DRUG DEVELOPMENT

Dr. Agus Siswanto, S.Si., M.Si., Apt.

Introduction
• Pharmaceutical R&D can be defined as
“converting ideas into candidate drugs for
development”
• Product development as “converting candidate
drugs into products for registration and sale
• The high risk of failure in drug discovery and
development throughout the pharmaceutical
industry statistically shows that, on average,
only 1 in 5000 compounds screened in research
will reach the market
• Most failures in early development are due to
drug toxicity or safety issues, whereas a lack of
efficacy is the primary reason for late-stage
attrition
Drug development
• Product development usually begins when an active
chemical entity has been shown to possess the
necessary attributes for a commercial product
• The product development activities for the active
chemical entity, formulation, and process form the
foundation upon which the subsequent validation
data are built
• Product development activities can be subdivided
into: formulation and process development, along
with scale-up development
A. Formulation Development
• Formulation development provides the basic
information on the active chemical, the formula, and
the impact of raw materials or excipients on the
product
• Typical supportive data generated during these
activities may include the following:
▫ Preformulasi
▫ Formulasi
▫ Efek formulasi thd BA
▫ Metode analisis
▫ Key product spesification
▫ Optimasi formula
Typical supportive data generated during these
activities may include the following:
• 1. Preformulation profile or characterization of
the components of the formula
▫ includes all the basic physical or chemical
information about the active pharmaceutical
ingredients (API, or the chemical entity) and
excipients
▫ Studi pendekatan sifat fisika-kimia
▫ Misal: stabilitas, parameter farmakokinetik
▫ Terkait dengan karakteristik produk yg spesifik,
misal: metode kempa langsung  sifat alir &
kompaktibilitas bahan dlm studi preformulasi
• 2. Formulation profile
▫ consists of physical and chemical characteristics
required for the products, drug-excipient
compatibility studies, and the effect of formulation
on in vitro dissolution
▫ Dari studi preformulasi dapat ditentukan formula:
metode, dosis, peralatan, pengemas shg
didapatkan parameter optimum kualitas produk
• 3. Effect of formulation variables on the
bioavailability of the product
▫ Formulasi hanya bertanggungjawab thd
ketersediaan farmasetik shg perlu dilakukan uji
bioavailabilitas produk
• 4. Specific test methods
• 5. Key product attributes and/or specifications
▫ Misal: Tablet  sifat fisik, kimia, dan disolusi
• 6. Optimum formulation
▫ Formula optimum  karaktereristik produk
maksimum  sulit dicapai krn ada beberapa
parameter yang kontradiktif (Contoh: pengaruh
viskositas thd profil sedimentasi dan daya tuang
suspensi)
• 7. Development of cleaning procedures and test
methods
▫ Jaminan keamanan dan kemanjuran produk
▫ Produk bebas dari kontaminasi dan cross
contamination
• Formulation development should not be
considered complete until all those factors that
could significantly alter the formulation have
been studied.
• Subsequent minor changes to the formulation,
however, may be acceptable, provided they are
thoroughly tested and are shown to have no
adverse effect on product.
B. Process Development
• Even though the process development activities
typically begin after the formulation has been
developed, they may also occur simultaneously
• The majority of the process development
activities occur either in the pilot plant or in the
proposed manufacturing plant
The process development program should meet
the following objectives:
• 1. Develop a suitable process to produce a product
that meets all
▫ a. Product specifications
▫ b. Economic constraints (hambatan ekonomi)
▫ c. Current good manufacturing practices (CGMPs)
• 2. Identify the key process parameters that affect
the product attributes
▫ Contoh1: tablet granulasi basah  parameter:
kelembaban granul  sifat alir & kompaktibilitas
▫ Contoh2: tablet  pencampuran  parameter:
homogenitas  kadar & dosis zat aktif
• 3. Identify in-process specifications and test
methods
▫ Kualitas produk  kontrol kualitas: bahan baku, In Process
Control, final product
▫ Bahan baku: zat aktif & eksipien produk
Proses ??

Spesifikasi mutu tiap proses

(pencampuran  homogenitas)
• 4. Identify generic and/or specific equipment that
may be required
Process development can be divided
into several stages
• Design
• Challenging of critical process parameters
• Verification of the developed process

Typical activities in these areas are illustrated in Figure 2.

