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 (IChemE)
2003
• Reference Books:
– M. E. Aulton, Pharmaceutics. The science of dosage form design.
- 2nd ed. Churchill-Livingstone, London 2002.
– L. Shargel, S. Wu-Pong & A.B.C. Yu. Applied Biopharmaceutics &
Pharmacokinetics. McGraw Hill. 2005
– D. M. Collett, M. E. Aulton. Pharmaceutical Practice. 1996.
– Crommelin, D.J.A., & Sindelar, R.D. (2002). Pharmaceutical
Biotechnology. An Introduction for Pharmacist and
Pharmaceutical Scientist. (2nd 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 catalysisprediction 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 coatedprotect against degradation in stomach.
Physical Pharmacy: Physical-Chemical
Principles
• Salt Forms and Polymorphs
– Drug substances can often exist in multiple solidstate forms, including salts (for ionizable
compounds only), solvates, hydrates, polymorphs,
co-crystals or amorphous materials.
– The solid form of the compound affects the solidstate 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 pHsolubility 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 (Vd)
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
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(i)
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. Patient considerations
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
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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
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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.
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area under the curve (AUC),
peak concentration (Cmax),
time to peak concentration (Tmax)
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.