Review Article
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ISSN:2277-4564
Rakhee et al /International Journal of Pharmaceutical Sciences Letters 2014 Vol. 4 (2)| 351-358
Short Review on Processes Involved In Development of Generic Solid Oral
Products
Rakhee Kapadia and Krutika K. Sawant*
Drug Delivery Research Laboratory, TIFAC Center of Relevance and Excellence in NDDS, Pharmacy Department, G. H. Patel Building, Donor’s Plaza, The M. S. University of Baroda, Fatehgunj, Vadodara-390002, Gujarat, India.
ABSTRACT
Pharmaceutical product development is an interdisciplinary and creative activity that transforms a market opportunity and technological innovation into successful products. It is a set of activity based processes in a productoriented enterprise, and is essential to the economic success of such organizations. The objective of this work is to
summarize the important aspects in development of generic solid oral products like tablet and capsules, including
information on pharmaceutical drug product, applications required for launching a new chemical entity/ new product in the pharmaceutical market and finally in detail about the various steps involved in a pharmaceutical drug
product development. Understanding these important aspects of pharmaceutical product development and their role
in pharmaceutical market would give us insights into the product development dynamics.
Introduction
Pharmaceutical Drug Product
According to FDA, “Pharmaceutical drug product
means a finished dosage form of a drug, for example, a
tablet, capsule, solution, etc., that contains an active
drug ingredient generally, but not necessarily, in association with inactive ingredients”.
The term ‘pharmaceutical drug product’ also includes a
finished dosage form that does not contain an active
ingredient but is intended to be used as a placebo
[1].On the basis of marketing authorization pharmaceutical drug products can be categorized as:
Innovator Drug Product
Generally, the innovator pharmaceutical product is that
which was first authorized for marketing, on the basis
of documentation of quality, safety and efficacy [2].
Generic Drug Product
A “generic product” is a multisource pharmaceutical
product which is intended to be interchangeable with
the comparator product. It is usually manufactured
without a licence from the innovator company and marketed only after the expiry of patent or other exclusivity
rights of Innovator product [3].
According to the US FDA, developing a new
drug and getting it approved for sale can take approximately 12-15 years and cost almost $800 million. One of the reasons R&D is so costly in pharmaceuticals is that most new drug candidates fail to reachKey words: Pharmaceutical drug product; processes in
product development; pharmaceutical market, Generic
products, validation, applications for product development
Received Feb 2014; accepted
28 Feb 2014;
*Corresponding Author: Krutika K. Sawant
Mobile: +91-265-2434187
Email: dr_krutikasawant@rediffmail.com
Copyright ©2011 Published by IJPSL. All rights reserved
-the market. Failure can result from toxicity, carcinogenicity, manufacturing difficulties, inconvenient dosing
characteristics, inadequate efficacy, economic and competitive factors, and various other problems. Typically,
less than 1 percent of the compounds examined in the pre
-clinical period make it into human testing. Only 20 percent of the compounds entering clinical trials survive the
development process and gain FDA approval [4]. Furthermore, the full R&D process from synthesis to FDA approval involves undertaking successive trials of increasing size and complexity. The pre-clinical and clinical
testing phases generally take more than a decade to complete [5].
Applications Required For Launching a New
Chemical Entity (NCE)/ New Drug Product
in Us Market
Launching a pharmaceutical drug product to the market
takes a very long path from idea generation to ANDA
approval and generally it involves submission of three
types of applications to US FDA:
Investigational New Drug (IND):
IND application contains sufficient pre-clinical data on
the investigational new drug to support proceeding with
human trials.
New Drug Application (NDA):
If the IND is approved by the FDA, the investor company begins clinical trials. Once Phase-3 of clinical trials
is complete, the investor or Drug Company submits the
application to US FDA as New Drug Application
(NDA) for bringing the new drug product in market.
Abbreviated New Drug Application (ANDA):
Generic medicines are copies of brand name drugs
(innovator product). To bring generic drugs to the market
the generic company has to file Abbreviated New Drug
Application (ANDA) to US FDA.
