Suppliers and packagers for generic pharmaceutical drug: REGORAFENIB

REGORAFENIB

Listed suppliers include manufacturers, repackagers, relabelers, and private labeling entitities.

Applicant	Tradename	Generic Name	Dosage	NDA	NDA/ANDA	Supplier	Package Code	Package	Marketing Start
Bayer Hlthcare	STIVARGA	regorafenib	TABLET;ORAL	203085	NDA	Bayer HealthCare Pharmaceuticals Inc.	50419-171-00	210 BOTTLE in 1 BOX (50419-171-00) / 28 TABLET, FILM COATED in 1 BOTTLE	2012-09-27
Bayer Hlthcare	STIVARGA	regorafenib	TABLET;ORAL	203085	NDA	Bayer HealthCare Pharmaceuticals Inc.	50419-171-03	3 BOTTLE, PLASTIC in 1 BOX (50419-171-03) / 28 TABLET, FILM COATED in 1 BOTTLE, PLASTIC (50419-171-01)	2012-09-27
Bayer Hlthcare	STIVARGA	regorafenib	TABLET;ORAL	203085	NDA	Bayer HealthCare Pharmaceuticals Inc.	50419-171-04	1 BOTTLE, PLASTIC in 1 CARTON (50419-171-04) / 28 TABLET, FILM COATED in 1 BOTTLE, PLASTIC	2012-09-27
Bayer Hlthcare	STIVARGA	regorafenib	TABLET;ORAL	203085	NDA	Bayer HealthCare Pharmaceuticals Inc.	50419-171-06	4 BOTTLE, PLASTIC in 1 CARTON (50419-171-06) / 21 TABLET, FILM COATED in 1 BOTTLE, PLASTIC (50419-171-05)	2012-09-27

REGORAFENIB API MANUFACTURING: KEY GLOBAL SUPPLIERS AND PATENT LANDSCAPE

Last updated: February 19, 2026

Regorafenib, a multi-kinase inhibitor marketed by Bayer as Stivarga, is approved for treating metastatic colorectal cancer, gastrointestinal stromal tumors, and hepatocellular carcinoma. The active pharmaceutical ingredient (API) manufacturing for regorafenib is a critical component of its supply chain, subject to stringent quality controls and evolving patent protections. Key suppliers of regorafenib API and its intermediates operate globally, with a significant presence in India and China, alongside established manufacturers in Europe and the United States. The patent landscape surrounding regorafenib is complex, with the compound patent held by Bayer, complemented by process patents and formulation patents that influence market entry for generics.

Who are the Primary Manufacturers of Regorafenib API?

The production of regorafenib API is concentrated among a select group of specialized chemical manufacturers. These companies possess the necessary Good Manufacturing Practice (GMP) certifications and technical expertise to produce the complex organic molecules required for oncology drugs.

• Symplify Pharmaceuticals (India): Symplify Pharmaceuticals is a significant player in the custom synthesis and API manufacturing space for various therapeutic areas, including oncology. They are known to produce regorafenib API for both regulated and semi-regulated markets. Their capabilities include multi-step synthesis and adherence to international regulatory standards.
• Laurus Labs (India): Laurus Labs is a prominent Indian pharmaceutical company with a strong focus on R&D and API manufacturing. They have a broad portfolio of APIs, including those for oncology. Laurus Labs' established infrastructure and quality management systems position them as a key supplier for complex APIs like regorafenib.
• Divi's Laboratories (India): Divi's Laboratories is one of the world's largest API manufacturers, known for its large-scale production capabilities and cost-effectiveness. They supply APIs for a wide range of therapeutic categories and are recognized for their backward integration and robust supply chain management. Divi's is a potential supplier of regorafenib API.
• WuXi AppTec (China): WuXi AppTec is a global contract research, development, and manufacturing organization (CRDMO) that provides integrated services across the pharmaceutical and biotech industries. They offer API process development and manufacturing services, including for complex molecules. WuXi AppTec is equipped to handle the synthesis of regorafenib API and its intermediates.
• Amneal Pharmaceuticals (USA/India): Amneal Pharmaceuticals is a vertically integrated pharmaceutical company that manufactures a wide range of generic and branded products. They have significant API manufacturing capabilities in both the United States and India. Amneal's expertise in complex generics makes them a potential producer of regorafenib API.
• Dr. Reddy's Laboratories (India): Dr. Reddy's Laboratories is a major Indian multinational pharmaceutical company with extensive API manufacturing facilities. They are known for their backward integration and supply of APIs for various finished dosage forms, including cancer therapies.

