EPM March/April 2016

A DETAILED ACCOUNT NATOLI LOOKS AT FORMULATION DEVELOPMENT PLUS SPOTLIGHT ON INNOVATION THE CHALLENGES FOR PHARMA

MARCH/APRIL 2016

MEDIAMORPHOSIS.it

More than hand made.

MADE IN IMA

We could explain that everything we create has a unique tone.

We could tell you that we use all our skills in every single detail, or that each project is tuned to your needs.

But maybe all you need to know is that the technology you use is made by IMA. Visit us at Pharmintech 2016 April 13-15, 2016Â Bologna, Italy Hall 19 -Â Stand D27-E27

www.ima.it

Powtech 2016 April 19-21, 2016 Nuernberg, Germany Hall 3A - Stand 3A-308

Interphex 2016 April 26-28, 2016 New York, USA Booth # 2545

Contents March/April 2016 | Volume 16 Issue 2

Regulars 5

6 Features 23

COMMENT

MAKING YOUR MARK

6

What challenges face the pharma sector? Rotech, PCI, Patheon & Lime Associates speak up

NEWS ANALYSIS

10 OPINION Counterfeit goods under the spotlight

34

12

MY GENERATION Catalent looks at the the new generation of antibody drug conjugates

16

37

COVER STORY

FIVE THINGS ABOUT...

Natoli explains why it’s all in the detail

Nemera’s new pump technology

39

50

FIXED POSITION

CHEMICAL REACTION

Recipharm explains how CDMOs can help optimise time-to-market

Featuring Amrita Banerjee, University of California

41 SUPPLY AND DEMAND

48

Quotient Clinical discusses reformulation drug development

43 GROWTH CHART Johnson Matthey’s recently expanded Cambridge facility showcased

45 CONTROLLING FACTS Wickham Laboratories explains environmental best practice

47 CHECK POINT Spectroscopy expertise from Cobalt Light Systems and Thermo Fisher Scientific

head office Carlton House, Sandpiper Way, Chester Business Park, Chester, CH4 9QE. Tel. +44 (0)1244 680222 Fax. +44 (0)1244 671074 Web: www.epmmagazine.com

editorial group editor lu rahman, lu.rahman@rapidnews.com associate editor dave gray david.g@rapidnews.com editorial assistant emily hughes, emily.hughes@rapidnews.com publishers mark blezard, duncan wood

production art robert wood

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

subscriptions subscriptions@rapidnews.com qualifying readers Europe - Free, ROW - £115 outside qualifying criteria UK - £80, ROW - £115 please subscribe online at www.epmmagazine.com

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

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

Volume 16 Issue 2 © March/April 2016 While every attempt has been made to ensure that the information contained within European Pharmaceutical Manufacturer is accurate, the publisher accepts no liability for information published in error, or for views expressed.

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

BPA Worldwide Membership ISSN No - 2052-4811

WWW.EPMMAGAZINE.COM

from the editor

Personal service So the pharma landscape continues to evolve. It’s interesting to witness the changes taking place, many of them using technology to improve the way medicine and drugs are administered, monitored and prescribed.

We can’t escape the personal at the moment.

Personalised medicine has attracted much attention over the last year with cost savings and improved patient outcomes being put forward as examples of the benefits it can offer. Recent reports have highlighted its potential role in the treatment of cancer as researchers have found that the genetic makeup of tumours means we could soon see treatment tailormade for individual patients.

While there is still much work to be done in this field its benefits could be far-reaching. Oxford Economics recently carried out research into the way that the healthcare and pharmaceutical sectors across Europe and North America were facilitating the movement of personalised medicine. The results were interesting, with two-thirds of those surveyed saying it is having a measurable effect on patient outcomes.

While we still need to make headway in certain areas –data sharing, building IT capabilities and finetuning business models – the scope for personalised medicine and the positive effects it can have on all our health is immense.

This new area of medicine is also having an effect on the drug delivery market. As personalised medicine becomes an increasingly popular treatment at point of care, it is likely that drug delivery devices will need to be manufactured nearby. Ricky Wildman, University

of Nottingham, offers an insight into the evolving role that 3D printing will play on page 8. It’s an exciting development and one which throws up opportunities for the 3D printing and drug delivery sectors.

Digital health, we know, has a key role to playing the pharmaceutical sector and here too the idea of personalised treatment is becoming a major topic, improving healthcare for patient, professional as well as the pharmaceutical supply chain. Not only are devices becoming increasingly sophisticated and improving user experience but are helping place significant emphasis on adherence. The development of digital medicines has seen this topic take centre stage as has digitally engaging the patient via apps and wearables. With the ultimate goal of preventing disease and monitoring treatment and medication, the personal digital experience is really starting to gain momentum.

It’s great to witness the concept of the personal taking on public awareness. The idea that we have to take responsibility for our own health and well-being is nothing new. But the opportunity for treatment, devices and care to be tailor-made to our own needs and genetic make-up is highly interesting. The patient and the patient’s role in treatment is becoming a central theme.

Personal medicine, devices and healthcare are big news for everyone involved in the process. The future looks very exciting indeed.

Lu Rahman

WWW.EPMMAGAZINE.COM

5

NEWS ANALYSIS

Is a ceramic pill from Stoke the answer to prescription drug abuse?

Gemma Budd, healthcare business manager, Lucideon, explains how the company’s development of a ceramic pill is helping tackle prescription drug abuse

6

WWW.EPMMAGAZINE.COM

NEWS ANALYSIS

P

rescription drug abuse is a global epidemic; in the USA, more people die from this than from abusing illegal drugs such as heroin.

As such, the FDA is leading a drive to make addictive drugs ‘abusedeterrent’, starting with the opioid family of substances eg, oxycodone and morphine; a guidance document was released to this effect last year.

is streamlined. The ability to offer both controlled release and abuse deterrence properties is partly due to the natural benefits of inorganic materials. Lucideon optimises these benefits through some clever materials science and processing to give the key features, including: They don’t melt until you reach in excess of 1000 degrees Celsius (meaning any attempt to heat the carrier to expose the drug will just result in destruction of the drug; Typical abuse mechanisms often revolve around crushing the pills down They don’t dissolve easily (meaning any intent to inject the product until they become powders. This provides easier access to the drug and would mean injecting hard particles into the veins – which is nigh on sometimes even direct access depending on the formulation design. impossible anyway; Abusers may then try to extract the drug from the powder (and even the Crushing these materials is very difficult – reducing the particle size pill in its uncrushed form) by trying to dissolve the powder/pill in solvents of these materials in a reasonable time period requires industrial such as alcohol, vinegar or orange juice. Melting the powder is another equipment. method that an abuser may use, to render it in a Furthermore, it is virtually impossible to crush liquid state that can then be injected. All of these these particles down to less than 10nm (whereby methods, including snorting of the powder, are used the pores become non-existent and the drug by the abuser to get the addictive euphoric ‘high’ becomes readily exposed) even with industrial Typical abuse as quickly and effectively as they can. Not only is equipment, so even with finely crushed powders this dangerous for the patient’s health, but society mechanisms often the formulation still retains significant control over too suffers from the crime and unemployment that revolve around crushing the drug release. In fact, Lucideon purposely drug abuse fuels. Drug abuse is a huge cost burden formulates the iCRT material as a powder – this the pills down until on national governments and one that is increasing. makes it easy for its pharmaceutical partners to they become powders. process the materials as usual into a final dosage This provides easier Technologies to combat this abuse are in form eg, tablet. development. Typically, these use polymer excipients access to the drug and and/or a complicated tablet design. The resulting Through extensive internal R&D and years sometimes even direct tablets are often big and hard and therefore difficult access depending on the of experience of these materials in industry, to swallow. While this makes them more difficult to Lucideon has identified a ‘sweet spot’ in the formulation design. abuse, it also makes them more difficult for the nonprocess design space that delivers powders that abuser to take – this is a challenge for many abuse give the desired drug release rate, yet result in a deterrent formulations. microstructure and surface functionality that does not encourage or allow for forced extraction Abuse deterrent technologies are often also an ‘add-on’ to a formulation, when exposed to organic solvents like alcohol. There is a very complex ie, they have a controlled release technology and a separate abuse interaction between the variables of the synthetic process, as well as deterrent technology. This adds time and cost both to the development between the drug compound and the surface of the pores, and if you of the drug and to its manufacture. venture outside a certain range of processing variables, the resistance to solvent extraction disappears along with half of the benefits. It is Lucideon’s expertise in controlling these materials that accelerates the Lucideon’s iCRT-deter technology offers a new optimisation of the technology, such that the technology can be tailored approach. and exploited quickly for multiple different drugs.

Lucideon has revitalised an age-old inorganic synthesis process to control the microstructure of these inorganic materials such that they Lucideon is already working with pharmaceutical companies to are highly porous – with pore sizes of less than 10nm and an extremely commercialise this technology for some opioids and, with the growing high surface area. The drug compound is encapsulated into these pores rate of drug abuse, and there is no doubt that the technology will be using proprietary processing techniques, and how quickly the drug is used in many different product formulations over the next few years – initially across the opioid space but also in drugs for treating ADHD, released over time is controlled by this resulting porosity.

Importantly, the iCRT particles act as both the controlled release depression and schizophrenia – all of which have high abuse potential technology and provide the abuse deterrence properties – this is and are no doubt next on the list for FDA and other regulatory bodies. beneficial for pharma companies and for patients as the formulation

“

”

Pre-melting the tablet contains the drug

Post melting the drug is destroyed but not the carrier

WWW.EPMMAGAZINE.COM

7

NEWS ANALYSIS

Getting personal — the changing role of 3D printing We have read about 3D printed pharmaceuticals but the technology has an increasing role to play in personalised medicine. Professor Ricky Wildman, University of Nottingham explains

A

dditive Manufacturing, also known as 3D printing, is a disruptive technology, that can potentially revolutionise the way we manufacture goods. It has become widely recognised due the expiration of a number of key patents that has allowed small manufacturers to explore the technology for home use. This use most often focuses on the creative and democratic aspects of 3D printing. However, it has the most utility when being used for the fabrication of objects that require complexity, multiple & graded materials or lend themselves to a distributed manufacturing model.

Most importantly, the near zero marginal cost of changing a design, means that the technology is particularly suitable for personalisation. These latter advantages also apply strongly to biomedical and pharmaceutical applications.

For both the need to personalise is becoming a driving force – biomedical devices are often required to have a personalised fit to be effective and the pharmaceutical world is moving beyond single blockbuster drugs and towards treatments that match the growing recognition that is the genotype that provides the key to treatment.

However, the manufacturing model developed to service large numbers of single dosage drugs – tabletting, is not best placed to offer personalisation. One possible route to achieving this ‘bespoke’ manufacturing is 3D printing. This is not without precedent – Aprecia has just received FDA approval for a 3D printed tablet. 3D printing of tablets is not 8

without challenges – it requires an intimate understanding of process and design, exquisite control over material process and production and in line characterisation for quality assurance. However, 3D printing offers significant benefits to companies and patients alike. We are looking at the production of personalised tablets, within which have been embodied one or more drugs with release rates that are tuned to the need of the patient and that can be placed near to point of care (in the local pharmacy for example). In the future these can be combined with sensors and diagnostics that provide clinical carers with real time information on the treatment.

To achieve this requires a multidisciplinary effort. At Nottingham, our team includes chemists and chemical engineers, pharmacists and physicists all working together, with support from the UK funding agency EPSRC and key movers in the industry such as GSK and Astra-Zeneca, to solve key challenges to realise mini desktop factories that can bring personalised treatments to the patient. 3D printed polypills and controlled release tablets are already available in the lab and have shown to be effective – in the future, new materials, new formulations and new processes offer the prospect of a new way of delivering drugs that will be more tailored, more precise and most importantly, more effective than the tablet 1.0!

WWW.EPMMAGAZINE.COM

Increasing your productivity Lowering your costs I Holland, developing technically advanced products to improve quality and output.

Visit www.tablettingscience.com or telephone +44 (0)115 972 6153

OPINION

The write stuff Perigord explains the importance of compliant, validated artwork and labelling solutions in the pharmaceutical sector

T

he number of pharmaceutical product recalls are growing. Some estimates show that over 50% of recalls are related to pharmaceutical packaging artwork and labelling1.

How many times have we heard these statistics over the last 20 years? And yet nothing changes.

The bottom line is that if there is an error with pharmaceutical artwork, the patient can die.

The absence of regulatory requirements within the pharmaceutical industry regarding the production of artwork is indicative of the lack of focus often given to this process.

There is increased pressure to improve operational performances and reduce the level of human error. If we make it easy for someone to make a mistake, they will. We need to make it easy to get it right first time.

To do this we have to take a realistic look at the challenges faced by the pharmaceutical industry over the next five to ten years which will impact the artwork process and determine what robust innovative measures we should take to ensure these recall figures don’t spiral out of control.

Attitudes towards artwork management within the supply chain need to change. There should be a focus on quality driven systems to enable continuous technological developments facilitate the automation and standardisation required to prevent mistakes.

Industry analysis Firstly we need to look at some of the key aspects of the pharmaceutical industry that are driving change.

1. Mergers & acquisitions in the healthcare sector set a new record in 2015 of $724 billion2.

As a result, the agile and secure management of digital artwork assets has become a key strategic focus.

10

2. Serialisation will result in a combination of more artwork content and stricter directives governing readability. This combined with reduced print space will drive an unprecedented demand for regulated artwork services and management systems over the next five years.

3. Product proliferation leads to significantly increased frequency of artworking events and far greater complexities in managing the artworking processes with many companies having reached or exceeded their capability to manage the process internally.

4. As a result of the patent cliff, a single innovative pharmaceutical product which has lost patent protection is being replaced with new generic products globally, leading to an exponential growth in demand for outsourced artwork solutions.

What needs to be done?

Why do we accept high levels of inaccuracy when we can standardise how artwork is created and automate how it’s managed?

Pharmaceutical companies need to understand how their present artwork processes should change to facilitate these future drivers. To navigate accurately through these changes a proactive and systematic approach to artwork is crucial. Companies have to ask themselves if the artwork process is clearly defined, optimised and quality driven.

Managing artwork for the pharmaceutical industry is a very specialised, niche service which can only be properly controlled by a GMP compliant partner. If using a vendor, it is critical to develop a partnership to ensure all aspects of the artwork supply chain are controlled and agile to meet the challenges of the industry.

