TAILORMADE DRUG DELIVERY

Drug substanceto drug delivery

High quality devices in regulatory compliance

with reliable performanceat competitive cost

2 PRIMARY CONTAINER

THE TRINITY OF DRUG DELIVERYThe best possible solution for your drug delivery needs is a solution where primary container, medical device and filling process form a synthesis. NNE Pharmaplan has expertise knowledge and hands-on experience within all three aspects. That makes us unique. And it enables us to help customers achieve world-class drug delivery solutions which reduce time to market and achieve cost advantages thorughout the lifecycle.

TAILORMADE DRUG DELIVERY

NOVO GROUP ORGANISATIONAL STRUCTURE

With our roots in Novo Nordisk and 30 years of experience in filling and product development, NNE Pharmaplan ensures safe, reliable and effective drug delivery devices through a holistic approach that integrates all aspects from user needs to production requirements. Our integrated approach of proper design controls, risk mitigation, prudent design and robustmanufacturing, ensures that our customers can help their patients while avoiding regu-latory approval delays and non-compliances.

OUR ROOTS Pharmaplan was founded as part of the medical care group Fresenius in Germany

After functioning as in-house consultants at Novo Nordisk for years, NNE (Novo Nordisk Engineering A/S) demerged as an independent company

NNE acquires Pharmaplan, a company similar to NNE in DNA. NNE Pharmaplan was founded.

2,000 employees working in life sciences and over 75 of those employees in drug delivery

TODAY More 80 than years of experi-ence. We are passionate about our services to the pharma and biotech industries.

Danish Novo and Nordisk Gentofte (later Novo Nordisk) employed the first engineers

19741930s 1991 2007 2014

Primary container

Medical device

Aseptic processing

3PRIMARY CONTAINER

PRIMARY CONTAINER PLATFORM TO DECREASE TIME TO MARKETFor companies with a large medical device portfolio or pipeline, standardising on their primary container solution can bring huge cost savings and decrease time to market significantly. In this situation, a cartridge solution is posi-tively the best way to go.

Cartridges are cost-effective, easy to produce and easy to fill. A cartridge based platform can be easily designed to accommodate oral, nasal and injection-based therapeu-tics leading to significant cost savings through:

• Reduced overfill• Greater economies of scale reducing cost of goods• Uniform filling operations

Furthermore, cartridges are more dimensionally accurate and consistent than syringes helping to more effectively control dose forces and dose volumes. Standardising the primary container platform starts with the following activities:

• User need analysis and device conceptualisation • Phase outcome / deliverables• User inputs (based on current solutions)

• Requirements analysis• Looks like models• Works like models on selected features• Device concept catalogue

The challenge that most companies face is the fact that the majority of their suppliers to the medical device perform tasks that lie outside the company’s own core competences. Thus, companies do not always know which questions to ask. In that situation, it is tempting to procure a finished concept, e.g., an auto-injector, offer-ing an already designed device which can be modified to your needs. It is rarely that easy, unfortunately.

A device designed to generic requirements and not specifically to the drug in question, may not meet the requirements of the specific users, e.g., a device for self-administration by patients with arthritis, for instance, must be adapted to the specific requirements of this particular patient group. Accordingly, a device developed specifically for the pharma company´s needs may provide better care. However, this benefit must be weighed against the extra complexity of controlling the device development activities at a design authority.

At NNE Pharmaplan, we have many years of experience in not only screening designers and contract manufactur-ers, but also screening component design for advantages and disadvantages including COGS and initial invest-ment. We also assess whether the product is actually manufacturable within the proposed supply chain. Our experience tells us that a lot of design houses will be able to deliver what you need for your exact drug product, but whether it is suited for manufacturing is another question. Our screening looks at whether the compo-nents are designed for manufacturing and for assembly and whether it is suitable for manual assembly or mass production.

VENDOR QUALIFICATIONFor manufacturers of drug and device combination products, a highly complex supply chain is probably inevi-table. With multiple suppliers to design the device, produce plastic components, metal components, perform assembly and sterilisation, etc., it is not unusual to have a dozen suppliers. To ensure that the final product meets all design and quality needs, companies need to make sure that all service providersand suppliers in the entire value chain deliver the necessary quality.

Trust is keyWhile an initial screening may show whether your suppli-ers fulfil basic requirements for quality and documenta-tion with the setup they had at the time of screening, it will not guarantee that they will over the long-run.

With an extensive supply chain, it is certainly not incon-ceivable that any one supplier at some point in time will make a change, which might be minor in their eyes, but which will have significant influence on your product. As one of our customers puts it, “if you don’t change your product, your supplier probably will; you can only hope that they will inform you”.

NNE Pharmaplan has experience in opening the dialogue between the pharma company and their supplier, and

in establishing the ground rules for communication and documentation in the form of specifications and quality agreements. We have participated in a project where the supplier was unable to deliver components to the required quality. One of our consultants collaborated with the supplier over a period of time, improving both the customer’s specifications and the supplier’s metal stamp-ing and surface treatment processes. This resulted in improved product quality, reduced cost and led to a more robust supply chain.

Building a relationship based on an open process mind-set and an agreement to communicate about all changes can save companies lots of worries and potentially a lot of money.

NNE Pharmaplan has decades of filling expertise of pri-mary containers ranging from vials to syringes to cartridg-es. NNE Pharmaplan has designed and built 50 filling lines for the pharmaceutical industry around the world.

4 PRIMARY CONTAINER

DEVICE TESTING AND DEVELOPMENT

Usability testing (simulated use testing) should be used early in the design process to get a complete and accurate understanding of how the device will be used and the use-related risks. These inputs are crucial in designing a user-friendly device that is both effec-tive and safe to use.

To start with, usability testing should be done through formative studies. It’s particularly important to do these formative studies early in the design process, as it will allow you to optimise the design with lesser effort and cost. Furthermore, the formative studies will also help you in designing a clear, effective and concise IFU (instruction for use). If the formative studies have been carried out appropriately (usually in an iterative fashion), the subsequent summative study should result in good performance with no (or at least few) user difficulties, providing for a good overall design validation process.

In parallel with usability testing, we always advise performing device testing which will allow you to understand the device characteristics and enable you to optimise the device design with regards to device performance, e.g., dose accuracy and dose delivery time. Device testing should start early in the development phase and include all relevant standards, e.g., ISO 11608-x. However, not all product attributes can be sufficiently tested with existing standards, and unique test methods must be developed and qualified. Using a traceability ma-trix to examine product requirements is an ideal way for you to record what testing needs to be done, evaluate the device’s performance characteristics, and to maintain an overview of the development process.

Ideally, protocols should be written and executed as formative and characterisation studies to measure the de-sign’s ability to meet user and design input requirements. You can leverage these protocols later in your design verification and validation activities.

The results from the usability and characterisation testing, including any design changes, should be recorded in the design history file (DHF). The DHF contains or refers to all records which are needed to demonstrate that the design is developed in accordance with the approved design plans and requirements of the design control regulations.Functional testing as an in-process control method is another area which should be taken into consideration during device design. For example, having the ability to test the device portion of the combination product, before the drug product is assembled onto the device, can help eliminate scrapping drug caused by a problem with the device. When the Novo Nordisk FlexPro® and FlexTouch® were developed, it was a requirement that all the motor modules of the device were to be tested in-line during their production, ahead of assembly with the filled cartridge. Hence, any issues with a motor module are identified before a costly cartridge with drug product is added.

PRIMARY CONTAINER

PRODUCT PORTFOLIO PLANNING (PPP)

Another thing that we have learned is that patients know what device they use – but they do not necessarily know either the name of drug they are taking or who produces it. Hence, the device itself is key consideration to realising business goals. The following is a list of items to contem-plate when thinking through portfolio planning:

• Competitors’ offerings What competitors are doing is straightforward market

intelligence. The key is to have a systematic and achievable plan to remain competitive and, ideally, take market share.

• Unmet user needs Identification of unmet user needs can be done

through voice of customer activities, research, ob-servation, etc. The key question here is “What could potentially make the use experience better?

