Shefali et.al International Journal of Drug Regulatory Affairs.

2021; 9(2): 66-76

Available online on 15 Jun, 2021 at https://ijdra.com/index.php/journal

International Journal of Drug Regulatory Affairs

Published by Diva Enterprises Pvt. Ltd., New Delhi
Associated with Delhi Pharmaceutical Sciences & Research University
Copyright© 2013-21 IJDRA

Review Article Open Access

Indian Active Pharmaceutical Ingredient (API) Industry- An overview on

Challenges, Opportunities & Regulatory prerequisites
Shefali Singh* and Harvinder Popli
Department of Regulatory Affairs, School of Pharmaceutical Sciences, Delhi Pharmaceutical Sciences and Research University, New
Delhi, India

Abstract
Active pharmaceutical ingredient is a chemical compound which is most important raw material to formulate a finished
pharmaceutical medicine and has a pharmacological effect. India has a long history of being heavily dependent for these raw materials
on China due to one major reason i.e. Low manufacturing cost. But overdependence of APIs imports from China brought various
liabilities to India including supply chain disruption and price hikes during pandemic, leading to shortage of various important
APIs/KSMs. This COVID 19 widespread has solidly put the center of our country on being “Atma Nirbhar”. And this activity had
brought out the strengths, market patterns and opportunities in five divisions counting Healthcare, which are basic from country‟s point
of view. In view of changing geo-political situation and recalibrated trade arrangement, it is crucial that India become self-reliant within
the generation of APIs and KSMs, which is why decreasing the Import reliance for Active pharmaceutical ingredients (APIs) & Key
starting materials (KSMs) particularly from china has been focused upon with the assistance of productive linked incentive scheme
(PLIS) passed by Department of pharmaceuticals, Government of India to thrive Indian API industry.
Hence, this review highlights the current state of Indian API industry, evaluates challenges, opportunities give suggestions for moving
forward for self-sufficiency of APIs as well as centers on current regulatory prerequisites for Active pharmaceutical Ingredients.
Keywords: Active pharmaceutical ingredients, Indian API industry, overdependence, PLIS scheme, API market insights, Regulatory
prerequisites

Article Info: Received 21 May. 2021; Review Completed 12 Jun. 2021; Accepted 14 Jun. 2021
Cite this article as:
Singh S and Popli H. Indian Active Pharmaceutical Ingredient (API) Industry- An overview on Challenges, Opportunities
& Regulatory prerequisites. Int J Drug Reg Affairs [Internet]. 2021 Jun 15 [cited 2021 Jun 15]; 9(2):66-76. Available from:
http://ijdra.com/index.php/journal/article/view/471
DOI: 10.22270/ijdra.v9i2.471
*Corresponding author
1. Introduction billion. There are about 3,000 pharmaceutical companies
and 10,500 industrial units in this sector. Despite a very
According to WHO, Active Pharmaceutical
strong foundation, domestic pharmaceutical companies
Ingredient is defined as “a substance used in a finished
have consistently stopped manufacturing APIs in lieu of
pharmaceutical product(FPP),intended to furnish
importing APIs, which was a cheaper option with higher
pharmacological activity or to otherwise have direct in
benefit margins on drugs, due to low benefit margins and
the diagnosis, cure, mitigation, treatment or prevention
a non-profitable industry. In 2019, India imported Rs
of disease, or to have direct effect in restoring, correcting
249 billion of intermediates and APIs, with China
or modifying physiological functions in human beings.”
accounting for about Rs 169 billion. (4)
(1) The effectiveness and safety of drugs are entirely
dependent on the quality of APIs, implying that low- A total of 600 APIs and Drug Ingredients are
quality APIs can cause serious problems such as imported into India, with 58 molecules coming
illnesses and even death. API has a direct effect on the exclusively from China. Due to the availability of lower-
quality and cost of pharmaceutical products. (2) India is cost APIs from China, the pharmaceutical industry has
a major player in the API market and counted among become increasingly reliant on imports and has shifted to
world's fastest-growing economies. The Indian API more productive formulations. Imports from China have
industry has progressed from being known for producing been steadily increasing, and now account for around 68
simple API molecules to becoming the preferred percent of total imports. The API market in India was
destination for high-value and complex API. (3) The worth Rs 574 billion in 2018 and has grown at an annual
global pharmaceutical market is valued at USD 1.2 rate of 8.6% to reach Rs 735 billion in 2019. By 2024,
trillion, with the API market valued at USD 182.2 the Indian API market is expected to be worth around Rs

