Special Report On Injectables PDF
Special Report On Injectables PDF
Special Report On Injectables PDF
ARE YOU READY TO OUTSOURCE INJECTABLES? Key things you need to know
ARE YOU READY TO OUTSOURCE INJECTABLES? Key things you need to know
Product development for injectable drugs requires a rigorous strategy and process consisting of four steps: (1) characterization, (2) formulation and process development, (4) lyophilization and (3) assurance of sterility. The process can be lengthy, expensive and risky, so its important to outsource to an experienced partner who can address the challenges involved. This white paper provides a roadmap for understanding how injectables are developed and offers suggestions on how to nd the right outsourcing partner to manage the process. This report is sponsored by CARBOGEN AMCIS AG, a leading service provider, offering a portfolio of drug-development and commercialization services to the pharmaceutical and biopharmaceutical industry at all stages of drug development.
The global injectable drug delivery market is expected to reach roughly $30 billion in 2015
Most biotechnology drug ingredients, including peptides, proteins and chemotherapeutic agents, are inactivated in the gastrointestinal tract when taken orally, hence the need for an injectable drug form
Since 1982, the year human insulin became the rst biotechnology product approved by the Food and Drug Administration, there has been enormous growth in the pharmaceutical biotechnology market segment. In fact, the global injectable drug delivery market is expected to reach roughly $30 billion in 2015 - more than double the amount reached in 2009. This trend has spurred the rapid development of drugs that can only be administered through injection, due to the bioavailability and stability of biomolecules. Most biotechnology drug ingredients, including peptides, proteins and chemotherapeutic agents, are inactivated in the gastrointestinal tract when taken orally, hence the need for an injectable drug form. Moreover, for metabolic disorders treated by small molecules with an immediate therapeutic action, the parenteral route is considered as a must. Despite rapid growth in the demand for injectables, also known as parenterals, the formulation and manufacturing process of these drugs continues to face complex technical challenges.
The market for injectables is expected to reach $30 billion in 2015 - more than double the amount reached in 2009
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Striking the right balance between safety and costeffectiveness is a delicate process that requires a knowledgeable partner who can mitigate the risks involved
Solubility
Solubility is another major challenge formulation scientists must overcome. Ideally, an injectable drug formulation contains an active ingredient and water. However, most of the common active ingredients are poorly soluble in water. As a result, additives are often required to improve the solubility of an injectable drug product. Finding the right additive to conserve the bioavailability of the molecule, while improving solubility may lead to manufacturing difculties and/or increased cost of production. Striking the right balance between safety and cost-effectiveness is a delicate process that requires a knowledgeable partner who can mitigate the risks involved.
Sterility
The third major challenge for manufacturers in the parenteral drug industry is sterility. Sterility means that the drug product is free from microbial contaminants and, by extension, essentially free from endotoxins. However, sterility testing requires a signicant amount of time, money and resources. Sterility tests only use a small sample of a much larger product population. In other words, sterility cannot be proven, only assured. Pyrogens are metabolic or/and constituting products of microorganisms, which are known to induce fever in humans. Some of the most common forms of sterilization, such as aseptic ltration and heat terminal sterilization cannot destroy pyrogens. Therefore, preventing pyrogenic contamination from the beginning of the product development process is crucial. Prevention requires using solutes prepared under clean conditions, pyrogen-free constituents including pyrogen-free water and pyrogen-free packaging materials. For complex process that considers heat treatments, the implementation of ion-exchange resins is advised to reduce the endotoxins charge. Additionally, manufacturers must ensure injectables are free from all particulate matter contamination. The heat sterilization and the gamma radiations represent the most efcient ways to sterilize a drug product when a compound that resists to heat and radiations. But in any case these techniques are leading to pyrogens generation if the preliminary preparation steps and are not ensuring a low level of contamination. When the drug substance is heat sensitive, such as biomolecules, the 0.2 m ltration represents the preferred method to sterilize a drug product. The lter membrane and the parameters must be determined carefully.
Finding the right additive to conserve the bioavailability of the molecule, while improving solubility may lead to manufacturing difculties and/or increased cost of production
Sterility means that the drug product is free from microbial contaminants and, by extension, essentially free from endotoxins
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PRODUCT DEVELOPMENT
Product development for injectable drugs can be lengthy, expensive and risky, so its important to outsource to an experienced partner who can address the challenges involved. Development requires a rigorous strategy and process consisting of four steps: (1) characterization, (2) formulation and process development, (4) lyophilization and (3) assurance of sterility.