Rakhee et al /International Journal of Pharmaceutical Sciences Letters 2014 Vol. 4 (2)| 351-358
Investigational New Drug Application (IND)
Researchers search medicinal molecules p rincipally
from source of plants, animals, bi- products, related
impurities and pharmacological a c t i o n s of discovered
d r u g m o l e c u l e s . After identification of medicinal
compounds as well as some relevant biological works
of identified drug compounds on animal models, researchers published their works in different journals,
known as primary research work. Secondary researchers study on published primary research work and
investigate the potentiality as well as manufacturing suitability of medicinal molecules. After that, the researchers
or investors apply the potential medicinal molecule as
an Investigational New Drug (IND) to US FDA legally
to test the drug on human subjects. This IND application
is based on pre- clinical data, typically from animal
studies, that shows the drug is safe enough to be
tested in humans. If the IND is approved by the FDA,
the investor or drug company can begin the first phase of
development. The IND consists of three phases trail:
Phase-1 known as clinical trials using healthy subjects
to determine "drug product's" basic properties, such
as the extent of drug absorption, drug absorption rate
and its safety profile in humans, Phase-2 known as
small-scale toxicology study using animal subjects and
then a long-term, small-scale clinical study to assess the
product's efficacy and safety in humans, Phase-3
known as large-scale testing for safety and efficacy
conducted in multiple centers among a few hundred to a
few thousand patients 6. Once Phase-3 is complete, the
investor or Drug Company submits the drug to US FDA
as New Drug Application (NDA) in Common Technical
Documents (CTD) format [6].
New Drug Application for Innovator Product
For decades, the regulation and control of new drugs in the
United States has been based on the New Drug Application
(NDA). Since 1938, every new drug has been the subject of
an approved NDA before U.S. commercialization. The data
gathered during the animal studies and human clinical trials
of an Investigational New Drug (IND) becomes part of the
NDA [7]. Basically, NDA describes the manufacturing
process, composition, quality & control parameters of the
drug substance and drug product, it also provides evidence of its safety and effectiveness to US FDA [6]. In
whole, the documentation required in an NDA is supposed to tell the drug's whole story, including what happened during the clinical tests, what the ingredients of the
drug are, the results of the animal studies, how the drug
behaves in the body, and how it is manufactured, processed and packaged. Depending on the drug product the
NDA consist of as many as 15 different sections 7.
The US FDA usually takes one to two years to review and
approve the NDA. During the NDA stage, the US FDA
consults advisory committees made of experts to obtain
advices on drug safety, effectiveness and labeling. Once
FDA approves the drug product, the company can market
the drug product with US FDA regulated labeling. According to Prescription Drug User Fee Act, 1992
(PDUFA date) FDA gives a date within which it will
review the application of applicant company
Abbreviated New drug Application for Generic
Products
According to the definition established by the FDA, a
generic drug is “a drug product which is comparable to
a reference (brand) listed drug product in dosage form,
strength, route of administration, quality, performance
characteristics, and intended use”. Before a generic
medicine can be made available to the public in USA
market, it must go through a rigorous quality control
review process to receive approval from the U.S. Food
and Drug Administration (FDA). The US FDA reviews
each generic to make sure it’s equivalent to the brand
name product in effectiveness, safety, active ingredients,
performance, strength, dosage forms (tablets, capsules,
liquid, creams, etc), and dosage regimen. If any generic company submits dossier to US FDA, then it is
called ANDA (Abbreviated New Drug Application) file
for US FDA [6].
Generic drug applications are termed "abbreviated"
because they are generally not required to include preclinical (animal) and clinical (human) data to establish
safety and effectiveness. Instead, generic applicants
must scientifically demonstrate that their product is
bioequivalent (i.e., performs in the same manner as the
innovator drug) [8].
ANDA = NDA- (Toxicology studies + clinical studies)
Using bioequivalence as the basis for approving generic copies of drug products was established by the
"Drug Price Competition and Patent Term Restoration
Act of 1984" also known as the Waxman-Hatch Act.
