8.4 DRUG METABOLISM

It is defined as the chemical alteration of a drug in the body. This chemical alteration

converts nonpolar compounds to polar and lipid-soluble compounds to lipid-insoluble

compounds. The products of drug metabolism are called metabolites. Drug metabolism

includes conversion of:

i. Active drug to inactive or less active metabolite (pharmacological inactivation).

For example, phenobarbitone to p-hydroxyphenobarbitone.

ii. Active to a more active metabolite (bio-activation or toxicological activation).

For example, codeine to morphine.

iii. Inactive to more active toxic metabolite (lethal synthesis)

Drug Development and Non-Clinical Studies 127

iv. Inactive drug (pro-drug) to an active metabolite (pharmacological activation).

For example, phenacetin to paracetamol.

v. Active drug to an equally active metabolite (no change in pharmacological

activity). For example, digitoxin to digoxin.

vi. Active drug to an active metabolite which is having different pharmacological

activity (change in pharmacological activity). For example, iproniazid to

isoniazid.

Sites of Drug Metabolism

The main and major site of drug metabolism is liver. Other sites of biotransformation

because a variety of metabolising enzymes are present in Liver. If metabolism

occurs outside the liver or in organs other than the liver, then it is known as extrahepatic metabolism. Secondary organs are kidney, lungs, testes, skin, intestines.

Some drugs also metabolised without enzymes. It is known as non-enzymatic

metabolism.

Advantages of Drug Metabolism

i. It is necessary for the termination of drug action. Therefore, decrease toxicity.

ii. It also reduced lipophilicity.

iii. It increases renal excretion.

There are two phases of drug metabolism:

Phase I: Non-synthetic/functionalization

In this phase, the metabolite may be active or inactive.

 

v. To determine the route of administration.

Non-clinical Drug Development Process (Figure 8.2)

Fig. 8.2: Non-clinical drug development

Drug Development and Non-Clinical Studies 125

Types of Non-clinical Study

There are two types of non-clinical study. These are:

1. Pharmacodynamics (What drug does to the body or how the drug makes the body

to react?)

2. Pharmacokinetics (What the body does to the drug?)

Pharmacodynamics

Primary

The main objective of this study is to determine the effect of the compound on the

target organ. These can be done either in vitro or in vivo or both.

Secondary

The main objective of this study is to determine the effect of the compound on organs

other than target organs.

Safety

This study helps in determining the lethal dose of the compound. Its main objective is

also to determine undesirable effects of the compound within the therapeutic dose

range or higher dose. Mainly the undesirable effects on CNS, cardiovascular system

and respiratory system are determined (Fig. 8.3).

Pharmacokinetics

The main aim of this study is to determine parameters related to absorption,

distribution, metabolism and excretion of compound. This study also deals with

toxicokinetics (to determine where and when undesirable effects occur due to

compound)

Fig. 8.3: Types of non-clinical studies

126 Industrial Pharmacy II

8.3 TOXICOLOGY

This study helps in determine the toxicity of the compound (Fig. 8.4).

Fig. 8.4: Factors lead to the stopping of the development of the compound

Sr. no. Name of study Objective

1. Single-dose and dose-range To identify target organ of toxicity

finding studies To determine the reversibility of the toxic effect.

Establish the dose for future reference

To determine the maximum tolerated dose.

To determine non-observed adverse effect level.

2. Genotoxicity To detect possible interactions with chromosomes and

DNA

To detect any gene mutation or chromosomal damage.

3. Carcinogenicity To detect if the compound causes cancer.

4. Reproductive and To study the effect on

development studies • Fertility

• Foetus

• Lactation

 

Legal group: The legal group main responsibility is to file a patent at the appropriate

time to protect the intellectual property right of drug developers. This group includes

lawyers and patent agents who have experience in filing the patent.

Others: This section comprises supporting staff that assists the other groups in

running their business smoothly and efficiently.