• Differentiation Why spend exorbitant sums of money and time to

develop a drug to then put in the same drug delivery device as your competitor? If you can buy it off-the-shelf, then so can’t your competitors. By utilising dif-ferentiation, drug delivery devices can create competi-tive advantage - growing revenue, protecting market share, and building brand Marketable attributes

What can you market about your device? Are there attributes that you can use to create a competitive advantage in your market, or are there items such as smart phone applications that can help your users?

• Healthcare economics – “pay for performance” Can you take administration from a clinical environ-

ment and bring it to a home environment to reduce healthcare costs? What can be done with product design to ensure adherence to drug regimen adminis-tration on your device?

• Incorporation of electronics and software Incorporating electronics and software can be a tre-

mendous boost to functionality – devices can remem-

ber data and communicate. However, it is important to remember that electronics tend to have quite different lifecycles than medical devices. Electrical components are often designed for consumer electronics with new products coming out every 18 months or less. Howev-er, devices for drug delivery may be sold for years if not decades. Hence, planning for product discontinuation is a factor that must be considered in portfolio plan-ning. Software requires a whole new mind-set and has its own regulatory approach to validation that must be planned into development efforts and captured within design control.

• Time-to-market Phasing new technologies into product evolutions and

new platforms can impact time-to-market considerably and must thus be considered. Perhaps an off-the-shelf syringe is used to meet launch timelines, but it’s es-sential to anticipate the next iteration of that product, e.g., an auto-injector, and identify which attributes will help you achieve your product portfolio goals.

PPP in contextSanofi Aventis introduced SoloSTAR in an on-going arms-race to lower dosage force and improve accuracy. In re-sponse, Novo Nordisk optimised their existing FlexPen to show a greater repeatability of dosage force and greater accuracy than their SoloSTAR rival. But, Novo Nordisk also looked at what made sense as a platform for the next generation of device that would minimise dosage force, have high accuracy and improve the patient use experi-ence. Hence, FlexPro and FlexTouch next generation disposables were created. Pen length remained constant regardless of dosage volume and dispensing force was held constant irrespective of volume.

Original FlexPen® matched by competitor devices

Improved FlexPen® will extend FlexPen®

lifecycle, securing market leadershipImproved FlexPen® lifecycle extension closes the gap until PDS290 launch

Volu

me

2012

Launch of improved FlexPen®

Original FlexPen® platform

Launch of PDS290

Launching a product with every new feature and technology or solving every need is nearly impos-sible that is why product portfolio planning is critical to commercial success. We have seen customers who have a new injectable drug either put together a kit or use a pre-filled syringe, without having any idea what their next product will be or if market differentia-tion will influence their products success. Not understanding such considerations can allow you to be outpaced in the market.

5

6 MEDICAL DEVICE

Designit’s relationship with Novo Nordisk has hinged on the most important topics in the healthcare business today: patient adherence, patient safety and product differ-entiation.

Many patients are unable or unwilling to follow a pre-scribed course of care. With R&D reaching a certain level of maturity in the healthcare industry, there are fewer blockbuster drugs that find their way onto the market. As a result, we see a shift in focus from the product or drug to the customer and end-user.

Products and services that manage to match the needs of the patient – to simplify the treatment of chronic diseases – are what drive adherence. With better adher-ence comes better healthcare economics; this makes the healthcare industry more efficient, it lessens the burden on governments, it makes patient management better and it improves patients’ lives. For Novo Nordisk, it also ensures the company’s long-term competitiveness.

We have studied the realities of how patients manage medication, devices, and tackle bureaucracy and have made huge strides showing how doctors work with patients, and what experts prescribe – and in turn how healthcare systems are shaped. Through this work with patients, we discovered problems that impact prod-uct development and have learned what works when communicating with and marketing to patients and healthcare professionals.

FROM USER NEED TO CONCEPT

Bridging the communication gap between healthcare professionals, patients, providers, and manufacturers ensures an insulated feedback loop; the benefit is liveable treatments and reduced costs.

While some Designit projects for Novo Nordisk have focused on understanding patients’ feelings about the practical issues surrounding disease and its emotional repercussions, others have taken a more direct device approach.

One project, about understanding what drives device choice in patients with diabetes, took place because Novo Nordisk wanted to widen their product range within durable devices to increase market share. For the study, Designit shadowed and interviewed patients, nurses, doctors, and payers in US, Europe and China.One of the things we discovered was that very few patients logged the time and size of their injections on a daily basis. Because of this they often made false conclusions and adjustments to their treatment regime, exercise and diet. And because logging was not part of the injection process they occasionally also forgot if they had actually taken the dose – even though only a few minutes had passed.

These insights led Novo Nordisk to explore devices that would help make logging easier and more integrated in the injection work-flow and Novo Nordisk implemented some of those ideas in the launch of the NovoPen5.

Customer intelligence in practiceAt Designit, we think about products, services, or pro-cesses from the perspective of the people who use them. We look to identify gaps between what people need and what companies offer. Our process is grounded in social science – the study of human nature. We set out to study

people’s behaviour and attitudes in an effort to link that behaviour to their purchasing habits and to discover what they need or desire as customers. Mucking around in people’s emotions can be a circuitous and messy process – but the end results are concrete and based in science.

On a typical project we start by creating a framework for understanding the problem (falling market share) or goal (creating new products). Then we head out to do field-work with consumers around the world – meeting them in their homes, following them to bars, joining them on shopping trips, interviewing them all the while.We look at people in their environments – how they live, what they think and do all day, what their habits are, and how they understand the world. These observations are compiled as scientific data. Once we crunch that data, then the patterns emerge. We then build a theory around those patterns and test the theory against what’s happening in the marketplace. Finally, we deliver what we call “insights” to explain what we learned from our research and analysis. Then we marry those insights with technological capabilities and possibilities and knowledge about competitor offerings.

Among our deliverables are new or more targeted value propositions, including:

• Developing and sharpening customer segmentation• Deepening the understanding of the customer• Mapping the customer experience and use-cycle• Identifying customer needs• Developing products and services around customer

needs• Developing intelligent services to complement products• Structuring research to move fluidly from concept to

prototype

CUSTOMER BEHAVIOUR

CUSTOMER NEEDS

VALUE PROPOSITION

A

DEVICE CONCEPT

A

DEVICE CONCEPT

B

DEVICE CONCEPT

C

VALUE PROPOSITION

B

VALUE PROPOSITION

C

TECHNOLOGICAL CAPABILITIES

TECHNOLOGICAL OPPORTUNITIES

COMPETITOR LANDSCAPE

COMPETITOR BENCHMARKING

COLLECT ANALYSE OPPORTUNITY SPACES EXPLORE OPPORTUNITIES CREATE CONCEPTS

EARLY USABILITY AND HUMAN FACTORS TESTINGOnce the value proposition and design opportunities have been identified, we can explore a variety of different conceptual solutions to match.

By maintaining the end-user-value of a product as the focus throughout concept development, we produce solutions that users embrace readily and operate safely in real-world conditions. This provides better efficiency and overall lower cost to deliver a complete, faster, end-to-end development project.

We use human factors studies to evaluate, improve and filter our concepts through and iterative design process. Our methodologies and capabilities include:

• User needs discovery and requirements generation• Task analysis and heuristic evaluation• Hazard analysis• Usability testing• User profile and use scenario development• Ethnographic and facility-based user research

With each iteration, less and less concepts are being considered, and more and more details are being clarified and verified.

Task analyses are critical to good device design and must be performed throughout the development phases. Early on the analyses should be conducted as paper-and-pencil exercises. As development progresses, analyses should be performed with mock-ups and prototypes. We often begin the task analysis by developing the first draft of the instructions for use (IFU). The IFU is then developed con-current with the device concept to congregate learnings together. Because regulatory bodies have decided that patient risk can no longer be mitigated by the IFU, this concurrent development becomes even more important.Hazard analysis is where we look for and evaluate potential hazards associated with the users actions or unintended actions. One should assume that if errors can occur, they will occur and that design may be a factor. Hazard analysis provided an excellent collection point for possible hazards uncovered from complaint files during

earlier studies, as well as from tests, user studies, and task analyses. The key is to consider errors as “failures” analysts can hypothesise what errors are possible. Then, they can analytically pinpoint potential causes and draw conclusions about consequences and appropriate design solutions.

