialogue with the regulators at an early stage of drug development is beneficial in understanding true clinical requirements for such complex generics and obtaining successful registrations at the end

If the bioequivalence is demonstrated for a particular generic inhaled product then again there is hardly any precedent of approval solely based on the PK approach for an abridged application. So in the case of multiple country filing and with the need for further harmonisation amongst different EU member states, the granting of marketing authorisation can be delayed and sometimes impossible.

of quite a long product development journey.

Dr Siddharth Chachad is the head of global clinical development and medical affairs at pan-European regulatory affairs organisation ELC Group.

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Failure to show bioequivalence and need for therapeutic equivalence study using assay sensitive study design is a Herculean task; more so when innovators have not managed to show statistical dose response in certain instances, especially in the case of inhaled steroids.

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www.noxilizer.com EPM 7

NEWS PROFILE

On point: Gerresheimer has a comprehensive portfolio of sterile and non-sterile syringe systems

W

hen you seen the new building complex at this Gerresheimer plant, it’s hard to imagine that the company was founded back in 1947 as Bünder Glas by the Hennings and Zimmermann families. Gerresheimer took over Bünder Glas in 1987 and since then it has gradually developed it into an international specialist for sterile ready-to-fill syringes which are marketed under the Gx RTF (Gerresheimer Ready-toFill) brand name.

Glass ready-to-fill syringes are supplied to pharma and biotech customers around the world, where they are filled with pharmaceuticals.

Gerresheimer has a comprehensive portfolio of sterile and non-sterile syringe systems. Gx RTF syringe systems are supplied to the customer in a ready-to-fill state washed, siliconised, pre-assembled with cap and sterilised.

The new production bay The fourth production line for ready-to-fill syringes is currently being commissioned in the new production bay. Key process improvements include the avoidance of glass-glass and glass-metal contact through the use of pick-andplace robots and segment transport

Point of interest The Gerresheimer Bünde facility is continually growing.

As well as boasting a new building complex, a fourth production line is being commissioned. With around 800 employees this is Gerresheimer’s Group’s competence centre for ready-to-fill glass syringes systems, optimized washing and siliconisation processes and more effective, camera-based quality inspections. This gentle handling results in a lower syringe cosmetic defect rate. A new washing process guarantees even better compliance with both present-day and future regulatory requirements. Improved spraying technology and 100% inline inspections in the siliconisation process ensure consistent syringe function. All these measures improve the syringes’ processability during the filling process and their general function. The syringes from all production lines are packed into PP boxes in clean room environments to ensure maximum product hygiene.

The first RTF production line was installed and commissioned at the Bünde plant in 2001. Before long, the RTF syringes were a

major success on the international markets.

Two further production lines were subsequently installed, followed by the fourth RTF line in Bünde ten years later. Today syringes account for the majority of Bünde’s production output, and it will have the capacity to manufacture over 400 million RTF syringes when the RTF4 line is put into operation at the end of 2014.

Bünde has 24/7 production operations because this is the only way to exploit the plant’s capacity to the maximum while maintaining stable processes and quality.

Maximum syringe quality Syringes are primary packaging products, which means that they come in direct contact with the

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medication. That’s why utmost care must be taken when manufacturing them. The syringe has to be perfectly clean because even the tiniest amount of contamination could alter the medication. The syringe also has to be absolutely intact. It cannot have cracks and must be firmly sealed so that no germs can come into contact with the medication.

The inside of the syringe is coated with silicone to ensure that the plunger can slide up and down it.

The rule of thumb is to use as little silicone as possible and as much as necessary. You have to use enough, because you want to make sure that the plunger will slide just as easily after three years of storage. But if you use too much, it can cause lumps to form in the medication.

When syringes are manufactured, each one of them is inspected several times - by cameras, sensors, computers and the human eye. Employees have special responsibility for ensuring that no patient suffers harm as a result of defective syringes.

Gerresheimer Bünde has been equipped for successful production operations which it looks set to build upon with the fourth production line.

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NEWS ANALYSIS

O

ne of the defining features of cells is their membranes.

Each cell’s repository of DNA and protein-making machinery must be kept stable and secure from invaders and toxins. Scientists have attempted to replicate these properties, but, despite decades of research, even the most basic membrane structures, known as vesicles, still face many problems when made in the lab. They are difficult to make at consistent sizes and lack the stability of their biological counterparts.

Now, University of Pennsylvania researchers have shown that a certain kind of dendrimer, a molecule that features tree-like branches, offers a simple way of creating vesicles and tailoring their diameter and thickness. Moreover, these dendrimer-based vesicles self-assemble with concentric layers of membranes, much like an onion. Such a structure opens up possibilities of releasing drugs over longer periods of time, with a new dose in each layer, or even putting a cocktail of drugs in different layers so each is released in sequence.

The study was led by Penn chemistry professor Virgil Percec, and was published in the Proceedings of the National Academy of Sciences.

Cell membranes are made of two layers of molecules, each of which has a head that is attracted to water and a tail that is repelled by it. These bilayer membranes self-assemble so that the hydrophilic heads of the molecules of both layers are on the exterior, facing the water that is in the cell’s environment as well as the water encapsulated inside.

Penn Research develops ‘onion’ vesicles for drug delivery The University of Pennsylvania has shown that a certain kind of molecule with concentric layers of membranes offers new possibilities for drug release For decades, scientists have been trying produce stripped-down versions of this arrangement by removing out the additional proteins and sugars that cells naturally have in their membranes.

“The problem,” Percec said, “is that once you remove the proteins and the other elements of a real biological membrane, they are unstable and don’t last for a long time. It’s also hard to control their permeability and their polydispersity, which is how close together in size they are. The methodologies for producing them are also complicated and expensive.”

membranes found in nature. But like those molecules, these dendrimers are amphiphilic, meaning that one face’s branches is hydrophilic and the other is hydrophobic.

In 2010, Percec and his colleagues found the smallest possible amphiphilic Janus dendrimer.

Dissolving those molecules in an alcohol solution and injecting them into water, the researchers found that they formed stable, evenly sized vesicles.

The Percec group’s breakthrough came in 2010, when they started making vesicles using a class of molecules called amphiphilic Janus dendrimers.

Not all cells are content with just a single bilayer, however. Some biological systems, such as gramnegative bacteria and the myelin sheaths that cover nerves, have multiple concentric bilayers.

Having a model system with that arrangement could provide some fundamental insights to these real-world systems, and the added stability of extra layers of padding would be a useful trait in clinical applications. However, methods for producing vesicles with multiple bilayers remained elusive.

Like the Roman god Janus, these molecules have two faces. Each face has tree-like branches instead of the head and tail found in the molecules that make up biological

“The only way it has been achieved in the past was through a complicated mechanical process, which was a dead end,” Percec said. “This was not a viable option

Research in this field has thus been focused on finding new chemistries to replace the fatty molecules that normally make up a vesicle’s bilayer.

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for mass-producing multilayered vesicles, but, with our library of amphiphilic Janus dendrimers, we were lucky to find some molecules that have in their chemicals instructions needed to self-assemble into these very beautiful structures.”

By testing different dendrimers with different organic solvents, the research team found they could produce these onion-like vesicles and control the number of layers they contained. By changing the concentration of the dendrimers in the solvent, they could produce vesicles with as many as 20 layers when that solution was introduced to water. And because the layers are consistently spaced, the team could control the overall size of the vesicles by predicting the number of layers they could contain.

One of the more enticing clinical applications for these vesicles is as drug-delivery vehicles. Many drugs are not water-soluble, so they need to be packaged with some other chemistry to allow them to flow through the bloodstream.

The additional stability of multiple bilayers makes these onion vesicles an attractive option, and their unique structure opens the door to nextgeneration nanomedicine.

“If you want to deliver a single drug over the course of 20 days,” Percec said. “You could think about putting one dose of the drug in each layer and have it released over time. Or you might put one drug in the first layer, another drug in the second and so on. Being able to control the diameter of the vesicles may also have clinical uses; target cells might only accept vesicles of a certain size.”

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OPINION

The whole truth New EU pharmaceutical manufacturing and distribution compliance is expected to tighten up safety within the supply chain and eliminate falsified medicines. According to Omron, companies need to factor in the importance of machine vision, to read and verify the four key data elements proposed by the European Stakeholder Model (ESM) if they are to meet the 2017 deadline

F

aced with the growing and substantial threat of falsified medicines penetrating the European market, ESM has developed an end-to-end medicine verification solution, consisting of four key data elements, to combat the entry of falsified medicine. This verification system plays a pivotal role in aiding manufacturers to adhere to the 2011 EU Falsified Medicines Directive (FMD) which requires manufacturers to apply safety features to verify the authenticity and identity of individual packs of medication, which will be mandatory by 2017.

To drive implementation of the FMD, a consultation has been undertaken to define the characteristics and specifications of a unique authentic pack identifier. While these findings, which will come under a Delegated Act, are not anticipated until later in 2014, it is highly predicted that it will include the adoption of a DataMatrix barcode.

Furthermore, the verification system proposed by the ESM features a DataMatrix code carrying four key data elements which will also be required in a human readable format (manufacturer product code, randomised unique serial number, expiry date, and batch number) and the definitive way to read this system is through machine vision.

In sight: Machine vision is the only way to read and verify the four key data elements on medicine packs to eliminate falsified medicine

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Traditionally human readable code and data encoded within barcodes has remained fixed between batch runs of pharmaceutical products. The significant challenge arising from the proposed ESM, is with regard to the data management of the randomised unique serial number and the synchronisation of data between the printing device and verification solution.

Omron’s flexible vision solutions are built on IPC technology, providing the flexibility to cope with a wide range of data management requirements and allowing interfacing with 3rd party devices such as printers. Omron’s vision solutions can interface with high level production management software to request the data required to verify the unique serial number, whether through database integration or simple manipulation of .csv data files.

Dan Rossek, Omron’s product marketing manager, sensing, safety and vision comments: “To ensure compliancy is met we are working with pharmaceutical manufacturers to install the appropriate software which will offer them the assurances needed. As a company we continually review our development strategy to ensure our products are optimised to meet the changing needs of manufacturers.”

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OPINION

Talking point Dave Taylor, Prisym looks at how label lifecycle management systems can improve local language labeling

I

n an increasingly global market for clinical trials, pharmaceutical manufacturers could perhaps do more to mitigate the risks associated with the local language labeling of clinical trial supplies. If companies are to optimize emerging markets, they must adopt a more uniform approach.

The accurate labeling of pharmaceutical products is imperative to safeguard patient safety and meet legislative requirements.

But with clinical studies now being conducted all over the world, local language labeling has grown in importance. And it has implications right across the supply chain.

With most languages subject to localized nuances, achieving accurate translations remains a great challenge. And with trial data, randomization data and production data captured across a range of systems, managing the process is made even more complex. The challenge is further muddied by country-specific regulations and, of course, the widespread industry objective to reduce costs and improve efficiencies.

To succeed, organizations need an integrated data management system to bring version-controlled information from all systems together to print at the point of dispatch.

But at present, many companies struggle to find a reliable way of approving and locking down local language data – heightening the risk of products being incorrectly labeled.

There remains huge variability in how organizations across the sector are managing this key process. The lack of a uniform approach to clinical trial labeling is building avoidable inefficiencies into the supply chain – leading to an increase in unnecessary and duplicated quality checks, the deceleration of product to market and an escalation in development costs.

Companies must therefore collaborate to bring disparate processes together in a single, secure, version-controlled and auditable process to manage every stage of label lifecycle management; from the physical translation and

storage of phrases, to the design of labels, final printing and postprint verification. The introduction of a single-solution strategy can help organizations reduce errors, remove duplicate quality checks and eliminate the costly and avoidable return of materials.

The tools to progress already exist. Innovative new label lifecycle management (LLM) solutions can provide connectivity and visibility right across global organizations.

Furthermore, they can enable standardization and ensure that processes are controlled centrally, distributed locally and accommodate local language and country-specific requirements.

“

Written off: The lack of a uniform approach to clinical trial labeling is building avoidable inefficiencies into the supply chain, says Dave Taylor, Prisym

”

LLM is data-led, with labels considered merely the final output.

