INTRODUCTION:

The European Medicines Agency (EMA) is an authorisation of the European Union for the assessment and assessment of medicinal products. It works as a decentralized organization. In order to achieve harmonization of the regulations of the existing national medicine regulatory institutions, the European Medicines Agency (EMA) was created by the European Union in 1995 with the funding provided by the European Union and Pharmaceutical Industry together with subsidies from Member States.

At present, the European Union is responsible for introducing about one third of new products annually on the global market under the direction of EMA. The European Medicines Agency (EMA) was known as the European Medicines Assessment Agency (EMEA) until to the year 2004. This marketing authorization will ensure that the product follows all the guidelines and directives of the European Medicines Agency that are put forth by it that the public of Europe will receive quality products. There are various countries in the European Union like UK, Germany, Ireland, Sweden etc. These countries have different registration processes like Centralized Procedure, Decentralized Procedure, Mutual Recognition Procedure and Nationalized Procedure¹.

Active substance master file formerly referred to as European Drug Master File (ASMF) entitles the applicant, the marketing authorisation holder and the applicant to take full responsibility for the medicinal product, as well as for quality and quality monitoring for the active substance, for the protection of valuable confidential information on the production. The European Medicines Agency (EMA) has full access to product information required for the assessment of the suitability of the medicinal product to the use of the active substance. Detailed scientific information on the active substance is provided in this active substantive Master File. The competent authority of a particular country may not accept certain information that has been provided by the Marketing Authorization Holder, in such cases the Authority may ask to make changes to the Applicant’s part. This Active Substance Master File can only be submitted in support of Marketing Authorization Application (MAA)².

Regulations for marketing authorization in European Union:

The European Medicines Agency (EMA) must issue a Marketing Authorisation in order to market a drug product in the European Economic Area (EEA) consisting of 28 Member States and 3 EFTA countries. Generic drug product usually follows Decentralised Procedure where as for other drug products the marketing authorization may be applied through Centralized Procedure.

For the submission of marketing authorisations and make it easy to evaluate the application for that substance, the active substance master file is crucial. Where the active agent is not listed or is prepared by a method in the European Pharmacopeia or Pharmacopoeia of one of the member state or where the active agent is listed in one of the pharmacopoeias, and where the monographs do not include proper quality control measures to maintain its quality. The applicant may provide a detailed description of the manufacturing process, quality control methods required during production process, and the validation process which the manufacturer of the active substance must provide directly to the regulatory authority. If any changes are needed, the relevant regulatory authority shall be provided with such modifications together with all the necessary documentation and details. This has been further clarified in the revised and amended Directives 75/318 and 81/852/EEC.

A Marketing Authorisation from the Regulatory Authority of that Member State must be issued to place a drug product in the European Economic Area (EEA). In accordance with European Commission Regulations EC No: 726/2004 for authorisation across the European Union, the marketing authorisation may also be granted. The candidate should be from the EEA for the marketing authorisation. In order to obtain a marketing authorization for a drug product on the market the Regulations have certain terms which need to be followed. Authorisation to market consists of:

· Decision to grant marketing authorisation by the competent authority.

· Dossier comprised by technical information for the drug product submitted by the applicant pursuant to Article 726/2004 or Article 7 EC Regulation No 1394/2007 or Article 8(3) of Directive 2001/83/EC and Annex 1, followed by Article 6(2) and Article 31(2).

The primary goal is to ensure the safety of the public with these rules and regulations governing the medicines entering the market. Only by ensuring there is nothing that prevents the evolution of or trade in the pharmaceutical industries within the European Union can this be achieved³.

Validity of marketing authorization:

The European Union's issuance of a marketing authorisation takes five years. Once the five years are finished, a new evaluation of the risk and benefit balance will need to renew the marketing authorisation. In addition, the Marketing Authorisation Holder shall supply an updated version of the file for the quality, safety and effectiveness of the product to EMA or the national regulatory authority with all the amendments introduced since the marketing authorisation has been granted. The renewal should be made at least 9 months preceding the end of the marketing authorisation, but it should be avoided premature submissions. The guidelines on the processing of renewals through a centralized procedure and guidelines for the CMDh process of renewals under a mutual recognition process or decentralized procedure contain recommendations in this regard. After this renewal the Marketing Authorization is valid for unlimited period unless it decided by the European Commission or the National Regulatory Authority under the pharmacovigilance grounds with justification that one additional five year renewal shall be granted⁴.

Procedures for marketing authorization:

1. Centralised procedure:

A centralized authorisation for the marketing is valid throughout the market of the European Union, which means that the drug product can be marketed in any of the Member States. Applications shall be made to the European Medicines Agency for drugs products falling under the mandatory scope of the Centralized Procedure as provided in the European Commission Annex No: 726/2004.

Submission of dossier:

The following request must be submitted by EMA:

· Complete Dossier including part of the master file of the applicant.

· Draft copy of Product Characteristics summary including labelling and package leaflet, including two copies of Module 1 and Module 2

· Module 1 and 2 electronic copy in word format.

