Key Challenges Facing Biomanufacturing · biopharmaceutical product. Outsourcing to an experienced...

Robert J Broeze is the Presidentand Chief Executive Officer of

Laureate Pharma. He has over 20years of experience in the

biopharmaceutical industry, withtechnical expertise spanning

research, development,characterisation, validation and

current Good Manufacturing Process(cGMP) manufacture of

biopharmaceutical products, frompilot to phase III clinical and

commercial scale with a strongemphasis on monoclonal antibodyproducts for parenteral use. Prior

to joining Laureate, Dr Broeze heldpositions as Vice President, BiologicsResearch at Purdue BioPharma L.P.and Vice President, Operations at

Bard BioPharma L.P, where he wasresponsible for the development and

manufacture of the company’sproprietary monoclonal antibodyand biopharmaceutical products.

Prior to this, he held positions ofincreasing responsibility at CytogenCorporation and ultimately held the

position of Vice President,Operations, with overall

responsibility for development andcGMP manufacture of Cytogen’s

products. Dr Broeze served on theBoard of Directors of the Council of

Radionuclides and Radio-pharmaceuticals, Inc. (CORAR)

(1998-1999) and currently servesas a Director on Laureate Pharma’s

Board. Dr Broeze was aPostdoctoral Fellow in the

Department of Molecular Biophysics& Biochemistry at Yale University,where he studied the molecularbiology of the interferon system. He is a graduate of Rensselaer

Polytechnic Institute, where he earned both his BS and PhD

in biology.

a report by

Rob e r t J B r o e z e

President & Chief Executive Officer, Laureate Pharma

There are a number of challenges facing thebiomanufacturing industry, from both the contractmanufacturing organisation (CMO) and industryperspectives. Biomanufacturing is a complex,labour-intensive and expensive process andtherefore it is extremely important to understandand balance capacity versus demand and staffinglevel. Identifying, hiring, training and retainingproperly qualified personnel are very critical to thesuccessful operation of a facility, sincebiomanufacturing requires a very specialised andexperienced workforce. Staff must have technicalexpertise in specific areas including upstream ordownstream current Good Manufacturing Practice(cGMP) manufacturing operations, processdevelopment, project management, processengineering, quality assurance, analyticaldevelopment, quality control, regulatorycompliance, and many other highly specialisedfunctions. Once on board, new employees must betrained on facility, process and testing standardoperating procedures (SOPs) in order to bequalified to perform their job functions. Trainingand qualification in some aseptic operations can bequite complex, taking several months to complete,and can involve on-the-job training and, in somecases, qualification testing using establishedprocedures such as media fills.

Ke y I n d u s t r y D r i v e r s

Global manufacturing of biopharmaceuticals hasincreased significantly over the last decade due toseveral factors. A major industry driver has been theexpansion of the market for biopharmaceutical pro-ducts. Biopharmaceuticals can be highly effectiveand potent, can have fewer side effects and can curediseases rather than merely treat the symptoms.These advantages, combined with the increasingnumber of new diseases treatable with biopharma-ceuticals, are driving demand for these drugs world-wide. In 2005, biotechnology revenues worldwidewere forecast to reach more than US$45 billion, oralmost 10% of total global drug sales. The thera-peutic antibody market represents over US$8billion. More than 100 biotechnology drugs have

been approved since 1997 and, today, at least sevenof the top biotechnology drugs bring in more thanUS$1 billion annually. It is estimated that 300biopharmaceutical products are in clinical trials,with another 600–700 in pre-clinical or earlyclinical development. Large pharmaceuticalcompanies continue to outsource manufacturingand filling of selected products, but the real growthis from the many biotechnology companies thatelect to outsource pre-clinical to commercialdevelopment to avoid the cost and risk ofestablishing in-house manufacturing.

Ou t s o u r c i n g B i omanu f a c t u r i n g

Certainly a key advantage of outsourcingbiomanufacturing pertains to capital utilisationrequirements. Not all companies have the capital,internal expertise or time to invest in constructing acGMP-complaint facility for manufacture of theirbiopharmaceutical product. Outsourcing to anexperienced CMO can lower production costs,improve manufacturing efficiency and have apositive impact on the balance sheet. Companies canbuy and make capacity at the same time, accessingexternal technology and expertise early in the clinicaldevelopment of the drug and maintaining flexibilityuntil internal manufacturing capability becomesstrategically important. Companies are finding thatcertain operations, such as lyophilisation and asepticprocessing, that are not core competencies are noteconomical to run in-house. They are looking tooutsource more of these activities. Outsourcingbiomanufacturing also reduces time-to-market asconstructing a new, fully validated facility takesseveral years. Outsourcing manufacturing givescompanies an opportunity to place greater focus ontheir own core competencies.

When selecting a contract manufacturer, a companyneeds to evaluate the contractor’s capacity,capability and track record. The two businessesshould also be aligned behind common scientificstandards.A CMO’s ability to take over themanufacturing process and its experience makingsimilar products with similar production processes

Key Cha l l enges Fac ing B iomanufac tur ing

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Key Cha l l enges Fac ing B iomanufac tur ing

needs to be considered. The CMO’s capacity andflexibility to handle current volumes and its abilityto expand operations if needed down the line isanother critical factor. The company also needs toassess the CMO’s ‘corporate culture’ – that is, howwell the contractor’s management team will workwith the sponsor and how smoothly the project islikely to go. Other factors that could affect theoutsourcing decision are the goals and scope of theoutsourcing initiative: which products will bemanufactured in what volumes and on whattimeline? Which functions will be handed over tothe contractor and which will be retained by thesponsor or outsourced to another third party serviceprovider? Careful planning and well thought-outexecution can eliminate any obstacles to successfultechnology transfer.