The two fundamental areas which need to be addressed are the physical production of the

WWW.EPMMAGAZINE.COM

artwork and the management of the artwork process.

Artwork production Perigord recommends a one touch process in building compliant artwork which increases efficiency, reduces costs and minimises risk through fewer stages, thus eliminating the historical prepress stage. Effectively this means that artwork is built to high quality standards (and print ready) and the layer structure and font integrity is maintained throughout the approval cycle. Perigord ensures this process sits in a robust quality management system with a change management procedure that facilitates the efficiencies to be gained through the introduction of automated technology.

Artwork management systems The most obvious way to remove the dangers of human error is to automate. Managing the amount of stakeholders and the input they have in this complex process by email is inconsistent with every company’s objective of getting product to market on time and right first time. This needs to be replaced by a highly configurable system that can be easily adapted to align with a customer’s current and future processes, giving the flexibility of a systematic approach to managing products and product related information.

In summary, reducing the number of recalls in the pharmaceutical industry requires better regulation, improved operational procedures and a change of attitude towards artwork production and management. The challenges that lie ahead have been identified, all we need now is to face them head on, in a controlled GMP fashion.

1 http://www.xtalks.com/Pharmaceutical-Packaging-Management. ashx

2 http://news.yahoo.com/global-mergers-acquisitions-volume-hitsrecord-2015-163303085.html

A Trusted Partner Expertise and Care in Clinical Development

PCI Clinical Trial Services Come experience what makes PCI different. We support clients as a true partner and extension of their business, offering expertise and experience guiding products to successful outcomes. With over 50 years experience, an integrated supply network to meet the needs of global studies, and an exemplary regulatory profile, we offer adaptable and innovative services to offer our clients real solutions enabling speed-to-market for their lifesaving medicines.

Expertise

Experience

Partnership

Clinical Services Manufacturing | Packaging & Labeling | Global Storage & Distribution

Commercial Services Manufacturing | Packaging | Serialization

www.pciservices.com Š Copyright 2015 Packaging Coordinators, Inc. All Rights Reserved

OPINION

The read deal Farzad Henareh, Stericycle ExpertSolutions, discusses ‘fake Europe’

and the impact of counterfeit pharmaceutical products

C

ounterfeit or knock-off drugs - whatever term we want to use, intellectual property violations in the pharmaceutical sector are growing and with every counterfeit product that reaches the market, the risk of harm, both to people and to businesses grows.

In 2013 the World Health Organisation (WHO) launched a global surveillance and monitoring system to encourage Member States to report incidents relating to substandard, spurious, falsely labelled, falsified and counterfeit (SSFFC) medical products. The aim was to help develop a more accurate and validated assessment of the scope, scale and harm caused by this issue. As of January this year, over 920 medical products had been reported, representing all main therapeutic categories and representing both innovator and generic medicines.

Farzad Henareh, Stericycle ExpertSolutions, says that every counterfeit product that reaches the market, risks harm, both to people and business

Despite more effort being made to combat counterfeiting of products across the board, the acknowledged links to organised crime, and the harm it causes to brands and consumers, it is proving difficult to police and control, and the criminals behind it continue to make vast returns.

In 2009, 20 million pills, bottles and sachets of counterfeit and illegal medicines were seized in a five-month operation coordinated by the International Criminal Police Organization (Interpol) across China and seven of its South-East Asian neighbours; this resulted in over 30 arrests and the closure of 100 retail outlets. In Europe in 2009 customs officials seized 34 million counterfeit pills in just two months.

12

“

Along with the electrical goods sector, pharmaceuticals suffers one of the biggest international counterfeiting problems

Impact significant

”

While these figures are shocking, it is the impact on businesses and consumers in their everyday lives that has to be prioritised. This is not always easy because the criminals behind the counterfeit products have gone to great lengths to evade detection and to successfully introduce their products into the market. The WHO warns that some fake medicines are almost visually identical to the genuine product. They recommend the following steps: examining the packaging for condition, spelling mistakes orgrammatical errors; checking the manufacturing and expiry dates and ensuring any details on the outer packaging match the dates shown on the inner packaging; ensuring the medicine looks correct, is not discoloured, degraded or has an unusual smell; and talking to a pharmacist or doctor as soon as possible if you suspect it is not working properly or you have suffered an adverse reaction.

WWW.EPMMAGAZINE.COM

Visit us at Pharmintech | Italy | Pad./Pav. 22 Stand C47 Powtech | Germany | Hall 3, Booth #3-556 Interphex | USA | Booth #2263

How efficient is your quality control?

Our tablet hardness and disintegration testers allow you to save time & money by maximizing the efficiency of your quality control process.

Innovative technology paired with proven mechanics makes operation simple, reduces processing time, and provides precision results you can rely on. www.pharmatron.com

Dr. Schleuniger ÂŽ Pharmatron is a brand of

Quality matters.

155.004.025-PHT-EPM-Pharmintech2016-220x156-lay..indd 1

PT16_220x156_INT_EN_EPM_C4_PHARMA.indd 1

09.03.16 13:24

WWW.EPMMAGAZINE.COM

26.02.16 14:26 13

OPINION Affects genuine goods

Fake condoms

While there are health and safety risks to consumers there are other issues for pharmaceutical manufacturers and retailers to deal with. Counterfeit products can reduce demand for genuine goods which lowers revenues, but in order to protect their brand reputation, companies often have to get involved in product recalls, investigations and legal action which is costly in terms of both time and money.

Away from medicines, a case arose in Australia where fake Durex branded condoms, which may have had serious flaws in the latex, were recalled by the Australian Competition and Consumer Commission after they were sold at a discount on Groupon Australia. They had to inform consumers that they may be at risk of unwanted pregnancy or sexually transmitted disease from using the condoms.

Some well-known drug recall cases have hit the headlines in recent years. In 2007, for example, an emergency recall was issued by the Medicines and Healthcare products Regulatory Agency (MHRA).

This related to drugs that included Casodex, the prostate cancer medicine; a drug for heart complaints called Plavix, and another, Zyprexa, used to control the symptoms of schizophrenia. In every case the drugs were counterfeit. The MHRA successfully seized 40,000 packs before they were distributed to pharmacies but 25,000 reached chemists across the UK and were dispensed to patients - a further 7,000 were recovered following a recall.

“

Away from medicines, in Australia fake Durex branded condoms, which may have had serious flaws in the latex, were recalled after they were sold at a discount on Groupon Australia. They had to inform consumers that they may be at risk of unwanted pregnancy or sexually transmitted disease

More recently in 2013, a recall was issued for pain relief and type 2 diabetes medicines. Whilst there was no risk to patients, the recall was a precautionary measure following concerns about the manufacturing process during an inspection of the manufacturing site in India. They included, poor record keeping relating to the manufacture and testing of the medicines made at the site and inadequate validation and production controls for medicines.

14

”

Along with the electrical goods sector, pharmaceuticals suffers one of the biggest international counterfeiting problems and a number of different methods are being used to tackle the issue. One of these is serialisation. Regulations typically require the product number, batch number, serial number and expiry date to be included in the complete serialised number. This registered number is applied on the units to be scanned by retailers at the point of sale to verify authenticity. It cannot be scanned twice. Serialisation makes tracing and tracking recalled products much simpler. Numbers that correlate to an item’s serial number are also placed on the cartons, pallets and containers, which enables manufacturers to quickly locate products in the event of a recall. A 3D barcode system is also being developed currently which would take advantage of the injection moulding by which many tablets are produced.

From the manufacturer’s viewpoint, if they are faced with a situation in which their products have been counterfeited, it might be advisable to consider a recall in order to take control of the situation. This will allow them to protect their brand and the safety of their valued customers, and to err on the side of caution when it comes to ensuring they comply with industry regulations. It’s worth bearing in mind too, that a good recall experience will enhance customer loyalty, particularly if they understand that the company is working with their best interests at heart.

WWW.EPMMAGAZINE.COM

s low F n

ere h W

OPHTHAL

tio va o n

In

M

IC EAR, NOS

ROAT TH

E,

Single-Use Pumps

PULMONA R Y

for

PARENTER

Biopharma Processes

AL

Quattroflow™ quaternary diaphragm pumps

deliver high-value solutions for your applications.

Depending on your requirements, Multiple-Use and Single-Use models are available.

DERMAL/ T RA NS

D ER

MAL

• Ideal for critical processes such as filtration (TFF), chromatography, and many more • Single-Use Pumps offer faster speed to market at lower costs • No risk of product contamination

• No identifiable particle release (verified by thirdparty test) • Self-priming and risk-free dry running • Ensures product safety, efficiency and reliability • High turn-down ratio

• Seal-less technology with constant, low-pulsing flow

For more information, please go to:

psgpumps.com/epm416q

See Us at INTERPHEX Booth 2253

Nemera provides solutions for the pharmaceutical industry, including standard innovative products, development of custom devices and contract manufacturing.

ophthalmic

pulmonary

dermal/ transdermal

parenteral

nasal/ buccal/ auricular

ALMATEC Maschinenbau GmbH Carl-Friedrich-Gauß-Str. 5 47475 Kamp-Lintfort, Germany P: +49/2842/961-0 info@almatec.de quattroflow.com

www.nemera.net information@nemera.net Phone: +33 (0)4 74 94 06 54

WWW.EPMMAGAZINE.COM 16-QTRO-0141 Quattroflow - European Pharmaceutical Manufacturer - Mar Apr 2016.indd 1

15 2/29/16 5:05 PM

COVER STORY

It’s all in the detail Robert Sedlock, Natoli Engineering Company, explains how detailed formulation development helps avoid production problems

C

ompression tooling and tablet press manufacturers are faced with ongoing challenges in the tablet manufacturing environments. Providing support in all aspects of the tablet compression process should be expected from your tooling and tablet press partner. These services should include: press operator training, maintenance/calibration services, quick delivery of replacement parts, tooling, tablet design, and powder formulation support.

If changes to compression conditions do not address tablet quality problems, then changes to the formulation may be needed to remediate the problems. These changes can be time-consuming and costly; in addition scale-up and post-approval change (SUPAC) guidelines must be followed. It is important to perform compaction studies during the formulation development process, before final regulatory submission.

This ensures formulation performance and will minimise the risk of postapproval changes. The following examples of formulation performance evaluation were performed at the Natoli Institute for Industrial Pharmacy Research and Development at the Arnold and Marie Schwartz College of Pharmacy and Health Sciences on the Brooklyn New York campus of Long Island University.

Discussion Developing a robust tablet formulation that can be scaled into product manufacturing without any issues can be a difficult challenge.

Formulators and research professionals alike are tasked with the development process and must have an understanding of the science involved with powder compaction. Formulators must also maintain proper communication with the scale up or manufacturing group, which can accelerate the time to achieve a marketed product with a higher return on investment.

Single station tablet presses Single station tablet presses offer many advantages during early development. These machines require a very limited amount of material to characterise a potential formulation. The die filling process can be performed manually, allowing the use of only a few grammes of formulation. Characterising just the active pharmaceutical ingredient (API) can also be performed on these machines allowing the scientist to select the appropriate excipients using the results of the compacted API to guide their selection.

Figure 1 describes a tabletability profile performed on the Natoli NPRD10A single station tablet press. This example is of an evaluation of a

Figure 1

16

high drug load directly compressible APAP (acetaminophen) formulation (DB) versus a wet granulated APAP formulation (WG).

There is an advantage to normalise the compression force for the punch tip face area and utilise compaction pressure instead of analysing the data using the compression force (kN) values. With any new formulation, the compression force required is determined by the material properties and the tablet’s diameter and thickness. Performing a compaction study from 50MPa – 300MPa covers the typical pressure ranges for compressing pharmaceutical tablets of all sizes. Furthermore, by utilising the tablets diameter and thickness, the tablet’s required breaking force is normalised for the tablet geometry. Tablet breaking force values (kilopond or Newton’s) are determined by post compression testing.

The values for breaking force are normalised by the tablet geometry yielding tablet tensile strength. Target tablet tensile strengths in the range of 1 to 2MPa are representative values for a robust tablet that will withstand normal handling and the coating operation.

Figure 2 depicts the tabletability profile performed on the BLP-16 rotary tablet press at 20-RPM turret speed for the dry blend and wet granulated formulations. The BLP-16 rotary tablet press is a 16-station, ‘B’ tool machine that is capable of running at variable turret speeds.

Although there is a cost advantage with directly compressible blends, as the equipment investment costs and process times are much lower, the profile (Figure 2) clearly shows that the wet granulation blend yields stronger tablets than the directly compressible blend throughout the compaction pressure ranges.

It is clear that the profiles shown in Figure 2 illustrate different results as compared with the Natoli RD-10A single station tablet press data shown in Figure 1. This data is representative of what can be expected at the manufacturing level, since the manufacturing machines utilise the rotary press design with upper and lower compression rollers. Due to the rotary press design, the upper and lower punches are moving horizontally across the rollers in addition to moving vertically to compress the powder. Single station tooling can only move vertically for non-eccentric tablet designs in the tablet press. The movement difference changes the dynamics of the compression event and has an impact to the final tablet attributes as shown in Figure 2.

Compaction profiles for the dry blend formulation and wet granulated formulation on both the Natoli NP-RD10A single station and the BLP-16 rotary press are depicted in Figure 3. The wet granulated formulation run on the BLP-16 yields robust tablets above 1MPa tensile strength at a reasonable compaction pressure. In this range the addition of

Figure 2

WWW.EPMMAGAZINE.COM

more compression force yields tablets with higher tensile strength, whereas the dry blend formulation exhibits capping above 100MPa of compaction pressure. It is clear that the wet granulated blend is the choice formulation and that the dry blend will likely fail on a larger scale rotary press.

Many factors can impact the tabletability curve including the powder deformation characteristics, particle size, shape, moisture content and proportion of powder fines. Variation in formulation performance is often traceable to changes in the properties of the API and excipients from batch to batch. It is crucial that your product has a robust tabletability profile as illustrated by profile A in Figure 4. Figure 4 is an illustration of typical compaction profiles for various formulations.

