Test -2 Study material (CO-3 and CO-4)

2019-2020

• Explain different countries’ guidelines of Good Manufacturing Practices (GMP)

Ans: GMP (Good manufacturing practices) is defined as “that part of quality assurance which
ensures that products are consistently produced and controlled the quality standards appropriate
to their intended use and as required by marketing authorization”. GMP reduces the risks in
pharmaceutical production. Such risks are: Unexpected contamination of products, Incorrect
labels on containers, insufficient or too much active ingredient, resulting in ineffective treatment
or adverse effects.
Guidelines of GMP: different countries have different guidelines,

Sl No Guidelines To which country

1 Schedule M of DCA-1940 Indian GMP
2 WHO- GMO WHO
3 MHRA – GMP UK
4 TGA – GMP Australia
5 ICH – GMP ICH members
6 cGMP as per FDA USA

• Briefly describe the role of ISO 9000 and GMP in maintaining quality
Ans:GMP requirements are largely will help companies to adapt a quality approach using
continuous improvement. GMP ensures that the products are consistently manufactured to the
Quality standards appropriate to their intended use. GMP will ensure products manufactured will
have required quality. GMP is designed to minimize the risks involved in any pharmaceutical
production that cannot be eliminated through testing the final product. Thus, unexpected
contaminations etc, can be eliminated or minimized.

ISO is a worldwide applicable quality standard, it covers core competencies. ISO is an effective
quality management system that can be applied to any company. An organization applying for ISO
9000 series will be audited based on functions, products, services, and processes. ISO takes PDCA
(Plan, Do, Check, Act) approach. It stresses on look for cause, investigate, take corrective action,
preventive action and review. These continuous improvement processes will help greatly reduce
incidents and improve quality management systems.

That is how both ISO and GMP are helpful in maintaining the quality of a product

• Briefly explain Master Formula Record (MFR)

Ans: A document or set of documents specifying the starting materials with their quantities
and description of the procedures and precautions (SOPs) required to produce a specified
quantity of End as well as the processing instructions. MFR records for each product should be
prepared, endorsed and dated by a competent individual and should checked, endorsed and
dated by another competent individual. Master Formula records relating to all manufacturing
procedures for each product and batch size to be manufactured should be maintained. MFR
should contain:
 i) Name of the product, description and dosage form and strength
ii) Complete list of ingredients,
iii) Quantity by weight or volume of each ingredient.
iv) The standards and specifications of each ingredient used
v) An appropriate statement concerning any calculated excess of an ingredient
vi) Manufacture and control instructions, specifications, precautions, to be followed
vii) Detailed description of the closures, containers, labeling, packaging

• Explain mission and objectives of ICH

Ans: ICH’s mission is to make recommendations towards achieving greater harmonisation in the
interpretation and application of technical Guidelines and requirements for pharmaceutical product
registration.
Objectives of ICH:
More economical use of human, animal, and material resources.
Elimination of unnecessary delay in the global development & availability of new medicines.
Maintaining safeguards on Quality, safety & efficacy, and regulatory obligations to protect public health.

Q S E M

"Quality" Topics, "Safety" Topics, i.e., "Efficacy" Topics, i.e., "Multidisciplinary"

i.e., those relating to those relating to in those relating to Topics, Topics
chemical and vitro and in vivo pre- clinical studies in which do not fit
pharmaceutical clinical studies: human subject: into one of the
Quality Assurance: Carcinogenicity Dose Response above
Stability Testing Testing, Studies, categories;
Impurity Testing Genotoxicity Good Clinical MedDRA,
GMP Testing, Practices, CTD
Reprotoxicity Clinical Studies

• Explain in detail objectives of Drugs & Cosmetics Act, 1940

The Objectives of DCA, 1940 is
To regulate the import, manufacture, distribution and sale of drugs & cosmetics through
licensing.
To Manufacture, distribution and sale of drugs and cosmetics by qualified persons only.
To prevent substandard in drugs.
To regulate the manufacture and sale of Ayurvedic, Siddha and Unani drugs.
To establish Drugs Technical Advisory Board(DTAB) and Drugs Consultative
Committees(DCC) for Allopathic and allied drugs and cosmetics.