The best solutions give companies a 360° view of all their data assets, enabling an integrated organizationwide approach to production processes. They provide a centralized platform that can be leveraged across all sites, regions and divisions – and are interoperable with existing enterprise systems. Moreover, these scalable web-based tools deliver complete label integrity – from data management, design and approval, through to label production and inspection – to meet strict regulatory requirements.

As pharma seeks to exploit opportunities in developing nations – as well as improving performance in traditional markets – there is little doubt that packaging and

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labeling processes could be more efficient. Historically, companies have managed the design, data management and print process as three distinct and separate areas – in the process, building in multiple manual visual checks to ensure quality control. This is costly, inefficient and vulnerable to human error. Labeling solutions cannot sit in isolation, they must be built into a 360° view of all variable data components.

LLM solutions can facilitate a more strategic approach to the management of global data, and help companies capture, store and disseminate data quickly, safely and accurately. The benefits are significant. LLM platforms can reduce unnecessary manual checks, improve quality control by optimizing automated validation systems, and accelerate market access. Centralized data creates a platform for a ‘single version of the truth’ that can be used to generate labels ‘just in time’ – ensuring that the right information goes on the right product at the right time, every time. And holistic systems enable production managers to ensure no errors have crept into the process; vision verification solutions carry out automated audits, assuring approved imagery and data has been printed correctly on every label, as well as delivering lifecycle traceability.

In short, LLM provides data visibility for stakeholders right across multinational, multi-site organizations.

360° systems that can capture and manage data right across a trial, and bring it all together at the right time, could transform the industry’s approach to clinical trial labeling and reduce the cost of drug discovery. In a competitive multi-language, multicountry marketplace, Label Lifecycle Management can standardize labeling processes and ensure that stakeholders across a pharma company’s value chain can, quite literally, overcome the language barrier and assure regulatory compliance.

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13:4

OPINION

Up and away: Many pharmaceutical companies start out manufacturing from a modest base then scaling-up as demand grows

Liquid assets Trials and validation for pharmaceuticals may take years and revalidation as a result of changes made to your process are expensive; the most cost-effective way to produce pharmaceuticals is to develop an understanding of the critical phases involved and get the equipment specification right from the outset, explains Mark Bosley, business support divisional manager at Purite.

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any pharmaceutical companies start out by manufacturing from a modest base, often working from a small business unit and then scaling-up their operations as demand grows or new product lines are taken on.

This is also true for established manufacturers that are developing new products, as they will start from a low base, using smallscale laboratory testing before bringing new pharmaceuticals to market. From a ‘benchtop’ or laboratory operation, a successful pharmaceuticals enterprise can soon migrate to a pre-production pilot plant and then ultimately on to high volume production.

From the perspective of water purification, moving from low volume laboratory trials through to batch or full production should not be a complex process. The key consideration is that the inherent nature of the product being manufactured remains unchanged as does the quality of purified water required to produce it.

The first step would be to commission the drafting up of a document typically referred to as a (URS) or User Requirements Specification. The (URS) typically scopes out and defines the requirements of the water purification system. It should be detailed enough to provide sufficient information to allow any water purification system provider to propose a working

solution to meet the requirements necessary to provide purified water at the specified quality, quantity, consistently; day in, day out.

The first stage of the water audit would typically involve the taking of representative samples of your incoming feedwater supply for detailed mineral and microbiological analysis. This information may already be available from your local authority or water supplier if you are using a mains supply but should nonetheless be checked; if a surface water or borehole source is being used then a detailed analysis of water characteristics is crucial. An evaluation of the pretreatment system can be made and a specification be drawn up. If water conditions are variable, then the design of raw water treatment systems and the provision of pretreatment will need to be suitable for worst case conditions.

The next stage would be to evaluate the necessary size of the water purification units. Calculating the maximum demand and also establishing the volume needed on a regular basis will ensure that any immediate and forthcoming needs are catered for and prevent any unnecessary expense further down the line that may be incurred by altering the design and necessitating revalidation.

The method by which pure water is drawn into the process must also be considered. For example, if supplies

are required at different locations a centralised system feeding a ring-main may be more appropriate, offering an unobtrusive and spacesaving option that can deliver high volumes and high quality. Providing the right capacity can also mean that storage has to be part of the solution.

Depending on the application, higher volume production operations essentially use scaled up versions of the smaller water purification systems, perhaps supplemented by systems such as: sand and multi-media filters, for eliminating particulates; activated carbon adsorption systems for the removal of organic contaminants and chlorine compounds that can affect colour, taste and odour; cartridge filtration, for pre-treatment; and reverse osmosis for the removal of ionic contaminants. In addition, ion exchange technology is often used to soften and deionise water, with UV irradiation and membrane filtration commonly being added to maintain microbiological integrity.

Reverse osmosis (RO) is one of the most commonly used technologies and incorporates specialised semipermeable membranes through which pressurised feed water is passed to remove inorganic ions and dissolved organic contaminants.

Once the water side of the audit has been completed consideration should be made as to the operation and functionality of the intended equipment. Within the (URS)

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Pivotal point: A key consideration is that the inherent nature of the product being manufactured remains unchanged as does the quality of purified water required to produce it

document a section relating to ‘System Definition’ may include for example, details as to the preferred functionality and operating regime.

Once you have considered all of these areas you will then be in a much stronger and clearer position to create a small final ‘model’ of what will be the larger system.

To assist you in all these considerations, select a suitable water purification provider with a proven track record; the best supplier is unlikely to be the one with the cheapest unit price for the system but one you feel you can work with and which can provide ongoing expertise and support.

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4 MINs

CLEANROOMS Keep it clean: The ideal product performance for a cleanroom wipe is that it does not add to the contamination whilst performing the removal of particles, spills, biofilms or dirt >

High fibre Karen Rossington, Contec, looks at the significance of wipes in the cleanroom environment and tells us why it is that they need to arrive clean and leave dirty

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leanroom wipes have their origins in the nuclear industry when the first critical wipes were cotton twill used to control radioactive particles from leaving nuclear reactor containment. The emergence of microelectronic manufacturing required cleaner wipe options and the cotton twill was replaced by nylon monofilament. By the mid 1980s polyester monofilament became the standard critical environment wipe.

The pharmaceutical and life science industry which were more concerned with viable contamination, were later to adopt critical wipes but today cleanroom wipes for all types of critical environments is big business.

As manufacturing technology innovated so the demand for even cleaner wipes increased.

This split structure gives the wipe the ability to pick up particles even when dry, and can easily remove residues often without solvent. The split fibres create microscopic “hooks� which collect and hold dust, dirt and particles more effectively than rounded fibres such as cotton, this can be seen in fig 2. The microfibres are also positively charged so electrostatically attract the negatively charged dirt. The virgin wipes are very soft so won’t scratch and damage surfaces, however can should be taken when re-using wipes as the very structure which makes them so good at picking up particles also means that particles get stuck in the fibres which can then scratch a sensitive surface.

Substrate innovations In the late 1980s microfibre was introduced. The definition of a microfibre is a fibre with less than 1 decitex per filament, where a decitex is a measure of linear density which is commonly used to describe the size of a filament or fibre. 1 One decitex is 9/10th of a denier. To put this into perspective it is 1/16th the diameter of a human hair. The fibres can be combined to create yarn which can be then be knitted or woven into a variety of constructions.

Microfibre fabrics can be broken down into two main types, splitable microfibre and straight filament microfibre.

Straight filament microfibres tend to made from 100% polyester. Splitable microfibre consists of very fine threads of polyester and polyamide (nylon) that are combined to form a single thread. The nylon is used to glue the fibres together until they are split later in the process. Split microfibre (Fig 1) possesses numerous wedges rather than the rounded threads found in other yarns. It is these wedges that provide the ability to collect microscopic particles off a surface. This expanded surface area and the capillary action of the fine threads dramatically increases a microfibre wipes sorbancy.

A change in the percentage of the microfibre blend will yield slightly different properties.

Fig 1.

Fig 2.

Microfibre has a high sorptive capacity around 6 to 8 times its own weight in water. The fast wicking ability means a wipe can remove spills quickly and easily, so it is very suitable for mop to dry situations.

However in cleanroom environments there are some downsides to the use of microfibre, the fibres are less durable and also create much higher levels of fine particle contamination. The microfibre would need to be laundered to reduce these levels of contamination. Microfibre is high in cost so not ideally suited to being a single use material. Microfibre is most relevant to applications where mop or wipe to dry performance is paramount and the activity of continual relaundering does not create problems.

A split microfibre containing nylon is not compatible with bleach based disinfectants.

Risks of relaundering microfibre Microfibre is not an inexpensive fabric - see table 1 for a comparison of different blends of microfiber versus 100% polyester and the corresponding attributes. In many instances this high initial cost is balanced by relaundering and where relevant the resterilisation of the mop or wipe.

Mops especially are laundered and reused. However, in a cleanroom environment this is not without risk. Microfibre is very delicate and can be easily damaged by high heat or harsh chemicals, this can lead to a mop or wipe degrading over time and affecting both the cleaning ability and the sorbent capacity of the mop over time.

As cleaning is carried out from the cleanest to the dirtiest area within a cleanroom complex the soil load on mops can be significantly different.

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It is not easy for the laundry to guarantee getting all the mops back to the same level of cleanliness every time. The structure which makes the microfibre so good at picking up particles and retaining them for removal from the surface also makes it equally difficult for them to be cleaned as small or microscopic particles remain embedded in the wedges of the microfibre structure. A question which must be asked of the laundered is what other products your mops are washed with. Mops and wipes often do not make up enough volume for a full wash load and so laundries will often combine mops and wipes (of all colours) into one washload. This can lead to cross contamination which can leave particles or other contaminants trapped in the microfibre product and returned to the critical environment.

Recent developments The drive for a product which could provide the benefits of microfibre whilst minimising the downsides lead to the introduction of the first new category of wipe in almost 30 years. MicroGenesis combines the best features of knitted, nonwoven, and microfibre technologies to deliver unprecedented performance to critical wiping applications.

The MicroGenesis wipe is designed with a micro-terry pile to give the fast and efficient pick-up and retention of particles for which microfibre is known.

However the wipe utilises 100% polyester microfibre yarn knitted into a thermally bonded polypropylene substrate limiting the amount of microfibre required and making the wipe more suitable for single use. This structure applies microfibre only to the wiping surface where it is needed while sealing the base of each stitch in a thermally bonded base. This more cost effective structure still delivers the required amount of microfibre to pick up and retain microscopic particles, dust and light oils from critical environments.

Particle attraction technology There are other developments which can provide a wipe with exceptional pick up and retention of particle properties without the use of microfibre.

All fabrics can be treated to improve different elements of their performance.

One patented treatment by Anticon which permanently bonds to the fabric, traps 35 more particles than an untreated wipe and retains 95% of the particles which are trapped. Interestingly this performance is enhanced and not degraded in the presence of alcohol or solvent.

The IEST test methods for testing wipes, test how many particle and fibres a wipe releases but there is no standard test method to show how many particles a wipe picks up. In order to prove that the wipes were truly achieving this level of particulate pick up Peter K Kang and David Hildreth developed a new robust test method2.

Basically, by creating suspensions of known particle size in deionised water and then submerging treated and untreated wipes in the particle suspension, they were able to show how many particles were both collected by each type of wipe and held onto by each type of wipe.

The test results for fine particles showed treated wipers captured over three times more small particles than traditional wipers, releasing only 14% of the particles they captured. Additionally, the test results for large particles showed that treated wipes captured over 35 times more particles than the other wipes tested. Only a very small percentage of those captured particles were released.

To paraphrase Peter Kang, cleanroom wipes need to arrive clean and leave dirty. The ideal product performance for a cleanroom wipe is that it does not add to the contamination whilst performing the removal of particles, spills, biofilms or dirt. Various innovations in both wipe substrates and wipe treatment have aided in this, creating wipes which are ideal at not only particle pick up but retention of those particles until the wipe is removed from the cleanroom. Alternative ways of blending microfibres have allowed the creation of wipes with microfibre properties at the cost of a disposable wipe.