• Dalam pengembangan proses, aspek yg perlu
diingat adalah kapabilitas produk shg realitas
dan praktek operasional selama produksi selalu
harus diperhatikan
▫ Skala laboratorium variabel untuk skala
produksi
1. Design
• initial planning stage of process development
▫ The design of the process should start during or at the end
of the formulation development to define the process to a
large extent
• One aspect of the process development to remember is
end user (manufacturing site) capabilities.
▫ In other words, the practicality and the reality of the
manufacturing operation should be kept in perspective
• Process must be developed in such a manner that it can
easily be transferred to the manufacturing site with
minimal issues
▫ During this stage, technical operations in both the
manufacturing and quality control departments should be
consulted
Flow diagram
• Identifies all the unit operations, the equipment
used, and the stages (tahap) at which the
various raw materials are added
• Provides a convenient basis on which to
develop a detailed list of variables and
responses
• Contoh: The flow diagram for a typical
granulation solid dosage from product
▫ outlines the sequence of process steps and
specific equipment to be used during development
• Regardless of the stage of formulation/process
development being considered, a detailed
identification of variables and responses is
necessary for early program planning
• Typical variables and responses that could be
expected in a granulated solid dosage form are
listed in Table 1.
▫ This list is by no means complete and is intended
only as an example
2. Challenging of Process Parameters
• Identified process parameters are critical to the
product and process being developed
• These studies determine:
▫ The feasibility of the designed process
▫ The criticality of the parameters
• transition stage: the laboratory  the projected
final process
• Figure 4 also shows typical responses that may
have to be evaluated during the ranging studies on
the tableted product
S = strong (faktor sangat kritis)
M = moderate
W = weak
N = none
I = Unknown
Catatan…
• Faktor kritis untuk tiap proses pembuatan suatu
produk tidak sama
▫ Tablet pencampuran, pengeringan, pencetakan
▫ Suspensi pencampuran, pengisian
• Identifikasi variabel proses
• Dampak perubahan proses terhadap variabel
kritis
 Pemasaran PPIC