• Briefly explain the purpose of ISO 9000; Explain different parts of ISO 9000 series
Ans: ISO 9000 is a series of International standards for quality management. ISO 9000 is not a
product standard. ISO 9000 requirements are generic and applicable to any organization providing
any product or service.
 The Purpose of ISO 9000 is to provide concept of quality management systems and explanation
of terminology. By adopting ISO series, one can comply with customers who require ISO 9000,
to sell in the European Union market, to compete in domestic markets, to improve the quality
system, to minimize repetitive auditing by similar and different customers, and to improve
subcontractors’ performance

ISO 9000 standards family are:

ISO 9000: Guidelines for selection and use
ISO 9001: Quality Management Systems (QMS) – model for quality assurance in design,
development, production, installation and servicing. ISO 9001 is useful primarily for companies
that design and develop their own products.
ISO 9002: Quality systems – model for quality assurance in production, installation and servicing
ISO 9003: Model for quality assurance in final inspection and testing.

ISO 9002 and 9003 are complementary to the technical product specified requirements. ISO
9002 is applicable to manufacturers, distributors, and service vendors whose products have been
designed and serviced by a subcontractor, while ISO 9003 is applicable for testing laboratories
and equipment distributors.

ISO 9004: guidelines for quality management planning, implementation

• State various benefits of implementing Good Manufacturing Practices (GMP)

GMP ensures that the products are consistently manufactured to the Quality standards
appropriate to their intended use. GMP will ensure products manufactured will have required
quality. GMP is designed to minimize the risks involved in any pharmaceutical production that
cannot be eliminated through testing the final product.

Benefits of GMP:
A) GMP is a good business tool, which will help to refine both compliance and performance of the
Company.
B) GMP will help companies better itself as it moves toward a quality approach using continuous
improvement.
C) Most countries will only accept import and sale of medicines that have been manufactured to
internationally recognized GMP. The process minimizes the risks.
D) Directly it helps in improving exports: Governments seeking to promote their countries export
of pharmaceuticals will implement and promote GMO manufacturing units.

• Explain in detail QSEM based approach of ICH guidelines

ICH is defined as International Conference on Harmonization of Technical Requirements for
registration of Pharmaceuticals for human use.
The ICH Topics are divided into four major categories and ICH Topic Codes are assigned according
to these categories. They are QSEM
 Q S E M

"Quality" Topics, i.e., "Safety" Topics, i.e., "Efficacy" Topics, i.e., "Multidisciplinary"
those relating to those relating to in those relating to Topics, Topics
chemical and vitro and in vivo pre- clinical studies in which do not fit
pharmaceutical clinical studies: human subject: into one of the
Quality Assurance: Carcinogenicity Dose Response above categories;
Stability Testing Testing, Studies, MedDRA,
Impurity Testing Genotoxicity Testing, Good Clinical CTD
GMP Reprotoxicity Practices,
Clinical Studies

• Explain the importance of The Common Technical Document (CTD)

Ans: The Common Technical Document (CTD) is application dossier for the registration of Medicines
to be used across Europe, Japan and the United States. It is an internationally agreed format for the
preparation of applications regarding new drugs. The CTD is organized into five modules (Module 1,
2, 3, 4, and 5). Currently it is global format for regulatory submissions. Advantages of CTD include:
useful for consistent data organization; CTD applies to all NDAs, ANDAs, BLAs, INDs and master files.