1 Textile Terms and Definitions, 11th Edition, The Textile Institute 2 Testing Wipers for Particle Retention and Attraction, Controlled Environments Peter K Kang PhD David Hildreth

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EPM 19

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CLEANROOMS Open and shut case According to Sara / LBS, its Sprint door is the first to be certified for cleanroom environments.

The company outlines the benefits of this product

“

There are a number of features as standard or optional that can ensure the door is perfect for your application.

”

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ara / LBS claims to have overcome the historical problem of industrial doors with no specific certifications for cleanroom environments, by launching the Sara Sprint Cleanroom Door - the first door, it says, to be tested by the Fraunhofer Institute for cleanroom suitability, and certified to EN ISO 14644-1 Class 5.

Maintaining regulation Ed Wilks, operations manager for Sara / LBS, commented: “An ISO Class 5 cleanroom has at most 105 = 100,000 particles per m³; the Sara Sprint Cleanroom is able to consistently maintain this level of regulation in a normally functioning cleanroom. It is the only door on the market today that is designed specifically for cleanroom use with an internationally recognised certification.”

In common with the rest of the Sprint range from Sara, the company says the Cleanroom Door is capable of high opening and closing speeds, maximum speeds of up to 2 m/s are possible; this ensures that air exchange and particle emission is kept to a minimum when doors are in operation. According to Sara, the

Singled out: This is the only door on the market today that is designed specifically for cleanroom use with an internationally recognised certification, says Sara

high speed is made possible by the inclusion of its MCC Vector Control system that can deliver a range of speeds extremely smoothly as well as offering a variety of options for connecting control safety devices.

Easy to clean Motor and barrel cover, door frame and bottom profile are all constructed from stainless steel, the smooth surface is easy to clean and avoids the accumulation of particle deposits. The curtain uses PVC with fabric reinforcement strips; the strips are red or blue as standard but a wide variety of RAL colours are available as an option.

To ensure that high air ingress protection is achieved, gaps between the curtain and side columns are kept to a minimum and all components are well sealed, including the cable guide. The door

is suitable for use with rooms with a pressure difference of up to 50 Pa. The control panel is integrated into the side column, however a non-contact operator panel is also available for fast, hygienic opening. The option of including a patented non-contact safety beam further reduces the risk of touch contamination while vastly reducing the risks to personnel and equipment as the beam recognises when an object is obstructing the door and prevents it from closing.

Variety of application uses Sara can supply the cleanroom certified doors with a number of options and variations to suit the customer. The geared brake motor that drives the door can be fitted on either the right or left hand side,

EPM 20

a battery backup is also available to ensure the door still works in the event of a power failure. Door dimensions can be anywhere between 1000/3500 mm wide by 1000/3500 mm high; specially designed, narrow side frames allow doors to be installed in confined areas.

Ed Wilks said: “The Sara Cleanroom Door is suitable for a number of applications. There are a number of features as standard or optional that can ensure the door is perfect for your application. We have expert sales engineers available to provide advice on specific environmental requirements to ensure the correct specifications are met. This expert advice is available for all Sara customers from the initial quote, through to after sale support services.”

Cleaning up Parker Hannifin’s ultra-modern cleanroom manufacturing cell for elastomer and plastic components is specifically designed for meeting the demands of the medical and pharmaceutical industries

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arker Hannifin has followed the launch of an ultra-modern cleanroom cell at its Czech location in Sadská Parker-Prädifa with the extension of its capabilities specifically designed to meet the exacting demands of the medical and pharmaceutical industries. The central focus of the operation is on manufacturing custom solutions made up of elastomer and plastic components developed at the German locations in Pleidelsheim and Bietigheim.

The 130 sq m GMP-conformant cleanroom cell consists of several ISO 7 to ISO 9 cleanrooms and has been designed to allow quick-and-easy extension of the facility as needed. A connection of manufacturing cells exclusively dedicated to custom products is also possible.

The latest injection moulding technology to process a range of materials such as silicones (LSR and HCR), TPE and other elastomers is the centrepiece of the cell. 2-component solutions (such as silicone/plastic or TPE/ plastic) in cleanroom class 8 are possible as well. A new microinjection moulding machine in cleanroom class 7 is available for manufacturing high-precision, particle-free moulded parts and seals as well as processing hightransparency liquid silicones.

Advanced over-moulding technology for single-use systems is available as an alternative to conventional cable ties. This technology primarily serves to combine silicone and TPE tubes with other plastic components, such as aseptic connectors, filters or transport containers, or various tubes with each other. Due to the lower risk of leakage compared to cable ties, over-moulding is particularly well-suited for assembling products intended for use in critical process areas.

As well as conventional bonding or gluing, ultrasonic welding work is performed in a class 7 cleanroom.

The significant advantages of this method are high reproducibility and the elimination of the need to use additives, which benefits the purity of the product. PTFE or PES diaphragms can be securely and reliable affixed to plastic components. Ultrasonic welding is mainly used in the assembly of products for clinical use in the area of infusion therapies.

With the new cleanroom manufacturing cell in Sadská, growing quality requirements can now be met through faster and better support of relevant system solutions. For quality assurance Parker-Prädifa uses state-of-the-art inspection and testing technology that meets the exacting safety requirements of the medical and pharmaceutical industry as well as the needs for cost efficiency and economy. Various packaging options are available for products

manufactured in the clean room cell, these range from simple PE bags and PETG single blisters with Tyvek covers through to moulded pallets.

The Sadská location is currently certified to ISO/TS 16949.

Certification to ISO 13485:2012 is planned for the beginning of 2014.

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Czech it out: Parker Hannifin’s cleanroom cell at its Czech location in Sadská ParkerPrädifa is designed to meet the demands of the medical and pharmaceutical industries

CLEANROOMS

& A Q

Immaculate collection Phil Jeyes tells EPM about Pharma Hygiene’s experience and expertise working with some of the sector’s most well-known companies

Knowledge centre: According to Phil Jeyes, Pharma Hygiene Products, the company understands the exacting standards and importance of GMP compliance in drug manufacture

EPM: Tell us about the company’s involvement in cleanrooms background and expertise.

new premises and increasing our own stock levels of high demand products.

PJ: Pharma Hygiene Products’ (PHP) heritage boasts 10 years experience working in the pharmaceutical industry installing and maintaining process equipment all over the world. As mechanical maintenance engineers, we have worked with some of the industry’s leading companies such as GSK, Pfizer, AstraZeneca, Boots and Sanofi. Many of these currently use our products, as do the NHS, Fuji Film, and Actavis.

We are also working with DHL to offer next day delivery in the UK and around the world.

Where there is a shrinking availability of products (products being discontinued by suppliers) but demand is still high, we are currently developing our manufacturing capabilities to produce similar products unique to us.

EPM: How important is the service you offer in terms of meeting the needs of a cleanroom environment?

PJ: PHP understands the exacting standards and importance of GMP compliance in drug manufacture. Having experience working alongside pharmaceutical production engineers, PHP also appreciates the importance of process continuity and the costs associated with losing control over it. This is why we have brought together a range of quality products specifically for pharmaceutical manufacturing.

All our products are manufactured from FDA-approved materials, to GMP compliant designs and appropriately certified to provide the highest levels of hygiene and reliability.

EPM: What are the main challenges you face servicing the cleanroom sector and how do you overcome these?

PJ: One of the main issues we face are long lead times, Examples are delays in supply of 6-12 weeks or waiting for large orders to be produced by our suppliers. We are addressing this in a number of ways including a recent move into

Added value: PHP has recently added hygienic butterfly valves to its product range

EPM: What is your latest offering for cleanrooms?

PJ: Our growing product range demonstrates the company’s commitment to providing a single source of supply for drug manufacturers. Recently added products include open top drums and hygienic butterfly valves and represent the company’s introduction of powder handling products.

products and bespoke solutions with great customer care.

Another thing we do is try and make the sourcing of cleanroom supplies dependable reliable and straightforward.

We also offer a range of ancillary products including, clamps, lids, seals, and drum skids (to aid transportation), along with custom made discharge cones. We also offer a drum refurbishment service.

EPM: What is the company’s USP? PJ: PHP provides confidence and reliability to pharmaceutical manufacturing companies by offering certified quality products, which meets the needs of drug manufacturers and helps to make production processes run effectively and efficiently.

As a specialist supplier, we have a knowledgeable team that offers a fast, reliable service, bespoke advice and a constantly expanding product range. We also like to think that we do things differently by making it easy to source certified

I guess if I were to sum up what sets us apart it would be reliability, operational excellence and industry knowledge. I would also add to that product flexibility - we offer modification and tailoring of products to suit customers needs - excellent customer service and quick response times.

EPM: Where do you see cleanroom developments taking place over the coming years?

PJ: Over recent months we have seen increasing requests for product modifications and bespoke solutions. Coming out of the recession, we see this trend continuing as the pharmaceutical industry increase productivity and innovation once more.

We are also experiencing a growth in exports to international companies wishing to buy from

EPM 22

Britain due to our regulations and high quality standards.

Companies trust British-sourced products and customers have commented that having tried cheaper products from developing countries they have found them to be inferior and unreliable, proving more costly in the long run.

EPM: Any plans for the future?

PJ: We have a mobile phone app in development that will be available very soon. In addition to the obvious advantages offered with mobile devices, the app will feature a product gallery and news and events.

We are also looking at developing our website to include full e-commerce functionality - with most product prices available to credit account customers. Our range of laboratory products will be increased to include consumables and disposables and cleanroom garments.

Long-term plans include providing distribution hubs in the USA, Australia and Malaysia.

Show and tell

POWTECH

Powtech is a key event for powder, granule and bulk solids technologies. Reflecting the current trends and developments in mechanical processing technology, the exhibition offers a valuable overview for those working in the pharmaceutical sector

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owtech is a must-visit event for those involved in the processing, analysis and handling of powder and bulk solids.

The show, which takes place on 30 September to 2 October in Nuremberg, focuses on equipment for size reduction, grinding, mixing, fractionating and screening, filtering, agglomerating, dosing, weighing, emptying and filling, as well as the complete particle analysis process.

More than 700 exhibitors from over 25 countries will showcase the latest mechanical processing technology and another 250 exhibitors will present the latest developments in sterile production processes for pharmaceuticals, food and cosmetics at the parallel TechnoPharm show.

“Powtech is much more than just a trade fair for the individual stages of mechanical processing,” said Willy Viethen, director exhibitions at NürnbergMesse. “In Nuremberg, designers and operators of equipment for the powder and bulk solids processing industry will also find a lot of innovative solutions for linking up these process stages.”

to play a pivotal role as well. For designers and above all operators of powder and granulated material plants, environmental protection, explosion and fire protection, emission control and occupational safety are always a top priority.

Dust explosions, workplace concentrations, filter monitoring and particle separation are just some of the key issues that represent a daily challenge for plant operators in the materials processing industry.

Around 80 exhibitors at Powtech 2014 will specifically focus on innovations relating to safety issues.

Highlights from the supporting programme The trade fair experience also includes numerous presentations.

On the second day of the show, the Powtech forum is devoted to the issue of efficient explosion protection. Technical presentations on fire and explosion protection will be followed by a panel discussion and an exclusive guided tour.

Also worth seeing, says the organizer, are the live explosions in the exhibition centre parklands.

There will also be a series of presentations offering an overview of the technologies available to transport sensitive bulk solids from A to B carefully and without segregation.

Award entries Interested companies still have until 29 August 2014 to apply for the Innovation Award 2014.

