Biopharmaceutics & Drug

Product Quality & clinical

efficacy

Uttam Budhathoki, PhD, PDF

Associate Professor
Department of Pharmacy
Kathmandu University
Biopharmaceutics???
Risks of medicines
 Side effects from the use of drugs are the major cause of drug-
related injuries, adverse events, and deaths.
 Side effects are observed in clinical trials or postmarketing

surveillance.
 Some side effects are avoidable, and others are unavoidable.
 Avoidable side effects:

◦ drug–drug or drug–food interactions,

◦ Contraindications,
◦ improper compliance, etc.
◦ Medication errors: wrong drug, wrong dose, incorrect administration
 Unavoidable side effects:
◦ Nausea from antibiotics
◦ Bone marrow suppression from chemotherapy
◦ Unexpected adverse events, long term therapy, unstudied population & (1
in 10,000 population not identified in premarket testing)
Risks of medicines (Adverse events)
Conventional Approach

LEARN
SPECIFICATION
Current Approach
Drug product quality only
Pharmaceutical Development
 The pharmaceutical development process must
design a quality drug product, using a
manufacturing process that provides consistent
drug product performance and achieves the desired
therapeutic objective.
 The product development program is based on a
sound understanding of the mechanistic activity of
the drug substance and its optimal delivery to
achieve the desired therapeutic outcome.
 The integration of biopharmaceutics and QbD
optimizes drug product development and
performance
Biopharmaceutics risk assessment roadmap as a
connecting and translational tool for improving and
enhancing product quality. (From
 Pharmaceutical Development
 This manufacturing process is carefully designed using scientific
principles throughout and integrating assurance of product quality
into the design of the manufacturing process (quality assurance).
 Information gained from pharmaceutical development studies and
from the manufacturing process provides scientific understanding
to support the establishment of the design space.
 specifications, and manufacturing controls that ensure that each
batch of the drug product will be produced with the same quality
and performance.
 Every step that affects drug manufacture must also be tested to
demonstrate that the desired physical and functional outcomes are
achieved (process validation).
 Every single lot produced by this method must meet the desired
specifications (quality control).
Quality Risk in Drug Product
 Various risks related to drug product quality
and performance can impact patient
medication.
 Quality risks are occasionally very serious.
 Mostly, quality risks compromise the

intended effect of medicine or produce

unintended adverse reactions
 BioRAM uses biopharmaceutic tools to

identify and address potential challenges to

optimize the drug product for patient benefit
Biopharmaceutics risk assessment
roadmap (BioRAM)
 As stated by Selen et al (2014),
“Understanding the mode of action of a drug
substance and its optimal delivery for
generating the desired therapeutic effect is
the central tenet of BioRAM.
 Based on mechanistic knowledge gained

about the drug substance and how it elicits

the intended response,
 BioRAM can help to select the optimal drug.”
biopharmaceutics risk assessment roadmap (BioRAM)
Examples of Quality Risk
1. Imported drugs: Quality of API,
2. Development pharmaceutics:selecting
appropriate excipients, the API source, and
the fabricating development concept to the
drug product.
3. Drug development risks:A risk in QbD may be
easily overlooked with an inadequate quality
strategy. For example, a tablet may be friable
and soft due to poor formulation or the tablet
blend may be excessively compressed.
Some Molecular Organic Complexes of Pharmaceutical Interest*

Compounds That Form Complexes with the Agent Listed in the First Column Agent

m-Hydroxybenzoic acid, p-hydroxybenzoic acid, salicylic acid,o-phthalic acid,

acetylsalicylic acid, resorcinol, catechol, phenol, phenobarbital, iodine (in I 2 · KI Polyethylene glycols
solutions), bromine (in presence of HBr)

Benzoic acid, m-hydroxybenzoic acid, p-hydroxybenzoic acid, salicylic acid, sodium

salicylate,p-aminobenzoic acid, mandelic acid, sulfathiazole, chloramphenicol, Povidone (polyvinyl-pyrrolidone, PVP)
phenobarbital

Quinine, benadryl, procaine, pyribenzamine Sodium carboxymethylcellulose

N-Methylpyrrolidone,N,N-dimethylacetamide, γ-valerolactone, γ-butyrolactone,

sodium p-aminobenzoate, sodium salicylate, sodium p-hydroxybenzoate, sodium Oxytetracycline and tetracycline
saccharin, caffeine

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Examples of Quality Risk
4. Method of preparation risks: Preparation
broadly describes synthesis, manufacturing,
and packaging steps.
5. Control of starting materials in API
synthesis:Sources of impurities such as heavy
metals, solvents, and impurities are risks that
may impact quality in subsequent steps in
unknown ways.
6. Control tests on the finished product:stability,
dissolution, and other special product tests.
Quality (by) Design (QbD)
 is a systematic, scientific, risk-based, holistic,
and proactive approach to pharmaceutical
development that begins with predefined
objectives and emphasizes the understanding
of product and processes and process
control.
FRAMEWORK OF QbD
Quality target product profile (QTPP)
 a prospective summary of the quality
characteristics of a drug product that ideally
will be achieved to ensure the desired quality,
taking into account safety and efficacy of the
drug product. As part of the quality system,
the concept QTPP was introduced in QbD.

