The shift to high potency actives in new drug development is forcing contract manufacturers to rethink their strategy. Susan Birks reports on the rush to demand for high containment manufacturing
The nature of pharmaceuticals development is changing all the time with research efforts today focussed on producing specific target molecules that are more potent and produce fewer side effects compared with conventional therapies.
Many of these anti-cancer, anti-viral or CNS-active drugs currently in clinical trials may soon be in full-scale production, but the potency of the drugs and the fact that they are very targeted, mean the commercial quantities required are small.
As the market expects fewer block-busters and more personalised medicines in future, demand for high volume manufacturing is likely to be limited. Producers are already shifting such operations to cheaper locations in India and the Far East. Western manufacturers, meanwhile, are refocussing on higher-value production of these more personalised products.
New data to be published soon by management consultancy Becker Associates suggest there are 3-400 highly potent materials currently in production either for clinical trials or commercial sale (see table 1).
"While not all of these materials in trials will make it to market, it does illustrate the growing number of high potency materials currently in drug development, and there are more to come," said Dr Abram Becker, founder of Becker Associates.
Many hazardous molecules such as cytotoxics, hormones, steroids, potential mutagenics or ingredients that may produce toxic intermediates, are also frequently assigned occupational exposure levels (OEL) of less than 1 µg/m3. Working to these levels requires more planning and risk analysis to ensure every stage of manufacture and waste disposal is safe for workers and the local environment.
It can mean changes in manufacturing approach as it requires more dedicated production suites and discrete waste disposal systems, specialised equipment such as barrier isolators and glove box technology, more sophisticated personal protective equipment and stringent certification.
Until recently, such factors meant that high potency (HP) production was restricted to a handful of specialist producers. However, as contract manufacturers have recognised the trend, the sector has witnessed a flurry of investment in new HP facilities.
One company to have recently acquired certification for HP manufacture is Almac Sciences. The custom manufacturer and analytical services company has added speciality offerings in cytotoxic and potent manufacturing to its peptides, protein and oligo synthesis, chirals and radiolabelling service.
The company's 80,000 sq ft production complex at Craigavon was expanded in 2003 and now has development, kilo-lab and cGMP manufacturing suites designed to operate at 0.1 µg/m3 OEL for cytotoxic compounds enabling manufacture of such products at commercial scale. For HP compounds, the cGMP manufacturing plant (also operated at 0.1 µg/m3 OEL) allows production at ten-fold higher levels.
Almac also collaborates with the Center for Pharmaceutical Science and Technology (CPST) at the University of Kentucky, in the US for cytotoxic fill-and-finish services.
CPST provides IV formulation and sterile fill of cytotoxics and potents for clinical trial applications. These are delivered through CPST's Euro 12m sterile manufacturing facility opened in 2006, at the University's Coldstream Research Campus, near Lexington.
"The sterile fill capability will meet the company's emerging requirement in formulation of cytotoxic peptide conjugates," said Dr Rosaleen McGuckin, Almac's business manager for cytotoxics programmes.
Almac also has a 14C radiolabelling service offering the capability to radiolabel biomolecules, such as peptides and proteins, small molecules, including potents and cytotoxics.
Meanwhile. NPIL Pharma has responded to strong customer demand for anti-cancer cytotoxic APIs - and in particular to the emerging monoclonal antibody (mAb)-conjugate sector. A key element in anti-cancer chemotherapies, cytotoxics are increasingly combined with mAbs to create immunoconjugates. These offer a more targeted treatment, with fewer side effects. As a result, immunoconjugates are forecast to take a significant future share of the oncology treatment market. The number of pre-clinical and active clinical programmes is over 20 and growing.
NPIL Pharma (UK) recently expanded its HP facility in Grangemouth, spending €367,324 on containment upgrades and recruiting additional staff. Additional biochemists and purification specialists will bring the total HP team at the Scottish site to more than 50.
The move follows the recent acquisitions of Avecia's business in 2005 and of Pfizer's facility in Morpeth, Northumberland in 2006. Current capabilities include a multi-product kilo scale suite to supply cytotoxic APIs for Phase I and II clinical trials, and process development services to support pre-clinical r&d.