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Customized Containment Solutions for Weighing, Dispensing, Sampling

Automation a key component Automation will be a key element of this year’s show with over 200 exhibitors at the event offering automation solutions, reflecting the importance of this technology in conventional mechanical processing. Safety and environmental technology is set

WIBOclean® Decontamination Lock

WIBObarrier® CCS

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EPM 23

WIBObarrier® OCS

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Make it werk

POWTECH

in handling powder Special requirements the daily concerns of and granule are part of ustry and production the pharmaceutical ind son, the German rea departments. For that derwerk has spent xan Ale r machine enginee different machines 125 years developing ts. At this year’s for different requiremen will display its y an Powtech, the comp re efficient and mo for gy latest technolo n. cost reducing productio about its portfolio, t only be on hand to talk Alexanderwerk will no Small machines s. ine ch eral displays of ma sev ow sh o als l wil t bu rs can be seen, as lators or grater/shredde such as rotor fine granu ine for the highest n and granulation mach well as the compactio tical industry, the eu ards of the pharmac requirements and stand /h (lactose) kg 0 40 to a throughput up WP 200 Pharma. With ction of a large n be used for the produ the WP 200 Pharma ca the compaction for batches as well as all sm in cts du pro of range nuous operation. gle products in a conti and granulation of sin hnology can be design, the process tec Because of its modular ial ec tools. A vertical assembled without sp almost completely dis of feed flow as well ol ntr lers for a better co rol the of nt me ge an arr gn, which should lation in Diagonal-Desi as the two-stage granu , too. to 100%, are included increase throughput up

Read all about it

Freeman Technology specialises in systems for measuring the flow properties of powders and has ov er a decade of experience in powder flow and powder characterisation. The company invests significantly in R&D an d applications development, and pro vides detailed knowhow alongside its unive rsal powder tester, the FT4 Powder Rheo meter.

The FT4 Powder Rheo meter uses patented dynamic me thodology, a fully autom ated shear cell and several bulk property tests, including density, compressibility and permeability, to qu antify powder propertie s in terms of flow and processability. Sy stems are installed aro und the world in the chemical, pharmaceu tical, toners, foods, po wder coatings, metals ceramics, cosmetics, , and many other, indus tries. They deliver data that maximise process and product understan ding, accelerating R&D and formulation towards successful co mmercialisation, and supporting the long ter m optimisation of powd er processes.

Freeman Technology has recently published a new educational guide entitled ‘An Introd uction to Powders’. Th e booklet explains how and why powders behave the way they do , and how this impacts powder proce ssing and characterisa tion. It provides a valuable foundation for those with little prior kn owledge of powders as well as being a usefu l resource for anyone looking to expand their understanding of the factors relevant to product development and processing perform ance.

Freeman Technology

Hall 5 Stand 5-425

Book in: Freeman Tech nology has recently pu blished a new educational guide entitl ed ‘An Introduction to Powders’ visitors can pick up a copy from the compan y’s stand

Alexanderwerk Hall 1

Stand 1-448

be on hand nderwerk will not only Double whammy: Alexa , but will also show to talk about its portfolio machines several displays of the

Sample size Fritsch, manufacturer of application-orientated laboratory instruments for sample preparation and particle sizing, is inviting visitors to its stand to see its new premium line models as well as new innovations for particle sizing.

The company has extended its premium line with the addition of four new high-tech laboratory mills. These have been functionally designed to offer the highest performance and maximum safety, says Fritsch.

Discover the new dimension of Fritsch particle measurement with the Analysette 28 for analysis of particle shape and size by Digital Image Analysis. This has been designed to be effective, user-friendly and guarantee accurate results while acting as a fast alternative to sieving.

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Fritsch Hall 5 Stand 5-362 Measure up: The particle sizer Analysette 28 image sizer

Touch of class

The L-series of ploughs hare laboratory mixers manufactured by Gebr Maschinenbau, has be Lödige en designed with ease of use in mind. Conve push buttons have be ntional en replaced by a mode rn touchscreen panel has also improved the and Lödige handling of the L-series of laboratory mixers. Th development was focus e ed on making the contr ols more user-friendly and uniformly designe - a clear d screen display has be en incorporated, for exa Basic functions are pe mple. rformed using what the company has describe easy-to-understand ico s as ns to enable intuitive op eration of the mixer.

With the replacement of pushbuttons in the L-s eries of laboratory mix has expanded its portfo ers, Lödige lio of mixers with a tou chscreen panel for the and process developme product nt or pilot operation. Th e basic version of the MG laboratory mixing granu TL lator is also available wit h this equipment featur e.

Lödige Hall 5 Stand

5-222

Push off: The L-series of ploughshare labora tory mixers by Lödige been designed with tou has chscreen panels instea d of push buttons EPM 24

TechnoPharm 2014

Sept 30 â&#x20AC;&#x201C; Oct 2, 2014 NĂźrnberg, Germany Visit us in hall 6, booth 241 We are looking forward to seeing you!

Processing

equipment

and

packaging

machinery

from

Bosch

achieve

the

agreed

performance. Day after day. Year after year. GMP-compliant systems ensure the required pharmaceutical product quality. Simple validation, cleaning and sterilization processes and low maintenance requirements increase production efficiency. Experienced employees with extensive know-how guarantee professional service worldwide. Learn more at www.boschpackaging.com

EPM 25

schwarzspringer

Processed and packaged as promised. Bosch.

Second sight

POWTECH

Chemical and pharmace utical manufacturers oft en justify the purchase of used equip ment (which can be up to 70% cheaper than new equipment) for the ir operations on the ba sis of lower prices and faster delivery. It is als o typically available im mediately, cutting leadtime for delivery by mo nths. Even so, many ma nufacturers have never considered used equip ment. Perhaps some are worried about the potential risks such as regulatory issues, valida tion and perfomance.

The risks, says Perry Pro cess Equipment, can be reduced by working with a reputa ble equipment dealer that only sources equipment from reputa ble manufacturing comp anies and develops strong relationships wit h original equipment ma nufacturers. The dealer should also be able to provide affordab le back-up equipment fast or equipment for inc reased capacity when a customer demands additional supply. A rep utable dealer will offer equipment on a rental basis for short-te rm projects. Many als o offer a sale or return scheme, ensuring tha t the used piece is suitab le for your process.

Perry Process Equipme nt has been buying an d selling used process equipment since 1932 . It claims to be one of the largest stockists of used process equipme nt, with over 25,000 item s in stock relevant to the chemical, pharmac eutical, food, cosmetic s, brewing and power generation industries.

Pressing engagement

eering specialist At Powtech 2014, engin presenting the new s Romaco Kilian will be machine generation wa tablet press. The latest d ee sp h try. us hig ind 0X l 42 tica P KT armaceu for application in the ph especially developed eed be a versatile, high sp co Kilian is designed to for al ide is It ur. ho KTP 420X from Roma an to 360,000 tablets up ses res mp d co t an ), tha tablet press tablets (Tab-in-Tab -layer, bi-layer or core the production of mono terials. According to ma g win mpress poorly flo co to lers ed us be o als n ca rable compression rol ar-free torque motor, du very low the rlie de un Romaco Kilian, the we ets gn lower punch brake ma and wear-free patented ine series has already (TCO). This latest mach ip rsh ne Ow of st Co al Tot for innovative design. won the iF Award 2014

Romaco Kilian Hall 6

6

Stand 6-357 and 6-45

signed to be a m Romaco Kilian is de fro 0X 42 P KT r: rke wo Fast ses up to 360,000 let press that compres versatile, high speed tab tablets an hour

Perry Process Equipm

ent Hall 4 Stand 4-41

Dissolution solution d to

Safety first

SteriValves experience in the pharmaceutical field allows the compan provide safe products y to , made accurately and in compliance with Eu standards (EN 1935/20 ropean 04) and FDA. Its Pharmalite valve wa s specifically designed for food industry which increasingly demanding is in terms of hygiene, qu ality and innovation. Th company believes tha e t it is crucial to underst and pharmaceutical an regulations and guida d food nce in order to successf ully manage a product’s lifecycle and protect en d-users health.

Pharmalite is a butterfly valve with a design us ed to intercept bulk so products (powders, gra lid nules). Its compact de sign should allow for ea maintenance and cle sy aning, ensuring produ ct quality.

Its features and benefits include an eccentric sh ape which should dra reduce seal wearing, stically and an essential desig n for reduced mainten and costs. A low opera ance time ting torque should als o help reduce costs.

SteriValves provides co nformity declarations for all material that co contact with product an me into d supporting docume ntation on the methods maintenance, cleaning of and sanitising.

flexibly respon The ability to s rence ange in today’ make the diffe ch ronment can permanent vi ents, en m al ire tic qu eu armac to-market re etim st fast-paced ph Fa . an pacities d ess and failure ufacturing ca an m between succ ble of ift sh , r equally flexi relocations erations ask fo able id outsourcing, al ns sc co t lly fu en m ’s invest ries. Sotax to ra bo la and short return on C e Q is d sic prem ns in R&D an sed on this ba ba eds. is testing solutio t ne ep re nc tu t and fu XtendTM co to both curren g and modular in st te n io ut g dissol olution bath, allows tailorin ch as the diss su es ul od m XtendTM n be flexibly Standardized e manager ca pl m sa d m manual an ation, irements – fro qu re n io pump, filter st at m Irrespective of different auto ion systems. ut ol ss combined for M di ed at s of the XtendT fully autom d component to semi- and an es ng ul di an od m m l t de tion, al ed for the mos the configura hours per day. ve been design 24 ha g e in lin nn n ru io ut em st sy dissol ed at m n a fully auto dTM dissolutio conditions of art of the Xten he e s th nt is ne th po ity com ssolution ba s robust qual The new AT di sign combine de ible testing its uc ys od sa pr arantee re line. Sotax gu to gy lo no tech with the latest y after day. da s, on iti cond

SteriValves Hall 1 Stan

d 1-333

Safety first: SteriValves provides safe products , made accurately and in compliance with Eu ropean standards

Take the test

tem that aims dular tablet testing sys The AutoTest 4 is a mo vides realpro It ity. ibil cision and flex to offer the highest pre d an evaluated ta that can be identified time, accurate test da ity, efficiency and ctiv increased produ in ing ult res – tely dia imme liance. ease of regulatory comp test a wider variety on, the AutoTest 4 can atr arm Ph to ng rdi co Ac ter on the market. any other automatic tes of tablets shapes than long, diamond, ble design, including ob Practically any imagina ally positioned atic tom ecial shapes, are au sp er oth d an on xag he rdness. kness, diameter and ha to measure weight, thic

9

Sotax Hall 6

Stand 6-333

ular XtendTM able and mod al sc lly current fu s x’ Sota sting to both te n tio lu Future proof: so is s tailoring d concept allow s ed and future ne

-resistant the solid and vibration Pharmatron says that iable test results at toTest 4 guarantees rel construction of the Au d linear feed track ine mb system with co all times. Its SmartRake ion of each test ensure correct orientat has been designed to object.

-alone operation, toTest 4 include stand Other features of the Au design. lar du control (IPC) and mo automatic in-process

and 6-333

Pharmatron Hall 6 St

est 4 can test a wider Pharmatron, the AutoT

ng to Testing testing: Accordi market the on ter tes automatic

EPM 26

es than any other

variety of tablets shap

More protocols. More equipment.

More reasons to choose ASCO when you automate.

Working with a single automation supplier who offers a selection of protocols and a large range of associated equipment ensures effective communication and reduces integration issues.

ASCO Numatics valve islands, solenoid valves, aseptic valves, air preparation equipment and cylinders are proven-in-use and combine to provide a complete automation solution, no matter what communications protocol you use.

To find out more information call ASCO Numatics on (0) 44 1695 713 600 or visit www.asconumatics.eu

Visit us at POWTECH 2014, 30 Sept – 2 Oct, Nuremberg Germany, stand 112 in Hall 4

The Emerson logo is a trademark and a service mark of Emerson Electric Co. The ASCO logo is a registered trademark of ASCO Valve Inc. © 2014 ASCO. All rights reserved.

3933 ASCO automation ad 156x220 UK.indd 1

09/07/2014 11:32

Visit us at Technopharm in Hall 6, Booth 333 30 Sept – 02 Oct 2014

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 Dr. Schleuniger ® Pharmatron is a brand of

Quality matters.

155.004.021-PHT-EPM-final.indd 1

30.06.14 10:32

EPM 27

INSPECTION & TESTING

In the mix Dawn Yang, B&W Tek, offers an insight into quantitative analysis of APIs in blending mixtures and tablets

P

harmaceutical tablets consist of an Active Pharmaceutical Ingredient (API) with excipients including fillers, binders, and lubricants. In tablet manufacturing, blending is the process where APIs and various excipients are blended together to form a homogenous mixture. The blending process control is very important for final tablet quality, and yet blending process control can still be very challenging when it comes to detection or characterization of raw material variations and final blend homogeneity.