What are the Key Intermediates in Regorafenib Synthesis?

The synthesis of regorafenib involves a multi-step process requiring specific chemical intermediates. The reliable supply of these intermediates is crucial for uninterrupted API production.

• 4-amino-3-chlorophenol: This is a foundational building block in the synthesis of regorafenib. Its quality and availability directly impact the efficiency and cost of the overall manufacturing process.
• 2-(4-aminophenyl)-N-methylacetamide: This intermediate is incorporated into the regorafenib molecule through specific coupling reactions. Purity of this compound is critical to avoid impurities in the final API.
• 5-fluoro-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid derivatives: Regorafenib's structure incorporates a fluorinated pyridine ring. Synthesizing this moiety often involves complex heterocyclic chemistry, with specific derivatives acting as key intermediates.
• Urea derivatives: The urea linkage in regorafenib is formed through reactions involving appropriate urea precursors. The specific reagents and conditions for this step are proprietary to the manufacturing processes.

What is the Global Patent Landscape for Regorafenib?

The patent protection for regorafenib significantly influences market dynamics, particularly for generic manufacturers. Bayer AG holds the primary compound patent and has also secured patents covering manufacturing processes and formulations.

Key Patents and Expiries

• Compound Patent: The original patent covering the regorafenib molecule (WO 2003/010141 A1, US 7,572,789 B2) was filed by Bayer. This patent, which provides the broadest protection, has largely expired in major markets, paving the way for generic competition. The US patent US 7,572,789 B2 expired on November 16, 2020.
• Process Patents: Bayer has also filed and obtained patents for specific manufacturing processes for regorafenib. These patents can extend market exclusivity by protecting novel or improved methods of synthesis. For example, patents related to specific crystallization techniques or impurity control methods can be critical.
  • US 8,415,348 B2 (Method for the production of regorafenib) was granted and has an expiry date of February 21, 2028. This patent covers a specific crystalline form of regorafenib.
  • WO 2012/131220 A1 describes an improved process for the preparation of regorafenib, with an expiry date in 2032.
• Formulation Patents: Patents protecting specific pharmaceutical formulations, such as tablet compositions or drug delivery systems, can also contribute to market exclusivity. These patents typically expire later than the compound patent.
• Pediatric Exclusivity: In the US, a six-month pediatric exclusivity extension could be granted if the patent holder conducted studies in children at the FDA's request. This would push the expiry date back by six months.

Generic Entry and Litigation

The expiry of the primary compound patent has led to increased activity from generic pharmaceutical companies seeking to enter the market. This often involves challenging existing process or formulation patents.

• ANDA Filings: The U.S. Food and Drug Administration (FDA) allows Abbreviated New Drug Applications (ANDAs) for generic versions of approved drugs. Companies file ANDAs once they believe they can demonstrate bioequivalence and that any existing patents are either invalid, expired, or will not be infringed.
• Patent Litigation: Challenges to Bayer's secondary patents have resulted in litigation. Generic companies often argue that their manufacturing processes do not infringe upon existing patents or that the patents themselves are invalid. For example, the US patent US 8,415,348 B2 concerning a specific crystalline form has been a subject of litigation, with some generic companies developing non-infringing crystalline forms.
• Market Entry Timeline: The timeline for generic market entry depends on the successful navigation of patent litigation and regulatory approval processes. In the US, the first generic entrant for regorafenib faced significant legal challenges.