This Act expedites the availability of less costly generic drugs by permitting FDA to approve applications
to market generic versions of brand-name drugs without conducting costly and duplicative clinical trials. Brand-name drugs are subject to the same bioequivalence tests as generics upon reformulation [9].
Generic company is the company which must manufacture the product similar to brand or Innovator
Company in term of dosage form (tablets, capsules,
liquid, creams, etc), active ingredient(s), strength
(10mg, 20mg, etc), dosage regimen. Generic company
generally distributes medicine in regional area and the
outside of regional area after getting approval from
regional respective government regulatory agency [6].
PHARMACEUTICAL MARKET
Basically the global pharmaceutical market can be divided into three categories depending upon the spectrum of control a government body [Pharmaceutical
products are generally governed by Food and Drug
Administration (FDA)] institutes on pharmaceutical -
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-industry, from requiring papers of R&D departments,
reviewing results of clinical drug trials, and controlling
the environment in which a drug is manufactured through
stringent licensing laws.
Regulated (US, Europe, Japan)
Regulated pharma market constitutes 88 % of the total
global pharmaceutical market. Regulated pharma markets
(eg.USA, Europe) markets require submission of dossier
in Common Technical Dossier (CTD) format containing
exhaustive information about clinical trial and bioequivalence studies of the drug.
Semi-regulated (Africa, Australia, Latin America and
Russia)
As against this, semi-regulated pharma markets require
Asian Common Technical Dossier (ACTD) format which
does not require exhaustive details like CTD.
Domestic (Other world countries)
Semi regulated and Domestic market constitutes 12% of
the global pharmaceutical market 10.
The global pharmaceuticals market is worth US$300 billion a year, a figure expected to rise to US$400 billion
within three years. The 10 largest drugs companies control over one-third of this market, several with sales of
more than US$10 billion a year and profit margins of
about 30%.Out of ten, six are based in the United States
and four in Europe.
The United States accounts for almost half of the global
pharmaceutical market (revenue wise) and for bringing a
product into US market, new pharmaceutical products
must be approved by the Food and Drug Administration (FDA) as being both safe and effective [11].
Role of Indian Pharmaceutical Market in Generic Products
The Indian pharmaceutical industry consists of both
domestic companies and subsidiaries of multinational
corporations. Indian companies manufacture a wide range
of generic drugs, intermediates, bulk drugs and Active
Pharmaceutical Ingredients (API). However generic drugs
continue to remain the mainstay of these industries. Over
the last 30 years, India’s pharmaceutical industry has
evolved from being a marginal global player to becoming
a world leader in the production of high quality generic
drugs. India exports pharmaceutical products to more
than 200 countries, primarily the United States, Russia,
China and the United Kingdom. India’s single largest
export market continues to be the United States, which is
the world’s largest generic drug market [12].
Benefits of Generic Drug Products
India also has the largest number of US FDA approved
manufacturing sites outside the US. The Hatch-Waxman
Act enacted in 1984 allowed generic drugs to enter the
market (after patent expiry) without repeating expensive
animal, clinical and bioavailability studies required for
their brand-name counterparts, resulting in substantially
lower price of the drugs, which benefits the public and
makes healthcare more affordable. But, the rules that
govern generic drugs ensure strict oversight of quality
so that lower prices do not necessarily translate to
lower quality drugs [13].
Processes in Generic Product Development
Generic drug companies bring the generic version of
the innovator/ brand drug product to the market at a
substantially lower price, which benefits the public and
makes healthcare more affordable. The process of
bringing a generic version of an established brand
name drug to market is not as simple as just copying
the brand-name product. The generic company, too,
must conduct certain studies, and pass strict standards
set forth by the regulatory bodies [13].
Generally, generic product development process has
following steps as shown in the figure 1:
Fig 1: Flow Chart depicting different stages of pharmaceutical product development
Note: The order of performing the various stages may
change depending on the product under development.
These guidelines may be modified for other geographic
zones.
