quality and stability of drugs and medicines

Intended learning outcomes:<ul><li>To learn various factors affecting stability of drugs and medicines and importance of quality assurance in safeguarding against risks</li><li>To understand nature of degradation of API and how stabilisers and storage conditions help minimise some of the concerns</li><li>To introduce likely instability issues with protein/peptide drugs</li><li>To learn how shelf-life of a drug is estimated and why it would differ by climate zones</li></ul> Quality assurance if formulated products:<ul><li>Standards are enforces by MHRA (guidance for manufactures and distributors on human medicines and active substances) and BP</li></ul> QA, GMP, QC:<ul><li>Quality assurance is a wide range concept covering all matters that influence the quality of a product</li><li>Good manufacturing practice ensures that products are produced and controlled to meet appropriate quality standards</li><li>Quality control is a process dedicated to sample, test and specify materials at each level of manufacturing, determining if they met the requirements</li></ul> GMP:<ul><li>that part of quality assurance which ensures that products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by the marketing authorization.</li><li>aimed primarily at diminishing the risks inherent in any pharmaceutical production</li><li>All manufacturing processes should be clearly defined and known to be capable of achieving the desired ends.</li></ul> QC:<ul><li>QC is part of GMP and carries out sampling, testing and checks</li><li>carry out examination and testing of starting materials, packaging materials and intermediate and finished product testing.</li><li>Before product release, the QC department take into account the analytical results as well as other essential information such as production conditions, in-process controls, manufacturing documents and conformity of the product to their specification (including the final finished pack).</li><li>Sample of each batch of finished product shall be retained for at least one year after the expiry date.</li></ul> Need for documentation:<ul><li>Extensive documentation needs to be maintained as critical part of quality assurance.</li><li>Records are made during manufacture which demonstrate that all the steps required by the defined procedure were in fact taken</li><li>Records of manufacture and distribution should enable the complete history of a batch to be traced, and retained in a legible and accessible form</li></ul> Standard quality requirements:<ul><li>Identity: existence of API(s) indicated on the label;</li><li>Purity: no harmful contaminants, no cross-contamination;</li><li>Strength or potency: API(s) content range [90-110], ensuring long shelf life;</li><li>Uniformity of the dosage form in: consistency, colour, shape, size of tablets/capsules, etc.;</li><li>Bioavailability: speed and completeness with which the pharmaceutical enter the bloodstream;</li><li>Stability: the medicine should retain its properties until the expiration date.</li></ul> Role of pharmacist:<ul><li>Delivery of safe & effective medicines to patients.</li><li>Increasingly being asked to make decisions on stability of drugs. Knowledge on stability of drugs goes beyond just drug formulation and industry</li></ul> Pre formulation assessment:<ul><li>Assessment is to evaluate:<ul><li>Susceptibility to hydrolysis, oxidation, light degradation and other common chemical degradation reactions.</li><li>Identify and minimize drug excipient interactions.</li><li> Reaction mechanism and kinetics.</li><li>Shelf life by accelerated stability testing (stress testing)</li></ul></li></ul> Shelf life:<ul><li>length of time during which a pharmaceutical product retains acceptable chemical, physical and microbiological stability so that the product remains fit for its intended purpose.</li></ul><img alt="Main factors affecting stability Factor pH Temperature Humidity Light Dosage form Oxygen Metal ions General consideration Acid & base catalysis tends to raise chemical degradation. Extreme pH changes change can induce epimerisation. Many (not all) drugs are stable between pH 4 and 8. High temperature accelerate oxidation, reduction and hydrolysis reaction Promotes, hydrolysis and oxidation/reduction reactions as well encouraging microbial growth Photons provide energy leading to radical formation, oxidation & polymerization reactions. Photolysis of covalent bonds can occur. Solid usually more stable than liquid dosage forms Promotes autoxidation Promote oxidation This means expiry is likely to change after opening the package 14 " src="https://knowt-user-attachments.s3.amazonaws.com/e78873c0-57c2-49f7-b210-c6dde2e17298.png" /> Causes of chemical instability:<ul><li>Hydrolysis</li><li>Oxidation</li><li>Dimerization and polymerization<ul><li>Reaction of a drug molecule with another molecule of the same drug may result in the formation of a dimer or a polymer.</li></ul></li><li>Isomeric change<ul><li>Isomeric change may affect pharmacological or toxicological activity</li></ul></li><li>Photodegradation<ul><li>Natural sunlight (wavelength range 290-780nm) cause photodegradation of drug through its highest energy range (290-320nm).</li><li> Light-induced degradation is called photolysis</li></ul></li></ul><img alt="Susceptible amino acids Oxidation CH3 —coo- Cysteine (CYS, C)

H3N Deamidation o NH2 CH2 o sczNH2 CH2 +H3N SH CH2 coo- Disulfide bond (cross links) +H3N —coo- +H3N —coo- Asparagine (Asn, N) Methionine (Met, M) Methionine s OXI e Glutamine (Gin, Q) Lead to their respective acids 27 " src="https://knowt-user-attachments.s3.amazonaws.com/91d1c66b-057a-4d5f-953f-614238250fcc.png" />