The USFDA guidance on pharmaceutical manufacturing process control indicates that each batch incorporated into a blend should meet established purity specifications when involving APIs; also, blending validation should show homogeneity of the blended batch for dry blended APIs.

Experiment In this study, Raman spectroscopy, along with chemometrics, was used to establish the analytical method to quantify the API Naltrexone HCl in blended powder mixtures as well as in the final product 3mg tablets.

Naltrexone and excipient powder blends were used for a preliminary feasibility study. Five powder samples with different known concentrations of an API, ranging from 2.70mg to 3.14mg per tablet, were used for creating a chemometric model. Two final product tablets of Naltrexone HCl 3mg/tablet were used for prediction with the model created.

Table 1. Samples: Sample

Naltrexone HCl (mg/tablet)

1

100% Naltrexone HCl powder

2

2.70 (mg/tablet) powder

3

2.85 (mg/tablet) powder

4

3.00 (mg/tablet) powder

5

3.06 (mg/tablet) powder

6

3.14 (mg/tablet) powder

7

3mgT1

8

3mgT2

By collecting multiple spectra from different locations on a sample, the API uniformity within the blending mixtures is taken into account, and a more complete representation of the mixtures is built into the chemometric model.

In order to remove fluorescence variability, the data was baselineâ&#x20AC;&#x201C;corrected using an adaptive iteratively reweighted Penalized Least Squares (algorithm provided in BWIQ. With the concentration of Naltrexone HCl (mg/tablet) set as the response, the Partial Least Squares (PLS) regression was used for building the model.

Since the Raman bands for Naltrexone HCl are within the range of 800 â&#x20AC;&#x201C; 3000 cm-1, the PLS regression was performed on the same range.

The model gives a good linear fit to the data (R2=0.9922, RMSEC = 0.01384), as shown in Figure 2.

Some sample spectra were reserved for cross-validation. The model gives a linear fit to the validation data (R2=0.76866, RMSECV= 0.05287).

feasibility evaluation

The predicted results on the two (3mg) tablets are shown in Table 2.

Two spectra from each sample were collected.

chemometric model

Table 2. Predicted results: prediction

An i-Raman Plus with a 785nm laser excitation and fiber optic probe were used. A probe holder was used to provide stability for sampling and data collection, which is very important in the accuracy of the chemometric model.

Spectra were collected at three different locations from each sample through plastic bags. All measurements were taken at 100% laser power (~300mW) with a 6s integration time.

The software BWIQ was used for chemometric analysis.

Prediction Tablet

Predicted Naltrexone HCl (mg/tablet)

3mgT1-1

2.9668

3mgT1-2

2.9244

3mgT2-1

2.9038

3mgT2-2

2.9296

Conclusions Raman spectroscopy with chemometrics can be used to develop a quantitative method to measure the concentration of APIs such as Naltrexone HCl in blending mixtures and final product tablets. The method provides quick predictions of API concentrations in blending mixtures, allowing for use in online monitoring for blending processes. The high sensitivity, high resolution, and stability of the i-Raman Plus instrument conform to the requirements in developing reliable quantitative Raman analysis methods.

Chemometric Analysis Figure 1 compares the Raman spectra for samples with different concentrations of the API to 100%. The distinctive Raman peaks belonging to Naltrexone HCl are apparent in the Raman spectra of the samples used to build the chemometric model.

Figure 2. PLS model: measured vs. predicted curve

The physical non-uniformity within a sample (powder or tablet) could directly affect the accuracy of the model. Multiple measurements at different locations within a sample are needed for collection of calibration spectra. That being said, an estimation of the sample API uniformity can also be assessed when the actual API concentrations of the prediction samples are known.

Figure 1. Raman spectra of samples with different Naltrexone HCl concentration compared to pure Naltrexone HCl

Good practices require that standard samples with known API concentrations are used to verify the stability of the method as well as the hardware on a regular basis.

EPM 28

Inspection & Testing: Case Study Who:

GlaxoSmithKline

What:

Maintaining in-house product inspection and automating production lines

How:

Using Keyence’s XG vision system which also reduced the amount of human error

Check this out The company GlaxoSmithKline’s site in Evreux, France, covers 18 hectares, employs 2,000 people and produces 130 million boxes of inhaled forms (aerosols, inhaled products) each year. 85% of its production is exported to 130 countries with AFSSAPS, MCA and FDA approval. Every minute, 15,000 patients around the world take a dose of medication produced at GSK Evreux.

Looking good: GSK was looking for a vision system that did not require any direct operator intervention and would eliminate the risk of incorrect adjustments

The production This high production volume entails a highly complex traceability system. One of the inhaled forms produced by GSK is the Diskus, a multidose powder inhaler that delivers a metered dose of medication. The marking of each Diskus is checked using a threecamera XG vision system. The first camera uses OCR to check an in-house code that is engraved with a YAG laser. The second checks the placement and diameter of the label; this inspects it for tears and makes sure that the legal notices printed on it are legible. The label is printed on a white background at a rate of 110 to 150 strokes per minute. The last camera is used to check a special label with a black background used for the Japanese market.

The solution “We were looking for a vision system that did not require any direct operator intervention and thus would eliminate the risk of incorrect adjustments,” explains Christophe Fourcin of GlaxoSmithKline.

“Operators simply enter the code of the product to be inspected into the PLC controlling the vision system.

That way they don’t have to deal with the complex matter of programming the thirty or so sizes used.

“The very nature of the detection performed means that we have to routinely make changes to the vision system. That’s one of the reasons why we chose Keyence’s XG vision

system. We wanted to have a tool that was ours and that we could modify as needed. With competing brands, reprogramming takes time and money. We have to wait for the estimate and then wait again for the new programming to be done.

It makes us feel somewhat hogtied. With the XG, we’re in control and can even contact Keyence for assistance,” says Fourcin.

“It was easy to set up. Keyence’s engineer provided us with the programming template so that we could go on from there. I make the necessary changes myself, which I learned how to do during a oneday training session provided by Keyence. The language is intuitive and the programming tools aren’t that complicated. As a result, we were self-sufficient in no time. Lastly, it has a decent GUI,” adds Fourcin.

The XG VisionEditor software toolset is designed to be intuitive, fast, flexible and allows fully customisable programming. Its flowchart functionality allows users to create programs simply by dragging and dropping processing blocks’. It also features a range of algorithms and filters. The system’s flexibility also stems from the fact that users can add C-language source to create custom algorithms and filters.

The XG vision system is part of GlaxoSmithKline’s full process control system. “Our aim is to reduce human intervention to a minimum in order to increase the reliability of our processes. The next step is to control the PLC remotely with a takt time solution. Once that is done, detection with the Keyence system will be fully automated and centralised,” concludes Fourcin.

“The flowcharts enable us to quickly see which functions should be used,” explains Fourcin.

Breathe easy: One of the inhaled forms produced by GSK is the Diskus, a multi-dose powder inhaler that delivers a metered dose of medication

Debugging tools and a trace log (a log that traces the program’s I/Os and sequencing and the commands and I/Os in the PLC) allow the vision program and the interface with the PLC to be tested to reduce integration time.

The benefits “The vision system integrated very easily with the PLC. We also noticed that detection is stable over time and does not cause any false rejects. Determining the right inspection settings is very easy with the XG Series,” says Fourcin.

EPM 29

INSPECTION & TESTING

Fig. 1

I

Put to the test

n his study Dixon compares a number of different packaging types and materials, and tests them both using destructive blue dye method and Sepha’s nondestructive Pakscan ‘force decay’ technology at various levels of micron defect.

The results of Dixon’s paper raise questions as to the ability and reliability of current blue dye testing to detect sub 250 μm defects in flexible medical and pharmaceutical packaging.

The importance of intregity testing of pharmaeuctial and medical device packaging is recognised within the respective sectors and robust leak detection systems are necessary to demonstrate package intregrity and minimise risk of costly recalls. Packaging faults such as pin holes, faulty seals, tears and pack misalignment can adversely affect efficacy, shelf life and may result in a loss of sterility. In addition, it is a requirement under both medical device and pharmceutical regulations to demonstrate package intregity and to valiadate the package manufacturing processes.

This study evaluated the ability of Sepha’s Pakscan force decay system and traditional methylene blue dye testing to detect 10, 15, 25, 250 and 1000 μm sized holes in four different package designs.

The 10, 15 and 25 μm holes were prepared by laser drilling stainless steel foil. All the holes were then inspected using scanning electron microscopy (SEM) to ensure that the holes were complete and contained no debris. Any faulty holes were removed from the study.

A new whitepaper by medical device packaging expert, Dr Dorian Dixon, has examined the validity of traditional destructive test methods for pharmaceutical and medical device pouch, sachet and flexible container packaging which come into contact with the packages when the system is closed, can also be seen. These plates hold the packages in place when the vacuum is applied allowing forces generated by the packages to be measured through a load cell.

Findings

The packages are then held for a period of typically 5-15 seconds to allow the system to equilibrate and then the force is measured under constant vacuum. This measurement period is typically 10-60 seconds, depending on the sensitivity of the test and the size of the package being tested. This test phase permits small defects to be detected as the force generated by such a package will decay as air leaks from any defects present. Threshold values for the minimum force after the evacuation phase and for the allowable force decay during the test phase are used to detect large and small holes respectively. The threshold values vary depending on the pack design and are determined by testing good packs and those containing known defects.

Figure 2 shows the applied vacuum and the forces generated in a good pack compared to those containing small or large holes. A vacuum pump evacuates the chamber up to the target vacuum level (typically 500-750 mbar). The applied vacuum causes the packs to try to expand generating a force on the load cell.

A package containing a large hole will generate very little force as the large hole will allow the air inside the package to escape allowing the pressure inside the package to equalise.

The most notable finding is that the blue dye test failed to correctly identify any of the packs containing 10, 15 or 25 μm holes as defective.

In addition, the blue dye method only correctly identified 25% of the packs containing a 250 μm sized as faulty and also missed some of the 1mm holes for the most flexible packaging type tested (tube package).

The Sepha Pakscan achieved considerably higher reliability with detection rates across all pack types of over 90% at 25 μm and 100% at 250 μm.

Commenting on the results Dixon said: “The failure of the industry standard test method, blue dye, to reliably and consistently detect significant package integrity defects below 250 μm is concerning. It is clear that modern non-destructive technologies offer significantly more accurate and reliable integrity results compared to traditional test procedures.”

The vacuum cycle used during the blue dye test is illustrated in Fig 3.

Test method Figure 1 shows the test chamber and the tooling used to locate the sample packs within the Pakscan system. The white reaction plates,

Fig. 2 Fig. 3

Figure 2, typical vacuum and force profiles observed during testing

Good Packs

10µm

Figure 3, Blue dye test vacuum cycle

15 µm

25 µm

250 µm

1000 µm

Pakscan

Blue Dye

Pakscan

Blue Dye

Pakscan

Blue Dye

Pakscan

Blue Dye

Pakscan

Blue Dye

Pakscan

Blue Dye

Vials

0/8

0/8

7/8

0/8

8/8

0/8

8/8

0/8

8/8

2/8

8/8

8/8

Sachets

0/8

0/8

2/8

0/8

6/8

0/8

8/8

0/8

8/8

4/8

8/8

8/8

Tube

0/8

0/8

1/4

0/4

0/4

0/4

5/8

0/8

4/4

0/4

8/8

6/8

Syringe

0/8

0/8

3/4

0/4

2/8

0/8

8/8

0/8

4/4

0/4

4/4

8/8

100%

100%

54%

0%

57%

0%

91%

0%

100%

25%

100%

94%

Pack type

Percentage correctly Identified

EPM 30

Q& A

STERILISATION

Life begins at 4 40 0 Olivier Mazille, product manager, Merck Millipore, chats to EPM about the company’s sterility testing expertise

EPM: Outline the expertise you offer in sterility testing.

EPM: How does Steritest benefit lab technicians?