The recent containment upgrades, to an existing 500m2 GMP suite, include additional high integrity barrier isolation for the safe handling for category 4-5 toxins used for conjugation to mAbs and other targeting agents. Room classification has been upgraded to class C 10,000 throughout.
"These latest developments pave the way for significant further expansion in high potency substance capacity", said Charlie Johnson, NPIL Pharma (UK)'s business manager for HPAPIs.
Driven by rising HPAPI demand, SAFC has completed an €8.8m expansion of its Madison, Wisconsin facility in the US. Its new on-site solid-state chemistry research laboratory is due to become operational this month.
SAFC is a manufacturing partner for Vion Pharmaceuticals, and produces Vion's HP anti-cancer drug Cloretazine, which is currently in Phase III and Phase II trials. This supply agreement has just been extended to 2009.
The 38,000 sq ft expansion more than doubles the capacity of SAFC's existing cGMP manufacturing. The two-story structure adds new analytical labs; expanded r&d labs; three new kilo labs; a hydrogenation suite; cGMP drying suite; and increased storage capacity.
Total capabilities at Madison (the former principle manufacturing facility of Tetrionics) now include: eight process r&d labs; eight GMP kilo lab suites; a main- and a mini-pilot plant suite; a hydrogenation suite; two isolated drying suites; a packaging suite; analytical labs; and a solvent storage area.
Looking to strengthen its position in what Steven Klosk, executive vice-president and coo of Cambrex Corporation sees as a "strategically important market", Cambrex too has announced plans to augment its HP development facilities at Charles City, Iowa, US.
Cambrex Corporation will construct an 11,500 sq ft facility with five new process development/kilo lab production suites for HPAPIs as well as enhanced facilities for analytical development and quality control activities.
Cambrex has organically grown its HP offering to the market since 1998. Services include r&d, analytical method development, process and analytical validation and commercial production at two sites. Existing HP resources include multiple kilo-labs and isolators, a micronization suite, and a commercial production suite with 1,100 litre reactors.
The expansion will accommodate up to 40 scientists and engineers and is expected to be completed in early 2008.
The company has other products and services that will be served by this expansion, including the development and manufacture of HP polymer therapeutics, development and manufacture of controlled substances and HPAPI micronization.
Ferro Pfanstiehl Laboratories" strategic focus is also the development and manufacture of pre-clinical, Phase I-III and approved HPAPIs. The company's facility has the staff and equipment necessary for cGMP development, synthesis, purification and packaging in quantities from sub-kilogram to 40kg/lot quantities.
A new full containment kilo lab has been added to serve clients with pre-clinical and phase I-II clinical HPAPIs, as well as other small-molecule APIs and advanced intermediates. The new facility features single fluid heating and cooling capabilities, a multi-purpose 50L and 100L Hastelloy based configuration and a separate 100L cGMP full containment hydrogenation capability.
Ferro has a HPAPI 1,200 gal multi-purpose reactor suite with class 100,000 API recovery area; a Carlisle class IV full containment isolator; HP class IV product recovery, drying and milling suite; a HP class IV product recovery, drying and milling suite.
Aesica Pharmaceuticals" recent purchase of a second manufacturing site from Merck and Co has enabled its move into HP manufacture.
At its Cramlington, Northumberland HQ, Aesica has two multi-product plants and technical development facilities. But the new site in Enfield, London adds three plants including a 7 t.p.a HP facility and a newly commissioned 200 t.p.a API manufacturing facility .
The company has secured a contract with Merck & Co to supply APIs and intermediates. It plans to fill additional capacity by expanding its custom synthesis business. The new site contains a technical centre with an ECL4 lab, which Aesica plans to use for process development and scale-up of cytotoxic compounds.
As production capacity for HP materials in the West increases rapidly, inevitably, more Eastern companies are looking to get into this specialist sphere too, which means greater competition and the possibility of overcapacity in future.
