Biopharmaceutical Engineering ERT 4 20/2 Pn. Khadijah Hanim bt. Abdul Rahman 21/12/2010

Biopharmaceutical Engineering Course Code ERT 4 20/2 Learning outcome – Ability to explain the basic concept of drug absorption and disposition, and evaluate related pharmacokinetics. – Ability to design and demonstrate biopharmaceutical production facilities. – Ability to formulate and evaluate the biopharmaceutical engineering processes in biopharmaceutical formulation and production.

Evaluation – Final examination: 70% Mid Term Examinations (10% x 2) = 20% Final Examination = 50% – Kerja kursus/Course work : 30% Assignments /Quizzes/Tests

Lecturers: Pn. Khadijah Hanim bt. Abdul Rahman Dr. Muhammad Syarhabil B. Ahmad

Text Book – B. Bennett and G. Cole. Pharmaceutical Production, An Engineering Guide. Institution of Chemical Engineers (IChem E ) 2003 Reference Books: – M. E. Aulton, Pharmaceutics. The science of dosage form design. - 2 nd ed. Churchill-Livingstone, London – L. Shargel, S. Wu-Pong & A.B.C. Yu. Applied Biopharmaceutics & Pharmacokinetics. McGraw Hill – D. M. Collett, M. E. Aulton. Pharmaceutical Practice – Crommelin, D.J.A., & Sindelar, R.D. (2002). Pharmaceutical Biotechnology. An Introduction for Pharmacist and Pharmaceutical Scientist. (2 nd ed). London: Taylor and Francis.

Introduction to Biopharmaceuticals

Pharmaceutical Engineer – The engineers involve in the manufacture of the active ingredient (primary manufacture) – and its dosage form (secondary manufacture)

Biopharmaceutics Pharmaceutics defined as a field of science that involves the preparation, use or dispensing of medicines. Bio from greek bios related to living orgnism or tissues. Biopharmaceutics is the interdependance of living organism (the patient) and the physical and chemical principles that govern the preparation and behavior of the medicinal agent or drug products.

Biopharmaceutics Examines the interrelationship of the physicochemical properties of the drug, the dosage form and the route of administration on the rate and extent of systemic drug absorption Biopharmaceutics involves factors that influence: -Stability of drug within drug product -The release of the drug from the drug product -The rate of dissolution/release of the drug at absorption site -Systemic absorption of the drug

Physical Pharmacy: Physical-Chemical Principles Physical pharmacy is a term that came into common use in the pharmacy community in the mid-twentieth century, and the field has grown and evolved over the years. Physical pharmacy is a collection of basic chemistry concepts that are firmly rooted in thermodynamics and chemical kinetics.

Physical Pharmacy: Physical-Chemical Principles Solubility – Solubility is one of the most critical and commonly studied physical—chemical attributes of drug candidates. – Solubility is a thermodynamic parameter that defines the amount of material that can dissolve in a given solvent at equilibrium. – The amount of drug in solution as a function of time prior to reaching equilibrium is often referred to as the "kinetic solubility," which can be exploited in pharmaceutical applications to manipulate drug delivery. – A compound's solubility impacts its usefulness as a medicinal agent and also influences how a compound is formulated, administered, and absorbed.

Physical Pharmacy: Physical-Chemical Principles Stability – The chemical stability of a drug is important in order to avoid generation of undesirable impurities, which could have pharmacologic activity and/or toxicologic implications, in the drug substance or drug product. – Chemical stability of the API in a dosage form influences shelf-life and storage conditions of drug products to minimize generation of undesirable impurities.

Physical Pharmacy: Physical-Chemical Principles The pH-stability profile is also important- plot of the reaction rate constant for drug degradation versus pH. Drug decomposition occurs by acid or base catalysis- prediction of degradation of drug in the GI tract may be made. Eg: erythromycin (has pH-dependent stability profile) -Acidic medium (stomach), decomposition- rapidly -Neutral/alkaline pH (intestine), relatively stable -Therefore, erythromycin tablets are enteric coated- protect against degradation in stomach.