Both the rapporteur and co-rapporteur must submit the dossier to the EMA in conjunction with the applicant. If this is any no consensus, a period from the validation by EMA and the confirmation received by the Rapporteur and Co-Rapporteur after receipt of the dossier may take place in the event of delays to commence the procedure. If the Active Substances Master File is to be included, the applicant shall ensure that the ASMF is presented to the EMA, Rapporteur and Co-Rapporteur by the Active Substance Manufacturer at the time the main application is submitted.

Transfer of European Union marketing authorization:

The transfer of marketing authorisation from the centralized procedure shall be subject to Regulation No: 2141/96 of the European Commission of 7 November 1996. The Marketing Authorization Holder shall, under this Regulation, submit the application and supporting documents to the European Medicines Agency. The Holder of the Marketing Authorization should also transfer to the Orphan drug product designation during the transfer of the Marketing Authorization, states Article 5(11) of Regulation No: 142/200 of the European Commission⁵.

2. Decentralised procedure:

Decentralized procedures may obtain marketing approvals in more than one Member State, but they should not be approved during the time of the drug product application. The applicant can use this process for applying for marketing licenses for products which have not been approved in EU in more than one Member State. A booking slot must be made via the slot booking procedure with the intended RMS. Four steps comprise decentralized procedure:

a. Pre-procedural step:

The applicant will conduct discussions with the RMS at this stage and be assigned the RMS procedure number. On day 14, RMS and CMS shall receive the dossier.

b. Step One of Assessment:

RMS initiates the assessment process at this stage. RMS is prepared for the preliminary evaluation report and transmitted to CMS. CMS shall assess and comment on PrAR. CMS shall evaluate PrAR. The RMS, CMS and the applicant will be consulted. If there is no consensus, RMS will stop the clock and the applicant is asked to answer the questions raised and supplement the file. The applicant shall answer the questions raised within 3 months, and if the justification is provided, they shall be extended.

c. Step Two of Assessment:

If consensus is not reached between RMS and CMS, RMS will forward to CMS its DAR, SPC draft, etiquette draft and PL draft. The draft reports will be evaluated by the CMS and the RMS will comment. The procedure shall be closed if consensus is reached. If not, the RMS will inform the applicant and request further information by 150th day.

d. National Marketing Authorization Step:

All SPC, labelling and PL data shall be sent in high quality translation by the applicant to CMS and RMS. The national authorisation for marketing in RMS and CMS shall be granted if not referred to the coordination group⁶.

3. Mutual recognition procedure:

This procedure may be applied when the product is already authorized in other Member States when this type of marketing authorisation is applied for in more than one Member State. Any of the Member States shall apply to the Mutual Recognition Procedure. The evaluation report shall be documented by the RMS by 90th day and sent to the CMS for 90 days in which to assess the report for grant of marketing licences. The evaluation report is returned to the RMS. Additional 30 days for authorisation will be given to the Member State concerned. The initial marketing permit takes approximately 9 months and after addition there will be 7 months to complete the application. Where a drug product is approved for the first marketing authorisation in the European Union, the applicant may request a marketing authorization for one or more Member States⁷.

Once the first marketing authorisation is granted, further marketing authorisation will become easy in the Member States of the EU, because the product is already placed on the European market and helps to demonstrate that the product is therapeutically effective. Some of the advantages of this process is as follows:

i. In several Member States simultaneously, the authorisation of the drug products may be obtained.

ii. The drug product is faster to market.

iii. Application can be withdrawn from critical CMS procedures.

iv. Second time application is possible.

v. Different trade names for a single product are possible.

vi. 6 out of 10 years of data protection from the initial date.

4. National procedure:

Marketing authorisation may be obtained only in one Member State by applying to the appropriate regulatory authority through this process. In no other Member State should the condition for the product have been approved. Given that the approval is obtained directly from the Member State concerned, the approval is faster than other proceedings. The request should be filed within 210 days⁸.

Scientific evaluation of the application:

When application is validated the rapporteurs and co-rapporteurs shall establish that the dossier is received, EMA will commence the procedure as per its website dates. If one of the CHMP members fails to receive the required information within a month, the EMA ceases to receive a clock until confirmation from each of the CHMPs that receive the requested document is received. The CHMP shall give its final opinion. Every science consultant group has experts who, according to the specific experts required, are selected from the list of European experts. CHMP Chairperson shall receive the opinion of the Scientific Advisory Group. CHMP shall examine the Rapporteur's or Co-Rapporteur's preliminary assessment report ⁹.

CHMP will consider the Rapporteur's or Co-Rapporteur's preliminary assessment report. This report should identify the issues that should be addressed by the peer review comments and other comments from members of the CHMP. This will then be transmitted to the candidate together with the CHMP recommendation and scientific debate. At this time, the clock ends. In the specified timeframe (3 months), The CHMP shall examine this matter and reach agreement on it¹⁰.

Post-authorization inspection:

After the authorisation is given, the following routine inspections are performed:

GMP Inspection:

The main purpose of this re-inspection is to ensure that manufacturers are continuing to comply with the GMP of the European Union and the marketing authorisation requirements. Each site in a third country without an operating MRA is inspected every 3 years¹¹.

