CELL THERAPY INSIGHTSinsights.bio/cell-and-gene-therapy-insights/wp-content/uploads/... · E GENE...

www.insights.bio

157

CELL & GENE THERAPY INSIGHTS

EXPERT INSIGHT

Innovation in management as a tool for accelerated translation of advanced therapiesNicholas Medcalf

The manufacture, delivery and administration of advanced therapies (cell-, tissue- and gene-based treatments) comprise a sensitive chain of custody that may be thought of as an integrated service system. The sys-tem is challenging to assemble for the predominantly small businesses that seek to compete in this sector. The current investment climate is not favorable to proposals unless they have a high probability of success or are capital-efficient or both. Business models based around the ex-tended enterprise, the collaborative enterprise and the franchise models are relatively under-explored for the sector. This paper sets out the main characteristics of these models and the reasons that they may increase the pace of innovation: by reducing investment burden, by encouraging co-ownership of the chain of custody and by allowing early data capture to assist with investment proposals.

Submitted for Peer Review: Dec 15 2017 u Published: Apr 5 2018

SUPPLY CHAIN MANAGEMENT PART 1: GETTING IT RIGHT FROM THE START

MANAGING MANUFACTURE FOR NEW ADVANCED THERAPIESInnovation is at its most efficient when it conserves the import-ant achievements of the past and modifies them or builds on them to accommodate new insights and new solutions. This process of

optimization can be likened to the progressive ascent of optima in a solution space. The peak of adap-tation is gradually approached and what was once unusual becomes the commonplace. Management sys-tems assume that this way is how it should be done and it is relatively unusual to find the management

system introducing its own radical change. ‘Disruptive technology’ is technology that necessitates a change in ways of working because the old operational model no longer fits [1]. However, disruptive tech-nology is usually the product or the service enabled by that product. The ways of working change to meet the


158 DOI: 10.18609/cgti.2018.011

clear and present challenge. By con-trast, when an organization is fo-cused on a particular product and a non-obvious disruption to the cur-rent ways of working is required to attain it, the innovator will find that the investment of time and money that has proved worthwhile to date in a particular enterprise can often result in a reluctance to disturb the status quo [2,3].

The purpose of this paper is to highlight a disruptive approach to innovation in manufacturing for advanced therapeutic products that may offer advantages over current ways of working. It has not so far been put to the test in practice (al-though some organizations offer signposts to this, see below) but has withstood many conversations and criticisms from specialists in a variety of backgrounds. It is offered here for consideration as a potential alternative to accepted approaches to translating advanced therapy in-novations to commercialization.

Innovation in advanced therapies (cell-, tissue- and gene-based treat-ments) is an unusual business for several reasons.

These are complex products. Ex-citing innovations are the result of deep understanding of the biology of the target disease states and are offered for translation to manufac-ture by expert biologist-inventors. It would be unrealistic to expect that such knowledge would necessarily be accompanied by a similarly deep understanding of regulatory affairs, process economics, operational research, manufacturing science, logistics and an understanding of clinical and patient pathways, and this is generally the case. Expertise in these topics is sought when new enterprise is set up. The unfortunate corollary of this situation is that the

early proof-of-concept work and demonstration of efficacy will be based on a lab-scale process, which is unlikely to be directly scalable in a manner that conserves the desired characteristics. These will comprise the critical quality attributes, the target cost of goods and the crite-ria that make the process operable at large scale and suitable for in-corporation into supply chains that may involve long-distance chilled or frozen transit. At the very least, ex-tensive bridging studies will be indi-cated before Phase 3 clinical trials to establish comparability of early- to late-stage product.

While open innovation is be-coming more frequent in the whole healthcare products sector, the ad-vanced therapies arena operates to a larger extent than normal on the basis of innovations that arise from small, often academic, groups rath-er than big business [4,5].

The process engineer for ad-vanced therapies is at a disadvan-tage compared with their historical counterparts in medicines man-ufacture based on chemistry or on fermentation-based processes. Chemical (and hence biochemi-cal) engineering grew up around a series of bench-scale activities that were enlarged to plant scale using scaling criteria that were established along the journey. The result was, broadly speaking, that a manufac-turing plant could be built around a set of large-scale pieces of equip-ment that were expected to provide service, and hence a spread in cost, over many different drugs with relatively minor variations in con-nectivity and sequence. The design criteria of the equipment would be known to the process engineers and, by the 1980s and 1990s, the empirical, step-wise approach to

EXPERT INSIGHT

159Cell & Gene Therapy Insights - ISSN:2059-7800

scale-up had been replaced in many companies by process simulation in silico, permitting large single-step increases in scale with safety and confidence and reduction in waste. A visitor to a pharmaceutical com-pany from the post-war years up to the 1990s would expect to see a predictable series of manufacturing tools in the pilot and manufactur-ing plant (staffed by operators who understand the generic engineering principles of the kit, and treat it as product-agnostic). With the excep-tion of stirred-tank fermenters and centrifuges, the same cannot be said of the equipment for manufacture of advanced therapies. Some plat-forms of manufacture using closed and semi-closed systems, such as Miltenyi Biotech’s CliniMACS Prodigy®, Octane’s CocoonTM and GE Healthcare Life Sciences’ Xu-riTM systems, are offered with the intention that they be used at full scale. Otherwise the pre-clinical innovation work is done largely at small scale using manual operations based around plastic disposables with the result that the impact on the product, of changes to process characteristics on scale-up is diffi-cult to predict.

