EPM September 2017

DWELLING ON IT I HOLLAND LOOKS AT THE IMPACT OF DWELL TIME ON TABLET PRODUCTION PLUS: SEPTEMBER 2017

• THE PERFECT PARTNERSHIP • INSTRUMENTS OF CHANGE

For dry forms For powder form

Packaging Primary

For doughy formulations Material for capsules

Pharma

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Contents September 2017 | Volume 17 Issue 6

18

Regulars

Features

5

12

EDITOR’S DESK

BIOLOGICS

With the ever-increasing popularity of apps, we take a look at how pharma is competing in this space.

Discussing the key considerations of manufacturing, the importance of strategic partnerships, the best biomanufacturing strategy and patient-centric packaging in biologics.

6 REGULATORY AFFAIRS

23

Examining outsourcing projects in more detail.

DRUG DELIVERY DEVICES

8

Highlighting various forms of drug delivery devices and how patient adherence can be improved through technological innovation.

OPINION Exploring the differences between the Building Information Modelling levels, their benefits and what it means for pharma.

10 ON THE COVER I Holland details how Dwell time impacts tablet manufacturing.

50

27 42

30 HIGH POTENCY FACILITIES Here, Mike Avraam from ChargePoint Technology describes the growing sector of high potency facilities in detail.

32

LAB DIARY

DIGITAL HEALTH

Looking at how cloud-based software can help with accuracy.

Exploring the challenges, opportunities and technological advancements in the advancing field of digital health.

39 PACKAGING Reviewing label management, the challenges of child-resistance, traditional options, future trends, automation and temperaturecontrolled requirements in pharma packaging.

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 editor felicity thomas felicity.thomas@rapidnews.com deputy group editor dave gray david.g@rapidnews.com group editor lu rahman, lu.rahman@rapidnews.com reporter reece armstrong reece.armstrong@rapidnews.com publisher duncan wood

production art robert wood

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

Volume 17 Issue 6 © September 2017 While every attempt has been made to ensure that the information contained within European Pharmaceutical Manufacturer is accurate, the publisher accepts no liability for information published in error, or for views expressed.

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

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editor’s desk Don’t worry be ‘App’y Apps are ever more popular and becoming part of daily routine and lifestyle in this digital age, but how are pharma companies measuring up in this space?

Most of the time when I hear ‘apps’, what springs to mind are the social or gaming type applications, yet, many pharma companies have been knee deep in this digital minefield for a few years and health and lifestyle apps are becoming ever more popular with the masses.

Despite attempts to infiltrate this lucrative area, however, pharma companies are struggling to keep up with the competition. A recent report from Research2Guidance1 found that even though there was an increase in the number of pharma apps available for download last year most have struggled to gain a significant number of downloads within target groups.

So, what are pharma companies doing wrong? An interesting article from Fliplet — a company focused on improving business mobility — stresses the importance for pharma companies to keep putting the effort in with app development as in their opinion these will become key tools for all industries. However, they believe that the focus of current pharma apps is perhaps to blame for the disappointing downloads — most pharma apps are ‘customer-facing’ and B2C in focus, Fliplet believes enterprise apps should be considered.2 Giving some examples, Fliplet reveals ways that an app can optimise internal operations whether through improving the sales reps’ knowledge, offering a useful resource for medical information or as a time saving tool to help train new employees. Through focusing on enterprise, pharma companies could optimise workflows and increase productivity, which is critical in this innovative sector.

The fourth example given is, however, focused on the customer — a medication tracking and analytics app — which they specify can help the patient and also give the company better insight into how a product performs. This possibility opens the door not only to products currently available to patients but also those undergoing clinical trials — an avenue that some, such as AstraZeneca, have already explored.3 Even with a decline in ‘successful’ pharma apps,1 we have seen some recent success stories involving collaborative efforts. Roche, for example, signed an agreement to acquire all shares of mySugr — a specialist in app-based all-round care for diabetics.4 The mySugr platform combines apps and services to coach diabetic patients and help them manage their disease, as well as offer automated data tracking and integration with numerous medical devices to ease disease burden. For Roche, the plan is for this platform to be the focal point of

its integrated diabetes management strategy and offers a patientcentric service.

Another collaborative effort in the diabetes mobile app field, from Novo Nordisk and Glooko, was announced earlier this year.5 These companies offer Cornerstones4Care, an app that syncs a user’s blood glucose and activity data from many currently available medical devices, tracks glucose, meals and activities, identifies trends and offers resources to diabetic patients for disease management.

To do this the companies have combined their relative fields of expertise, those being Glooko’s digital platform and data analytics and Novo Nordisk’s diabetes knowledge and personalised patient support.

So, the key messages for a successful pharma app seem to be the focus — could it be beneficial to have an app focused on internal operations rather than the patient? — the benefits it will offer — can it raise brand awareness, help with data analytics or patient adherence in clinical trials? — and collaborative opportunities — would it prove advantageous to partner with a specialist in the field of mobile apps to ensure success?

Perhaps it is safe to assume there will be a reduction in the number of apps we see launched by pharma companies in the near future but hopefully, if some of the basics are carefully considered (as highlighted above), those that are released will be optimised and focused, benefitting those using them as well as the companies that developed them.

Thanks, Felicity

References: 1. https://www.epmmagazine.com/news/report-finds-that-chances-of-pharma-companies-creating-a-suc/ 2. https://fliplet.com/blog/pharmaceutical-apps-ideas/ 3. http://digitalhealthage.com/astrazeneca-launches-app-for-cancer-clinical-trial/ 4. http://www.roche.com/media/store/releases/med-cor-2017-06-30.htm 5. http://digitalhealthage.com/novo-collaborates-with-glooko-to-develop-a-range-of-digital-health-tools-for-diabetics/

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5

REGULATORY AFFAIRS

Practically popular As pressure to get drugs to the human clinical trial stage increases more companies are looking to outsource not only non-core functions but major areas of R&D. Here, Praveen C. Surana, senior director of Business Development, ELC Group, examines outsourcing projects in more detail.

W

ith increasing pressure to take potential drugs from discovery to human clinical trials as quickly as possible, many companies are moving towards outsourcing at least a portion of their drug development. Previously, major pharmaceutical companies outsourced mainly non-core functions. Now, more companies are outsourcing major areas of research and development activities, including formulation development — ranging from early formulation development for animal studies to optimisation for Phase I, II and III under cGMP compliance, to clinical or commercial Companies planning to supplies. outsource need to realise

“

that such projects require management and oversight by people familiar with the science of the project and of the project’s place in the larger scheme of things.

Outsourcing compresses the product development timeline, providing a cost-effective alternative to adding specialised resources and allowing variable cost structures.

Crucially, a higher degree of efficiency can be attained at a lower cost, thus achieving early access to technologies and expertise. Outsourcing projects generally fall into two broad categories: those requiring specialised solution provider services to solve an existing product development problem, and those that have been planned entirely as outsourced activities from start to finish, as in the case of many generics.

”

Outsourcing is operated in multiple business models, the most common including: a) Full time equivalent (FTE)-based model — a simple, risk-free model whereby the sponsor pays the service provider a set fee for a fixed period, depending on the number of scientists engaged for the specific project. b) Fee for service — works on milestone-based payments, which are pre-determined and time-bound. The risks associated with the fee for service model are higher on the sponsor and the costs are less. c) Out-licensing model — the service provider develops the product or technology until proof of concept is established, and then scouts for partners to invest further in formulation research or in manufacturing the drug product (a substantial part of the development). d) Co-development — currently gaining popularity. Sponsor and service providers share the risk and reward in proportion to their respective investments. However, ownership of intellectual property here is a tricky

6

issue. Co-development is suitable for companies with fewer financial resources, or companies with niche capabilities that come together to provide integrated solutions or products.

All outsourcing comes with potential challenges, including closure or takeover of facilities, breaking up of specialist teams or weakening of R&D capabilities and so on. Service providers are under intense productivity pressure, thus have less time to reflect, learn and train. The cost savings that result from outsourcing R&D can be easily overshadowed by the added complexity required to manage the process throughout the organisation.

Once the decision to outsource is made, sponsors may evaluate the following factors in choosing a contract service provider: 1. Is formulation development the core business of the service provider, are they specialised in it and do they have necessary capabilities to meet the requirements of the sponsor?

2. While many traditional service providers are focused on small molecule new chemical entities (NCEs), many are building speciality groups to deal with the increasingly diverse and specialised needs such as cytotoxic drugs, gene therapy, drug delivery technologies and biotechnology products.

3. For NCEs, an integral part of formulation development is defining the ultimate clinical dosage form. This decision is a combination of science and business. Once the delivery decision is made, it is important to check whether potential service providers have capabilities with the required dosage form.

4. For outsourcing decisions on formulation development, cost is obviously a factor, but choosing the most appropriate resource based on outsourcing objectives will be far less aggravating and result in less hand-holding.

In the current climate of declining research productivity and increasing pressure to maintain profitability, outsourcing formulation development can provide an effective approach to decrease the overall cost of drug development. It can also lead to faster formulation development, and incremental innovation leading to the creation of intellectual property.

Companies planning to outsource need to realise that such projects require management and oversight by people familiar with the science of the project and of the project’s place in the larger scheme of things.

There is no place for a ‘throwing it over the fence’ mentality.

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expand the rules continuous has come

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OPINION

Come up to standards For many years, the construction industry was said to be behind the times in adopting new technology. Whilst the automotive, energy and aerospace industries evolved and incorporated concepts such as Industry 4.0, construction was left behind. Neil Pullman, principal architect at, Boulting Environmental Services, explores the differences between BIM Levels, their benefits and what it means for the pharmaceutical sector.

I

n 2011, the UK government formed a new mandate calling for the construction and infrastructure sectors to adopt the Building Information Modelling (BIM) concept as a way of changing the dynamics and behaviours of the industry.

By incorporating BIM Level 2, the government hoped to trigger a revolution in the sector and welcome a new era of digital construction. But what does this mean for the businesses working with this new breed of construction company?

”

What is BIM?

Benefits of BIM to the pharmaceutical sector

BIM is all about integration. It is a concept that manages information from a variety of sources linked with the construction, renovation or demolition of a building. The key output of the process is a digital model of the building. The level of detail within this drawing is dependent on the criteria the developer is using.

One of the key benefits of incorporating BIM into a pharmaceutical build is the ability to detect clashes and extract data from the model. With a 2D model, it is very easy to miss clashes which can cause severe problems when the facility is in construction. A 3D CAD model allows you to de-risk construction, minimising problems on site.

BIM in pharmaceuticals When building cleanrooms and laboratories, there are many more factors to be taken into consideration than in a conventional office. With working parts built into the structure of a room, an object orientated database needs to be created detailing exactly how equipment works.

Although BIM promotes best practice, it’s important to involve the client as early as possible to see to what extent they will use the model postbuild. While many within the pharmaceutical sector can see the benefits of BIM, some are reluctant to embrace it. This is attributed to a lack of understanding of the concept.

While there is a natural progression towards the standard, a debate has emerged about when to train people on BIM. Up until now the process has evolved organically, and it will continue to do so as people introduce the skills to those entering the sector. Soon we will reach critical mass where decision makers are educated in BIM and incorporate it in all their projects.

8

“

BIM is a powerful tool for showing clients exactly how their facility will work.

BIM is a powerful tool for showing clients exactly how their facility will work. GlaxoSmithKline (GSK) is a prime example of a client which has embraced BIM. We have carried out construction works on several GSK sites within the UK. For each one we have produced a full 3D model, providing users with almost photographic images of the proposed facility.

The collaborative process allowed us to work off-site and pre-fabricate certain elements of the build, which were then installed later. BIM ensured that all the pre-fabricated elements fitted perfectly with the pre-installed elements. Without BIM, the idea of pre-fabricating a build would not be possible. The process not only saved time and money, but the client was left with a cleaner site throughout the build.

The seeds of revolution have been sown in the construction industry, but for the BIM concept to be truly embraced, suppliers must continue to educate and inform clients of its benefits, post-construction.

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COVER STORY

Dwelling on it In an environment where production speed is becoming more important and efficiency while being economical is a driver for manufacturers, acknowledging the significance of dwell time in tablet production is a must. Here, I Holland details how dwell time impacts tablet manufacturing and reveals the new technology that may help with the production process.

M

any tablet formulations are dwell-sensitive and require more time under compression to ensure they come off the press without any faults. In tablet compression, dwell time is the time that the punch head remains in contact with the compression roller. It is defined as the amount of time that the compression force applied when forming the tablet is above 90% of its peak value.

Some granules are extremely difficult to compress effectively and require extended time under peak compression to obtain the required tablet hardness and prevent any difficulties like sticking, one of the most frequent and challenging problems in tablet manufacture. Sticking By adding new is the build-up of granule on the punch tip face, this leads technology, like to tablet press downtime and reduced tablet output. Quite often to solve the problem, the press speed is reduced or a extended flat higher compression force is applied. Both these solutions head tooling, can solve a sticking issue but can also cause other issues dwell time can such as lower productivity and a longer dissolution time be increased due to the increased tablet hardness.

“

to form quality tablets and at an increased output.

It is not just sticking that can cause production problems, capping and delamination may also be an issue. Trapped air pockets in the forming tablet can cause severe problems during manufacture. If the air is insufficiently squeezed out and/or density variations occur in the tablet volume, the tablet tensile strength is negatively affected and the risk of tablet capping or delamination increases.

�

One of the most effective methods to reduce the risk of air entrapment is to extend the dwell time to expel air from the tablet, alternatively tapered dies can be used or the press can be slowed down but this again has a negative effect on production rates.

Do you know your formulations characteristics?

If problems like sticking or capping do occur, consideration must also be given to the characteristic of the ingredients within a formulation. They can feature plastic or elastic properties, which play an important role in the compaction of a tablet as they influence the contact between particles.

Particles that display elastic form will change shape during applied stress, however this is reversible, with the particle returning back to its original shape when the applied stress is alleviated. Plastic properties on the other hand display very different characteristics. When stress is applied they are permanently deformed. Their behaviours can change depending on the force employed and the length of time beneath it. In formulations that have more time-dependent consolidation behaviour, a long dwell time is important to create strong bonds between the particles and form a solid dose that does not result in problems like capping.

10

A formulation may also have non-cohesive characteristics where particles fail to bind together adequately resulting in friability with tablets having the tendency to crack, chip or break during compression. By analysing key production factors including dwell time, weight control, expansion and the tooling condition, the possibility and impact of friability can be minimised to produce a quality tablet.

Moisture within a tablet also plays an important role within dwell time. When the adhesive forces of the formulation to the punch tips overcome the cohesive forces within the tablet then sticking can occur.