Profile B is an example of where your tablet attributes might be acceptable at the research level or even scale up level due to lower Figure 4 compaction rates but fail at the higher levels of the manufacturing process. Operating too close to the peak of the curve or on the descending side does not give any flexibility to the press operator when issues are found, which is crucial due to the previously described variables. The use of pre compression can improve your tabletability profile as it de-aerates and consolidates the material before the main compression event but it is wise to save this tool as a back up when issues arise at the manufacturing level. Profile C indicates a poor tabletability profile and would not be acceptable tablet attributes. Developing a robust formulation will allow the manufacturing press operators to make press adjustments to solve these issues.

In figure 5 we can conclude that the wet granulated formulation is not strain rate sensitive at dwell times as low as 13 milliseconds. Ultimately the product will be produced on a high speed manufacturing press and the dwell times can be calculated with further studies being performed at full scale. As most research presses are designed with smaller diameter turrets, reaching similar velocities as the manufacturing machines cannot be achieved, so your tooling head profile can be designed to simulate similar dwell times. (For further explanation see EPM November/ December 2015 Pressing Points by Natoli Engineering Company) The methods above are ways to evaluate your potential formulations tabletability and scalability.

With the many challenges in the pharmaceutical manufacturing world today, tooling and press manufacturers are your key partners in the support of delivering a quality product. Tablet manufacturing issues arise from many variables including operator training, maintenance/ calibration of equipment, and the formulation that is compressed.

Conclusion Speed to market is important when developing and delivering a branded or generic medicine to the market. Despite the need to minimise drug product development time, the time invested in ensuring that your product and process are capable of not only clinical supply, but also full market supply has lasting value. It is crucial in the development process to optimise the formulation and evaluate tablet robustness from tabletability and scalability studies. This will help minimise the challenges faced at the manufacturing level and will allow the press operators to make press adjustments if there is a change in suppliers resulting in API or excipients with unexpected variability in their physical properties. Natoli Engineering Company offers hands on training opportunities for formulation development and scale up to the tablet manufacturing process.

Figure 6

Another study that is valuable in the formulation development process is a strain rate study, where the compaction pressure is held constant.

In this case we selected 150MPa since tablets were robust at this level, the turret speed was incrementally increased and tablet attributes were evaluated.

Instead of evaluating tablet tensile strengths at different turret speeds, it is a more scalable approach to normalise for the turret pitch circle diameter, punch head flat diameter and evaluate the tablet tensile strengths as a function of dwell time (the time formulation is under maximum compression force in the die or when the punches are no longer moving vertically). Another important parameter to consider for press scalability is the punch vertical velocity or loading rate and the decompression event.

Figure 3

Figure 5

WWW.EPMMAGAZINE.COM

17

Are you ready for EP compliance?

Thermo ScientificTM TruScanTM analyzers are fully compliant with the revised standards in the European Pharmacopoeia Supplement 8.7, effective April 1, 2016. Unlike other handheld Raman analyzers that require either factory recalibration or frequent field recalibration, TruScan is ready to meet your EP 2.2.48 compliance challenges out of the box.

Worry-free compliance with TruScan

Š 2016 Thermo Fisher Scientific Inc. All rights reserved. All trademarks are the property of Thermo Fisher Scientific and its subsidiaries.

• Get compliant at thermoscientific.com/quality

ADHERENCE

Learning curve Chris Evans, vice president, innovation, West Pharmaceutical Services, guides us through patient education – the missing piece of the adherence puzzle

S

everal biologics coming onto the market offer the potential to make a difference in the lives of patients with incurable-but-controllable conditions such as diabetes and Crohn’s disease. These innovative therapeutics aim to improve patients’ quality of life by not only reducing symptoms, but also offering new independence enabled by at-home treatment.

Joining forces: Chris Evans, reveals how West recently announced a collaboration with Noble to develop validated training solutions for self-injection systems

Many of these new drug formulations are being paired with self-injection systems that may require a little extra training for effective use and, therefore, need innovative approaches to patient education. The typical illustrated instruction sheets can be greatly assisted by ‘lookalike’ training systems that allow patients to practice administering medications before actually doing it with a live product.

West recently announced a collaboration with Noble, a patient onboarding innovator, to develop validated training solutions for self-injection systems. Together, West and Noble will offer multisensory education programmes and technologies for patients using West’s SmartDose Electronic Wearable Injector and other self-injectors. Collaborations like this can positively impact patient safety, medication adherence and satisfaction. Additionally, they can improve data and feedback collection to lend valuable insights regarding potential product refinements.

Such training initiatives are a way drug packaging and delivery system manufacturers can add significant value to their pharmaceutical customers’ drug development cycles.

Custom training systems & feedback to patients An essential element of training for self-injection systems is customising them to offer precise feedback so the patient is assured they’re following the instructions correctly. Delivery system education programs can help ensure patients administer the right dose in the right place with the least amount of discomfort to improve the patient experience and maximize the benefits of both the drug and the delivery system.

Feedback can include sounds and lights that indicate correct use of the trainer. They can also indicate incorrect use in the form of negative feedback, in real time, thus prompting patient or user correction.

Auditory and visual cues are particularly important in this era of global drug procurement, because they cut through language barriers and regional contrasts in healthcare delivery.

Why are these training systems suddenly more important? Patients are self-administering care in their own homes more than ever. Yet, a recent study by Noble analysed by Auburn University indicated that more than 60% of patients self-reported that they didn’t completely read the instructions for their self-injection systems before using them the first time.

If instructions with pictures are worth a thousand words, how many is a copy of the actual drug delivery system worth, especially when it is enabled to show right and wrong in terms of operation? With that in mind, manufacturers of injectable drugs can greatly benefit from offering this level of patient education.

Insight for manufacturers The second element of training systems afforded by the latest technology is data tracking and analysis. Drug delivery systems can be programmed to store or transmit statistics on patient learning – what goes well, what mistakes they make – back to the manufacturer who, in turn, can analyse and make design improvements.

This data is incredibly valuable – even more so when coupled with analysis from human factors studies. West works closely with Insight Product Development to conduct human factors testing and examine the usability of drug delivery systems. Combining feedback from training systems with insights from real-world usage studies leads to the development of self-injectors that are user-friendly and meet patient’s lifestyles needs throughout their treatment journey.

Addressing patient motivation The missing piece in patient education, as the Noble-Auburn study shows, is motivating patients to take the time to complete their training. Well designed training systems can not only offer feedback, but also validate that the patient completed training and demonstrated competency in using the drug delivery system.

To help address barriers to adherence, West collaborated with HealthPrize Technologies to develop a connected health offering that is designed to improve and reward medication adherence with unique technologies in a gamified environment. The offering integrates HealthPrize’s Software-as-a-Service (SaaS) medication adherence and patient engagement platform into injectable drug delivery systems with an app that tracks and rewards patients for taking their medication. This type of rewards-based patient motivation and engagement can be tied into delivery system training regimens as well.

While the technology creating these exciting new patient-education programs might be cutting-edge, the idea behind it is timeless: Enriching patient wellness by improving medication adherence. Drug manufacturers need partners who are constantly innovating to deliver on this over-arching goal that ultimately benefits all the partners involved in drug development and procurement. Creating a digital health ecosystem that accounts for all pieces of the adherence puzzle—from education to ongoing treatment—is the next-generation means to get there. The combination of West’s experience, internal capabilities and external collaborations provides a full-service offering to customers that supports both drug product lifecycles and patient adherence.

WWW.EPMMAGAZINE.COM

19

integration of the drug and device

DRUG DELIVERY

Device development companies need to understand the mechanics of drug dispersion (e.g. aerosol, transdermal, subcutaneous) to identify key device features that may impact drug delivery.

device Performance Describes how the device will interact with the user and how the drug will be readied for delivery.

Drug Performance Requirements that focus on the drug alone typically describe how the molecule and formulation need to be configured such that the drug will have its desired affect once it is interacting with the patient. Those requirements often include pharmokinetics, pharmodyanmics and other pharmacological performance definitions.

It is worth noting that human factors engineering, design research and industrial design (collectively known as humancentered design) all have a significant role in establishing these device requirements.

Drug development companies need to understand the nature of device manufacturing and variation as well as pay close attention to the material selection as it could impact drug delivery and drug performance.

Both groups need to understand the iterative nature of device develop-ment and clinical nature of drug development, so that these critical interfaces can be identified, quantified and stabilized as early as possible in order to generate robust clinical data.

Formal usability studies conducted early in the development process should inform the device design as much as the technical performance studies..

All in the delivery Phillips-Medisize outlines device development for pharmaceutical and biological combo products

A

t this year’s Pharmapack in Paris, Bill Welch, CTO, Phillips-Medisize, presented on Integrated Development and Scale-Up of Combination Products. He talked about drug delivery devices becoming more user-friendly, increasingly designed as “smaller and smarter” humancentered devices.

When developing a combination product, there are many considerations – the critical relationships between device development and the pharmaceutical or biologic, early establishment of regulatory and clinical strategies, understanding ‘user’ needs, determining product requirements, as well as device manufacturing variation. The drug formulation may determine how the drug moves, interacts with and is delivered through the device. Some formulations may be sensitive to molecular shearing and require slow, laminar delivery through the device. Other formulations may have high static charges that attract to plastic, requiring device materials that dissipate static electricity. Some formulations need to be developed with the purpose of the device and sterilisation method in mind. Some substances – especially peptides – are extremely heat labile where protein molecules can break apart, degrade, or get altered into a new form with

20

high impurity profiles that can become toxic if administered. The device can have a significant impact on product performance.

Welch said: “Merging a biologic or pharmaceutical regulatory requirement with device regulatory requirements to sell a product is exceedingly difficult.

Few know how to do it well and that is what creates opportunities for Phillips-Medisize”.

He pointed out that Phillips-Medisize gets involved in biocompatibility issues: “Sometimes we may have to certify biocompatibility, even if it’s not an implant”.

Starting with a development strategy Engaging in efficient combo product development begins with understanding the regulatory and clinical strategies to ensure the device development is well aligned with the pharmaceutical or biologic development and applicable regulatory requirements and is also in-line with the clinical milestones. An integrated regulatory/clinical strategy between the client

WWW.EPMMAGAZINE.COM

To ensure a combination product will perform as intended, the multiple subsystems need to be well defined and understood

and CMO/supplier will de-risk the product in development stage and help scale device development.

In combination products, regulatory submission involves fulfilling biopharma requirements and a scaled version of the device-design history file. The extent of device development documentation can vary. Although there could be multiple modes of action, designating the one with the simplest form of intended use as the PMOA (main therapeutic component in a combination product that zeroes in on the product’s intended use) is the key to submission expediency. Depending on the PMOA and the lead FDA centre, a manufacturer may be required to undergo clinical trials using one or more of the following – investigational device exemption (IDE) for a device, and investigational new drug (IND) or new drug application (NDA) for a drug. Determining the submission pathway is essential to understanding the clinical trial strategy. Consequently, that knowledge will be important in identifying the device development schedule and level of product robustness necessary to be met before submission can occur.

The clinical strategy helps establish critical milestones for device development. Critical milestones may include things such as when feasibility prototypes or breadboard-level electronics and software development are needed. Early clinical studies, for example, may be conducted with prototype devices that produce the essential core device technology, but do not require the device to be in its final commercial configuration. There is however, a point says Welch, at which the device needs to be “productionlike” and manufactured under full cGMPs, verified against the design input requirements and validated to show it meets its intended use and needs.

Understanding product needs Defining the needs of the user, business, or stakeholder is fundamental. The product must be: Useful – meet a specific need; usable – easy to understand and manipulate; desirable – appealing to the intended user so it will be adopted into their daily use and manufacturable – the process output is true to the actual value or target desired but is also repeatable.

An integrated product development process combines human-centred design principles with a solid design for manufacturing philosophy. Also, appropriate levels of design research are needed in order to fully understand user needs. Combination products consist of multiple subsystems that need to be well defined to ensure the product will perform as intended. When software and electronics are an integral part of the drug delivery device, an additional layer of complexity exists. A set of requirements needs to be developed for the integration of the drug and device with emphasis on the ways each constituent part can adversely affect the other.

Once the Target Product Profile (TPP) of the drug substance has been established, relating this to the materials science aspects of device development is key for stability, toxicity and ADME studies. One way of defining this relationship is in the early stages of development, through the use of Quality By Design (QbD). QbD (drug standpoint) and proof of concept (device) are not mutually exclusive. Through the development of a design space, QbD helps establish the target product profile (TPP) of the drug substance. But the design space for the TPP could be impacted by the properties of materials (drug delivery device) where product contact is made. This potential interaction over time (stability) can alter the efficacy of the drug, sterility, etc, which lowers the efficaciousness and effectiveness of the drug product for therapeutic effect.

Container closure system Devices are often considered a part of or the entirety of a container closure system (CCS). Per FDA Guidance for Industry-Container Closure Systems for Packaging Human Drugs and Biologics: “A container closure system refers to the sum of packaging components that together contain and protect the dosage form. This includes primary packaging components and secondary packaging components, if the latter are intended to provide additional protection to the drug product.”

This distinction is important as the vials, bottles or moulded components that a company uses to house a drug must be tested in conjunction with the drug and be considered a ‘whole’ throughout the product development

Inhalation Activated Trigger

User Interface (Mouth Piece)

User Interface (Dust Cap)

Drive Mechanism Cocking Canister Activation

Stem and Opening

Drive Mechanism (Spring) Successful Targeted Drug Delivery User Interface (Dose Counter)

Dose Counter Mechanism

Canister Design or Drug Formulation

process. Drug product integrity and effectiveness are important aspects for why CCSs need to be thoroughly tested against edge-of-failure conditions.

Any potential breach of a CCS for a sterile product, parenteral, or injectable could introduce by-products, etc that could impact the drug product stability profile. This could make the drug product less effective and / or cause adverse reactions. The CCS must be designed to allow for the integrity of the product all the way through the supply chain until the end of expiration.

A liquid vial and plunger in a spring-loaded syringe highlights how the container closure system can impact product performance. The drug development team may specify the vial that will be used and how much time is allowed to deliver the drug, while the device development team must characterise the amount of force needed to push the plunger to extrude the drug through a needle of a certain diameter in a set amount of time.

We know device A is not the same as device B when viewed on a microscale. This is where specifications come into play. A device will be manufactured to specifications that most commonly control the size of a feature and/or its position relative to another feature. This is important from a pharmaceutical or biological background. A device comprises multiple components, with every feature requiring some level of manufacturing tolerance, so there device performance variation can alter.