Process design is frequently based upon small-scale manual processes in the laboratory at the pre-clinical stage. It is therefore easier to scale-out than to scale-up as the latter will require additional investment of time and money in bridging stud-ies if a different process is designed part-way through the development cycle.

Pursuing the synthetic drug anal-ogy still further, we are now dealing with products that do not stand still. Unless the process scientists introduce a hold step, such as cryo-preservation of cells or product, the

manufacture and supply must take place on a timeline that is defined in the main by the natural behavior of the product.

This time-dependency is com-plicated further by the fact that, without the hold step, the product is changing during the transit stage and the administration. Some of the steps needed to administer the therapy may themselves be regarded as part of manufacture in the sense that the successful outcome de-pends on the willingness and ability of the healthcare professional to be-come an effective link in the chain of custody and to ensure that the way that they work in clinic is, in effect, the last step of GMP. Histori-cally the distinction between manu-facture and supply has been deemed to be so obvious that manufacture did not require a definition in the regulations. That is no longer the case and manufacture plus adminis-tration may be better thought of as a ‘service system’ [6].

The fixed costs of operation ac-count for a high proportion of the total costs of manufacture. Anec-dotally, the cost of quality (Quali-ty Assurance plus Quality Control) can be as high as 30% of the total ex factory manufacturing cost. This is much higher than in, for example, the automotive industry.

There is an unusually strong re-lationship between know-how and the ability to operate processes re-producibly and with a high pro-cess capability. This reveals itself during late-stage development as a tendency to rely upon specific highly skilled manufacturing staff with experience that arises from the pre-clinical development phase of the product. Such reliance places the manufacturer at risk of inter-ruptions to supply in the event of


160 DOI: 10.18609/cgti.2018.011

any later process changes that may be necessary, such as addition of a site to meet unusual demand or the departure of a key member of staff.

Little distinction is made between the intellectual property that relates uniquely to the product to be manu-factured and that which is generic to the process that is used. This reveals itself as a reluctance to share know-how about process management that contrasts sharply, for example, with the commonplace sharing of knowledge about generic aspects of chemical processes that is normal among chemical engineers [7].

The transfer of technology from site to site is laborious and therefore undertaken only with reluctance. As the products can be challenging to transport and, in many cases, are best made close to the patient, this leads to limited patient access.

While the small numbers of manufactured units during the clinical trial stages of development may permit careful custody, by the time that full-scale manufacture is reached that state of affairs may be a luxury that can no longer be afford-ed. Fatigue, repetitive activities and sheer intensity of manual handling will conspire to increase the risk of mix-ups, contamination and batch loss post-launch. Small deficiencies in early process design will become major annoyances [8,9].

The marketplace clearly wants faster, more effective commer-cialization [3]. Recent regulatory initiatives such as the European Medicines Agency’s PRIME, the MHRA’s EAMS scheme [10] and the Breakthrough Therapy Des-ignation in the USA are evidence of this. Patient expectations have been raised by the media and through easy access on the internet to information about trials [11,12].

Meanwhile, since 2008, it has be-come more difficult than usual to raise investment for business development that is likely to be ‘capital inefficient’, i.e. for which a large proportion of funds will go towards bespoke manufacturing installation, rather than utilizing existing frameworks as in the past [13,14]. The unusual unit opera-tions of advanced therapies tend to make capital efficiency difficult un-less the operation stays within the care of a CMO.

THE PREFERRED PATH-WAY TO MANUFACTURE FOR LAUNCHThe characteristics of the sector mean that unless an innovator is able to sell the value proposition to a large existing company as their exit strategy they would be well advised to keep the operation under the shel-ter of an existing, probably academ-ic, development facility with a GMP orientation as long as possible [14]. This works well with licensed facili-ties that have arisen in the university setting, for example the unit in the Orbsen building at NUI Galway, and those that operate to GMP-like conditions and can smoothly transfer the manufacture to a CMO, such as the Centre for Biological Engineering at Loughborough Uni-versity and the Advanced Centre for Biological Engineering at University College London.

In the absence of adoption by big business the innovator faces a difficult choice: whether to attempt to estab-lish their own facility with appropri-ate compliance or to stay long-term within the walls of a CMO such as the Tigenix-Cognate Bioservices ar-rangement at Memphis, Tennessee.

EXPERT INSIGHT


While research has been going on in cell- and tissue-based therapies for several decades and commercializa-tion since the 1990s, there has been little operational research. In fact, research into business models began at about the same time as the first companies, such as Advanced Tis-sue Sciences, began supplying [15]. In short, there has been, and is, a lot of investment in advanced therapy R&D but relatively little in how to manufacture in a way that provides the features listed above. Perhaps lo-gistics can be turned into a strategic tool for growth [6]. We have been here before in another sector.

ALTERNATIVE ENTERPRISE FORMATSIn the late 1990s and the early 2000s the concept of the Collabo-rative Enterprise was examined and promoted by some of the Regional Development Agencies in the UK [16]. The interest had been sparked by experience overseas, particularly in the Swiss microelectronics indus-try [17], where a sector downturn had occurred and companies need-ed to find ways of remaining oper-ational and flourishing while incur-ring lower fixed costs of operation.