The success of any drug development team depends upon time management and

resource management which can be done by the following ways:

i. Plan and re-plan carefully

ii. Execute the plan appropriately

iii. Hire the people who want to get the project done

iv. Differentiate what is necessary and what is not

v. Have patience

124 Industrial Pharmacy II

8.2 NON-CLINICAL DRUG DEVELOPMENT

A targeted drug has to go through from various studies such as non-clinical and clinical

studies. Non-clinical studies are also known as pre-clinical studies. It is a stage of

research that happens before clinical studies. During non-clinical studies important

drug safety data is collected. These studies are necessary before filing Investigational

New Drug (IND) application. Pre-clinical studies have an important place during whole

drug development process as shown in Fig. 8.1.

Objectives of Non-clinical Drug Development

The main objective of non-clinical study is to confirm that either the target drug is safe

for use in human or not. This is done by studying animal pharmacology and toxicology

testing.

The Need for Non-clinical Studies

Non-clinical studies are essential

i. To determine the lethal dose, toxic dose (like LD50, ED 50, etc.).

ii. To determine the pharmacological action of the target drug.

iii. It is necessary to submit the animal testing report during the IND application.

iv. To determine the pharmacokinetic properties of a drug.

 

7.5 RESPONSIBILITY OF REGULATORY AFFAIRS PROFESSIONALS

Drug development involves a huge amount of money as well as time. This arises the

need for effective management of the approval process and post-approval maintenance

process. The drug regulatory affairs professional plays an important role in every phase

of these processes. The drug regulatory professionals are highly qualified and

experienced in their respective fields. There are some qualities which make efficient

regulatory professionals. These are:

i. Good communication skills

ii. Good computer knowledge

iii. Work independently

iv. Active listeners

v. Good presenter

vi. Good data management skills

vii. Patient worker

viii. Effective negotiator

ix. Punctual

x. Have sound knowledge

Because of the critical nature of this job, there are several important responsibilities

of regulatory affairs professionals. These are as follows:

Ensuring the compliance: Regulatory affairs professionals ensure that their

companies comply with the guidelines, policies and laws related to their business.

Ensuring the ease of business: Regulatory affairs professional ensure the ease of

business for their company. The effective and efficient communication with regulatory

agencies and concerned staff on specific issues related to drug approval or renewal

makes the business easy for the company.

Ensuring effective communication: It is the responsibility of regulatory affairs

professionals to effectively present the documents in front of regulatory authorities

and discuss the application related issues.

Ensuring effective coordination: Any query, change in guidelines, change in

application, etc. need to be addressed by regulatory affairs professionals. The

professionals ensure the collection of accurate data or response from the related

department and send it to the concerned authority.

Applying and monitoring drug approval application: It is the responsibility of

regulatory affairs professionals to prepare the application for the drug approval process.

The professionals are the one who decides the mode of applying, and the documents

need to be attached as per guidelines. After applying, it is the responsibility of the

regulatory affair professionals to check its status and progress.

120 Industrial Pharmacy II

Updating the changes: Guidelines related to the drug regulation keep on changing

as per the requirements and become stricter. It is the responsibility of regulatory affairs

professionals to remain updated with the changes and ensure the compliance of the

company’s business with these changes.

Assisting product launching: Various activities related to product launching like

reviewing advertising material, presenting the product, marketing strategies for

product, etc are assisted by regulatory affairs professionals so that to ensure compliance

with rules and guidelines.

Reviewing of documents: There are many documents which need to be submitted

with the drug approval application. The regulatory authority mentioned specific format

for these documents in their regulatory guidelines. Regulatory affairs professionals

review these documents to ensure that the documents are the same as expected by the

regulatory authority.

Liaisoning between authorities and companies: This is the most important and

critical responsibility of regulatory affairs professionals. He is the presenter of the

company in front of government authority. Any loophole in the preparation of

regulatory affairs professionals cost a huge to the company. Regulatory affairs

professionals have to maintain the balance between expectations of government

authorities and profit of the company through his strategic solutions.

Miscellaneous: It is the responsibility of regulatory affairs professionals to regulate

and control any activity which directly or indirectly affects the drug development

process, drug approval process, or drug monitoring process.

 

PRACTICE QUESTIONS

Long Answer Type Questions

1. What is regulatory affairs? Explain the evolution of regulatory affairs.

2. How does government regulatory authority regulate the pharmaceutical products

in a country? Explain regulatory affairs of different countries.

3. What are the responsibilities of regulatory affairs department in a company? How

regulatory affairs department of a company related with other departments of the

company?