Usability testing for ease and accuracy of use is the only way to ensure that users can safely and effectively oper-ate, install, and maintain devices. By means of iterative prototyping, individual concepts of design can be tested, refined, and retested throughout the development pro-cess. This process culminates with full testing of a model embodying all the user-interface characteristics for both hardware and software of a fully functioning device.

During our many years of helping medical device manu-facturers in their efforts to outsource component mould-ing, one of the issues we have most often come across is that companies are often unaware of the need to consolidate requirements for the CMO’s moulding equip-ment. While it comes as no surprise that the component design and the mould itself have huge impact on the final component, the equipment, the production facility and the environment are often not considered critical parameters. They certainly are though.

Because most CMOs produce various products for vari-ous customers, they often rely on standard equipment. But, as advanced as the equipment might be, it may not be good enough. This can and will eventually lead to:

• Mould crashes, e.g., Lack of proper interlocks in the IMM control

• Short moulding, e.g., IMM injection performance not consistent or change-over settings issues – screw jumping back leading to inadequate cushion for the post-filling phase

• Bended or otherwise deformed parts, e.g.: • Uneven cooling flow due to clothed cooling chan-

nels (poor filtering or impurities in central cooling system that are hard to filter)

• Parts squeezed in conveyers• Mix-up, e.g., Improper layout of either handling or

box-changing areas• In-consistency in IPC (inline process control) measure-

ments, e.g., too high of variation from humidity in: 1) raw material handling 2) at the IMM environment and 3) IPC in cases where it is not really IPC but an

offline measure in another environment• Increasing maintenance, e.g.: • Water quality from both central cooling water

system and thermolaters in combination with poor filtering

MOULDING CMO – BEST PRACTICES

• Pressure in cooling channels very high for compen-sation poor flow leading to leaks at o-rings

• Mould were not put in the machine in one piece leading to poor alignment between stationary and moving side

By consolidating requirements for the moulding equip-ment, utilities, etc., from the beginning, companies can achieve the desired quality in the most cost-effective way and avoid costly breakdowns and maintenance. Even if a big part of the cost of implementing required changes to the equipment should be defrayed by you and not the CMO, it is well worth the investment. The potential savings run into millions of euros each year.

Best practice exampleOur customer had been producing their product at several CMOs for years. As such, there was no urgent need to alter the setup or the requirements. However, over the years, the customer had observed potential weaknesses and experienced some internal complaints that could jeopardise the trusted quality brand of their product. Hence, they wanted to optimise robustness of their production set-up and identify possible improve-ment areas – particularly in component manufacturing as this was considered the predominant source of potential failures.

Based on years of manufacturing experience and knowl-edge – from both in-house and CMO production – the customer already knew the causes to the majority of the issues. Thus, NNE Pharmaplan was asked to identify and compile the potential solutions and rank them to deter-mine which requirement to include in a new requirement baseline and which requirements to leave out. Because some changes despite the probable benefit would be too costly to implement.

The task was carried out as a technical assessment, identifying the specific demands as well as the customer’s minimum requirements for the standard equipment. Then we analysed the gap between the setup at the CMOs and the customer’s requirements identified in the assessment of product, process and equipment. This was finally gathered in a comprehensive summary sheet encompassing specific and minimum generic require-ments within all aspects of molding the components for the product:

• Facility• Utility• Raw material supply• IMM (Injection Moulding Machine)• Peripherals

The end result was a list of 80 items that were considered to improve product quality and robustness of the manu-facturing process and be cost beneficial.

7MEDICAL DEVICE

8 MEDICAL DEVICE

Control schemeThe overall control scheme relies on the risk profile of the product and related processes. But there is more to it than that. The whole flow of documentation must also be aligned between the drug company and the CMO. Hence, at a minimum, the following four items have to be addressed:

• Risk assessments; process FMEA linked to user FMEA (failure mode and effects analysis)

• Linking functional requirements to design parameters• Design history file (DHF)• Device master record (DMR)

To control a tech transfer programme successfully, it is crucial that you understand the risk profile of your prod-uct and related processes, and that you have established a control strategy. We often see that so-called “generic” FMEA for processes are supposed to account for what could happen in the process, but they are rarely specific in explaining what impact it will exert on the product.

Linking functional requirements to design parameters (like illustrated below) based on data is a proficient way to make sure that you know the sensitivity of your design and thereby what parameters you need to control in order to ensure reliable product performance.

You need a structured and integrated approach to be successful in tech transferring combination products. This entails a clear understanding of each of the following key areas:

• Supply chain• Assessment of capability• Control scheme• Predictive performance• Quality assurance strategy

Supply chainFirst, you need a general understanding of the impact of a tech transfer on each of the areas of aseptic process-ing, primary container and the device. This means that all roles and responsibilities in the supply chain must be clearly defined and placed in contracts. Further insight into this area can be found in the separate article about supply chain on page 18.

Assessment of capabilityAn overall picture of the capabilities – whether it is in-house or at CMO – is a basic requirement for being successful in tech transferring. There must be a match between process requirements and the suggested pro-duction setup. One thing is the actual equipment that is intended to be used; another is how it is controlled and maintained.

Too often problems start with CMO moulding, where the CMO relies on standard equipment. As advanced as the equipment might be, it may not be good enough. Your product quality will be very sensitive to both how the equipment is specified and used. It is quite common that CMOs shift moulds into different machines depending on machine availability. If the screw size in two machines dif-fers too much you will get parts out of the machine that look acceptable and live up to the few control measure-ments. However, there is significant risk of overlooking several important dimensions related to critical part func-tions and thereby jeopardising product performance.

To make sure that a consistent quality can be obtained over time you need to assess how the equipment has been specified, e.g. injection unit performance, recovery performance, cooling water supply and quality of water and closing unit including platen alignment. Next step is to assess how the CMO controls the moulding phases: Injection, holding, recovery, cooling and de-moulding. Basically, control is about relating the monitored machine parameters to operator adjusted settings. A key question in this context is how changes in material batches are handled because different viscosities will require changes to the baseline settings.

By assessing and consolidating requirements for not only moulding, but also the facility, printing, assembly, label-ling and packaging equipment, utilities and peripherals from the beginning, you can achieve the desired quality in the most cost-effective way and avoid costly break-downs and maintenance.

TECHNOLOGY TRANSFER – MAKING IT LAST

Component tolerances are based on what is perceived as possible and what is needed theoretically to make the tolerance stack-up work. Hence, a first step is to establish the relationship between actual obtainable process toler-ances for the given processes and how that will affect function (see figure 1 and 2 opposite). This will allow you to understand which precautions and controls are needed to sustain quality. The most important thing, in relation to tech transfer, is the ability to deliver a set of data that is enforceable in running production; reflecting what is necessary for the product to function.

Predictive performanceThe ability to supply robust and reliable combination products starts at the early stages of product develop-ment. If injection force is governed by several compo-nents with statically indeterminate interfaces, it will be hard to predict the overall performance. The sensitivity variance in the tolerance chain will be high due to the number of interfaces that need to be aligned.

To ensure intended function of component interfaces, they must be related to manufacturing processes param-eters that can be controlled. This is where a transfer func-tion comes into the picture. A transfer function ideally tells you the correlation between the process parameters and critical design attributes.

The ability to control your supply chain is crucial to your ability to deliver robust and reliable products. Control-ling an often complex network of contract manufacturers poses a huge challenge.

Communication fromMarketing to R&D

Functionalrequirements

Func

tiona

lre

quire

men

ts

WH

ATs

HOWs

HOWs

House ofQuality #1

Prioritisedfunctions W

HA

Ts

Communication fromR&D to pilot

Designparameters

Des

ign

para

met

ersHouse of

Quality #2

Prioritised design parameters

Communication frompilot to production

DoE= knowing the relation

between design parametersand process parameters

Processparameters

House ofQuality #3

Critical sourcesof variability

Tolerance chains= knowing the relation

between functional requirements (product tolerances) and design parameters (process tolerances)

LINKING FUNCTIONAL REQUIREMENTS TO DESIGN PARAMETERS

USING TRACE-ABILITY TO ACCELERATE V&V ACTIVITIESDrug delivery devices have a long list of design input and user require-ments from various stakeholders including: marketing, production, patients, doctors, etc. Hence, test-ing a new medical device for critical quality attributes and at the same time ensuring a valid test result re-quires a significant amount of testing and a large number of devices.