Water can be one of the causes of a rise in adhesive forces; this happens by the increase in capillary action between the tooling surface and the granule. Capillary bridges form causing high adhesion areas, and so initiating sticking. Moisture can enter into the process either in wet granulation or due to excess humidity in the compression chamber of a non-environmentally controlled area; the latter can even impact direct compression formulations.

To form effective tablets from granulate, significant compression force is required, however, the exact amount of force and period of time that is applied needs to be carefully calculated. Too much or too little of either can result in irreversible tabletting or tooling issues during production.

If dwell time is significant then the area of punch head flat available can be a major factor in determining the overall success and profitability of tablet production. In a situation whereby a greater compression period is required there are tools on the market to help. Extended dwell flat tooling, which uses an elliptical head form to lengthen dwell time, enables a suitable compression dwell time for a formulation without the disadvantage of slowing the press.

I Holland has developed an innovative tool to do this, the eXtended Dwell Flat (XDF). By using XDF, turrets and cams do not have to be modified, unlike other tooling and equipment used to increase dwell and the press speed does not have to be reduced. For XDF tooling both the upper and lower punches are required to travel under the compression roller in the correct orientation to extend the dwell time. With punches used to manufacture a shaped tablet, the punches are already held in the correct orientation so no further change of specification is need to run XDF tools.

When round tablets are being manufactured, anti-turn keys are added to the tooling to keep the tool in the correct orientation (just like it would be for shaped tooling).

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Dwell time (ms) =

(

)

Head Flat Diameter (mm) Press pitch circle Diameter (mm)) x (RPM) x (π)

x 60 x 1000

It has been proven that extended dwell flat tooling can have a huge impact on tablet output, for example a press with a Pitch Circle Diameter (PCD) of 450 mm with Euro ‘B’ tooling (9.5 mm head flat) compared to XDF tooling (15 mm dwell flat) would have the following dwell times when the press is run at increasing RPMs.

Extensive studies have taken place to look at the benefits of XDF tooling when compared to other dwell time increasing options. The tests showed that XDF tooling outperformed competitors tooling when compressing tablets from difficult to compress formulation, for example plastic or elastic forms.

In a recent study for a difficult to compress elastic formulation (approx.

90% starch), the tensile strength of the tablet increased significantly over the standard tooling with increasing compression forces.

RPM of turret

EU 19 Dwell time (ms)

XDF Dwell time (ms)

Tensile Strength of Tablets (Mpa)

35

11.52

18.19

Tooling Manufacturer

Dwell Time (ms)

50

100

200

400

45

8.96

14.15

I Holland XDF

20.0

0.1

0.4

1.5

2.7

55

7.33

11.58

Competitor A

11.6

0.1

0.3

1.1

2.0

65

6.21

9.79

Competitor B

9.0

0.1

0.3

1.0

2.0

Competitor C

12.0

0.1

0.3

1.2

2.1

Competitor D

9.7

0.1

0.23

0.8

1.5

The use of XDF tooling increases tablet output (tablets per hour — tph) by nearly 60% on the same dwell time as an Euro ‘B’.

CASE STUDY These results were proven in a production environment. A leading pharmaceutical manufacturer had been experiencing problems with tablet friability when running the press at high speeds.

The customer’s production expectations were as follows: Run speed

= 225k tph

Target tablet hardness

= 8.5 kP

Tablet weight specification

= 3.46–3.66 g

Friability (20 tablets for 30 mins at 25 rpm) = No tablet failures (capping or broken) Using their existing Euro B tooling, the customer was able to run their tablet press at just 150k tph due to a variation in tablet hardness. It resulted in a reduced output of 75k tph against their target.

During these trials, it was identified that slowing the press seemed to eradicate the friability issues. It was this conclusion that led I Holland to recommend increasing the dwell time with XDF tooling. The elliptical head

Stress (Mpa)

flat design fitted directly into their current tablet press and turret without costly changes to the machine and would potentially increase the dwell time by almost 60%.

In this case, as the press was running smoothly at 150k tph (with a standard head flat), using XDF tooling with an optimised head flat allowed production to be increased. The required speed of 225k tph was achieved using all the standard cam tracks and press equipment, presenting a significant cost saving.

The customer was able to produce excellent quality tablets to the correct hardness, friability and weight specifications at an optimum tablet press speed of 225k tph. This resulted in a 50% increase in tablet output and a significant time saving in production.

Following the trial, the customer independently performed a very comprehensive validation process, concluding that XDF tooling should always be used with this difficult formulation.

Overall it has been demonstrated through rigorous trials that the use of tooling like I Holland’s XDF helps to prevent problems like sticking, capping and friability. It also has the added benefit of being used to stop poor embossing definition and improve tablet hardness.

Summary Dwell time plays a significant part in determining if a tablet can be produced successfully, especially those incorporating formulations that are challenging to compress.

Many tablet formulations are dwell sensitive and the time they are under compression has a huge impact on the final product. If a formulation displays difficult non-cohesive characteristics, for example, plastic or elastic properties, the amount of time the formulation is under compression has an impact on production, for example, stopping the press due to problems like sticking and capping.

By adding new technology, like extended flat head tooling, dwell time can be increased to form quality tablets and at an increased output. There is also the benefit of the tooling running on an existing table press without the need for time-consuming and expensive modifications.

With the increasing requirement to produce quality tablets quickly and efficiently in the most economical way possible, implementing tooling that will help in the production process is essential.

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11

BIOLOGICS

Top choice?

In this article Steve Lam, senior vice president and head of biologics, Patheon, looks at which choice is best when developing a biomanufacturing strategy.

“

The key is to develop a manufacturing strategy that balances responsiveness and cost while enabling the company to meet its forecasted demand.

G

lobal pharmaceutical companies are expanding their biologics pipeline, and biologics represent an increasingly large share of new drug approvals, accounting for 32% of total new molecular entities (NMEs) in 2016, up significantly from only 10% in 2005. There are currently 12,382 biologic projects in clinical development, 1,600 of them underway in neurology alone.

The maturing biologics pipelines at major pharma companies has created a dynamic in which smaller biotech companies need to keep their assets for longer. This means they need funding during the later stages of development and need to continue manufacturing products for late stage clinical trials. This is changing the already-challenging funding dynamics for biotech companies and increasing their reliance on external capacity.

Bulk product requirements are increasing, but at a lower rate than the size of the biologics pipeline. Changes in capacity requirements are due to advances in cell lines and processing technologies; the increasing focus on rare disease therapies, which target small patient populations; and competition for market share. This creates an interesting opportunity for biopharmaceutical companies and contract development and manufacturing organisations (CDMOs) alike, demanding new investment strategies and increasing demand for flexible, mid-scale capacity.

Commercial production of approximately half of the biologics currently in development could be met with reactors of 5,000 litres or less (figure 1), due to higher titres and product yields. Demand for 70% of new monoclonal antibody products approved between 2016 and 2020 is expected to be less than 100 kg per year per product.

Figure 1: Proportion of biologics in development that will require 5,000 litres of capacity or smaller.

12

�

Figure 2: Biologics by therapeutic class.

The number and complexity of therapeutic classes for biologics is rising, and these products are increasingly targeted, with more competition for the first-to-market position (figure 2).

The total manufacturing capacity available to the biopharma industry is greater than demand, with overall biologics capacity utilisation currently estimated at 62%, and forecast to rise to 72% by 2020 (figure 3).

However, capacity may not be aligned with demand. Many large-scale bioreactors are available, but these may not be the best solution to meet current expectations for titres. Mid-scale expertise may instead be needed.

A recent study by ORC shows that the number one challenge faced is access to biologics capacity within the timelines requested.1 This is a consequence of the very large existing capacity and inflexibility, due to historical industry efforts to drive down costs

Figure 3: Forecast biologics capacity utilisation to 2020.

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Manufacturing advances Advances in biologics manufacturing over the past two decades have included: • Maturing process technology, producing higher yields.

• Development of single-use manufacturing systems.

• High and increasing titres.

• Smaller bioreactors.

Biologics executives may believe they do not need to think about manufacturing early in development, as their limited resources are focused on securing funding and establishing proof-of-concept for their molecules. It may also seem too early to consider the likely final dose range, delivery mechanism or manufacturing plans. Yet, the earlier the manufacturing strategy is developed, the more options a company has at launch and beyond.

Responsive manufacturing strategy

• New operational strategies.

• Significant increases in capacity.

• Availability of multiplexing, where multiple bioreactors are processed in a single downstream batch.

As a result, biopharma companies have access to a wide range of manufacturing choices, and need strategies to take account of this flexibility.

The challenges of forecasting

The key is to develop a manufacturing strategy that balances responsiveness and cost while enabling the company to meet its forecasted demand.

This can be done by mixing and matching the options for outsourcing, single-use, scale, and existing or new capacity through the duration of the commercialisation process. An effective strategy will have key decision points from Tox studies through launch and beyond when changes in the strategy can be made to react to any new available data.

Flexible biologics manufacturing models

When a biologics company is preparing to launch a new product, it must forecast the required manufacturing capacity, but this remains a major challenge (figure 4). Key drivers of forecast inaccuracy are market size (based on approved indications, reimbursement and competition), launch timing, dosage (it is not unusual for forecast and actual dosage to vary by a factor of three), titre and price. Variations in these factors can lead to sharply differing demand scenarios, opening the firm to the risks of investing in too much capacity, paying more per unit of product, or not being able to satisfy demand. Inaccurate forecasting can lead to delays in the clinic, tied-up capital and foregone profit, which, for a small, earlystage company, can be catastrophic.

In addition to the traditional capacity approach, several flexible biologics manufacturing models exist: • Dedicated capacity: Companies with two or more products with similar bioprocessing requirements, launching within 18 months, need a dedicated facility or manufacturing line to enable them to modify their manufacturing schedule until they fully understand the market demand for each product. Within the dedicated facility, the company can determine how much is used for each product and can transfer technology in and out of the line.

• Fractional ownership: Fractional ownership is an option for companies that lack the budget (or volume) for a dedicated facility or line. This is where the CDMO partner builds a single manufacturing facility or line for two or three clients, providing flexible capacity for each. This model is less expensive than the dedicated line, but still provides flexibility and scalability.

• Flexible network access: For regulatory purposes, global companies may need manufacturing capabilities in multiple regions, or may require on-demand access to capacity without preference for location. Flexible network access provides biopharma companies with access (within a specified period) to a specific type of capacity within the CDMO’s global network. Companies can adjust the product mix with the assurance they will have the right type of capacity when they need it.

Figure 4: Key variables to consider when forecasting.

To address these often inaccurate predictions, biopharma manufacturing executives have many options for meeting capacity, including in-sourcing vs outsourcing, one-step development vs two-step development, largescale vs small-scale, single-use vs stainless steel, and existing capacity vs new capacity (figure 5).

• Condominium capacity: This is a fully customised solution for a company introducing a new product with unique characteristics (e.g., novel product types or platforms) that cannot be manufactured on a conventional line. Here, the CDMO partner provides design services, works with equipment suppliers, validates the process, builds the line and manages operations on behalf of the client. Overheads are shared and the line can operate as needed to meet demand.

• Enterprise: This is a solution for companies that own facilities that are in need of operational improvements. Some facilities may need to repurpose existing equipment, while others may need to be closed.

The CDMO partner manages the facilities to accomplish these goals, allowing biopharma companies to focus on their core competencies.

Ultimately, a flexible biomanufacturing strategy is essential in addressing the inevitable inaccuracies of forecasting. While there is no single, right manufacturing strategy, companies should consider manufacturing at the earliest possible stage of product development. Having a biomanufacturing strategy and revisiting it regularly enables biopharma companies to build in the necessary flexibility, and preserve as many options as possible. Working with an experienced CDMO partner in this space will allows them to optimise their planning — and their chance of success — in the face of an uncertain environment.

Figure 5: Biologics manufacturing options

Planning should take account of both volume and scale, with target product cost calculated from likely dosing and pricing.

Reference: 1. https://www.bioprocessonline.com/doc/challenges-risks-and-strategies-for-biologicsubstance-manufacturing-0001

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BIOLOGICS

Intelligent logistics In this article Robert L. Moore, PhD, from Cryoport Services discusses the key considerations of manufacturing biologics in a commercial environment and the benefits of intelligent logistics.

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T

he art of manufacturing biologics is best summed up in the adage — ‘you only get out what you put in’. As biologics are produced from living cells, the drug product you get out of a bioreactor is only as good as the cells and critical reagents you put in.

Companies that have adopted intelligent logistics have already seen dramatic improvements in their manufacturing process and the global distribution of biologics

The key challenge to manufacturing biologics in a commercial environment stems from the need to maintain and control living, enzymatically active systems within both an optimised and tightly regulated manufacturing environment.1

While responsibility for research, development and CMC remain largely in the US and Europe, manufacturing is being increasingly outsourced to places such as India.2 Therefore, master and working cell bank production, maintenance and distribution logistics have become critical in biologic manufacturing.

”

This need arises from the sensitivity of cGMP cell lines to many factors including, but not limited to, temperature excursion, genetic instability and contamination among many others. It is, therefore, of utmost importance to ensure that clear temperature-controlled logistics ensuring the chain-of-condition and custody of all cell lines and critical reagents is maintained to ensure quality and maximise manufacturing efficiency.

Commercial considerations The response to the criticality of and risks to cGMP manufacturing logistics in a commercial environment is largely two-fold; first, evolving good distribution practice (GDP) standards primarily centring on maintaining a digital pedigree regarding all materials involved in manufacturing from the bioreactors themselves to the finished product;3 and second, technological advancements in temperature-controlled packaging combined with real-time condition monitoring and regulatory compliant data-management and logistics IT platforms — ‘intelligent logistics’.4

Before discussing the benefits of intelligent logistics in commercial manufacturing, it is important to note that concerns over increased regulatory burden from the adoption of GDP standards and the infrastructure needed to maintain chain-of-condition and custody monitoring over long logistics networks, not only for critical reagents, but also for drug product, are very real and understandable. First and foremost, because there is no codified standard, participation in and compliance with GDP standards is largely voluntary at this point and thus varies wildly based on the physical (stability, formulation, etc.) and economic characteristics of the biologic being manufactured, leading to justifiable disagreement as to what the best practice throughout the industry should be.3 Second, the availability and scalability of monitoring technology can be rather limited. For instance, technologies such as RFID tags and bar codes, while inexpensive in themselves, require a significant amount of infrastructure investment in RFID tag/barcode readers, estimated to be between $10 million and $25 million per supply chain. This technology is also limited in that while it will record the location, provide security and confirm authenticity of material in transit, it offers nothing by way of changes in condition of the material being shipped.5

Strong incentives Barriers aside, there are strong scientific, medical and economic incentives to adopt stringent GDP standards, powered by intelligent logistics. First, manufacturing biologics is very expensive. In 2011, the average price per gram of drug product from a small mammalian cell culture project was estimated to be $280,000.6 Market pressures to lower costs of biologics have combined with advances in manufacturing technology, such as improved production techniques coupled with the move within the industry to smaller batch, multiple product and even single use facilities. These advanced techniques are dependent on tightly controlled conditions, and thus are highly sensitive to the effects of confounding factors on critical reagents and cell lines that result in sub-optimal production.7 Therefore, advanced temperature-controlled packaging and logistics solutions that limit these confounding factors while critical reagents are in transit should be a front-line risk mitigation and cost-reduction strategy.

