Formulation Of Biologics PDF

Formulation of biologics This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 101007939. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and...

Formulation of biologics This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 101007939. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA companies.  What to achieve with formulation Safety and efficacy – Correct dose – Safety and stability of the pharmaceutical – Correct pharmacokinetics Patient conveniency and compliance – Pain – Intrusion in daily life Convenience for Healthcare system – Safe handling at hospitals To live a full life - not only to survive – Shelf-life – Self medication Risks related to Infection Adverse reactions injections – allergy – endotoxin – particles – ADA Bleeding and bruising Damage to nerves or blood vessels, The potential for accidental intravascular injection Det här fotot av Okänd författare licensieras enligt CC BY-SA- NC  Anti-Drug Antibody (ADA) Unwanted immune response of the host against the therapeutic protein Two types of ADA non-neutralizing ADA neutralizing ADA This Photo by Unknown Author is licensed under CC BY Anti-Drug Antibody (ADA) Unwanted immune response of the host against the therapeutic protein Two types of ADA non-neutralizing ADA neutralizing ADA Can lead to; Loss of activity Changes in pharmacokinetics- faster clearance Det här fotot av Okänd författare licensieras enligt CC BY Immunological reactions to infusion Immunity against endogenous proteins Chemical stability General issues effecting degradation Key degradation mechanisms Temperature Deamidation and Isomerization Proteins structure Oxidation – Primary sequence Hydrolytic fragmentation – Tertiary and quaternary structure Racemization and β-Elimination pH Mailard reactions Choice of buffer and ionic strength Presence of contaminants from excipients and production - for example catalytic metals and ROS Light and air (oxygen) Heat and cold Proteins can denature/change structure both at high and low temperatures Ice formation can change composition of the drug product Dropping a product can cause cavitation and local high temperature Proteins can adsorb to ice crystals Interfaces, Shake Induction of aggregation through contact with interfaces and flow – Air bubbles – Silicon oil Extensional flow aggregation Dilution Change in composition of formulation – pH – Ionic strength – Concentration of surfactant Example Trastuzumab – OK to dilute in 0,9% NaCl – Not ok 5% Dextrose How to evaluate structural stability 60000 UV spectra,fluorimetry and Circular dichroism c spectra 30000 Size – Rheology 0 450 250 350 450 – Light scatter, DLS m) Wavelength (nm) – AUC – SEC and FFF Changes in the electrophoretic pattern Immunological tests Affinity binding DSC and DSF Det här fotot av Okänd författare licensieras enligt CC BY-SA-NC NMR  Key things to know when formulating a biological drug Things to know Wanted pharmacokinetic profile Stability and compatibility of the active substance Known risks to patients Decisions to make Route of delivery Type of formulation Choice of excipients Choice of primary packing or device  All ingridients except the active substance Excipients There to give the pharmaceutical product it’s wanted properies – Physical characteristics – Pharmacokinetics Enhance uptake Controlled release – Stability Only use if necessary Be safe or proven safe Use excipients for injection Det här fotot av Okänd författare licensieras enligt CC BY-NC-ND  Primary packing The packing material in contact with the pharmaceutical formulation material Typical packing materials for injections – Vials – Ampoules – Prefilled syringes – Auto-injectors – IV-bags – Pumps Be aware of extractables – Plasticiser's and monomers from plastics – Alkali from glass Det här fotot av Okänd författare licensieras enligt CC BY Type of formulation Solutions Lyophilized powder Controlled release and targeted delivery  Why Easy to produce and handel Solutions Fast onset Why not Stability issues Patient compliance Excipients Tonicity agents Buffers for pH controll Stabilising agents Surfactants Preservatives Rheology modifiers  Why Lyophilized Stability product Mild drying technology Easy to reconstitute Why not Needs more handeling and more expensive production Patient compliance Excipients Stabilzers similar to solutions Cryoprotectants and Lyoprotectants Diluent  Controlled release The material used must be biocompatible and not trigger formulations immune or blood clotting responses. Dose dumping is of particular concern 1.6E-04 There is often a risk for burst effects. 