Product development for injectable drugs can be lengthy, expensive and risky, so its important to outsource to an experienced partner who can address the challenges involved
Characterization Studies
At the beginning of development, it is important to analyze the structural characteristics of the proposed active ingredient and clearly dene the clinical specications of the parenteral drug product. This process, referred to as characterization, involves assessing the physicalchemical properties of the bulk active ingredient and of the biomolecule. Nowadays, the characterization of most chemical compounds is relatively easy thanks to the wide availability of technology, including infrared (IR), differential scanning calorimetry (DSC), X-ray diffraction, and mass spectrometry. For biomolecules such as peptides and proteins, it is also often necessary to assess the primary structure and the amino acid sequence of the active ingredient to conrm principal properties. Characterization also involves impurity proling and tracking, determination of degradation pathways, as well as stress tests to determine the sensitivity of the molecule to heat, humidity, oxygen and light.
Parenteral drugs are formulated as solutions, suspensions, emulsions and powders to be reconstituted as solutions and at this step, it is critical to ensure that the additives dont trigger unintended chemical degradation processes
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Lyophilization
When the main active ingredient is too unstable and the injectable cannot be formulated as a ready-to-use liquid dosage form, the drug may undergo lyophilization, a dehydration method that makes it possible to keep the product stable in a dry state. Many biopharmaceutical drugs, such as proteins and peptides, or even small molecules, are unstable in water and therefore must be freeze-dried for clinical and commercial use.
Many biopharmaceutical drugs, such as proteins and peptides, or even small molecules, are unstable in water and therefore must be freeze-dried for clinical and commercial use
Assurance of Sterility
To address sterility in the production of injectables, manufacturers must follow current good manufacturing practices (cGMPs). Strict adherence to cGMP principles plays a critical role in ensuring the highest quality standards in manufacturing processes as well as in end products. The manufacturer starts with the procurement of the active ingredient, excipients and packaging components (containers, closures, etc.) and ends with the sterile product sealed in its dispensing package. Using FDA approved GRAS (Generally Regarded as Safe) excipients helps to assure sterility as these ingredients have low endotoxin and bioburden levels. During production, there are a variety of methods available to achieve sterility, including autoclave, dry heat, sterile ltration and aseptic processing. Each sterilization procedure must undergo signicant testing to ascertain that the method offers a high degree of assurance. Qualication of sterilizing processes or specic validation of a sterile ltration method should be done throughout the clinical stages and prior commercialization. This validation of an aseptic process, an integral part of cGMP requirements, helps ensure there are no microorganisms present that could contaminate the nal drug product.
Strict adherence to cGMP principles plays a critical role in ensuring the highest quality standards in manufacturing processes as well as in end products
The aseptic process should be by validated by media ll testing, microbiological and analytical controls and 100% visual inspection
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Choosing a CMO with strong project management capabilities and economies of scale in all development phases (preclinical to phase III projects) will expedite the production process and create cost savings
Its critical to choose a partner with a exible and collaborative team to ensure frequent and open communication on both sides of the table
REFERENCES: 1) Development and Manufacture of Protein Pharmaceuticals (Pharmaceutical Biotechnology) by Steve L. Nail (Editor) and Michael J. Akers (Kluwer Academic / Plenum Publishers) 2) Sterile Drug Products - Formulation, Packaging, Manufacturing, and Quality, Michael J. Akers (Informa Healthcare) 3) The Development of Injectable Bioproducts: The Perfect Three-Step Waltz, Maxime Laugier, Life Science Leaders, 2010
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DEVELOPMENT
Formulation Development Characterization Studies GMP Lyophilization Services Analytical Methods
SUPPORT ACTIVITIES
Microbiological controls Analytical controls 100% visual inspection Stability studies (ICH guidelines)
MANUFACTURING
Process Development & Scale Up Pre-clinical & Clinical Batches Media Fill Testing Cross Contamination Management
GMP COMPLIANT
Successfully Inspected by - Health Authorities - Pharmaceutical Companies 340 batches Produced since 2000
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