Details of Common Steps Involved In Generic Product Development:
Product development processes are organized in a
way that requires participation by virtually all the major functions within the organization such as strategic
planning, marketing, product design, manufacturing
and financial planning and budgeting [14].Prior to generic product development a product for development
must be selected. In order to properly select a product,
input is needed from a variety of disciplines including:
• Research and development
• Regulatory Affairs
• Legal
• Marketing & Sales
• Finance, etc.
Depending upon the outcome from these departments
the generic product to be developed is selected. But, the
main driving force behind the selection of generic drug
product for manufacturing is the estimated sales volume for the marketed product [15, 24].
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Literature Survey: Once the product is selected generic
company should to extensive literature survey, which
involves the following steps:
• Study on Research and Development,
• Patent expiry,
• Data exclusivity,
• Regulatory affairs,
• Legal country requirements,
• Marketing & sales,
• Finance,
• on-line computerized search (websites etc.)
After literature survey, the selected product should be
recorded into some kind of document to include information such as:
• Innovator Product Description and Dosage Form
• Innovator Product Packaging Description
• Innovator Product Sales
• Generic Product Description and Dosage Form
• Generic Product Packaging Description
• Generic Sales Forecasts
• Intended Manufacturing Site
• Intended Production Batch Size
• Any other relevant information
Based on patent expiry, product exclusivity, forecasts,
availability of the active ingredient etc., the project needs
to be scheduled and its’ progress tracked and managed
with the goal of being the first generic drug manufacturer
(for that particular product) on the market [14, 15].
Active sourcing/evaluation/purchasing/testing
The successful development of a generic drug product
starts with the Active pharmaceutical ingredient (API).
The government health authorities are concerned about
the quality and safety of API which generic companies
use in their product and which is not only maintained by
the generic company but also bulk manufacturing company of API. Therefore, the company should identify and
evaluate at least two potential suppliers of the API based
on the following points:
Drug Master File (DMF) availability: A drug master file
(DMF) is a master file that provides a full set of confidential detailed information about facilities, processes, or
articles used in the manufacturing, processing, packaging,
and storage of one or more human drugs.
Compliance with USP monograph: The specifications
developed for a new generic API must meet all USP
monograph requirements, if an USP monograph exists for
that API.
Statement of non-patent infringement: It states that, the
process pathway does not infringe any patent(s) that may
be in force and must be verified by the generic company’s
patent lawyers.
Impurity profile and stability: API supplier should give
information about the total impurity profile (identified &
unidentified) of the said API.
Potential Polymorphic forms: Obtain complete information on the various polymorphic form of the API, as
they affect the final efficacy of the product.
Commitment for physical specifications: The API supplier should give complete details of the physical form
characteristics of the API like particle size, shape, distribution etc which ultimately affects the performance
characteristics of the product [15, 19].
API Testing and Analytical Method Development:
API Testing:
After Identifying and purchasing, perform actual testing of the API in R&D analytical lab as per:
•Pharmacopoeia monograph (if present)
•Pharmacopoeia Forum (if available)
•In-house method (based on manufacturer)
•Supplier's test methods and specifications [15, 16]
Analytical Method Development
Analytical methods should be developed for API as
development of a generic drug product begins with full
analytical testing and reproducible characterization of
the API. Once the API method is developed, the analytical chemist can begin the method development for
the dosage form. Method’s specificity, sensitivity, linearity, reproducibility, precision, and accuracy for quantification of the drug in a dosage form should be established [15].
Pre-formulation
Prior to preparing actual trial formulations of generic
product, “pre-formulation” work must be performed to
obtain as much information about API and the innovator/
reference drug product as possible. Common preformulation activities include the following: review of
the product selection document, review of any pertinent
patent information, the physicochemical and biological
properties of the drug substance that can influence the
performance of the drug product and its manufacturability should be identified and discussed. Examples of
physicochemical and biological properties that should
be examined, as appropriate, include determination of
drug form (i.e. crystalline, powder, amorphous), drug
solubility, polymorphism, particle size, bulk density,
flow characteristics, chemistry (i.e. pKa, functional
groups),
drug
absorption
characteristics
(pharmacokinetics), incompatibilities, sensitivities (light,
heat, moisture), etc, identification of a discriminating
dissolution procedure with relevant in-vitro/in- vivo correlations. These properties could be interrelated and,
when appropriate, should be considered in combination
[14].