1.2E-04 The active substance needs to be stable throughout the Blood concentration Sustained release duration of the release. 8.0E-05 4.0E-05 Delayed release 0.0E+00 0. 15. 30. 45. 60. Time (h) Implants and Implants Biodegradable – Can be removed particles – Often composed of non degradable polymer such as polyethylene vinyl acetate Biodegradable particles – Most common PLGA (poly lactic glyco acid) particles – New generations on the way, for example pure protein particles Det här fotot av Okänd författare licensieras enligt CC BY  Fluid when injected Insitu gelling form a gel or solid like structure after injection systems Triggers Heat Ions pH Systems Polymers - Chitosan, PEG-based Lipids- Laminar to Cubic Peptides et här fotot av Okänd författare licensieras enligt CC BY  Modification of the protein Use excipients or drug formulations that Improve uptake –Inhibits or protect from enzymes –Enhance transport over epetheiliel barrier –Prolong the residence time in the intestinal Type of formulations and excipients Nanpoarticles Microparticles tand polymers that open thight junctions- Chitosan Receptor mediated uptake -Transferrin, Det här fotot av Okänd författare licensieras enligt CC BY-SA Cholix Penetration enhancers -Sodium caprate Targeting and To obtain enhanced uptake Higher specificity Uptake to target cells Typical targeting molecules Antibodies Proteins (e.g., lectins, transferrin) Peptides Carbohydrates (e.g., galactose) Det här fotot av Okänd författare licensieras enligt CC BY-NC Lipid nano-formulations for drug delivery Det här fotot av Okänd författare licensieras enligt CC BY  Delivery of polynucleotides as active substance Pharmaceutical challenges Very short half life in the body –Chemical modification –Encapsulation Transport into the cell –Viral vectores –Non viral vectores –Naked DNA Viral vectors Several viruses are employed Adenovirus -50% -Trigger immune response AAV- Adeno associated viruses Retrovirus -25% 2021 - 3 products on the market. 1140 Clinical trials There have been reports of sever effects when viral vectors been used Cancer Immunological responses Only limited amounts of DNA can be used Det här fotot av Okänd författare licensieras enligt CC BY-SA Stability is key for function Chemical Physical Risks related to handling of protein biological drugs in real life This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 101007939. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA companies. Transport with care During transport avoid: The drug product being exposed to the wrong temperatures Too much shaking, vibrations and chock Det här fotot av Okänd författare licensieras enligt CC BY-NC-ND Dropping Do not use transport systems like pneumatic tubing or other systems that induce stress on the product without ensuring that product quality is not impacted Store safe At the right temperature At the right humidity Protected from light If possible in its secondary package Away from products that can harm the product In ways that reduce risk for mix-ups  The pharmaceutical companies must do transport Evaluate validation transport effects – Validation process design – Qualification on product – Continues monitoring To prepare conduct – drop test – Shock and vibration tests – Photostability – temperature and humidity  Mix-ups Critical mistakes – Preparing the wrong drug to avoid during – Use of the wrong diluent – Mixing the wrong concentration preparations Follow safety procedures such as working aseptically Mix in a mild manner Using materials that are compatible with the product Mixing biologics The wrong mixing technique can lead to aggregates Avoid Shaking Flicking Dropping Material and devices used for preparation Proteins might be sensitive to different materials. Risk of aggregates, loss of substance etc when introducing new types of materials – syringes, tubing, or IV-bags – spikes and CSTDs Closed system transfer devices Benefits with CSTDs Protect healthcare workers Some extent of improved aseptic handeling Risks related to CSTDS Aggregation and particle formation Reduction of the dose Protein adsorption … and uses biological drugs Infusion Biologics can be incompatible with some diluents and other drug products If possible, avoid the mixing of biological drugs with other drugs within the same infusion line Avoid direct sunlight when administering Be careful when it comes to compatibility with inline filters Det här fotot av Okänd författare licensieras enligt CC BY-SA-NC