I s s u e s i n T e c h n o l o g y T r a n s f e r

Technology transfer is critical to the success of anyproject that is outsourced and is typically a long,tedious and labour-intensive process. Many times,sponsors underestimate the time required forsuccessful transfer. Due to ‘time to market’ pressures,they will push contractors to move as quickly aspossible. It is important to assign project teammanagers who have technical expertise with severalyears of experience in manufacturing or qualitycontrol. Successful technology transfer requiresspecific documentation of all product stability data;completed product batch records; properly qualifiedequipment; analytical methods; specifications for rawmaterials and excipients; assay validation; anymanufacturing or process experience that the sponsorhas with the product; and cell line stability data,product purification data and any undocumentedverbal information about the product. The challengeof technology transfer is to determine how a processcan be completed using the facilities, equipment andspace available to the contractor withoutcompromising the quality and specifications of theprocess or product. Once the information transfer iscompleted, a well designed plan to duplicate theprocess at the contractor’s facility and a productionplan or method by which a product will bemanufactured during an actual production campaignneed to be developed. Technology transfer can beconsidered to be complete only when severalconsistent production batches are completed and theresultant product meets specifications.

Cu r r e n t C a p a c i t y

There is a lot of speculation about the demand andsupply equation for biomanufacturing capacities.The prevailing wisdom is that the sector has beensuffering from undercapacity and a number of

When outsourcing is not enough

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sources suggest that a capacity gap exists. In asurvey conducted by BioPlan Associates in 2005,over 34% of respondents agreed that theirorganisation is currently experiencing significantcapacity constraints. Over 42% of respondentsbelieve they will experience constraints in fiveyears. The survey also found that overallworldwide biopharmaceutical manufacturing isperceived to be 70% of capacity with mammaliancell culture production being currently at 74%capacity, compared with microbial fermentation,which is at 68% capacity.

However, Frost & Sullivan suggest that the globalmanufacturing capacity of biopharmaceuticals wasaround 2.27 million litres in 2004 and is expected toincrease to 3.69 million litres in 2011, at a compoundannual growth rate (CAGR) of 7.2%, and willexceed demand through to 2011. Currently, globaldemand stands at 1.37 million litres and is likely toincrease to 3.13 million litres in 2011. Companies arenow achieving improvements in productivity from1g/litre to 2–3g/litre and above. Bioreactor andpurification capacity requirements are very sensitiveto these improvements.

Sma l l e r C ompan i e s a n d Ou t s o u r c i n ga t a n E a r l i e r S t a g e i n t h e D r u gD e v e l o pmen t C y c l e

Contract manufacturing is very well suited for smalland emerging companies and can serve as the basis ofa company’s product development strategy. Theycan gain access to external technologies and expertiseearly in the clinical development of their drugthrough outsourcing and can utilise these resourcesuntil an internal manufacturing capability becomesstrategically important. Contract manufacturingcompanies provide a high-quality and economicalalternative for small and medium sized biotech anddiagnostic companies. By handing over theresponsibility and complexity of daily production toCMOs, these companies can significantly minimisetheir risk and decrease their development timelines.Their time and resources can be better spent in drugdiscovery and lead optimisation.

S e r v i c e s O f f e r e d b y CMO s

CMOs can offer services ranging from cell linedevelopment, cell banking, bioreactor production,process development, protein purification, scale-up,pilot scale production, cGMP production, analyticaland testing services, validation, quality control testing,protein conjugation, modification, radiolabelling, tofinal formulation, lyophilisation, fill and finish. Thisessentially covers the entire drug development andmanufacturing process.

F u t u r e o f t h e I n d u s t r y

The future for CMOs is very bright. The market isgrowing for the foreseeable future at double-digitrates. There is a steady stream of biopharmaceuticalproducts in clinical trials and approvedbiotechnology drugs are generating high levels ofrevenue. Outsourcing is key not only for small tomedium biotechnology companies that do not havethe resources or have decided not to build their ownmanufacturing facility, but also can be beneficial forlarge pharma and biotech companies. A surveyrecently conducted by BioPlan Associates found that,by 2008, nearly half of all biopharmaceuticalmanufacturers might contract out production ofbiologics. Currently, 35% of biomanufacturersoutsource at least some of their biologics productionin mammalian, microbial, yeast, plant, or insectsystems. These manufacturers project that, by 2008,this number will increase by over 30%. The fact thatthe contract manufacturing industry is projected togrow at these multiples suggests that it is deliveringvalue to its customers.

P r o t e c t i n g J o b s a n d L e a d e r s h i p

Globalisation could effectively move manufacturingjobs overseas, so companies will need strategies toprotect jobs and leadership. The best way to do thisin contract manufacturing is to offer customers thebest value. Time and language differences, long traveldistances, variations in experience level, conflictsregarding intellectual property and processcompatibility issues are major barriers to overcomebefore manufacturing jobs move overseas. In the pre-clinical and early clinical areas it is believed thatcompanies will be reluctant to move overseas due tothe evolving nature of the manufacturing process, andthe benefits of being closer to where the developmentis occurring. Commercial production of less complexand well-characterised processes is more likely to gooverseas in the medium- to long-term.

In time, companies wishing to produce biogenericproducts may base their production operationsoverseas, to achieve production economies. In abiogenerics market, US companies need todifferentiate themselves by successfully adding value toexisting products. For example, companies canformulate proteins with novel delivery systems orgenerate products in a more cost-efficient manner.Companies need to balance the increased costs of novelformulations made in the US with lower productioncosts of bulk material manufactured overseas. ■

This article is continued, with graphics, in the ReferenceSection on the website supporting this briefing(www.touchbriefings.com).

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