Innovator’s product purchase and evaluation:
This step includes obtaining samples of reference product
(innovator product) and packaging, evaluation of physical characteristics of the reference product, determination of reference drug release characteristics through
“in-vitro” dissolution profiling, obtaining and review of
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all available public information about the innovator or
“reference” product t h r o u g h PDR, CPS, Merck Index,
product labels and inserts, published literature in
pharmaceutical and medical journals, etc. In general
for each strength at least 3 different lots in smallest and
largest pack size are purchased and evaluated [6, 14,16].
Excipients Selection
A generic product formulator quantifies the inactive
materials to develop a convenient size and shape of
product as well as to develop the manufacturing process
for solid dosage form, such as sieving, direct mix, dry
granulation/ wet granulation, drying, grinding, lubrication, ready granules, compression into tablets or fill into
capsule shell [6].
The excipients chosen, their concentration, and the characteristics that can influence the drug product performance (e.g., stability, bioavailability) or manufacturability
should be discussed relative to the respective function of
each excipients [25]. This should include all substances
used in the manufacture of the drug product, whether they
appear in the finished product or not (e.g., processing
aids). Compatibility of excipients with other excipients,
where relevant (for example, combination of preservatives in a dual preservative system), should be established. The ability of excipients (e.g., antioxidants, penetration enhancers, disintegrants, release controlling
agents) to provide their intended functionality and to perform throughout the intended drug product shelf life
should also be demonstrated [26].
Selection of inactive ingredients (excipients)
Generally, following points are considered during
selection of inactive material:
Composition of reference product (if available) - Physicians’ Desk Reference (PDR), CPS or product labels
will often list qualitative composition of formulations,
Requirement for specific excipient- formulations should
start out simple, with additional, specialized excipients
being incorporated as needed through experimental
trials,
Drug/Excipient Incompatibilities- Drug characterization
and pre-formulation studies may exclude specific excipients due to potential incompatibility or stability issues,
Excipient characteristics/Affect on drug substance release- Depending on the drug substance, certain excipients may be selected due to their affect at enhancing
or retarding the release of the drug substance to produce
the desired “in-vitro” dissolution release profile.
Formulation process- certain excipients are specialized
for direct mixing processes whereas others are more
suitable for wet granulation processes.
Availability- Excipients most readily available are usually
selected over excipients that may be equally adequate, but
not readily available,
Experience- Formulators usually select excipients with
which they have the most experience, even though there
may be equivalent excipients to perform the same function,
Cost- with two functionally equivalent, equally available excipients, the cheaper of the two may be selected
[6, 14].
Container closure system
The choice and rationale for selection of the container
closure system for the commercial product should be
thoroughly reviewed. Consideration should be given to
the intended use of the drug product and the suitability
of the container closure system for storage and transportation (shipping), including the storage and shipping
container for bulk drug product, where appropriate.
Following points should be considered while choosing
a container-closure-liner system:
• Material composition,
• Type of thermoplastic resin and resin pigments,
• Manufacturers and suppliers,
• Liners and seals used by closure manufacturer,
• Cotton and desiccants.
Manufacturer's DMF numbers for all component parts
[16,17].
Formulation Development
Following the “pre-formulation” activities, decisions
can be made about the type of formulation and process to be considered for development of generic product.
Once pre-formulation work and a development strategy
are completed, a series of small-scale trials are performed. These trials involve processing the drug substance with excipients using the selected process to
produce a dosage form with the desired strength and
appearance dictated in the product selection document.
The dosage form is then physically and chemically
evaluated to determine its acceptability relative to the
reference product.
Example: The following represents the common types
of testing performed on tablet formulations under development:
Blends
Physical Testing: Bulk and tapped density, particle size
distribution, flow index, angle of repose, moisture and/
or L.O.D.
