Pharmaceutical Aspects of Fractionation Lecture 2024 PDF

PHARMACEUTICAL ASPECTS Quality and Safety Trisha Chetty, M.Clin.Pharm, MBA, Responsible Pharmacist UKZN 4th Year Pharmacy Students Presentation September 2024 Presentation Outline Fractionation The Quality Cycle of Fractionation Integrated Quality & Safety UKZN 4th Year Pharmacy Student...

PHARMACEUTICAL ASPECTS Quality and Safety Trisha Chetty, M.Clin.Pharm, MBA, Responsible Pharmacist UKZN 4th Year Pharmacy Students Presentation September 2024 Presentation Outline Fractionation The Quality Cycle of Fractionation Integrated Quality & Safety UKZN 4th Year Pharmacy Students Presentation September 2024 History of Plasma-derived Therapy 1918 Influenza pandemic→ Expanded to many Late 1800’s serum from recovered infections (measles, 1940’s-1950’s patients was used to polio, bacterial 1940’s Advanced by Immune animal treat acutely ill infections) Fractionation→ purification of sera → patients first half of 20th Dried plasma albumin replaced antibodies & century with in WWII plasma as volume clotting factors diphtheria & demonstrated clinical expander tetanus Plasma→ substitute for whole blood and benefit for transfusion purposes UKZN 4th Year Pharmacy Students Presentation September 2024 History of Fractionation UKZN 4th Year Pharmacy Students Presentation September 2024 History of Fractionation Dr Edwin J. Cohn studied the nature and structure of proteins Developed foundation principles of cold ethanol fractionation World War II → separation of blood into components Major advances between 1940’s and 1950’s Equipment and procedures are still the basis of current production 1970’s: Kistler and Nitschmann improved the process UKZN 4th Year Pharmacy Students Presentation September 2024  Therapeutic proteins are Solubility extracted and separated Charge according to physical instabilities Affinity under certain conditions Stability according to Alcohol concentration Involves varying the following Temperature parameters to precipitate plasma pH proteins (fractions) Ionic concentration Time of interest using PLASMA FRACTIONATION PRINCIPLES UKZN 4th Year Pharmacy Students Presentation September 2024 UKZN 4th Year Pharmacy Students Presentation September 2024  Pharmacopoeias FDA CFR Council of Europe Regulatory Framework SAHPRA European Law Blood Directive PICS Annex 1 &14 WHO Technical Report EMA Note for Guidance series UKZN 4th Year Pharmacy Students Presentation September 2024 Components of Blood UKZN 4th Year Pharmacy Students Presentation September 2024 Plasma Collection “Recovered Plasma” Donation “Source Plasma” Donation UKZN 4th Year Pharmacy Students Presentation September 2024  South African National Blood Service (SANBS) Western Cape Blood Service (WCBS) Starting Plasma Material Sources for fractionation in SA UKZN 4th Year Pharmacy Students Presentation September 2024  Voluntary non-remunerated Fresh Frozen AND paid donors Plasma from Anti-D, anti-hepatitis Namibia B & anti-rabies plasma Fresh Frozen Plasma from USA Ongoing sourcing of suppliers of Cryoprecipitate for FVIII; quality plasma Fraction V for Albumin materials SAHPRA must approve ALL plasma materials imported into South Africa UKZN 4th Year Pharmacy Students Presentation September 2024  Minimum information required from plasma material suppliers Regulatory framework of blood transfusion/plasma collection centre National standards for blood transfusion/plasma collection Quality Management System Donor selection Blood/Plasma collection Processing & cold chain management Testing Donor epidemiology data for HIV, HBV & HCV and emerging diseases UKZN 4th Year Pharmacy Students Presentation September 2024  Other proteins – C1 esterase 20% inhibitor; fibrinogen; α -1 antitrypsin 15% Immunoglobulins polyvalent & hyperimmune 60% Albumin 1% Coagulation Factors Factor VIII, Factor IX, other factors Examples of therapeutic proteins extracted from human plasma for parenteral use UKZN 4th Year Pharmacy Students Presentation September 2024  All NBI Products are manufactured from Fresh Frozen Plasma (shock frozen to less than -30 0 C, less than 24 hours after donation) UKZN 4th Year Pharmacy Students Presentation September 2024  Plasma transport and receipt by NBI plasma stores from a refrigerated truck UKZN 4th Year Pharmacy Students Presentation September 2024  Plasma Reconciliation UKZN 