Specifications are derived from requirements however, specifications are not requirements themselves. If the requirement of a spring-loaded syringe is to deliver the drug within 1-2 seconds of actuation, the device team must create manufacturing specifications and tolerances that will create this result.

When software and electronics are involved, complex algorithms may be developed early on to perform a function using one, two, or three prototype devices. But during development the software and electronics team needs to understand the manufacturer’s tolerances for sensors, processors etc, as well as for any moulded or fabricated components. Software development may require on-going development as additional units are produced and additional component variation begins to enter the picture. It’s important not to overlook regulatory expectations on configuration management for medical devices with software platforms.

This is where design for manufacturing comes into play. When making a single component or a low volume of components, often smaller tolerances can be achieved. In higher volumes, more variation is inserted into the manufacturing process, including but not limited to, multiple cavities for tools, different operators and multiple assembly lines. At this point process optimisation begins prior to transfer. Once the initial specifications and tolerances have been established (with manufacturing input), parts can be prototyped at their specification limits in order to determine if these tolerances are appropriate.

According to Welch, Phillips-Medisize’s goal is, “to partner with large and small biopharma companies, helping them to design, develop and manufacture their drug delivery devices. The partnership typically starts early on in the design phase; so by the time the drug is brought to market, we have already been working with the company for years and are well positioned to provide a low-risk manufacturing launch.”

Phillips-Medisize is becoming more involved with drug handling, and it manufactures finished and labeled combination products, including products with cold chain requirements, UDI, and serialisation.

WWW.EPMMAGAZINE.COM

21

Making Pharmaceuticals Research to Finished Product

70+ Seminars & Workshops 100+ Exhibitors

FREE to Attend

Source Manufacture Outsource

Exhibition & Conference

National Conference Centre, Birmingham

26-27 April 2016 Supported by:

PROCESSING REGULATORY CLINICAL TESTING DATA MANAGEMENT OPERATIONAL EXCELLENCE PHARMACEUTICAL QUALITY INGREDIENTS / EXCIPIENTS MICROBIOLOGY AND PHARMA PHARMACEUTICAL ENGINEERING PACKAGING NEW TECHNOLOGIES BIOSIMILARS

Register now at www.making-pharma.com

Stamp it out: In the near future, a UDI (unique device identification) number will be required on all pharmaceutical products

CHALLENGES FOR PHARMA

Making your mark From pharmaceuticals to surgical equipment, every product being manufactured by the healthcare industry will be required to have a unique device identification (UDI) number.

Richard Pether, Rotech, explains how healthcare suppliers can deal with implementation

I

n 2013 the US Food and Drug Administration (FDA) mandated unique device identification (UDI) for most medical devices distributed in the United States.

Supported by the International Medical Device Regulators Forum (IMDRF), regulators in the rest of the world are considering similar legislation.

International guidance on UDI has been developed, and this will serve as the basis for the EU’s future identification and traceability infrastucture, building on the pharmaceutical pack serialisation requirements set out by the Falsified Medicines Directive (FMD), which comes into force in 2018.

The ultimate aim is that there will be one, globally harmonised system for identification of medical devices - from surgical instruments, inhalers, contact lenses and dressings to diagnostic tests - by healthcare providers such as the NHS. So, for producers and packers of healthcare products, it’s no longer a question of whether item-level serialisation will become a legislative requirement in the EU. It’s a question of when.

UDI explained A UDI is a unique number or alphanumeric code that consists of two parts: a UDI-DI (device identifier) and a UDI-PI (production identifier).

The DI element of the code identifies the specific version or model of a device, for example, through a GSI global trade item number (GTIN), whilst the PI element gives production data – typically batch code, lot number, expiry date or date of manufacture.

encrypted in a 2D code, with the same data also presented in humanreadable format. The idea is that the creator of the UDI (usually the manufacturer), submits the code to a central database, so that it can be checked at various stages in the supply chain, via a scanner or smart phone. For this purpose, the US FDA has created the Global Unique Device Identification Database (GUDID).

How it works GS1 is the main accredited issuing agency for UDIs. With the GS1 framework, every party in the supply chain is given a unique global location number (GLN), while every product that enters the supply chain is given a unique global trade item number (GTIN). GTIN and GLN data is shared electronically through a global data synchronisation network (GDSN). The idea is that as products pass through the supply chain, they are scanned by each stakeholder and both GTIN and GLN information is updated automatically.

Why UDI? UDI will make it quicker and easier to identify and track products in the supply chain, from supplier to patient. This has a number of potential benefits – for patients, heathcare providers and manufacturers. Patient safety should be better safeguarded through a reduction in medical errors, industry and regulatory authorities will be able to identify products involved in adverse events more rapidly and issue more targeted safety alerts and recalls, and the traceabililty provided by UDI should serve as an effective anti-counterfeiting measure. From a business operations and supply chain perspective, UDI should allow for improved procurement, security, inventory management and accounting.

This information must be presented in two formats: human readable and machine-readable.

What do I need to do?

Although not stipulated by the legislation, the GS1 2D DataMatrix is frequently selected as a machine-readable carrier for UDI data. So, as an example, the UDI could consist of GTIN, batch code and expiry date

Soon, all healthcare suppliers wishing to deal with providers such as the NHS will need to apply UDI identification to their products, at an individual item level. In order to print serialised data and 2D codes,

WWW.EPMMAGAZINE.COM

23

secure, hygienic and simple communication

melaphone

visaudio

Clean Rooms Food Industry Hospitals Certified to ISO 14644-1 Level 5 needs:

& Environmental Control

Call us now on

UK 01359 233191 Int +44 1359 233191 info@melaphone.co.uk melaphone.co.uk Mu?llerGmbH_EPM_e_107x156_2016 .qxd:MüllerGmbH_Chemical EPM

e 1.2 Messehinweis

Engineering_e

107x156 mm

2016

POWTECH NUREMBERG from 19/04 to 21/04/2016 Hall 1 / Stand 349

For

perfect

production

methods Handling equipment – Lifting, weighing, blending, pallet transfer – Mobile or stationary – Manual or fully automatic – Loads up to 2500 kg handled – Hygienic stainless steel – GMP-compliant design – ATEX conformity Müller GmbH - 79618 Rheinfelden (Germany) Industrieweg 5 - Phone: +49(0)7623/969-0 - Fax: +49(0) 7623/ 969-69 A company of the Müller-Group info@mueller-gmbh.com - www.mueller-gmbh.com

24

WWW.EPMMAGAZINE.COM

CHALLENGES FOR PHARMA printers will have to be digitally addressable, which means any old embossing kit and the hot foil coders will have to go.

Code quality is crucial for machine-readable codes, and that quality needs to be maintained from the day the code is applied to the day it is scanned by a patient or healthcare provider, which could be a year or two later. Ink fade is a potential problem, and any codes that are slightly fuzzy, blurred or out-of-position might be unreadable further along the supply chain. Whilst most manufacturers will deploy an on-line camerabased system to verify the code, vision system performance will also be influenced by the quality of the code, and rejection and rework of any packs carrying unreadable codes will have serious implications for overall equipment effectiveness (OEE).

Thermal inkjet printers (TIJs) place their pixels more accurately and offer higher resolution printing (typically 300 dpi or above) than CIJ systems.

This makes TIJ the obvious print technology of choice for 2D codes.

However, even where manufacturers are using TIJ, print quality is still dependent on the presentation of the product to the printer. DataMatrix barcoding requires near perfect presentation to achieve the highest verification grade. As many medical devices are awkwardly shaped, feeding can be a problem, resulting in mis-coded items that cannot be validated by an online vision system or a scanner further along the supply chain.

Producing high quality serialised codes at the line speeds required by some healthcare operations is no mean feat either, and compromises between quality and speed often have to be made.

Offline coding: a consideration For many healthcare suppliers, the answer to these issues could lie in taking coding offline. Rotech, for example, has designed a modular system that incorporates printing, labelling, inspection and automatic stack-to-stack feeding technology. This system has already been

supplied to a number of pharmaceutical manufacturers in advance of the FMD and is equally applicable to medical device manufacturers who want to implement UDI without impacting their production lines.

Offline overprinting systems come into their own where a large amount of text is required or the print is required to meet an exacting standard, such as the 2D DataMatrix code on a medical device pouch. By taking this process offline, the packs are brought to the line ready printed and inspected, eliminating any delays due to coding issues. The potential for rejects is massively reduced because the pack can be presented to the printer in the most favourable orientation.

Offline systems can be fitted with either a thermal inkjet or a thermal transfer printer.

Many companies assume that an online system will be faster and more efficient than an offline one, but once you take into account the impact that inline verification, serialised code printing and mis-codes could have on line efficiency and OEE, offline coding starts to look like an attractive option. Speeds of up to 200 packs per minute are well within the capabilities of an offline coder and a range of packaging formats can be coded offline, including cartons, wallets, pouches, bags, sleeves and crash-lock cartons. In fact, small batches are more efficient and economical coded offline.

Systems can be positioned either near or next to a line to keep it supplied during running or can supply a second line in a central location.

Get ready for UDI From pharmaceuticals to surgical equipment, every product being manufactured by the healthcare industry will, in the very near future, be required to have a unique device identiďŹ cation (UDI) number. Now is the time for manufacturers of pharmaceuticals and medical devices to get their coding systems UDI ready, and oine coding could just be the best route to compliance.

WWW.EPMMAGAZINE.COM

25

FLEXIBLE MANUFACTURING SOLUTIONS

Thomas Flex 500® Batch Tablet Coater Features:

Scan the QR code to view a video of the Thomas Flex 500® high performance features!

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 - tel. 800-634-9910

WWW.THOMASENG.COM

WWW.EPMMAGAZINE.COM

CHALLENGES FOR PHARMA

Relationship advice James Cooper, Lime Associates, supply chain specialist, looks at how strengthening supplier relationships can help pharmaceutical manufacturers to protect their businesses in 2016

I

n 2016, pharmaceutical manufacturers are under closer scrutiny than ever. The industry is changing, and growing concern about pharmaceutical pricing and profit margins is increasing the financial pressure on manufacturers.

At the same time, a growing number of deaths attributed to pharmaceutical products through misuse, misdiagnosis and quality issues means it’s never been more important to stay compliant.

The increasing cost of pharma On the financial side, we can see some worrying trends emerging in 2016.

As regulations tighten, the industry as a whole is incurring bigger and more frequent financial penalties than ever before. Whilst this is more prevalent in the US market – there’s a really good chance that European manufacturers could face similar scrutiny over the year ahead.

At the same time, the commercial environment is becoming more difficult. New cost constraints, and an increasing awareness about the profits made by the pharma industry means that healthcare providers are weighing up the cost of products like never before.

The traditional business model, in which pharma companies would invest a significant proportion of R&D expenditure into developing ‘blockbuster drugs’, before charging an appropriate premium for the product is under serious threat. Now, there’s an increasing expectation on manufacturers to carefully examine production costs, in an effort to protect margins.

Slashing costs in the supply chain This creates a real challenge. Putting pressure on suppliers or switching sources might seem like the best way to cut costs, but this comes with serious risk. Tiny changes to seemingly inactive ingredients can make a huge difference to pharmaceuticals.

Despite this, many manufacturers still trust suppliers to provide the right grade and quality of materials, especially when it comes to excipients.

If these suppliers get things wrong – it’s the manufacturers who face the consequences.

To minimise risk, pharmaceutical manufacturers need to take a closer interest in their suppliers and the ingredients they provide, examining existing procedures, and working hard to strengthen relationships.

Quality testing beyond the key ingredients Every manufacturer knows the importance of in house quality control and testing processes. However, many don’t have the same processes in place for the materials sourced from elsewhere.

In 2015, Lime Associates worked with a successful UK-based pharmaceutical manufacturer following a buyout. They had enjoyed a meteoric rise, going from small start-up to a leading manufacturer

WWW.EPMMAGAZINE.COM

in the field. Despite the extensive development of the business – the purchasing and supply chain procedures hadn’t kept up with growth.

Apart from the key ingredients manufactured in-house, everything was sourced from a single lab supplier catalogue. The manufacturer had little knowledge and absolutely no control over where ingredients were sourced from, and left it to the catalogue to find and test appropriate grades of excipient.

Should the suppliers have got anything wrong, there was a real risk that the manufacturer would have sent products to market without noticing – which could have had far reaching impacts on patient safety, business finances and reputation.

Sustainability of sourcing and threats to the ‘crown jewels’ The pharmaceutical industry relies heavily on key ingredients – the essential ‘crown jewel’ raw materials that cannot be replaced. Securing the supply chain for these materials is essential – but usually the sustainability of these ingredients lies in the hands of the supplier.

This can be challenging, especially in cases where this material is rare, or can only be sourced from a single supplier. Large pharmaceutical companies get around this by purchasing the supplier outright, but this simply isn’t feasible for smaller businesses.

The problem can be compounded if a key ingredient or feedstock comes from an exotic source, or isn’t a key part of the supplier’s business. In 2016, the industry is sourcing more and more ingredients from marine organisms – but these resources need to be carefully managed if they are to be sustainable over the long term.

Should suppliers exhaust a key resource, it could have serious implications!

Understanding and testing suppliers To minimise risk in the supply chain, effective supplier relationship management is essential – but it’s becoming a lost art in 2016.

Manufacturers need to know exactly how important they are to their suppliers, and work to develop stronger relationships – but this can be hard in a world dominated by digital communication and e-procurement systems.

Nothing beats meeting people face to face. Taking the time to visit suppliers, getting to know them and building trust can be the difference between success and failure, and will help to keep pharmaceutical businesses compliant in the year ahead.

27

www.lbbohle.com

BOHLE TECHNOLOGY CENTER

Continuous Manufacturing Starts Here • Standard of excellence from Bohle and nine partners • Pharma systems and expertise from one source • Complete hardware and software integration • Measuring, monitoring and controlling continuous production under excellent conditions • Comprehensive process support and service

Our partners:

28

.

ur success

as for yo Smart ide

WWW.EPMMAGAZINE.COM

CHALLENGES FOR PHARMA

Ahead of the curve Michael Lehmann, executive vice president, global sales & marketing, Patheon shares his views on the challenges ahead for the pharma sector and how they could mean greater opportunities ahead for pharmaceutical manufacturers

I

nterestingly enough, the types of challenges facing biopharmaceutical companies in 2016, while not too different from previous years, are intensifying and point to greater opportunities for pharmaceutical development and manufacturing service providers.

diseases for which biopharma companies are researching treatments. The complexity of new molecules has led to the demand for technical expertise in not just solubility and formulation, but also in the approach to scale up and manufacture these complex compounds — expertise that many biopharma companies do not possess.