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1109 billion. API currently accounts for about one- number of FDA-approved plants in India is the highest
fourth of the Indian pharmaceutical market, with in the world (665),), accounting for 44 percent of all
formulations accounting for the remainder. With around global abbreviated new drug applications (ANDA). The
1,500 units, India's API industry is highly fragmented. Government of India has launched a number of
During 2018-19, the top 14-16 companies (which also initiatives, including clusters and the Production Linked
included larger detailing firms) accounted for 16-17 Incentive (PLI) scheme, to advance API (bulk sedate).
percent of the total market share. According to a KPMG The PLI scheme makes a difference by assisting
report, India's share of total pharmaceutical exports for domestic manufacturers with the „Make in India'
bulk drugs and intermediates has declined from 42 initiative. Over the last few decades, India's
percent in 2008 to 20 percent in 2018. In 2020-2021, pharmaceutical industry has grown tremendously. In
India is expected to export APIs worth Rs 303 billion. terms of volume, India supplies 20 percent of the global
The revenue generated by the export of bulk drugs is demand for generic drugs and more than 60 percent of
roughly one-fourth of the revenue generated by the the global demand for various immunizations and
export of formulations. (4) India had stopped producing antiretroviral (ARV) drugs. About 57 percent of APIs on
APIs for various antibiotics, vitamins, and even steroids. the World Health Organization's prequalified list come
Intermediate preparations such as atorvastatin, from the Indian region. (6)
chloroquine, ciprofloxacin, cephalosporins, immune-
History of API imports from China to India 2012-2019
suppressants, and others have also been discontinued in
(INR crore)
India. India has increased its imports of API from China
as a result of the globalization of Indian pharmaceutical Low-quality APIs supplied by Chinese API
companies and the growth of mega manufacturing manufacturers, on the other hand, have resulted in the
facilities in China. The lower production cost is a key recall of a number of products due to API impurity
driver for the increased import of APIs. issues in recent years. Along with it, the COVID-19
pandemic has disrupted the API supply chain, resulting
An overview on market insights of Indian API industry
in a shortage of many drugs. These factors have
During the forecast period, the market of Indian bulk prompted the government to promote a self-sufficiency
drug Industry is anticipated to grow at an elevated rate plan in order to reduce reliance on China. The Indian
(2020-2026). India's pharmaceutical industry lies at the government approved a production-linked scheme worth
third position among the largest pharmaceutical INR 6,940 crore in March 2020 to encourage domestic
industries in the world, in context of production volume manufacture of essential drug intermediates and APIs, as
and in context of value, it is termed as the thirteenth well as a 3,000 crore scheme to promote bulk drug
largest in the world. The rising prevalence of chronic parks. Concerns about the quality of imported APIs from
diseases, as well as the growing importance of generics, China, as well as supportive government programmes to
is two main elements driving the flourishment of Indian increase domestic API production, have reduced reliance
bulk drug market. The market is also growing due to on China and are creating significant opportunities for
advancements in API manufacturing and the new and existing domestic API producers. Figure 1
development of the biopharmaceutical division. (5) The reflects the extent of dependency on different countries
industry's growth has been fuelled by the adoption of to outsource APIs/KSMs, with largest percentage of low
international standards and the establishment of large- value and high volume being sourced from China despite
scale manufacturing plants within the country. The of proven strong chemistry skills of Indian industry. (7)

20% China
2% US
3%
3% Italy
4% Singapore
68%
Hong-Kong

Rest of the world

Figure 1. High dependence on China for API & KSM Imports (7)

2. Comparative Study of India and China (8, 9) important vitamins, antipyretics, analgesics,
antihypertensives, hypocholesterolemics, and anti-
By volume of API production, China has surpassed
anginals are among the APIs and intermediates that
the United States as the world leader in API production
China produces in large quantities.
and export. Precious antibiotics like penicillins,
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Table 1. China vs. India: Manufacturing Potential for Selected APIs (4, 8)

