1. A Summer Internship report on
Analytical and Process Development of Generic Drugs
Department of Chemical Engineering, Summer 2016
Submitted to: Dr. Anuj Chauhan
Interning Company: Esjay Pharmaceuticals LLC.
Name: Pranav Champaknath Attavar
UFID: 3475-6526

2. Table of Contents
1. Acknowledgements…………………………………………………… 3
2. Acronyms……………………………………………………………… 4
3. Abstract……………………………………………………………….. 5
4. Introduction…………………………………………………………… 6
a) Quality Assurence…………………………………………….. 7
b) Quality Control……………………………………………….. 7
c) Product development…………………………………………. 7
d) R&D…………………………………………………………… 8
5. Method……..………………………………………………………… 9
6. Results and Discussion……………………………………………….. 11
7. Proposed future task…………………………………………………. 12
8. Conclusion…………………………………………………………….. 13
9. References…………………………………………………………….. 14

3. Acknowledgements
I would like to express my heartfelt gratitude to Mr. Samy Shanmugam for giving
me this opportunity to intern at Esjay Pharmaceuticals LLC in the Research and
Development department. Apart from interacting with the best pharmaceutical
brains in the country, I have also been acquainted with contemporary technologies
in the field of Chemical and Pharmaceutical Engineering. A special thanks to Dr.
Vijayaraj Thorappadi, Mr. Siva Kumar Chinniah, Mr. Ugendra C and Mr.
Srinivas for spending their valuable time and for patiently explaining me the
concepts whenever needed. Their encouragement was undoubtedly my incentive to
work harder and make full use of this opportunity given to me.

4. Acronyms
HPLC: High Pressure Liquid Chromatograph
FTIR: Fourier Transform Infrared
UVD: Ultra Violet Detector
GMP: Good Manufacturing Practices
LOD: Loss on Drying
PPM: Parts per million
USP: United States Pharmacopeia
FDA: Food and Drug Administration
SDS: Safety Data Sheets
API: Active pharmaceutical ingredients
RLD: Reference listed drug
BU: Blend Uniformity
CU: Content Uniformity
GC: Gas Chromatograph
EP: European Pharmacopeia
IP: Indian Pharmacopeia
QA: Quality assurance
QC: Quality control
PD: Product development
PO: Purchase order

5. Abstract
The aim of this report is to introduce the general principals of operation and the
various experiments conducted in the R&D department (from product receiving to
manufacturing of exhibit batch) of a pharmaceutical company.
One of the pivotal factors which effects the success of a pharmaceutical company
is the synergic working of the various departments viz, quality control, quality
assurance, product development and research & development. This report gives an
overview of the duties of each department and how they comply with the
regulation and guidelines provided by USP and FDA (with emphasis on the
analytical development of tablets, suspensions, liquids and powders). Another
important factor discussed is how the use of state of the art equipment like HPLC,
UV detector, FTIR detector and GC impact important decision making in the field
of drug delivery and medicinal chemistry. Also, a great length has been discussed
about how in-vitro studies and their results effect the design of experiments and in
turn effect the formulation of drugs.

6. Introduction
The development of a generic drug is a demanding process which requires proper
design of experiments and meticulous planning. The initial stages for any drug
development is the procurement of materials, both API and excipients, from a
vendor. Once these materials have been received, they are analyzed for their
quality and purity by the quality control (QC) department and deemed fit if they
are within a reasonable range of their claimed purity (each material received has a
certificate of analysis (COA) which provides details about the purity test from the
vendor’s side). Once this stage has been passed, the next step is the development of
a drug, with proper ratio of placebos (excipients) and API. This stage takes from a
few weeks to several months before the final batch of the drug has been
determined. Each batch of the drug is tested in the R&D department for various
factors like percentage release of the drug (In-vitro studies) in different conditions
which simulate the human digestive track, the degradation studies of the drug (loss
on drying and forced degradation) to get an idea of how stable and in what
condition the drug is stable. There are various experiments like dissolution studies,
plate recovery (cleaning verification), loss on drying tests etc, which provide an
idea on how close the drug is to its brand/RLD counterpart (discussed in grater
length in the following sections of the report). Once the drug has passed the
various guidelines provided by USP and FDA, a final review called validation, is
carried out to fix a method. This indicates that every time the drug is tested in the
future, it has to be in accordance with the steps followed in the validation report.
The purpose of going through these elaborate steps is to ensure that the generic
drug is exactly similar, in turn of its chemistry and the drug delivery, to the
brand/RLD. The next and crucial step is to scale up the process and manufacture
large batches of the drug for FDA filing and stability studies called executive
batches. The preparation of a pilot scale batch requires the qualification of all the
equipments being used in the batch. The “IQOQPQ” is an integral part of the QA
department and stand for Installation qualification, operational qualification and
performance qualification. This is done to every new equipment that is used by the
company. A greater detail of the R&D process, from design of experiments to the
use of engineering tools to draw conclusions, is discussed in the following
sections.