Solubility enhancement capability, combined with optimal technology that can be scaled up through commercialisation, is but one of the hurdles for biopharma companies seeking to move their products to market in an efficient, cost-effective manner.

Pricing pressures

In the EU, individual countries have put up hurdles to reimbursement that require therapies to demonstrate more than incremental improvement over standard of care before they are reimbursed. The barriers include, but are not limited to, measurement of disease burden, comparative effectiveness, crossPersonalized medicine border reference pricing and even selection of clinical endpoints. Dozens of countries have been Looking ahead: According to Patheon’s The long-awaited personalised medicine revolution successful in lowering drug prices through reference Michael Lehmann, The combination is finally arriving. With the price of personal genome pricing – a system in which drugs are grouped into of an ageing population and chronic sequencing falling significantly, researchers are disease is creating greater demand classes by therapeutic effect. A standard price is among patients for targeted treatments increasingly focused on personalised medicine set for each class, so if a company sets a higher approaches. value, the payer only covers the reference cost. The consequence of reference pricing is that the squeeze on pricing by the In 2014, according to analysis conducted by the Washington DCEuropean countries places pressure on pharma companies to realise based Personalized Medicine Coalition, more than 20% of the 41 new drugs approved by the US Food and Drug Administration (FDA) were global revenues. personalised medicines. Today up to 50% of new medicines in the This continuing pressure on biopharma companies to reduce the price pipeline are reportedly personalised medicines across all therapeutic of the medicines is also evident in the US during a presidential election categories. year, as the candidates elevate the debate around drug pricing, President Obama’s health care law and access to care.

These global pricing pressures are pushing biopharma companies to seek new ways to increase productivity, improve efficiency and ultimately become more cost effective. The focus on improving efficiency and cost-savings is driving more and more companies to reconsider their infrastructure costs, and evaluate the savings derived by collaborating with a pharmaceutical development and manufacturing service organisation.

Shifting demographics The combination of an ageing population, together with the prevalence of chronic disease, is creating greater demand among patients for targeted treatments, medicines and therapies. The challenge for biopharma companies will be to drive innovation in R&D, and create novel products while tempering costs. Again, this requires companies to explore alternative business models that involve more strategic partnerships and collaborations to meet the rapidly growing needs of the marketplace.

Forecasting Drug forecasting done by pharmaceutical companies drives numerous decisions in their development programmes — sales force resources, geographic resource distribution and of course, manufacturing planning.

It is well recognised in the industry that predicting forecasts accurately is a challenge, especially for new drug launches. A variety of models are used to develop the forecast, but these models are not perfect and cannot predict uncertainties in the marketplace. Forecasting will continue to be a challenge for biopharma companies. Innovative companies will explore avenues to improve accuracy, but also look for ways to manage in a volatile market. Flexible manufacturing solutions will become an attractive option for companies looking to manage their business more efficiently and maximize market opportunities with affordable solutions to scale.

Complex molecules It is estimated that a third of all clinical failures in the drug development process can be attributed to solubility and bioavailability challenges.

The increase in low solubility drugs is directly related to the challenging

WWW.EPMMAGAZINE.COM

29

www.creativehub.agency

((

Containment systems:

)

Safety and Control )

SECURITY FOR OPERATOR, PRODUCT AND ENVIRONMENT ARE THE GROUND WHERE WE PLAY OUR MATCH FPS is specialized in containment systems and fine size reduction equipment for many industrial applications. We win the match by providing performing and reliable solutions for our customers needs. www.foodpharmasystems.com info@foodpharmasystems.com Ph +39 031 543429 ISOLATORS | CLEANROOMS | DOWNFLOW BOOTHS | PACK OFF SYSTEMS | RABS |

Micronization & Containment Solutions

Joining Forces in Containment Solutions.

Visit us, Interphex New York, April 26 – 28, 2016, Booth 1033.

Weiss Umwelttechnik • Weiss Klimatechnik Weiss Pharmatechnik

Vötsch Industrietechnik Umweltsimulation • Wärmetechnik

www.weiss-pharma.com

30

WWW.EPMMAGAZINE.COM DD-Anz.3-WPT_107x156.indd 1

03.03.16 09:10

CHALLENGES FOR PHARMA

Expert witness Justin Schroeder, PCI Pharma Services, takes an in-depth look at the issues affecting the pharmaceutical sector – past and present

2

015 closed as a turbulent year in the world economy. Across the globe significant factors have stressed the marketplace as oil prices fall, stock markets swing dramatically, capital markets retract, and humanitarian crises persist with no end in sight. The global pharmaceutical and biotech market continues to push forward, evolving and adapting, despite these challenges.

approvals, or 16 of the 45 total, designated as ‘first-in-class’, and 47%, or 21 approvals, going to orphan disease indications(2).

14 approvals utilised Fast Track status, 10 were Breakthrough therapies. 24 approvals utilised Priority Review, and six followed Accelerate Approval, designated for drugs for a serious or life-threatening illness that offers benefit over existing treatments(2).

In total, 60% of the new drug approvals utilised one of the four expediting categories FDA has created to inspire development of therapies for unmet needs(2).

Within the industry, merger and acquisition activity persists. Drug companies continue to rethink their pipeline development strategies and it is clear that acquisition will increasingly be a key strategy in supplementing their own internal pipeline development, even as companies pay significant premiums to acquire developing companies.

Drug pricing for these breakthrough therapies continues to be a hot topic. Gilead scored a major win with the commercialisation of Sovaldi and was thrust into the spotlight for its pricing. Despite significant pressure from Tremendous pressure from the investment payers, both private and governmental, space has driven companies to buy or be treatment continues to be quite costly. The bought, and speculation of who is next is revenue has helped fuel substantial growth compelling daily reading. With the evolution and market speculation about Gilead’s own of tax inversion strategies, a remarkable new plans for M&A. To date Gilead has weathered wrinkle has entered the equation. The tables Thought process: According to Justin Schroeder, the storm and the company now sits with a have turned and it is not simply the traditional PCI, drug companies continue to rethink their substantial war chest. It had $26.2 billion pipeline development strategies and acquisition will model of ‘big buys small’. The ability of a increasingly be a key strategy in cash, cash equivalents and marketable company to relocate its stake in the ground securities at the end of December(3). Many has major financial ramifications. To that end, the ongoing saga between believe the organisation will be responsible for the next large acquisition Mylan, Teva, and Perrigo captured much of the pharmaceutical world’s in the market. attention. Likewise, the industry is eager to see how Pfizer and Allergan will look 12 months from now. It is apparent that, M&A will continue to Despite the challenges to the global economy, emerging markets be a major prevailing wind driving the future direction of the industry. continue to be an attractive area for industry growth. The world was caught off guard by retraction in China’s economy, however – according There is also continued reconciliation for pharmaceutical company to leading analyst McKinsey & Company, pharmaceutical spending strategy around maintaining complimentary businesses such as in overall emerging markets has now overtaken the EU5 economies consumer over-the-counter medicines, vaccines, and animal health (Germany, France, Italy, the United Kingdom, and France) and has medicines. On the heels of Novartis selling its animal health business a total market size of USD 281 billion(4). Between 2015 and 2020 to Elanco, GSK completed its acquisition of the Novartis vaccine emerging markets are expected to account for USD 190 billion in sales business. Novartis, in turn, acquired GSK’s oncology business as well as growth(4). It is clear that the industry is committed to its investment in entering a partnership in marketing a portfolio of leading OTC products. emerging markets.

Meanwhile, Bayer significantly doubled down in the consumer space in acquiring Merck’s OTC portfolio which it had acquired from the While the global and domestic economies continues to face challenges, Schering merger. While Pfizer has divested its interests in animal health the pharmaceutical industry ploughs forward, all the while adapting and through the Zoetis spin-off, many analysts believe Bayer will continue recalibrating to look for new areas of growth. With a track record for to diversify and will make a future play for a larger presence in animal success, it seems a safe bet. health. For every leading company going one way, it seems there is 1) http://blogs.fda.gov/fdavoice/index.php/2015/01/cderanother going the opposite. approved-many-innovative-drugs-in-2014/ 2014 was a record year for new ethical drug development and 2015 2) http://www.fda.gov/downloads/Drugs/ continued that trend. Companies have focused attention on novel DevelopmentApprovalProcess/DrugInnovation/UCM485053. therapies and unmet needs, supported by regulatory changes that have pdf encouraged development in this space. In 2014, 17 approvals, or 41% of the total, were for rare diseases that affect 200,000 or fewer 3) http://www.biospace.com/News/gileads-new-ceo-johnmilligan-hints-at-probable/409188 Americans (1). These 17 approvals were regarded as ‘first-in-class’ (1) therapies or 41% . 19 NDAs were approved utilising the Fast Track 4) http://www.mckinsey.com/industries/pharmaceuticals-andor Breakthrough status (1). That trend continued in 2015, with 36% of medical-products/our-insights/pharmas-next-challenge

WWW.EPMMAGAZINE.COM

31

SPOTLIGHT ON INNOVATION

Leading lights Super group: Can cancer drugs reverse antibiotic resistance?

The Antibiotic Research UK (ANTRUK) charity has launched a research programme to test whether existing therapies for the treatment of medical conditions can reverse the antibiotic resistance of superbugs.

Team TB: Bayer teams up to tackle TB

ANTRUK’s programme will challenge the rise in antibiotic resistant bacteria (superbugs) by screening antibiotic resistance breakers against antibiotic resistance in Gram-negative bacteria.

Bayer has teamed up with the Universities of Dundee and Cape Town (UCT) to develop new treatments for tuberculosis (TB).

TB is still one of the deadliest infectious diseases in the world killing 1.5 million people globally each year.

The trio are members of the Tuberculosis Drug Accelerator (TBDA), a programme aiming to identify novel therapies to reduce the treatment time for TB. The collaboration will optimise hits from the Bayer compound library that were identified within TBDA, developing them into potential preclinical drug candidates.

The Drug Discovery Unit (DDU) at the University of Dundee and UCT’s Drug Discovery and Development Centre (H3D) are two of the leading centres for drug discovery globally.

Paul Wyatt, director of the DDU, said: “The collaboration with UCT and Bayer will expand our TB effort, taking us from early stage drug discovery to more advanced design, synthesis and testing to identify potential drug candidates.”

32

Future investment: AstraZeneca funds robotic drug AstraZeneca has invested in Rani Therapeutics’ robotic platform that converts injectable drugs into pills.

Rani has developed a technology platform to convert injectable drugs such as TNF-alpha Inhibitors, interleukin antibodies and basal insulin among others into pills The robotic pill consists of an ingestible polymer and tiny hollow needles made of sugar that are designed to safely deliver drugs to the small intestine, according to the Wall Street Journal.

With its latest round of funding, the company’s total investment is more than $70 million and has come from companies including AstraZeneca, Novartis, Google Ventures, Buttonwood, GF Ventures, KPC Pharmaceuticals, InCube Ventures and VentureHealth, among others.

WWW.EPMMAGAZINE.COM

ANTRUK’s programme will challenge the rise in antibiotic resistant bacteria (superbugs) by screening antibiotic resistance breakers against antibiotic resistance in Gram-negative bacteria.

The charity has asked scientific organisations and universities to submit tenders for this testing to see if therapies already in use and being safely administered in humans can be co-administered with antibiotics.

Colin Garner, ANTRUK chief executive, said: “Our Antibiotic Resistance Breaker programme could potentially find new ways of extending the life of our existing antibiotics at a fraction of the cost and time compared to conventional drug development”.

David Brown, chair of ANTRUK’s scientific and technical advisory committee, said: “Our committee has been developing this programme for the past 12 months.

“I believe it offers the possibility of finding new antibiotic therapies to meet our goal of bringing one into clinic by the early 2020’s. The charity is delighted to be starting real research now”.

Innovation – it’s everywhere in the pharmaceutical sector. Sometimes it’s a small step or an accidental finding. More often it’s continued effort into drug development, delivery or research that leads to the constant stream of new products and formulations

Blow your mind: Cancer-targeting ‘grenades’ Researchers have developed cancer drug-packed ‘grenades’ armed with heat sensitive triggers, allowing for treatment to be targeted directly at tumours.

The team based at The University of Manchester has been developing liposomes – small, bubble-like structures built out of cell membrane that are used as packages to deliver molecules into cells – to carry drugs into cancer cells. The challenge, as with any treatment, is to direct the liposomes and their payload directly to tumours while sparing healthy tissue.

The team based at The University of Manchester has been developing liposomes – small, bubble-like structures built out of cell membrane that are used as packages to deliver molecules into cells – to carry drugs into cancer cells. The challenge, as with any treatment, is to direct the liposomes and their payload directly to tumours while sparing healthy tissue.

The team has taken a step closer to solving this problem by fitting liposomes with a heat-activated trigger. By slightly heating tumours in the lab and in mouse models, the researchers have been able to control when the pin is pulled so that the cancerkilling ‘grenades’ release the drug and target the cancer.

In the mix: Implant delivers chemo cocktail directly to cancer tumours An implantable device delivers treatment for pancreatic cancer directly to tumours, bypassing bloodstream and limiting widespread side effects, according to The University of North Carolina (UNC).

A team of researchers from UNC has shown that the device can deliver a particularly toxic dose of drugs directly to pancreatic tumours to stunt their growth or in some cases shrink them.

A team of researchers from UNC, including Jen Jen Yeh and Joseph DeSimone, has shown that the device can deliver a particularly toxic dose of drugs directly to pancreatic tumours to stunt their growth or in some cases shrink themUNC has also said that this approach would also spare the patient toxic side effects.

Jen Jen Yeh, researcher, said: “We use the device to hit the primary tumour hard. It’s an exciting approach because there is so little systemic toxicity that it leaves room to administer additional drugs against cancer cells that may have spread in the rest of the body.”

The work, published in the Proceedings of the National Academy of Sciences, highlights the cocktail Folfirinox, a combination of four chemotherapy drugs that UNC said has been shown to shrink tumours or halt their growth in nearly a third of pancreatic cancer patients.

