Taxanes as a drug class produce worldwide annual revenues of more than $3 billion. The two approved taxane APIs, paclitaxel and docetaxel, are both derived from plant extracts. The question of whether to make taxanes synthetically or to isolate them as natural products has much to do with their molecular structures, the source of the starting raw material and manufacturing economies. As demand and price pressure on these APIs increases, having access to both synthetic and natural routes will prove to be the most balanced, economical and stable supply approach.
Taxanes are a class of compounds that are derived from plant sources, typically yew species from the Taxus genus. These compounds are cyclic diterpenoids used as active pharmaceutical ingredients primarily in cancer chemotherapy.
Paclitaxel is a generic product in the major markets of North America and the European Union (EU). Docetaxel is the active ingredient in Taxotere, an approved and patented drug product manufactured by Sanofi-Aventis. Patent protection for docetaxel begins to expire in 2007, with formulation patents extending through 2013 in certain territories. The taxanes are approved for use alone or in combination with other chemotherapy agents for the treatment of breast, ovarian, non-small cell lung and other cancers.1-2 They have also been used off-label for treatment of several other cancers.3
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Docetaxel, which does not exist naturally in plants, is a synthetic taxane similar in structure to its natural analog. Both compounds are comprised of a base baccatin ring system and an ester linked phenyl isoserine side chain. On the side chain, docetaxel differs from paclitaxel by substitution of an O-tertiary butyl (BOC) group for a phenyl at the amide carbonyl. The 10-position on the baccatin ring is substituted by a hydroxyl rather than the acetate group found in paclitaxel.
Historically, semi-synthesis of either API has started with an intermediate taxane, 10-deacetylbaccatin III (10-DAB), isolated from the European yew, Taxus baccata. There are several key patents covering processes and composition of matter on 10-DAB intermediates leading to these APIs. Reaction of the hydroxyl at the 13-position on the baccatin ring with the side chain amino acid produces the ester linkage. Straight addition of the open side chain to the baccatin intermediate can be accomplished, but with low yield.4-6 The key patents have process claims, but not composition of matter on the side chain itself. Cyclic side chain analogs with lower streric hindrance improve side chain addition yields. A four-member beta-lactam ring,7 the five-member oxazolidine ring8-9 or an oxazoline ring with metal alcoxides10-11 can be used to add the side chains for paclitaxel or docetaxel.
Bioxel has developed a high efficiency, non-patent infringing cyclic side chain addition process using novel chiral auxiliaries coupled to a unique baccatin found in high levels in the Canada yew (Taxus canadensis). This process can be used for the semi-synthesis of paclitaxel or docetaxel, and it complements the natural paclitaxel process already being used for commercial paclitaxel manufacturing. With both natural and synthetic approaches, Bioxel has created a robust and sustainable taxane supply position.
Three Segments with Common Concerns
The market for paclitaxel and docetaxel APIs is driven by generic formulators, specialty pharmaceutical companies and medical devices. Price and supply chain reliability are key purchasing criteria for generic manufacturers as they develop and market identical or bioequivalent formulations of the original finished drug. Freedom to operate is also critical to generic manufacturers who can ill afford the time delays and expense of patent infringement lawsuits.
 SMB equipment is used for the cGMP purification of paclitaxel at Bioxel’s dedicated manufacturing facility operated at the AmPac site. |
Following the 2004 approval of Boston Scientific’s Taxus stent, more medical device companies are using paclitaxel.12 The API that is released from the surface of the coronary stent helps reduce restinosis, post surgical re-closure of the arteries near the implant. The volume of paclitaxel used in these applications is lower than in chemotherapy, but the market is growing. In this segment, API price sensitivity is somewhat lower, but reliability of supply and regulatory compliance are very important.
Independent of the market segment, a stable raw material position, high-purity product and cGMP compliance are minimum requirements for supply to North American and EU markets. This has been highlighted by recent EU legislation requiring that all APIs going into drugs sold in Europe meet good manufacturing practices.13 (For more on the EU’s GMP initiative for APIs, see the November/December 2005 issue of Pharma & Bio Ingredients.)
The question of natural versus synthetic paclitaxel is often based on the perception that synthetics are either more pure or less costly than natural products. Neither is necessarily the case. There is a standard for paclitaxel purity, the USP monograph [USP 28, NF 23]. A corresponding EU monograph is currently being drafted. Both natural and synthetic paclitaxel must meet absolute minimum purity standards as well as strict limits on trace impurities. As for the cost, companies that make the most out of the natural taxanes isolated from their own biomass will have the lowest cost of goods. In this regard, three things should be taken into consideration: the content of all taxanes in the biomass, the full utilization of these taxanes and the cost/efficiency of manufacturing.
Natural and Synthetic Approaches
Bioxel currently manufactures natural paclitaxel API isolated from the Canada yew. The company has also developed synthetic routes to paclitaxel and docetaxel via proprietary intermediates starting from 9-dydro-13-acetylbaccatin III (9-DHB), a unique taxane found in large quantities in the Canada yew. The company has garnered an extremely strong starting raw material position. It has exclusive access to more than a quarter million square kilometers of harvesting territories throughout Eastern Canada. The Canada yew is widely recognized as the world’s largest sustainable natural source for taxanes. In addition, the Canada yew has among the highest contents of paclitaxel occurring naturally in the needles and stems of the plant, typically between 350 and 500 ppm. With 9-DHB content that is three to four times that of paclitaxel, the total available taxanes in the Canada yew approaches 0.2%.