Active pharmaceutical A Chinese firm's average An Indian firm's average

ingredients potential(Million tones/ potential(Million tones/
annum) annum)
Simvastatin 500 150
Cefexime and lactic acid 600 200
Pregablin 500 150
Gabapentene 14000 3000
Amoxycillin 14,000 5000
Losartan 600 200

The Indian bulk drug (API) industry is worth INR ~800 common steam supply, cooling water, chilled water,
billion in 2020 and is anticipated to grow at an annual nitrogen gas, and compressed air are available in China's
rate of 8.57 percent to INR 1,307 billion by 2026. bulk drug parks. To provide an uninterrupted power
supply and steam, coal-fired power plants with
The Chinese bulk drug (API) industry is worth INR
capacities of up to 250 MW and dual power transmission
~1000 billion in 2020 and is anticipated to grow at an
lines are typically constructed. The capacity of most
annual rate of 6.49 percent to INR 1,431 billion by 2026.
effluent treatment plants ranges from 50,000 to 100,000
Support for Chinese policies (10) MT per day. Companies are charged INR 30 per MT of
waste water with a COD level of 500.The clusters are
China has strategically implemented a number of
also close to ports and airports, allowing for better
programmes and initiatives, including policy and
logistical support.
infrastructure reforms, to help the pharmaceutical and
related raw material industries gain traction and scale. Investor-friendly culture
This entails fostering innovation across the value chain,
Greater transparency in central and provincial
shortening approval processes, improving efficiencies,
procurement processes China provides an income tax-
and delivering essential utilities at reduced rates.
free period for the first three to five years after
Faster approval process commercial operations begin. A portion of the VAT tax
is refunded, as is a portion of the employers' income tax.
By joining the „International Council for Direct price control is being phased out, and
Harmonisation of Technical Requirements for administrative price supervision is being strengthened.
Pharmaceuticals for Human Use (ICH),' the Chinese
Electronic monitoring system for pharmaceutical
government improved its integration into the
products is being implemented.
international bulk drug market and streamlined its
regulatory procedures to meet international standards – Support for Indian policy (11)
This move paved the way for more foreign investment
India also intends to boost the production of APIs in
and cooperation in China's bulk drug companies. The
the country. The Indian government had tasked the
Chinese government has made significant investments in
Katoch Committee with recommending measures to
biologics and biosimilars, both of which are next-
ensure the country's bulk drug self-sufficiency. The
generation drugs. In recent years, the Chinese
following recommendations were made by the
government has spent around USD 1.6 billion on new
committee in its 2015 report:
drug growth, Adoption of Trade-Related Aspects of
Intellectual Property Rights (TRIPS)-compliant  Six large API manufacturing clusters or mega parks
intellectual property (IP) rules and regulations, as well as will be established in five to six states. These
increased administrative capacity in IP offices, to clusters would be equipped with common effluent
expedite patent application review. China has developed plants, testing equipment, reliable power, and IPR
a „Thousand Talents Plan' to attract 50,000 PhDs from management, among other things.
around the world through research funding, as well as a
collaborative research ecosystem in which returning  Manufacturers are given cash incentives: – A 15-
talent will form major alliances between multinational year tax break for cluster participants and
corporations, universities, and other businesses – A developers – If a Finished formulation is developed
national emphasis on PhD scholars with an interest in the from a locally produced API, the government is
pharmaceutical industry. 50 – Provincial and/or local considering exempting suppliers from the Drug
R&D „parks' have been established to provide economic Price Control Order (DPCO). – Subsidized land and
and/or infrastructure-related benefits. Low-cost facilities, other infrastructure, along with interest subsidies on
R&D grants or subsidies, loan access, and tax benefits bank loans (through interest subvention up to 7.5
are all possibilities. per cent) – provided the plant is first needed to be
approved by the environment ministry, API
Investing in infrastructure manufacturers will receive a single-window
It has also expressed a strong desire to improve environmental clearance for all drugs. – For each
supporting infrastructure, such as common facilities, product, income tax benefits are available for the
logistics, and continuous processing, all of which will first ten years from the date of launch.
help to boost productivity. Common utilities such as
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 A proposal was also submitted to provide venture Financing, logistics, production, and set-up costs are
capital funding to pharmaceutical SMEs with a all included in the cost of production and breakup.
corpus of around INR 5 billion. Infrastructure investment, labour productivity and cost,
large-scale manufacturing capacities, scale of operations,
Technology Upgradation Assistance Scheme Access and cost of capital, technological capabilities,
Small and medium enterprises (SMEs) in the pharma logistics facilities, land reforms and supportive
sector will get interest subventions on loans taken for government policies, among other factors, are
technology/infrastructure development to meet WHO anticipated to accelerate China to the top of the market.
GMP standards under the Scheme for Development of China's production costs are roughly 20-30% lower than
Pharma Industry in India. India's. In comparison to China, India's raw material
costs are 25-30% higher. In comparison to China, India's
India vs. China (Cost breakdown and comparison (4) labour costs are 1.85% lower.

