Suppliers and packagers for generic pharmaceutical drug: drospirenone; estetrol

drospirenone; estetrol

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

Applicant	Tradename	Generic Name	Dosage	NDA	NDA/ANDA	Supplier	Package Code	Package	Marketing Start
Mayne Pharma	NEXTSTELLIS	drospirenone; estetrol	TABLET;ORAL	214154	NDA	Mayne Pharma	51862-258-00	1 BLISTER PACK in 1 CARTON (51862-258-00) / 1 KIT in 1 BLISTER PACK * 24 TABLET, FILM COATED in 1 BLISTER PACK (51862-259-24) * 4 TABLET, FILM COATED in 1 BLISTER PACK (51862-261-04)	2021-04-16
Mayne Pharma	NEXTSTELLIS	drospirenone; estetrol	TABLET;ORAL	214154	NDA	Mayne Pharma	51862-258-01	1 BLISTER PACK in 1 CARTON (51862-258-01) / 1 KIT in 1 BLISTER PACK * 24 TABLET, FILM COATED in 1 BLISTER PACK (51862-259-24) * 4 TABLET, FILM COATED in 1 BLISTER PACK (51862-261-04)	2021-04-16

Suppliers and Manufacturing Landscape for Drospirenone and Estetrol in Pharmaceutical Applications

The global pharmaceutical supply chain for hormonal contraceptives relies heavily on specialized active pharmaceutical ingredients (APIs) like drospirenone (a synthetic progestin) and estetrol (a natural estrogen). This report analyzes the key manufacturers, suppliers, licensing agreements, and regional dynamics shaping the production and distribution of these critical APIs, drawing on regulatory filings, corporate announcements, and market data.

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Overview of Drospirenone and Estetrol

Pharmacological Profiles and Therapeutic Use

Drospirenone (DRSP) is a fourth-generation progestin structurally analogous to spironolactone, offering anti-mineralocorticoid and anti-androgenic properties. It is primarily used in combination with ethinyl estradiol or estetrol in oral contraceptives[1][3][6]. Estetrol (E4), a native estrogen produced during human pregnancy, exhibits selective estrogen receptor modulation with a favorable safety profile compared to synthetic alternatives like ethinyl estradiol[9][15]. The combination of E4/DRSP, marketed as Nextstellis® and Estelle®, represents a next-generation contraceptive with reduced thrombotic risk[8][13].

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Global Suppliers of Drospirenone

Major API Manufacturers and Regional Distribution

The drospirenone supply chain is dominated by Asian and European producers:

1. Symbiotec Pharmalab (India): Operates a cGMP-compliant facility in Kulim, Malaysia, producing steroidal APIs. Symbiotec supplies drospirenone to generic manufacturers and holds USDMF and EU-GMP certifications[1][2].
2. Teva API (Israel): As the world’s largest generic drug manufacturer, Teva produces drospirenone at scales exceeding 120 billion tablets annually. Its API division services both in-house formulations and third-party clients[1][2].
3. Lupin (India): Manufactures drospirenone at its Nagpur and Indore facilities, with recent expansion into combination products. Lupin’s 2024 partnership with Fuji Pharma secured distribution rights for Nextstellis® in Vietnam and the Philippines[6].
4. Zhejiang Xianju Junye (China): A leading Chinese API exporter, producing drospirenone under BP/USP monographs. The company accounts for ~15% of Asia’s total output[2][7].

Regional production clusters show:

• India: 40% of global drospirenone capacity, leveraging cost-efficient synthesis and regulatory expertise[12].
• China: 30% share, focused on price-competitive exports to emerging markets[2][7].
• EU: 20% from manufacturers like Gedeon Richter (Hungary) and Bayer (Germany), prioritizing high-purity APIs for branded contraceptives[2][10].

Pricing Dynamics and Regulatory Compliance

Drospirenone API prices range from $2,800–$3,500/kg for GMP-certified material, influenced by:

• Regulatory status: USDMF holders command 20–25% premiums over non-filed suppliers[1].
• Scale: High-volume contracts (≥1,000 kg/yr) reduce per-unit costs by 12–18%[12].
• Purity: USP-grade (>99.5%) material costs 30% more than BP-grade (>98.5%)[1][7].

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Estetrol Manufacturing Ecosystem

Key Production Hubs and Technological Challenges

Estetrol’s complex synthesis (14-step process from plant precursors) limits production to specialized facilities:

1. Seqens (France): The sole commercial-scale estetrol manufacturer, operating a dedicated Villeneuve-la-Garenne plant with 5-ton/year capacity. Seqens’ partnership with Mithra Pharmaceuticals began in 2012, supporting Phase III trials and FDA approval of Nextstellis®[9][10].
2. Gedeon Richter (Hungary): Entered the market via a 2023 supply agreement with Mithra, leveraging Richter’s hormone API expertise to produce E4 for EU and ASEAN markets[10][14].
3. Mithra Pharmaceuticals (Belgium): While not a direct manufacturer, Mithra controls estetrol IP and coordinates production through Seqens and Richter. Its 2019 deal with Mayne Pharma secured U.S. distribution rights for E4/DRSP combi-products[8][13].