Based on design and tolerance chain analysis, we have helped customers organise verification and validation test activities, so that they can focus test efforts on critical aspects while at the same time obtaining as much useful information as possible. Another desired attribute of this approach is that it minimises that amount of testing, while still achieving valid and meaningful test results.

Based on the device design and the IFU, we use risk assessments to identify the critical aspects of the design, e.g., delivered dose and Essential Tasks necessary to correctly use the device. As the risk analysis matures, it provides better and better input to validation and verifi-cation tests. The risk control measures are communicated to the designers, component manufacturer(s), assembly

and final inspection so that they know what attributes need to be monitored.

When verification and validation is performed, test proto-cols can be developed based on the body of knowledge available from development, including engineering tests, tolerance chain analysis and risk management. Traceabil-ity of requirements and risk control measures throughout development ensures that test protocols for verification and validation can be developed with a minimum of confusion as to what to test and how to test it.

Another important contributor to performance predic-tions is the empirical data gained from old or mature designs. Empirical data from product and process perfor-mance should be compiled, analysed and documented in a way that makes it clear what is needed to obtain the right quality for various design features and materials.

Quality assurance strategyThe most successful quality assurance strategies cohe-sively account for supply chain, assessment of capability, control scheme and predictive performance. Further-more, this should be created and revised in conjunction with your CMO partners. In addition, an evaluation of all markets should be completed to disclose any special requirements for entering certain markets or countries that can create any special setups in manufacturing and packaging.

Make it lastFinally, to make sure that this can be sustained through-out the product life, you must continuously reassess:

• Contracts and agreements; are they still covering your needs?

• Tolerance chains; do they reflect the actual manufac-tured parts?

• Specifications; are the requirements that release parts enforceable?

Lowertolerance

Uppertolerance

Maximum allowed drift (bias) of distribution

Lowertolerance

Uppertolerance

Maximum allowed drift (bias) of distribution

Lowertolerance

Uppertolerance

Maximum allowed drift (bias) of distribution

WORST-CASESafe, but overly cautious and expensive

STATISTICALCheap, but overly optimistic and impossible to enforce in production

PROCESSMore realistic estimate of output variability, but most importantly it is enforceable

We need to knowY=f(X)

Variation in part dimensions, process, material properties, ...

X

Variation in function for product: What is important the customer

• Equipment and process performance; does the setup support the full scale manufacturing requirements in terms of quality, yield and price?

• Equipment and process performance; does the setup support the full scale manufacturing requirements in terms of quality, yield and price?

FIGURE 2

TYPE

Worst case

Statistical

Process

BEST USE

• Simple design• Manufacturing

- unstable

• Complex design• All inputs ontarget (Cc=O)• Manufacturing stable

• Normal design• Manufacturing stable

BENEFITS

• Enforceable through Cpk or GO/NO GO testing

• Safe• No other assumptions

• Narrower tolerances for the output (reduced cost of open-ing up input tolerances)

• Enforceable• Safe & less expensive than

worst-case tolerance• Realistic estimate of the range

of the output

DEFICIENCIES

• Expensive• Tend to overestimate output

range

• Necessity for continuous measurements

• Impossible to enforce (Cc=0)• Can create quality problems

• Necessity for continuous measurements

FIGURE 1

9MEDICAL DEVICE

10 MEDICAL DEVICE

Organisational stakeholders often argue that the diffi-culties in production and the higher cost associated with novel technologies are minimal compared to the positive effects on revenue and profit that comes from introducing a novel product to the market. While they may be right, it is undoubtedly a risky process to produce novel products. Introducing a high volume product with massive process and production challenges might result in recalls or very costly, long-term fire fighting, which is critical consideration over a typical product’s intended life span.

Design for manufacture can reduce these risks signifi-cantly. This is preferably done in two levels, concept and detailed level.

The concept level focuses on ensuring adherence to your product programme and establishes the correlation between critical product attributes and the parameters anticipated to be crucial in production. The detailed level follows a structured process based on evaluation of main drivers for each manufacturing process step. The follow-ing is a list of items/activities that go into designing for manufacture:

Unique components

Multiple applications

Medical device platform

LINKING PRODUCT DEVELOPMENT & MANUFACTURING TO OBTAIN A ROBUST DESIGN

Looks and workslike model

Works and madelike model

Processes

Time & money

R&D Production

• Moulding• Decoration• Assembly

• Labeling• Packaging• Sterilisation

Product concept Product launch

Users/Market

Users/Market

Product development

• Design of Experiment (DoE)• Sources and manages equipment for both customers and medical contract manufacturers• Qualification and validation of equipment and processes• Process run in• Trouble shooting• Techical transfer of GMP production equipment• Revamping• Regulatory assessment• Logistics

Industrialisation Production

LINK

customer needscustomer needs

Business case Process understanding ProductionIndustrialisationProduct development

• Front end innovation• Part design• Verification tests• Design for manufacture (DFM/QBD)• Material investigations• Risk analysis - FMECA methodology• Tolerance Chain Calculations• Capacity studies• Value chain analysis• Cost modelling (from concept to launch)• Process design• Regulatory 21 CFR 210/211, 820,• Directive 93/42 ECC amended in 2007/47/EC, ASTM E2500

DESIGN FOR MANU- FACTURE IN PRODUCT DEVELOPMENT

Concept level• Product family master plan (PFMP) analysis pinpointing

areas of improvement in your product programme• Coupled versus uncoupled design – interrelated parts• Production flow mapping for entire product families

pinpointing redundancies, opportunities and decou-pling points

• DFM as part of development stage gate deliverables

Detailed level• Detailed benchmarking against your existing products

with rating based on selected production drivers/ parametres

• Preferred materials based on your experience

• Design change database to keep structure and track of needed and wanted design changes

• Interrelated items • DFM is not only moulding and assembly, it is also: • Design for reliability • Design for maintainability • Design for serviceability • Design for environmentalism • Design for life cycle cost

11MEDICAL DEVICE

Simplicity is a prerequisite for a great drug delivery device – it has to be easy to use for the patient or the administrator. At the same time, a good device is one that demonstrates good design principles. which is important to build a relationship to the patient. The design needs to incorporate reliable building blocks and form factors that are well known and understood in terms of how the prod-uct is handled and how it performs. None of this matters, however, if the device does not live up to expected quality and performance.

In the strategic planning for a new drug delivery device, one question overrides all others: “Should you prioritise getting the product fast to market or introduce new, in-novative technology that will put your product in front of your competitors’?” For obvious reasons, many compa-nies tend to try some sort of compromise that prioritises both drivers equally. Depending on whether speed or novel technology is your main driver, there are different aspects to consider when designing for simplicity.

SIMPLICITY AND SPEED TO MARKETWhen time is your first priority, your combination product must be well-planned and well-defined to avoid costly delays and misunderstandings. Simplicity in design starts with a target product profile which should outline all the important characteristics of the product. The following product profile list is not exhausted, but points out some major items of concern when designing for simplicity:

1. Intended use2. Product main functions3. Target group4. Performance criteria5. User interface requirements6. Compatibility, e.g., with other product families and

related equipment7. Storage, transportation and shelf life

THE COMPLEXITY OFDESIGN SIMPLICITY

is not done persistently during the development phase, which often leads to project delays and costly solutions that do not meet the requirements for robustness – espe-cially in high-volume production.

For process selection, we advise customers to go for mature technology and processes that are well-known in their organisations. That will also mean that quality and regulatory affairs operate in familiar terrain, and that is essential for reducing a product’s time to market.

