SubscribeThe past decade has seen many acres of print given over to the short comings of the manufacturing capacity for the biopharmaceuticals industry.
The past decade has seen many acres of print given over to the short comings of the manufacturing capacity for the biopharmaceuticals industry.
Almost weekly we are being told that the demands of the therapeutic industry, in particular for therapeutic monoclonal antibodies, are greater than supply can probably meet for the remainder of this decade.
In the ensuing rush to solve the problems of a market valued in 2004 at $1.7 billion dollars we may be in danger of overlooking the "Cinderella" components that in part have led to this success story.
"Cinderella" is the non-therapeutic contract manufacturing business sector and covers the supply of monoclonal antibodies to the diagnostics industry and all research environments.
Whilst successful therapeutics are the money spinners, the everyday consumption of antibody reagents in the diagnostics and research laboratories is such that they are now considered to be general laboratory consumables.
However such is the demand in this non-therapeutic manufacturing sector that supply can be as problematic as in the therapeutic arena. Successful companies need to be aware of the requirements of the diagnostics industry and research markets and of the compliance regulations on a worldwide basis.
The issues for manufacturers in this area are diverse and sometimes not of their making but compliance is needed even when continents apart. Some of the major aspects of non-therapeutic antibody manufacturing are:
- Method of production, the appropriateness of in vitro versus in vivo manufacturing is still very much at the discretion of both the purchaser and seller of the service.
- The relevance of quality systems and ensuring that the relevant quality control requirements are identified before the commencement of production.
- Diagnostics beyond human healthcare may well become significant to those involved in manufacturing in that there are new demands from the veterinary, food, water industries and environmental groups to diagnose monitor and treat within their own business sectors.
- Demands of research organizations both for standard production procedures and to see adaptation to a changing approach of antibody selection and manufacturing in the recombinant area.
- Supplying bulk biologicals to the non-biologists with a "feast to famine" requirement.
Manufacturing Methodology - in vitro versus in vivo
Whilst therapeutic manufacturers have not seriously considered the use of animals (except transgenics) for antibody manufacturing for well over a decade the same cannot be said for the diagnostics industry or research organizations. As evidenced by the continual success of contract ascites manufacturing companies in the USA and the growth of such organizations in India and China there is still a significant demand around the world for ascites derived monoclonal antibodies.
However, events are slowly changing particularly in the European Union where not only are there legislative controls but also a slow and inexorable drive from the diagnostics industry for in vitro produced products. In fact looking forward another decade, the specification for tissue culture derived antibodies will probably be re-written to exclude the use of foetal calf serum.
Interestingly enough at Morphosys a recent contract for the manufacturing of one of our own products represents the current trends rather neatly:
- The customer evaluated an existing ascites produced catalogue antibody in their assay system.
- The product worked well but there was a real issue with using ascites manufactured product.
- Therefore, Morphosys started an internal programme of tissue culture work to adapt the cell line to in vitro production. This was successful with the antibody produced in tissue culture supernatant showing identical characteristics to the ascites derived material.
- The cell line was then further subjected to adaptation to a serum free environment and still its performance met all specifications.
- Eventually, Morphosys was able to undertake a small batch production run yielding 50mg of Protein A purified and antibody acceptable to customer.
- The customer's comments were as follows: "my congratulation, you did a perfect job. The IgG derived from cell culture meets our "short-time" specifications very well. We can reproduce your QC-data. Our titer test is perfectly congruent with yours. The labeled IgG is also functioning well and equivalent to the conjugate from ascites IgG. Please proceed to the 1gram production run"
This adaptation to a serum-free environment may become the norm for many in vitro production laboratories if the hybridoma can be successfully switched to these conditions.
The appropriate quality system
Quality systems whether they be ISO, cGMP or something in between are often viewed by research scientists as restrictive covenants placed on their freedom of expression within the laboratory. In a manufacturing environment this is not a relevant argument since the ability to produce to a defined specification is an absolute requirement, providing all parties (customer and supplier) understand the term "biological variation".
No process is 100% efficient and when the unpredictable happens it can throw all procedures to one side, however if the expectations and capabilities are thoroughly examined during the negotiation phase this variable can be protected against.
All to often it is assumed that because there is a quality system all will proceed smoothly. A word of caution on any quality system: in SME's or larger biotech/diagnostic companies the Quality Manager must not be allowed to become the Sales Prevention Officer! A quality system is needed that ensures that products are made in a reproducible, traceable and cost effective way.
Beyond human healthcare
It is 30 years since the monoclonal antibody story began and in that time the uses of these proteins have become diverse to say the least. For a moment forget direct human healthcare and consider:
- Detection and identification of environmental pollutants.
- The scale and cost of providing potable water supplies.
- Safe and acceptable standards in the food industry
- Veterinary medicine where livestock has to be maintained to the highest levels in order to enter the food chain.
- Biomarker industry where using antibodies to known haptens allows detection of fraudulent products.
These and many other areas are examples of where, as non-therapeutic contract manufacturers, we will see the next surge in demand for product come from. The requirements of these industries will be different in terms of specifications, shelf life, unit cost etc., just imagine having to provide antibody for a sequestration column capable of flow rates at 60,000 gallons of water per day. Can it be done? Not yet but the demand is there.
Antibodies for research
As global research institutes, be they academic or commercial, grow larger and international collaborations expand the demand for antibodies on a lesser scale is none the less significant.
At Morphosys we now specialise in the supply of 10's and 1000's of milligrams of antibodies whether they be from researcher supplied clones or our own cell banks.
Where they may have a defined project which very often has an element of animal modelling. As a contract manufacturer we are there to do various scales of preparations from whatever species of hybridoma to whichever isotype it secretes.
Feast to famine production
Over the last 10 years there has been much use made of antibodies as detection reagents in chemical and biological terrorism. Whilst the methodologies of detection (and capture) vary form country to country there is a wide acceptance that antibodies play a fundamental role in this area.
There are two facets to manufacturing here:
- Production that is almost a continuum to allow for routine monitoring; for example when was your hand luggage last swiped with a solvent cloth at an airport which was then scanned for certain residues using antibody based technology platforms.
- Production that has high demand for a specific purpose such as large international meetings or sporting events where the customer has a short term, point in time requirement. How do you manufacture multi-gram batches of numerous different hybridomas all at the same time to meet a specific event to a fixed budget? The answer is that we all have our secrets and in this sector we are keeping this to ourselves!
No matter how diverse the specification of your antibodies may be, with the experience and expertise of Morphosys you have the best chance of success in fulfilling your needs when contracting out production.