In 2004, Bioxel brought on-stream a state-of-the-art large scale cGMP paclitaxel purification facility to supply the growing API markets. The fully validated process featured in Pharmaceutical Manufactur-ing14 employs a highly efficient simulated moving bed (SMB) chromatography process. Paclitaxel manufactured by Bioxel under U.S., Canadian and European drug master files is being used in commercial generic products in North America and Europe as well as in products under clinical development. Key competitive advantages for Bioxel include strong raw material position, competitive cost of goods, complete freedom to operate and manufacturing flexibility.
A side stream of Bioxel’s natural paclitaxel process contains the two taxane intermediates 9-DHB and 10-DAB, the former in a >1000 ppm excess compared with paclitaxel alone. Each baccatin is readily isolated as a >98% pure material. Manufacturing flexibility is enabled by the fact that Bioxel can synthesize from 9-DHB any one of the other taxanes, 10-DAB, paclitaxel or docetaxel. In 2005, the company filed for patent protection on 9-DHB intermediates and the process routes to paclitaxel and docetaxel. This includes composition and use claims for unique chiral auxiliaries that are employed in the highly efficient addition of the corresponding side chains for paclitaxel and docetaxel to a baccatin intermediate.
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As docetaxel patent expiration nears, generic pharmaceutical companies are positioning themselves now for supply of this important ingredient for their formulation development and dossier filings. Since it can only be manufactured through a semi-synthetic route, docetaxel represents a challenge for these companies. The route of synthesis and the corresponding taxane intermediates are well protected by the originator. A thorough due diligence on freedom to operate coupled with sustainability of API supply are key criteria for selecting the right docetaxel API supply partner.
Likewise, generic formulators and specialty pharmaceutical companies are seeking options for synthetic paclitaxel. This may be driven by several factors. The addition of new API suppliers allows these companies to apply pressure on price. Flexibility in the API source could also be a strategic consideration for regulatory filings. No matter what the reason for seeking a synthetic paclitaxel, the issues of sustainability of supply and IP freedom remain the same.
Novel Taxane Side Chains
The new technology for synthetic taxanes developed and patented by Bioxel takes advantage of the overwhelming supply of 9-DHB and unique chiral auxiliaries used to add the taxane side chain (Figure 3). Since much of the early work on synthetic taxanes was focused on 10-DAB, a different taxane intermediate, the company had a good starting point for development of a non-infringing synthetic route.
The first part of the synthesis involves transformation of 9-DHB into proprietary intermediates for paclitaxel and docetaxel that are protected at the 7, 9 and 13-positions on the ring. The next step involves the addition of the side chain corresponding to paclitaxel or docetaxel. This is accomplished with a unique chiral auxiliary that directs the side chain addition in the proper sterochemical configuration. After addition, the auxiliary is cleaved, the hydroxyl groups are de-protected and the API is purified.
Advantages of this new process are that the side chain materials are readily synthesized from low cost ingredients, the side chain addition is high yielding and chiral purity is preserved through the process. There is an additional safety benefit in that cytotoxicity occurs only in the final steps. This provides some flexibility in manufacturing as high levels of containment are not required until the end of the process where the volumes are relatively low. Scale-up of this process is already underway at Bioxel. With large quantities of starting baccatin intermediate in stock, launch supplies of synthetic docetaxel and paclitaxel are guaranteed - without any further harvesting. A validated DMF process for both synthetic taxanes will be on-stream this year.
In the world of taxane APIs, the question of whether to use natural or synthetic is partly strategic and partly economic. Each company has its own criteria for API selection.
But the question might well be reframed as “What is the most flexible, economic and reliable source for paclitaxel and docetaxel?” From this point of view, it’s not a mater of either/or. Rather, the winner in taxane API supply will be the company that has both. What’s really critical is that the API manufacturer extracts and utilizes the most taxanes from its biomass, has complete freedom to operate and is competitive in the market.
About the Author
Paul Metz is president of Bioxel International, the commercial arm of Bioxel Pharma, Inc. Sainte Foy, Quebec, Canada. He has worked at Bioxel since 2000. Previously, Mr. Metz worked at Hauser, Lonza and Merck & Company in various roles in natural product and fine chemical development, engineering, manufacturing and marketing.
References
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2. U.S. Food and Drug Administration, Center for Drug Evaluation and Research. Listing of Approved Oncology Drugs with Approved Indications. Taxotere. Last revision, Nov. 2002
3. ICD-9 Codes that support medical necessity. CPT / HCPCS policy codes: J9265 for Paclitaxel, J9170 for Docetaxel. 2005.
4. Denis et al. A Highly Efficient, Practical Approach to Natural Taxol. J. Am. Chem. Soc. 1988, 110, 5917-5919.
5. Colin, M., et al., Process for preparing derivatives of baccatin III and of 10-deacetyl baccatin III. US Patent 4,924,012. 1990.
6. Swindel, C., et al. Synthesis of taxol, taxol analogs and their intermediates with variable A-ring side chain structures and compositions thereof, US Patent 5,770,745. 1998.
7. Holton, R.A., Method for preparation of taxol using b-lactam. US Patent 5,175,315. 1998.
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10. Holton, R. A., Beta-lactams as taxol intermediates N-acylated. US Patent 5,574,156. 1996.
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12. Press release. Boston Scientific Announces FDA Approval for its Taxus Express2 Paclitaxel-Eluting Coronary Stent System. March 4, 2004.
13. Restructuring of GMP guide - Revised basic requirements for active substances used as starting materials now public as GMP Part II. Article 47 and Article 51 of Directive 2001/83/EC and 2001/82/EC.
14. Metz, P., et al. SMB Takes on Paclitaxel Purification. Pharmaceutical Manufacturing. Nov. 2004.