7. Quality Assurance
The quality assurance department is responsible to ensure that there are no defects
in equipments or problems during the manufacturing of pharmaceutical drugs.
Among the various duties of QA engineer, the major ones include proper
documentation, perform IQ, OQ and PQ to all the equipments being used during
the preparation of pilot and executive batches. They keep a systematic track record
of the procedures, which closely comply with that of USP and other regulatory
agencies, so as to reduce the errors that might occur. In case of any error that might
occur during the process, leads to an investigation which calls for a detailed
analysis of the entire process (from scratch till end) and to identify the mistake that
occurred.
Quality Control
The quality control department a.k.a QC, is responsible to ensure that the products
being used in production (raw material, intermediate products, finished product)
meet the quality standards set forth for each product by USP and other regulatory
organizations. Many engineering tools like HPLC, FTIR and UV are an integral
part of QC. These tools are used to identify the components or impurities present in
any of the products mentioned above. It is only after the approval of QC that a
product is deemed fit for stability testing. Both QA and QC work hand in hand to
provide the raw materials for product development to be converted into generic
drugs and further tested by the R&D department.
Product Development
The product development department involves the harmonious working of process
engineers, Quality assurance engineers and formulation scientists. This department
is responsible to receive raw materials (with proper PO documentation and COA
form), its storage and to manufacture the final product. They work closely with the
R&D department and make changes in the fundamentals of drug chemistry to
manufacture the required drug that meets the guidelines within an acceptable range
of deviation.

8. Research and Development
The R&D department forms the backbone of any pharmaceutical industry. This
department is responsible to evaluate the work done by all the other departments
and to speed up the process of manufacturing a drug. Each manufactured drug is
unique and undergoes different set of studies and experimentation but, the most
common tests performed are listed below:
Ø In-vitro studies (dissolution and percent release tests)
Ø Assay (purity and stability tests of the drug)
Ø Engineering tools to assist in conclusions
In-vitro study is an integral part of the R&D department. It is the study of how a
drug behaves during a controlled environment (which simulates the human
digestive track). The general experiment that is associated with in-vitro studies is
called dissolution studies, this experiment is conducted to calculate the percentage
release of a drug in a given point of time. Each drug consists of two broad
components namely, placebos (excipients) and the API itself. Dissolution results
are an indication of how the drug might dissolve under various conditions inside a
human body (conditions like before food (low pH) and after food (high pH)). A
detailed description of this experiment and its engineering aspects is given in the
following section.
Assay, refers to an investigative procedure that gives the quality of a certain drug.
In pharmaceutical R&D, assay is used to test the purity of a sample with a
reference. This procedure gives an indication as to how a finished product (FP)
compares to its API (which does not have any excipients). This gives a glimpse
into the chemistry of the final product and how the excipients effect the API.
Finally, the results of each experiment is evaluated with the help of advanced
engineering tools like HPLC, UV and GC. It is imperative to realize which
technique is apt for which products. For example, there are many drugs which have
UV inactive groups and hence cannot be tested for on a UV spectrometer. These
drugs are tested using alternate techniques like HPLC, UPLC or GC.

9. Methods
As explained in the R&D section of the report, in-vitro studies play an important
part in any pharmaceutical industry. In generic pharma companies, these studies
are the most vital towards method development. The most common form of in-
vitro study is called the dissolution apparatus.
Fig 1. A general image of a dissolution apparatus
The apparatus consists of six vessels of 900ml (the volume of an empty stomach)
volume each. These vessels are placed inside a water bath that is maintained at
about the same temperature as a human body i.e 37 ° C. Each vessel has a paddle
type shaft which is calibrated to occupy 85-90% of the vessel volume. The rpm of
the paddle is adjusted to simulate an average mixing inside a human body.
Fig 2. A dissolution vessel with paddle

10. The objective of this experiment is to calculate the percent release of the drug at
various time intervals (called Q-point). This gives an indication as to how the drug
dissolves inside the human body. A delayed release would mean that it takes a
relatively long time for the drug to release the API. The timing of release can be
varied by increasing the pressure used during manufacturing of the drug (tablets)
or by adding additional coating of excipient using a fluidized bed reactor.
Loss on Drying
This is another experiment that is carried out during the analysis of the components
in a drug. This experiment is used to get an idea of the moisture content in the
finished product. A known quantity of the drug is manually broken down to fine
powder and is placed inside an oven for a specific duration of time and at a specific
temperature.
Fig 3. Oven used for LOD analysis
After a certain time has passed, the powder is weighed and placed back inside the
oven. This process is carried out until a saturation of the liquid content is reached.
The loss in weight is calculated as
𝐿𝑜𝑠𝑠 𝑜𝑓 𝑤𝑒𝑖𝑔ℎ𝑡 =
𝐼𝑛𝑖𝑡𝑖𝑎𝑙 𝑤𝑒𝑖𝑔ℎ𝑡 − 𝐹𝑖𝑛𝑎𝑙 𝑤𝑒𝑖𝑔ℎ𝑡
𝐼𝑛𝑖𝑡𝑖𝑎𝑙 𝑤𝑒𝑖𝑔ℎ𝑡
∗ 100