In order to stimulate business de-velopment, generate more regional jobs and create better access to the resources necessary for operating high-technology SMEs, two mod-els of operation were put forward in particular. These have some simi-larities and one is a development of the other.

In July 2016, these two ideas were examined in a one-day informal workshop at Kegworth chaired by Loughborough University and fund-ed from the Health and Wellbeing at

Loughborough (‘HWB@LU’) bud-get (“Collaborative Enterprise Net-works for Aseptic Products, a Model for the Midlands?”) [18]. The pur-pose of the workshop was to bring together key opinion-leaders from the NHS Trusts in the region (East and West Midlands) with represen-tation from the regional Academic Health Science Networks, to exam-ine the strengths and weaknesses of an approach that has the capacity, at least in principle, to satisfy these requirements. This approach is re-ferred to as a Collaborative Enter-prise [19] and is a specific form of the operation more generally known as an Extended Enterprise.

EXTENDED ENTERPRISESThe Extended Enterprise (EE) has its origins in the management of sup-ply chains [20] and has been applied commercially in several sectors [21–23]. Its character is fundamentally relational rather than purely custom-er–supplier. The relationships fall broadly into two categories: those outside the EE, where the familiar transactional relationships apply in which vendor and customer act to maximize their personal advantage through negotiation, and those with-in the EE where the relationships are collaborative rather than adversar-ial because of their long-term per-sistence and the mutual advantage.

The primary motives for creating an EE can be listed as:

f Cost reduction through the avoidance of vertical integration of the necessary services within each collaborating organization. Resources are instead shared throughout the network;

f Management of fluctuations in demand through spreading the operational capacity over more than one center;


162 DOI: 10.18609/cgti.2018.011

f Recruitment of customers through multiple entry points throughout the enterprise, leading to distribution of opportunities to mutual benefit that would otherwise be restricted to one party or merely declined due to lack of capacity or poor ‘fit’;

f The ability of each actor to focus on their own area of excellence rather than attempting to address all the aptitudes that are needed to manufacture, supply and react to market changes;

f Stability in time by creating an enterprise that is resilient to market forces through enhanced horizon-scanning, greater expertise and higher purchasing power than would be possible if the actors were separate;

f Greater market reach and penetration through regional nodes that can supply markets with differing requirements or in different locations;

f Optionally, an increase in the pace of innovation through an open innovation model.

COLLABORATIVE ENTERPRISESA Collaborative Enterprise (CE) or Collaborative Enterprise Network (CEN) has the advantages of the EE and acts as a single business when appropriate, permitting the partner organizations to operate independently as well [17]. It is “a … business entity of legally inde-pendent, … selected enterprises, which, due to a common purpose coordinate the operation of sub-tasks through negotiation and agreement [24]”.

Shared ownership of outcomes is managed through operation via an over-arching legal entity with representation at Board level from the collaborating organizations.

A review of the literature [24] produced a set of five features that

are generally characteristic of any CEN. They are:

f The presence of at least one collaborative purpose

f The presence of at least one collaborative task

f The necessity of selecting members

f The organized structure and system of rules of collaborations

f The existence of legal regulations of the CEN concerning the internal and external representation

There are similarities to the Ex-tended Enterprise [20]:

f Both emphasize a close relationship upstream and downstream (suppliers and customers);

f Both emphasize containment of development costs and reduction in innovation time;

f Both employ an open innovation model, drawing on partners’ skills as necessary to supply products from outside innovators and inventions from within;

f The collaborators participate early in planned innovation based upon explicit identification of their collective and individual capabilities, know-how and limitations;

f The EE and the CE aim to prosper by applying knowledge and resources to the mutual benefit of the collaborators;

f The two key ‘enablers’ for the enterprise are technology (without which the CE could not remain agile) and trust (without which the collaborators would break away to their own competitive advantage).

The role of customers is vital to the CE. In the context of a CE for advanced therapies, this key relationship can be viewed as a two-way flow of informa-tion with products flowing from manufacturer to customer. On

EXPERT INSIGHT


the one hand the clinics provide insights and forecasts that allow the production features of the CE to adapt and optimize their sup-ply model. On the other, the close communication between user and manufacturer has the capacity to create a just-in-time variant, for advanced therapies, of the more familiar ‘Specials’ supplier [25–28].

Even under existing business ar-rangements there is a much great-er degree of shared responsibility between healthcare professional and manufacturer for the safety and efficacy of an advanced ther-apy medicinal product (ATMP) treatment upon administration than there is for a more tradition-al medicinal product. Rather than the hand-off transaction of pur-chase and transfer of ownership the role of the healthcare profes-sional effectively supplies the final stages of manufacture. This is par-ticularly clear when considering the measures necessary to dress and apply a tissue implant. Un-der these circumstances the role of customer is shared between the patient (who wishes an effective treatment), the healthcare pro-vider (who has requirements that must be met in order to execute their part in the chain of custody) and the clinic itself (who will have an interest in the balance of cost of the treatment and the cost of the facilities in which the last hundred meters of custody takes place [29]. The enterprise will need to make a decision about which manufac-turing platform technologies to adopt (production, quality con-trol, communications, track-and-trace) to satisfy these stakeholders and there will need to be some careful analysis of the core busi-ness intention in order to target capital investment at the needs of the true customer at each point.