• Briefly describe differences between paper CTD and e-CTD

• Explain in brief Schedule C/C1 and Schedule X drugs as per Drugs&Cosm Act
Ans: DCA is an Act that regulates import, sale, manufacture and distribution of drugs and
cosmetics. According DCA, the list of biological and special products (Injectable) applicable to
special provisions are included in Section C, and the list of Biological and special products
(nonparenteral) are included in Section C1. As per DCA, import, manufacture, sale of Drugs
included under Sch C/C1 need special license and permissions.

Narcotics drugs and psychotropic substances are included in Sch-X of DCA. Similar to Sch C/C1
drugs Sch-X drugs are also require special permissions to manufacture, import and sale.
• State the powers given to Drug Inspector under DCA
Ans: DCA is an Act that regulates import, sale, manufacture and distribution of drugs and
cosmetics. The powers give to Drug Inspector under DCA are:
To Inspect:
(i) any premises where in any drug or cosmetic is being manufactured.
(ii) any premises where in any drug or cosmetic is being sold, or stocked or exhibited or offered
for sale, or distributed ;
ToTake samples of any drug or cosmetic:
(i) which is being manufactured or being sold or is stocked or exhibited or offered for sale, or is
being distributed;
(ii) from any person who is in the course of conveying, delivering or preparing to deliver such drug
or cosmetic to a purchaser or a consignee

• Explain the products developed by ICH

Ans: ICH has developed over 50 harmonised Guidelines (or products) aimed at eliminating
duplication in the development and registration process, so that a single set of studies can be
generated to demonstrate the quality, safety and efficacy of a new medicinal product.

▪ Quality-21 Guidelines (or Products)

▪ Safety-14 Guidelines
▪ Efficacy-20 Guidelines
▪ Multidisciplinary-5 Guidelines
▪ Electronic Standards for the Transfer of Regulatory Information (ESTRI, E2B)
▪ Common Technical Document (CTD &eCTD)
▪ Medical dictionary for adverse event reporting and coding of clinical trial data (MedDRA)

• Discuss why ICH is an unique approach; list the representatives of ICH

Ans: ICH is International Conference on Harmonisation of Technical Requirements for Registration
of Pharmaceuticals for Human Use (ICH). ICH is a joint initiative involving both regulators and
research-based industry representatives of the EU, Japan and the USA. It is unique because both
regulators and Industry associations are involved as representatives.

Region Regulatory Body Industrial Organiation

Japan the Ministry of Health & Welfare Japan Pharmaceutical
(MHW) Manufacturers Association (JPMA)
EU European Commission (EC) Federation of Pharmaceutical
Industries’ Associations (EFPIA
USA Food & Drug Administration (FDA) Pharmaceutical Research and
Manufacturers of America (PhRMA)

OBSERVERS WHO, TPP (Canada), Intl Federation of

Pharmaceutical Mfrs

• Describe objectives and benefits of ICH

 Ans: The objectives of ICH are:
▪ More economical use of human, animal, and material resources.
▪ Elimination of unnecessary delay in the global development & availability of new
medicines.
▪ Maintaining safeguards on Quality, safety & efficacy, and regulatory obligations to protect
public health
▪ and to minimize the use of animal testing without compromising safety and effectiveness.
The benefits include:
▪ ICH developed more than 50 harmonized guidelines
▪ Streamline R&D process
▪ Rapid access to new medicines
▪ Benefits for the regulators
▪ Reference and ICH products for non-ICH members

• Illustrate Common Technical Document (CTD) structure with triangle:

Ans: The Common Technical Document (CTD) is a set of specification for application dossier
for the registration of Medicines and designed to be used across Europe, Japan and the United
States. It is an internationally agreed format for the preparation of applications regarding new
drugs intended to be submitted to regional regulatory authorities in participating countries.
Modules of CTD are five: they are Modules 1-5 as described below:

• Explain in detail Batch Production Record (BPR)

