FOUR SATGES OF PHARMACEUTICAL PRODUCT DEVELOPMENT

1. Preformulation Aspects in Pharmaceutical Product Development

An appropriate characterization of the physicochemical properties of the drug has been shown to
effectively enable the determination of the suitable formulation process and delivery method of
the developed drug. It has been reported that the main objective of preformulation studies is to
develop drugs with the desired stability, efficacy, and safety .

The term preformulation comprises the applications of the principles of biopharmaceutics to the
physicochemical properties of the drug substance. Preformulation studies have been reported to
be done for the sake of designing new delivery systems with the optimum characteristics .

Preformulation studies have been reported to act as, accurate predictors that effectively predict
the changes that may be associated with the combination process of the active pharmaceutical
ingredient (API) with a suitable delivery system that is intended to safely and effectively deliver
the active ingredient to the patient.

Potential new drugs are known to extensively undergo studies of pharmacological and
toxicological purposes before starting with the human trials. The outcomes resulting from the
preformulation studies determine whether further development of the drug is going to be done or
not.
2. Prototype development

Ideas are the descriptive statements that can either be written or verbalized. Ideas are usually
converted into a concept that in the case of pharmaceutical products includes the product’s
benefits and features. Like a seed, this concept is further germinated by wet lab work into a
prototype. The prototype development is an important stage during the development of a new
product that represents the primary working model of the product which will then be perfected in
the form of the final product.

In this section, some of the considerations needed to be taken into account during the
preformulation stage of drug development are discussed. Aspects regarding the active
pharmaceutical ingredients (APIs) and their chemical nature are covered. Safety and efficacy
concerns during the preclinical and the clinical stages of drug developments are also discussed in
addition to the issues of regulation and intellectual property
  API Chemistry and Preformulation
 Biological Considerations (Preclinical and Clinical Activity) w.r.t. Safety and Efficacy
 Intellectual Property

2A: Experimental Design and Product Optimization

Experimental design is an essential part of the pharmaceutical product development process

because experiments are required in order to ensure that the product has the desired
characteristics. Experimental design can be defined as the process of strategic planning to
conduct an experiment that can be used to obtain the required information in a precise and
efficient manner. Experiments are generally costly, time-consuming, and require many resources,
thus, it is important to make experiments more efficient to reduce the time and costs required

The product optimization process is required in the development of pharmaceutical products in

order to ensure that the product fulfills the specified requirements of the regularity authorities
and complies with the quality standards. The general outputs that should be attained from the
optimization step are mainly a defined active ingredient, excipients, pack and product
specifications, in addition to a quantitatively defined formula of the active ingredients and the
excipients amounts used.

 Parenteral Dosage Forms

Besides chemical parameters (assay and related substances), other physical parameters (pH,
osmolality, fill volume, particulate matter, etc.) and microbiological parameters (sterility,
bacterial endotoxin, preservative efficacy) are important for the simple injections. In complex
types of parenteral systems, in addition to the parameters given in simple injections, certain other
physicochemical quality attributes are critical. Those attributes (e.g., particle size distribution,
percent in vitro drug release, entrapment efficiency, drug loading, zeta potential) play critical
roles in defining the efficacy and safety profile of the finished product. To achieve these critical
attributes (CQAs), critical material attributes and critical process parameters (e.g., sequence of
addition, mixing type-time-temperature, etc.) must be studied and optimized.

 Oral Solid Dosage Forms

The shape and size of the particles of the powder substance can influence the powder flow,
which is an important factor in the tableting process since improper flow can lead to a variation
in the filling of the tablets, which in turn can cause variability in the content of the tablet
produced. Other processes affected by the particle size and shape are the mixing and the
compaction processes. Thus, careful consideration of particle size selection is required in order
to ensure proper formulation manufacturing.

 Topical/Dermal/Transdermal Dosage Forms

n. Drugs applied to the skin are required to penetrate to the stratum corneum first in order exhibit
their action or to penetrate further for systemic delivery. The main factors that determine the
penetration of the drug into the stratum corneum are the concentration of the drug substance, the
ability of the drug substance to diffuse across the stratum corneum and the partition coefficient
of the drug substance between the stratum corneum and its vehicle. The absorption process
across the skin is also affected by biological factors such as age, sex, and the ability of the skin
for metabolism. The absorption can be enhanced by using a penetration enhancer such as
phospholipids and urea which can increase the ability of the drug to penetrate in the skin.