DIFFERENCES FROM TRADING ASSOCIATIONSIt can be argued that the CEN con-cept is simply an extension of the familiar idea of a trading associa-tion. Trading associations have been long established and have operated with varying degrees of success. The main weakness of a trade associa-tion is the tendency of the individ-ual parties to break away and seek commercial advantage through in-dependent activity in direct compe-tition with the remaining members of the TA. This disadvantage arises from the main purpose of the TA, which is normally to act as a form of protective practice. In the case of a CE, the mutual advantage arises from the shared resources and from access to manufacturing and supply deals that may not be operable by individual parties acting alone.

WHAT CHARACTERISTICS WILL A COLLABORATIVE ENTERPRISE FOR ADVANCED THERAPIES POSSESS?To derive a typology of CEs is dif-ficult as there has been no generally accepted morphological model [24]. Instead it is more helpful to describe the features of a CE that would be advantageous to a community of interest that intends to manufacture and supply advanced therapies.

What we are talking about is a geographically based cluster for the aseptic healthcare products sector [30]. Within this the manufacturing research group is a single node in the network of relationships.

What form should the collabora-tion take between the participants?

The typology of useful CEs for ATMPs can then be defined by


164 DOI: 10.18609/cgti.2018.011

proposing and examining the main features that such a system of sys-tems needs to possess in order to be of value. This can be generated from a stakeholder analysis as shown in (Table 1). Note that more than one collaborator in each category may be present in a CEN and that for any one node the manufacturing site may be in a long-term collabo-ration with preferred process devel-opment collaborators, who could be academic.

An illustration of an archetypal CE for the UK context will help and the description here is the one that was discussed and approved at the workshop described above. The system is shown diagrammat-ically in (Figure 1). It comprises a non-adversarial business system co-owned by a group of organi-zations to include investors, NHS Trust directors, clinicians and li-cense holders for the GMP man-ufacturing site and operated for mutual benefit by making shared use of some of the resources of the Trusts. The shared resources would be, for example, negotiat-ing leverage for purchasing of raw materials, use of existing logistics and manufacturing system and access to NHS employees (nurs-es, clinicians) and departments (IT, Finance, Procurement). The system would undertake clinical, managerial and research activities in order to accelerate the delivery of conventional aseptic products, where appropriate, and new ad-vanced therapies. The CE would operate to ‘just-in-time’ principles and would provide a delivery plat-form enabling the easy transfer of operational knowledge into pro-cess development. The CE would be based on a shared belief that an economical and beneficial service

can be provided whilst recogniz-ing the constraints coming from patient perceptions, market con-ditions, availability of necessary structures with the healthcare Trusts and the regulations.

The current regulatory oversight for medicines in the UK is subject to the Human Medicines Regula-tions 2012 (SI 2012/1916), which include the transposition into re-gional law of Article 5(1) of EU Directive 2001/83/EC on medic-inal products [26]. The Directive and the UK Regulations allow for exemptions from these provisions under certain circumstances. One category of exemption route may lead to market access at an earli-er stage in product development than the usual Phase 3 clinical trials followed by application for a Marketing Authorisation (MA). This ‘Specials’ category [25,28], if used responsibly and within the intention of the regulation, per-mits the supply of limited quanti-ties of a product on a non-routine basis without the prior acquisition of a MA. Such a product must be supplied only in response to an unsolicited order and must be used only in cases of ‘special need’, hence the name, in cases where there is no fully licensed equivalent product. ‘Specials’ may not be supplied for use outside the European Economic Area. This arrangement implies close com-munication between clinician and manufacturer and agreement with the patient or their representative. The ‘Specials’ route is not a substi-tute for the clinical evidence that is needed for a MA Application. Neither does it exempt the man-ufacturer from the obligations of Good Manufacturing Prac-tice. The ‘Specials’ route may not

EXPERT INSIGHT


f FIGURE 1Format of a CEN derived by the Kegworth workshop. Solid arrows denote flow of materials/products and information. Dotted arrows denote flow of information. Asterisks denote a relationship of shared resources.

Horizon

H3 H4H2H1

Procurement

Quality

ManufacturingProcessdevelopment

MHRAABPIBIA

I1 I2 I3

Innovators

Customers (hospitals or NHS Trusts)

Environment

Academia

CEN

CEN Management Group comprising:Trust DirectorsManagers from CEN companiesAcademic liaisonIndustry liaison


166 DOI: 10.18609/cgti.2018.011

readily be used to glean clinical data from a hospital because that would make the patient an unwit-ting participant in a clinical trial. Nevertheless, the application of a product as a ‘Special’ carries with it the obligation to collect and re-port adverse reaction information

and knowledge that there has been effective, though limited, use of a product as a ‘Special’ could be a contributing factor in increasing the confidence needed to support investment in full-scale manu-facturing development at a later stage.

f TABLE 1Stakeholder analysis.