Ans: Batch Production Record (BPR): Batch Manufacturing Record is the necessary quality and
GMP documentation for tracing the complete cycle of manufacturing batch or lot. BPR should
be prepared, maintained, and controlled for each batch. The record should be maintained for a
period of five years, BPR shall contain an accurate reproduction of MFR, procedure, and product
specifications to be used in production of a batch of a product. The records include dates, specific
code or identification numbers of each ingredient employed, weigh and measures of each
component and products in the course of processing, results of in-process controls. In addition, a
lot number is assigned that permits the identification of all procedures performed.
▪ Briefly provide requirements and guidelines for permission to import / manufacture new drug
under Sch-Y of Drugs & Cosmetics Act, 1940
Ans: In Drugs & Cosmetics Rules,
• Rule 122-A: Application for permission to import new drug,
• 122-B: Application for approval to manufacture new drug other than the drugs classifiable
under Schedules C (biologics, etc),
• 122-DA: Application for permission to conduct clinical trials for ND/IND.

Application for grant of permission to import or manufacture a New Drug or to undertake clinical
trial include: 1. Particulars of New Drug, 2. Data submitted along with the application (A-
Permission to market new drug, B-Subsequent approval / permission for manufacture of already
approved new drug, C-Approval / permission for FDC. D-Subsequent approval or approval for new
indication –new dosage form).

• State the purpose of DMF (Drug Master File-USA); Describe types of DMF
Ans: DMF is a submission to FDA that provide detailed information about processes and
facilities used in manufacturing, packaging and storing of pharmaceutical products. There is no
legal or regulatory requirement to file a DMF. A DMF may be filed to provide CMC information
that the FDA reviews instead of including this information in the Application (IND, NDA, ANDA). A
DMF is neither approved nor disapproved by the FDA. There are five types of DMF Viz.,
Type I: Manufacturing Site, Facilities, Operating Procedures, and Personnel [No longer accepted
by the FDA (as of January 2000)],
Type II – Drug Substance, Drug Substance Intermediate, and Material Used in Their Preparation,
or Drug Product,
Type III – Packaging,
Type IV – Excipients, Colorant, Flavor, Essence, or Material Used in Their Preparation,
Type V – FDA Accepted Reference Information (Used for sterile manufacturing plants and contract
facilities for biotech products)
Role of DMF: Supporting documents for the registration / approval of drug products
(In the Chemistry, Manufacturing and Controls (CMC) sections of the drug submission, the DMF
documents the drugs identity, purity, strength and quality) and to Protect Proprietary and
Confidential Information

• State goals of NDA (New Drug Application); what are various conditions or
classes under which NDA is applied?
Ans: The NDA application is the vehicle through which drug sponsors formally approach FDA to
approve a new pharmaceutical for sale and marketing in the U.S. The application will be evaluated
by highly qualified technical experts. CDER is the group at FDA authorized to review NDA for drugs
and some biologics. One can go for NDA filing after completion of Phase-III clinical studies of the
new drug.

NDA is classified into following: a) New Molecular Entity, b) New Salt of Previously Approved Drug
(not a new molecular entity), c) New Formulation of Previously Approved Drug (not a new salt OR
a new molecular entity), d) New Combination of Two or More Drugs, e) Already Marketed Drug
Product - Duplication (i.e., new manufacturer), f) New Indication (claim) for Already Marketed
Drug (includes switch in marketing status from prescription to OTC), g) Already Marketed Drug
Product - No Previously Approved NDA
• Discuss what are the requirements and benefits of e-CTD?
Ans: CTD is an ICH standard that FDA adopted in a consensus process, as a member of
ICH, together with other member regions, Europe and Japan. It is currently global format
for regulatory submissions. It provides consistent data organization. CTD applies to all
NDAs, ANDAs, BLAs, INDs and master files. e-CTD is electronic form of common technical
document. In the US, eCTD-only NDAs, BLAs and INDs are accepted. e-CTD is designed to
facilitate to creation, review, assists project management and information management,
lifecycle management, archiving and drug development planning.