4th Year Pharmacy Students Presentation September 2024  Raw Material Quarantine UKZN 4th Year Pharmacy Students Presentation September 2024  Artificial Pool testing HIV-1 Anti-HIV 1 and 2 HBV DNA HBsAg HCV RNA Anti-HCV B19 Parvovirus DNA Anti-HAV HAV RNA UKZN 4th Year Pharmacy Students Presentation September 2024  1 Plasma Pool = ± 1,600 recovered or ± 700 source donations Pooling and controlled thawing of ± 450 litres plasma - HIV-1, HBV, HCV , HAV, by NAT - Parvovirus B19 (10kDa will be retained UKZN 4th Year Pharmacy Students Presentation September 2024  Formulation Formulation Filling Addition of caprylate, dextrose 4% Albumin: filled as and NaCl to 4% protein solution 200ml or 400ml doses Addition of caprylate and N- 20% Albumin: filled as Acetyl Tryptophan to 20% either 50ml or 100ml protein solution UKZN 4th Year Pharmacy Students Presentation September 2024  Sterile Filtration UKZN 4th Year Pharmacy Students Presentation September 2024  Filling and Capping Bottle loading Outfeed Capping UKZN 4th Year Pharmacy Students Presentation September 2024  Pasteurization Terminal Pasteurization - Treatment with liquid heat (60 °C) for 10 hours - Inactivates enveloped and non-enveloped viruses. UKZN 4th Year Pharmacy Students Presentation September 2024  2. IVIG Process Dissolution of fraction II paste & Depth Filtration pH 4 / Pepsin Treatment Viral Inactivation Ultrafiltration Formulation and Filling UKZN 4th Year Pharmacy Students Presentation September 2024  Paste Dissolution & Depth Filtration Fraction II paste is dissolved and temperature controlled Supernatant is further clarified and depth filtered using AF9 filter sheets UKZN 4th Year Pharmacy Students Presentation September 2024  pH4 & Viral Inactivation pH 4 / Pepsin Treatment Dilution pH adjustment Pepsin addition Sterile filtration Viral Inactivation Viral Inactivation parameters: pH 4 37 °C 16 hours UKZN 4th Year Pharmacy Students Presentation September 2024  Ultrafiltration TFF system is used as a protein concentration step to achieve a final protein concentration of 6-8% NBI uses 100kDa NMWL UF/DF membranes in the IVIG process – protein molecules >100kDa will be retained Immunoglobulins - 156kDa UKZN 4th Year Pharmacy Students Presentation September 2024  Formulation and Filling Formulation Filling Addition of sucrose IVIG can be filled in 4 for protein stability different dosage Final dosage forms: formulation o 1g o 3g o 6g o 12g UKZN 4th Year Pharmacy Students Presentation September 2024  3. IMIG Process Dissolution of fraction II paste & Depth Filtration Freeze Drying Powder Formulation & Dissolution Dilution Formulation Filling UKZN 4th Year Pharmacy Students Presentation September 2024  Paste Dissolution & Depth Filtration Fraction II paste is dissolved and temperature controlled Supernatant is further clarified and depth filtered using AF9 filter sheets UKZN 4th Year Pharmacy Students Presentation September 2024  Powder Formulation & Dissolution Freeze Drying Filtered solution bagged in 2.8L aliquots Freeze dried over a period of 72 hours Dried powder – bagged and weighed Powder Formulation and Dissolution Powder is dissolved to achieve a target protein concentration of 16% with addition of glycine to stabilize proteins pH is checked/adjusted Dissolved powder solution (Bulk Liquid) is sterile filtered UKZN 4th Year Pharmacy Students Presentation September 2024  Filling Batch is filled once QC analysis is complete and within specification. Filled IMIG derivatives: o Human Normal immunoglobulin o Rabies immunoglobulin o Varicella Zoster immunoglobulin o Hepatitis B immunoglobulin o Tetanus immunoglobulin o Anti-D immunoglobulin UKZN 4th Year Pharmacy Students Presentation September 2024  4. Bioplasma Process Plasma Pooling, Control Thawing 1st Filtration / SD Addition Viral Inactivation / Phase separation 2nd Filtration / Column Application Filling UKZN 4th Year Pharmacy Students Presentation September 2024  4. Bioplasma Process Plasma Pooling and Control Thawing Starting plasma is temperature controlled Pooled plasma is controlled thawed and gently heated for the suspension of coagulants Addition of phosphate buffer Addition of glycine as a stabilizer 1st Filtration and SD Treatment Plasma is passed through a clarification filter Volume of filtered plasma is determined to calculate the quantity of SD (TnBP and Triton