Bag. Produksi
Bag. Tablet

Penimbangan

Granulasi basah Granulasi kering Cetak langsung

Pencampuran awal Pencampuran awal

Pengeringan Slugging

Pengayakan Pengayakan Pengayakan

Pencampuran akhir Pencampuran akhir Pencampuran

KARANTINA IN PROCESS

Pencetakan Tablet

Produk jadi Pengemasan KIP

CREAM Penimbangan sentral

Seksi Cream

Pembuatan Basis cream

Pembuatan fasa air Pembuatan fasa minyak

Pencampuran

Bahan aktif Basis cream

Pencampuran Pencampuran Gudang bahan kemas

Massa cream Tube

Lab pengujian KIP

Persiapan tube
Pengisian cream

KIP
 SUSPENSI
Penimbangan sentral

Cairan

Pembuatan massa
Bahan lain
suspending agent

Pencampuran

Viskositas KIP
pH
Kadar zat aktif Pengisian

KIP
3. Challenging of Critical Process
Parameters or Characterization of the
Process
• Process characterization provides a systematic
examination of critical variables found during process
ranging
• The objectives of these studies are
▫ Confirm critical process parameters and determine their
effects on product quality attributes
▫ Establish process conditions for each unit operation
▫ Determine in-process operating limits to guarantee
acceptable finished product and yield
▫ Confirm the validity of the test methods
• The information summarized in the process
characterization report provides a basis for defining the
full-scale process
4. Verification
• Verification is required before a process is
scaled up and transferred to production
• Untuk menjamin bahwa proses yg didesain
mewakili kondisi produksi yg disimulasikan dan
untuk menentukan reprodusibilitasnya
• Proses tidak boleh diubah selama verifikasi
• Untuk 3 batch  hasilnya konsisten
FULL-SCALE PRODUCT/PROCESS
DEVELOPMENT
• Process scale-up studies
• Qualification trials
• Process validation runs
A. Scale-Up Studies
• The transition from a successful pilot-scale
process or research scale to a fullscale process
requires careful planning and implementation
• Many scale-up parameters are nonlinear
▫ scale-up factors can be quite complex and difficult
to predict, based only on experience with smaller
scale equipment
• the more complex the process, the more
complex the scale-up effect
B. Qualification Trials
• Once the scale-up studies have been
completed, it may be necessary to manufacture
one or more batches at full scale
▫ to confirm that the entire manufacturing process,
comprising several different unit operations, can
be carried out smoothly
• This may occur prior to or after the regulatory
submission, depending on the strategy used in
filing
C. Process Validation Runs
• After the qualification trials have been
completed, the protocol for the full-scale process
validation runs can be written
• The validation protocol is usually the joint effort
of the following groups:
▫ Research and development
▫ Pharmaceutical technology or technical services
▫ Quality control (quality assurance)
▫ Manufacturing
▫ Engineering
 The development of a new medicinal
product is a long and complex procedure
and involves many different disciplines
working together
 new medicinal product
 a novel synthesized chemical compound,
 a chemical extracted from a natural source or
 a compound produced by biotechnological
processes--
 The drug discovery and development
process for a typical research-based
pharmaceutical company can be broken
down into five distinct stages as described
briefly below
 At each stage, there will be several activities
running in parallel, with the overall objective
of discovering a candidate drug and
developing it to market as efficiently as
possible
 Strategic Research
 Exploratory Research
 Candidate Drug Selection
 Exploratory Development
 Full Development
 The strategic research of a particular
company is usually guided by factors such as
its inherent research competence and
expertise, therapeutic areas of unmet
medical need, and market
potential/commercial viability
 Companies often wish to develop a portfolio
of products within a specific therapeutic area
to capture a segment of the market
 Product life cycle management is important
in achieving this aim
 an investigation of the biological mechanism
and identification of a “chemical or biological
lead”
 diverse compounds are screened for the
desired biological activity
 to find a chemical or molecular entity that
interferes with the process and to provide a
valuable probe of the underlying therapeutic
problem
 the organic chemist synthesizing compounds
one at a time for the biologist to test in a
linear fashion
 The chemical or biological lead is used to
generate specific chemical compounds with
the optimal desired characteristics, for
example, potency, specificity, duration,
safety, and pharmaceutical aspects
 One or more candidate drugs are nominated
for development
 the molecular lead is optimized by testing a
range of selected compounds in in vitro and
in vivo (animal) studies
 to select one or more candidate drugs for
development with the most desired characteristics
 Pharmacological characteristics might include
acceptable absorption, potency, duration of action,
and selectivity for the receptor or enzyme
 Safety characteristics will normally include
noncarcinogenicity, nonteratogenicity,
nonmutagenicity, and general nontoxicity.
 The potential for these characteristics can be
predicted from relatively short-term preclinical
toxipharmacological animal studies and in vitro
tests
 involve the administration of single,
subtherapeutic dose of the new drug
candidate to a small number of human
subjects (10–15)
 to gather preliminary data on the
pharmacokinetics and pharmacodynamics
 gives no data on safety or efficacy, but drug
developers can carry out these studies to
rank drug candidates to decide which to take
forward
 to help to establish the first dose for the
subsequent phase I study
 Higher priority in the selection process
will, in most cases, be given to a
compound’s optimal pharmacological and
safety characteristics
 to gauge how the candidate drug is
absorbed and metabolized in healthy
human volunteers before studying its
effect on those actually suffering from the
disease for which it is intended
 phase I clinical studies
 healthy volunteers (20–80) receive the drug
candidate provided as a simple formulation
 For example, a simple aqueous oral solution or
suspension may be used, rather than a capsule or
tablet, to minimize the formulation development
work at this early stage
 Phase I studies are the first stage of testing
in human subjects to assess the safety
 These studies often include dose ranging or
dose escalation so that the appropriate dose
for therapeutic use can be found
 Completion of longer-term safety and
clinical studies (phases II and III) in
patients suffering from the disease are
accomplished at this stage
 dose-ranging studies in a reasonable
patient population (several hundred) to
evaluate the effectiveness of the drug and
common side effects
 During phase II, the intended commercial
formulation should be developed, and the
product/process optimized and eventually
scaled up to commercial production scale
 Large patient populations (several
hundred to thousands) are involved to
statistically confirm efficacy and safety
 Some patients will be given the drug,
some a placebo product, and some may
be given a known market leader
 The doctors and patients in the study will
not know whether the patients are getting
the test drug, placebo, or market leader
 post-marketing surveillance trials
 conducted to evaluate the safety
surveillance of a drug after it receives
permission to be sold
 to detect any long-term or rare adverse
effects over a much larger patient
population and longer time period than
phases I to III trials
Early Drug Development:
Product Design
 The quality of the design activities can strongly
influence the success of development of the right
product to the market and ultimate return on
investment (ROI)
 to start development and get products to the
market quickly
 market research will have been completed to
ensure customer requirements are being met
 The product definition and technical specifications
will have been agreed on, and the cost of goods
(CoG) estimated
PRODUCT DESIGN
CONSIDERATIONS
 Target product profile (TPP)/minimum product
profile (MPP)
 Design specification and critical quality parameters
 Commercial and marketing considerations
 Technical issues and risk assessment
 Safety assessment considerations
 Environmental, health, and safety considerations
 Intellectual property considerations
1. Target Product Profile/Minimum
Product Profile
 the product attributes
 shouldbe established for the intended marketed
product based on all “customer” and “end-user”
needs
 Each customer wants the right product
(meeting their quality expectations) at the
right time and at the right price
 each customer will have his or her own
specific requirements
preformulation studies
 to characterize the candidate drug and to determine the
physicochemical properties considered
 important in the development of the intended dosage form to support
product design
 Solubility, stressed stability, excipient compatibility, and other
preformulation studies
 may influence the selection of the formulation dosage form and
excipients
 The results may also influence the choice of manufacturing
process (Table 2)
 terminal sterilization by autoclaving has been shown not to
be feasible
 The preformulation data should also help to establish
the critical quality parameters for the product
Meeting Customer Needs