*Source: CII-KPMG Report 2020, Ind-Ra

Figure 2. Comparison of India and China on factors of cost competitiveness for API (9)
3. Challenges impacting Indian bulk Drug Industry setting up operations, and accessing utilities has
(4,12) increased.
Indian bulk drug industry has great potential, but it Issues with environmental clearances (4)
must overcome key challenges such as limited
The clearance process is complicated because it
government support, insufficient infrastructure, long
necessitates approvals from several agencies, including
environmental clearance time lines, complicated
Prior Environmental Clearance from the State
regulatory structure, price control regime, and price
Environment Impact Assessment Authority; Coastal
volatility due to high import dependence. Following
Regulation Zone (CRZ) clearance from the concerned
discussions with industry leaders, the following key
State/Union Territory Coastal Zone Management
challenges have been identified:
Authority (CZMA); authorisation for the handling of
In the past, the government provided only limited hazardous waste from the State Pollution Control Board;
assistance (12) and an assessment of the surrounding environment
(MoEF & CC). Even if companies choose Zero Liquid
The government has taken no proactive steps in terms
Discharge, they may face delays in receiving approvals
of funding options and tax benefits, single window
and production quantity limitations.
clearance and fast-track approvals, capital subsidies, and
a budget for API clusters The Katoch committee's Complex approval process for setting up a
recommendations for improving the bulk drug industry, manufacturing plant
which were made in February 2015, have seen some
Multiple regulatory bodies set rules and guidelines for
progress.
the pharmaceutical and bulk drug industries, either
Inferior Infrastructure facility (12) directly or indirectly. At the policy-making level, this
multiplicity can lead to inefficiencies in resource
Due to a lack of infrastructure support, Indian API
allocation and, as a result, a split agenda. Due to
farmers are facing higher operating costs. There aren't
different decision makers, problems relating to
enough bulk drug clusters, low-cost utilities (waste
legislation can often take longer to resolve. With
management systems, steam, water, electricity, and so
different stakeholders, the approval timelines are long
on), R&D support, and skilled manpower. As of July
(about two–three years) and voluminous (about 20–25
2019, 11 of India's 232 special economic zones (SEZs)
approvals).
were devoted to the pharmaceutical industry. Due to the
lack of API-focused SEZs, the cost of acquiring land, Due to a high reliance on imports, price volatility exists
(4)

