How many FDA approved Non-recombinant coagulation factor are there?

Introduction to Coagulation Factors

Coagulation factors are a group of proteins that play a critical role in the physiological process of hemostasis—an intricate cascade that stops bleeding after vascular injury by forming a clot. In the bloodstream, these proteins interact in a highly regulated sequence to convert blood from a liquid into a gel-like clot at the site of tissue damage. This process prevents excessive blood loss and ensures proper wound healing. Each coagulation factor (commonly designated by a Roman numeral or by its name, such as factor VIII or prothrombin) contributes unique enzymatic or cofactor activity essential for the progression and regulation of the clotting cascade. 

Types of Coagulation Factors 
Coagulation factors can broadly be categorized into two groups on the basis of their source and method of production: recombinant and non‐recombinant. Recombinant coagulation factors are produced via genetic engineering techniques in cultured cell lines and offer high purity and consistency. In contrast, non‐recombinant coagulation factors are typically derived from human plasma through fractionation processes. These plasma‐derived concentrates retain a natural profile of proteins, including not only the target coagulation factor but often additional regulatory proteins or binding partners, which can enhance their biological function in vivo. The balance, arrangement, and activation of these factors are key to maintaining normal hemostasis and preventing both excessive bleeding and thrombosis.

FDA Approval Process

Overview of FDA Approval for Biologics 
The United States Food and Drug Administration (FDA) employs a rigorous and stepwise evaluation process to assess biologics—including coagulation factor products—before granting approval for clinical use. The process involves preclinical studies, clinical trials (Phases 1 through 3), and comprehensive reviews of safety, efficacy, and manufacturing consistency. This process is designed to ensure that any biologic product meets stringent quality standards and performs as expected when used in patients. For coagulation factors, the FDA also reviews detailed pharmacokinetic (PK) and pharmacodynamic (PD) data, immunogenicity profiles, and comparative analyses against existing products to affirm that their benefit‐to‐risk ratio is acceptable. 

Criteria for Approval of Coagulation Factors 
When considering a coagulation factor product, the FDA evaluates several crucial aspects: 
• Safety and Efficacy: Clinical trial data must demonstrate that the product effectively promotes hemostasis with an acceptable risk profile. 
• Quality Control and Manufacturing: The manufacturing process is closely scrutinized, ensuring that plasma‐derived products adhere to current Good Manufacturing Practices (cGMP). For both recombinant and non‐recombinant products, consistency in purity, potency, and absence of contaminants is mandatory. 
• Pharmacokinetic and Pharmacodynamic Evaluation: These studies show how the product behaves inside the human body, confirming that dosing regimens can achieve therapeutic plasma levels and that the factor performs its intended function reliably. 
• Immunogenicity: As with any biologic therapy, the risk of developing neutralizing antibodies must be evaluated and minimized.

Non-Recombinant Coagulation Factors

Definition and Characteristics 
Non‐recombinant coagulation factors are those that are derived directly from human plasma rather than through recombinant or genetic engineering processes. Plasma fractionation methods are used to isolate these proteins from donated blood, and due to the naturally derived source, they often retain additional components (such as von Willebrand factor in certain factor VIII concentrates) that can contribute to their overall hemostatic function. Because they are extracted from a naturally balanced human milieu, non‐recombinant coagulation factors are sometimes perceived as having a “natural” bioactivity profile, although they undergo extensive viral inactivation and purification processes to ensure safety and efficacy. 

Comparison with Recombinant Factors 
The broad differences between non‐recombinant and recombinant coagulation factors can be viewed from multiple perspectives: 

1. Source and Production: 
 • Non‐Recombinant: Sourced from pooled human plasma, these products benefit from a production process that, while subject to rigorous safety screening (including viral inactivation), depends on the availability and quality of donated plasma. 
 • Recombinant: Produced in cell culture using genetic engineering, these products provide a high level of consistency and freedom from blood‐borne pathogens, but may sometimes lack certain native plasma components.

2. Immunogenicity: 
 • Non‐recombinant products may have a more “natural” profile which can be favorable; however, since they originate from human plasma, there is a historical concern about potential transmission of pathogens—although modern inactivation methods have greatly minimized this risk. 
 • Recombinant products, while eliminating risks related to blood donations, sometimes exhibit differences in post‐translational modifications that may affect immunogenicity.

3. Clinical Performance: 
 • Some studies suggest that plasma‐derived products, by virtue of retaining a broader array of interacting proteins, might offer advantages in hemostasis for certain patient populations. 
 • Recombinant products are designed to mimic natural coagulation factors and have shown excellent efficacy and safety profiles, but differences in efficacy in specific clinical circumstances can sometimes be noted.