The new device currently tested in mice, delivers the drugs directly to the tumour, providing an alternative to sending this toxic cocktail through the bloodstream and UNC said this limits harsh effects throughout the rest of the body.

WWW.EPMMAGAZINE.COM

Joint forces: Big Pharma signs up to Parkinson’s consortium Pfizer, AstraZeneca, Merck and other Big Pharma companies have signed up to a consortium aimed at accelerating the development of safe and effective therapies for Parkinson’s.

The Critical Path for Parkinson’s consortium was formed by Parkinson’s UK and Critical Path Institute (C-Path) to increase investment into research and development of new Parkinson’s treatments.

The consortium will bring together academics and industry members including AbbVie, Biogen, Eli Lilly and Company and UCB to share data, expertise and resources to promote and develop new treatments for Parkinson’s, according to Parkinson’s UK. Arthur Roach, director of research at Parkinson’s UK, said: “Despite significant advances in our understanding of the genetics, biochemistry and pathology of Parkinson’s, the development of new treatments has not kept pace.

“Investing in clinical trials for brain disorders currently carries a high cost and high risk of failure. As the world’s largest patient-led Parkinson’s charity, we know that people living with conditions such as Parkinson’s have often been disappointed when drugs that showed significant promise early on failed in late stage testing.

“We see the consortium as a crucial part of strategies to develop new treatments that work at the earliest stage of the condition, with the goal of slowing its progression and eventually finding a cure.”

33

FOLIO

My generation Jennifer Mitcham, SMARTag business development, Catalent Biologics, offers insight into the new generation of antibody drug conjugates and the increasing importance biologics play in the fight against disease

A

decade ago, the world’s top ten selling medicines were all small molecules. In 2014, just half of the ten biggest sellers were small molecules, with four monoclonal antibodies and a modified form of insulin.

With drugs for the ‘easier’ targets available and many now adequately served with generic medicines, pharma and biotech companies have become more creative. Biologics have become an important part of the fight against disease and the challenges facing the medicines market are how to make safer, more efficacious drugs; exploring innovative combination therapies; and developing more efficient manufacturing processes. Antibody–drug conjugates (ADCs) are one example of how combining a biologic’s targeting mechanism action with the potency of a chemotherapeutic toxin can have significant benefits.

The first generation The first ADC, Wyeth’s Mylotarg, launched in 2000 and although later withdrawn for lack of efficacy, two others have since reached the marketanti-cancer products Kadcyla (Genentech) and Adcetris (Seattle Genetics).

Dozens more are in development and have great potential against solid tumours and haematological malignancies.

ADCs harness the targeting ability of an antibody to direct a highly potent cytotoxic agent to cancer cells, while sparing healthy ones. The two components, antibody and cytotoxin, are joined by a chemical linker.

The nature of the linker and the conjugation chemistry critically impacts the characteristics of the resulting product. First-generation ADCs pose challenges in manufacturing and characterisation, mainly because of the variability of the conjugates produced.

“

Crucial role: Biologics have become an important part of the fight against disease and the challenges facing the medicines market are how to make safer, more efficacious drugs, says Catalent’s Jennifer Mitcham

34

”

These ADCs relied on linkers that reacted with surface-accessible nucleophilic amino acid side chains – either the amine group on lysine, or the thiol moiety on cysteine. Lysine technology, used to make Kadcyla, relies on linkers with active esters including sulfosuccinimide or N-hydroxysuccinimide that react with accessible lysine amines on the antibody. The downside is that the typical antibody has dozens of such reactive lysines, precluding control over the precise location of conjugation, resulting in a heterogeneous mixture of molecules bearing between zero and eight drug molecules, conjugated at a diversity of sites.

Adcetris uses a cysteine conjugation approach that takes advantage of thiol moieties existing as disulfides in an intact antibody. Before conjugation, a reducing agent such as tris(2-carboxyethyl) phosphine or dithiothreitol must be used to reduce the disulfide bonds, releasing free thiol groups that can be reacted with maleimide-containing linkers. A maximum of four of these disulfides can be reduced in an antibody, producing up to eight thiols for conjugation. This number can be varied by altering reducing conditions.

Although there is still variability in the number and location of the attached cytotoxic molecules, the overall complexity of cysteine conjugates is lower than that observed when using lysine conjugation.

WWW.EPMMAGAZINE.COM

SPOTLIGHT ON INNOVATION A new breed of ADCs The heterogeneity of the first-generation lysine and cysteine conjugation approaches has led to second generation ADC technologies, designed to reduce variability and optimise drug to antibody ratio (DAR). A DAR that is too low results in suboptimal efficacy, while too high makes side-effects more likely. Site-specific conjugation is a new approach targeting tighter control over the DAR, while reducing complexity and variability in terms of conjugation site.

Site-specific conjugation, pioneered by Genentech with its THIOMAB-drug conjugate (TDC), involves engineering reactive cysteine residues at specific locations on the antibody, and using these for conjugation rather than reducing native disulfides. Genentech has reported a comparison between the ADC and TDC equivalents of an anti-MUC16 antibody conjugated to the cytotoxic agent MMAE. The product gave the same cytotoxic effect with half the payload in preclinical studies, and was better tolerated.1 Similar results were seen with TDC versions of Kadcyla (trastuzumab emtansine).2 Further investigations indicated that the precise location of the conjugation site on the antibody also has affects ADC biophysical and functional properties. Conjugates within the antibody’s light chain showed the greatest activity, conjugates in the in the heavy chain moderate activity, and conjugates in the Fc region negligible activity in in vivo efficacy studies. A similar trend was seen for stability, with clearance slowest when conjugation was in the light chain, and fastest when it was in the Fc region.

Early work on TDC encouraged the development of other potential techniques for site-specific bioconjugation. These techniques use protein engineering to move the conjugation site around the antibody so the properties of different potential ADCs can be explored. While all capable of creating more homogeneous ADCs than first generation techniques, not all facilitate creation of the optimal conjugation patterns for any specific combination of antibody and payload.

Allozyne, Ambrx, and Sutro Biopharma have developed ways to introduce non-natural amino acids into the antibody via genetic engineering, then using them to give specific conjugation patterns. Recombinant protein expression systems have engineered transfer RNA synthetase pairs, used to introduce non-natural amino acids bearing bioorthogonal reactive groups anywhere on the antibody backbone, allowing site-specific conjugation.

but better safety and tolerability than conventional products can be made in this way. It is scalable and compatible with multiple different payloads, and amide bonds in the conjugates are generally stable, with no need to incorporate non-natural amino acids within the antibody.

Redwood Bioscience, part of Catalent Biologics, introduced aldehydetagged antibodies created via naturally occurring enzyme, formylglycinegenerating enzyme (FGE), to produce site-specific conjugation. SMARTag technology uses FGE to introduce formylglycine residues into protein backbones via insertion of a short FGE consensus sequence in the conserved regions of the antibody’s heavy or light chains. The ‘tagged’ antibody is then produced in cells that overexpress FGE, converting a cysteine within the consensus sequence to a formylglycine residue bearing a bioorthongonally-reactive aldehyde group. With FGE-mediated chemoenzymatic modification occurring cotranslationally during antibody production, no additional enzymes or protein-modifying agents are required during conjugation. Expression levels of 3 g/L and high yields (>95%) of formylglycine conversion have been demonstrated up to 100 L scale. After standard purification methods, proprietary aldehyde-specific conjugation chemistries form stable carbon–carbon bonds between payload and antibody at the tag locations.

This technique can create site-specific ADCs with maytansine payloads conjugated at different locations on an anti-HER2 antibody. Site-specific conjugation achieved via a carbon–carbon bond results in a highly stable product that is independent of the local protein microenvironment, demonstrated by serum stability experiments. However, the nature of the different conjugation sites influences pharmacokinetic behaviour and efficacy in tumour xenograft models, indicating that the conjugation site matters when building a better ADC. Although the aldehyde tag approach entails the introduction of a few exogenous amino acids into the antibody backbone, in silico and ex vivo tests assessing the immunogenicity potential of various aldehyde tag sites and conjugation products showed that the risk was low, and was similar to the native, untagged antibody. The safety of SMARTag ADCs has been demonstrated in exploratory toxicology studies conducted in rat and cynomolgus monkeys, with doses up to 60 mg/kg being well tolerated in single and repeat dose studies.

What’s next?

For example, Ambrx incorporated p-acetyl phenylalanine into antibodies using mammalian expression systems. The arylketone side chain can be used to conjugate cytotoxic drugs using oxime bonds. Ambrx and Agensys show that ADCs made in this way are, chiefly, just as efficacious as engineered or conventional cysteine-conjugated ADCs, but have better pharmacokinetic and safety properties. This is attributed to the greater stability of the oxime bond by researchers at both companies.3,4

Creating new ADC molecules is complex, with many different parameters needing to be orchestrated to generate the optimal conjugate. However, the ability of site-specific conjugation to produce increased homogeneous populations of ADCs should be a significant advantage in the development process. Manufacture, characterisation, and CMC processes should all benefit from a degree of simplification. The ability to optimise both DAR and payload placement may also improve the therapeutic index for ADCs.

Sutro Biopharma can introduce a non-natural amino acid bearing an azide-containing side chain into antibodies made in a cell-free expression system. Resulting antibodies are conjugated to cytotoxic drugs via coppercatalysed or copper-free click chemistry.

The field is still relatively young, with the majority of new ADCs still created using the conventional cysteine or lysine conjugation processes that generate heterogeneous ADCs. However, site-specific ADCs are now starting to reach early phase clinical development. With various different techniques available for making site-specific ADCs, and preclinical studies showing the potential to offer significant benefits in terms of efficacy, pharmacokinetics, and safety over first-generation iterations, the future of ADCs is bright.

Enzymatic techniques Pfizer employs an alternative strategy. It uses the enzyme transglutaminase to mediate conjugation reactions between glutamine residues and primary amines, with the site directed using a glutamine tag, engineered into the primary sequence of the antibody. Pfizer and scientists at ETH University, Zurich, have shown that site-specific ADCs can be made in this way, as natural glutamine residues in the antibody backbone are not affected.

Pfizer has also shown that a small glutamine-containing tag can be used as a transglutaminase substrate when introduced in surface-accessible antibody sites, before being conjugated to a cytotoxic payload using an amine-functionalised linker. Cleavable and non-cleavable linkers can be used, along with a variety of payloads. ADCs with comparable efficacy

References 1 Junutula JR, et al. Site-Specific Conjugation of a Cytotoxic Drug to an Antibody Improves the Therapeutic Index. Nat. Biotechnol. 26(8) 2008: 928–932.

2 Junutula JR, et al. Engineered Thio-Trastuzumab-DM1 Conjugate with an Improved Therapeutic Index to Target Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer. Clin. Cancer Res. 16, 2010: 4769–4778 3 Tian F, et al. A General Approach to Site-Specific Antibody Drug Conjugates. Proc. Natl. Acad. Sci. 111(5) 2014: 1766–1771.

4 Jackson D, et al. In Vitro and In Vivo Evaluation of Cysteine and Site Specific Conjugated Herceptin Antibody-Drug Conjugates. PLOS One 14 January 2014: 1–14

WWW.EPMMAGAZINE.COM

35

DRUG DELIVERY

FIVE

facts about Nemera’s new pump technology

2

Nemera outlines the thought process behind its new pump technology and the benefits it offers

1

Advancia is Nemera’s new generation pump technology developed for multidose nasal spray applications. The technology has been designed to meet increasingly demanding regulatory expectations in a user-friendly nasal spray.

Works every time

Accuracy is at the heart of the dosing pump function and even after 12 weeks without use, the pump will still deliver a dose in specification without the need to reprime. It has been designed to provide a consistent spray while limiting particle size and spray variations resulting from the patient’s method of use. It’s therefore ideal for drugs with infrequent use.

3

Meets ever-stringent regulation

No-clean technology

Advancia also has a specific closing tip technology to avoid the clogging that can occur with some formulations and eliminates the need to clean the applicator after each use.

There is no metal part to come into contact with the drug – this should improve both the patient experience and compliance. Advancia is available for preserved drugs in three doses (50, 100 and 140 µl)

5 4

Designed with the patient in mind

Patient non-compliance is a serious issue. It can result in ineffective treatment or, in the case of potent drugs, harmful results. Advancia had been designed to deliver consistency of dose and spray – irrespective of the manner in which the patient uses it.

The patient experience was key to the development of this pump, says Nemera. Its activation speed is higher than other pumps and its patented design means the user cannot stop the pump actuation before the end of the stroke, ensuring effective therapy. In other words, the patient cannot get a partial dose.

WWW.EPMMAGAZINE.COM

Ideal for the pharmaceutical manufacturer

Nemera says pharmaceutical companies now have an alternative device to choose from for their nasal sprays to increase compliance. This is a valuable option for lifecycle management and new drugs delivered to the nose and offers adifficult-to-copy pump technology.

Advancia is compatible with both plastic and glass bottles with 20 mm standard neck .

37

VISIT US AT

POWTECH

THE NEW FE SERIES

19 – 21 APRIL HALL 3, STAND 3-341

NEW FE SERIES +

Design – Simplicity as a key to efficiency + 360° accessibility + Guaranteed easy and safe operation www.fette-compacting.com

SOLID DOSAGE

Fixed position Sophisticated solid dose formulations for fixed dose combinations – Jean-François Hilaire, Recipharm, explains how CDMOs can help optimise time-to-market

T

he solid dose market is looking healthy with strong prospects for continued growth. The market faces multiple challenges yet offers opportunities to CDMOs with advanced scientific and technological skills and can provide customers with solutions.

One of these challenges is the increasing demand for capabilities that support the formulation and development of fixed-dose combination drugs. This need is being fuelled by the mounting pressure on pharma to find ways of differentiating their branded products in the market place.

Whether it’s virtual pharma companies out to establish a niche product with a strong differentiator, Big Pharma that wants to Demanding situation: add novel products to its pipelines or There is an increasing established pharma companies that want demand for capabilities to extend lines and diversify their brands – they are the impetus bringing products that support the to market. Consequently, proactive testing formulation and and monitoring of interaction between development of fixed-dose various APIs is increasingly leading to combination drugs, says findings showing it is safer and feasible Recipharm for certain active pharma ingredients to be successfully mixed together as one fixed-dose combination.

“

”

As a result CDMOs with advanced technical expertise plus technologies and facilities that are suitable to this specialist market are in demand.