Chemical Testing: Blend uniformity
Tablets
Physical Testing: Appearance, average weight and
weight variation, hardness, thickness, friability, disintegration time
Chemical Testing: Dissolution profiles vs. reference
product, assay, content uniformity, chemical identification, impurities and related substances, ICH stability
Development trials continue until a formulation with a
matching dissolution profile, relative to the reference
product, is obtained in one or more dissolution media
[14].
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In-vitro dissolution profile
A generic product formulator adjusts the quantity of
excipients and modifies the manufacturing process to
match in-vitro dissolution profile of generic product
(such as tablet, capsule, etc) with innovator or reference
product at these specified media (pH 1.2, buffer pH 4.5,
buffer pH 6.8 and purified water). Matching of in-vitro
dissolution profile with innovator or reference product is determined by f1 (difference factor) and f2
(similarity factor). If f2 value (similarity factor) calculated from in-vitro dissolution profile of generic product
with innovator or reference product is less than 50 and f1
value (difference factor) is more than 15, a generic product formulator must reformulate and modify manufacturing process till to get f2 value more than 50 and f1
value less than 15. The more the f2 value (limit 50-100)
and the less the f1 value (limit 0-15) indicates the more
matching of in-vitro dissolution profile of generic product with innovator or reference product, which ensures more probability to pass bioequivalent test.
If f1 (difference factor) is more than 15 & f2 (similarity
factor) is less than 50 = Reformulate product [6].
Pilot/Scale Up/Optimization/ Process Qualification
Batch
Once in-vitro dissolution profile is matched, the formulation should then be scaled-up (Scale Up batch) to a
slightly larger size (20,000 units) from the initial development batch size of 5000 units.
It is also termed as ‘pilot batch’ as it involves manufacturing of a drug substance or drug product on a reduced
scale by processes representative of and simulating that to
be applied on a larger commercial manufacturing scale.
Samples of the resulting dosage form are then packaged
in all possible configurations intended for future commercialization, and placed on accelerated stability stations for
monitoring. In the meantime, additional trials should be
prepared to optimize various formulation and process
parameters. These optimization trials are very important
and serve to:
• Determine limitations by challenging various process
parameters
• Identify significant formulation or processing issues
that can be addressed before the product formulation
and process is “locked” (i.e. prior to bioequivalency
testing)
Scale Up batch is also sometimes referred as ‘Process
Qualification Batch’ which is manufactured in order to
detect any problems that may arise during the manufacture of production size batches, allowing a solution prior
the manufacture of the pivotal demonstration batch. The
process qualification team and production personnel
should discuss formula and process instructions and decide on optimum batch size, and then define critical processing steps and test parameters to be evaluated [6,
18,19].
Pivotal Batch
If the product retains acceptable physical and chemical characteristics, it is further scaled-up under GMP
conditions to serve as the “exhibit batch” infront of the
regulatory bodies.
According to FDA, the exhibit batches intended to
support an ANDA submission comprise a minimum of
100,000 finished (net) dosage units. or 10% of the
batch size intended for commercial production, whichever is greater. Some firms prepare documentation for
100 000 dosage units gross, ignoring the fact that there
may well be 2% to 5% production losses. The net batch
yield turns out to be 98 000 or 95 000 dosage units well
below the 100 thousand net required by FDA’s Office
of Generic Drugs (OGD).
It is prudent to scale the pivotal batch for at least 120
000 dosage units. Remember the pivotal batch may
range from 10% net to 100% (i.e. full size) of the proposed commercial batch size. Experienced Generic
firms who do not anticipate any problems with the pivotal documentation often target the pivotal quantity to
70% of the proposed commercial lot thus achieving
appropriate scale-up and pivotal in a single batch.
This batch is also known as Bio-Batch , as it is sent
to bio centre (approved by regulatory bodies) for invivo bioequivalence testing vs. the reference product. Aim of bioequivalence study is to measure the time
it takes the generic drug to reach the bloodstream in 24
to 36 healthy, volunteers. This gives them the rate of
absorption, or bioavailability, of the generic drug,
which they can then compare to that of the innovator
drug. The generic version must deliver the same
amount of active ingredients into a patient's bloodstream in the same amount of time as the innovator
drug. US FDA publishes product-specific guidelines
for BE studies. All details are mentioned regarding
conditions of BE studies [14, 19, 20].