 Inhalational Formulations

The drug delivery systems/devices are of particular importance in the inhalational formulations
and can highly impact the decision of the physician and the acceptance of the patient for a
particular formulation. There are various devices that are used in delivering inhalational
formulations, these mainly include dry powder inhalers, metered dose inhalers, and nebulizers.
The choice of inhalers varies according to different factors, for example, nebulizers are preferred
for pediatrics. An important factor to be considered in the inhalational formulations is the
particle size of the inhaled powder because it is the particle size of the powder that determines
whether the powder will reach the lung and to what extent it can go in the respiratory tract.

 Nasal Solutions/Suspensions

Nasal formulations require a proper choice of excipients used, administration device, and
avoidance of any incompatibilities in the formulation. Other important factors include the
selection of proper preservative in the solutions and suspensions to prevent the microbial growth,
e.g., benzalkonium chloride (BKC) is usually used as a preservative in nasal formulations. In
cases where a poor penetration is observed, such as with proteins or peptides, a penetration
enhancer may be used to increase the nasal absorption.

 Ophthalmic Formulations

Considerations in the optimization of ophthalmic formulations include the adjustment of the pH

value and the osmolarity of the solution, ensuring the sterility of the formulation and solubility of
the drug in the solution. In general, the pH of the solution needs to be as close as possible to the
physiologic pH, although there is a close range of acceptable pH values that are close to the
physiologic pH. The osmolarity of the solution also requires adjustment in order to ensure that
the solution is isotonic with the tears, in order to avoid any irritation. The sterility of the
ophthalmic formulations is also of prime importance, usually a preservative is used to prevent
microbial growth in the product, examples of preservatives used in ophthalmic formulations are
BKC and methylparaben. The role of the viscosity modifier (polymer) is to retain the drug
molecule on the ocular surface for a longer duration to increase retention time and thereby
bioavailability. Some of the formulations may include solubilizers and/or penetration enhancers.

3. BIOLOGICAL ASPECTS IN PHARMACEUTICAL PRODUCT DEVELOPMENT

3A :The Preclinical Tenure and Strategies

Three essential parts are involved in the preclinical stage of drug development.

 The first part focuses on the in vitro models and their importance in the preclinical stage.
 Second part provides a brief discussion about the application of new in silico models and
how simulation prediction has aided in the efficiency of the drug development process.
 Third part covers the issue of using animals as models for testing some properties of the
newly-synthesized drugs.
  In Vitro Screenings and Importance

The use of in vitro models usually provides information in the early stage of preclinical
development regarding probable biological performance of the drug product. . Nevertheless, in
vitro screening models are known to be mostly used for the understanding of drug product
behavior. However, whatever the purpose of in vitro models employment, it is proven that data
obtained by these models provide very useful information to be further used for in vivo testing.
In the early stages of the drug development process, the use of in vitro models is considered
more useful than precise, because, at these stages, absolute precision is not required until
validation is recommended. In the case of using in vitro methods for regulatory purposes, these
in vitro methods have to be validated.

 3B : In Silico Models and Simulation Predictions

Computational prediction models are shown to have an observable role in modern medicinal
chemistry since these models offer a high potential to transform the drugs’ early research phases,
in terms of saving both time and cost. This has shown to have a direct effect on the rate of
success of a new chemical entity (NCE) development and, hence, improve the productivity of the
pharmaceutical research and development (R&D). Nowadays, virtual screening models are
considered as essential components in the modern process of drug discovery.

 3C: The Use of Animal Models

It is known that testing pharmaceutical formulations directly in humans is an unaffordable and

unethical process. Thus, the establishment of in vivo in vitro correlation (IVIVC) is essential for
the prediction of the performance of such formulations in humans, which may, therefore,
minimize the risk of failure in the first-in-human (FIH) studies. Animal models that are
commonly used in the pharmaceutical field include rats, mini-pigs, dogs, and monkeys. These
animal models are used for the evaluation of the performance of the newly-formulated drug
product before testing in humans. Each model has advantages and limitations regarding its
capability to predict the behavior of the new formulation in humans.