OM: For 40 years, we have been helping our customers to develop, improve and validate their sterility test methods. The knowledge we’ve accumulated is really valuable to help our customers through seminars (the ‘Steritest schools’) and application services. It’s also helpful for us to design and improve test devices fitting to multiple sample containers and compatible with many formulations.

OM: Our customers will find among our extensive range of needle adapters and accessories the device that best fits their needs.

The Steritest devices, operated on our advanced filtration pumps, are designed to maximize safety and convenience for microbiologists around the world. Thanks to our double-packed filtration devices and media, the packaging decontamination before loading the testing environment can be skipped.

The technicians save time and again reduce false positive risks.

EPM: What are the key developments that have taken place in this field during the 40 years you have been carrying out this service?

OM: First of all, Merck Millipore invented the concept of a presterilised closed filtration chamber to protect the sample from external contamination. We made the sterility testing reliable. This is highly critical for our customers, knowing that a false positive test result requires a thorough investigation and that retests are allowed by the current Pharmacopeias only under very specific circumstances.

We have constantly improved our devices, firstly by sealing the filter membrane to the canister wall to avoid sample bypass and adsorption of inhibitory products on the filter edge. Another action against false negative risks was to extend the filter offering with the PVDF membrane, a low binding material recommended to filter and efficiently rinse antibiotics. We have also introduced a device resistant to solvents. We are still the only ones on the market to offer those unique features!

EPM: What is the secret to the company’s success?

OM: We’ve always listened to our customers in order to create easyto-use products that provide reliable results and streamline their testing workflow.

In addition, we are helping them to ensure compliance. Our service experts provide a comprehensive range of application and validation services (ready-to-use validation protocol compliant to GMP/GLP requirements, on site IQ/OQ execution and PQ consultancy).

I should not forget the maintenance agreements ensuring hardware reliability over time. We have developed a real partnership with our customers.

EPM: What’s next for the coming 40 years?

OM: I am excited to announce that the sixth generation of Steritest pumps will be launched soon; reliable sterility testing will become even easier! Forty years is just a beginning.

“

Merck Millipore invented the concept of a pre-sterilised closed filtration chamber to protect the sample from external contamination. We made the sterility testing reliable

”

EPM 31

STERILISATION

Thinking clearly Noxilizer says it’s high time to rethink an innovate in sterilisation and explains why its nitrogen dioxide technology supports bio-pharma changes

‘Reduce cost and increase quality’ is a demand used by the leaders of industry and government.

In the bio-pharma world, ‘cost’ generally relates to production costs and productivity, whilst ‘quality’ relates to regulatory compliance and safety, and generally, these are pulling in opposite directions, so this demand is increasingly difficult to deliver on.

To address the challenge, biopharma manufacturers and (passing the challenge down the supply chain) their suppliers are innovating; finding new technologies that will achieve one or both of these demand objectives.

Examples include progressively more sophisticated drug delivery devices, and the ever increasing use of prefilled syringes, both of which are designed to make drug administration simpler, safer and have lower total cost.

The trend towards injectable biologic and other large molecule drugs, which are generally heat labile and cannot be terminally sterilised by traditional thermal

methods, forces a trend towards aseptic processing. When administration of a drug is intraoperative (in particular), additional measures are necessary to minimize the risk of contamination of the packaged device.

As an example of the needed innovation to meet this demand, Noxilizer has developed a solution using gaseous nitrogen dioxide (NO2) to sterilise packaged injectable drug delivery devices without penetrating sterilant into, or otherwise interacting with, the drug product.

Nitrogen Dioxide (NO2) is well suited to most common packaging materials including glass, cyclic olefin (co)polymers, polypropylene, silicone, and thermoplastic polymers. It can penetrate typical secondary packaging such as Tyvek, enabling the ‘terminal’ sterilisation of devices in final packaging.

The sterilant is used in a room temperature process that has no effect on a heat labile drug. This is an ideal adjunct step to enhance safety and minimize the probability

of microbial contamination in product packaging. This innovation addresses both elements of the industry challenge: reducing cost – by reducing the focus on the aseptic processing related to the packaging, and improving quality by reducing risk of microbial contamination of the packaged device.

In another example from Noxilizer, the same sterilant, NO2, may be used to rapidly decontaminate enclosures, such as those used in bio-pharma manufacturing. As a true gas, and not a condensing vapour (the traditional agent used is vapourised hydrogen peroxide), it readily diffuses in air and is easily removed by dilution.

Accordingly, decontamination cycle time is reduced, improving productivity, and smaller ventilation systems may be used, reducing running costs. Moreover, NO2 is an active depyrogenation agent, and has been demonstrated to provide a 104 reduction in endotoxins on treated materials.

This technology has already seen its first deployment in a

EPM 32

collaboration between Noxilizer and Weiler Engineering, manufacturer of the Asep-Tech series of blowfill-seal filling machines, where biodecontamination of the exposed critical zone surfaces enhances the sterility assurance of the packaged product.

As the bio-pharma industry moves forward, it’s clear that the status-quo of the traditional sterilisation industry will not meet the future demands.

New drugs, new materials, new delivery devices, coupled with the need for greater productivity and reduced production/running costs will require innovation in sterilisation technology.

Clean and clear: Noxilizer has developed a solution using gaseous nitrogen dioxide (NO2) to sterilise packaged injectable drug delivery devices without penetrating sterilant into the drug product

STERILISATION The lack of knowledge of the polymers that make up the bags or connectors can result in burst or deformed bags, damage to the twist-off or a milky appearance during terminal sterilisation. But these problems can be avoided.

How? First, by gaining a better understanding of the molecules’ resistance to heat, and by using sterilisation methods that are adapted to the contents. But also through the perfect command of the sterilisation cycle, from the temperature and the length of the cycle phases, to the pressure, the volume and shape of the bags to be sterilized, the number of bags in each load, etc.

Coming clean Sterility is the absolute criterion of an injectable product.

Pathogenic elements are essentially neutralised by exposure to heat 1. Sylvie Ponlot, Technoflex Autoclave says terminal sterilisation is essential for the safety of patients and does not allow the slightest error. She discusses the risks and best practices

PVC bags with over-packaging may turn white when terminal sterilisation takes place in a spray or stream autoclave. This occurs when the vapour works its way between the macromolecules that make up the material. The only alternative is an air-vapour autoclave with ventilation that cools down the load.

The solution itself represents another threat. When the solution is exposed to heat, it expands and applies pressure to the walls of the bag. This pressure results in deformation that can sometimes cause the bag to burst. Regulating the pressure inside the autoclave can solve this problem.

And when it comes to the temperature, each material has its own limits. Polypropylene bags must not be heated to more than 125°C, while the limit for PVC bags is just 122°C. There are also a few special cases.

Proteins that do not tolerate severe heat, such as albumin, must be pasteurised. In this case, stream autoclaves are used to expose the solution to a temperature of 60°C for about 10 hours.

Gas safe

In the bag: Sterilisation is a critical process in the pharmaceuticals industry. Technoflex inspects and tests its bags under the real-life conditions of use of the products

Sterilisation is a critical process in the pharmaceuticals industry that demands in-depth knowledge of all the parameters in play. Technoflex inspects and tests its bags under the real-life conditions of use of the products. Strict monitoring and regular checks of the autoclaves are also necessary. All new appliances must undergo initial qualification, or retrospective qualification for

The Ozilla from Amsbio is a purpose-built ozone gas generator.

Measuring 32 x 28 x 13cm, it will fit in most standard laboratory cell culture incubators, air incubators, cell culture hoods, PCR hoods, or any other environment where a sterile atmosphere is critical.

Ozilla is designed to completely eliminate airborne as well as surface contaminants and germs including bacteria, phage, and fungus.

autoclaves that are already routinely used2. The conformity, quality and safety of the injectable products depend on it.

1

Apart from molecules that do not tolerate heat and are conditioned in aseptic media

2

GMP recommendations, Chapters 3 and 4 - § 4.26 & 4.28

With its extra free radical oxygen molecule, ozone is able to destroy germs, viruses, and microbes that may cause surface or air contamination. It leaves no chemical residue typical of alternative detergent or synthetic cleaners, and if handled properly - by converting ozone back to oxygen molecules - it can be one of the most effective sterilising tools. Ozone is a powerful and natural purifier, and now with

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The three terminal sterilisation processes Air-vapour autoclaves, with a ventilation system that drives the fluid flow, are commonly used in the pharmaceuticals industry. The solutions are heated by directly injecting saturated vapour into the sterilisation chamber. The autoclave’s internal heat exchangers are filled with chilled water and the flow of cold air cools down the load.

The two other processes, which use stream or spray autoclaves, involve spraying the load with water. After being superheated in the heating phase, the water is chilled in the cooling phase.

The only notable difference between these systems lies in the fact that, in the former, the fluids are dispersed by gravity, while, in the latter, the water is sprayed by jets.

Each system has its subtle differences when it comes to installing the load. Tiling consists in stacking the bags on the sterilisation trays in an airvapor autoclave. Enough space must be left between the trays to allow the vapor to circulate optimally. This technique cannot be used in spray or stream autoclaves, because the stacked bags interfere with the free flow of the heating fluids.

In these cases, the bags are placed side by side on the trays.

the Ozilla Ozone Sterilizer, it is safer and easier than ever to use ozone gas for sterilising and deodorising lightly contaminated pipettes, pipette tips, gloves, plates, small instruments, and even personal items such as keys and glasses.

Tablet Tooling Maintenance: Case study Who:

Thompson & Capper & I Holland

What:

Achieving cost savings on the manufacture of siliceous earth products

How:

Using a set of punches with I Holland’s PharmaCote RS coating, applied to HPG-P (Holland PharmaGrade premium) steel.

The user Thompson & Capper is a contract manufacturer of pharmaceutical and nutritional tablets, based in the UK. It produces over 2.5 billion tablets every year, mainly for clients in Europe.

Maintaining the edge

Thompson & Capper claims to have been involved in the history of tablet making, and its partnership with I Holland has been longstanding.

Over the years, medicines, food stuffs and chemicals have formed the bulk of its work but its processes have also included novelties such as tea tablets and tablets used to inflate tennis balls!

These steps should be followed: 1. CLEAN: Tooling should be cleaned and dried to remove any oil or product residue.

2. ASSESS: Visually inspect tooling for signs of obvious damage and establish if maintenance is required.

The challenge I Holland has recently helped Thompson & Capper to make major cost savings on the manufacture of one of its siliceous earth products.

The tablets compressed well during the development phase, but it was not until the tablet hit full-scale production that it became clear the formulation was extremely abrasive.

The first batch produced only 1.5 million tablets on the Manesty D4, 20 station machine, and wear on the punch tips was visible when detooling the press. Only 4.5 million tablets were produced per tool set which is far below output levels expected for typical formulations, where tablet output per set would be in the region of 50-60 million tablets.

The initial tools supplied were on I Holland’s standard steel HPG-S (Holland PharmaGrade Standard).

After Thompson & Capper ran three sets, it was obvious to I Holland that a more sophisticated, wear resistant solution was required. Working with the I Holland customer support group it was agreed to run a set of punches with I Holland’s PharmaCote RS coating, applied to HPG-P (Holland PharmaGrade premium) steel. A full set was supplied and after producing 35 million tablets, they were still in a useable condition. Operators in Thompson & Capper’s production team inspected the condition of the tool set daily, and it was finally agreed to remove the coated tools at 45 million tablets.

measure, polish, lubricate and store has been designed to help users extract the maximum life from tablet tooling. It aims to provide a consistent approach to tooling maintenance and aids production by sitting alongside tablet production processes. Having a coordinated tooling SOP ensures punches and dies are ready for production, with the assurance that they are clean, un-damaged and within specification.

3. REPAIR: Light surface corrosion and damage can be polished out and repaired.

The results

The business case

According to Kevin Fairhurst, production manager at Thompson & Capper, they were surprised by the results: “We were completely astounded by the increase in tablet output on just one set of tooling.

Despite an increase in the cost of the tooling for the coated set,we were able to increase output per set by 10 times. Even then, the decision to stop production at that point was based on wear to the compression rollers, rather than tip wear. More significantly, we were able to save on nine tool changes per set. One tool change taking a whole production shift.”