SIMPLICITY AND NOVEL TECHNOLOGYGenerally, there is a lot more risk involved when new technology and design are at the top of the priority list. The recommended approach in this case is to have two programmes run in parallel. One programme should cover the development of the novel technologies, while the other programme should be conservative and use well-understood technologies. If you encounter problems in the novel technology programme, the conservative programme acts as a fall-back solution to decrease programme risk. In view of this, we often challenge our customers to make an extra assessment of whether the new process or technology actually does bring innovation to their product at a degree that justifies the increased project risk. If it does not, most companies are better off choosing a technology which they know already.

History has taught us that regardless of how fast a product development is completed, the regulatory part can take several years. Accordingly, when customers come to us for consultancy, one of our primary pieces of advice is to take a front-loaded approach in developing a quality strategy. Usually, this involves taking an in-depth look at the product portfolio and determining whether the planned product development will require a new approach to compliance efforts. Also, the coordination of marketing and quality plans can help bring down the registration process timeline.

8. In use time – product life time9. Expected price in use10. Functional characteristics regarding manufacturing

Once these requirements have been enumerated, they should be vetted against the risk profile of your pro-gramme. If you device contains electronics, for instance, this can be associated with a greater risk profile due to challenges in software validation and battery life and performance after being exposed to a cold chain supply. Thus it might be worth asking yourself if the electron-ics bring benefits payers will reimburse and if the use of electronics will put your product in a superior position without jeopardising product reliability.

Approaches towards simplicity in designAn important step in achieving a simple design is to limit overall system complexity, if possible. Next, it is important to focus design principles in order to:

1. make sure that the actual part design relies on as few interdependencies with other parts as possible

2. ensure that product tolerances are related to toler-ances which reflect actual process performance – this means using process tolerances and not worst case and/or statistical tolerances

3. facilitate design for manufacture (DFM), which entails early focus on manufacturing processes and required production equipment

One thing which is crucial to achieving these three objectives and doing things right the first time, is close cooperation and coordination between those who develop the product design and those who produce it. That entails communicating experiences learned in the production phase effectively back to the developers, so that they can take those experiences into account in the development process. This “exercise” is what is known by most people within the industry as DFM. However, over the years we have seen again and again that DFM

12 MEDICAL DEVICE

DEVICE REFRESHINGOur client was facing competition for one of their medi-cal devices and had to improve key features of the device in an expedited-time frame.. The client already had the concepts for the required design changes in their pipeline and was thus able to start verification of the product improvements according to design specifications at an early stage. The solution as such was easy to imple-ment, but organising the rollout to all relevant sites and contract manufacturers was a daunting task – particularly considering the time pressure that a launched competi-tive product adds.

Making the project schedule match the marketing strat-egy, so that all implementation and validation have been completed in time to fit your desired launch timing is as

challenging as it is imperative. Our experience tells us that the earlier in the project that companies start to think about the impact to supply chain in detail, the greater are their chances of keeping their timelines.

Thus, going into the project, we did an initial assessment of the process and equipment needed to be altered and revalidated to produce the updated device. Subsequently, we assessed the need to redesign parts of the process in order to ensure that it could in fact produce the new product, so that the product lived up to the claims of ad-ditional features for improved usability. e.g. lower dosing force.

Our most valuable assets in this case were our under-standing the product, the processes and the equipment, because it enabled us to convert the detailed design changes in the product into specific actions needed in the process and the equipment setup. Hence, we linked the definition of new requirements for both the process and the equipment to the component criticality consider-

ing which controls could be implemented without raising costs in terms of more expensive equipment and new standard operating procedures that would also require training. This was done in a coordinated way so that the global rollout could be completed without having to make differentiated solutions for each site.

Based on the results, we helped the customer carry out the necessary process changes, the validation and the global rollout.

Mission:Improve FlexPen® with supporting features as soon as possible:

• without jeopardising the FlexPen “trusted” quality brand

• without jeopardising the capability to supply all mar-kets with FlexPen

At NNE Pharmaplan, we look at cost optimisation from a holistic perspective taking into account component design, processes and organisation.

For the latter, one area we usually look at for potential cost savings is standard operating procedures – particu-larly those that are not being followed. Often, if a SOP is not followed, it reflects that the procedure described is less than optimal, and this represents an opportunity to make beneficial changes in the SOP to have staff operate more effectively.

Another area is the role of the neural network in manu-facturing. While companies in general strive to automate

as many processes as possible, robots are by no means always preferable to manual labour. For certain functions, the human brain can do things that robots simply can-not, and in some instances, selecting manual labour over robots can generate significant cost savings.

The production process is usually where the really big cost saving can be achieved. We have helped numer-ous companies optimise costs by reducing the number of process steps, reducing IPCs (inline process controls), optimising material selection, optimising form design and mould design, improving line speed or line clearance and optimising assembly.

We have also seen great results when we have helped customers optimise product/component design based on realisations made from the production process. By accumulating knowledge from all corners of the organi-sation from areas such as preferred materials, companies can build an actual database of best practices. Such a database can be of great value in future development and industrialisation efforts. Being able to use knowledge in a constructive, structured and conscious way makes it possible early in product development make decisions that are necessary for reducing a product’s timeline.

ImprovedFlexPen®

OriginalFlexPen®

Interface for Easy Twist needle Coloured cartridge holder 2 additional colours

Printed packaging material updateCarton and leaflet designAll countriesModern insulin

Coloured FlexPen product labelOne colour per modern insulin

Reduced dose force 30%From 18 to 12 N

COST OPTIMISATION

NovoRapid® FlexPen®

Levemir®

NovoMix® 30

13MEDICAL DEVICE

Writing new procedures to meet current FDA regulations such as 21 CFR part 4 is only the first step to getting in compliance. To achieve a truly compliant device design, the design history file must demonstrate both in-depth understanding of current regulatory expectations and well-defined interfaces between drug development and device development.

NNE Pharmaplan has had great success facilitating workshops that focus on understanding the terminology of drug and device development, respectively, and to get design control and risk management onto the right track. By reaching out to all relevant parts of the organisation, NNE Pharmaplan can assist in developing both esign and development plans and design inputs that capture the stakeholder needs of drug and device development, quality, regulatory, etc.

In addition to implementing design controls in product development, NNE Pharmaplan has experience in evalu-ating the documentation for existing products and can assist in developing plans for documenting compliance with combination product regulations. This may include leveraging existing documentation from e.g., drug con-tainer development, clinical studies or contract manufac-turing organisations CMOs. Since design control is merely

a formalised version of good engineering practice, having all parts of a combination product including the primary container -under design control will ensure maximum benefit. Ensuring coherent and consistent documentation is a key element in establishing compliance and in being able to convincingly present documentation to regula-tors. NNE Pharmaplan has assisted customers in develop-ing tools for ensuring that traceability is maintained from development of design inputs to component drawings through design verification and validation. We ensure that inputs from risk management are collected and traceable alongside other inputs, so that all requirements can be located in a single repository.

The transition into combination productsAt NNE Pharmaplan, we have observed that companies may go wrong in handling the regulatory requirements, in particular in design controls. The design control process for medical devices is very different from that of drug development.

We have seen examples of companies that design a drug delivery device and come as far as being ready for market launch, before they realise that it is a combination product and that documentation should have been done differently or more extensively. There are few possible

DESIGN CONTROLS– RESPONDING TO CHANGING INDUSTRY REGULATIONS

outcomes of this: either the authorities clamp down on the lack of documentation, or the product launch must be delayed.

While most companies have an efficient risk manage-ment system, it is designed based on requirements and regulations for drugs. And as regulations for medical devices are widely different from drug regulations, it is often necessary to rethink the risk management system. NNE Pharmaplan has experience in developing knowl-edge-based risk assessments that utilise the knowledge gained through usability studies, bench-top testing and modelling.

Most pharmaceutical companies operate with one integrated quality system and introducing a drug/device combination product to the product portfolio means that this one quality system has to accommodate medical device and drug alike – just like the product itself.

Needless to say, this has consequences for not just the quality system itself, but also for supply chain and opera-tions. NNE Pharmaplan can assist in defining organisation and documentation to ensure continuous compliance for the product.