FDA Approved Non-Recombinant Coagulation Factors

List of Approved Products 
Based on the references provided and an extensive review of the product data available from the synapse source, there are several FDA approved non‐recombinant coagulation factor products. For the purposes of this discussion, and specifically addressing the query “How many FDA approved Non‐recombinant coagulation factors are there?”, the following products have been identified:

1. Balfaxar 
 • Developed by Octapharma Pharmazeutika Produktionsgesellschaft Mbh, Balfaxar is approved by the FDA_CBER. The referenced approval date is 2023-07-21, and it is an intravenous product with a dosage form administered by injection. Balfaxar represents a plasma‐derived coagulation factor concentrate used in the acute setting for rapid hemostatic correction.

2. Kcentra 
 • Kcentra, developed by CSL Behring GmbH, is a 4‐factor prothrombin complex concentrate that is plasma‐derived rather than produced recombinantly. Approved by the FDA_CBER on 2013-04-29, it represents one of the cornerstone products in the management of vitamin K antagonist reversal and bleeding control in patients requiring urgent intervention.

3. Monoclate/Monoclate-P 
 • This product, developed by CSL Behring LLC, received FDA_CBER approval on 2003-05-14 and is marketed under the trade names Monoclate and Monoclate-P. As a plasma‐derived coagulation factor concentrate, it is used in the management of coagulopathy and as a critical component in treatment protocols for patients with clotting deficiencies.

4. Humate-P 
 • Humate-P, another plasma-derived product from CSL Behring GmbH, was approved by the FDA_CBER on 2000-04-11. It is a von Willebrand factor (VWF) and Factor VIII concentrate used primarily for the treatment of hemophilia A as well as von Willebrand disease. Its natural plasma origins and comprehensive protein profile provide a robust treatment option in hemostatic management.

5. Corifact 
 • Corifact is a plasma‐derived coagulation factor concentrate developed by CSL Behring GmbH and approved by FDA_CBER on 2011-02-17. It is used for the management of specific coagulation factor deficiencies and is an example of a product where extraction from plasma is leveraged to achieve optimal physiologic function.

6. Hemofil M 
 • Developed by Takeda Pharmaceuticals U.S.A., Inc. and approved by the FDA_CBER on 2001-03-14, Hemofil M is a plasma‐derived coagulation factor concentrate marketed under the trade name Hemofil M. It has been utilized in the treatment of bleeding disorders requiring clotting factor supplementation and is an important product in the armamentarium for managing coagulopathy.

7. Fibrogammin P I.V. Injection 
 • Fibrogammin P, developed by CSL Behring KK, is a plasma‐derived Factor XIII concentrate. Its FDA approval as “Fibrogammin P I.V. Injection” indicates its role in the prophylaxis and treatment of patients with Factor XIII deficiency. The product was approved with specific labeling by regulatory agencies and serves as a critical treatment option despite being derived from plasma and not produced recombinantly.

Thus, based on the evidentiary references extracted from the synapse database and the detailed product approval information, there are seven FDA approved non‐recombinant coagulation factor products. These products exemplify the in‐depth regulatory oversight applied to plasma-derived products as well as the diversity in clinical application across various bleeding disorders.

Clinical Applications and Indications 
Each of the approved plasma‐derived coagulation factors plays a specific role in the management of bleeding disorders: 

• Balfaxar is utilized for immediate correction of coagulopathy in critical conditions where rapid hemostasis is required. Its approved label underscores its utility in emergency and surgical settings. 
• Kcentra is well recognized for the reversal of vitamin K antagonists such as warfarin and is therefore used in scenarios—often arising in emergency medicine—where timely correction of coagulopathy is paramount. 
• Monoclate/Monoclate-P and Humate-P have established roles in the management of hemophilia A and von Willebrand disease, providing essential factor replacement for patients with congenital deficiencies. 
• Corifact is used in the context of rare factor deficiencies and is a valuable option in maintaining appropriate clotting function in select patient populations. 
• Hemofil M serves as a treatment for bleeding episodes where supplementation of coagulation factors is critical, particularly in patients with complex coagulopathies. 
• Fibrogammin P addresses the specific needs of patients with Factor XIII deficiency, helping to prevent spontaneous bleeding and ensuring effective clot formation in vulnerable patient groups.

Collectively, these products cater to a broad spectrum of clinical needs, ranging from the acute management of bleeding during surgery or trauma to the long-term prophylaxis in congenital bleeding disorders. Their approval by the FDA underscores the emphasis on both safety and efficacy in the design, manufacturing, and clinical application of non‐recombinant coagulation factors.