Total increase in cost of tooling = 78%

Thompson and Capper has now purchased further sets of PharmaCote RS coated tooling and is looking to roll it out to other abrasive products as their portfolio expands.

It is also considering other solutions from I Holland’s PharmaCote range for its sticky formulations and will be using the TSAR Predict service to facilitate selection of the right coating for these.

Total increase in tablet output = 900%

Tablet tooling maintenance Maintaining tablet tooling should be a priority if you are to produce the best tablet possible. There are many problem that can contribute to tablet manufacturing problems, such as sticking caused by old product adhering to the surface of the punch tip due to inadequate tablet press maintenance and poor condition of tablet tooling.

To ensure tooling is maintained to the highest standard, I Holland has designed a system to ensure complete tablet tool maintenance.

The PharmaCare 7 Step process was developed following years of research and experience in tablet tooling manufacture. Each of the seven steps; clean, assess, repair,

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4. MEASURE: Measuring is essential after repair to ensure that critical tooling dimensions have stayed within tolerance and also ensures that tablet weight variation is controlled.

5. POLISH: Polishing should result in a smooth mirror finish.

6. LUBRICATE: Lubrication is important to protect, preserve and aid the smooth operation of tooling.

7. STORE: Storage cabinets should be specially designed to maximise security, safety and minimise damage of tooling during transportation.

Tip top: Maintaining tablet tooling should be a priority if you are to produce the best tablet possible, says I Holland

TABLET TOOLING The secret to a long life Dr Charles Kettler, director of Natoli Scientific, explains the importance of taking care of tablet tooling to ensure lower costs, better press and tool performance

C

ompression tooling suppliers strive to meet the dimensional and performance requirements of their customers. We design, manufacture and deliver tooling to meet their needs and work to provide service after the sale to assist clients whenever the need arises. The reality about compression tooling is that the tools are a consumable item. Just like a pair of latex gloves; when the utility and value provided by the tools falls to an unacceptable level, the tools are discarded and replaced by new tools. The casual observer would surmise that since the tools are made of steel and are simply being used to press powders together that the tools would last a long time. If all powders were made the same and all tools were handled in the same manner then that might be the case. The reality is that many formulations are abrasive, some tablet presses are not well tuned and many compression tools are not handled in a friendly manner. The result is significant tool wear and shorter tool lifetimes.

Tooling care

Ensuring long life

It is typically not the fault of the tablet press mechanic or the tool room manager that they are not well oriented or trained on the proper methods to handle and maintain tablet compression tools. We often see punches and dies thrown together in pans and buckets with the attendant attitude that the tools are made of hard steel and how can this possibly impact the tools? The reality is that minor tool damage caused by mishandling can evolve to other problems. Taking short cuts during tablet press setup like skipping barrel lubrication, improper die insertion technique and failure to preload shaped punches before final die lock can impact tablet press wear along with tool wear due to improper lubrication. Tools left in a tablet press overnight in contact with formulation can lead to minor corrosion issues that are then amplified if the tools are cleaned in an ultrasonic bath and not properly dried and protected. As tools wear and are not inspected at uniform intervals then the tools can and will cause problems with tablet product quality. Failure to inspect and polish punch cups will lead to scratched cups that accumulate powder in surface blemishes in the cup, and sticking of formulation will result. Scratches on the barrels and heads of punches will impact the travel of the punch in the turret as well as the impact of the head with compression roller. Small problems can be propagated to big issues when one considers the high speed of modern tablet presses and the high compression forces often being utilized.

The handling, installation, cleaning, inspection, storage and refurbishment of tools play a significant role in determining tool longevity. Expectations for proper handling and maintenance of compression tools must be clearly communicated by plant management to all workers. Proper training must be provided so that every person, from the tool room manager to the tablet press operator understands that they own the responsibility for proper tool handling, care and press optimization. The protocols authored to address all of the aspects of tooling maintenance must provide logical steps that are coupled to the best devices available for tool maintenance. The care and maintenance path for a tool set taken from storage must be defined so that the tools return to storage in as close to the same condition as the tools which were removed from storage.

The cost of poor tool care and maintenance results in additional unnecessary tool purchases and that cost is passed along to the customer as a component of the higher costs of medicines as well as taken out of the pockets of company owners and shareholders. Implementing common sense policies to address tool handling and maintenance will provide a return on the investment in short order. Talk to your tooling supplier for advice and guidance and the result will be lower costs, better press and tool performance as well as fewer tools sets that have to be retired early.

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The cost of poor tool care and maintenance results in additional unnecessary tool purchases and that cost is passed along to the customer

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COATINGS & CAPSULES Hot stuff: A scanning electron microscope image of an API particle showing a homogeneous coating layer created by using HMC

P

harmaceuticals are often administered via the oral route – the cheapest, simplest and safest approach. However, many active pharmaceutical ingredients (APIs) need to be effectively coated to ensure stability, efficacy and the desired API release profile.

Commonly, pharmaceutical coating involves dissolving the API and/or excipients in a solvent and using the mixture to coat a seed particle via a fluid-bed process. While well established, solvent-based coating suffers from several important drawbacks. Firstly, the coated particles must be dried, which takes considerable time and heat energy, particularly when using water.

In some cases, the constituents cannot be dissolved in water and organic solvents such as alcohols, ketones and ethers must be used instead. These are frequently toxic, flammable and expensive, making them less than ideal for use in pharmaceutical coating.

Some like it hot Hermes Pharma explains how to improve pharmaceutical formulation using hot melt coating

HMC offers many advantages over conventional solvent-based coating technologies. The need for solvents is eliminated, while the process is also faster than solvent-based methods. In addition, HMC does not suffer from curing or sintering effects and there is very little risk of forming unwanted products such as agglomerates. The lipid coat increases the hydrophobicity of the final product, inhibiting the uptake of moisture from the environment and further improving stability.

Hot melt coating (HMC) is becoming a go-to technique for companies looking to avoid the drawbacks of solvent-based coating, while simultaneously gaining greater control over taste characteristics and API release parameters.

While formulation development requires specific expertise and coating set-ups, the unique conditions required for each product can also prove advantageous, as they provide a means of protecting intellectual property. Pharmaceutical companies can therefore employ HMC to revitalise ageing products and/or create new formulations that are more difficult for competitors to copy.

When carrying out HMC, the seed API particles are suspended in a fluid bed coater, while the excipients are heated in a suitable external container until they are molten. The molten mix is then transported via a heated tubing system into the fluid bed coater and sprayed directly onto the seed particles using a heated nozzle.

Both novel and traditional dosage forms can benefit from HMC, as it enables formulators to develop fast- and delayed-release profiles with optimal stability characteristics.

HMC parameters can be optimized to create both immediate and extended release forms – including both types within a single dose if required. This can be used to

simplify complex dosage regimens – which have traditionally required multiple tablets taken throughout the day – down to one or two doses per day, increasing patient compliance and treatment effectiveness.

HMC is also especially powerful for innovative dosage forms such as orally disintegrating granules (ODGs), a member of a new class of pharmaceutical dosage forms known as user-friendly dosage forms, which have been specifically designed with all the needs of the patient in mind.

ODGs can be applied directly into the mouth and do not require any water, making them a much more convenient option for today’s busy consumer. As they start to dissolve in the mouth, they are also easier for patients to take, making them ideal for people who have difficulties swallowing solid tablets. However, as ODGs tend to spend more time in the mouth, they are tasted more thoroughly than solid tablets or capsules. This means that an effective coating is necessary to mask the unpleasant taste inherent to most APIs, as well as to create a good mouth feel and protect the API from being released too early. HMC is an effective option for creating ODGs with the necessary characteristics.

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HMC can also be used for solid tablets. In this case, the HMCcoated particles are blended with further excipients and compressed to form a tablet called a multiple unit pellet system (MUPS). The main reason to select HMC for the constituents of solid tablets is to manipulate the release profile of the API and improve the stability of particularly sensitive APIs. Tablets composed of uncoated constituent particles tend to absorb saliva and can feel unpleasant in the mouth. MUPS tablets created using HMC coated particles avoid these problems and are therefore easier for patients to swallow. Hard gelatin capsules (HGCs) with altered API release profiles can also be created using HMC, without compromising on API stability.

HMC offers significant advantages in comparison to conventional solvent-based pharmaceutical coatings and is frequently both cheaper and faster than traditional approaches. It can be used to coat constituents of traditional solid oral dosage forms such as capsules and tablets, as well as user-friendly forms, enabling the formulation and production of dosage forms with fast and extended release. The technique is now commercially available and ready for utilization by pharmaceutical companies interested in formulating new or existing medicines with specific API release, taste and userfriendly characteristics.

COATINGS & CAPSULES

Made in Wales Penn Pharma’s new manufacturing facility in South Wales has allowed the company to boost its capacity for new and existing customers Penn Pharma’s £3 million largescale commercial manufacturing capabilities at its site in South Wales is now operational.

The new manufacturing suite includes granulation, tableting and coating capability and allows Penn Pharma to increase capacity for both current and future clients and improve its ability to service the growing market need for large-scale commercial outsourcing solutions.

Over 0.5 billion doses of capacity are now available on site ranging from 1kg to 300kg scale for non-potent and 1kg to 120kg scale for potent molecules. Penn says it can provide scientific support for customers looking for outsourced coatings expertise. It can take a product from small-scale development through to commercial scale.

Clinical manufacture for Phase I to Phase IIa products and larger scale development batch sizes for Phase IIa/b and Phase III products can be delivered for both highly potent and non-potent products.

With its experience in tablet coating for aesthetic purposes Penn can provide smooth homogenous aqueous film coated tablets or multi-particulates. It also offers functional coating for tablets and multi-particulates and has also manufactured multi-particulate products with both delayed and sustained release profiles.

“

Penn says it can provide scientific support for customers looking for outsourced coatings expertise. It can take a product from small-scale development through to commercial scale.

”

be flexible Bring efficiency and flexibility to your tablet coating production with Thomas Flex® line of Accela-Cota® technology tablet coaters with exchangeable drums.

The new contained manufacturing facility gives Penn the capability to film coat molecules classed as being highly potent with an Occupational Exposure Limit (OEL) down to 0.01μg/m3. The new facility uses contained processing to minimise the need for PPE (personal protective equipment) for routine operation and Penn says it has adopted a clear design-for-manufacture approach, so there will be reproducibility from development scale (1kg) to commercial scale (120kg) offering true speed to market.

Penn Pharma chief operating officer, Mark Dean-Netscher commented: “We continue to grow and invest in new technology and our people.

The decision to invest in additional capacity ensures we are able to offer our clients leading-edge technology across all manufacturing areas, continuously improve our service offering and exceed our clients’ expectations by offering the best possible service.”

WORLD’S MOST ADVANCED TABLET COATING SYSTEMS & TABLET PRESS TOOLING THOMAS ENGINEERING INC. 575 West Central Rd. Hoffman Estates, IL, 60192 USA sales@thomaseng.com

THOMAS ENGINEERING INC. EUROPE KORTE LOZANASTRAAT 28 2018 ANTWERPEN, BELGIUM sales@thomaseng.com

WWW.THOMASENG.COM

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CLINICAL TRIALS Time trials Cutting clinical trial start-up time through innovative randomisation and trial supply management services,

By Xavier Flinois, president, Parexel Informatics

B

iopharmaceutical companies share a common goal - make the drug development process more efficient without compromising patient safety or data quality. The operative word here is ‘efficient’ particularly in the early stages of a clinical trial when companies are challenged to conduct a range of crucial activities simultaneously.

It’s a delicate period, and yet one of the few where drug developers have an opportunity to save time and resources and increase the likelihood of a successful trial from the beginning.

Every day that a treatment is delayed from reaching the market means potential financial losses amounting to millions of pounds.

With such a small percentage of drugs receiving approval from regulatory agencies, the aim is to clear roadblocks and complete trials quickly so that drug sponsors can bring new and effective drugs and treatments to patients rapidly.

Building, integrating and maintaining IT systems and infrastructure is a costly and complex undertaking for a biopharmaceutical company.