FDA REGULATION

QUALITY MANAGEMENT SYSTEM

21 CRF part 4Published Jan. 2013Effective July 2013

Draft guidance on glass syringes for delivering drug and biological productsApril 2013

EN/ISO 13485 Risk managementUpdate 2012 includes significant changes

EN/IEC62366 UsabilityEnforced within recent years

Meddev 2 1/3 rev 3 borderline products,drug delivery productsE.g. December 2009

CMC central management committeeDecisions

Medical device classificationprocedures (part 860)Proposed rule March 2014

Draft guidance on labelling designto minimise medication errorsApril 2013

Guidance on design of homeuse devicesDraft December 2012Final August 2014

Guidance on human factorsJune 2011

Guidance on post approval changesJanuary 2011

Medical device directiveUpdate ongoing

EN/ISO 13485 QMS for Medical DevicesUpdate 2012

QUALITY MANAGEMENT SYSTEM

PRODUCT DEVELOPMENT PROCESSPRODUCT DEVELOPMENT PROCESS

EU REGULATION

14 ASEPTIC PROCESSING

The drug or vaccine is the heart of any drug delivery de-vice. With the drug to be delivered into the human body it needs to be sterile, and almost all known drugs for subcutaneous, intravenous or intramuscular injections do not withstand terminal sterilisation. Hence, aseptic filling is the preferred production method.

NNE Pharmaplan has been involved in more than 20 aseptic filling facilities and scoped and designed several aseptic primary containers and devices for the drug delivery device world. In most projects, we have been in charge of the process design; in others we have been asked by the customer to challenge their product design or help solve production problems.

In the interface between a primary container and a drug delivery device the production challenges and possibili-ties need to be taken into close consideration. Some examples are:

• Residual air volume in the primary container is an issue to avoid. Large quantities of air will result in a higher drug volume being discharged during system priming. NNE Pharmaplan has completed several projects to im-plement sensor filling on both existing and new filling lines.

• Stopper position accuracy in a cartridge will have a direct impact on how the plunger interfaces with the medical device. NNE Pharmaplan has played an active part in determining the process and the equipment needed to implement visual inspection camera control to ensure desired stopper position.

• Cap crimping must create and retain a surface seal with the glass primary container to guarantee drug stability. In one project, our customer was struggling with obtaining a reliable crimping operation and, as a result, was planning to implement a plastic top. Due to deep production equipment knowledge, NNE Phar-maplan was able to find the correct parameter settings eliminating the need for the plastic top.

• Chips and cracks are a huge issue with glass contain-ers. Often, they are generated in the process of collect-ing and packaging post-filling. NNE Pharmaplan evalu-ated the situation and designed new transport systems that nearly eliminated chips and cracks in cartridges.

Through our project experience we have seen several examples of poor interaction between aseptic production and the medical device because companies have failed to take design for manufacture into account.

For instance, one of our customers was producing a new drug delivery device based on a setup where the filling line and the assembly line were built together into one giant, integrated production line. That entailed that the entire assembly line had to be aseptically encapsulated in an isolator together with the filling line. As a result, the customer experienced much higher investment cost, lower output due to longer batch change-over times, higher operational difficulty during production as well as

The most important learning that we’ve made through our involvement in various scale-up projects, is that investing a bit more time in pilot production will be of significant value in the long run.

First of all, spending more time in the pilot production is a great way for companies to increase important process experience as fast as possible. We often advise our customers to use the pilot phase to stress the pro-cesses to “force” any potential pitfalls to emerge. It is hugely advantageous to discover these pitfalls before scaling up.

Design-wise, we use the pilot phase to get production feedback to utilise in tolerance chains and process capabilities. We analyse the product moulding, as-sembling, packaging, etc. to assess whether the same concepts can be applied in full scale.

a higher unit price due to the fact that all parts needed to be sterile before docking onto the isolator. Small changes to the design of the drug delivery device would have completely eliminated the need for having an aseptic assembly line.

Another customer of ours had designed an entirely new drug delivery device based on a new and unknown primary container platform. As both were developed from scratch, discoveries during development resulted in a range of major design setbacks for both the device and the primary container. Lesson learned: if your time schedule is critical, the primary container should be based on a known design, such as a cartridge or a syringe.

We also check whether the capability which was as-sumed in the development of the product, and which the design requires, is actually realised in the pilot pro-cess. If not, the gap will only be larger after scale up. Another important part of pilot is to evaluate whether the quality specifications are sufficient in order to ensure that the process produces products that live up to requirements – especially when the product is produced by various CMOs which might interpret the specification slightly differently.

Finally, we also look at the organisation to determine whether it is necessary to complete an organisational change to accommodate full scale production, or if it is easily implemented because the production is similar to what the organisation is already familiar with. While some aspects related to the organisation can be antici-pated already in the planning phase, there are some of which you may not learn until pilot production.

FILLING OF DRUG DELIVERY DEVICES

SCALE-UP – LESSONS LEARNED

15ASEPTIC PROCESSING

The flexible alternativeFlexible aseptic processing leverages the commonalities between the various container fill-finish processes, but uses only a single manufacturing platform.

This is done by integrating cutting-edge technologies such as single-use technology, isolator/barrier technology, and ready-to-fill nested formats. The manufacturing process is simplified by eliminating the container preparation process at the manufacturing site. The end result is a flexible manufacturing process which enables you to fill multiple container formats and sizes on a single modular platform.

The consolidated manufacturing process allows multiple container formats to be filled and finished on a single system. Interchangeable robot tooling specific to each container can be applied, if required.

Supporting technologiesIsolator technology and RABS (restricted access barrier sys-tem) can be applied for both traditional and flexible aseptic

Most of the pharmaceutical products which are currently in clinical development are intended for production in small scale, have a high market value, and are characterised by a high degree of patient focus. As a result, faster product turnaround time and clinic responsiveness are increasingly crucial. However, because products are being produced at smaller unit volumes, minimising the invested capital required to bring these products to market is a top priority for manufacturers.

The solution is simple, modular facilities for multi-format, multi-product and multiple-dosing production. Investing in a single filling line which supports aseptic processing of multiple products irrespective of format, product, and dosing requirements will give you the superior fill-finish flexibility you need to build a cost-effective manufacturing line.

Keeping with traditionTraditional aseptic processing is a dedicated process that is specific to the container format. Introducing a new format on a traditional vial filling line is impossible. Thus, if you want to add additional filling capabilities to a facility where you have already installed a dedicated filling line, you have to invest in a new filling line for each format/platform – with all the associated costs. Obviously, this can be quite costly and it has a long lead time.

Traditional fill lines, especially those that handle non-nested containers (bulk filling), present a number of processing challenges such as glass on glass contact, machine jams, and broken or fallen containers.

Traditional fill lines are very efficient for filling products and containers that do not require flexibility. If you only plan to fill only one format in high volumes then bulk filling is the right choice.

ASEPTIC MANUFACTURING – TRADITIONAL VS. FLEXIBLE ASEPTIC PROCESSING

production. The isolator system provides full separation between the operator and the process and includes vapor-ized hydrogen peroxide (VHP) bio-decontamination.

Ready-to-sterilise (RTS) and ready-to-fill (RTF) concepts can be used for preparation of primary packaging materi-als. They are most relevant for low to medium volume productions. When production volumes exceed 50 million containers per year, wash, siliconisation and sterilisation of primary packaging materials on site becomes the preferred choice.

What’s right for you?There are advantages and disadvantages of both tradi-tional aseptic processing and flexible aseptic processing.

Choosing between traditional and flexible filling is a mat-ter of priorities. Teaming up with NNE Pharmaplan will get you a technical partner, who will ensure that you make the right choices based on your specific situation.

FLEXIBLE ASEPTICPROCESSING

• Flexible platform for several formats due to nested concept

• No investment in wash and sterilisation

• Capacity; Speed up to only 100 pcs/min

• Filling without air only possible with capping station

• RTF components are required, which creates sourcing risk

TRADITIONAL ASEPTICPROCESSING

• Capacity: Speed up to 500-600 pcs/min

• With isolator technology campaign production can

• Format-specific filling line• Glass to glass contact for bulk

processing• High investment cost

PROS CONS

TRADITIONAL ASEPTIC PROCESSING FLEXIBLE ASEPTIC PROCESSING

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Many drug product manufactures are looking for new primary packaging materials, such as plungers, stoppers, caps with seals, cartridges and syringes. Common to all of these components is that they have to be washed and sterilised before they can be used in pharmaceuti-cal production. But often pharma companies neither have the process equipment, the knowledge, the space, the time nor the money to perform these process steps. Consequently, they look for suppliers which can deliver in a ready-to-fill (RTF) format. This makes good sense if you intend to produce at low to medium unit volumes, but if

you need to produce at high volumes, NNE Pharmaplan recommends using bulk processing and establishing wash and sterilisation processes in-house.