Physical Pharmacy: Physical-Chemical Principles Salt Forms and Polymorphs – Drug substances can often exist in multiple solid- state forms, including salts (for ionizable compounds only), solvates, hydrates, polymorphs, co-crystals or amorphous materials. – The solid form of the compound affects the solid- state properties including solubility, dissolution rate, stability, and hygroscopicity, and can also impact drug product manufacturability and clinical performance

Physical Pharmacy: Physical-Chemical Principles – For example, salts can be chosen to impart greater solubility to improve dissolution rate of an Active Pharmaceutical Ingredient (API). – Polymorphs (arrangement of a drug substance in various crystal forms)and solvated (form that contain a solvent) forms of drug candidates can also affect not only the stability and manufacturability of a drug substance but also potentially impact biopharmaceutical performance due to their differing solubility

Physical Pharmacy: Physical-Chemical Principles Particle and Powder Properties – Bulk properties of a pharmaceutical powder include particle size, density, flow, wettability, and surface area. – Some are important from the perspective of a manufacturing process (e.g, density and flow) – Others could potentially impact drug product dissolution rate (particle size, wettability and surface area) without changing equilibrium solubility.

Physical Pharmacy: Physical-Chemical Principles Ionization and pKa – The ionization constant is a fundamental property of the chemical compound that influences all of the physical–chemical properties discussed above. – The presence of an ionizable group (within the physiologically relevant pH range) leads to pH- solubility effects, which can be used to manipulate the physical properties and biological behavior of a drug.

Physical Pharmacy: Physical-Chemical Principles – For an ionizable compound, the aqueous solubility of the ionized species is typically higher than the unionized due to the greater polarity afforded by the presence of the ionized functional group. – The ionizable functional group and the magnitude of the pKa determine whether a compound is ionized across the physiological pH range, or if conversion between ionized/nonionized species occurs in the GI tract, and if so, which region.

Formulation Principle The goal of a formulation scientist is to manipulate the properties and environment of the API to optimize its delivery to the target tissue by a specific route of administration and to do so in a manner compatible with large-scale product manufacture The formulation is key to a compound's biopharmaceutical profile since the composition, dosage form type, manufacturing process, and delivery route are intimately linked to pharmacokinetic results.

Formulation Principle Excipients are added to – solubilize, stabilize, modify dissolution rate, – improve ease of administration (e.g., swallowing or taste-masking), – enable manufacturing (e.g., ensure sufficient compactibility to make tablets, – improve powder flow in a manufacturing line), – control release rate (immediate vs. prolonged vs. enteric), – or inhibit precipitation

Physiological/Biological Principles Pharmacokinetics -Describes- the body affects a specific drug after administration -The study of: 1.Mechanisms of absorption and distribution of administered drug 2.Rate- drug action begins and duration effects 3.Effects and routes of excretion of the drug metabolites - Divided into 4 areas: Adsorption, distribution, metabolism and elimination (ADME)

Physiological/Biological Principles Absorption: – In most cases, a drug must be absorbed across a biological membrane in order to reach the general circulation and/or elicit a pharmacologic response. – Even drugs that are dosed intravenously may need to cross the vascular endothelium to reach the target tissue or distribute into blood cells. – Often multiple membranes are encountered as a drug traverses the absorptive layer and diffuses into the blood stream.

Physiological/Biological Principles Absorption: – Transport across these membranes is a complex process, impacted by ionization equilibria, partitioning into and diffusion across a lipophilic membrane and potential interaction with transporter systems (influx and/or efflux). – The concepts of permeability, absorption, and bioavailability (BA) are sometimes used interchangeably, while in fact each represents a different aspect related to membrane transport. Permeability refers to the ability of a compound to cross a membrane. This drug is absorbed, yet it is not bioavailable

Physiological/Biological Principles Distribution: – Distribution is a measure of the relative concentrations of a drug in different body tissues as a function of time and is related to its ability to diffuse from the blood stream, tissue perfusion, relative lipophilicity, and tissue/plasma protein binding. The apparent volume of distribution (V d ) is reflective of the extent of tissue distribution.

Physiological/Biological Principles Metabolism and Elimination: – Metabolism is one of the most important mechanisms that the body has for detoxifying and eliminating drugs and other foreign substances. Drugs delivered by the oral route must pass through the liver before reaching the general circulation. – Oxidation, reduction, hydrolysis, and conjugation are the most common metabolic pathways, generally leading to more hydrophilic compounds that can be readily excreted renally.

Physiological/Biological Principles Metabolism and Elimination: – Elimination of drugs from the body can occur via metabolism, excretion (renal, biliary, respiratory), or a combination of both mechanisms.

Strategies to Achieve Target Pharmacokinetic Profile Although many biopharmaceutical properties are determined by the chemical structure of the compound, there are multiple strategies available for exploiting the properties of any given molecule to try to achieve the desired clinical behavior. The choice of paths to explore is dependent on the nature and extent of the delivery issue to be solved. For example, if poor BA is caused by high first-pass metabolism, delivery via a non-oral route may yield sufficient blood levels for activity.