 QTPP helps to maintain the quality

throughout the life cycle of the product.
 Integrated approach for safety &
clinical efficacy

 Quality target product profile (QTPP)-driven

specifications
 BioRAM
 Advancing and leveraging science and technology

including mechanistic understanding, in silico

tools, statistical evaluations
 Knowledge sharing and collaborations based on

multidimensional collaborations and shared

database.
 CQA
 a physical, chemical, biological, or
microbiological property or characteristic that
needs to be controlled (directly or indirectly) to
ensure product quality.
 The CQAs should be based on clinical relevance.
 the manufacturer of the drug product designs

and develops the formulations and

manufacturing processes to ensure a predefined
quality.
 critical manufacturing attributes
(CMAs)
 critical process parameters (CPPs), and
sources of variability that ensure the quality
of the finished dosage form.
 Design Space
 defined for critical processing variables and
formulation variables that impact in vivo product
performance.
Characteristics of Space Design

 The multidimensional combination and interaction of input

variables (eg, material attributes) and process parameters
that have been demonstrated to provide assurance of
quality.

 Working within the design space is not considered a change.

Movement out of the design space is considered to be a
change and would normally initiate a regulatory
postapproval change process.

 Design space is proposed by the applicant and is subject to

regulatory assessment and approval.
Process Analytical Technology (PAT)
 Like design space, process analytical technology
(PAT) also uses critical processes and materials to
improve the quality of the product
 But, in PAT the emphasis is on monitoring these

variables in a timely manner.

 PAT is intended to support innovation and

efficiency in pharmaceutical development,

manufacturing and quality assurance.
 PAT assesses mitigating risks related to poor

product and process quality, and then monitors

and controls them.
 PAT characteristics

 Product quality and performance are ensured

through the design of effective and efficient
manufacturing processes.

 Product and process specifications are based on

a mechanistic understanding of how formulation
and process factors affect product performance.

 Continuous real-time quality assurance.

 PAT characteristics

 Relevant regulatory policies and procedures are

tailored to accommodate the most current level of
scientific knowledge.

 Risk-based regulatory approaches recognize:

◦ The scientific understanding of how formulation and
manufacturing process factors affect product quality
and performance.
◦ The capability of process control strategies to prevent
or mitigate the risk of producing a poor quality
product.
 PAT
 PAT enhances manufacturing efficiencies by
improving the manufacturing process,
through scientific innovation and with better
communication between manufacturers and
the regulatory agencies.
 PAT may be considered a part of the overall

QbD such that quality is built into the product

during manufacture.
EXCIPIENT EFFECT ON DRUG PRODUCT
PERFORMANCE
 Each excipient must be evaluated to maintain
consistent performance of the drug product
throughout the product’s life cycle.
Common Excipients for Solid Oral Dosage Forms &
possible impacts
RISK ASSESSMENT
 RISK ASSESSMENT
 one‐off activity that utilizes an appropriate
tool to capture perceived risks to a process or
procedure and then with appropriate
expertise to determine options to control or
mitigate the risk.
Medicinal product development flow
chart
RISK ASSESSMENT TOOLS
1. FLOW CHARTS,PROCESS MAPPING
2. FISH-BONE DIAGRAM
3. FAILURE MODE EFFECT ANALYSIS [FMEA]
4. HAZARD ANALYSIS & CRITICAL CONTROL
POINTS [HACCP]
1. FLOW CHART
WALK AROUND
OBSERVE

ENGAGE
INCIDENTS
RECORD
2. Ishikawa/ fishbone/cause-effect
diagram
3. FAILURE MODE EFFECT ANALYSIS [FMEA]
Risk Probability level
Severity level
Risk Category
 4.HACCP
Priliminary tasks of HCCP plan
4.
1. Hazard analysis
 Purpose to develop list of hazards
 Conducted by asking question?
2.CCP DECISION TREE
3.Establish critical limits
4. Establish monitoring system
 Continuous preferred if possible.
5. Establish corrective action
 (a) determine and correct the cause of non-
compliance;
 (b) determine the disposition of non-

compliant product
 (c) record the corrective actions that have

been taken.
6. Establish verification procedures
 Verification is defined as those activities,
other than monitoring, that determine the
validity of the HACCP plan and that the
system is operating according to the plan.
7. Establish record-keeping and
documentation procedures
Quality Risk Management[QRM]
 is a systematic and methodical approach to
developing an understanding of the variability
of a process or procedure, including all
associated hazards and failure modes, and
implementing means of controlling or
eradicating the risk in a given process or
procedure.
 to control and mitigate harm to the

consumer.
 Risk to axcceptable range
 ALARA stands for “As low as reasonably
achievable”