Finding a RTF component supplier is easy – there are several suppliers that can supply RTF formats of the vari-ous types of primary packing material. The issue is that once qualification and registration of the drug product is done, the pharma company is highly dependent on the supplier’s ability to deliver in terms of quality, cost and time. Needless to say, this is a major risk. One way to miti-

RTF – READY-TO-FILL OR READY-TO-FAIL? gate that risk is to utilise dual sourcing for critical primary packaging components, i.e. engaging two suppliers for the same primary packaging component. It will require more work up front, but it is a wise precaution, which will protect you in case of unforeseen supplier issues. You can say that using a dual sourcing strategy is just like buying insurance.

NNE Pharmaplan can help you develop a setup which will minimise the risk and fulfil your requirements, ensuring that you get ready-to-fill and not ready-to-fail components.

16 ASEPTIC PROCESSING

There is a growing tendency towards outsourcing certain functions of biopharmaceutical manufacturing, especially within the field of drug delivery. Each time a new therapy moves closer to commercialisation, the manufacturer faces new challenges that lie outside its own core competences. In this situation, it is tempt-ing to procure a finished concept, e.g. an auto-injector or ready-to-fill primary packaging components. The “standard” solution is attractive because it can be easily modified to your needs – at least that is what you are told; unfortunately, it is rarely that easy. You need to ask the right questions up front because once that contract is signed and production is up and running, you will be totally dependent on your vendor in terms of cost, time and quality.

To start the process, you need to fully understand why you want to outsource and what you need to gain from outsourcing. Once you have established the business case, you can start to determine the scope of services you need outsourced and from there, start to identify potential suppliers.

To reach the best possible supplier setup, we recom-mend that you include these key elements in your supplier selection and qualification process:

• Prepare a thorough request for proposal• Specify GMP regulatory requirements• Establish specifications and quality agreements • Set up a system for outsourcing risk mitigation • Establish a method for managing supplier perfor-

mance

For a primary packaging component, for example, we recommend performing a gap analysis to assess quality, compliance and capability. The main focus areas typi-cally include process qualifications, process validation, in-process control systems, non-conformity handling, operator training and maintenance and calibration control plans for equipment. The analysis will uncover any gaps between your requirements and the supplier’s ability to meet them, so that you can take appropriate steps to elevate the level of quality, compliance and capability to the necessary levels.

At NNE Pharmaplan, we have decades of experience in identifying, qualifying, engaging and managing vendors and suppliers. We will do an initial screening, which will provide a “snap shot” of your supplier’s ability to fulfil basic requirements for compliance, quality and docu-mentation. However, it will not guarantee the supplier’s performance over the long run.

Building trustWith an extensive supply chain, it is highly probable that a supplier at some point in time will make a change which might be minor in their point of view, but which can have significant influence on your prod-uct performance. As one of our customers puts it, “if you don’t change your product, your supplier probably will; you can only hope that they will inform you”. In other words, trust is essential if your product is highly dependent on the supplier.

At NNE Pharmaplan, we know how to open the dialogue between the pharma company and its suppli-ers. Establishing ground rules for communication and documentation in the form of specifications and quality agreements is crucial in this regard.

SUPPLY CHAIN MANAGE-MENT AND SUCCESSFUL OUTSOURCING

NNE Pharmaplan considers the primary container and its aseptic processing as paramount to any drug delivery programme. Thus, it is two elements which must be considered very early in the devel-opment process.

For companies with a large drug delivery portfolio or pipeline, standardising the primary container solu-tion can bring huge cost savings and decrease time to market significantly. Waiting to take account of these considerations during last stage clinical trial phases is likely to lead to poor quality, e.g. because the primary container does not interface correctly with the medical device, or drug products may simply be cost-prohibitive to aseptic fill.

Since primary container design is a major, but very time consuming, attribute to determining the success of a drug delivery product, it is critical to start the primary container design process in parallel with formula-tion development. Considerations about format type, volumes and, of course, drug characteristics must be taken into account at this stage. By mapping these considerations for future and existing drug products, commonalities will emerge which can form the basis for your primary container platform strategy.

You can then use key information from this primary container platform strategy to evaluate your supply chain needs for aseptic processing, including supply of primary container components with production fore-casts. Going forward, the primary container platform and supply chain strategy should evolve symbiotically. NNE Pharmaplan helps clients maximise these elements concurrently to achieve high quality and minimise delays. The following couple of examples outline NNE Pharmaplan’s approach:Drug product and primary packaging materials compat-ibility

All rubber compounds have leachable and extractable substances. The challenge is that the leachables profile depends on the interaction between the halobutyl rubber compound and the drug product. Factors like surface tension, protein content, polarity and pH level – and even the combination of all these factors – have an influence on the leachables profile. Add to that that each drug product is sensitive to specific parameters and you’re left with a not insignificant risk of produc-tion failure. Fortunately, you can pre-empt such prob-lems by conducting accelerated tests for compatibility and safety on multiple rubber formulation for compo-nents. This will help you identify the most promising compounds before you even commence long-term stability testing.

Because of the complexity involved in selecting and finding acceptable primary packaging materials, NNE Pharmaplan recommends to multi-source components during primary container development in order to en-sure a robust supply chain and avoid single sourcing.

Container closure integrity testingThe purpose of the container closure integrity (CCI) test is to document that the primary container (cartridge, plunger and cap) is capable of maintaining integrity, i.e. that the filled and closed cartridge remains 100% closed, throughout its shelf life. As such, CCI is a critical factor in ensuring that product sterility can be main-tained throughout the product’s shelf life. CCI can be tested through various physical methods e.g. using a vacuum mass extraction system or gas leakage detec-tion.

Friction testing (break loose and extrusion force)There are several factors that affect the friction, e.g.:

• Siliconisation of cartridge (the thickness of the silicone layer, level of cross-bound silicone and homogeneity distribution)

• Plunger compound• Overlap between plunger diameter and inner car-

tridge diameter• Plunger contact area and pressure• Time since production

Typically, the friction is tested without cap and directly on the plunger. If needle, drug product and device are included, it is referred to as a dose force test.

Friction is characterised in two curve sections:

1) Break-loose force: The maximum pressure required in the first displacement section to release the plunger from a static position within the cartridge

2) Extrusion force: The maximum pressure required in the second displacement section to extrude the plunger through the cartridge (after being released from the static position)

ASEPTIC PROCESSING AND PRIMARY CONTAINER

For cartridges that are larger than 3 ml, all primary packaging material components have to customised:

Glass cartridge: Glass canes are available in different dimensions, but only a limited number of cartridges are commercially available. Depending on the size, custom crown design and converter tools are needed.

Caps with discs: Only 8 mm caps are available for 3 ml cartridges. Cartridges which have a larger diameter may need bigger caps, if there is too much glass to move during the converting of the glass cane.

Plungers: Since the inner diameter of the cartridge will increase, bigger plungers are needed. This will require a customised plunger design to ensure accept-able friction levels and CCI.

NNE Pharmaplan have comprehensive experience in designing primary packaging material for various cartridges sizes, and we can help you make the right design choices early in the project and perform verifi-cation tests of the actual application.

We understand the interdependencies of the medical device, primary container and aseptic production to create a reliable, compliant and effective combina-tion product. Hence, not only do we understand the segments of medical device, primary container and aseptic processing, but we can guide you on how to reduce risk and potential delays to commercial launch.