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High reliance on a single country for imports can production of 41 products including 53 essential APIs
make us vulnerable to externalities (commodity price which are highly imported from China, including anti-
fluctuations, policy changes, etc.). This can lead to price TB drugs, anticonvulsants, antiretroviral, antibiotics
volatility and supply disruptions, all of which can harm (tetracycline, neomycin, azithromycin, norfloxacin, etc.)
domestic industry. By tighter enforcement of cardiovascular, vitamins (vitamin B1, B6, B12, etc.),
environmental laws, the Chinese government took a hormones, and steroids, is a major step forward in this
proactive approach to address the country's pollution respect.
levels, minimize the concentration of hazardous fine
Economic support
particulate matter, and become compliant with
international standards. As a result, 150 API suppliers in Along with policy support, financial assistance in the
China have had to close their factories since 2018. This form of subsidized loans, partial/full waivers, capital
resulted in a 50-200 percent (short-term) increase in the subsidies, tax and duty exemptions, credit system,
cost of most widely sourced APIs and intermediates affordable interest rate for capital goods imports are
from China, depending on the product. among several necessary inputs needed to boost
domestic API production.
The effect of the Coronavirus outbreak on the supply
chain (4) Using less expensive raw materials with good quality
Smaller companies suffered more from China's The cost of raw materials from the petrochemical
production slowdown during the coronavirus outbreak industry is another advantage that India needs to achieve.
than bigger companies with diversified drug portfolios. We need to work on lowering raw material costs in India
Several pharmaceutical ingredients have increased in by bringing in a sufficient number of petrochemical
price, at least temporarily, for Indian drugmakers. companies. We have the biggest Pyridine manufacturing
Various potential antibiotics, such as Azithromycin, plant in North India, but we only use 35 percent of its
have risen in price by at least 50% since January 2020. capacity. Companies tend to purchase from outside
To address a domestic shortage of essential medicines, sources because they save money. India should consider
the Indian government has imposed export restrictions how to become more self-sufficient in basic raw
on around 26 pharmaceutical ingredients.. materials
4. Measures or ways for reducing the dependency on Utilization of Green Technology (8)
others and to promote the indigenous production (7,
13) The API industry has been recognized by the
Pollution Control Board as one of India's 18 most
The availability and cost of raw materials, technology polluting industries, necessitating the use of greener
and conversion effectiveness, maintenance, manpower, technologies. For illustration, Shri Gopinathan .C,
infrastructure, cost of capital, and logistics are just a few Associate professor of Biotechnology at University of
of the factors that influence operations in the Calicut has discovered a new process for effective
pharmaceutical industry. India must reduce the cost of production of penicillin from waste(orange peels and
all of these variables. For long-term viability and to pulp) generated during production of orange juice. This
make a mark in the global market, India needs to reduce technology not only cost effectively produces the
costs by 20% to 25%. antibiotic penicillin, but also is environmental friendly.
The process technology used is solid state
Aggregations of Bulk drug manufacturing plants
fermentation/microbial fermentation.
Companies will improve operational efficiency and
R&D on low-cost API production technology (7)
decrease their dependence on imports by generating API
manufacturing clusters. Also with the Provision of The government, for its part, must support industry-
essential facilities such as training centres, logistic academic collaboration by providing appropriate grants
centers, industrial wastewater treatment plant, testing and scholarships. Native med-tech start-ups should be
facilities and required R&D centres, all backing up with rewarded for exploiting cutting-edge technologies like
sufficient and cost-effective power supply within a 3D printing, artificial intelligence, smart sensors, and
designed facility can be harnessed by various robotics
pharmaceutical companies to incite the production of
APIs. Furthermore, operations at the current clusters in 5. Opportunities for Indian Active Pharmaceutical
Ingredients Manufacturers (14)
few states needed to be expedited.
Using policy support to encourage domestic production Alternate sourcing and self‐sufficiency in APIs /
intermediates (6)
A set of production-related policy schemes must be
implemented by the government that include incentives Maintaining Indian firm's competitiveness and
for environmental, quicker land and utility clearances, ensuring supply security for the local market would
among other things through a single window. require ensuring India's self-sufficiency in
Simultaneously, land power and water supply must be API/intermediates. Investing in next-generation APIs
made widely accessible at low prices, which is currently will help India pharma stay on the cutting edge of these
a significant competitive disadvantage. With assistance technologies and set itself apart from the competition.
of policy support by government of India, for Greenfield While indigenous skills and capacities ramp up, the
plants and different investments in order to uplift the industry should look at alternative sourcing regions