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For example, exposure to temperature instability or excursion can reduce cell viability. Cells subjected to room temperature of 21°C, as in the event of a failure of temperature controlled packaging, will undergo caspase dependent apoptosis.8 Cell viability has been studied under dry ice conditions as well, with cell viability dropping by more than 90% when stored at –80°C over a 72hour period following cryogenic storage.9 In fact, a recent collaboration between Cryoport, Kansas City Analytical Services and Heat Biologics, performed a logistics study investigating the effects of shipping a GMP working cell bank via dry ice shippers vs cryogenic dry vapour shippers.

The results indicate that transportation of GMP cell lines via dry ice shippers at a temperature above the glass point of –135°C, leads to a marked decrease (up to 60% in this study) in cell viability, regardless of whether the shipment is domestic or international.10 The consequences of a failure of a GMP cell line to meet release specifications, which is generally set at 70–80% viability after transport, due to inadequate cold chain management, can lead to the loss of the cell bank, millions of lost dollars of CMC development and ultimately billions of dollars in lost product and revenue.

Short of a loss of viability, GMP cell lines can also show the effects of improper cold-chain logistics management in other ways, namely performance. Confounding factors can lead to deviations from established process controls such as time in bioreactor, pH sensitivity, O2 requirements and biomass formation. This can lead to a manufacturing run being sub-optimal, failing to meet acceptance criteria and even result in run termination. Therefore, the key logistics challenge to front-end biologics

manufacturing is keeping cell quality to the highest possible standards.11 Companies that have adopted intelligent logistics have already seen dramatic improvements in their manufacturing process and the global distribution of biologics.12 As opposed to RFID tags or barcodes, cellular enabled condition monitoring equipment depends on existing telecommunications infrastructure, dramatically reducing the investment required to implement global track and trace supply chain systems.

Coupled with existing, regulatory compliant data-collection and logistics management IT platforms, global commercial manufacturing logistics has the potential to enjoy never before seen improvements in manufacturing efficiency and drug product quality over global logistics supply chains.

Driving growth Ultimately, the continuing transition to biologically based pharmaceuticals is driving the growth of what is already a $12.6 billion temperaturecontrolled pharmaceutical logistics industry.13 Market expansion worldwide of both the contract manufacturing as well as the consumer market for biologics is already the primary driver for innovation into technologically advanced manufacturing methods.

Intelligent logistics technology will ensure that clear visibility on product quality is maintained over long and complex supply chains as well as improve commercial biologic manufacturing efficiency, patient access to biologics as well as clinical outcomes alike.

References: 1. Ho, K. (2011). Manufacturing Process of Biologics. Retrieved from Afssaps, France: http://www.ema.europa.eu/docs/en_GB/document_library/Presentation/2011/06/WC500107832.pdf 2. Siddharth J., e. a. (1 June 2014). The Rise of Biologics Outsourcing to Indian CDMO’s. Retrieved from BioProcess International: http://www.bioprocessintl.com/upstream-processing/upstreamcontract-services/the-rise-of-biopharmaceutical-outsourcing-to-indian-cdmos/ 3. Health Service Authority. (2015, August). Guidance Notes on Good Distribution Practice. Retrieved from Health Service Authority: http://www.hsa.gov.sg/content/dam/HSA/HPRG/ Manufacturing_Importation_Distribution/Guidance%20documents%20for%20Industry/GUIDE-MQA-013-010.pdf 4. Cryoport. (18 November 2016). Intelligent Logistics. Retrieved from Cryoport: http://www.cryoport.com/why-cryoport/intelligent-logistics 5. A. Coustasse, e. a. (2016). Could the Pharmaceutical Industry Benefit from Full-Scale Adoption of Radio-Frequency Identification (RFID) Technology with New Regulations? Perspectives in Health Information Management, 1b.

6. Downey, W. (6 June 2011). Contract Pharma. Retrieved from Biopharma CMO Pricing Trends: http://www.contractpharma.com/issues/2011-06/view_features/biopharma-cmo-pricing-trends/ 7. Jacquemart, R. (2016). A Single-Use Strategy to Enable Manufacturing of Affordable Biologics. Computational and Structural Biotechnology Journal, 309–318.

8. Shimura, e. a. (1998). Room temperature-induced apoptosis of Jurkat cells sensitive to both caspase-1 and caspase-3 inhibitors. Cancer Letters, 7–16.

9. Kilbride, e. a. (2016). Impact of Storage at -80C on encapsulated liver spheroids after liquid nitrogen storage. Biores Open Access, 146–54.

10. Moore, R. (1 March 2017). Packaging, IT and Cold-Chain Logistics Advances for the Future of Medicine and Clinical Trials. Retrieved from Applied Clinical Trials: http://www. appliedclinicaltrialsonline.com/packaging-it-and-cold-chain-logistics-advances-future-medicine-and-clinical-trials?pageID=2 11. Mogilyanskiy, L. (2015). Mastering Cell Bank Production. Biopharm International, 20–24.

12. Cryoport. (17 July 2017). Cryoport Wins 2016 Cold Chain Global Forum Excellence Award. Retrieved from Cryoport Investor Relations: http://ir.cryoport.com/news-releas es/2016/10-04-2016-130528372 13. Pharmaceutical Commerce. (15 March 2017). Pharmacuetical Cold Chain Logistics is a $12.6B Global Industry. Retrieved from Pharmacuetical Commerce.com: http:// pharmaceuticalcommerce.com/supply-chain-logistics/pharmaceutical-cold-chain-logistics-is-a-12-6-billion-global-industry/

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BIOLOGICS

The perfect partnership Strategic analytical partnerships are important in the development of new pharmaceutical products, especially biologics. Here, Michael Merges, Catalent Biologics, and Brian Fahie, Biogen, discuss the growing need for partners who can provide niche technologies to accelerate development projects.

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ontract research organisations (CROs) and contract manufacturing organisations (CMOs) play an important, and growing, role in the development of new pharmaceutical products, especially for biologics. Big pharma companies are increasingly shifting key internal resources from small molecule programmes to biologics The growth in programmes. As a part of this shift, many companies are outsourcing is not becoming more reliant on outsourcing for a range of showing any signs operations from analytical science to product manufacture.

Start-up biotech companies can be entirely virtual, with of slowing down, inclusive of more all practical functions performed by experts elsewhere.

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complex products getting closer to the market.

The market for biopharmaceuticals is growing dramatically, with the increasing penetration of protein therapeutics such as antibodies, and the development of more esoteric treatments such as gene therapy and cell-based products.

A 2016 Frost & Sullivan report highlights that annual sales across the board for biologics have now topped $200 billion, and with an annual growth above 15%, it is currently the fastest growing sector of the healthcare industry.1

�

As a result, CMOs have been expanding their reach towards partners, investing in capacity and new technologies to meet the changing demands of pharma companies. However, a never-ending stream of mergers and acquisitions continues to reshape and consolidate the biopharma landscape, which poses a threat to the contractors; and M&A activity has been occurring on their side of the business, too, which remains very fragmented.

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This may, on the face of it, appear to be an extremely optimistic biopharma growth rate but in reality, while the CMO market for small molecules is extremely well developed, the same is not true for biologics. There remains a lot of scope for expansion in the market for protein therapeutics and more complex biologic products, and estimates put the market for this sector as large as $60 billion in 2020. This will involve CMOs investing heavily in both the technology and expertise that will be required to make these products efficiently and effectively, and in full compliance with all requirements of the regulators.

Within the overall market, mammalian cell culture in particular represents a huge opportunity, and bioassays are currently the fastest growing individual analytical function to be outsourced. The high growth rate across the board for pharmaceutical manufacturing outsourcing, and for biologics specifically, will require a combination of skills and capital investment for companies to succeed in this space.

Companies engaged in providing contract development and manufacturing services are increasingly looking further up the value chain, into earlier developmental projects. Increasingly, CROs and CMOs are also becoming broader organisations by integrating development and manufacturing capabilities. These contract development and manufacturing organisations (CDMOs), can now work across all phases of development from the early stages of lead discovery, right through to the production of final packaged dosage forms.

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Creating a successful model The drivers behind outsourcing were originally to either save money, gain access to a new technology, or meet a changing business environment.

Often, decisions needed to be made quickly, such as to react to a changed sourcing model demanded by a merger or acquisition, or to provide a rapid increase in capacity for a project whose importance has been reprioritised. Although all these instances could meet a short-term requirement, in the long term they are inefficient, and thus unlikely to offer optimum scientific success or maximize investment returns.

The most successful relationships between pharma companies and contractors are now operated as strategic partnerships. At the outset, the two (or more) partners will need to discuss the process openly and candidly, and fully integrated teams that include people from both sides are developed to manage and run the project.

The operations involved in developing and bringing a drug product to market fall into four groupings, in terms of where that work is best done.

In-house at the pharma company — as long as the capabilities are present — is usually the best place for any processes that are urgent and provide a strategic advantage. Strategic projects include anything that might be classed as a novel application or emerging technology, or a step for which the turnaround time or proximity is rate-limiting and could cause delays and hold-ups to other important operations.

When internal resources become limited, a CDMO can be the appropriate choice for strategically urgent work. The best option from the pharma perspective is a suitably sized CDMO full time equivalent (FTE) team. This strategy of outsourcing non-predictable work limits the number of people on the project, and the FTE team priorities can be adjusted quickly, for example to stay in line with the manufacturing functions.

In contrast, a fee-for-service outsourcing strategy to a CDMO is the best option for more mature and predictable work which, while it is important, is not urgent. This predictable work is likely governed by qualified or validated methods tied to protocols, which determine how much work will be required, and by when the results are due. By its nature, although this work is predictable and non-urgent, it is not routine.

There is likely also to be the case for niche or specialty processes that are time-dependent but non-strategic, and require the input of experts with very specific talents or that are driven by meeting the needs of compliance.

Many operations that fall into this category are likely to be governed by regulatory requirements and thus require specific expertise; examples include analysis of trace metals, extractables and leachables and now even bioassay. Such analytical techniques require very experienced scientists and often require expensive analytical equipment, and thus would represent a significant investment to the pharma company if they were done in house.

Contract development and manufacturing organisations have invested in the same high quality equipment, scientists and engineers as pharma and biotech companies. Working closely together in strategic partnerships and building strong relationships will lead to significant benefits for both parties in terms of speed, cost, efficiency and overall risk reduction.

Case study: Catalent and Biogen The first step for implementing the strategic partnership at Catalent Biologics was to agree on what was meant by all of the standard terminology used within the collaborative model. Teams of subject matter experts were then put to work to pin down which work streams were strategic, predictable, non-predictable and niche. In the first instance, this was done across two specific work streams — gene therapies and antisense oligonucleotides.

It rapidly became clear that almost nothing fell cleanly into a single category, so the best match was applied for each task, and a potential work stream collaboration for antisense oligonucleotides was progressed with Biogen.

As the appropriate Catalent facility was geographically very close to the Biogen manufacturing plant, this enabled important and urgent work to be shifted into a programme that is appropriate for an FTE resourcing model — from sample receipt to quality review within 48 hours — providing flexibility and the ability to respond to changing priorities.

Over the subsequent few months, additional work streams for proteins and peptides were added into the collaboration discussion. It became apparent that it could be appropriate for Biogen to outsource its non-strategic work in these areas as the technology was mature, but its more recent moves into the gene therapy field would strategically be best kept in-house, at least for the time being.

After eight months of discussions, a host of opportunities for partnership had become apparent. Automation was an important topic of conversation from an early stage, and as the two organisations were already using common platforms for bioassay and molecular assays, plans for manual method transfer and development projects that moved manual operations to automated ones were proposed. The next step was to consider platforms for data transfer, and collaborations with vendors of data analysis technology. It was already clear that shorter turnaround times should be possible across the board.

Future outlook The growth in outsourcing is not showing any signs of slowing down, inclusive of more complex products getting closer to the market. As this pattern continues, the need will increase for partners who can provide niche technologies as pharma recognises it will be uneconomic for them to implement the niche capabilities in-house. This is yet another example of an evolving contract market where success is far more likely to be achieved through the formation of strategic partnerships, and individual transactional agreements will become less important.

Reference: 1. Analysis of the Global Biologics API Market, Frost & Sullivan, July 2016.

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BIOLOGICS

Putting the patient first With patient-centric approaches to drug packaging becoming more prevalent certain aspects of biologics must be considered. Here, Fran DeGrazio, vice president of Scientific Affairs & Technical Services at West Pharmaceutical Services, runs through key considerations and how specific designs can help with patient adherence.

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O

ver the past several years there has been a steady shift in the industry toward a more patient-centric approach to the development of drug packaging components and delivery systems — elements that play a key role in helping to ensure the integrity of injectable drug products — largely driven by concerns around patient safety.

With more manufacturers implementing the use of prefilled syringes and self-injection systems for biologics interactions between the drug, the container and the patient are vital considerations. In some cases, interactions between the drug, certain components and materials used with prefilled syringes (e.g., silicone oil) may cause issues such as protein aggregation that can contribute to quality or safety issues.

Most biologics currently in development take an injectable form and the top-line consideration for any injectable drug is the patient. As many injectable biologics are highly viscous, they may require larger containment systems and slower dosing of large volumes of the drug over time.

It is, therefore, integral for manufacturers to pay close attention to the material characteristics of the prefilled syringe selected for their biologics.

Through a careful consideration of all elements of the integrated drug delivery system the potential for protein aggregation can be minimised and drug product stability improved.

Advanced biologics often have very specialised needs around containment and delivery that can, in turn, influence the selection of appropriate packaging components.

”

Additionally, biologics can have sensitive chemical compositions that pose the potential for interaction with materials traditionally used for packaging and delivery systems. Therefore, it is essential to package biologics with components that can help protect the quality, safety and efficacy of the drug product.

Special considerations

One overarching consideration is the quality of drug packaging and delivery systems. Regulatory bodies around the world are asking manufacturers to build quality into their products from the start to ensure consistency throughout a drug’s lifecycle and to minimise risks.