Short Answer Type Questions

1. How does regulatory affairs department of the company work as a bridge between

the company and the government?

2. Why regulatory affairs department is essential for the company?

3. Explain the role of regulatory affairs department of the company.

4. Explain the responsibilities of regulatory affairs professionals.

Objective Type Questions

1. All the applications for getting a pharmaceutical product approved for entering

into the market have been prepared by:

a. Regulatory affairs department b. Manufacturing department

c. Accounts department d. None of the above

Regulatory Affairs and its Role 121

2. The sulphanilamide disaster occurs in:

a. 1945 b. 1946

c. 1947 d. 1948

3. The use of which drug by pregnant women in 1956 led to phocomelia in newborn

babies:

a. Sulphanilamide b. Penicillin

c. Thalidomide d. None of the above

4. The first pharmacopoeia developed in 1581 is known as

a. German pharmacopoeia b. Spanish pharmacopoeia

c. British pharmacopoeia d. Indian pharmacopoeia

5. Introduction of Federal Food, Drugs and Cosmetics Act is enacted in:

a. 1938 b. 1939

c. 1948 d. 1949

6. Yellow card scheme was introduced in:

a. 1966 b. 1964

c. 1970 d. 1971

7. Food and Drug Administration (FDA) is drug regulatory authority of:

a. USA b. UK

c. Sweden d. India

8. MHRA is drug regulatory authority of:

 a. USA b. UK

c. Sweden d. India

9. CDSCO is drug regulatory authority of:

 a. USA b. UK

c. Sweden d. India

10. Match the following

Country Drug regulatory authority

a. Australia i. Centre for Pharmaceutical Administration Health

Sciences Authority

b. India ii. Department of Health: Pharmaceutical Services

c. Canada iii. Therapeutic Goods Administration (TGA)

d. Europe iv. Central Drug Standard Control Organization (CDSCO)

e. Singapore v. Health Canada

f. Hong Kong vi. European Medicines Agency (EMEA)

g. New Zealand vii. Irish medicines board

h. Ireland viii. Medsafe—medicines and medical devices safety authority

ANSWERS

1. a 2. c 3. c 4. b 5. a 6. b 7. a 8. b

9. b 10. a(iii), b(iv), c(v), d(vi), e(i), f(ii), g(viii), h(vii)

 

Role in drug approval: A dossier is to be submitted to the competent authority for

drug approval. This dossier is prepared by regulatory affairs department in compliance

with the respective guidelines. Each aspect of the dossier/application is taken care by

the regulatory affairs department and all the queries from competent authorities

regarding the application are also answered by the regulatory affairs department.

Keep other departments updated: It is regulatory affairs department which keeps

other departments such as production, marketing, quality control, pharmacological,

etc updated with recent rules and norms to be followed during developmental stages.

This helps in ensuring quality and safety of drugs.

Acts as interface: It is the most critical role played by the regulatory department.

The department acts as an interface between health agencies and the company. It also

acts as a link between different departments of the company.

Acts as an adviser: During the lifecycle of a drug there are several occasions when

it becomes difficult for the company to take the decision. Regulatory affairs department

acts as an advisor and gives strategic advice which helps in taking extreme difficult

decisions.

Maintenance of licences: Regulatory affairs department keeps track on when a

licence is going to expire and file the renewal within appropriate time to avoid the loss

of the company. The department also ensures availability and maintenance of the

marketing licence. Any change in the formulation, labelling, manufacturing site, etc is

informed by the regulatory department to the health agencies.

Preparation of documents: Regulatory affairs department helps other departments

in preparing the company related documents as per rules and guidelines. For example,

Standard Operating Procedure (SOP), Batch Process Control Record (BPCR), Master

Formula Record (MFR), Certificate of Analysis (CoA), CTD, etc.

Helps in the execution of clinical plan: Clinical studies are very important part

when it comes to the market approval of new drugs. The clinical plan should be in

accordance with GCP and drug should be approved for clinical investigation. Much

other legal documentation is also required like investigators brochure, informed consent

Fig. 7.3: The regulatory professionals act as bridge between company and government drug regulatory

authority

Regulatory Affairs and its Role 119

form, clinical study protocol, etc. Regulatory affairs department helps the company in

execution of the clinical plan by assisting in preparing the documents in compliance

with guidelines and filing the application for clinical trials approvals. This is same in

the case of execution of non-clinical plan as well.