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(such as Vietnam and Indonesia). The government years to support bulk drug parks and fund common
should play a critical role in assisting the sector in infrastructure facilities at three of them. A Production
achieving API/intermediate self-sufficiency. It may look Linked Incentive (PLI) scheme to promote domestic
into establishing three to five dedicated API/intermediate manufacture of essential key starting materials (KSM),
clusters across the country. It could go even further by drug intermediates, and active pharmaceutical
providing extra incentives for players to invest in R&D ingredients has also been approved by the government
in these areas and also provide grants to academic (APIs). For a period of six years, eligible manufacturers
institutions and public-sector organisations to invest in of 53 identified essential bulk drugs will receive a
this area, as well as establish dedicated research centres. financial incentive based on incremental sales over the
base year (2019-20). Despite the fact that the initiatives
Recent initiatives taken by the government (4, 15-17)
have been approved, their timely implementation is
“AatmaNirbhar Bharat Abhiyaan Package” critical. Table 2. provides insights of schemes in Atma
nirbhar bharat abhiyaan for promotion of indigenous
The government announced a package worth INR
manufacturing. (17,18)
9,940 crore for the bulk drugs industry in March 2020, in
order to increase domestic production and exports. The
Cabinet has approved INR 3,000 crore over the next five
Table 2. Production Linked Incentive (PLI) Scheme to Encourage Indigenous Production of Essential KSMs, Drug
Intermediates, and APIs
Outline For the next six years, qualifying producers of 41 goods will receive a financial
reward based on incremental sales over base year FY2019-20.
Benefits For the next six years, qualifying producers of 41 goods will receive a financial reward
based on incremental sales over base year FY2019-20.
Total Expenses INR 6,940 Crore (US$ 938 Million)
Tenancy FY2020-21 to FY2029-30
Scheme for the promotion of bulk drug parks
Outline States will receive a one-time grant-in-aid to help them construct three bulk drug parks
with shared infrastructure, such as effluent treatment plant, monitoring and logistics.
Benefits INR 1,000 Crore (US$ 135 Million)/bulk drug park
Total Expenses INR 3,000 (US$ 405 Million)
Tenancy FY2020-21 to FY2024-25
In the wake of the Coronavirus, the government is detailed – and thus confidential – information on the
speeding up the Green Nod process for bulk drug manufacturing process, are referred to as "Drug master
project. (19) files" in most cases. A Drug Master File (DMF) is a
document that contains all of the details about an
The Indian government has agreed to speed up the
Active Pharmaceutical Ingredient (API) and submitted
environmental clearance process for projects proposing
by the API‟s manufacturer to the regulatory authority.
bulk drug projects involving bulk drugs and bulk drug
A typical DMF includes accurate and full information
intermediaries so that they can commence as soon as
on its chemistry, manufacturing, quality controls,
possible. The issue has been resolved, according to a
stability, packaging, and current GMP condition. But
memo issued by the Environment Ministry's office, and
there has been no significant guidelines generated by
will be implemented immediately. The government has
Indian regulatory authority i.e. CDSCO (Central drug
also established a committee to address the issue of
standard control organization) for DMF filling. Hence
drug shortages caused by trade restrictions caused by
India has been following US format of DMF filling for
the spread of the Coronavirus. The committee stated in
the submission of confidential data regarding drug
its report that the current stock of APIs may only be
substance (API) to CDSCO
useful for 2-3 months in order to manufacture
formulations. To avoid a shortage in India, the The Function of Drug Master File (DMF)
government has already put a halt to the export of
The DMF system was designed to enable suppliers
certain medicines such as antibiotics.
to directly share product details with regulatory
6. Current regulatory requirements for Active authorities for the analysis of applications of
Pharmaceutical Ingredients (20) pharmaceutical firms involving the material sent by
supplier. DMF allows the parties to reference the
Authorisation of API
material without any disclosure of the content of this
The API information must be included in the document to those parties and keeps the intellectual
registration document for the medicinal product itself property right protected as well.
in India. However, bulk manufacturers should file
DMF can be submitted to support following types of
separate dossiers for APIs (and in the US, also for
applications:
intermediates) with the authorities as "supporting
information" to the registrations of medicinal products  New drug application (NDAs)
in the United States, the EU Member States, and many  Abbreviated New Drug Application (ANDAs)
other countries. These dossiers, which typically contain
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 Investigational New drug Application (INDs) approval nor disapproval. Only when the technical
 Biological Licence application(BLAs) contents of a DMF are cited in other regulatory filings
 Another DMF as discussed before, then they are reviewed. After a
 Export Applications review of the DMF, an inspection at an API
manufacturing site may be requested by regulatory
Also, A DMF is NOT used as a substitute for an IND, authority.
NDA, ANDA, or Export Application. It has neither
Table 3. Type of DMF‟s (20)
TYPE 2 Information based on chemistry, manufacturing and controls of Drug substance, Drug Substance
Intermediate, Drug product and Material used in their preparation
TYPE 3 Information regarding Packaging
TYPE 4 Information based on Excipients (colorant, flavor, Essence, or Material)
TYPE 5 Information related to FDA- accepted Reference material which are not covered in other
types.(sterile manufacturing plant, toxicology etc)
*DMF Type 1 gives data regarding plant information such as manufacturing operations and facilities and not applicable
now
Prerequisites for DMF Registration 1. Original submission includes Name and
address of the following
The term "drug substance" is sometimes used to
illustrate a pharmaceutical ingredient. The registration a) DMF Holder
of active substances occurs in tandem with pre-market
b) Corporate Headquarters,
approvals such as the NDA and ANDA. That means
API does not need a separate registration process. API c) Manufacturing Processing Facility,
manufacturers are required to send data compiled in a
d) agent(s) if any
DMF. The regulatory authority examines the data and
assigns a unique DMF number. And when a finished e) contact for FDA correspondence.
product manufacturer applies for approval from the
regulatory authority, they include the DMF of the drug Also, the responsibilities of each personnel involved in
substance as a supporting document in applications manufacturing facility are Listed along with Statement
such as NDA and ANDA (Generic). of commitment.