Participant Direct needs Indirect needs (all relate to business sustainability)

Advantageous role

Innovator Receipt of a revenue stream or payment for a direct buy-out

Esteem; credibility to pursue further innovation; protection of ‘back of shop IP’

Member of an Innovation Pool nurtured over the long term, e.g. offering technology options to the CE Board

Development team Revenue stream Deep and growing ex-pertise in specified unit operations

Preferred supplier of services

Manufacturer Revenue stream Recognition as the ‘go-to’ centre for a chosen tech-nology platforms; avail-ability of tools and tech-niques from more than one supplier


Carrier Revenue stream; non-fragmentary volume of work (scale)

Establishment as the carrier of choice due to: a) reliabili-ty, b) flexible carrier modes, c) economies of scale


Regulator Monitoring of compliance; Accel-erated access to safe, cost-effective treatments

Establishment of preferred tools and techniques from more than one supplier

Promotion of best practice through scientific advisory route

Equipment factors Reliable revenue stream based on acceptance of equip-ment as ‘default’

User requirement specifica-tions that enable confident new product development

Provider of goods and services; partner in pro-cess development through equipment evaluation

Users (healthcare professionals)

Ease of access to safe, effective treatments

Supply arrangements that fit with clinical and pro-curement practices

Partner in development

Patients Effective treatment Ease of access, early access;Patient-focused treatment pathway

Informed early recipients of products

Investors Return on investment

Acceptably low risks; avoid-ance of capital-intensive proposals

Preferred source of invest-ment as options

Regional society Job creation, im-proved healthcare

Ease of patient access Host market

EXPERT INSIGHT


IS THERE A PLACE FOR THE FRANCHISED OPERATION?When manufacturing start-ups be-gin in the advanced therapies sec-tor, in order to comply with GMP and GDP it is first necessary for them to create a Quality Manage-ment System (QMS) of sufficient scope and detail to address the important business processes un-der a Site Master File and accom-panied by a library of SOPs and Controlled Documents to define practice. The key elements of train-ing (together with proof of com-petency), procurement processes, supplier audit schedules, respon-sive (on-call?) support engineering, specialist microbiology services and accurate track-and-trace (perhaps with predictive ordering) are all essential elements for such a small operation and contribute to the fixed, indirect overhead costs of the operation when it is running, and to much management time during set-up. Add to this the necessity to arrange suitable supply agreements with the clinics and an intimidat-ing hurdle in time and money ap-pears in the business plan.

Recently the sector has seen the emergence of joint ventures and resource-sharing arrangements be-tween companies. Examples are the Cognate-Tigenix agreement, the Lonza-Sanofi JV and the Smith & Nephew-ATS JV. The drivers be-hind these agreements include the advantages of resource-sharing and rapid set-up.

Taken to its logical conclusion, these needs and drivers may be sat-isfied by that well-established busi-ness format, the franchise.

The advantages of operating as a franchise can be listed as (for the franchise taker):

f Boilerplate QMS

f Established (re)training packages

f Agreement templates (quality, supply)

f A degree of support service to be matched to the portfolio needs

f Buying into an established reputation and management processes

f Lower start-up costs than establishing the operation from scratch

f Validation and qualification packages (that still need to be executed)

f Support services for equipment failure

f Negotiating power with upstream suppliers as a result of membership of a larger operation

f Standardization of techniques

f Access to expertise

f Higher probability of success than going it alone

…and for the franchise giver:

f Distribution of manufacture (thus avoiding the need to generate revenue from single factories that may be difficult to operate at scale for out-scaled and/or autologous processes)

f Access to market regions via a hub-and-spoke network

f Progressive growth of a revenue stream

f Economies of scale in providing the necessary support to several franchise-holders

f Repeat business from the franchise holders

f Income from an agile, responsive network

f Market development by the franchisee

The concept of a franchised oper-ation carries some risks. These arise in the specific context of the regu-latory constraints that apply to all medicinal products and to ATMPs in particular.


168 DOI: 10.18609/cgti.2018.011

For a centralized, single-owner manufacturing company there is no ambiguity in the current regulations about the process by which a me-dicinal product is released onto the market or to a patient. In the EU, it is obligatory for that decision to be made by a Qualified Person (QP). The QP bases their decision on two pieces of information. The compli-ance of the batch to specification is necessary but insufficient condition to enable release and it is supported in practice by the QP’s knowledge of, and confidence in, the compe-tent and GMP-compliant opera-tion of the manufacturing facility. This last point can only be assured through a program of audits, site visits, training, preventative main-tenance, corrective and preventative action and Quality Reviews with the management. In the case of a de-centralized enterprise, franchised or single-owner, the same degree of assurance of quality must be main-tained if patient safety is to be pro-tected. If a franchise-taker is negli-gent and damages the reputation of the franchise through malpractice or non-compliance then the effect can negatively impact the whole network. To mitigate this risk the concept of licensure of the franchi-see may be based on quality over-sight from the Hub. Such oversight is desirable at several levels: as a sup-port service (locum QP, QA man-agement), detection of and response to manufacturing trends and deal-ing early with resource shortfalls or poor use of resources. The complex-ity and depth of such oversight will need to be much higher than is nor-mal for conventional franchises. A system of oversight is needed which confers on the QP, acting on behalf of the franchise-giver, the authori-ty, the resources and the capacity to

discharge their duties at an equiva-lent level to the current centralized model. This feature, without which the de-centralized model cannot be operated effectively, will need to be addressed with appropriate opera-tional research in which the issues of data management and secure transmission, rotas of inspection, automation (with monitoring at a distance) and the introduction of intermittent testing of the staff and the equipment to verify that manufacture is capable of deliver-ing goods of adequate quality and of screening out defective product.