Data collection and storing: All the data from the drug development stage to postmarket approval phase is collected and stored by the regulatory affairs department.

The data from the drug development stage is collected to use in licensing application.

The data stored for future reference and the renewal of licence.

 

13. Ireland Irish Medicines Board

14. Italy Italian Pharmaceutical Agency

15. Malaysia National Pharmaceutical Control Bureau, Ministry of Health

16. Netherlands Medicines Evaluation Board

17. New Zealand Medsafe: Medicines and Medical Devices Safety Authority

18. Nigeria National Agency for Food and Drug Administration and Control

(NAFDAC)

19. Pakistan Drugs Control Organization, Ministry of Health

20. Paraguay Ministry of Health

21. Singapore Centre for Pharmaceutical Administration Health Sciences Authority

22. South Africa Medicines Control Council

23. Sri Lanka SPC, Ministry of Health

24. Sweden Medical Products Agency (MPA)

25. Switzerland Swissmedic, Swiss Agency for Therapeutic Products

26. Thailand Ministry of Public Health

27. Uganda Uganda National Council for Science and Technology (UNCST)

28. Ukraine Ministry of Health

29. USA Food and Drug Administration (FDA)

Regulatory authorities ensure the safety, efficacy and quality of drugs which are

available to the public. These authorities also identify the strengths as well as

weaknesses of drug regulation and remedies to improve drug regulation. They also

play an important role to ensure and strengthen regulatory implementation in the

non-regulated world. The international regulatory organizations like WHO, ICH play

an essential role in manufacturing, approval, distribution, price control, research and

development, marketing and intellectual property rights protection.

7.4 ROLE OF REGULATORY AFFAIRS DEPARTMENT

Drug regulatory affairs is a dynamic and challenging field in the pharmaceutical

industry. It has to deal with government authority on one hand and applicant/company

on the other hand. Because of the crucial nature of the job, the regulatory affairs

professionals should be experts in managing the product life cycle. They should have

the capability to solve technical as well as administrative problems within the limits of

laws and regulations. Regulatory affairs department is a bridge between government

regulatory authority and pharmaceutical company. It also has a connection with all

the departments of the company internally (Fig. 7.3).

118 Industrial Pharmacy II

Regulatory affairs department plays many important roles. These are as follows:

Role in drug development: It is the regulatory affairs department that guides the

other professionals involved in product development regarding guidelines and norms

to be followed. Any change in the guidelines is monitored by regulatory affairs

department.

 

7. Regulatory Affairs and its Role

8. Drug Development and Non-Clinical Studies

9. INDA and NDA

Summary

3

Regulatory Affairs and Regulatory

Requirements for Drug Approval

114 Industrial Pharmacy II

7.1 INTRODUCTION

Medicines have their existence in parallel with the existence of mankind. It is perhaps

as old as a human being. The current pharmaceutical industry is more systematic,

well organised and in compliance with respective guidelines. This is because of effective

pre- and post-approval regulation of new drugs and the existing drugs. Regulatory

affairs play this role for pharmaceutical manufacturing companies and the government

of the country. It is a new profession which emerges after government and

manufacturing companies felt the need for a bridge in between them which promotes

coordination and communication. The regulatory affairs act as an interface between

government and manufacturing companies (Fig. 7.1).

Regulatory affairs is actively involved in every stage of drug development in case

of new drug and post-approval surveillance in case of an existing drug. All the

applications for getting a pharmaceutical product approved for entering into the market

has been prepared by the regulatory department of companies. The regulatory

professionals act as liaison with government regulatory agencies. These applications

are reviewed by government regulatory agencies to check the compliance with issued

guidelines. The regulatory department of the company internally also liaison with

QC, marketing, production, administration and other departments of company to keep

them updated with changes in guidelines and to ensure their compliance with the

guidelines (Fig. 7.2).