Regulatory Requirements for the submissions 2. Amendments, when required

DMFs submitted must be in ENGLISH. In case of Drug Master File Contents

other language, a certified English translated version PART 1: Type II DMF for drug substance (Quality
must be included. information based on Module 3 of ICH CTD format).
A DMF encloses the following documents:- The general technical content is as followed. (21)

a) Transmittal Letters a) Manufacturing Sections

b) Administrative Information b) Quality operation and controls

c) Drug master File contents c) Impurities

-Quality information according to each Type. d) Validations

In case of active pharmaceutical ingredient e) Stability data
(Drug substance), Type II is taken under
consideration f) Packaging and labeling

Transmittal letters PART 2:- General information and Suggestions

1. Original Submission Environmental assessment

a) Identification of original submission: Type and DMF must include the statement of commitment from
subject of DMF as classified by FDA. the holder of DMF, stating the compliance with all
local applicable environmental laws and regulations.
b) Identification of the application (To which the
DMF is proposed to support): Name and Stability
address of sponsors, applicants/Holders and Stability study design, protocol, commitment,
documents numbers. interpretation and other information should be attached,
c) Statement of commitment: Signature of the if applicable.
Holder or authorized representative and title of PART 3:-Authorization to refer to DMF
signer typewritten.
Letter of Authorization: If the DMF is in paper format,
2. Amendments, when required all Letters of Authorization (LOAs) should be sent in
Administrative information two copies. The name of the particular item being cited,