Given this shift and what is at stake, the application of quality by design (QbD) principles in the development and manufacture of biologic drug products driven and supported by regulatory guidance has been widely adopted within the biopharmaceutical industry. A solution offered by West utilises this approach — NovaPure components — which help to mitigate the risks and maximise the efficiencies of fill-finish processing.

Another consideration in evaluating drug packaging is the need to understand storage and distribution temperatures. Some of these conditions can present a significant challenge for drug packaging. To combat these challenges, West offers Daikyo Crystal Zenith vials and containers made from a novel cyclic olefin polymer. These are compatible with extreme low temperatures and the polymer’s low reactivity reduces the risk of drug contamination.

Another important consideration for biologics containment systems is mitigating the risk of particulate caused by potential interactions that can occur at the biologic-container interface or the biologic-air interface.

Quality expectations have risen such that one contaminated vial or syringe can cause an entire lot to be discarded, and this can have a huge financial impact on the pharmaceutical industry. Concerted efforts to reduce particle generation at all steps of the manufacturing process can bring large benefits.

Patient adherence Proprietary drug delivery systems are being developed to aid patients with self-administration while also addressing the specialised needs of biologics.

An emerging trend is wearable injectors. These systems may include polymer cartridges that can be designed to hold high-volume doses of sensitive biologics and offer subcutaneous, programmable electronic injections, delivering the drug over an extended time period.

While many patients are comfortable loading their devices — especially those who have been treating a chronic condition for years — others may take their medication once a month or suffer from conditions where they are at risk of forgetting the steps of properly loading the device. For these patients, a single-use, preloaded large volume injection device can make sense.

Additionally, user interfaces can be optimised by incorporating human factors practices and appropriate electronic indicators and feedback, aiding patient adherence and caregiver monitoring.

Patient-centricity Advanced biologics often have very specialised needs around containment and delivery that can, in turn, influence the selection of appropriate packaging components. It’s important to consider how the biologic will be delivered to the patient.

Most patients are not trained medical practitioners; therefore, they need delivery systems to be intuitive. As such, self-injection systems for administration are becoming more popular.

These systems can give patients newfound freedom to self-manage their diseases outside of traditional healthcare settings. The design of these systems is, therefore, important and should have a patient-centric focus to help improve adherence and outcomes.

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DRUG DELIVERY

Joachim Koerner, director e-Device, R&D Prescription Division, Aptar Pharma, discusses intranasal drug delivery and how an integrated electronic lockout device can assist with patient adherence and help prevent drug misuse.

I

ntranasal drug delivery has been a popular option for many therapeutics over the years. Not only does it offer an easy route of administration, it is also convenient for patients, meaning adherence is usually less of a concern.

Delivering a therapeutic product via the nasal passage is non-invasive and essentially pain-free, thereby affording manufacturers the option to create a product fit for all patients, including seniors and paediatrics.1

Easily accessible route The nasal cavity has an abundance of blood vessels within the mucosa.2 This facilitates drug adsorption as it increases the surface area available and has been reported as nearly equivalent in absorption rates to intravenous injections in certain instances.2 Administering drugs through the nose means that the issue of degradation within the gastrointestinal system is avoided, ensuring that more active product is systemically delivered, benefitting the patient. Moreover, the nose offers a route to the brain through the olfactory nerves, offering the potential to bypass the difficult to transverse blood–brain-barrier.

However, what needs to be considered if the drugs to be administered can be addictive, such as opioids? How can the safety of patients be ensured?

Locked out!

The e-Lockout is an integrated electronic nasal lockout device that features a lock-out mechanism, limiting the number of doses available within a 24-hour period.8 As such, patients can only use the device at specified intervals.

Further safety features include keeping track of the priming strokes, number of doses remaining inside and if the system is locked or readyfor-use, which is shown on an electronic display.

When the device locks itself, the display starts a visual countdown to let the patient know when it will unlock. Furthermore, the e-Lockout features a child-resistant cap, as a further safety measure.

Mark of approval Earlier this year, the European Medicines Agency (EMA) approved the e-Lockout technology for a new version of Instanyl — a nasal spray used to treat breakthrough pain in adult cancer patients from Takeda.

This new packaged product, Instanyl DoseGuard, will be launched in Europe, where the device is manufactured, and will be available in various multidose strengths.

This approval follows a multi-year development process between Aptar Pharma and Takeda, and represents the first fully integrated electronic nasal drug delivery device with time interval properties that has achieved regulatory approval in the EU or US.

The issue with opioids Opioids are a class of drugs that are commonly used for pain relief as they are strong and effective for this purpose. However, as they can also give a sense of euphoria when taken, an unwanted by-product of using these substances can be addiction and overdose (accidental or intentional).3 Rising rates of opioid abuse is a serious issue4,5 affecting patients both in Europe and the US. Some regulatory bodies are looking at the various ways in which they can reduce the incidences of addiction and misuse of these powerful drugs.6,7

References: 1. Surber, C., et al., (eds): Topical Applications and the Mucosa. Curr. Probl. Dermatol., Basel, Karger, 2011;40:20–35. https://www.karger.com/ProdukteDB/Katalogteile/ isbn3_8055/_96/_15/CUPDE40_04.pdf 2. Ghori, M.U., et al., American Journal of Pharmacological Sciences, 2015;3(5):110–119. http://pubs.sciepub.com/ajps/3/5/2/ 3. https://www.drugabuse.gov/drugs-abuse/opioids 4. https://bmcpsychiatry.biomedcentral.com/articles/10.1186/s12888-016-0909-3 5. https://www.hhs.gov/opioids/about-the-epidemic/index.html

A potentially beneficial way to manage patient adherence and prevent misuse of a therapy is to control the delivery via the mechanism of the device. It is this aspect that has been addressed in a novel device available from Aptar Pharma.

6. http://www.emcdda.europa.eu/topics/pods/preventing-diversion-of-opioid-substitutiontreatment 7. https://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm484714.htm 8. https://pharma.aptar.com/en-us/dispensing-solutions/e-lockout.html

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DRUG DELIVERY DEVICES

Pharma’s going soft Soft gels have seen huge growth in the pharmaceutical industry in recent years thanks to versatility and convenience, here, Pierre-Albert Thomas, global technical support manager, Rousselot, discusses this trend and how soft gels can benefit the sector.

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W

hile relatively new to the pharmaceutical industry, soft gels have seen huge growth in recent years. They hold universal appeal to consumers and manufacturers alike, thanks to their versatility and convenience.

To meet the rising requirements of consumers, new formulations are constantly being developed, to accommodate specific fills. The market is changing; 90% of recently developed APIs have low solubility, creating a range of formulation challenges.3

Soft gels’ unique functional benefits provide extended shelf life and stability of active pharmaceutical ingredients (APIs), as well as allowing accurate dosing and optimal delivery. As they are easier to swallow than other formats, such as tablets in particular, soft gels are a popular choice with consumers.

Soft gel capsules are a viable option, as they can carry dispersions, emulsions or self-emulsifying systems, which improve the absorption of poorly soluble nutrients. Manufacturers are therefore looking at different gelatine types, to optimise the delivery of APIs to the body.

When formulating soft gel capsules, not only is it important to prepare a gel mass that displays consistent high quality, it also needs to display minimal foaming and enable perfect films, to maintain high production efficiency.

Manufacturers are now turning to gelatine soft gels to meet the rising demand for clean label nutraceutical and pharmaceutical products. As the main excipient in the capsule market that offers pharmaceutical grade standards and a high degree of stability, gelatine also provides additional reassurance in the delivery of more complex and sensitive compounds.

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A trusted choice Gelatine is widely used as the preferred excipient in soft gels — and has a longstanding heritage in capsules of over 100 years. This is because it meets stringent pharmaceutical regulatory requirements, and has robust functionality and full compatibility with the human body.

A fully digestible, natural protein extracted from collagen found in the skin, bones and connective tissues of animals, gelatine is regarded as a safe and natural excipient. It is extensively used in many pharmaceutical applications, thanks to its functional benefits, such as film forming, thermo-reversibility and rapid absorption.

Rising popularity The popularity of soft gel capsules shows a clear increase — it is predicted that the global market for such applications will grow at a CAGR of 5.4% over the next decade, reaching an estimated $316.6 billion by 2025.1 This growth has been driven by innovation in capsule formulation, as well as the high consumption of supplements and pharmaceuticals — it is estimated that nearly half of all adults (50% of women and 43% of men) in the UK now take prescription drugs.2

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Optimising gelatine for API delivery Despite its advantages, formulating and manufacturing soft gel capsules to fulfil the latest specifications and end-use requirements can be complex and challenging. As different grades of gelatine can be selected to produce soft gels, there can be different rates of stability and dissolution, which affect the delivery of APIs to the body. As such, soft gels are being developed to work with specific delivery systems, such as delayed release or chewable capsules.

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There are several factors that impact delivery of the active ingredient, including the speed of dissolution of both shell and fill, as well as its gastro-resistance. A key requirement of soft gel capsules is to protect against early degradation while in storage. However, they are particularly sensitive to heat and moisture, affecting the shelf-life stability. To counteract this, a high-quality gelatine should be used, and all steps of the process strictly controlled, such as the drying stage, to achieve suitable moisture.

An internal study performed in 2013 on fish oil formulations showed that soft gels moisture levels of below 11% help avoid instability and subsequently, a sticky texture.4

The correct choice and combination of gelatine and processing conditions can help retain shell inertness in soft gel capsules. This is important in such dynamic systems, as components may move between shell and fill, as well as from the external environment into the shell. Capsules are then at risk of becoming unstable and brittle, as different components to react together. Shells can also lose their shape, softening and lowering the level of protection available for APIs. Without adequate protection, the likelihood of oxidation and recrystallisation increases, lowering the overall effectiveness of the capsule.

Choosing a compatible gelatine can help to prevent crosslinking — the undesirable formation of strong chemical linkages between gelatine chains. Capsule shells can become tough, rubbery and insoluble, causing soft gel instability and lowering the API delivery rate to the body. Research has shown that some parameters, including gelatine molecular weight distribution, may impact the ability of gelatine to crosslink. In response, Rousselot has developed a protocol to predict how gelatine will behave under adverse conditions. Being able to accurately assess the crosslinking behaviour of different gelatine types allows the pharmaceutical industry to choose the right type for their soft gel capsules. As tailored gelatines become recognised for their ability to prevent crosslinking and instability, they are increasingly being used by manufacturers to create innovative customised solutions.

Rousselot has developed safe, non-allergenic and fully compatible pharma gelatines that help to meet the needs of manufacturers, both for hard capsules and soft gels. Compliant with safety, quality standards and practices, like IFS, HACCP and GMP, the range of gelatines can help to minimise risk of soft gel defects during manufacture, maximise productivity throughout the formulation process, and save costs. Offering certified Halal and Kosher gelatine options also provides additional appeal to consumers with religious requirements.

Continuing to innovate Ensuring optimum API delivery with the use of soft gel capsules can be a challenging process for pharmaceutical manufacturers. Complex production methods, coupled with increasingly stringent industry regulations means that choosing the right type of gelatine is fundamental to achieving optimum soft gel capsules.

As such, it is important to pay close attention to the specific properties of gelatine and benefits they confer, including absence of crosslinking and increased bioavailability, to ensure a smooth and efficient manufacturing process of pharmaceutical soft gels.

All gelatines are not equal For soft gel manufacturers, it is important to choose the right high-quality gelatine that can provide the necessary benefits, without any of the typical defects, such as poor encapsulation yield, twins and leakages.

When formulating soft gel capsules, not only is it important to prepare a gel mass that displays consistent high quality, it also needs to display minimal foaming and enable perfect films, to maintain high production efficiency. To ensure optimum manufacturing and API delivery to the body, gelatine must also be highly soluble, easy to use and exhibit excellent mechanical strength.

References: 1. Research and Markets, 2016, Softgel Capsules Market Analysis & Trends — Application (Health supplement, Vitamins & Dietary Supplements, Cardiovascular Drugs, AntiInflammatory Drugs and Antibiotic & Antibacterial Drugs), End-User — Forecast to 2025.

2. The Health Survey for England 2013.

3. Kalepu, S., and Nekkanti, V., Acta Pharmaceutica Sinica B, 2015;5(5):442–453.

4. Internal Rousselot study, Ghent Application Lab, 2016.

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DRUG DELIVERY DEVICES

Only skin deep In this article Vasiliki Nikolaou and David M. Haddleton from Medherant, The Venture Centre University of Warwick Science Park, detail transdermal drug delivery, a non-invasive option that has the potential to improve patient adherence.

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Imagine a drug delivery technology that is more comfortable than an injection, with fewer side effects than pills, capsules or liquids.

Imagine a technology convenient enough for patients to use at home but easy to stop at any point. Finally, imagine a system able to maintain a more consistent drug level than either a simple pill or an injectable but still be inexpensive.

These are some of the benefits of transdermal drug delivery (TDD), a non-invasive technology for delivering drugs via the skin, the largest organ of the body. TDD is not a new idea, with a scopolamine patch (for motion sickness) being first launched almost 40 years ago. Despite this pharmaceutical companies Topical drug have often seen TDD as a niche delivery mechanism, delivery offers effective only for a limited range of drugs with specific compelling advantages over physicochemical characteristics and unable to deliver the required therapeutic levels across the skin.

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conventional routes of administration.

Today this is changing, thanks to the rapid development in TDD technology and a growing consumer need for non-invasive yet effective drug delivery. With ageing populations, the massive growth in obesity and lifestyle induced ailments placing patients at risk of diseases — cancer, cardiovascular disease, diabetes, Alzheimer’s disease and so on — TDD provides an opportunity to improve outcomes by enhancing patient compliance and minimising undesirable side effects. Additionally, the ability to self-administer drugs circumvents the inconvenience of intravenous injections and avoids the risk of disease transmission by needle reuse, which could have a huge impact on healthcare in the developing world.

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Over the past few years a wide range of drugs, including lidocaine, methyl salicylate, hormones, nicotine and fentanyl, have been formulated into a transdermal patch form to treat various conditions. In 2015, the global market for TDD was estimated at $30.3 billion by Research Nester1 and it is expected to reach $81.4 billion by 2024 (Grand View Research).2

Benefits of TDD Topical drug delivery offers compelling advantages over conventional routes of administration. Apart from the obvious benefits relative to injectables of being self-administered and pain free, these systems deliver a defined dose of drug at a specific site and avoid the problem of first pass metabolism seen with some drugs following oral delivery. Drugs with low bioavailability or those that interact with the gastrointestinal mucosa can be administered via TDD to increase drug exposure, and thus efficacy, and reduce side effects, respectively.