Who holds the MA in a fran-chised business? A feature of the arrangement is that the franchise taker is gaining expertise so the giver is best placed to manage the process for this yet the locations of the Spoke and the Hub will be different. Again we are back to a CE model in which a central busi-ness entity holds overall respon-sibility and enforces compliance through responsible management of the franchise license, which is dependent upon the holder’s man-agement of the MA for their site. These points are, to the best knowl-edge of the author, yet to be de-bated with a regulatory authority and would form a useful topic for an industry-regulatory workshop. They are of dominant importance for the viability of de-centralized manufacture and will require an extension of the current reporting arrangements for single-site oper-ations in which the quality pro-fessionals report separately from production staff to senior manage-ment to avoid conflicts of interest. In the de-centralized case, a peri-patetic arm of the quality unit, ac-countable only to the franchise giv-er, may be the only viable solution.

EXPERT INSIGHT


How can the franchise offer be so structured that the multiplicity of products can be managed economi-cally? The most likely route to man-age this is by reducing the options for manufacturing process design to a small set of types, around which a given site can vary the steps to ac-commodate several products. This typology of manufacture for ad-vanced therapies needs to be avail-able for the community in a practi-cal, standardized form if it is to be useful in the future and there are a few ways of making the knowledge explicit. The use of ‘partial models’ of processes set in the context of overall operations can be achieved by applying standard IDEF0, an internationally-recognized form of the operational modeling tech-nique known as Structured Activi-ty and Design Technique [31–34]. This approach allows the creation of reconfigurable, customizable models in a similar way that, say, computer programs are built from reusable blocks of code and tailored to the application [35]. Inclusion of cost roll-ups in the models, a fea-ture of some commercial SADT modeling software, would then allow rapid examination of the to-tal costs of operation to different structures, enabling choices to be made between them based on pres-ent savings and future strategy for growth. At present such calcula-tions are rarely addressed in plan-ning for delivery of advanced ther-apies and then only with difficulty. The SADT approach allows the total costs of the operation to be estimated, including management, transport and support services, in a way that allows apportionment of overhead to different products if that is relevant to strategic deci-sion-making [36].

SIGNPOSTS TO THE FUTUREThe importance of innovation in operational and business models when commercializing cell-based therapies is shown in some recent creative examples of real-world product translation. Novartis enjoys an advanced position in the com-mercialization of their CAR-T cell therapy Kymriah™ and has encoun-tered two of the issues described above. Their work to date has cap-italized on a productive relation-ship with an existing center, in this case the University of Pennsylvania. Novartis has also carefully consid-ered the implications of centralized versus de-centralized operation for their manufacturing process, which involves two interactions with the patient, one involving harvest of cells (followed by transfer to manu-facturing facility, genetic manipula-tion and expansion of the cells) and one involving administration of the expanded population to the patient. The option to move to regional manufacture-and-treatment cen-ters offers the potential to reduce the risks involved in the two-way supply chain and to facilitate clin-ical coordination [37]. The Morris Plains facility appears to offer the potential to act as a training and refresher center for manufacturing staff on other sites. It could there-fore act as a ‘franchise prototype’, a manufacturing and training center from which training and assess-ment can take place that will en-able satellite operations. Novartis is currently working on a centralized model and this will satisfy the mod-est numbers of units that must be manufactured each year. The Com-pany rationalized its R&D base in 2016 [38]. If the decision is taken to extend the platform technology to


170 DOI: 10.18609/cgti.2018.011

other indications that require larg-er manufacturing volumes then the de-centralized model will increase in its relevance to Novartis’ com-mercial growth.

The Milan-based Fondazione Telethon San Raffaele is an exam-ple of the creative use of business structure and financing in order to facilitate the investment in, and execution of, cell therapy product development. This not-for-profit organization was founded in 1990 to provide treatments for rare dis-eases and combines rigorous screen-ing of candidate projects, using an independent scientific and medical committee, with close management of partner institutes avoiding the use of liaison organizations. The Foun-dation has formed an operation based around a management board that coordinates funding granted to hospitals, universities and other research technology institutes asso-ciated with the R&D program. The model is certainly productive with four-figure numbers of researchers now involved and in excess of 2000 projects funded to date. Nearly 500 diseases have so far been studied and nearly half a billion euros raised in investments [39].

IS THERE AN ALTERNATIVE?In order for the sector to flourish, it would be helpful for many catego-ries of advanced therapy manufac-turers to establish operations with the following characteristics:

f Reduction of the fixed costs of operation, so far as is reasonably practical, by sharing existing resources with the clinics to which they supply. Many hospitals already have just-in-time procurement and order fulfillment systems for medicines

or transplantable goods that are of short shelf life and/or which have temperature and shock sensitivity;

f Early access to the patients, subject to responsible controls within the current legislation, in order to generate early revenue for the innovators, thus creating experience that, while it will not replace the need for clinical trials, will generate greater investor confidence in financing the trials when the time comes [40];

f A small set of well-established pathways for patient recruitment, subject to prudent and responsible qualification criteria based on the usual risk-to-benefit assessments, agreed with the regulatory authority and NHS England;

f An in-built personal motive for each actor in the chain of custody to manage the quality of the product proactively;

f A network of centers that promote and share best practice in manufacture using characteristic unit operations and who distinguish between, so to speak, IP at the ‘front of the shop’, i.e. generic capability based on a deep and growing understanding of the critical control points in the unit operations in which they excel and IP at ‘the back of the shop’, i.e. know-how that is unique to the products that they manufacture.