These novel and exciting fixed-dose combination products fall in to a special category of their own, offering several common APIs incorporated together into a proprietary formulation.

One such example of this is RHB-105 The product is a proprietary fixeddose oral combination therapy, owned by RedHill Pharma. It comprises two antibiotics (amoxicillian and rifabutin) and a proton pump inhibitor (omeprazole), combined into an all-in-one oral capsule. It has a planned indication for treatment of H. pylori infection – a product that has successfully met its primary endpoint in its first Phase III study. This shows the higher efficacy and safety of the three components when combined into this particular fixed-dose drug – proving that the new combined product is more reliable its predecessor. This product will benefit from a fasttrack review status from the FDA, as well as strong regulatory protection in place as a stamp of approval bearing testament to its medical value to the patient.

combination, CDMOs need the skills and development capabilities to prepare the pharmaceutical part of the regulatory submissions in accordance with the expectations of various authorities – with the goal of getting the submissions to the regulatory authorities as early as possible.

Producing these products also further heightens the growing market and customer demand for CDMOs to develop the capability to provide one-stop-shop solutions – carrying out everything from formulation and development, clinical supply and then full commercial-scale product manufacturing. First they need to redesign the formulation then enact full redevelopment of the product before carrying out the manufacturing – both initially at a clinical batch scale and then full-scale commercial supply. Contained within the full suite of services, there is an imperative need for full product resource, project management and manufacturing capabilities.

The high quality one-stop-shop CDMOs meets their customers’ need to optimise time-to-market – this includes removing redundant activities and adding additional value to the services that they provide their customers.

Significant time and resources are saved for customers who no longer have to engage with multiple partners. Moreover, there is no loss of time due to tech transfers with the seamless transition from development through to clinical batch and then on through to commercial scale manufacturing.

The ultimate aim of go-ahead one-stop-shop CDMOs is to apply continuous improvement across the supply chain of formulation, development and clinical and commercial scale manufacturing and to bring products to market in as a swift fashion as can be achieved.

Recipharm has partnered with Redhill on this product. Developing the formulation and meeting the complex production demands for such drugs requires sophisticated formulation skills. It also demands development and manufacturing expertise, combined with the implementation of a highly integrated solution across three FDA approved sites – each with their own specialist manufacturing capabilities. Recipharm’s Fontaine and Pessac sites are manufacturing the omeprazole mini-tablets; in Strängnäs we have devoted further to encapsulating and packaging the finished product ready for final release.

There is especially strong demand from customers for CDMOs to work on modified release and fixed-dose products. With fixed dosage

WWW.EPMMAGAZINE.COM

39

Successfully managing the unique demands of cell therapy supply chains

WEBINAR Date: 20/04/2016 Time: 14:00 Europe/London Price: Free The unique complexity of an autologous therapy supply chain Cell-based therapies are being used increasingly to treat many diseases for which no other adequate treatment options are currently available. These therapies contain modified human cells that can regenerate or augment a recipient’s dysfunctional cells, tissues or organs. Cells’ biological characteristics are typically altered ex vivo before administration of the final product to patients.

Every constituent of the supply chain must be seamlessly orchestrated for a cell therapy product to reach every patient. From collection of cells through production into a drug product and reverse logistics back to the patient, this process is very complex but a risk based approach can mitigate potential challenges.

Join us for this free webinar to: • • •

Understand how product characteristics can influence your approach to managing the Cell Therapy supply chain.

Understand what might influence the decision to have centralized or localized manufacturing strategies.

Understand the information that is required to successfully import and export Cell Therapy materials.

Speakers: RACHEL GRIFFITHS, Associate Director, Technical Services at PCI Clinical Services DR. MATTHEW LAKELIN, Vice President Scientific Affairs and Business Development at TrakCel HOST: DAVID GRAY, Deputy Group Editor, Rapid Life Sciences

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

PCI Clinical Services are an integrated full service provider and a trusted partner to leading companies in the Clinical Trials arena.

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

FORMULATION

Meeting demand: To address the growing demand for formulation development and testing, Quotient has expanded both the breadth and depth of its services

Supply and demand Mark Egerton, CEO, Quotient Clinical, discusses reformulation drug development services for a changing market

O

utsourcing of drug development activities is now a core strategy for many organisations across the pharmaceutical sector, allowing internal resources to be focused on activities mostly likely to result in a marketable product. However, managing a network of CROs and CDMOs brings new communication and logistical challenges – which can be particularly evident once a candidate drug enters the clinical phase – potentially delaying the regulatory approval and launch of new drug products.

One approach which has been designed to streamline the outsourcing of clinical phase development is Quotient Clinical’s Translational Pharmaceutics platform. This innovative approach integrates formulation development, real-time GMP drug product manufacturing and clinical testing, helping to significantly reduce the time and cost of drug development by eliminating the difficulties of coordinating formulation development, tech transfer, manufacturing and clinical trials across multiple organisations and, sometimes, continents.

An elegant solution The benefits of this innovative approach have already proved popular, with over 50 leading pharmaceutical and biotech companies globally choosing Translational Pharmaceutics to accelerate development of products for a variety of indications and routes of delivery. As more organisations recognise the advantages of combining formulation development with real-time manufacturing and testing, there is a noticeable shift in the way companies use these services. Just a few years ago, only around 10% of Quotient Clinical projects involved formulation development; clients approached the company with formulations they had already developed, only outsourcing the real-time manufacturing and clinical testing. In contrast, 50-60% of Quotient’s projects now include on-site formulation development.

This shift correlates with the growth of Quotient’s formulation development experience and strengthening credentials, in combination with pharma and biotech customers recognising the time and cost savings available by performing the whole process under one roof. This has had a ‘ripple effect’ within the industry, with an ever increasing number of pharma companies re-evaluating the way they go about drug development, challenging the traditional approaches and working in partnership with specialist providers to create more efficient, streamlined and integrated workflows.

Meeting demand

Making success: 50-60% of Quotient’s projects now include on-site formulation development

To address the growing demand for formulation development and testing, Quotient has expanded both the breadth and depth of its services. For example, it has recently doubled the size of its formulation development laboratories and created an additional GMP manufacturing facility based at the MediCity life WWW.EPMMAGAZINE.COM

science innovation hub, just a few miles from the main Quotient Clinical site in Nottingham.

The new MediCity manufacturing centre has also delivered an unexpected benefit for the company’s formulation services – the addition of formulation development specialist Co-Formulate to the Quotient Clinical group. Based adjacent to the GMP facility, Co-Formulate is ideally placed to complement existing Quotient Clinical capabilities, bringing a wealth of expertise in helping customers to develop diverse solid, semi-solid and liquid formats, as well as formulations for paediatric and geriatric patients.

Broader horizons Integration of formulation development with clinical testing isn’t only applicable to newly developed drugs either. The Co-Formulate team has many years of experience in managing product life cycles, working with over-the-counter medicines and generic products to improve consumer satisfaction. By combining this expertise with Quotient Clinical’s GMP manufacturing and clinical facilities, Translational Pharmaceutics can be used to enhance existing products, creating key differentiators in a competitive marketplace.

The continued expansion of Quotient Clinical’s formulation development services into these new markets will further support the current industry trend towards outsourcing early drug development. With the added knowledge and understanding of consumer healthcare that Co-Formulate brings to existing capabilities, it will also provide additional tools for the life cycle management of existing drug products through the development of new formulations and routes of delivery, and will be interesting to see how this flexibility affects the future direction of the market.

41

FINE CHEMICALS

Growth chart Johnson Matthey recently expanded its Cambridge facility to add process development and small-scale manufacturing capabilities. Brian Fairley and Antonio Zanotti-Gerosa explain how this will benefit pharmaceutical manufacturing

J

ohnson Matthey’s facility in Cambridge, UK, is a recognised centre of excellence for catalyst discovery, chiral technologies and process identification. Earlier this year the company expanded the facility to add process development and small-scale manufacturing capabilities to the site, which also now incorporates the company’s recently acquired Pharmorphix solid form services business.

Johnson Matthey Fine Chemicals provides pharmaceutical services, active pharmaceutical ingredients (APIs) and catalyst technologies for companies in the pharmaceuticals, fine chemicals, agrochemicals and flavour and fragrances industries worldwide. The fine chemicals division’s teams of scientists work in an integrated fashion across eleven global sites to deliver broad services through four core offerings: catalysts, controlled substances, custom pharma solutions and APIs & life cycle management.

Until recently, the Cambridge facility largely focused on catalyst discovery and route identification. “It was recognised as a centre of excellence for catalytic processes and the development of new catalysts, for both chemo- and biocatalysis. Over the past fourteen years, it has become an important hub for catalyst development within Johnson Matthey,” said Antonio Zanotti-Gerosa, R&D director.

“We focused on four key aspects: heterogeneous catalysts for reductions, such as palladium carbon or sponge metals; coupling catalysts, such as homogeneous palladium catalysts; homogeneous reduction catalysts, such as those used in achiral reductions and other asymmetric catalyses; and also biocatalysis, which was strongly enhanced by our acquisition of X-Zyme in 2008.”

In Cambridge, these capabilities were limited to catalyst R&D and bench-scale manufacturing, typically up to 100 grams. “We usually worked with customers on specific transformations, developing new catalysts, and providing feasibility or proof-of-principle studies. Our projects have qualified numerous catalysts, such as palladium carbons or coupling catalysts, for transformations that have then gone on to be scaled up at the customer’s site,” Zanotti-Gerosa added.

Broadening the capabilities of the Cambridge facility to support scaleup and non-GMP kilo-scale manufacture of APIs was a driving force behind the expansion. Brian Fairley, director, business operations, explained: “We can now provide an integrated and synergistic approach to meeting customers’ catalysis, API development and scale-up needs.

Our catalyst teams will be working closely with the development teams to ensure all parameters are considered during scale-up of the catalytic step.”

Fairley added: “The expansion also means we can also work on other steps of customers’ API synthesis and this is important because their specific catalyst requirements are often just a small component of a much greater goal, to identify the overall most efficient and sustainable manufacturing routes.”

Services at the site now include route scouting, process development, optimisation and scale-up of heterogeneous, homogeneous and biocatalytic processes, as well as non-GMP kilo-scale manufacturing of APIs and intermediates for pre-clinical and toxicology studies.

Johnson Matthey Fine Chemicals already offers development and kilo-scale manufacturing services at some of its other global sites, but being able to provide these in Cambridge is advantageous for many local pharmaceutical companies. Once the product moves through development and receives necessary approvals, the project can be transferred seamlessly to the fine chemical division’s other European or US-based facilities for GMP manufacturing of clinical supplies, according to the customer’s needs.

“These early stage pre-clinical capabilities are an important addition to the Cambridge site, particularly given that this site serves many innovator customers from the growing Cambridge biotech hub who are developing new chemical entities (NCEs),” Fairley explained. “We’ve seen this at our Massachusetts site, which works closely with customers around the major Boston biotech hub, and found that such customers place great importance on being able to work closely with our chemists and analysts on-site, to be able to view the chemistry and receive local support to pre-clinical supplies and beyond.”

“In a recent example, one of our customers moved very quickly from early phase clinical development to very late phase clinical development and that would not have happened without the valuable expertise that our Cambridge scientists were able to bring,” Fairley continued. “We see these types of opportunity increasing now that we have our development and catalytic capabilities working hand-in-hand at the site.”

In October 2015, Johnson Matthey announced the acquisition of the Pharmorphix solid form sciences business from Sigma-Aldrich, bringing a number of specialist services and differentiating technologies to complement the fine chemicals division’s existing analytical capabilities.

“Pharmorphix is fully integrated into our expanded Cambridge site, providing valuable solid-state expertise that’s immediately available to strengthen our early-stage API development services,” Fairley said.

The newly completed Cambridge expansion adds significant capability, as it will accommodate double the previous numbers of process R&D scientists, with twice as many fume cupboards, and two new kilo labs with a 20-litre hastelloy hydrogenation vessel that can operate at up to 50 bar pressure. “ The expansion will also bring opportunities for the fine chemicals division to collaborate with the wider Johnson Matthey group, by making available its internal expertise for any catalytic development projects within Johnson Matthey’s Process Technologies, Emission Control Technologies and Precious Metal Products divisions.

WWW.EPMMAGAZINE.COM

43

EXHIBITION | CONFERENCE | NETWORKING

31ST INTERNATIONAL EXHIBITION FOR FINE AND SPECIALITY CHEMICALS

Chemspec Europe is exclusively dedicated to the fine, custom and speciality chemicals sector.

With its focussed profile it is the place to be for international industry professionals. Leading manufacturers, suppliers and distributors will present a wide spectrum of fine and speciality chemicals for various industry sectors.

Establish new business contacts, benefit from excellent networking opportunities and be inspired by the latest results in Research and Development at top-class conferences. Be part of the show where ideas become innovations!

TOP-CLASS CONFERENCES & WORKSHOPS! • Royal Society of Chemistry Symposium • REACHReady Regulatory Services Conference

• Agrochemical Intermediates Conference • The Pharma Outsourcing Best Practices Panel

www.chemspeceurope.com

Organisers:

1- 2 JUNE 2016 / BASEL MESSE, SWITZERLAND

Mint condition: By performing certain tasks in controlled environments and the use of well-defined hygiene and cleaning procedures, product contamination risk is minimised

CLEANROOMS

Controlling factors Laura Bailey, Wickham Laboratories, outlines best practices in microbiological qualification and monitoring of environmental contaminants

A

s anyone involved in the development and manufacture of pharmaceutical products and medical devices knows, a clean environment is crucial to ensuring the safety and viability of the end product. Environmental monitoring describes the processes and activities that need to take place to characterise and monitor the quality of the environment. This monitoring provides evidence that the facility and documented procedures are fit for purpose in controlling product or device bioburden within specified limits.

Because aseptic processing relies on the prevention of microorganisms from entering open containers during testing, microbial bioburden of the environment must be evaluated on a regular basis to ensure compliance with Good Manufacturing Practice (GMP). Criteria for the assessment of bioburden varies according to the classification of the room itself however the basic principles of environmental monitoring and good housekeeping procedures remain the same regardless.