TDD systems also eliminate multiple peaks and troughs in pharmacokinetic profiles as they provide prolonged release of the active with a single application. This can improve patient compliance by reducing the need for multiple daily dosing and potentially improve the safety and/or efficacy profile of the therapy.

Finally, the treatment can easily be terminated by simple removal of the patch from the skin surface. In terms of cost, TDD systems remain generally inexpensive when compared with conventional therapies mainly because they can be worn for extended periods of time (even for a few days).

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Rapid technological improvements The history of TDD can be traced back to China where plasters containing medicinal herbs were applied to the skin. The first TDD product was approved by the US Food and Drug Administration (FDA) in 1979 and was a patch to tackle nausea and vomiting due to motion sickness.

various stages of clinical development or they have already been delivered as a marketed product. Although promising, these active systems are less mature and more complex technologies than traditional transdermal patches and challenges remain to be overcome.

Novel adhesive platforms During the 1990s, patches that delivered nicotine to aid smoking cessation became the first TDD blockbuster products. In the following 22 years the FDA has approved 35 transdermal patches covering 13 molecules for applications as varied as birth control to treating Alzheimer’s disease.

The main drawback of TDD systems is that they are frequently unable to convey the desired active ingredient through the skin. The skin is the body’s main line of defence against the environment and consequently it is designed to stop things entering the body.

The main barrier is the stratum corneum, the outermost layer of skin, which provides protection against harmful chemicals and infectious agents entering the body whilst stopping us from dehydrating. The stratum corneum is complex and for a drug to get through and into the tissue or blood-stream it is forced to travel between multiple hydrophilic and hydrophobic domains which hinders the passage of most drug molecules.

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Typically, the drugs successfully formulated into TDD patches have had a molecular weight of < 500 Daltons and are of relatively high potency because the amount of drug that can be loaded into most TTD systems is low. These limitations have severely reduced the range of drugs which can be delivered by TDD. last 10

over the to 15 years, TDD technology has seen significant innovation in techniques to improve drug penetration

These two factors — the difficulty in getting drugs through the skin, and restrictions in what can be formulated into a TDD patch — led to stagnation in the development of new TDD patch products.

However, over the last 10 to 15 years, TDD technology has seen significant innovation in techniques to improve drug penetration. These range from new formulations, such as nanoparticles, to the addition of chemical permeation enhancers that increase drug solubility or disrupt the stratum corneum on the micron scale. There are also ‘active’ (physical) approaches which use a wide range of energy sources, such as ultrasound or high-voltage electrical pulses, to reduce the barrier properties of the skin and/or increase the penetration of drug molecules.

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These innovative techniques aim to expand the range of molecules that can be delivered by TDD to include, for example, proteins and peptides, and to better regulate the rate of drug delivery.

Iontophoresis is an example of an ‘active’ approach; a low-level electrical current is applied to the skin to enhance the penetration of drug molecules.

Transdermal iontophoresis can provide continuous drug delivery but it can also be programmed for an on-demand delivery.

Microneedles and systems, which use laser microporation, are also among the ‘active’ technologies that disrupt the barrier function of the skin. Specifically, microneedles painlessly penetrate the stratum corneum to create pores through which drugs can travel and laser systems disrupt the surface of the skin to reduce its resistance to the penetration of drugs.

A typical transdermal patch consists of various components including: (i) a release liner to protect the drug during storage, which is removed prior to use, (ii) the drug (iii) the adhesive matrix which binds the patch to the skin and (iv) a backing which protects the patch from the outer environment. Additional components The effectiveness such as membranes to control the release of the of the of the adhesive drug from the reservoir or permeation enhancers, which increase the delivery of the drug, can also be utilised matrix is one of the most depending on the type of the TDD system employed.

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important factors

The effectiveness of the adhesive matrix is one of the that determines most important factors that determines the success of the success of a transdermal patch. The overall performance of the a transdermal system depends on good skin adhesion under a range of patch conditions as if the patch becomes detached the amount of drug permeated across the skin is reduced, compromising the efficiency of the therapy. Nevertheless, some of the currently available transdermal patches utilise adhesive matrices that do not provide sufficient adhesion to all body parts or under specific circumstances (e.g., while bathing).

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Other issues related to the adhesive matrix which impact the user experience are that patches can be painful to remove and/or leave a residue of adhesive on the skin. One area of innovation has therefore been to improve the adhesive formulations used in patches.

Many polymers are routinely employed as the adhesive matrix including polyacrylates, polyurethanes and silicone based polymers. Among the different adhesive formulations, hot-melt pressure sensitive adhesives (HMPSAs) are of interest due to their low irritation and good adhesion.

Moreover, they are solvent-free systems and they can be formulated to contain little or no chemical functionality reducing the possibility of interactions with the active drug.

Medherant’s TEPI Patch technology uses a hot-melt silicone based pressure sensitive adhesive (PSA) as the drug reservoir. This novel polymer adhesive has widened the range of drugs that can be employed in patches and enabled the drug loading to be increased while improving patch adhesion, appearance and comfort. The polymer adhesive can contain up to 30% of a drug by weight, which allows low potency drugs to be used, and releases drug at a steady rate over 24 hours.

Currently, Medherant is developing an ibuprofen TEPI Patch for pain relief, which it plans to license to pharmaceutical companies for commercialisation; it is due to undergo clinical testing in 2018.

Furthermore, the company is developing a lidocaine TEPI patch and is working in collaboration with other pharmaceutical companies to develop other novel patch formulations with proprietary drugs. The potential is enormous, the benefits huge for pharmaceutical companies and patients alike.

References:

Research on increasing the energy of drug molecules to improve penetration has focused on testing a variety of energy sources, such as ultrasound, heat and even magnetism. Most of these systems are at

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1. http://www.researchnester.com/reports/global-transdermal-drug-delivery-market-analysisopportunity-outlook-2021/111 2. http://www.grandviewresearch.com/press-release/global-transdermal-drug-delivery-systemmarket

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HIGH POTENCY FACILITIES

Highly potent Demand for high potent active pharmaceutical ingredients is driving the need for high potency handling capabilities. Here, Mike Avraam, global product manager for ChargePoint PharmaSafe, ChargePoint Technology, discusses this growing sector n detail in this Q&A. 1. What is driving the need for more high potency capabilities?

with the design and correct operation being key to maintaining appropriate containment performance.

Global demand and growth in the oncology market, including the development of antibody drug conjugates — ADCs, and an increase in conventional drug manufacturing using high potent active pharmaceutical ingredients (HPAPIs) is driving the need for high potency handling capabilities, particularly high-containment manufacturing facilities.

Ideal for handling larger process operations, extracted booth technology offers a secondary level of containment protection, however it does also require a high level of PPE.

2. What challenges face manufacturers developing high potency products in their facilities?

Handling of these ingredients in the drug supply chain is the primary concern, where specialist equipment should be employed to avoid cross contamination, product protection and to ensure operator and environmental safety.

One of the biggest challenges is choosing an appropriate solution based on a wide range of requirements. It is a matter of finding a balance that prioritises protection whilst maintaining productivity and operability.

Also, extending capabilities can mean upgrading/ investing in new equipment — a significant challenge for smaller manufacturers.

3. How have manufacturing facilities for potent compounds changed over the past decade?

Lots of new technologies have entered the market but some primary go-to solutions remain. The main change has been how these solutions have advanced, offering higher levels of protection and less reliance on personal protection equipment (PPE) and respirators.

New design technologies to remove the risk of airborne exposure have been pivotal in achieving high containment. Split butterfly valves have evolved over the last 25 years to meet the increasing demand in containment performance of potent compounds.

These can be integrated with many other containment solutions to enable the transfer of potent compounds.

5. What are some of the handling challenges and how can they be overcome?

The increasing use of HPAPIs presents handling challenges and the need to invest in containment equipment to protect employees and the environment from exposure.

One of the biggest challenges is establishing and selecting the correct containment solution to suit the process operation. The selection, specification and compatibility of materials also has an important role to play.

The correct installation and set-up of the solution is of primary importance, as this will support employees in the safe and proper handling of the equipment.

Additionally, training is essential alongside monitoring of operating methods to ensure maximum protection.

Frequent maintenance also helps safeguard the reliability of the solution.

6. How is the growing demand for HPAPIs impacting the outsourcing sector?

4. What current technologies are available to help minimise the risks associated with potent compounds?

Some existing manufacturing facilities do not meet the necessary requirements to handle HPAPIs and there is an increasing need to upgrade, develop and even construct new facilities to accommodate the intake of potent compound contract manufacturing.

There are several technologies that can help minimise the risks associated with potent compounds.

For example, rigid and flexible barrier isolators offer a very good level of containment security,

Manufacturing facilities need to be designed and dedicated to certain production processes that can adapt and cater for varied production volumes.

An increase in varied, validated manufacturing

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processes can also require investment in associated bespoke equipment technology. While production campaigns of high potency drugs can be small in volume, they can be highly lucrative particularly for smallscale niche CMOs and CDMOs.

7. What qualities should manufacturers look for in outsourcing partners?

Manufacturers should look for experienced outsourcing partners who have a track record of success. A considered approach to managing risk and validation of equipment should be a key consideration, this is particularly important when working with HPAPIs where health and safety is paramount. A partner that can demonstrate flexibility in their solution will also be important as business priorities change and when scaling up production, reacting promptly to meet the demand is essential.

8. In your opinion, what does the future hold for high potency facilities?

Technological advances will drive future change in all manufacturing facilities. Given the risks involved with operator exposure to high potency drug products, however, there are certain technologies that we can expect to eliminate the potential risks — namely the use of robotics that will remove the operator from physically working with harmful substances.

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The increasing use of HPAPIs presents handling challenges and the need to invest in containment equipment to protect employees and the environment from exposure.

In the same vain, automated systems are already in operation across many facilities but this is likely to increase as processes become more integrated and Industry 4.0 really starts to take a hold.

As the demand increases for high potency drugs and developments in biotechnology occur, there is the potential for closed systems to be developed to further protect operator and environment safety, however this will coincide with a reduction in production volumes.

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DIGITAL HEALTH

Unify and improve A new life sciences survey has revealed near-universal agreement across the industry that clinical systems and processes must be streamlined to improve study speed and quality. Here, Rik Van Mol, vice president of R&D strategy, Europe, Veeva Systems, outlines key survey findings and what they mean for the life sciences industry.

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any of the challenges companies face today in managing clinical trials stem from disparate processes and systems. Nearly all those surveyed (99%) report the need to unify their clinical applications, including CTMS, EDC and eTMF. Respondents cite faster study execution (65%), improved study quality (63%) and cost savings (59%) as the top three most important drivers.

The average number of applications used to manage clinical studies is four, with more than one-third of respondents (38%) saying they use at least five applications. Not surprisingly, EDC, introduced nearly 20 years ago, is still the most commonly used application (81%), followed

by CTMS (59%) and eTMF (57%).

The negative impact from silos is obvious. Respondents cite integrating multiple applications (69%) and reporting across applications (61%) as the two biggest issues facing them in using clinical applications.

In the case of study start-up, the greater the number of separate applications used, the greater the number of challenges that are reported.

Respondents using two or more applications (76%) more often cite issues with site contracting and budgeting (60%), site identification (49%), and study planning during protocol design (40%).

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While the number of applications is an issue, the study also reveals that CTMS applications are not keeping up with the demands of today’s clinical trials. Nearly all sponsors (98%) report challenges with their current CTMS applications, while the most frequently cited shortcomings are tracking and reporting (38%), and integrating with either an eTMF application (37%) or an EDC application (37%). Sponsors also report significant deficiencies with CTMS applications, including inability to support key functions such as resource management (77%), study and site feasibility (76%), financial management (75%), and issue/task management (73%).

Monitoring is the only process that a majority of sponsors (54%) say their CTMS applications fully support.

Yet, adoption of modern, active eTMF applications is on the rise. More specifically, however, the research shows that there is a major move away from ‘passive’ systems to ‘active’ eTMF solutions. One in three sponsors (31%) now uses a purpose-built eTMF application — more than double the number reported in 2014. Sponsors find that active eTMF applications have significant, positive impacts on inspection-readiness. They also improve activities that are key to unifying clinical operations, including automated tracking and reporting of documents (68%), central and remote auditing (62%), and visibility into key study performance metrics (50%).

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Streamlining collaboration In an effort to streamline collaboration and implement end-to-end processes, sponsors are moving away from manual systems. Previous surveys have shown that sponsors are decreasing their use of paper, and that trend continues in this year’s survey. Across almost all functional areas measured, the number of TMF documents managed on paper is down by at least half among sponsor companies since 2014. This is a very positive trend, given that a unified clinical environment requires collaborative processes and technology.

Clinical operations departments lead the way, with just 16% of sponsors now reporting that most to all TMF documents managed are on paper — a 25 percentage-point drop since 2014. Given that more than half of the documents in a trial master file are managed by clinical operations, the potential impact of this reduction is significant.

However, there is still room for improvement in the areas of collaboration with external partners. More than two-thirds of sponsors (68%) use email to exchange TMF documents with CROs. In contrast, only 19% use their eTMF applications to exchange TMF documents with external partners. The problem, of course, is that emailing documents puts information outside of the controlled processes, making it harder to track and collaborate efficiently.

Using data to improve the study process Metrics can help to identify trends to drive process improvements across an individual study or portfolio of studies. Yet, almost one in four (23%) is not using or rarely uses data to improve study processes, while roughly half (46%) only use it in some cases.

However, the amount of data collected, and the extent to which it is leveraged, has a direct impact on improvements to clinical operations

efficiency. Organisations that extensively use data to improve clinical trial processes see more benefits than those not leveraging data, including easier collaboration (50% to 25%, respectively), central and remote auditing (50% to 31%, respectively), and automated tracking and reporting of documents (54% to 38%, respectively).

The drive for a unified clinical model There is industry-wide recognition that a move to a unified clinical model is necessary to address the growing need to improve the quality and speed of study execution. Clinical leaders are looking to achieve higher levels of performance across their study portfolios by implementing end-to-end processes There is industry-wide and systems, streamlining collaboration recognition that a move to and leveraging insight from across the a unified clinical model is trial lifecycle.

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necessary to address the growing need to improve the quality and speed of study execution.

The majority of challenges sponsors face today in managing clinical trials stem from the siloed nature of their processes and applications. Some of the most prevalent applications in use today, such as EDC and CTMS, are based on first-generation technology. They lack the core functionality, modern architectures and usability required to enable true end-to-end processes and visibility.