11. Results and Discussion
The dissolution experiment data is collected and is studied in detail to extract the
relevant information required to draw conclusions. The general formulae used to
calculate the recovery/ percent release of the drug is
%𝑟𝑒𝑙𝑒𝑎𝑠𝑒 =
𝑆𝑎𝑚𝑝𝑙𝑒 𝐴𝑏𝑠 𝑜𝑟 𝐴𝑟𝑒𝑎 ∗ 𝐶𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑤𝑜𝑟𝑘𝑖𝑛𝑔 𝑆𝑡𝑑 ∗ 𝑙𝑎𝑏𝑒𝑙 𝑐𝑙𝑎𝑖𝑚
𝑊𝑜𝑟𝑘𝑖𝑛𝑔 𝑠𝑡𝑎𝑛𝑑𝑎𝑟𝑑 𝐴𝑏𝑠 𝑜𝑟 𝐴𝑟𝑒𝑎 ∗ 𝐶𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑠𝑎𝑚𝑝𝑙𝑒 ∗ 𝑝𝑜𝑡𝑒𝑛𝑐𝑦
∗ 100
Abs = Absorbance (in case a UV spectrometer is used); Area is a HPLC is used
Label claim = The amount of API in a unit of sample (for eg 5mg/ml of smaple)
Potency = The strength of the drug
For any given drug, the USP provides a Q-point (certain expected level of recovery
at a specific point). During this internship, there have been quite a few cases where
the drug does not meet the required Q-point. At that point of time, the fundamental
chemistry of the components is questioned and a reason has been found for such
results, for instance, a certain drug might have tendency to stick to the walls of a
glass container or a few might degrade due to sensitivity of light. These reasons
were taken into account and the formulation was changed accordingly. As
discussed earlier, the most common type of techniques used to characterize a drug
in a pharma industry are HPLC, UV or GC. Each equipment has its own
advantages and limitations. Depending on the drug, one of these techniques is used
for analysis. For example, a drug which has no UV active groups, is generally
analyzed in a HPLC or GC. The most common type of detectors used in HPLC are
ultra-violet, photodiode array detector or refractive index detector.

12. Proposed future tasks
A recent survey by PricewaterhouseCoopers (PWC) has shown that the
pharmaceutical market will shift from mass market to target market in the next few
years. This change in market trend will cause a surge in the research and
development of specific drugs. Target drugs require a greater level of research and
background study before they can be launched into the market. Their complicated
structure and chemistry demand improvements in current characterization
techniques or introduce more powerful ones.
One possible area of improvement could be the HPLC unit. A powerful technique
which uses the affinity of the sample to the stationary phase to identify the
components in the drug. The past fifty years, have shown a dramatic change in this
area, from making high efficiency columns, which can withstand pressures up to
5000 psi, to compact fully automated systems which minimize the error involved
with manual work. Also, the sensitivity of the equipments have increased in the
recent past and still have a lot of scope to improve.
Statistics has shown that, this year (till date) more than 150 diseases are reported to
have out-broken in different parts of the world. The number of new diseases
discovered each year has been increasing for the past 20 years and will remain so
even in the future. This trend is a strong incentive for pharmaceutical engineers
and scientists to come together and improve the R&D facilities to help minimize
the lives lost and eventually eradicate these diseases from the phase of earth.

13. Conclusions
This internship has given an opportunity to understand the general operations of a
pharmaceutical company with a deeper understanding of analytical development
and the use of powerful instruments like HPLC, UV and GC in determining key
results which contribute immensely towards product development.
Over the past three months, I have been involved with more than a few projects
and have contributed towards understanding the chemistry of drug delivery and the
process engineering aspects of scaling up. The importance of performing in-vitro
studies, assay and impurity and analyzing the results using proper characterization
techniques is vital to the process of drug development. Experiments like
dissolution give a real time idea as to how the drug might perform when subjected
to in-vivo studies.
All in all, it is important to use the apt engineering tools for the characterization of
formulations and before venturing into the experiment, it is important to design the
experiment and completely understand the science behind the product so as to save
resources and time.
*Note: Due to the confidentiality agreement with the company, no details
regarding the names of the generic drugs nor their associated results are being
disclosed.

14. References
1. U.S Food and Drug Administration (http://www.fda.gov)
2. United states Pharmacopeia (http://www.usp.org)
3. World health organization (http://www.who.int/csr/don/archive/year/en/)
4. European Pharmacopeia (http://www.edqm.eu)
5. www.drug-dissolution-testing.com
6. Direct Industry (www.directindustry.com)
7. Orange book (http://www.accessdata.fda.gov/scripts/cder/ob/)
8. Sigma-Aldrich (http://www.sigmaaldrich.com/united-states.html)
9. Agilent (http://www.agilent.com/home)
10.Waters (http://www.waters.com/waters/home.htm?locale=en_US)