By performing certain tasks in controlled environments, such as laminar flow cabinets or isolators, and by the use of well-defined hygiene and cleaning procedures within the facility, the product contamination risk is minimised. Initial qualification of these controlled environments, including room set up and cleaning procedures, should be carried out both in rooms empty of equipment to assess any air flow issues and after equipment has been installed to verify the impact of any changes made to the air handling change rates.

Factors which should be considered in selecting sites for routine monitoring are: • Where would microbial contamination most likely have an adverse effect on samples during testing?

• Which surfaces represent the most inaccessible or difficult areas to disinfect?

• What activities are performed in the area which might contribute to the spread of contamination?

• Which areas are closest to high traffic areas or are situated nearby to doors opening in or out?

• What are the flow processes in the lab – personnel, waste, etc?

• What is the potential for contamination from interventions and manipulations?

Once the specifics such as which areas should be assessed and how much sampling there should be have been decided, the method of monitoring must also be considered. Microbiological monitoring can be undertaken by active air sampling utilising a validated viable particle

collection device (air sampler), or passive sampling via settle plates and contact plates. Which method is most appropriate is determined by the requirements of each particular assessment.

Active air sampling is an effective method of determining airborne contamination in a clean room environment through a microbial air sampling unit or a compressed gas monitoring system. This does require either the purchase or hire of equipment, training and qualification of the device, however active air sampling is often advantageous in a low bioburden environment.

On the other hand, passive air sampling is cost effective and offers a longer sampling period from which to assess any contamination present.

Settle plates (using TSA and SDA) are best utilised for determination of viable particulate contamination for a defined area over a specified time period.

Contact plates are used in estimation of the microbial contamination present on surfaces within the laboratory environment. All surfaces not just those used directly in testing must be assessed, in particular those which are located nearby high traffic areas or which undergo regular use before and after testing procedures. Examples of commonly used surfaces which should be routinely monitored include telephone handsets, exit doors, and product bins. Contact plates containing lecithin and tween are used to minimise the effect of residual disinfectants on the recovered microorganisms’ growth.

For surfaces where the use of a contact plate is impractical, environmental swab tests may be used to assess contamination. The method applied to these environmental swabs is semi-quantitative and should be used as an indicator of overall contamination or to monitor trends or sanitisation procedures.

Given the paramount importance of cleanliness within the laboratory, manufacturing unit or any other area in which a product or device may be exposed to latent contaminants, a confirmed schedule must be in place to monitor the air and aseptic processes within the facility that may affect test results. Should any contaminants be identified during the monitoring process, root cause analysis should then be performed in order to identify and address the cause of the contamination.

Characterisation of recovered microorganisms is also useful within an environmental monitoring program of trending and identification as these isolates often correlate with the contaminants found in the working environment. Providing a complete overall environmental picture provides valuable information for any required investigation as well as facilitating the introduction of additional procedures to ensure aseptic processing in future.

WWW.EPMMAGAZINE.COM

45

SPECTROSCOPY

How Transmission Raman works

Check point Darren Andrews, business development director, Cobalt Light Systems, outlines the way that Transmission Raman spectroscopy is replacing HPLC and more in QC laboratories

T

ransmission Raman spectroscopy (TRS) has been used for over five years as an alternative to HPLC for API dose quantification and as a means to determine residual crystallinity quickly in intact tablets. It has earned its place in QC laboratories with well-matched analytical characteristics and by demonstrating cost-reductions of 75% for the more expensive end product tests. Using TRS, content uniformity and assay tests can be completed in minutes with no sample preparation or consumables used. TRS has gained regulatory approval for several products, replacing content uniformity (CU), assay and ID as the release method. As real-time release testing increases in interest by pharmaceutical companies and regulators TRS is beneficial because of its short analysis time – up to 10 tablets per minute.

Tablets and capsules are manufactured in hundreds of thousands per batch in campaigns that produce millions of dosages in total. The mandatory tests of uniformity of dosage units (UDU), assay and ID, are used to ensure that the patient receives the correct active ingredient at the right potency. Content uniformity testing is the most common method for UDU, traditionally using HPLC, which has become the industry standard method. HPLC is slow and resource-intensive and, as anyone who has visited a QC laboratory will know, manufacturing sites need tens of instruments and many people to service the numbers of batches produced by a typical plant. UPLC systems can reduce the run time of individual measurements but the cost and time is still dominated by the manual steps needed to prepare the tens of solute samples from each batch.

TRS is not an absorption technique, unlike near-infrared spectroscopy, but relies on the weakly interacting Raman scattering process. This means that TRS can measure through coated or uncoated tablets up to 10mm thick and also coloured gel capsules. The scattering process weakly interacts with the physical properties and is insensitive to moisture, which A TRS100 transmission Raman instrument in use

makes application development easier and measurements less prone to manufacturing variance. Because Raman spectra have sharp features, much like a mid-infrared spectrum, the data is easy to interpret and formulation problems can be easily diagnosed. Typically, Raman signals are greatest for the active ingredients compared with the excipients, which means that a low limit of quantification (<1%) is often possible.

Due to the ease of operation and fast measurement times with TRS the cost per test is reduced and, without a sample preparation step, the measurement error and reproducibility is significantly improved.

For some products or for process validation, larger numbers of tablets might need to be tested. A single sample tray of a Cobalt Light Systemsâ&#x20AC;&#x2122; TRS100 can hold up to 200 tablets, which might take around 30 minutes to analyse â&#x20AC;&#x201C; by comparison, HPLC would need at least four people and four HPLC instruments to complete the same number of measurements and would take around 30 hours to complete.

TRS is a non-invasive technique with no consumables and does not require extensive training to operate. This makes it ideal for use outside the QC laboratory. QC laboratories might analyse tablets three or four weeks after they are made, fitting it into other work they are doing, only then releasing batches to packaging and to sale. Putting a TRS instrument in a manufacturing area allows companies to do the most intensive tests with the highest failure risk (often CU and assay) during a batch run, allowing product to be released more efficiently and for companies to react more quickly to market needs. This kind of real-time release testing also enables an increase in quality; it is an interesting fact that the active ingredient content (by CU and assay) of a batch of 1 million tablets would normally be determined by testing as few as 20 of those tablets.

Implementing new technology in QC needs some internal development in QA and QC to create method submissions that can be approved by regulators. The view from US and European regulators is that the existing guidance on NIR submissions gives the appropriate starting advice for creating a TRS method. This is the usual route that has been taken to begin achieving regulatory approval for new methods, with relevant guidance appearing in USP1119, EP2.2.40 and EP2.2.48.

The growing interest in TRS and user-groups came together in a recent seminar in Oxford. Some of the talks, by leading industry experts, are available here https://www.cobaltlight.com/trs100seminar, including presentations about gaining regulatory acceptance for release test methods. Given the increase in production of pharmaceuticals and the drivers to reduce manufacturing costs with increases in testing, TRS has an important future in the pharmaceutical industry.

WWW.EPMMAGAZINE.COM

47

SPECTROSCOPY

What do you need to know about European Pharmacopoeia compliance?

Thermo Fisher Scientific looks at the key points for compliance…

Are you ready for EP compliance?

History of industry-leading performance

The use of handheld Raman for the identification of raw materials has become increasingly prevalent in the pharmaceutical industry over the past five years, resulting in a need for definitive performance criteria for handheld Raman spectrometers. In response to an obvious need for specifications that can ensure reliable verification and the safe manufacture of medicines, the European Pharmacopoeia (EP) is introducing new standards for benchtop and handheld Raman analysers this year.

The Thermo Scientific TruScan family of instruments boasts over 1000 GMP installations worldwide since its introduction in 2008. These handheld analysers are used at leading pharmaceutical companies to ensure the efficient release of raw materials and to screen for falsified or substandard medicines. TruScan’s patented chemometric algorithm, in conjunction with superior spectrometer stability, allows sharing across large numbers of instruments without the need to establish a spectral library for each instrument. TruScan analysers are designed to be used in GMP raw materials identification (RMID) testing without the need for recalibration. They do not require any user calibration and their laser and spectrometer stability is designed to eliminate the need to update the analyser’s hardware or manufacturing operations to ensure compliance.

European Pharmacopoeia Supplement 8.7 In October 2015, the European Pharmacopoeia Supplement 8.7 was published, including a revision to Chapter 2.2.48: Raman Spectroscopy.

This supplement will be effective on April 1, 2016. Of particular note, the revised chapter includes separate acceptable Raman shift band position tolerances for benchtop and handheld Raman analysers for polystyrene, paracetamol and cyclohexane.

EP changes impact pharmaceutical manufacturers For the first time, the European Pharamcopoeia has established specific wavenumber accuracy requirements for handheld Raman spectrometers. These new specifications give pharmaceutical manufacturers clear guidance on the requirements for use in GMP environments. Manufacturers will now have well-defined parameters without the need to justify analytical performance individually. Overall, these changes should streamline the deployment of handheld solutions for the release of raw materials.

48

In anticipation of the new requirements, Thermo Fisher Scientific has adjusted all validation procedures and acceptance criteria for initial instrument calibration as well as annual calibration re-certifications.

The company says it is closely monitoring regulatory expectations to best meet customer requirements going forward.

All the above are well used methods to safely control dust ignition and explosions. However, any pharmaceutical dust explosion risk would always warrant further attention.

Protecting against dust explosions requires due diligence, which informs appropriate preventative measures. To do anything less would invite disaster because just one spark could destroy lives and livelihoods, not just on site but along a vital supply chain.

WWW.EPMMAGAZINE.COM

CAD/CAE SOFTWARE 3D PRINTING ADDITIVE MANUFACTURING MOULDING & TOOLING MACHINE TOOLS METROLOGY INSPECTION

28 SEPT - 29 SEPT 2016

REGISTER NOW

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 an eye on ...

Delivery service Amrita Banerjee, post-doctoral scholar, University of California Santa Barbara talks oral insulin and needle-free delivery of protein EPM: Who are you and what do you do?

AB: I am a postdoctoral scholar in the department of chemical engineering at the University of California Santa Barbara. My research is geared towards development of novel platforms for delivery of protein and peptide drugs, especially for the treatment of diabetes. This includes development of both nanotechnology-based parenteral formulations as well as oral drug delivery device for needle-free delivery of protein drugs.

Q & A

EPM: What have you focused on recently?

AB: The focus of my work recently is to develop an oral delivery device for insulin. There are many barriers to oral delivery of protein/peptide drugs such as low intestinal permeability and instability in the gastrointestinal tract due to stomach acid and proteolytic enzymes present in the intestine.

The oral drug delivery device that has been developed in the laboratory addresses all the oral delivery concerns of protein and peptide drugs.

It consists of insulin loaded mucoadhesive patches that are placed in enteric-coated capsules for site-specific delivery to the intestine.

Enteric coating on the capsules prevents capsules to break open in the stomach while mucoadhesive polymers in the patches enable strong adhesion of patches to intestinal mucosa that eventually swell and release insulin in a controlled fashion.

The patches not only prevent access of proteolytic enzyme to breakdown insulin but also provide a large depot of the drug for higher concentration gradient dependent transport across the intestine.

The patches are coated on all but one side with a water impermeable backing layer that prevents drug loss into intestinal lumen from the sides that are not attached to the intestine.

To facilitate transport further, I have included a permeation enhancer in the patches that improve paracellular uptake of insulin at the intestine.

In vitro characterisation studies have demonstrated complete release of insulin and permeation enhancer from the patches and strong mucoadhesion of patches to intestinal mucosa.

Preliminary pre-clinical studies have indicated significant improvement in therapeutic efficacy of the oral device compared to other oral formulation controls.

50

Amrita Banerje e

EPM: How can you benefit the pharmaceutical sector?

“

Needle-free technology is a painless method of drug administration especially for management of chronic diseases such as diabetes.

”

EPM: What is your latest service/ innovation?

AB: Over the past few months I have been working to further improve the efficacy of the device for oral delivery of insulin.

I have miniaturised the patch design to bring about rapid drug release and obtain faster acting formulations.

In addition, I have incorporated specific or non-specific protease inhibitors in the device to further prevent proteolytic degradation of insulin in the gut.

The formulations are currently being evaluated for their efficacy in pre-clinical experiments.

WWW.EPMMAGAZINE.COM

AB: There is a big impetus within the pharmaceutical sector to develop effective oral delivery systems for peptide/protein drugs.

Needle-free technology is a painless method of drug administration especially for management of chronic diseases such as diabetes.

This makes it a more patient compliant alternative to insulin injections, especially for people with needle phobia.

The drug delivery device developed in our laboratory, if successful, will not only provide a much needed platform to the pharmaceutical industry for efficient oral delivery of peptide/protein drugs but also significantly improve the quality of lives of thousands of patients around the world that are suffering from diabetes or other chronic diseases requiring regular parenteral drug administration for disease management.

EPM: What are your future plans?

AB: Future plans include further testing of the devices and optimising the patches to obtain higher oral bioavailability of loaded drugs.

This includes using novel mucoadhesive polymers in the patches for stronger mucoadhesion to the intestinal mucosa and higher permeation enhancement effect.

CONTAMINATION CONTROL

This is What Safety Looks Like…

…and it begins with Klercide Sporicidal Alcohol You can’t put a price on a life. But you can improve your transfer disinfection processes to protect that life.

With regulations requiring the use of sporicidal agents when introducing components into aseptic areas, transfer disinfection is a major challenge to manufacturers and end-users alike.

Klercide Sporicidal Alcohol, the new patented* formulation from Ecolab, provides a range of potentially life saving benefits, including rapid flash-off and sporicidal efficacy in two minutes (EN 13697**).

TO FIND OUT MORE ABOUT OUR UNIQUE SOLUTION FOR TRANSFER DISINFECTION, PLEASE CONTACT YOUR ECOLAB CONTAMINATION CONTROL EXPERT, EMAIL US AT INFOCC@ECOLAB.COM OR CALL +44 (0)2920 854 390 ECOLAB CONTAMINATION CONTROL Brunel Way, Baglan Energy Park Neath SA11 2GA UK www.ecolabcc.com © 2016 Ecolab All rights reserved 8327/03.16

REFERENCES * patent pending ** modified EN 13697 sporicidal surface test - log 2 reduction achieved USE BIOCIDES SAFELY. ALWAYS READ THE LABEL AND PRODUCT INFORMATION BEFORE USE.

Scan here to see the full story of how safety starts with new Klercide Sporicidal Alcohol

CONTAMINATION CONTROL

WITHOUT COMPROMISE

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