Managing Risk in the Manufacture of Oncology Drugs

Containment, lyophilization and cleaning validation all must be top priorities when producing cytotoxic agents.

By Lee Karras, SVP of Operations, AAI Pharma

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WHILE THE GLOBAL MARKET for oncology treatments continues to grow at a lightning-fast pace, so do the challenges – specifically, those related to the manufacture of parenteral cytotoxic agents. Worldwide, the market for oncology treatments in 2005 exceeded $37 billion, ranking third behind cardiovascular and CNS at $77 billion and $63 billion, respectively. By 2009, the market for cancer treatments is expected to be $65 billion worldwide (Parexel’s Pharmaceutical R&D Statistical Sourcebook 2006/2007, p. 20; Lehman Brothers Universe, p. 20). This growth will be driven primarily by novel therapeutic biologics such as Avastin, Rituxan and Herceptin.

The market for oncology-related clinical trials has also grown. Oncology represented 17.8%, or the largest share of clinical trial starts in 2005 (Ibid p. 47). With regard to oncology products in development, anticancer compounds rank first worldwide with 2,467 compounds in development as of March 2006 (Parexel’s Pharmaceutical R&D Statistical Sourcebook 2006/2007, p. 49, IMS Life Cycle R&D Focus).

The increased understanding of the molecular basis of cancer pathology has led to cancer treatments becoming more specialized in terms of targeting molecular pathways. However, because these agents are essentially cytostatic in nature (i.e., they limit cell proliferation but do not result in a decrease in tumor mass), they will continue to be used in combination with traditional cytotoxic agents which will decrease tumor mass, ultimately leaving the patient tumor-free and able to live longer and with a better quality of life.

Currently, cytotoxic products represent about $10 billion of the $37 billion oncology market. Eighty percent, or about $8 billion, comes from three parenterally administered drugs — Eloxatin (oxaliplatin), Taxotare (docetaxel) and Gemzar (gemcitabine) — all of which will become generic by 2014. The global market for cytotoxic products is estimated by Datamonitor to peak in 2009 at about $13 billion, but shrink to about $11 billion in 2014 due to generic price erosion (source: Sarah Terry Johnston, Datamonitor).

Manufacturing Cytotoxic Products

In many cases, cytotoxic agents represent compounds whose exposure limits are as low as 0.03 µg/m3 over eight hours. In order to protect production operators and the surrounding environment from exposure, manufacturing operations typically are performed in barrier isolator systems or closed restricted access barrier systems (cRABS). The use of these systems allows for complete containment of the environment where the product is manipulated.

The use of barrier isolator systems allows for complete containment of the environment where the product is manipulated.

Within any cRABS or barrier isolator system, the air is HEPA-filtered before being exhausted out of the isolator via a dedicated duct that is directed out of the room. Many advanced isolator systems can both clean and sterilize in place to eliminate the need for disassembly and potential exposure between batches.

In a multi-product facility, disposable tubing/parts are typically used to facilitate quicker batch change-over. However, physical cleaning of the product-contact or product-exposed surfaces is necessary to show absence of the last product before the isolator is opened to the general room environment.

These isolator-based systems allow for not only containment during filling and stoppering but also during formulation/compounding. Further considerations to the flow of personnel, equipment and materials before, during and after manufacturing need to be made in order to ensure proper segregation of “clean” vs. “dirty.” In a normal GMP setting, where traditional parenteral manufacturing occurs, this is critical, but this is even more critical where highly potent, cytotoxic products are manufactured. In addition, this is especially important should the equipment need to be disassembled and taken out of the room for cleaning/sterilization.


Lyophilization of cytotoxic agents requires additional containment and specialized handling. In the case of manually loaded/unloaded lyophilizers, it is crucial to consider personnel protection from product spill as this could result in the personnel carrying residue into adjacent areas. Separate ingress and egress points with specific degowning areas will, in most cases, ensure residues are not carried into “clean” areas or into the general plant environment. However, manual loading/unloading is becoming less frequent with the advent of more modern and computer-controlled (and robust) loading/unloading systems.

Certain types of these automated systems can be controlled from a separate environment or even remotely from a site external to the plant. This arrangement eliminates the need for operators and thus, the exposure potential.

There are two types of automated loading systems that are currently used. The first is an “in-line” system that essentially feeds the filled/partially stoppered vials one row at a time onto the lyophilizer shelf. The feeding mechanism is usually either a set of vacuum/suction cups that grip the vials or a push bar. The second type is an “accumulation system,” where the vials are accumulated on a station (large flat stainless surface) adjacent to the lyophilizer and loaded with a transfer cart.

Both the in-line and the transfer cart/accumulator systems can be placed in a cRABS or isolator. However, the accumulation system does have several drawbacks. The most important is that if multiple products are to be produced in the manufacturing environment, additional cleaning/sampling would be needed because of the increased surface area exposure compared to the in-line system. This would result in more down time between batches. Further, docking considerations and transfer points are far more critical in the case of an accumulation system in an isolator compared to an in-line system where there are no transfer points between machines.

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