ANDA submission
If the products prove to be “bioequivalent” to the
reference product or innovator product, a submission
package is assembled and submitted to the respective
Government Regulatory Agency for review and eventual approval. At present when a generic company
wants to submit product for registration to EU, US
FDA & respective government regulatory agency
of developed countries, their government health
authorities demand for DMF (drug master file) of API
(drug substance and excipients), cGMP certificate of
API and manufacturing facility, FDA approval certificate of API, COS (certificate of suitability) to
identify reliable source of bulk API manufacturing
company. The government health authority concerns
about quality and safety of API which generic companies use in their product. Quality and safety of drug
product depends not only on generic company but also
bulk manufacturing company of API.
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Authorities of EU, US FDA and respective government regulatory agency of developed countries at present
tell generic company to submit registration dossier of
any generic product (ANDA) in Common Technical
Document (CTD) format whose contents are mentioned in ICH guidelines. Registration Dossier of a
generic product in CTD format consists of information
sufficient to reflect quality and safety of drug product.
India will soon be adopting a Common Technical Document (CTD) for the import, manufacture and marketing
approval of new drugs. India’s Union Ministry of Health
has produced a draft notification for the preparation of the
CTD in January, 2011. Until now, applicants have used
many different formats for the filing of their application
materials, making the review process difficult and time
consuming [14, 21].
Validation
The key to a successfully developed generic product
goes beyond a successful bioequivalency study, product
approval, and a successful process validation study. A
truly successful generic product is a product that can be
made repeatedly, by any trained operator, on any qualified piece of equipment, at any time of the year, without
any problems. We like to refer to a formulation and process with such characteristics as “robust”. Spending more
time, effort, and planning during the development of any
product will certainly generate the type of “robust” products desired.
According to the FDA’s guideline, process validation is
defined as ‘Process validation is establishing documented
evidence which provides a high degree of assurance that a
specific process will consistently produce a product meeting its pre-determined specifications and quality characteristics’.
The formal validation process may begin during the
manufacture of the bio-batch if the intended production
batch size is the same. As per the regulatory requirement,
three consecutive production size batches are required for
the completion of process validation [14, 22, 23].
CONCLUSIONS
This review encompasses the various aspects of pharmaceutical drug product, applications, pharmaceutical
market and important steps involved in the development
of generic solid oral formulations viz tablets and capsules. The review is intended for new researchers who are
interested in learning about the field of generic pharmaceutical product development perhaps for better understanding of the topic.
REFERENCES
[1] Code of Federal Regulations Title 21, Volume 4, Revised as of April 1, 2013, CITE: 21CFR210.3. Available from URL: http://www.accessdata.fda.gov/
scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=210.3.
[2] Guidelines on submission of documentation for
prequalification of innovator finished pharmaceutical products approved by stringent regulatory
authorities (Annex 11), World Health Organization, WHO Technical Report Series, No. 961,
2011. Available from URL: apps.who.int/prequal/
info general/documents/TRS961_Annex11.pdf
[3] Multisource (Generic) Pharmaceutical Products:
Guidelines on Registration Requirements to Establish Interchangeability, World Health Organization Mondiale De La Sante. Working document
QAS/04.093/Rev.4, 2005. Available from URL:
h t t p : / / w w w . wh o . i n t / m e d i c i n e s / s e r v i c e s /
expertcommittees/pharmprep/
QAS04_093Rev4_final.pdf
[4] Di Masi J A (1995) Success Rates for New
Drugs Entering Clinical Testing in the United
States. Clinical Pharmacology and Therapeutics.
58: 1-14.
[5] DiMasi JA, Hansen RW, Grabowski HG, Lasagna L (1995) Research and development costs for
new drugs by therapeutic category: a study of the
US pharmaceutical industry. PharmacoEconomics. 7:152-69.