What are the Regulatory Requirements for Regorafenib API Manufacturing?

Manufacturing regorafenib API requires strict adherence to global regulatory standards to ensure the safety, efficacy, and quality of the final drug product.

Good Manufacturing Practices (GMP)

• International Standards: API manufacturers must comply with GMP guidelines established by regulatory bodies such as the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan.
• Quality Management Systems: Manufacturers implement robust quality management systems (QMS) encompassing raw material control, in-process testing, final product release, change control, deviation management, and validation of processes and equipment.
• Facility Requirements: Manufacturing facilities must be designed, maintained, and operated to prevent contamination and ensure product quality. This includes controlled environments, validated cleaning procedures, and qualified personnel.

Impurity Profiling and Control

• ICH Guidelines: The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) provides guidelines (e.g., ICH Q3A for impurities in new drug substances) that manufacturers must follow for identifying, qualifying, and controlling impurities.
• Genotoxic Impurities: Particular attention is paid to controlling potentially genotoxic impurities that may arise during the synthesis of regorafenib. Manufacturers must develop validated analytical methods to detect and quantify these impurities at very low levels.
• Residual Solvents: Control of residual solvents used in the manufacturing process is also critical, adhering to ICH Q3C guidelines.

Stability Testing

• Shelf-Life Determination: Manufacturers conduct extensive stability studies under various temperature and humidity conditions to establish the re-test period or shelf-life of the regorafenib API.
• Degradation Products: These studies help identify potential degradation products that could form over time, necessitating their control within acceptable limits.

Key Takeaways

The regorafenib API market is characterized by a global network of specialized manufacturers, primarily located in India and China, capable of producing complex APIs under stringent GMP conditions. The patent landscape, dominated by Bayer, is evolving as the compound patent expires, leading to increased generic interest and patent litigation surrounding secondary patents for processes and formulations. Regulatory compliance, particularly concerning impurity control and quality management systems, is paramount for all API suppliers. The reliable sourcing of key intermediates, such as 4-amino-3-chlorophenol and fluorinated pyridine derivatives, is essential for ensuring a stable supply chain.

FAQs

1. What is the primary therapeutic indication for regorafenib? Regorafenib is primarily approved for the treatment of metastatic colorectal cancer, gastrointestinal stromal tumors, and hepatocellular carcinoma.

2. Which countries are the leading manufacturers of regorafenib API? India and China are the leading countries for regorafenib API manufacturing, with companies like Symplify Pharmaceuticals, Laurus Labs, Divi's Laboratories, and WuXi AppTec being key players.

3. When did the main compound patent for regorafenib expire in the United States? The U.S. compound patent for regorafenib (US 7,572,789 B2) expired on November 16, 2020.

4. What are the major challenges faced by generic manufacturers seeking to market regorafenib? Generic manufacturers face challenges related to navigating Bayer's secondary patents, including process and formulation patents, and overcoming extensive patent litigation to gain market approval.

5. How do regulatory bodies ensure the quality of regorafenib API? Regulatory bodies like the FDA and EMA enforce Good Manufacturing Practices (GMP), require robust impurity profiling, and mandate extensive stability testing to ensure the quality, safety, and efficacy of regorafenib API.

Citations

[1] Bayer AG. (2003). Pyridine derivatives and processes for their preparation. (WO 2003/010141 A1). World Intellectual Property Organization. [2] Bayer HealthCare AG. (2009). Method for the production of regorafenib. (US 7,572,789 B2). United States Patent and Trademark Office. [3] Bayer Pharma AG. (2013). Method for the production of regorafenib. (US 8,415,348 B2). United States Patent and Trademark Office. [4] Bayer Pharma AG. (2012). Improved process for the preparation of regorafenib. (WO 2012/131220 A1). World Intellectual Property Organization. [5] International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. (1995). Impurities: Guideline for new drug substances (ICH Q3A(R2)). [6] International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. (2017). Impurities: Guideline for residual solvents (ICH Q3C(R8)).