Organisations that adopt modern, purpose-built applications, such as ‘active’ eTMFs, report fewer challenges and see greater benefits to their studies. When unified, these applications enable life sciences organisations to establish repeatable, collaborative processes and increase oversight and accuracy by consistently leveraging insight across their clinical portfolios.

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Veeva 2017 Unified Clinical Operations Survey More than 300 clinical operations professionals worldwide were interviewed for the Veeva 2017 Unified Clinical Operations Survey*, which analyses the industry’s progress in improving clinical operations. The results reveal that the journey to unify clinical applications has begun, driven by the need to speed study execution, ease collaboration and achieve greater visibility across an increasingly complex trial landscape.

KEY FINDINGS: • Nearly all (99%) of respondents report the need to unify their clinical operations, including CTMS, EDC and eTMF. For more than half, this is driven by the need to speed study execution, improve study quality, ease collaboration, and achieve greater visibility.

• Almost half (49%) of sponsors say the challenge of integrating their eTMF or EDC applications with CTMS limits their organisations’ ability to improve clinical operations.

• Respondents that use two or more applications (76%) more frequently cite issues with site contracting and budgeting (60%), site identification (49%), and study planning during protocol design (40%).

• One in three (31%) sponsors now uses an eTMF application, up from 13% in 2014. Only 16% of sponsors say their clinical operations departments use paper for most or all

TMF documents, down from 41% in 2014. Half of document templates are now created electronically (52%), double the number from two years ago (25% in 2015).

• Reporting across multiple applications (60%) is among the biggest challenges organisations face when asked about their clinical solutions. Most sponsors (51%) report the need for better visibility, and one-third say clinical data is tracked outside of their systems.

• Organisations that extensively use data to improve clinical trial processes achieve greater benefits than those that do not leverage data, including easier collaboration (50% to 25%, respectively), central and remote auditing (50% to 31%, respectively), and automated tracking and reporting of documents (54% to 38%, respectively). *http://go.veeva.com/eu_unified_clinical_operations_report

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9th 8th Pre-Connect Congress

October 23, 2017 | Portalhaus, Frankfurt Messe

Explore the Future of Pharma

VIEW THE AGENDA:

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Organised by:

DIGITAL HEALTH

Instruments of change In this article, François Feig, head of Global General Medicine and Endocrinology, Merck, explores technological advancements in healthcare and how they can be used to improve patients’ lives.

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2014 report from the World Health Organisation into eHealth and innovation in women’s and children’s health described the internet, smartphones and wearable devices as ‘instruments of change’ and talked of a ‘quiet revolution’ in healthcare. The report New smart describes how technological medical devices advancement, and eHealth record and specifically, is already helping submit accurate, people to live longer, healthier lives, largely through access to real-time data, accurate medical information allowing the physician to build and advice, and1better recording of patient data.

Living with a chronic disease introduces numerous challenges and stresses whatever your age, whether due to the effects of the disease, the burden of treatment, or feelings of uncertainty and lack of control. These stresses can contribute to emotional and behavioural problems among children and adolescents with chronic diseases and can compromise treatment adherence.3 Giving children a feeling of control is important in helping them to cope with their illness.

Traditionally, medicine has been something that has been done to children. Through eHealth technologies we can make children active participants in their treatment, handing them that feeling of control and ownership.

This quiet revolution is continuing apace, with a move towards a more patient-centric approach, seeking to make patients an active partner in their own disease management, and the instruments of change now include ‘smart’ medical devices that can send real-time data to a healthcare provider to aid clinical decision-making.

eHealth technologies can help to normalise treatment for children — educational apps and games can teach children about their disease in a fun way — encouraging engagement and motivation. As long ago as 1997 a study in children with type 1 diabetes showed a 77% drop in emergency-room visits among children who had played a video game which involved managing characters’ diabetes while saving a summer camp from marauding rats and mice.4

At Merck, we are focused on several areas tailor-made for eHealth technology such as chronic childhood diseases, in particular growth hormone deficiency (GHD). The quality of treatment that we give to our children can have a lasting effect for the rest of their lives — reflected in their educational achievement and employment prospects as well as long-term health outcomes in adulthood.2 Today’s children have grown up with technology permeating almost every aspect of their lives. It helps them to learn, to play and to communicate with their friends — it seems a natural extension to use it to help them to manage their illnesses.

An example from my own experience, is an educational smartphone app that we have developed at Merck, for children with GHD. As the treatment of GHD requires daily injections, and most patients are young children, medication adherence can be a real and ongoing struggle for all those involved in the treatment process. Our app combines gaming with facts and practical advice so it allows children to have fun whilst learning more about their condition and treatment.

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a fuller picture of the patient’s symptoms and intervene when necessary.

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Parents and children want these resources and it is the healthcare and pharmaceutical

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communities’ responsibility to provide them.

Only then can we ensure that the information within them is accurate, reliable and based on real medical knowledge. To maximise uptake and subsequent use, the interface must be user friendly and appealing and the content must be fun and relevant to the target age group, otherwise the all-important content will not get through. eHealth technology also offers benefits for the physician. New smart medical devices record and submit accurate, real-time data, allowing the physician to build a fuller picture of the patient’s symptoms and intervene when necessary. This may be particularly useful for paediatricians, whose young patients may be less able to describe their symptoms or recognise when a treatment is not working as it should.

At Merck, we strongly believe in the power of innovative digital technologies to improve the treatment experience, and ultimately the outcomes, of our patients. The instruments of change are becoming more numerous, more sophisticated and more effective. We should be proud of the impact this is having — forget the quiet revolution, we should be shouting this from the rooftops!

References: 1. eHealth and innovation in women’s and children’s health: A baseline review. Available at: https://www.itu.int/dms_pub/itu-d/opb/str/D-STR-E_ HEALTH.06-2014-PDF-E.pdf 2. Wijlaars, L.P.M.M., et al., Arch. Dis. Child, 2016;101(10):881–885.

3. Compas, B.E., et al., Annu. Rev. Clin. Psychol., 2012;8:455–480.

4. Brown, S.J., et al., Med. Inform. (Lond.), 1997;22(1):77–89.

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DIGITAL HEALTH

â&#x20AC;&#x153;

It is important that all patients can eventually profit from the developments that are being made.

A digital health age Digital health is a major trend topic in pharma right now with many companies investing in the field and looking at ways the tech can be utilised. In this Q&A, Norbert Haberland, VP New Processes and Products, Datwyler Sealing Solutions, speaks about how Datwyler is taking on the challenges of this advancing field.

Q. What is your view on digital health and how does your company engage in this field?

A. Digital health is a key focus for the healthcare industry at the moment. It has rightfully become one of the big trend topics and has a lot of potential for the future. It can open up a wide market, offering many opportunities to pharmaceutical and medical companies.

There are several factors, which promote the popularity of the topic.

Take the advancing age of the population, for example. As people get older health issues such as high blood pressure or cardiac arrhythmia can develop. These issues need constant monitoring, not only directly but also remotely. Digital solutions can offer a safe and reliable option for this purpose.

Apart from the diagnostic and therapeutic side, there is also the fact that people increasingly want to monitor their bodies and functions themselves, mostly for wellness or fitness purposes. Altogether, this triggers a growing demand for means and devices to monitor and record biological data.

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Digital health is becoming more relevant for clinical, therapeutic and private purposes, which, in the future, makes it an extremely important asset to the healthcare industry. This development has been growing for a few years now and obviously leads to a change in the medical world.

This also means that we have a lot more data at hand than we used to.

While in the past, simple and one-time laboratory tests were evaluated, todayâ&#x20AC;&#x2122;s much higher quantity of qualitative data can be used for both diagnoses and therapies.

Patients can now have access to long-term monitoring, which can even be performed by themselves, affording a much better foundation for a diagnosis. This is a definitive trend with potential for growth and further development.

In the medical world, Datwyler is predominantly present as a significant player when it comes to the packaging of drugs and the development and manufacturing of medical device components for the administration of drugs. So far, we have mainly explored the area of wearable devices

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and have started to pave the way for us to further expand in the direction of digital health. As we have been working in the field of digital health since 2014, we have been early birds in this segment and are trying to leverage this experience.

Combining wearables with drug administration could result in new therapeutic measures and devices, for example in the treatment of diabetes. As one of the most prevalent diseases worldwide, affecting all age groups and countries, it is an important endeavour to join the efforts to treat diabetes effectively and efficiently.

Q. Partnerships are commonplace in digital health as sharing and transfer of knowledge is of key importance. Is this something you are doing as well?

Most diabetic patients measure their blood sugar by pricking themselves with a needle and measuring the blood glucose level directly with a special device. Wearables give them the chance to continuously measure their glucose level and consequently be told when and how to balance out their insulin.

A. Since June 2016, we are closely cooperating with the Interuniversity Microelectronics Center (IMEC) Institute in Belgium and Holst Center in the Netherlands to do research in the wearables sector. This three-year research programme is centred on developing advanced materials for intelligent electrodes for brain monitoring platforms. Those are being developed for use in long-term and remote electroencephalograms (EEG) for clinical use, neurofeedback and multi-sensor brain monitoring applications. Further developments relate to smart electrodes for electrooculograms (EOG) and electromyograms (EMG) in the virtual reality/augmented reality field.

Q. What are the advantages of the electrodes and technologies you are developing?

A. As the name ‘wearable’ suggests, the electrodes are made to be worn on the body for a long time, over days and weeks. It is of great importance that the electrodes and their materials offer high wearing comfort, are waterproof, flexible and biocompatible. This offers a higher comfort to the patient and, therefore, a higher degree of relaxation, which in most therapies is of utmost importance. One of the key principles that we follow at Datwyler is the principle of Patient Safety. The patient and his or her safety is always at the centre of our attention and research.

When combining it with a wearable device such as an insulin pump, the device can directly and independently administer the exact amount of insulin the patient needs at that time. This can help to control and contain overdoses, as a constant level of medication gives the patient the security to always have a level that is fitting to their specific medical requirement.

Q. This addresses a point often made in the digital health discussion — who has decisive power over the constant stream of data generated by wearables and could this become a future problem?

A. We are very much aware of this discussion. However, sustainable solutions for this issue will need further consideration from different parties, and these debates have yet to take place.

It is not dissimilar to the discussion around autonomous driving and the self-driving car. The question of responsibility and the usage of data has not been entirely solved. However, it remains the subject of an intense debate.

Q. Are there markets that are especially receptive or predestined for digital health solutions and products?

One thing remains certain: the health and safety of our patients is always our first priority and main concern and we are working very hard to guarantee that this priority is always met with the highest importance and consideration.

A. I would not put it down to specific markets or countries. It is much more about the infrastructure that needs to be in place, for example when processing all the generated data.

Q. Which topic would you say has the most potential and will be of the highest importance to the digital health sector?

A data communication structure is important when patients are being monitored in the long-term. Not all countries can necessarily provide that. We know that activities are ongoing to enable this, such as sending or receiving the data in batches rather than having a continuing flow.

This makes it easier to submit data because it does not depend on an always present infrastructure.

It is important that all patients can eventually profit from the developments that are being made.

Q. What long-term goals or objectives do you see in the wearable sector?

A. The development of sensors will definitely be one of the most decisive future priorities, which will then also sort the wheat from the chaff. The better or more intelligent the sensors are, the better data can be generated and worked with.

Good sensors – for example soft and dry specially coated polymer electrodes to provide unrestricted wearing comfort — in combination with smart algorithms to process the data will be one of the key factors for digital health. This is something we are working on intensely and will continue to work on — with our partners, in our worldwide facilities and departments and with much ambition.

In the end, we hope that we can provide safe and innovative solutions for digital health – no matter what the future holds.

A. In general, we at Datwyler try to tackle challenges presented by market developments head on. For example, within drug packaging, we absorbed the new requirements of drug administration in biologics and biosimilars with our coating, Omni Flex, and the Omni Flex Coated Plunger for pre-filled syringes. Therefore, the topic of drug administration is something that is at the forefront of our minds, even when addressing the topic of wearables.

Of course, collecting patient data and bio signals, as well as the relevant technologies used for this data collection, are the most important tasks now, but concentrating on the future should be the key priority when focusing on digital health.

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PACKAGING

From reviewing consumer and market insights to identifying future trends that require packaging solutions, Essentra have created a pipeline of product innovations to meet individual customer’s needs. Here, we talk to Rupert Taylor, global category manager — Healthcare & Personal Care, about the importance of patient adherence and the various design features that help make packaging safe, simple and specialised.

Q. Why is patient adherence important and how can packaging help?

A. Patient adherence is the extent to which a person’s behaviour corresponds with agreed recommendations from a healthcare provider.

This is, therefore, extremely important, as patients not following their prescribed regime correctly will delay their recovery and hinder the efficacy of the medication. Low patient adherence levels are extremely expensive for the healthcare sector, with research demonstrating it can cost the NHS £500 million annually.

The extent to which patients follow their regime corresponds to the ease of access to the medication and ability to understand the instructions on the pack. For example, packs that are simple to open, access and close with clear, easily navigable information can help to improve patient adherence levels.

Q. Do you work within the clinical trials area?

A. Yes, Essentra is actively working in the clinical trials area. Here, the elements of patient adherence are even more vital to the successful completion of the trial. Absolute consistency throughout the entire clinical trials process is key for packaging, as is the designing of clear and simple instructions for the patients to help improve adherence to the regimens. A range of design solutions, as well as thoughtful structural design, can be brought into play.

Q. How do you tamper-proof?

A. At Essentra, we have developed a range of labels including three speciality variants — fibretear, void and frangible — to combat the issue of counterfeiting through tamper verification.

Fibre-tear labels irreversibly damage the carton board on to which they are affixed, void-release

labels leave a void message when removed, and frangible film labels use a specially engineered substrate that disintegrates when removed. Thus, they all allow end users to personally judge if the product they are opening has previously been tampered with, giving them confidence that the medication is authentic and originates from the legitimate manufacturer.

In addition, we have specialist gluing solutions — such as side seam, crash lock and four corner — for our pharmaceutical cartons, which simply and clearly demonstrate when they have been previously opened.

Q. What if the contents are temperature sensitive?

A. Thermochromic inks can be used on packaging to help patients monitor the storage conditions that may impact the efficacy of the drugs. These inks come with set limits of working temperatures and are carefully selected depending on the customers’ needs.

For example, one of the inks turns black if temperatures exceed 70°C.

perforations, allowing customers to create truly unique packaging that fits their brand.

We also incorporate sustainability into our packaging solutions if this is something that is important to the customer.

Q. What about protecting fragile contents?

A. Internal fitments are carefully designed and constructed by our structural engineers at our Design Hub, ensuring that the appropriate packaging is created for each of our customers’ products. For fragile contents, cartons with airspaces and cut out forms can be used to ensure products are protected and cannot move.