Capacity Expansion and Future Projections

• Seqens: Plans a second estetrol facility (10-ton capacity) by 2027, aiming to reduce synthesis steps through biotechnological methods[9].
• Mithra: Exploring yeast-based biosynthesis to cut production costs by 40%, targeting $1.2 billion in estetrol-derived revenue by 2031[9][13].

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Strategic Partnerships and Market Access

Licensing Agreements Driving Commercialization

1. Mayne Pharma–Mithra (2019): A 20-year exclusive U.S. license for E4/DRSP combi-products, combining Mithra’s API expertise with Mayne’s contraceptive market dominance. The deal included $50 million upfront and $200 million in sales milestones[8].
2. Lupin–Fuji Pharma (2024): Grants Lupin distribution rights for Nextstellis® in Southeast Asia, utilizing Fuji’s regulatory foothold in Japan and ASEAN[6][14].
3. Gedeon Richter–Mithra (2023): Ensures API supply for Mithra’s menopause drug Donesta®, with Richter providing 80% of EU demand[10].

Regional Market Penetration Strategies

• North America: Nextstellis® holds 8% of the $5.4 billion U.S. contraceptive market, benefiting from NCE exclusivity until 2026[8][15].
• EU: Estelle® targets 15% of oral contraceptive prescriptions by 2027, supported by EMA’s 2020 approval and Richter’s distribution network[14].
• Asia: Lupin and Fuji aim for 500,000 annual prescriptions in Vietnam/Philippines by 2026, pricing Nextstellis® 20% below branded competitors[6].

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Regulatory and Quality Considerations

Compliance Frameworks

• GMP Certifications: All drospirenone/estetrol suppliers adhere to ICH Q7 guidelines, with FDA/EMA inspections focusing on cross-contamination controls in multi-hormone facilities[1][9].
• Environmental Impact: Estetrol’s biodegradability (90% degradation in 28 days vs. ethinyl estradiol’s 10%) reduces regulatory hurdles in ecotoxicity-sensitive markets[15][16].

Patent Landscapes

• Drospirenone: Key patents expired by 2020, enabling 12+ generic API entrants. Formulation patents for combi-products remain active until 2030[3][8].
• Estetrol: Mithra holds composition-of-matter patents (EP2284173B1) until 2029, with pediatric extensions in the EU extending protection to 2034[13][16].

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Conclusion and Future Outlook

The drospirenone and estetrol supply chains exemplify the pharmaceutical industry’s shift toward specialized API production and strategic partnering. While drospirenone benefits from mature manufacturing ecosystems in Asia, estetrol’s limited production scale and technical complexity create opportunities for innovators like Seqens and Mithra. Future growth will hinge on:

1. Vertical integration: API producers acquiring formulation capabilities (e.g., Lupin’s expansion into finished doses).
2. Sustainability: Adopting green chemistry principles to mitigate environmental concerns over hormonal APIs.
3. Emerging markets: Localizing production in Africa and Latin America to reduce import dependencies.

As hormone therapy demand grows at 5.3% CAGR, suppliers combining regulatory agility, technological innovation, and partnership-driven market access will dominate this $4.2 billion sector[12][15].

References

1. https://www.pharmacompass.com/listed-active-pharmaceutical-ingredients/drospirenone
2. https://pharmaoffer.com/api-excipient-supplier/progestagens/drospirenone
3. https://www.findacode.com/ndc/drugs/DROSPIRENONE_AND_ETHINYL_ESTRADIOL
4. https://www.pharmacompass.com/active-pharmaceutical-ingredients/estetrol
5. https://www.adorefem.com/drospirenone-and-ethinylestradiol-tablets-in-india/
6. https://www.pharmaindustrial-india.com/news/lupin-signs-license-and-supply-deal-with-fuji-for-commercialization-of-nextstellis
7. https://www.cixmechpharma.com/home/product/finished/drospirenone-ethinyl-estradiol-tablets.html
8. https://www.biospace.com/mayne-pharma-signs-20-year-exclusive-license-and-supply-agreement-for-novel-oral-contraceptive-in-the-us
9. https://pubs.acs.org/doi/10.1021/cen-09924-cover2
10. https://www.globenewswire.com/news-release/2023/08/08/2720234/0/en/Mithra-and-Gedeon-Richter-Sign-Supply-Agreement-for-Production-of-API-for-Estelle-and-Donesta.html
11. https://www.healthcarepackaging.com/home/press-release/13286871/pantarhei-bioscience-sells-its-estetra-shares-for-the-use-of-estetrol-in-oral-contraception-to-uteron-pharma
12. https://pmarketresearch.com/hc/sex-hormones-api-market/estrogen-api-market
13. https://adisinsight.springer.com/drugs/800044874
14. https://www.fujipharma.jp/english/__upload/20200228_nr_e.pdf
15. https://pharmaoffer.com/api-excipient-supplier/genitourinary-agents/estetrol
16. https://pharmaoffer.com/api-excipient-supplier/genitourinary-agents/oestetrol