• Briefly state the information contained in DMF can be used to what purpose?
Ans: DMF is a submission to FDA that provide detailed information about processes and
facilities used in manufacturing, packaging and storing of pharmaceutical products. There
is no legal or regulatory requirement to file a DMF.A DMF may be filed to provide CMC
information that the FDA reviews instead of including this information in the Application
(IND, NDA, ANDA).A DMF is neither approved nor disapproved by the FDA.
Purpose of DMF: DMF is not a regulatory requirement. It gives supporting documents for
the registration / approval of drug products such as IND, NDA and ANDA. A DMF may be
filed to provide CMC information that the FDA reviews.The information contained in DMF may be
used to support an IND / NDA /ANDA,another DMF,an export application or amendments and
supplements of any of these.

DMF is NOT a substitute for IND / NDA / ANDA or export application.

Technical contents of a DMF are reviewed only in connection with the review of IND /NDA /ANDA
or an export application.

▪ State and explain any three types of drug applications submitted to US-FDA
Ans: Following are the types of drug approval applications that are submitted to FDA.
i) Investigational New Drug Application (IND): An IND is a submission to the food and drug
administration (FDA) requesting permission to initiate a clinical study of a new drug product
ii) New Drug application (NDA): The NDA application is request to FDA to formally approve
a new pharmaceutical drug for sale and marketing in the USA.
iii) Abbreviated New Drug Application (ANDA): A drug that is comparable to a
brand/reference listed drug or patented drug in dosage form, strength, route of administration,
quality and performance and intended use. It is also called generic drug

• State goals of ANDA (Abbreviated New Drug)

Ans: A drug product that is comparable to a brand/reference listed drug product in dosage form,
strength, route of administration, quality and performance characteristics, and intended use is
called generic drug. The application to file generic drug is called ANDA. Goals of ANDA is to
reduce the Price of Drug; To make available a good quality drug product to US general public; to
reduce the time of development.

• Describe four options (paragraphs) available while applying for ANDA

Ans: An abbreviated new drug application provides approval for generic drug to manufacture, and
market to provide a safe, effective, low cost generic drug. These applications are called
 ‘abbreviated’ because they are generally not required to include preclinical and clinical data to
establish safety and effectiveness Generic drugs are required to prove that they are
therapeutically equivalent to innovator drugs. Generic drugs are required to include certification
status of all patents to the listed (or innovator drug). The generic submissions are categorized as:
a. Paragraph I filings: No patent information has been previously submitted to the FDA
b. Paragraph-II filings: All the submitted patents relevant to drug have expired
c. Paragraph-III filings: if the applicant stated that he intends to market the drug only afte
expiry of listed patents
d. Paragraph-IV filings: If the applicant certifies that any product or patent is invalid or will
not be infringed by generic drug approval

• Discuss and explain IND (Investigational New Drug) in detail

Ans: Current US law required that a drug should be approved for marketing before it is
transported or distributed across states in the US. An IND (Investigational New Drug application),
is a submission to the US FDA requesting permission to initiate clinical study for a new drug
product in the US. During a new drug’s early preclinical development, if product is found to be
reasonably safe for human use and the product is pharmacologically active, then owner collects
data to support evidence that the product will not expose humans to unreasonable risk through
limited clinical studies and pre-clinical studies. Further testing of product for efficacy using
humans in clinical studies need permission. IND is applied to fulfil this condition. IND is for
requesting permission to initiate a clinical study of a new drug product, and IND application allows
a company to initiate and conduct clinical studies.
An IND is required:
• to conduct a clinical trial if the drug is a new chemical entity, not approved for the
indication under investigation in a new dosage form.
• If Being administered at a new dosage level.
• If in combination with another drug and the combination is not approved
• To conduct clinical studies where a new drug is administered to human subjects,
regardless of whether the drug will be commercially developed.
An IND is not required to conduct a study if the drug is not intended for human use, but is required
for in vivo testing or lab research animals. IND is not required if it is an approved drug and the
study is within its approved indication for use.