114

Regulatory Affairs and its Role

7

 

Fig. 7.1: Relation between regulatory professionals of company and the government regulatory

authority

Regulatory Affairs and its Role 115

7.2 HISTORICAL OVERVIEW OF REGULATORY AFFAIRS

The quality assurance and regulation of medicines evolved gradually over time. Many

unfortunate incidents have catalysed the development of regulations and guidelines

of assuring quality, safety and efficacy of medicines. In 1947, in United States over

100 died due to sulphanilamide elixir. This event led to the introduction of Federal

Food and Cosmetics Act for new drugs in 1948. In 1956, the introduction of Thalidomide

(a drug prescribed to pregnant women for morning sickness) in 46 different countries

resulted in an estimated 10000 babies born with phocomelia (Deformities related to

limbs). This event results in reshaping of the whole regulatory system. Due to these

types of incidents at different stage regulatory bodies introduce new laws and

guidelines which make norms related to drug approval or site approval stricter than

before. Due to more guidelines and laws, the need for regulatory affairs has been felt.

It led to the emergence of regulatory affairs as a profession (Table 7.1)

Fig. 7.2: The connection of regulatory affairs department with other departments in company

Table 7.1: Chronological evolution of regulatory affairs

Sr. no. Year Content

1. 1540 In England the manufacturers of medicines were subjected to supervision

under an act known as Apothecaries Wares Drugs and Stuffs Act.

2. 1581 The first pharmacopoeia is known as Spanish pharmacopoeia

3. 1618 The London pharmacopoeia

4. 1938 Introduction of Federal Food, Drugs and Cosmetics Act

5. 1940 and 1945 Drugs and Cosmetics Act 1940 and Rules 1945

6. 1962 Drug Amendment Act of 1962 was passed by FDA which for the first

time demanded that:

1. A new drug should be proven to be effective and safe

2. All manufacturing sites are required to comply with CGMP

7. 1963 Establishment of a committee on safety of drugs

Contd.

116 Industrial Pharmacy II

The whole world is divided into three types of countries: Regulated (like United

States, European Union, Australia, Japan, etc.) , semi-regulated (like India, Indonesia),

and not regulated (like Cambodia, Burundi, Burkina Faso etc.) depending upon the

organisation structure of government regulatory authority, availability of resources

and execution of guidelines.

7.3 REGULATORY AUTHORITIES

For every country, the health of its people is of utmost importance. To maintain the

health of the people, country has to ensure the quality of medicines and other

pharmaceutical products as well as devices. So, every country has its regulatory

authority which regulates the following: (Table 7.2)

1. Import of drugs from another country

2. Export of drugs to another country

3. Manufacturing of drugs in the country

4. Establishment of manufacturing companies in the country

 

Documentation: Documentation is the most essential part of the transfer process.

Every key task has to be documented. WHO guidelines mentioned list of important

documents that needs to be prepared. However, these documents can be amended

depending upon the need of time.

Qualification and validation: As per WHO guidelines the extent qualification

and/or validation to be performed and should be determined on the basis of risk

management principles and should be documented.

Authorities and agencies involved in TOT: The main concern of authorities and

agencies involved in TOT is to ensure the transfer of efficient, quality, and safe

technology. Government as well as private (belongs to SU or RU) agencies and

authorities are involved in TOT.

Success of technology transfer depends upon five Cs:

i. Communication

ii. Capacity

iii. Co-ordination

iv. Commitment

v. Cooperation

There are also 6Ps which are considered as constituents of technology transfer:

1. Proper research 2. Paperwork 3. Pricing

4. Publicity 5. Partnership 6. People acceptance

Summary 111

CASE STUDIES OF TECHNOLOGY TRANSFER

The process of technology transfer is actively emerging in India. There are many

technology transfer takes place successfully within the country or outside the country.

Some of them are as follows:

BARC developed technologies in areas like the environment and health, electrical,

mechanical, radioisotopes, electronics, etc. Till now, around 90 technologies have been

transferred by BARC and more are queued in line.

National Chemical Laboratory (NCL), Pune, has ties with various universities and

industries that help in scale-up of technology and its seamless transfer.

TOT AGENCIES IN INDIA

The process of technology transfer is very much active in India. There are many agencies

that are involved in TOT to regulate it so as to ensure effective and safe transfer within

the legal framework. The agencies involved are: APCTT, NRDC, TIFAC, BCIL, TBSE,

and SIDBI.