The concept of the Collaborative Enterprise has the potential to satis-fy several, if not all, of these criteria and is a worthy topic for future re-search and evaluation.

CONCLUSIONIn conclusion, advanced therapies present many technical challeng-es in their development and these can distract from the importance of applied research into operation-al choices for viable, sustainable

EXPERT INSIGHT


chains of manufacture and supply. Precedent for supply chains based upon novel relationships between inventor, CDMO, manufacturer and customer exist already (and there will be more) in the business and operational research literature for different sectors with character-istics that are shared with advanced therapies. No single precedent is likely to fit without modification, careful testing and scrutiny by the regulatory authority, but the re-wards may be significant for those that are willing to investigate the

possibilities. It is time for the sys-tems engineers to meet up with the quality professionals and examine the potential.

FINANCIAL & COMPETING INTERESTS DISCLOSUREThe author is a Visiting Professor of Regenerative Medicine Manufacture at Loughborough University and has no relevant financial interests in any of the entities involved in the paper. No writing assistance was utilized in the production of this manuscript.

REFERENCES1. Aldridge S. Facing up to the cell ther-

apy challenge. Pharmaceutical Tech-nology Europe. Advanstar Communi-cations Inc. 2007; 19 (4): 14–7.

2. Buchanan DA. The limitations and opportunities of business process re-engineering in a politicized orga-nizational climate. Human Relations 1997; 50(1): 51–72.

3. Gardner J, Webster A. The social management of biomedical novelty: Facilitating translation in regenerative medicine. Soc. Sci. Med. 2016; 156: 90–7.

4. Salmikangas P, Celis P. Current chal-lenges in the development of cell-based medicinal products. Regulatory Rapporteur 2011; 8(7–8): 4–7.

5. Hildebrandt M, Sethe S. Caught in the gap: ATMP manufacture in academia. ISCT Telegraft 2012; 19(1): https://mediatum.ub.tum.de/doc/1100606/document.pdf.

6. Nordström KM, Närhi MO, Ve-psäläinen APJ. Services for distri-bution of tissue engineering prod-ucts and therapies. Int. J. Prod. Perf. Manag. 2009; 58(1): 11–28.

7. Mansnérus J. Commercialisation of Advanced Therapies A Study of the EU Regulation on Advanced Therapy Medical Products. 2016. Academic Dissertation. Faculty of Law, Univer-sity of Helsinki: https://helda.helsinki.fi/bitstream/handle/10138/166228/Commerci.pdf?sequence=3

8. Warren RS. (Senior Director, RA/QA, Smith & Nephew Wound Man-agement, La Jolla.) Personal interview with the author, 2006.

9. Mason C. The time has come to en-gineer tissues and not just tissue en-gineer. Reg. Med. 2006; 1(3): 303–6.

10. Medicines and Healthcare Products Regulatory Agency. Guidance: Ap-ply for the early access to medicines scheme. 2014: https://www.gov.uk/guidance/apply-for-the-early-access-to-medicines-scheme-eams

11. Lee D. Patient expectations: A sur-geon’s perspective. MPS Casebook 2015; 23(1): 8–9.

12. Gremeaux V, Coudeyre E. The Inter-net and the therapeutic education of patients: A systematic review of the literature. Ann. Phys. Rehab. Med. 2010; 53: 669–92.

13. Bonfiglio GA. Investor Forum, Hori-zon Scoping: Why invest in RM? In: World Stem Cell and Regenerative Medicine Congress Investor Forum, London, May 22. 2015: http://www.slideshare.net/GregoryABonfiglio/world-scrm-congress-2015-investor-forum-horizon-scoping-why-invest-in-rm-london-may-22-2015final

14. Omidvar O, De Grijs M, Castle D, Mittra J, Rosiello A, Tait J. Regen-erative medicine: Business models, venture capital and the funding gap. Innogen and Economic and Social Research Council report 2014: http://www.innogen.ac.uk/reports/904.

15. Zott C, Amit R, Massa L. The busi-ness model: Recent developments and future research. J. Manage. 2011; 37(4): 1019–42.

16. Mawson J. Social enterprise, strategic networks and regional development. Int. J. Sociol. Soc. Pol. 2010; 30(1/2): 66–83.

17. Cheikhrouhou N, Pouly M, Huber C, Beeler J. Lessons learned from the lifecycle management of collaborative enterprises networks. J. Manufact. Tech. Manag. 2012; 23(8): 1129–50.

ACKNOLWEDGEMENTSThe author would like to acknowledge the support of Dr Antuela Tako and Dr Nicola Bateman (both at the time were Senior Lecturers in the School of Business and Economics at Loughborough University) in the organization and delivery of the Kegworth Workshop at which the format of Figure 1 was derived.