• Explain various classes of New Drug Application

Ans: NDA has following classifications for developing and applying for registration:
▪ New Molecular Entity
▪ New Salt of Previously Approved Drug (not a new molecular entity)
▪ New Formulation of Previously Approved Drug (not a new salt OR a new molecular entity)
▪ New Combination of Two or More Drugs
▪ Already Marketed Drug Product - Duplication (i.e., new manufacturer)
▪ New Indication (claim) for Already Marketed Drug (includes switch in marketing status
from prescription to OTC)
▪ Already Marketed Drug Product - No Previously Approved NDA
• Enumerate any three types of Drug Approval applications that are submitted to US-FDA
Ans: Following are the types of drug approval applications that are submitted to FDA.
i) Investigational New Drug Application (IND)
ii) New Drug application (NDA)
iii) Abbreviated New Drug Application (ANDA)
 iv) Biologic License Application (BLA)
v) Over-the-counter (OTC) drug application

• Briefly describe five modules of CTD

Ans: Module 1 (Administrative and prescribing information):
Module 2 (summaries) includes:
i) Quality overall summary: it provides reviews on overview of the data incorporated in
Module 3

ii) Non-clinical overview: the nonclinical overview should provide an interpretation of the
data, the clinical relevance of the findings, and the implications of the nonclinical
findings for the safe use of the pharmaceuticals

iii) Nonclinical summaries: the nonclinical written and tabulated summaries should provide
a comprehensive, factual synopsis of the nonclinical data.

iv) Clinical overview: the clinical overview should provide a succinct discussion and
interpretation of the clinical findings that support the application together with any
other relevant information such as animal data or product quality issues.

v) Clinical summary: the clinical summary should provide a detailed factual summarization
of the clinical information

Module 3 (quality): Module 3 contains the detailed technical information regarding CMC
information. This module contains a TOC, detailed information regarding the drug substance
and drug product

Module 4 (nonclinical study report): Module 4 contains table of contents (TOC) detailing
nonclinical study reports contained in the application, and literature references

Module 5 (clinical study report): Module 5 contains TOC for module 5 only and a tabular listing
of all clinical studies, clinical study reports, and literature references.

• Briefly describe types of IND with examples

Ans: IND is a submission to US- FDA requesting permission to initiate a clinical study of a new
drug product in the US. During new drug development phase, investigator, based on preclinical
data had established its safety. IND allows investigator to initiate clinical studies. Categories or
types of IND (classification of IND):
i. Commercial IND: Permits sponsor to collect data on clinical safety and effectiveness
needed for application for marketing in the form of NDA. goal is to obtain marketing approval for
a new product.
ii. Non-commercial IND: Permits the sponsor to use drug in research to obtain advanced
scientific knowledge of new drug, there is no plan to market the product: It further includes
ii a) Investigator IND: In this case, the physician is both the sponsor and investigator. A physician
might submit a research IND to propose studying an unapproved drug, or an approved product
for a new indication.
 ii b) Emergency IND: FDA authorize immediate dispensing of a non-approved drug in a
lifethreatening situation when no standard acceptable therapy is available.
ii c) Treatment IND: FDA will permit investigational drug showing promise in clinical testing to be
used to treat a serious or life threatening disease or if there is no comparable alternative drug
available. It can happen even while the final clinical study is being conducted.

• Discuss why Generic drugs takes less time and less cost to develop.
Ans: The generic drugs (which are similar to Listed drug or Reference Drug) are cheaper because
i) the manufacturers do not have to incur the costs of new drug development research, ii) the
manufacturers do not require to carryout clinical trials, only bioequivalence is mandatory, iii) The
companies get the advantage of marketing established by innovators, and iv) the manufacturers
also not required to spend much on the sales promotion. These advantages make generic drug
manufacturing cheaper.