Challenges and Considerations

Manufacturing and Supply 
While non‐recombinant coagulation factors offer the advantage of being derived from naturally occurring plasma, their manufacturing process poses several challenges. The reliance on donated human plasma means that supply can be subject to donor availability, and production is inherently limited by the volume of safe, screened plasma that is available. Each plasma donation must be rigorously tested for pathogens, and subsequent fractionation processes must adhere to stringent cGMP standards to avert contamination. Additionally, given the complex nature of plasma-derived products, ensuring batch-to-batch consistency remains challenging, even as modern purification and viral inactivation techniques have greatly improved overall product safety and quality. 

The supply chain for these products can be affected by factors such as donor shortages, regulatory changes regarding plasma collection, and increasingly complex global safety standards. In cases where demand outpaces supply, it can lead to issues in treatment availability for patients with rare coagulation factor deficiencies, necessitating careful inventory management and contingency planning by healthcare providers and manufacturers.

Safety and Efficacy 
Safety and efficacy in non‐recombinant coagulation factors have been historically well‐documented, yet ongoing vigilance is necessary. Over the past decades, the risk of transmitting blood‐borne pathogens via plasma-derived products has been minimized dramatically through robust testing and modern inactivation methods. However, despite these advancements, there remains an inherent risk when using human plasma as a source. Regulatory agencies, such as the FDA, mandate comprehensive viral inactivation and removal steps in the manufacture of these products, ensuring that the risk remains acceptably low.

Efficacy considerations include the balance between achieving hemostasis and avoiding the potential for thrombosis or adverse immune responses—issues that have been a focus of clinical trials for each product. The immunogenicity profile is critically evaluated both pre- and post-approval, as patients may develop inhibitors that can reduce the effectiveness of the treatment. In many cases, the natural complexity of plasma-derived factors (for example, the accompanying von Willebrand factor in some factor VIII concentrates) may confer a therapeutic advantage by preserving the physiologic regulation of coagulation, though this same complexity can potentially introduce variability in clinical response. 

Furthermore, long-term post-marketing surveillance continues to be an important component of the FDA’s oversight. The continuous collection of safety data and assessment of clinical outcomes helps to confirm that the initial approval conditions remain valid and enables adjustments to clinical guidelines if the risk profile changes or if new manufacturing improvements are identified.

Conclusion 
In summary, non‐recombinant coagulation factors remain a vital component of modern hemostatic therapy. Their plasma-derived nature allows them to closely mimic the natural clotting environment, providing robust therapeutic options in a wide range of bleeding disorders. The FDA has rigorously approved seven distinct non‐recombinant coagulation factor products based on comprehensive data on safety, efficacy, manufacturing quality, and clinical utility. These products include Balfaxar, Kcentra, Monoclate/Monoclate-P, Humate-P, Corifact, Hemofil M, and Fibrogammin P I.V. Injection.

Beginning with an understanding of the basic function and classification of coagulation factors, the rigorous FDA approval process emphasizes safety and reliability through detailed clinical and analytical evaluations. Non‐recombinant coagulation factors, being derived directly from plasma, offer a natural therapeutic profile, though they present unique manufacturing and supply challenges that require significant oversight and constant vigilance. The clinical applications of these products span emergency reversal of anticoagulation to the prophylaxis of congenital bleeding disorders, making them indispensable in the clinical setting.

From various perspectives—including production methodology, safety profiles, clinical effectiveness, and regulatory oversight—it is clear that these seven products exemplify the strengths and challenges associated with plasma‐derived therapies. As innovations continue in both non‐recombinant and recombinant domains, clinicians are provided with a spectrum of options from which they can select the most appropriate therapy based on patient-specific considerations. Rigorous post-marketing surveillance and continuous improvement in purification techniques ensure that these products remain a safe and effective option for managing bleeding disorders in diverse patient populations.

Conclusively, the seven FDA approved non‐recombinant coagulation factors represent a critical advance in the treatment of coagulopathies. Their natural derivation from human plasma endows them with characteristics that are often complementary to recombinant products, despite inherent challenges relating to supply and manufacturing variations. Overall, these products underscore the balance between innovative therapeutic development and the maintenance of rigorous safety and efficacy standards in the modern regulatory landscape.

Through this general-specific-general review, we appreciate that while the biopharmaceutical industry continues to innovate with recombinant technology, non-recombinant products remain invaluable—especially for conditions where maintaining natural protein complexes enhances the therapeutic outcome. This broad perspective confirms that there are exactly seven FDA approved non‐recombinant coagulation factor products, all of which meet the high standards required for clinical use in ensuring effective hemostasis and patient safety.

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