Biologics

• Biologics, also known as biological therapeutics or biologicals, are medicines grown and purified from bacteria or yeasts, encompassing vaccines, growth factors, immune modulators, monoclonal antibodies, stem cells, gene therapies, and more.
• Production and characterisation of biologics is different from small molecules.
• Biologics revolutionised treatment for some life-threatening and rare diseases, mainly for long-term diseases such as rheumatoid arthritis and cancer.
• Stability testing is defined in the ICHQ5C.
• Data must be provided with all container closure systems used in stress studies.
• Shelf life is determined during long term stability, which uses real time/real temperature data.
• Stress studies reveal patterns of degradation.
• Accelerated studies generate help to understand degradation profiles.
• Stress studies represent representative accidental exposures.
• Stability testing differs from other medicines.
• Test conditions in accelerated studies are normally done earlier than real storage conditions.
• Accelerated studies provide information on changes and validate stability tests.
• The complexity and size of biologics make them far more difficult to manufacture than small molecule medicines, contributing to 37% of the drugs market being biologics.
• Biologics are the strongest growth area for companies and are faster to have a new biologics on the market than a new small molecule.
• Traditional chemical agonist/antagonist and the “one drug suits all” blockbuster are mature with higher failure rates in discovery pipelines, drug development, clinical trials and post-marketing approval.
• Biologicals developed by biotech companies are filling gaps of large pharma companies, replacing diseased tissue functionality with protein hormones, blood factors, gene therapy and tissue engineering.
• Insulin was one of the first biologics on the market which revolutionised the pharma market, replacing diseased tissue functionality with protein hormones.
• Biologics have the advantage of being highly specific in modifying or blocking function to target, unlike small molecules which can have unspecific binding to molecular structures other than the molecular target, causing toxicity.
• The purification process takes place in a series of large chromatography columns which contain specialised resins, designed to separate the API from additives and by products.
• The active substance is produced by further modifications of the nutrient media inorder to prompt the cells into generating the desired active pharmaceutical ingredient (API).
• Parameters such as temperature, oxygen, pH and cellular debris is controlled and adapted as the cells grow.
• In phase 4 of the manufacturing process, the active substance, or API, is separated or harvested from the cells and then purified.
• In the final step of the manufacturing process, the drug products are filled into vials in a highly sterile environment.
• On an average a large scale production of a typical antibody can generate about 20 - 50kg of active substance from one upstream of manufacturing batch.
• This phase provides the cells with optimal growth conditions and generates a sufficient number of cells for the subsequent cultivation in a bioreactor.
• Either stored as a frozen liquid or lyophilised as freeze dried powder.
• In phase 2 of the manufacturing process, the cells are multiplied prior to use in a large fermentation vessel, also known as a bioreactor.
• Liquids are stored in syringes and stored under controlled refrigerated conditions.
• Several rounds of expansion are followed using an enriched nutrient solution specially designed to promote growth, which gradually increases the production volume.
• In phase 3 of the manufacturing process, the active substance is produced in a production bioreactor, which is the largest of its kind and can hold a volume of 15000Ltr.
• Blood levels of drug and duration of action in man are not appropriate for small molecular drugs, but are appropriate for therapeutic proteins.
• Biologics have different structures for each indication, unlike small molecular drugs which have similar structures.
• Protein stabilizers are preferentially excluded, lowering interaction with protein but not hydrophobic, leading to a higher concentration of co-solute in bulk than in the solvation shell of the protein, increasing the deltaG unfolding.
• Minimole solubility is 8.
• In order to stabilise the protein, stabilisers are used outside, increasing energy required to unfold the protein.
• Sugars such as sucrose and amino acids are used as lyoprotectants, working by preferential exclusion, lowering cold denaturation and stabilising the sample.
• Reactions and denaturation continue when lyophilised, with refrigeration recommended to reduce aggregation rates.
• Polysorbates 20 and 80 are the most common limiting unfolding.
• Common excipient is NaCl.
• When administered subcutaneously, there is a higher concentration which comes with the disadvantage of the monoclonal antibodies coming into close contact with one another, leading to their unfolding and becoming more viscous.