X-100) required SD is added and the pH is checked/adjusted UKZN 4th Year Pharmacy Students Presentation September 2024  4. Bioplasma Process Viral Inactivation / Phase Separation Viral inactivation at 30ᵒC for 4 hours Addition of castor oil - aids in removal of TnBP Decantation– separation of the plasma from the oil 2nd Filtration / Column Application The bottom plasma layer is passed through a 0.2µm filter Filtered plasma is passed through the C-18 chromatography column for the removal of Triton X-100 Bioplasma fill dose is either 50ml or 200ml UKZN 4th Year Pharmacy Students Presentation September 2024  Final Filtration UKZN 4th Year Pharmacy Students Presentation September 2024  Filling and Freeze Drying Tubing to filling needles Tube connection to pump Loading of freeze dryer UKZN 4th Year Pharmacy Students Presentation September 2024  Integrated Viral Safety Approach UKZN 4th Year Pharmacy Students Presentation September 2024  Integrated Safety Approach Population High (Schematic) Donor Selection Relative Risk Donation Screening (Serology) Inventory Management Donation Screening (NAT) Plasma Pool Testing Manufacturing of Plasma Derivatives Purification (virus removal) Very Low Virus Inactivation Step PROCESSING UKZN 4th Year Pharmacy Students Presentation September 2024 Quality Assurance An overall management plan to guarantee the integrity of data (“system”) and inspire confidence Wide-ranging concept covers all matters that individually or collectively influence the quality of a product totality of the arrangements to ensure that the drug is of the right quality for the intended use UKZN 4th Year Pharmacy Students Presentation September 2024 Quality Control System Validated analytical methods and equipment Specifications (SPCs) for Quality policy and standards each material Validated procedures (SOPs) UKZN 4th Year Pharmacy Students Presentation September 2024  Quality Control System In-process testing Final product SQE, in part, Raw materials testing confirmed by QC testing In-process samples analysis as an Certificate of Inactive raw API’s and analysis for all integral part of intermediate cGMP materials products products Active raw materials Other releases e.g. pack release UKZN 4th Year Pharmacy Students Presentation September 2024 Good Manufacturing Practice Aims: Ensure accurate and controlled implementation of viral inactivation and elimination treatments Avoid cross or down-stream contamination Medical testing of personnel Environmental monitoring Segregation of areas Flow of materials Flow of people Quality assurance Process Validation UKZN 4th Year Pharmacy Students Presentation September 2024 GMP System Clearly defined and systematically reviewed processes Critical steps validated Appropriate resources: personnel, buildings, equipment, materials Clearly written procedures & trained operators Complete records, failure investigations Proper storage and distribution Recall system & Complaint handling UKZN 4th Year Pharmacy Students Presentation September 2024 Sterile Manufacturing Minimizing risks of contamination microbiological particulate matter pyrogen Considerations Premises Equipment Personnel Environment Processing Finished product UKZN 4th Year Pharmacy Students Presentation September 2024 QA Assurance & Final Product Release Review of all manufacturing documentation Review of any incidents or deviations during the process Review of test results Panel consisting of QA, Responsible Pharmacist, Head: Manufacturing Release or reject product UKZN 4th Year Pharmacy Students Presentation September 2024 Summary Combined elements of product safety from donor to end user Methods of plasma processing to preserve therapeutic proteins Measures taken to minimize contamination of starting material Enhancement of safety by viral inactivation methods Testing of samples throughout manufacturing process for compliance QA audit of process documents and test results before product release Adverse event, product complaint monitoring and management UKZN 4th Year Pharmacy Students Presentation September 2024 Summary Viral safety Quality Donor testing HIV 1, 2 QC HCV QA (cGLP) HBV Plasma pool testing Cold ethanol fractionation cGMP pH 4 Pharmacovigilance UKZN 4th Year Pharmacy Students Presentation September 2024  Thank You and Questions? UKZN 4th Year Pharmacy Students Presentation September 2024