Strategies to Achieve Target Pharmacokinetic Profile are: – Route of Delivery – Chemical Modification – Strategies for Improved Oral Adsorption – Immediate or Modified Release

Biopharmaceutic considerations in drug product design 1.Biopharmaceutic consideration Most important in designing a drug product: safety and efficacy Drug product: effectively deliver the active drug at appropriate rate and amount at target receptor site. Should not produce any side effects due to the drug/excipient. Ideally, all excipients should be inactive ingredients alone or in final dosage form.

Biopharmaceutic considerations in drug product design 2. Drug considerations The physicochemical properties- major factors that controlled/modified by formulator Physicochemical properties- influence the dosage form and manufacturing processes Physical properties- dissolution, particle size, crystalline form- influenced by processing and manufacturing methods E.g: If a drug has low aqueous solubility, intravenous injection needed= a soluble salt of drug may be prepared

Biopharmaceutic consideration in drug product design 3. Drug Product Considerations (i)Pharmacokinetics of the drug Pharmacokinetic profile: to estimate appropriate dose of drug and release rate It determines the desired drug conc. that will be effective

Biopharmaceutic consideration in drug product design (ii) Bioavailability of the drug Bioavailability defined as the fraction of administered dose of unchanged drug that reaches the systemic circulation. Stability of drug in GI- some drugs is unstable in acidic condition. Poor bioavailability because of first-pass metabolism in GI/ liver- higher dose may be needed.

Biopharmaceutic consideration in drug product design 4. Patient considerations (i)Route of drug administration Affects the BA of the drug Factors that need to be considered by manufacturer in designing drug dosage: -Route of administration -Size of the dose -Anatomic and physiologic characteristics i.e. membrane permeability and blood flow -Physicochemical properties of the site i.e. pH, osmotic pressure -Interaction of the drug and dosage form at administration site

Role of Biopharmaceutics in Drug Development 1. Importance of Biopharmaceutics in the Overall Development Process: Biopharmaceutics is an integral component of the overall development cycle of a drug. Evaluation begins during the drug discovery process, proceeds through – compound selection, – preclinical efficacy and safety testing, – formulation development, – clinical efficacy studies, – and postapproval stages.

At each stage, biopharmaceutical scientists interface with colleagues in multiple disciplines including – discovery chemistry and biology, – drug safety assessment, – clinical development, – pharmaceutical development, – regulatory affairs, – marketing, – and manufacturing.

2. Discovery and Preclinical Development: Candidate Selection: – The preclinical development stage encompasses aspects of both drug discovery and drug development. – The process to identify a potential drug candidate is an iterative one, as discovery scientists strive to synthesize candidate compounds with appropriate activity and maximal potency at the intended target, maximal safety profile, and desirable ADME properties.

3. Preclinical Development: Preparation for Phase I Clinical Studies: – Once a drug candidate is chosen for clinical development, additional biopharmaceutical assessment is conducted to build on existing knowledge and experience. – A clinical candidate must be tested in formal animal safety studies in multiple species in order to establish a safety profile and provide guidance on the choice of clinical doses.

4. Early Clinical Development – The primary goals in early clinical development are to establish safety, PK, and pharmacodynamics, and also to provide guidance on a dose range expected to be efficacious, in both single-dose and multiple-dose studies. – pharmacokinetic comparison, the plasma concentration data are used to assess key pharmacokinetic parameters. area under the curve (AUC), peak concentration (C max ), time to peak concentration (T max ) and half-life.

5. Advanced Clinical Development: As a compound moves from Phase I into Phase II and eventually into Phase III, the objectives of the clinical development program evolve from primarily safety and PK to safety and efficacy. The data collected during earlier studies are used to – define a potentially efficacious clinical dose range and dosing regimen, – identify any special patient populations, – and guide selection of a drug product to be used in pivotal registrational clinical studies.

6. Postapproval Considerations As a product proceeds through the registrational process and into commercial manufacturing, additional considerations with respect to biopharmaceutics arise. A product approval is based on the evidence that a drug is safe and effective when administered according to the product labeling. Upon review of a product insert or other reference literature, the reader would find an extensive discussion of the properties of the drug product, including details on the ingredients, dosage form, available strengths, and pharmacokinetic properties, in addition to indications and dosing information.

6. Regulatory Considerations: Across the globe, numerous regulatory bodies are responsible for assuring safety, quality, and efficacy of medicinal products.