Further, it is not always efficient to retain operational expertise in-house. Given the complexity of running clinical trials, Contract Research Organisations (CROs) like Parexel are committed to developing innovative technologies and expert services that allow for easier implementation of activities and streamlined operations.

As part of that commitment, Parexel Informatics has released an enhanced version of its ClinPhone RTSM (Randomisation and Trial Supply Management) service.

A key element of the Perceptive MyTrials eClinical platform, it is designed to help clients rapidly design and implement studies by using pre-built, interactive web modules for patient, supply and site activities common to every study. Comprised of hundreds of highly configurable and prevalidated components, the service provides leading RTSM functionality to users through easyto-use and intuitive web interfaces.

Understanding that time to market is critical, biopharmaceutical companies have been looking to their strategic partners to develop progressive technologies that help simplify drug trials from start to finish. Drawing on the experience from working on thousands of studies, Parexel Informatics has identified ways to standardise common RTSM functionality for patient screening, medication re-supply and other fundamental study activities while maintaining the flexibility to easily adapt to study-specific needs. With these capabilities in hand, pharmaceutical companies can streamline trial management activities, cutting weeks off of study start-up time and getting trials off the ground quicker than ever before.

The need to simplify drug development is ever present in today’s marketplace. Part of that pursuit is the trend toward greater standardisation and a configurationdriven approach to RTSM system development. In the past, clients required a more custom approach with a high degree of variability from study to study; however, as the industry has matured, clients are approaching RTSM design in a more consistent and standardised way, which simplifies and accelerates development.

Until now, providing a service that could generate real improvements in clinical trial efficiency and speed, while ensuring patient safety and study integrity, proved challenging.

The problem came not just from the costs of pushing a drug through trials, but because of the time limit placed on patents, the pressure of weak drug pipelines and increasing market competition.

Today, however, by helping pharmaceutical companies simplify the clinical trial process through innovative technology services, biopharmaceutical research organisations can significantly impact the economics of current drug development. More than that, by increasing speed to market, they can help sponsors bring important treatments to patients in need.

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“

Money money money: Every day that a treatment is delayed from reaching the market means potential financial losses, says Xavier Flinois, president, Parexel Informatics.

”

CLINICAL TRIALS

It has been at least 25 years since technology first began to play a role in clinical research. Nowadays, technology solutions are available for almost every discreet process involved in the performance of clinical research – from subject recruitment and reimbursement to site training, from site-based data collection to electronic subject diaries, from site monitoring to drug supply management. To many in the clinical life sciences, however, technology is seen at best as a costly necessity. Why is this?

Many clinical research professionals believe that clinical research is a special case, where regulatory requirements drive the need for unique, complex and expensive systems requiring extensive validation. Also, technology tools in clinical research must be robust (capable of supporting many users) and stable (so that it always works). Indeed, technology used in clinical research is not particularly unique in this regard. For example, in the financial industry huge amounts of rapidly changing data must be available securely in real time, with regular data transfers to other applications or systems.

Other industries such also have similar requirements, for example in human resources in large organisations – personal details of employees must be held securely and updated regularly, with perhaps data transfers to the payroll system each month. Such systems must also be secure and validated, and so parallels with clinical research are apparent. Therefore, the environment for deployment of technology in clinical research is perhaps not so unique.

Critical thinking Silvio Severini, managing director, Techorizon, looks at technology in clinical research and asks if it’s time way a new way of thinking Some may also hold the view that validation of life sciences technology is detailed and costly, leading to acceptance of higher prices (and less innovation) in the industry.

When it comes to validation, however, there are two schools of thought. In the first, the validation process is undertaken solely by validation experts in order to ensure that the system meets the regulatory requirements, using what amounts almost to a checklist approach.

Those who support the alternative school of thought believe that validation should be viewed as an opportunity to pair validation specialists with technology experts to not only check that the application is ‘valid’ in relation to the regulatory requirements, but also that the technology is the best available to meet the needs of the individual users and the greater goals of the customer (i.e. the quality is high). The first approach to validation encourages an environment in which technology is validated but lags behind the stateof the-art. The second approach not only ensures validation in the strictest sense, but also promotes new approaches to support the work of the client.

It could be argued that the view that clinical life sciences are a ‘special case’ has slowed the adoption of

the latest technology and fostered an environment in which technology companies serving the industry are able to justify high costs for the their products. Whilst the cost for technology typically decreases over time as new knowledge and more powerful systems help to develop more efficiency and greater competition, the opposite seems true in the clinical research industry. When the mobile telecommunications industry first arrived, devices, line rental and calls were all extremely expensive.

The situation is entirely different now, to the extent that the majority of us have access to cheap mobile telecommunications. Technology in the clinical life sciences arrived at approximately the same time as mobile phones. The question could be asked why technology in the life sciences has not also become more affordable in the same period.

Perhaps this reflects the ‘comfort factor’ of selecting a large, well known supplier whose technology may be a few years behind that deployed in other industries and whose costs may be very high.

Perhaps it is a misplaced perception that when it comes to technology, the clinical life science industry is a special case. Whatever the reason, in many cases this situation means that clients are paying more than they need to for yesterday’s

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technology. Ultimately this means that budgets are stretched, less clinical research activity is performed, and perhaps fewer medicines are developed.

Techorizon offers a new approach to the life sciences industry, with senior staff who have experience in not only clinical life sciences technology, but also in technology deployment in other industries with similar requirements. The team also includes several members with operational experience in delivering clinical life science projects. By utilising the latest technology and leveraging our knowledge of best practice in other industries, our clinical life sciences team have developed a new approach where applications based on the latest technology are quickly and easily customised, are fully validated to GAMP 5 standards and compliant with CFR 21 Part 11 and are delivered to the customer at much more affordable budgets than existing tools. The challenge to the market now is to be open to evaluate the new these technology approaches.

“

Also, technology tools in clinical research must be robust (capable of supporting many users) and stable (so that it always works).

”

EXCIPIENTS

P

harmaceutical manufacturers have always been concerned with impurities in drug formulations. The reason is simple: Impurities in pharmaceutical and biopharmaceutical manufacturing materials can reduce the efficacy of active pharmaceutical ingredients (APIs). This is an issue of even greater concern to pharmaceutical manufacturers when they develop and work with new APIs that, while making better treatment options possible, are increasingly prone to stability issues and more sensitive to impurities.

Avantor Performance Materials provides high-purity products to help manufacturers meet the challenges of manufacturing complexity and lack of tolerance for impurities in formulations. Over the years, we’ve brought to market products that are consistent, more advanced and higher in purity – from solvents to sugars, buffering salts, chromatographic media, to denaturants and surfactants.

Among the products we’ve offered to the pharmaceutical industry are several types of polysorbate excipients. These materials often are used by formulators in parenteral dosage applications.

They also can be used in solid and liquid dosage form pharmaceutical and biopharmaceutical products.

Composed of fatty acid esters of polyoxyethylene sorbitan, polysorbates are surfactants

The perfect formula Impurities in drug formulations can of course affect efficacy and are a key element which needs to be addressed during manufacture. Avantor offers products to help manufacturers meet these challenges which are amphiphilic and nonionic. The surface activity of polysorbates serves to prevent surface adsorption and to stabilise proteins, by reducing the alteration or aggregation of proteins during manufacturing, distribution and storage. The largest fatty acid component dictates the general type of polysorbate – for example, polysorbate 20 is based on lauric acid - a saturated straight chain hydrocarbon - while polysorbate 80 is based on oleic acid - an unsaturated double bondcontaining hydrocarbon. These structures provide appropriate hydrophilic-lipophilic balance (HLB) numbers and low critical micelle concentration (CMC) values, the factors responsible for their common use in drug formulations.

Since surface active impurities can impact the CMC values, it is critical to control such impurities to maintain effectiveness of polysorbates.

When formulated with poorly soluble drugs, polysorbates provide improvements in solubilisation, and emulsions with polysorbates

are widely recognised among formulators for enhanced stability and improved shelf life of the formulation. (The choice between polysorbate types depends on their specific interaction with APIs or other excipients.)

Avantor’s JT Baker brand Polysorbate 20 and Polysorbate 80 products have been used to address stability and API effectiveness issues for several years. Formulators of biopharmaceuticals are becoming increasingly concerned with further reducing levels of endotoxins, peroxides and other impurities in excipient materials. In response to these concerns, we have introduced new versions of these polysorbate products which offer higher purity levels.

The Super Refined versions of Polysorbate 20 and Polysorbate 80 are created via a proprietary flash chromatographic process.

The process serves to reduce polar and oxidative impurities (such as peroxides and aldehydes) down to levels not previously achieved

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with traditionally produced polysorbates. The decreased level of impurities helps maintain API integrity and stability in formulations like parenteral drugs involving monoclonal antibodies or recombinant proteins (such as certain cancer drugs), and other formulations in suspension or emulsion dosage form.

As manufacturers look more closely at the issue of impurities in their formulations, they are demanding that suppliers match their own emphasis on purity and quality of materials through rigorous quality assurance. Customers increasingly are choosing suppliers that can offer features such as cGMP manufacturing and subdivision capabilities, FDA-inspected and ISO-certified facilities, and rigorous multi-compendial requirements.

Increasingly, customers are looking to work with companies that see themselves more as partners than suppliers. We make it possible for customers to match the right level of purity to their specific API needs. It’s an example of the type of collaboration between manufacturers and suppliers that will be needed to develop the excipient technologies necessary to support more effective drug therapies in the future.

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TABLET PRESS SUPPLIERS

CHEMICAL REACTION It’s important to keep on top of the latest services, companies and individuals. EPM’s Chemical Reaction highlights a technology or business we think would be worth your while keeping in the mix...

Looking good When it comes to x-ray inspection, Metrix NDT says you need look no further than its new service

EPM: Who are you and what do you do?

How can you benefit the pharmaceutical sector?

OM: Metrix NDT is a new UKbased ‘one stop shop’ for x-ray inspection; supplying high quality x-ray generators, tubes, and digital detectors, as well as complete turnkey systems, accessories, training and advice.

Safety and security requirements are paramount for the production of pharmaceutical products.

Detection of contaminants in solids, liquid or cream using x-ray can ensure product safety and security, protecting customers and brand image.

The team at Metrix NDT have over 20 years’ experience in the fields of x-ray inspection, instrumentation and industrial inspection and work closely with customers to understand their particular inspection needs.

We then propose appropriate and cost-effective solutions.

We can supply cost-effective integrated x-ray camera packages, bringing together matched generator and detector sets, which OEM customers can integrate into their own system designs, reducing R&D time and costs.

What have you focussed on recently?

Since its formation in early 2014 Metrix NTD has supplied equipment for inline / online inspection systems for quality control and research facilities. We have also started to look at the development of the next generation of advanced x-ray based NDT equipment.

What is your latest service / innovation?

Metrix NDT has recently signed an agreement with Detection Technology, Finland, to supply a range of high performance detectors.

Q & A

X-ray inspection can detect a wide range of contaminants including non-ferrous metals in foil, stainless steel, powders, bone, glass, wood, PVC, plastics, stone, ceramic, cement and rubber.

Foil and metallised film used in pharmaceutical packaging make contamination difficult to detect using conventional metal detection techniques. X-ray systems can scan foil blister packs and tablet/capsule containers with foil safety seals.

X-ray can also be used to monitor fill control to ensure the correct dose is supplied to the customer.

In addition, x-ray can be used for final inspection, eliminating the need for gravimetric or volumetric checking, to confirm pack integrity and completeness.

The team at Metrix NDT are experienced in the needs of the pharmaceutical industry and can supply x-ray components, systems and advice at cost effective prices.

Future plans?

We are working closely with customers and manufacturers to develop and offer new products which meet customers’ needs.

“

Safety and security requirements are paramount for the production of pharmaceutical products.

Detection of contaminants in solids, liquid or cream using x-ray can ensure product safety and security, protecting customers and brand image.

”

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FOLLOW THE LEADER. Discover why we’re the global leader in tooling manufacturing.

Contact Natoli to experience our unmatched service and exceptional quality.

Natoli Engineering Company, Inc. • natoli.com • info@natoli.com • +1 636.926.8900 • 28 Research Park Circle, St. Charles, MO 63304 USA EPM 44