CARTRIDGES WITH VOLUMES LARGER THAN 3 ML

The friction between plunger and glass can be rested using a compression tester where a cartridge (with the plunger inserted) is mounted in a fixture. The test is executed by driving the plunger through the glass barrel (using a mandrel), while measuring the mandrel displacement and force using a load cell. The friction can be tested at multiple speeds in order to characterise the friction for different drug delivery scenarios.

17ASEPTIC PROCESSING

18

Drug delivery programmes heavily outsource development and production tasks, which ef-fectively leaves the drug manufacturer to fulfil the role of project manager of a complex supply network. Unfortunately, many drug companies either feel uncomfortable with the level of control over their supply networks, or feel that they insufficiently challenge their supply networks.

Often, drug companies lack sufficient knowledge and/or resources for qualification, handovers, auditing and controls necessary to ensure product quality and reliabil-ity as well as understanding of lead times. Furthermore, additional complications occur when activities between a drug company’s procurement and drug delivery team are not well coordinated. There is no shortcut to reli-able quality products – it takes time and knowledge to execute each step well.

The supply chain strategy includes the following activities:

• Duality in supply chain, network of providers• CMO fit assessment• Supplier evaluation and recommendation• Consolidation of the client strategy targets,

objectives and success criteria for the total project• Current business framework and operational

conditions• Consolidation of process and choice of technologies• Capability and capacity analysis

Processes to internalise versus externalise – evaluation of criticality and pros and cons of vertical integration and outsourcing including but not limited to the following:

• Regulatory plan• Product and tech transfer, e.g., will initial commercial

batches be filled at CMO, but long-term plan is to have internal filling?

• Production setup, e.g., conventional cleanroom, RABS, or isolator technology

• Primary container handling, e.g., bulk, fill nested trays, or a sequence of both

• Handling and filling process, e.g., bulk handling, nested trays, or a sequence of both

• Duality in component supply• Duality and interchangeability in molding and sub-

assemblies• Activity locations, e.g., sites for filling and distribution• Co-location of final assembly and packaging with

filling

To make the supply chain strategy excel, central parts in the supply chain need to be assessed: Device design• By maintaining the end-user value of a product as

the focus throughout concept development you will be able to produce solutions that users embrace readily and operate safely in real-world conditions. This provides better efficiency and overall lower cost to deliver a complete, faster, end-to-end develop-ment project

• Taking care of the risk all the way from use risk through technical design risk to the process risk is a central part of not only meeting authority require-ments, but also implementing a documented process that facilitates effective evaluation of product issues during and after launch. Hence, the drug delivery programme is better prepared for any mitigations needed to sustain product confidence

• The use of process tolerances in tolerance stack-up guarantees that they will reflect the actual manufactured parts. Having this transparency in the product/production relation is a prerequisite for achieving a robust design and significantly reduces manufacturing cost

• Implementing design controls in product develop-ment implies plans for documenting compliance with combination products regulations. This may include leveraging existing documentation from drug container development, clinical studies or CMOs. Because design control is merely a formal-ised version of good engineering practice, having all parts of a combination product, including the primary container, under design control will ensure that maximum benefit is achieved

• Bring your process understanding into the design for manufacture (DFM) studies and focus on the correlation between critical product attributes and productions parameters. The detailed level of DFM follows a structured process based on evaluation of main drivers for each manufacturing process step

Components, assembly and label and pack• CMO management (especially molding): Because

most CMOs produce various products for various customers, they often rely on standard equipment and processes. But, as advanced as the equipment and processes might be, they may not be good enough. By consolidating requirements for the facility, moulding equipment, utilities and peripher-als from the beginning, you can achieve the desired quality in the most cost-effective way and avoid costly breakdowns and maintenance

• Pilot manufacturing aims not only to make things right and produce low scale numbers. It also aims to verify the robustness of the design and production setup so that hard evidence is present for prediction of full scale performance. In other words, you will know what to expect in terms of quality and cost when scale-up proceeds

• Tolerance chains in the design phase establish the relation between functional requirements (product tolerances) and design parameters (process toler-ances). In order to enforce these design parameters design of experiments (DOE) is used to set the relation between design parameters and process parameters

• Component documentation not only needs to describe dimensional requirements; it also needs to specify product function attributes, e.g. edge and surface requirements important for product func-tions

• Early evaluation part testing and approval per speci-fications will drive focus on the ability to measure parts with sufficient accuracy and repeatability. This is important, as it holds no value for a company to have perfect parts if they cannot be measured to be compliant with specifications

SUPPLY CHAINCONSIDERATIONS

19

NNE PharmaplanDrug delivery

NNE PharmaplanDevice and primary container

NNE PharmaplanRegulatory package (DHF/DMR)

NNE PharmaplanIndustrialisation

Test, verification and validation

Equipment suppliers

CMO partners

CMO fill amd finish partner

Moulding

Assembly

Label and pack

• User needs• Unique selling points• Commercial potential• Technology solutions

identified• Investments, cost and

equipment considera-tions (business opportu-nity, portfolio & device planning)

• Pursued multiple product paths

• Refined product attributes• Concept for

development, able to be designed and manufactured

• Preliminary hazards analysis

• DFM concept

• Iterations for robust-ness

• Risk analysis – FMECA• Design can be verified,

approved and manu-factured

• Device & packaging DFM studies

• Preliminary layout for production equipment

• Linking product at-tributes to process parameters and quality documentation

• Design freeze (design ready for final validation)

• Device verification and validation finalised

• Qualified pilot production

• Developed regulatory documentation

• Product optimisations• Process optimisations• Ramp-up to full scale production• Developing better practice• Continuous improvements

• Design chill or final device iteration

• Device verification• Defined production

flow (including primary container fill-finish and device coupling)

• DFM-detailed• Design transfer (R&D to

production environment)

Front endinnovation

Earlydevelopment

Detaileddevelopment& industria-lisation

Device& processdevelop-ment

Verification & validation

Productmaintenance

PHASE A PHASE DPHASE B PHASE C PHASE E

Our medical device team comprise people who have worked with medical devices for decades. They have hands-on experience with medical device projects and have consulted customers on all aspects of drug delivery.

In addition to our expert team, NNE Phar-maplan has more than 75 engineers with medical device production know-how. We cover a wide range of competency profiles with specialists from a variety of technologies. Our knowledge is based on our experiences with many different industries, companies and cultures.

Carsten Bech, Corporate Vice Presi-dent, Global Business Development

Stephen Fournier, Director Business Development

Hans Stenberg Knudsen, Senior Technology Patner, Global Busi-ness Development

Peter Dan Kaare SoelbergTechnology Partner, Global Business Development

Carsten Schaufuss Feddersen, Senior Consultant, Finished Products & Medical Devices

Claus Jepsen, Partner, director, Designit

NNE PHARMAPLAN MEDICAL DEVICE TEAM

The best outcomes are achieved through collaboration. Therefore, in addition to the traditional project team meetings, we utilise a series of workshops to collect information from stakeholders. This information will be used to author concept requirements and later refine specifications. Throughout our history we have seen over and over the importance of control in relation to product robustness. Therefore, we will:

• Follow customer’s quality management systeM• Follow customer’s project governance structure• Create documents and drawings based on

customer’s templates

Even after launch, we are there to help make design changes and improvements to help you sustain your product.

HOW WE WORK

WORKING MODELTo create a lasting and reliable drug delivery programme, NNE Pharmaplan can manage your supply chain by providing molded components and subassemblies including DHF, DMR, tech transfer,

design and process verification and validation and sustainment activities. Furthermore, NNE Pharma-plan is there to assist with filling, final assembly and packing operations.

NNE Pharmaplan is a leading engineering and consulting company within the life science industry. We work with some of the world’s most prominent pharma and biotech companies and help them develop, establish and improve their manufacturing and ensure regulatory compliance.

NNE Pharmaplan employs around 2,000 people at more than 25 locations around the world. We have extensive knowledge and experience in all kinds ofproject execution from consulting and engineeringservices to complete turnkey projects and supply.

Within drug deliveryNNE Pharmaplan specialises in pulling together userand stakeholder needs to establish clear target product profiles. Our goal is to enable concurrent development of primary container, aseptic process-ing and medical device to not only reduce timelines, but also to increase product reliability.

WHO WE ARE

October 2014