For example, our Parenteral Paper Packs (PPP) include IMA SAFE packaging equipment to erect the container trays or display boxes, and pick ‘n’ place systems lock the vials, bottles, ampoules or syringes in place inside.

Q. What does the future hold?

A. We work on a customer-by-customer basis, creating bespoke packaging solutions depending on their respective needs. Last year we opened our Design Hub, a service that brings together creative designers with backgrounds in marketing and branding with packaging and development experts.

A. We believe that more and more manufacturers will continue to turn to packaging to provide value added features and benefits for the consumer, particularly in the healthcare sector.

Thoughtful designs aimed at enhancing the patients’ experience with the product will be vital — not only will this improve adherence to treatment regimens, but it should also boost the manufacturer’s brand image as their products are differentiated to others.

By holding innovation sessions and creative workshops with our clients, we can understand what design features they require to meet their objectives. The design features that we offer include multi-colouring, structure, embossing, debossing, varnishes, foiling and micro-

In addition, areas such as biopharma rely on protective packaging where temperature can play a critical part of the drug’s effectiveness.

Therefore, we see features such as chill chain logistics and thermochromic inks playing a crucial role.

Q. How do you meet individual customer’s needs?

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PACKAGING

Age of automation Head of operations at Sharp Clinical Services, Dave Wilson, reveals how automating packaging lines can benefit clinical trial supply and what should be considered before introducing new technology.

T

he clinical trials landscape has changed drastically over the last 10 years driven by demand for complex oncology drugs and medicines to treat a wide range of therapeutic areas. As a result, there is more clinical development activity than ever before.

Added to this, ongoing technological development in the clinical trials space continues to change not only the way clinical trials are managed, but also how the drug supply is developed, manufactured and packaged.

In particular, companies are beginning to automate process lines as the need to With increasing focus on improve productivity and still achieve highimproving efficiencies to quality results becomes more important to combat the cost and risk meet demand.

“

of clinical trials, adoption of automation is increasing among pharmaceutical companies and their contract partners.

Clinical cost concerns

having an impact on blinding of the product. As such, more companies are choosing to label their products using a barcode or a 2D data matrix that can be scanned at kit level.

In the same way that automation can benefit commercial packaging lines that need to incorporate serialisation data, it can also help companies develop efficient labelling processes that meet varying market regulations for clinical trials. This is where a company with experience of serialisation can really add value by translating this approach to clinical packaging lines to support the verification of assembly processes and provide suitable coding for despatch. It also provides an easy way to generate the randomised labels that are essential for successfully blinding products.

Specialised Interactive Response Technology (IRT) can also automate activities including clinical supply management and distribution. In addition, it allows for the adapting of the study schedule as data becomes available, which helps to drive overall efficiency.

The average cost of getting a new drug to market is now estimated to be around £1.5 billion. If a drug fails in the late stages of a clinical trial, the financial and operational impact on the sponsor and its suppliers can be catastrophic. With this in mind, it’s easy to see why there is pressure from drug developers to reduce costs and timelines.

Automated processes can also dramatically increase the speed of inspection activity. Clinical trials require each product to be identical in appearance as any variation could influence the results and invalidate the study. Technological advancements in camera vision and verification systems over the last decade have allowed companies to replace manual inspection with an automated equivalent to ensure uniform presentation of packaging and labelling.

There are also wider cost concerns throughout the supply chain as a result of increased price pressures from governments. As such, pharmaceutical companies are looking for as many ways as possible to improve costefficiency and reduce the time to market.

Automation is also hugely beneficial when it comes to catering for evolving needs such as additional batches or scale-up. It can also make tech transfer simpler if the drug progresses to commercial supply. Capacity and scalability are vital and companies can benefit from using contract partners that can cater for both clinical and commercial supply, allowing sponsors to utilise the commercial technology for clinical projects and simplifying scale-up.

”

With increasing focus on improving efficiencies to combat the cost and risk of clinical trials, adoption of automation is increasing among pharmaceutical companies and their contract partners. This is particularly common across packaging operations, in a bid to reduce the time and resources associated with manual processes such as inspection and labelling.

The benefits of automation Packaging for clinical trials runs at smaller scale and frequency than commercial packaging, but this doesn’t mean automation can’t be introduced to improve operations. Companies just need to have a greater understanding of the investment involved in automating activity and the potential benefits it can offer.

In a clinical trial study, there are a number of ways automation can benefit packaging operation. Firstly, as a result of regulatory changes, labels for clinical trial supplies need to contain more detailed information, without

Summary There is no doubt that automation can benefit packaging for clinical supply, however it’s imperative that companies ensure such processes are fit for purpose. Manufacturing and packaging for clinical trials tends to be a more manual process and sometimes very small scale, so for some projects, the investment in automation equipment will not be a viable option.

However, selecting a contract packaging organisation (CPO) with experience of packaging products from clinical to commercial supply can enable the sponsor to gain access to facilities and technology that will add significant value to the clinical project.

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PACKAGING

“ Beyond surface value

By seeing the bigger picture around data management, life sciences firms open themselves to a range of new possibilities — to reduce complexity, cost and risk, while improving productivity, accuracy and speed.

As long as a product’s packaging and labelling is treated separately from internal regulatory and product information management, the scope for inefficiency, error and risk remains significant — especially with the growing frequency of regulatory updates around the world. With this in mind, AMPLEXOR’S Romuald Braun explores the potential to make label management a less superficial activity.

M

islabelling is one of the leading causes of costly product recall,1 and a particularly frustrating one given that it is so easily preventable. Yet, as long as product labelling is treated as a distinct, manually-driven process, life sciences organisations will continue to leave themselves open to the risk, not to mention a level of inefficiency they can ill afford.

Intensifying regulatory requirements and the evolution towards IDMP are causing regulatory and quality teams to look again at their processes and systems for managing content, however.

In this context, labelling management as a topic subject was the subject of much discussion at AMPLEXOR’s recent annual conference. As organisations start to think more laterally about regulatory information and greater efficiency in how they respond to new demands, they are beginning to realise that the only real way to manage this in a sustainable way is by creating and drawing from a definitive master data repository that is capable of supporting multiple applications. Instead of starting from scratch each time there is new content (such as new labelling) to create, regulatory teams and those responsible, can simply call up approved content from a central resource.

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”

Beyond single-purpose regulatory systems

At-a-glance data trails

This approach becomes a natural one as organisations move towards a more holistic, next-generation regulatory/product information management strategy. This is the vision advocated by Steve Gens, founder of Gens & Associates, one of the leading authorities on regulatory information management (RIM). He maintains that RIM should be as wide-ranging in scope as possible, encompassing dossier management, submission planning and tracking as well as manufacturing, change control, safety reporting, master data management as well as labelling and document management.

The clever part, where content is linked logically using metadata, is that by selecting one object it becomes possible to see at a glance the relationships to all the other objects, and therefore the knock-on effect of any changes to the content. So, the impact and risk assessment of any changes becomes a natural part of the design.

As long as such activities take place separately, each served by standalone systems and processes, companies risk repeatedly reinventing the wheel and introducing inconsistencies with each new content preparation task.

If a company has procured systems for each distinct process from a series of different vendors, integration can be an issue and data’s dominion may be unclear: which is the authoritative, correct version of content and how is this determined and controlled?

Next-generation RIM needs to facilitate a seamless, reliable end-toend process — from data/content collection to submission tracking and reporting. To further maximise the benefits, companies should be extending this same systematic process of content management to all important product data across a drug’s lifecycle. If this, rather than a targeted application of the data, becomes the core resource, it becomes possible to derive maximum efficiencies each time that content is repurposed for a particular use case.

So, ideally any master data management initiative should start with a product master data object model, of which regulatory intelligence is a part. The regulatory factors may not fit generic system data fields, being the proprietary IP of each company. However, if it the information is structured, it can still be reflected in the main product information system, contributing to that holistic, 360-degree resource, which caters for all information needs.

Right first time — every time Combining product master data with regulatory intelligence makes it possible to automate more processes — including labelling management.

Suddenly more becomes viable, and the need for heavy manual work is reduced each time there is a new content-related requirement. In the next-generation scenario, whether the result is new labelling or an IDMP-related submission, the output is ultimately just an expression of the company’s product data, in a particular format.

When content ‘fragments’ are used in several places in several documents, the master data and object-based approach means that if something fundamental needs to be changed, the ripple effect of those changes can be seen at a glance and the changes automatically reflected wherever this is needed, with full traceability. So, for instance the user might create the fragment name of a medicinal product once and then re-use it in multiple documents. As this is reflected in the master data, it can be referenced by other documents.

Each element is managed in the same way teams manage documents already, and creating the labelling structure is similar to the way teams create a submissions structure. It is a virtual document with all the respective sections: listed are the core company data sheet, a cover page, a table of contents and the name of the medicinal product, below which are the text fragments. The real leap is that those authorised to do so can now alter labelling elements fragments in a virtual document environment, and whole steps can be automated because the correct data will be applied automatically.

Once all of the necessary text elements have been input into the structure, it’s then just a case of deciding what to do. Similar to publishing, the submission structure is created independently from the published output.

In this case, it’s possible to transform the content to the desired format according to rules that have been pre-set.

Previewing makes perfect An ability to preview the document is desirable too, for instance as a complete PDF. The underlying enabler is the data-centric, object-oriented model, which allows labels and related documents to be created and amended using approved master data. Automated creation of labelling documents becomes something teams can do with confidence. And where regulatory intelligence is also reflected in the system, label creation can be done in accordance with the specific country requirements.

By seeing the bigger picture around data management, life sciences firms open themselves to a range of new possibilities — to reduce complexity, cost and risk, while improving productivity, accuracy and speed.

Taking a master data/complete product profile approach means all of the correct content for accurate, compliant labelling can be called up quickly and easily for the given use. In addition to ingredients and manufacturing information, it should be possible to call up detail for all authorised medicinal products alongside all the respective countries’ procedures, health authority organisation information and marketing authorisation programmes and processes. Labelling processes, change requests, sequences and templates should all be possible to manage in a clear and structured way.

Reducing complexity begins with reducing the number of systems in use for different tasks, the number of interfaces and, as a consequence, the number of manual interactions (and associated risk factors, and inefficiencies — i.e., as it becomes easier to re-use approved content and automate the editing and creation of new materials). It goes without saying that there need to be important safeguards, controls and checks — especially where affiliates are part of the process. However, ideally these checks will be built in to the core system, ensuring compliance and building confidence and, as an extension of this, user acceptance.

Proper provision for labelling, to reduce risk and improve efficiency, should include the ability to select approved content elements as selfcontained label ‘objects’ or assets. These might include the name of a medicinal product or its clinical particulars, pharmaceutical particulars or pharmaceutical form. Some elements might be market specific; others could be global/core content. However, using an object-based master data management approach, grouping fields becomes very easy to do, linking components as appropriate to the various applications — for example a particular artwork, or at a global level the company core data sheet or the core package insert. All of these fuller objects are referenced but the components are sourced from master data.

It has taken time to get there but quantifiable simplification and de-risking of labelling management is now within reach in life sciences, a day many across the industry have been greatly anticipating because of the many practical challenges it can now overcome with a palpable ROI.

Reference: 1. Characteristics of FDA drug recalls: A 30-month analysis, US National Library of Medicine/ National Institutes of Health, 2016: https://www.ncbi.nlm.nih.gov/pubmed/26843501

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PACKAGING

Traditionally packaged Ampoules are a traditional type of primary packaging for pharmaceutical drugs that offer a good choice for emerging markets. Here, Lothar Haaf, general manager of Gerresheimer and Dr Volker Rekowski, chairman of the Gerresheimer Quality Council, discuss the benefits of this product.

A

mpoules were developed at around the same time as injections were invented as a form of medical treatment. With this type of primary packaging, pharmaceutical drugs only contact the inert and gas/vapourimpermeable material — glass — which is also tamper-proof.

Although they have been competing with vials for quite a while, and increasingly with pre-filled syringes, ampoules are still the global number one choice of primary packaging for injectables, and growth is clearly being seen in the cost-sensitive markets of emerging nations.

Varying designs Most ampoules are manufactured in accordance with the DIN ISO EN 91871/2 standard in straight-stem, funnel-type and sealed designs.

Straight-stem and funnel-type ampoules are supplied open, so the customer must wash and sterilise them before filling.

Sealed ampoules, as the name indicates, are supplied sealed. They are sterile on the inside as a result of the high temperatures in the manufacturing process, which means the customer can open them with a sharp flame, fill them and then re-seal them.

Customised packaging solutions are available for pharmaceutical drugs with challenging requirements. Dimensions and glass quality can be tailored to the specific requirements of the drug itself and to the filling process.

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Total quality control Medical technology products must meet exacting quality requirements. One of the most important pre-requisites for high product quality is automation in the production and inspection processes.

Laboratory tests involving the destruction of the products are regularly performed on random samples taken from the production lines. They serve to check ampoule break force in the opening process, for instance. The hydrolytic resistance of the ampoule’s inside surface is also tested in the lab.

Every ampoule that is manufactured is inspected in detail by automated camera systems before the packaging process takes place. Advanced image processing technology not only ensures uncompromising quality, it also improves production process efficiency by substantially reducing the number of false rejects.

To exclude the risk of the wrong products being filled into the ampoules, an increasing number of customers are insisting on having their own inspection equipment on the production lines.

The length of the score on OPC ampoules is also checked to calculate its depth and whether the break force conforms to specification. If the ampoules are printed, the texts are checked for legibility, absence of errors and compliance with customer specifications. Special inline optical character recognition systems are used for this purpose.

Automatic cosmetic defect recognition equipment can be found on every single production line. Early identification of cosmetic defects in the ampoule production process makes the customer filling process more stable with fewer rejects.

Product by process Proof of process capability and supply reliability are becoming increasingly important supplier selection criteria for pharmaceutical customers in addition to product quality.

A defined product quality can only be delivered reliably and sustainably if both the product itself and the effects of material characteristics and process parameters on the product’s quality are understood.

Design of Experiment (DoE) is an indispensable tool for systematic statisticsbased analysis. Several factors are investigated concurrently in DoE and their effects are established in a multivariate analysis. The DoE results can be used to develop a strategy for production process control. The goal is a process window in which the process capability index (Cpk) is higher than 1.33.

In this context, product quality monitoring not only involves rejecting defective products, it also performs the second and equally important function of providing statistical data for process control that can be used for the real-time optimisation of the production process.

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The objective is a process that is so stable that hardly any adjustments are necessary.

In this kind of process, the products don’t just look identical on the outside, they are consistently identical in every respect.