 the pharmaceutical company to gain a

deep and clear understanding of the
needs and behaviors of its customers:
prescribers, patients, and all other
stakeholders involved in pharmaceutical
decisions
2. Design Specifications and
Critical Quality Parameters
 In addition to the preformulation information,
there will be other considerations in the
selection of the excipients and packaging
components for the product
 the intravenous injection
 any excipient used must be of parenteral grade
 a high-quality product specification can be
proposed
 appearance (clear, particle free), pH, osmolality,
particulate levels, sterility, and endotoxin levels
3. Commercial and Marketing
Considerations
 must be to maximize its ROI after launch
 the commercial viability of a new product
to be developed needs to be commercially
assessed at the product design stage to
satisfy the company that it will achieve a
satisfactory ROI
Some of the factors that should be
considered in the evaluation
 Development costs
 Timing to market
 Market size (disease prevalence, diagnosis and
treatment rates, market value)
 Competition (current, developing, and impact on future
market)
 Unmet medical need (effectiveness of current treatment,
improvements required)
 Pricing and reimbursement (current and future)
 CoG (target)
4.Technical Issues and Risk
Assessment
 Some of these risks will be related to
pharmaceutical development and others to
clinical, safety/toxicology
 the technical challenges anticipated in
developing a novel or complex drug delivery
system or manufacturing process
 Other areas of risk include the sources of
excipients and packaging components
 Some excipients or packaging components may only
be available from one supplier, with the risk that the
supplier could go out of business
 The importance of identifying these issues
in a product design report is to make the
company aware of the risks
 to make effective plans to overcome
problems and manage the risks
5. Safety Assessment
Considerations
 There may be incompatibility problems
with the candidate drug and existing
excipients or there may be a need to use
new excipients in a new drug delivery
system
 The replacement of chlorofluorocarbons
(CFCs) with new hydrofluorocarbon (HFA)
propellants in pressurized MDIs has been
driven by environmental factors
6. Environmental, Health, and
Safety Considerations
 increasing pressures on the pharmaceutical
industry to use environmentally friendly materials
in products
 biodegradable or recyclable and do no harm to the
environment
 Examples are the replacement of CFCs in
pressurized metered dose aerosols and the
replacement of polyvinyl chloride (PVC) for
alternative packaging materials
 The choice of appropriate materials to suit
product, customer, and environment may also
have cost implications
7.Intellectual Property
Considerations
 Few pharmaceutical companies would
venture into a long and expensive
development program without a strategy
for effective patent protection in place to
ensure market exclusivity
 Patents are legal property that prevents
others using the invention (for 20 years in
most countries) in exchange for a full
public disclosure of information
terimakasih