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as well as the date on which information about that standards of Active pharmaceutical ingredients under
item was submitted, should be specified in LOAs. The designated system for managing and maintaining the
letter of authorization should not be referred to as a utmost quality throughout. It includes the API
letter of access. Even if the DMF holder and the manufactured by either of the following types
approved party are the same company, a LOA is
a) Chemical manufacturing
required.
b) Extraction process
Statement of Right of Reference: Submission of a c) Derivation from natural sources like animals,
Letter of Authorization by the recipient, along with a plants etc.
copy of the LOA and a declaration of right of d) Communition
reference. e) Biotechnology fermentation or cell-culture
f) Or combination of processes.
Critical GMP Compliance: Although the processing of
APIs is similar to the production of chemicals in certain 7. Discussion and Analysis
ways, APIs are an important part of pharmaceuticals
Pharmaceutical organizations and the government
and must be subject to stringent controls over possible
of India showed concerned about the uncertainty of the
contaminants and cross-contaminants. As a result, the
Indian pharmaceutical supply chain as outsourcing
construction of an API facilty must avoid contributing
from the manufacturing facilities in China are stopped
to any possible API pollution. (21) With the fact that
in order to stop the coronavirus disease 2019 outbreak.
critical GMP compliance must be maintained, the
(26) This step came with the realization about the
guidelines to be followed in India are as the following:
extent of dependency on China for various APIs/KSMs
In India's revised Schedule M of the Drug and and in this emergency situation, this over-dependency
Cosmetics Act, GMP specifications for API are also brought out the various major negative effects like
listed. Since 2005, API manufacturers in India have disruption in supply chain, price hikes or shortage of
been required to meet the requirements outlined in pharmaceuticals.
Schedule M. (22)
Hence, Innovative business models for drug price
Schedule M, India (22): The Drugs and Cosmetics regulation and local manufacturing costs should be
Rules (1945) regulate the manufacture, import and established for a competitive market and a rapid
distribution of drug products (drugs) in India, enclosing growth rate, according to the scenario of API industry
different schedules presenting respective guidelines. prospects, which is very much required of the hour.
Schedule M under Drug & Cosmetics rules, 1945 states Figure 4. Depicts the key recommendations in order to
that the pharmaceutical manufacturing unit in India , thrive the Indian pharmaceutical industry. (27)
holding licence to manufacture drugs must adhere to
In the case of the recent coronavirus outbreak, it has
the GMP criteria outlined in the given guidelines.
the ability to interrupt critical drug holdings, causing
Schedule M included the information regarding
price fluctuations and eventually leading to a situation
premises, warehouse area, production area, Quality
where patients' medications are unavailable.
Control area, manufacturing operations and controls,
equipment, sanitation, documentation, master formula It's past time to resurrect our domestic API industry,
record, validation. Etc. It is divided in to 2 parts – Part I which has been severely harmed by policies such as
with further classification into part IA, part IB, part IC, tighter pollution control standards, the introduction of
part ID, part IE, part IF, and Part II .altogether these are DPCO (2013), the full collapse of the indigenous
the eight sections of the Indian GMP regulations. GMP fermentation industry and lower import duties. (28)
for premises and materials are covered in Part I and
Figure 3. Shows the application of the guidance to the
Requirement of plant and equipment are covered in
shaded steps and does not apply on the steps before the
Part II. Focusing on Part I, There are 29 chapters in all.
introduction of API starting material
All the parts except Part 1F cover basic specifications
for the manufacture of various dosage forms in terms of Indian regulators authored Indian GMP specifications
facilities, equipment, methods and personnel and in Schedule M of the "Drugs and Cosmetics Laws"
Buildings and structures, services, equipment, controls, from a regulatory standpoint. Unlike the ICH Q7,
and containers are all included in Part 1F [specific which only addresses APIs, the GMP regulations in
requirements of premises, plant and materials for India do not differentiate between GMP for medicinal
manufacture of active pharmaceutical ingredients (bulk products and GMP for APIs, with Part 1-F covering
drugs)], which covers basic specifications for the API manufacturing. Several revisions to Schedule M
manufacture of APIs. (23) have since been adopted, although others are also in the
development. To provide a level playing field for
Apart from Schedule M for GMP consideration, the
Indian manufacturers, regulatory agencies are
universally followed guideline of ICH Q7 is also taken
promoting the strategy of harmonising Schedule M
into account for good manufacturing practice for drug
with the ICH / PICS. Simultaneously with the review
substance.
and adaptation of Schedule M, it is recommended that
ICH Q7:- Good Manufacturing practice guide for the Indian inspection agency's GMP inspection norms
Active Pharmaceutical ingredients (APIs) (24, 25) be reviewed and harmonised with global norms to give
the Indian manufacturer the required boost on the
The objective of this guideline(Q7) by ICH is to
global stage. (29)
provide direction to the manufacturers regarding GMP
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Shefali et.al International Journal of Drug Regulatory Affairs. 2021; 9(2): 66-76

INCREASING GMP REQUIREMENTS

Source:-ICH Q7 guideline
Figure 3. Applicability of ICH Q7 Guideline (25)

Pharmaceutical regulatory relaxatipn specially

to API producer

Sustainable Reliable
financing and Promoting Indian Supply chain
tax relaxation API manufacturing management

Providing Special economic support for

domestic pharma hubs

Figure 4. Key Recommendations

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Shefali et.al International Journal of Drug Regulatory Affairs. 2021; 9(2): 66-76

8. Conclusion https://marketinsight.in/industry-reports/pharmaceutical-
industry-in-india
India is one of the world's top destinations for bulk 8. Sandhu G. Express pharma. Making India self-sufficient
drug production. Despite its global prominence as a [Internet]. India:expresspharma; 2020 Aug 28 [cited
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imports for many key intermediates and APIs, and sufficient/
China's export trade is becoming increasingly 9. Munde K. India Ratings& Research: A fitch Group
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We would like to thank Delhi Pharmaceutical local production of pharmaceutical products and protect
public health [Internet] Geneva: WHO; 2017 [cited 2020
Sciences and Research University, New Delhi and
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support and motivation to write this manuscript. mote_local_production_pharm/en/
Financial Disclosure statement: The authors received 11. World Health Organization. Indian policies to promote
local production of pharmaceutical products and protect
no specific funding for this work.
public health [Internet] Geneva: WHO; 2017 [cited 2020
Conflict of Interest Dec 31]. Available from:
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