TOT RELATED DOCUMENTATION

Confidentiality agreements: A confidentiality agreement is also known as nondisclosure agreement. It is a contract between two or more parties where the

aim/subject of the agreement is a guarantee that information transfer will be maintained

in confidential/secrecy.

Licensing: In this type the owner/developer of the technology grants permission

to another company (receiver/absorber) in the form of a license to use the technology

for certain purposes and for a certain period of time.

MoU: MoU (Memorandum of Understanding) is also known as commitment letter,

or letter of intent.

Legal issues: Technology transfer process should be in accordance with the legal

framework and the jurisdiction of the concerned country. Issues like tax, intellectual

property rights, infringement of contract, failure to comply with regulatory guidelines

comes under legal issues. Mentioning of recommended law and jurisdiction in case of

breach of conditions in the agreement should be there in technology transfer agreement.

 

QRM is a process that relates to all countries and has a rationale to understand risk.

It has measures to prevent and mitigate all risks by appropriate and robust controls.

QRM Application in Pharmaceuticals

i. Training and education

ii. Responsibilities

iii. QRM application during product development

iv. QRM application during validation and qualification

v. QRM application during commercial manufacturing

QRM related guidelines: Q9 of ICH and WHO expert committee on specification

for pharmaceutical preparations 47th report, Annexure 2, and TRS-981.

Tools of QRM: A variety of tools either alone or in combined form can be used for

the QRM purposes. There is no single or combined tool which is applicable to the

entire situation. The main criteria for selecting the tool are that it should support the

key attributes of good risk assessment, e.g. FTA, HACCP, flowcharts, check sheets,

HAZOP, FMEA, etc.

TRANSFER FROM R&D TO PRODUCTION (PROCESS, PACKAGING AND

CLEANING) AND GRANULARITY OF TT PROCESS (API, EXCIPIENTS, FINISHED

PRODUCTS, PACKAGING MATERIAL)

Transfer process is one of the most critical steps in technology transfer. Certain things

that should be ensured by sending unit are as follows:

i. The RU should be accommodated the intended production capacity.

ii. Consideration should be given to the level and depth of the detail which is to be

transferred to RU.

iii. Consideration should be given to the technical expertise, site technology and

capabilities of RU. It is done so that plans may put in place at the RU.

iv. SU should jointly develop a protocol with RU for relevant information transfer

and to help RU in developing comparable process.

Starting material: The specification and relevant functional characteristics related

with starting material, i.e. API and excipients which are to be used at RU should be

consistent with materials used at SU.

Finished pharmaceutical product: Detailed information related with qualitative

and quantitative characteristics of the finished product should be provided by SU

to RU.

Packaging: Packaging transfer has the same importance as production transfer.

110 Industrial Pharmacy II

Cleaning: It is very much necessary to have adequate cleaning procedure so as:

i. To ensure the best quality of product and

ii. To protect the product from contamination

iii. To protect the product from cross-contamination from the API or other

substances.

Analytical method transfer: In pharmaceutical sciences, analytical methods are the

techniques which deals with the process(es) to identify quantitatively or qualitatively

a substance or its components in the pharmaceutical preparation (solution, mixture,

etc.). These techniques are also used for determining the structure of chemical

components of the pharmaceutical product. Technology transfer process (as per WHO

guidelines) analytical method transfer is a critical step that ensures RU capabilities to

produce and test the same product as by SU. The analytical method transfer comes

under quality control section. All the analytical testing methods that demonstrate

compliance of product (which is to be transferred) will be transferred with registered

specifications. Analytical method used to test pharmaceutical products, starting

material, packaging components, cleaning should be first implemented in the laboratory

before process validation at RU. Process validation sample may be tested at RU, SU,

or at any other 3rd laboratory.

Premises and equipment: One of the major requirements needed for the

manufacturing of a pharmaceutical product is premises and the other one is equipment.

The premises and equipment should be designed, constructed, located, adapted and

maintained to suit the operations needed to be carried out. It is a layout of premises

and equipment that have a major effect on cleaning, maintenance, and risk of error

during production and finally affect the quality of the product.