3B : The Clinical Cycle Development

 Safety and Efficacy

Investigators and physicians working on clinical trials for the development of pharmaceutical
products, refer to the two concepts “safety” and “efficacy” as mutually exclusive concepts.
Before a newly-formulated drug product enters the market, monitoring and evaluating its safety
in all stages of the preclinical phase is required. It is a mandatory activity of pharmaceutical
sponsors before they apply for the approval to introduce the drug product to the market.
  Different Phases

Phase I studies: during this phase, assessment of drugs or devices’ safety takes place. This
testing phase can take up to several months to be completed. Typically, during this phase, a few
volunteers (usually around 20 to 100 healthy volunteers) are paid to participate in this study. The
purpose of this stage testing is to assess the drug’s or device’s effect on humans. This assessment
includes its absorption, metabolism, and excretion.

Phase II studies: during this phase, assessment of the drug’s or device’s effectiveness takes
place. This phase usually takes from several months to approximately two years to be completed
and is usually done on hundreds on participating patients. Most studies involved in this phase are
done by random trials by which patients are grouped into two or more groups represent control
group and patients will takes standard treatment. Rest groups represents test group and takes the
experimental drug. These studies allow the investigators to make a comparison regarding the
safety and efficacy of the drug.

Phase III studies: this phase of clinical trials involves random testing of the experimental drug
on hundreds to thousands patients. This phase can take several years to becompleted and
provides both the pharmaceutical company as well as the regulatory agency with thorough
understanding of the experimental drug’s or device’s effectiveness, intended benefits, and the
possible adverse reactions.

Phase IV studies: this phase is most commonly referred to as the post-marketing surveillance
trials. These trials are known to be conducted after approving the drug or the device to be used
by consumers. This phase may lead to the withdrawal of a drug or device from the market or in
some cases the use of these drugs or devices might be restricted.

3C :Regulatory Requirements Comparing Different Countries

In present scenario, drug development is not centric to a specific part of world, it has become
globalized to develop new good pharmaceutical products that fulfill the demands of patients
around the world. With the said aim of drug globalization, it has become important to generate
clinical data across the world. Currently, it is challenging both operationally and scientifically to
set up a global program for drug development, in part due to distinct and sometimes conflicting
requirements from different countries’ different regulatory authorities. Since there is no
harmonization between the regulation of different countries it is a challenge for reviewing
authorities to check and verify the generated data from multiregional clinical trials (MRCTs) for
the approval of new drug products. In order to overcome the current challenges, the International
Council for Harmonization (ICH) published a document in June 2016 containing a number of
guidelines related to the planning and design of MRCTs. Presently it is a draft guidance, entitled
“E17 General Principles for Planning and Design of Multi-Regional Clinical Trials.”
4. COMMERCIALIZATION ASPECTS IN PHARMACEUTICAL PRODUCTS
DEVELOPMENT

4A : Patent Listing With Different World Body

By law, it is mandatory for all countries that belong to the WTO (World Trade Organization) to
take authorization from a current patent-holder, not only to use the patented knowledge but also
to trade products embodying or produced by the patented technology across the territorial
boundaries. The WIPO Convention is the constituent instrument of the World Intellectual
Property Organization (WIPO). It has two major objectives, the first is to encourage the
safeguarding of intellectual property worldwide; and the second is to ensure administrative
support among the intellectual property unions recognized by the treaties that WIPO administers.

4B: Evergreening Strategies

It is defined as a“strategy by which technology producers, using serial secondary patents and
other mechanisms, keep their product sales protected for longer periods of time than would
normally be permissible under the law.

” Persons are continuously using newer ways of evergreening.

A few commonly used ways are:

1. Business strategy:

a. Collaboration with other business units to gain legal leverage of market exclusivity.

b. The use of aggressive litigation to fend off or delay entries.

2. Technical strategy:

a. Minor improvement in the current form of product by reformulation and repackaging.

b. Development of a successor product as an alternate product with an overlapping technology

base.

c. Use of multiple trademark protection (like brand name, appearance, color, etc.) and then
aggressive marketing of the successor product