[6] Dulal, M (2011) Development of Generic Drug
Product of Solid Dosage Form and International
Regulatory Affiars. Pharma Mirror. 4: 1-3. Available from URL: http://pharmamirror.com/
pharmaceutical-articles/development-of-genericdrug-product-international-regulatory-affairs/
[7] http://www.fda.gov/Drugs/Development Approval Process/How Drugs are Developed and
Approved/Approval Applications/New Drug ApplicationNDA/
[8] http://en.wikipedia.org/wiki/Abbreviated_ New_
Drug_Application
[9] http://www.fda.gov/Drugs/Development Approval Process/How Drugs are Developed and
Approved/Approval Applications/Abbreviated
New Drug Application ANDA Generics/
[10] http://www.marksanspharma.com/industryinfo.htm
[11] http://www.who.int/trade/glossary/story073/en/
index.html
[12] Asia Business Generator Project; Osaka International Business Promotion Center (2007). Overview of Indian Pharmaceutical Industry. Tata
Strategic Management Group, 1-5. Available
from URL: www.ibpcosaka.or.jp/.../e.../e_india_
abg_pharmacy_report200803.pdf
[13] Perkins D, Clemens R, Richmond F (Ed). The
Generic Pharmaceutical Industry, 15-19. http://
regulatory.usc.edu/Articles/
GenericPharmaceuticalIndustry.pdf
357
Rakhee et al /International Journal of Pharmaceutical Sciences Letters 2014 Vol. 4 (2)| 351-358
[14] Carter JC (2003). Developing a generic drug product. Carter Pharmaceutical Consulting Inc. Available from URL: http://www.carterpharmaceutical
consulting.com/articles/developing-a generic-drugproduct.html
[15] Shargel L and Kanfer I (2005) Generic drug product
development- solid oral dosage forms. Drugs and the
pharmaceutical sciences series, Marcel Dekker Series, Mcgraw-Hill Publications: New York, pp 257279.
[16] Handbook of pharmaceutical generic development,
sect. 2.22, chapter 2, oral tablets, Locum International Publishers.
[17] http://www.who.int/medicines/areas/quality_safety/
quality_assurance/Annex3TRS-970.pdf
[18] Levin M (Ed) (2001) Pharmaceutical process scaleup. Metropolitan computing corporation, East Hanover, New Jersey: Marcel Decker series.
[19] From Pre-formulation to End Formula, International
Journal of Generic Drugs 402-407. Available from
URL: http://www.locumusa.com/pdf/journal/
ijcomp.pdf
[20] Aurbindo Annual report 2009-2010 , page no 25
[21] http://www.massdevice.com/blogs/ames-gross/asianregulatory-update-new-industry-standards-medicaldevices-china
[22] Nash R A, Wachter A H (2003) Pharmaceutical
Process Validation, Third Edition, volume 129. New
York: Marcel Dekker, Inc. 59-180.
[23] The European agency for the evaluation of medicinal products; Note for the guidance on process
validation.2001. Available from URL: http://
www.ema.europa.eu/docs/en_GB/document_ library/Scientific guideline/2009/09/WC500002913.
pdf
[24] Liu B. Product development processes and their
importance to organizational capabilities, Massachusetts Institute of technology, 1994. Available
from
URL:
dspace.mit.edu/bitstream/handle/
1721.1/34796/57535687.pdf
[25] Gad, S. C. (ed) (2008) Front matter, in Pharmaceutical Manufacturing Handbook: Production and
Processes. Hoboken (Pharmaceutical Development
Series), NJ, USA: John Wiley & Sons, Inc.
[26] Guidance for Industry, ICH Harmonised Tripartite,
"Pharmaceutical development”, Q8, May 2006.
Cite this article as:
Rakhee Kapadia and Krutika K. Sawant. Short Review on Processes Involved In Development of Generic Solid Oral Products. Int. J. Pharm. Sci. Lett.
2014 : 4: (2) 351-358
Source of Support: Nil.
Conflict of interest: None declared.
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