Supporting the pharmaceutical industry The ampoule manufacturer must supply the pharmaceutical industry with products that optimally satisfy their primary packaging requirements for a specific pharmaceutical drug or a specific application.

Gerresheimer does this by working with the customer to select or modify products, sometimes even developing brand new ones, in order to meet all specifications.

Customers are recommended to fully take advantage of ampoule manufacturers’ expertise to optimise production processes.

In this way, even when customised solutions are demanded the number of rejects can be kept to a minimum.

“

…technically there is no such thing as a ‘child resistant cap’ as for a pack to be child resistant you should have a certificate of testing which specifies the container and cap.

PACKAGING

”

Child’s play Packaging technology has undoubtedly progressed, however, it is unclear as to whether this effort is paralleled in creating a suitable level of child resistance. In this article, Richard Quelch of Origin discusses some of the important aspects of making medicine packaging child resistant.

A

dvancements in packaging technology are undoubtedly to be viewed as a progression, it is questionable, however, whether there is a parallel effort in creating the child resistant packaging necessary to ensure these products are safe for the environments they occupy.

There is an abundance of information and even some creative solutions available to the packaging industry, with the ease of access to online information manufacturers are able to appraise themselves in consumer and regulatory concerns and safety is no exception. There is, however, possibly a lack of understanding what truly constitutes child-resistant packaging and also a preparedness to await regulatory obligation before introducing protection.

Regulations and testing We have effective and well recognised regulations for the safe containment of medicines and the necessity of a common test protocol has long been considered essential for these products. Re-closable packaging to BSEN ISO8317 and its American equivalent, 16CFR 1700.20 are still effective and the 2015 version of the ISO standard has cleared up some areas of confusion.

To gain approval the complete pack must be tested — container and closure. Whilst many pharmaceutical containers are produced with child resistance closures it is not possible to assume that because one pack combination passes another will also pass.

Child resistant is not child proof

Testing in the UK is performed at UKAS approved test centres in accordance with the relevant test protocol. Marginal differences apply between the European and US procedures.

An important consideration is the terminology used in matters pertaining to child safety, rarely if ever is packaging child proof. The balance between child resistance and senior accessibility is challenging. Accommodating both aspects in packaging design for pharmaceutical products is a significant task, regulating such a conflicting scope is probably harder still.

Some test centres provide an expedited ‘pre-application’ test service providing a smaller test panel for a lower cost (Origin can advise regarding this). The test conditions are as per the protocol and the results helpful in ascertaining whether there are any fundamental issues in the pack design.

Child resistance should, according to the ISO8404 standard (non reclosable), be considered the last line of defence, not the first. Whatever packaging is developed to meet the fine balance of abilities between children and seniors it should be always remembered that ‘child resistant’ is never ‘child proof’ and therefore the practise of keeping medicines out of sight and reach of children should be mandatory.

The official test protocol requires 200 able-bodied children between 42 and 51 months and can be performed either with the full 200 contingent or by a method of sequential testing. For the adult test a panel of 100 is required between the ages of 50 and 70 years.

Compliance — how do I know?

Senior friendly child resistance In many ways, the senior accessibility aspect of packaging is less definable than the child resistance. With children, we have fairly prescribed parameters of ability in the child safe testing age bracket of 42 to 51 months. The scope of abilities present in the adult test panel however of 50–70 year olds presents a hugely different picture.

The loss of dexterity and in some cases the ability to coordinate is often diminished in our latter years. The key principles required in achieving effective child resistance are by definition the same principles needed to enable the ageing population. As our ageing population is also increasing and advances in medicine is enabling us to retain our independence longer, questions could be raised as to whether 70 is still a relevant top end age for the testing protocol.

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With over 50 years’ experience in child safe packaging we know there are an increasing number of packs in circulation that cannot be considered child resistant. Research suggests to us that an assumption is often made that because a cap appears to have a push-and-turn mechanism it must be child resistant, however this is not a wise assumption.

We suggest a common practise should be to ask your supplier for a technical file and certificate of child resistance for the pack you are using.

Remember that technically there is no such thing as a ‘child resistant cap’ as for a pack to be child resistant you should have a certificate of testing which specifies the container and cap.

If your product is sold within the UK and EU then the BSEN ISO8317 certificate is the correct document for your activities. If your product is to be sold in the US you will need the 16CFR1700.20 certificate to comply with the regulations currently in force in the US.

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PACKAGING

Temperature control As temperature-control requirements to maintain a pharma compound’s stability are constantly evolving, innovation in packaging is increasingly playing a vital role in global cold chain logistics.

Paul Terry, director of sales EMEA, Peli BioThermal, tells us more…

“

I

n an ever-evolving industry various pharmaceutical compounds, used in the sector, are developed in certain temperature control conditions or designed to be stored at specific temperatures to maintain stability.

It’s not simply a case of saying these packaging systems work; you have to prove they work time and again.

”

It’s critical, therefore, when shipping pharmaceutical products between locations they remain at their storage condition temperatures to maintain effectiveness at the point of use. Within the industry there are certain typical temperature ranges such as deep-frozen, frozen, refrigerated and room temperature.

For example, if products are particularly reactive they may be frozen to stop them reacting or if they’re live culture products they need to be kept warm. These temperature ranges can be narrow for some pharmaceutical products with +2°C to +8°C or +15°C to +25°C being typical requirements. Other product temperature storage ranges can be far broader, based on the stability data the pharmaceutical company has for those products or the storage conditions set on the product label.

The innovation in the cold chain packaging industry is almost running in parallel with the pharmaceutical industry. It’s not running as a consequence of the change in drugs development, however the demand is changing.

With the pharmaceutical companies developing more complex and temperature sensitive drugs, the cold chain industry is having to meet the growing market demand for supply as well as improved packaging performance and efficiency. To help mitigate the supply chain risks the industry is seeing a greater demand for higher performing packaging products.

Advancements over recent years has seen the introduction of better insulation by using vacuum insulated panels (VIPs), reducing the thickness of the insulation required and increasing performance.

We’re also seeing an accelerated replacement of water-based systems with those using phase change materials (PCMs) where, through a combination of materials, the melting point of the coolants is designed to the ideal temperature, rather than water ice at 0°C. These systems provide far more stability inside the payload space to the desired temperature and by using less overall material.

These newer packaging developments are delivering significant payload benefits, as there’s less liquid in the system and the insulation is much thinner through more effective VIPs. The payload efficiency of these new systems can be more than double the traditional water based and foam insulated options, saving significant expense on logistics services.

The drawback of these systems is, while they provide excellent performance, they do tend to come at a higher unit price. However, the small, compact nature of their size means they actually pay for themselves with the lower spend on freight, more than justifying the extra unit price of the product.

This is certainly the case if you then take into account the reduced incidence of lost products due to temperatures not being maintained, which can be significant.

Technologies available There are currently different technologies available that offer the advantages of duration and temperature stability.

Traditionally, during the cold chain passive packaging industry’s embryonic development stage, the main forms of technologies deployed were ones using insulating material for the outer box of essentially polystyrene or foams, providing protection and insulation. Then to maintain the temperature inside the packaging combinations of chilled and frozen water were deployed.

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Although relatively cost effective, in terms of unit price, these systems needed fine-tuning to keep products at the right temperature, over the required duration. Using these systems often results in relatively heavy shipping solutions because you’re carrying a lot of water and bulky insulation, as well as the actual payload. Performance against highly variable external temperature challenges can also be below requirements.

There’s also an increasing industry trend towards reusability, such as the Credo system, rather than single use packaging. As these high performing systems contain higher value components, it is economically advantageous to retain, recapture and reuse that value through a good reuse programme. Plus reuse delivers better environmental sustainability.

Suppliers to the industry are increasingly providing the support infrastructure to help the transition to re-use, such as bespoke service centres and defined quality inspection processes.

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Shipping lanes Today most of the passive temperature controlled systems are used within a courier network and/or for air cargo freight. Most passive packaging systems have durations of less than 120 hours, whilst the requirements of the customers might only be 48 hours in terms of their courier express network.

The design of the packaging used can therefore be tuned to the requirement of the duration and the temperature sensitive nature of the product being shipped.

It’s about packaging companies offering a mixed menu of packaging solutions. The key is to specify your packaging choices around the shipping lanes you have, within reason, as you don’t want to have too many packaging options because that would become unmanageable in your warehouse operations.

So how do you define those lanes? One of the things we’ve seen during recent years is temperature monitoring becoming more commonplace, due to the cost of data loggers and the capture of the data becoming more affordable and accessible.

Increasingly pharmaceutical companies now have a far better understanding of the temperature stresses their products experience during shipment in certain lanes. They can better determine what is a high-risk or low-risk lane and then make the appropriate packaging choice to fit that requirement.

One of our roles is to match the appropriate packaging system used to the client’s lanes, so they’re not spending more than necessary, but are getting an appropriate solution to protect their pharmaceutical product, for both their brand reputation and ultimately the patient receiving those products.

Our approach is centred on reducing the total cost of ownership for a client in getting their products from the point of manufacture or clinical study centre to the end patient whilst maintaining that required product temperature.

That total cost of ownership includes the cost of handling the product in their own supply chain, third parties shipping and handling, the receiving party and the unit cost of the packaging itself.

We use several modelling tools and years of expertise to help with these decisions, recommending the most efficient system for customers. We’ve developed our packaging portfolio in such a way; it will fit with most of the scenarios we come across in the industry.

Packaging for the future Having the infrastructure we have, with the experience of our engineers and the amount of thermal chambers we have to qualify these systems makes a difference. It’s not simply a case of saying these packaging systems work; you have to prove they work time and again.

This qualification is crucial and is something the regulators, our customers and we can stand behind and makes sure the packaging systems perform as intended.

With the changing regulations, over the years, to make them more encompassing, such as the Good Distribution Practice (GDP) guidelines, this is critical.

As a result of these regulatory changes, challenges to the industry are continuously cropping up. Hence, we have seen an increased requirement of our expertise to ensure companies meet the latest regulatory requirements and ensure they’re getting the protection for their products in the market at the lowest cost.

The industry is in mid-transition with companies looking at how they can deploy more advanced VIP technology and PCM materials to improve the efficiency of the supply chain today.

In the short-term, I predict we’ll see some interesting play between various PCMs in different combinations and increasing use of vacuum technology to maximise the payload efficiencies and reduce handling and system preparation costs. The recently released Credo Universal system, is aimed at reducing customer costs and controls required for pre-conditioning, and offers ease-of-use and reliability for both high and low temperatures.

Over the longer period there will be an ongoing drive to look for the next generation of insulation to improve on costs or the payload efficiencies.

For example, how can new insulation both protect the payload from impact but also provide better thermal resistance than today’s solutions?

Innovators should be looking at more interesting ways of creating insulation and innovative ways of using PCMs to achieve optimal performance at a lower cost.

Ultimately the drive is to continue to reduce the supply chain costs and improve performance and reliability.

By increasing the payload efficiency of your packaging you will spend less money on shipping and ensure you’re not wasting money in the supply chain. It’s about being as efficient as possible while ensuring the quality is maintained throughout.

Single use versus reuse Whether it is single use or reuse the options can be assessed in terms of their cost effectiveness.

If the packaging is low cost and low performance it’s highly unlikely to be cost effective to reuse it. If, however you deploy high-performing, high value and well-engineered systems, it often makes good economic sense to recover them in a reuse process but only if you can achieve a good recovery rate.

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LAB DIARY

The reproducibility crisis This diary entry from R&D software provider, IDBS, looks at how individuals, laboratories and external collaborators can make their work more accurate with the help of cloudbased software.

According to a recent poll by Nature,1 70% of scientists polled have failed to reproduce at least one other scientist’s experiments.

Even more shockingly, more than half of scientists have failed to reproduce their own experiments. So, what can be done to address the reproducibility crisis in laboratories?

different people all working simultaneously with the same information, so the accuracy of this information is key — and using an ELN is only part of the solution, especially when collaborating with external organisations.

Quality of data

A cloud-based collaboration platform

The failure to replicate past experiments can be understandably frustrating for scientists who want a solid foundation of research to build upon. While no two labs are exactly the same, and a number of factors could affect the results of a reproduced experiment, there are also many factors scientists can control. The most important?

The quality of their data.

The continued use of external providers, such as contract research organisations (CROs) has increased the likelihood that experiments will need to be repeated by third parties — potentially working in different regions, countries and time zones.

In a laboratory environment, increased data quality accelerates workflows, enhances analysis and ensures the delivery of a higher quality of products and results. When data is of a poor quality, whether because of multiple errors or a disorganised format, businesses will be unable to gain insight into the project or experiment details.

However, errors can and do go unnoticed and the findings of flawed experiments often end up published in reputable journals — meaning they could be repeated by unknowing parties later.

Recording data accurately Although one or two data errors may seem like a relatively minor issue, they can escalate into much larger problems further down the line.

For scientists repeating experiments, even the smallest of errors could mean you’re wasting both time and money trying to replicate the impossible. The best solution is making sure scientists have the tools to record data accurately in the first place.

With the sheer volume of data being created each day, many businesses are seeking alternatives to the traditional paperbased recording methods to keep up with today’s technology. One of these alternatives is an electronic laboratory notebooks (ELN).

Digital solutions, like ELNs, reduce the time-consuming process of recording data into laboratory notebooks. They usve sophisticated technology, which can eliminate the manual transcription of data and maintain information integrity and quality when recording experiment information.

The results of in-house experiments will often form the basis of multiple follow-up experiments too and, in some cases, one experiment will form part of a group of 15 or 20 separate projects that combine to form one set of results. In this situation, there could potentially be hundreds of

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Collaboration projects can cause all kinds of logistical problems — with various stakeholders needing to coordinate activities and transfer data and reports. Results need to be easily searchable, dated and timestamped. Other contextual information should also be digitally recorded, meaning colleagues trying to repeat experiments have as much information as possible before replicating an experiment.

The best way to ensure data integrity when collaborating is using a cloud-based platform. This enables organisations to create and share templates with external collaborators and, when a study is completed, data can be seamlessly transferred back to your organisation’s internal systems with just a few clicks.

The benefits of the cloud Using the cloud provides you with both the flexibility and security you need to get your projects moving, saving you both time and money.

By using the right platform, collaborators — both internal and external — can enter their data directly into your system, eliminating the need for disparate data files and formats, and reducing the chances of errors creeping into work by standardising the data formats used.

No more misunderstandings and no more ambiguity: all data can be recorded and viewed as originally intended, giving anyone reproducing an experiment the best possible chance of success.

Reference: 1. http://www.nature.com/news/1-500-scientists-lift-the-lid-on-reproducibility-1.19970

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