This work is licensed under

a Creative Commons Attri-

bution – NonCommercial – NoDerivatives 4.0

International License


172 DOI: 10.18609/cgti.2018.011

18. Phillips W, Medcalf N, Dalgarno K et al. Re-distributed manufacturing in healthcare; Creating new value through disruptive innovation: www.rihn.org.uk.

19. Halal WE. The collaborative enterprise: A stakeholder model uniting profitabil-ity and responsibility. J. Corp. Citizen. 2001; 2: 27–42.

20. Filieri R, Alguezaui S. Extending the en-terprise for improved innovation. J. Bus. Strat. 2012; 33(3): 40–7.

21. Cullen P-A. Contracting, co-operative relations and extended enterprises. Tech-novation 2000; 20(7): 363–72.

22. Lin G, Ettl M et al. Extended-enterprise supply-chain management at IBM Per-sonal Systems Group and other divi-sions. Interfaces 2000; 30(1): 7–25.

23. Davis B. Managing the extended enter-prise. Prof. Eng. 2003; 16(11): 39–40.

24. Baum H, Schütze J. A model of collab-orative enterprise networks (45th CIRP Conference on Manufacturing Systems 2012). Procedia CIRP 3. 2012; 549–54.

25. Faulkner A. Special treatment? Excep-tions and exemptions in the politics of regenerative medicine gatekeeping in the UK in global context. ESRC Ris-ing Powers Research Working Paper No. 46. 2015: https://www.kcl.ac.uk/sspp/departments/politicaleconomy/research/biopolitics/publications/work-ingpapers/Working-Paper-46-(2015).pdf

26. European Parliament and Council. Di-rective 2001/83/EC of the European Parliament and of the Council of 6 No-vember 2001 on the Community Code relating to medicinal products for hu-man use (Article 5 (1)). Official Journal L – 311, 28/11/2004, 67–128.

27. Medicines and Healthcare products Regulatory Agency. Regulation (EC) No. 1394/2007 on Advanced Thera-py Medicinal Products (“The ATMP Regulation”): Guidance on the UK’s

Arrangements under the Hospital Ex-emption Scheme: https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/397738/Guid-ance_on_the_UK_s_arrangements_un-der_the_hospital_exemption_scheme.pdf

28. Medicinal and Healthcare products Regulatory Agency. The supply of unlicensed medicinal products (“spe-cials”). MHRA Guidance Note 14. 2014: https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/373505/The_supply_of_unli-censed_medicinal_products__specials_.pdf

29. Malik NN, Durdy M. Commercialisa-tion of CAR T-cell therapies: Business model spectrum. Drug Disc. Today 2016; 22(1): 1–4.

30. Taticchi P, Cagnazzo L, Beach R, Bar-ber K. A management framework for organisational networks: a case study. J. Manufact. Tech. Manage. 2012; 23(5): 593–614.

31. Cheng-Leong A. Enactment of IDEF0 models. Int. J. Prod. Res. 1999; 37: 3383–97.

32. Cheng-Leong A, Pheng KL, Leng GRK. IDEF*: A comprehensive model-ling methodology for the development of manufacturing enterprise systems. Int. J. Prod. Res. 1999; 37: 3839–58.

33. National Institute of Standards and Technology. Draft Federal Information Processing Standards Publication 183. Announcing the standard for Integra-tion Definition for Function Modeling IDEF0. Gaithersburg, National Techni-cal Information Service. 1993.

34. Mayer RJ, Painter MK, Dewitte PS. IDEF family of methods for concurrent engineering and busi-ness re-engineering applications. Knowledge Based Systems, Inc. 1992: https://pdfs.semanticscholar.org/b536/6957a82a3c8191e6d58991b-

d431096aa86ba.pdf?_ ga=2.66102441.644829360.1513158253- 759636193.1513158253

35. Cantamessa, M, Paolucci E. Using orga-nizational analysis and IDEF0 for enter-prise modelling in SMEs. Int. J. Comp. Int. Manufact. 1998; 11: 416–29.

36. Dowless RM. Using activity-based cost-ing to guide strategic decision making. Health. Fin. Manag. 1997; 51(6): 86, 88, 90.

37. Yin P. 3 Keys to scale up CAR T-cell therapy manufacturing. Bioprocess Online. 2017: https://www.bioproces-sonline.com/doc/keys-to-scale-up-car-t-cell-therapy-manufacturing-0001

38. Palmer E. Novartis commits to CAR-T manufacturing in restructure of cell ther-apy work. FiercePharma. 2016: https://www.fiercepharma.com/manufactur-ing/novartis-commits-to-car-t-manu-facturing-restructure-cell-therapy-work

39. Telethon. 2018. Our visiting card: http://www.telethon.it/en/about-us/our-visiting-card

40. Accelerated Access Review: Fi-nal report. 2016: https://www.gov.uk/government/publications/accelerated-access-review-final-report

AFFILIATION

Nicholas Medcalf Innovation Lead, Advanced Therapies, Innovate UK, Polaris House, Swindon, North Star Avenue, Swindon, SN2 1FL, UK.+44 07584 [email protected]

CELL THERAPY INSIGHTSinsights.bio/cell-and-gene-therapy-insights/wp-content/uploads/... · E GENE...

Documents

Transcript of CELL THERAPY INSIGHTSinsights.bio/cell-and-gene-therapy-insights/wp-content/uploads/... · E GENE...