Renewal of marketing authorization:

According to Article 14 of the European Regulation, a drug product is marketing authorized for five years, with the exception of conditional marketing authorisation. On the basis of an EMA / CHMP re-evaluation of the product benefit and risk balance, the marketing authority may be renewed after 5 years. Six months before the expiry of the application. A record containing all of the consolidated data, including changes made after the marketing authorisation was granted, should accompany this request. The date on which an invoice is notified about the validation shall be issued by EMA. The applicant shall receive this invoice and the charges will be due within 45 days of the notice date¹².

Figure 1. Flowchart of Centralised Process of Marketing Authorization

Figure 2. Flowchart of Decentralised Process of Marketing Authorization

Figure 3: Flowchart of National Procedure for Marketing Authorization

Figure 4: Marketing Authorization through Mutual Recognition Procedure

Filing of active substance master file (ASMF) in European union:

The main purpose of the ASMF procedure is to ensure that the applicant always knows the active substance aspects that would affect the safety, quality or effectiveness of the product. Every shortcoming present in the ASMF shall be addressed to the applicant of the Marketing Authorisation by the regulatory authorities. In order to avoid disclosure of confidential information which may be included in the restricted part of the Active Substance Manufacturer, General terms shall be used during the questioning process. The applicant will then ask the manufacturer of active substances to provide all the information necessary for the provision of the national regulatory authority and will ensure that its part of the ASMF is complete. The applicant for the marketing authorisation shall pay the ASMF assessment fees in accordance with the instructions provided by the competent regulatory authority. If the marketing authorisation is subject to changes due to the modifications of the ASMF, the holder of the marketing authorisation will have to pay additional charges¹³.

The ASMF shall replace the European Pharmacopoeial Suitability Certificate and the holder of the ASMF shall give withdrawal of the letter of access to the national competent authority or to the European Medicines Agency if the active substance is no longer delivered to that holder of the Marketing Authorisation¹⁴.

Role of ASMF submission:

· ASMF plays a very important role for the manufacturers of the drug product and helps them in the approval and registration of the drug product.

· In order to promote the marketing of this product the active ingredients registered are published on the website.

· The CMC part of a dossier documents the characteristic, purity, force and quality of the drug product. CMC (chemistry, production and control.

· It protects the proprietary and confidential information¹⁵.

Contents of ASMF:

1. Overall content:

All the necessary information shall be provided, as indicated in Part IIC, Checks on starting substances-active substances and Part IIF for the marketing authorisation of drugs product in all the Member States of the European Union, Stability-stability tests on active substances¹⁶.

2. Applicant’s part and restricted part:

The file of the Active Substance Master must include information explaining the know-how of a product which must be kept confidential and submitted to the authorities only. This is therefore split into 2 parts:

a. Applicant’s Part or the Open Part:

In order to evaluate the suitability of the active substance specification to control the drug substance, the Active Substance Manufacturer must provide the applicant with all required information. This may include information on production methods, information on the impurities from the method of production, the isolation process and the degradation as applicable, and information on the toxicity of certain impurities. In addition, information is provided¹⁷.

b. ASM Restricted Part:

Full information about the various actions involved in the production of the drug substance and about the various methods applied, such as reaction condition, temperature, data validation and data evaluation of critical manufacturing steps, quality control information, which can include valuable information, used in the manufacture of the drug substance. This information is therefore only provided to the authorities.

3. Discussion of potential toxicology of impurities:

The Active Substance Manufacturer should include in the applicant's part of the ASMF information on the potential toxicology of the impurities along with reference literatures. If the information provided regarding this is insufficient, additional information must be provided by the applicant¹⁸.

Changes/updates to the ASMF:

The national competent authority or the EMA will be informed by means of variation procedures of any changes that must be made to the ASMF. We shall also provide a letter of submission. In that case, due to certain provisions the contents of the ASMF cannot be changed at the same time. The holder of the ASMF shall still provide the MA Holder and National Authority / EMA with all necessary data¹⁹.

Requirements for submission of ASMF:

During the initial submission of the ASMF with the Reference number that has been allotted, the Active Substance Manufacturer has to submit the following data ²⁰:

a. Marketing Authorization Application form that states the correct ASMF Reference number.

b. Letter of Access

c. Submission Letter and Administrative Details

d. ASMF Dossier

Submission of ASMF:

The ASMF is submitted via the Common European Submission Portal (CESP). This submission system can be submitted from the Head of Drug Agencies (HMA). It is a simple and secure way for data exchange with applicants and regulatory agencies. This system is able to:

· Give a secure way to communicate with the Regulatory Agencies through one platform.

· Submission of application that shall reach all the required agencies.

· Decreases the stress on both, industry and regulators for handling of CD’s and DVD’s.

You may register with CESP if the application is first submitted via the CESP. After registration credentials, the registered e-mail address is sent to access the portal ²¹.

CONCLUSION:

Medicinal products consist mainly of two components, either in liquid, powder or in solid form. i.e. the active and excipients form of pharmaceuticals. The intended effect in a medicinal product is achieved by this Active Pharmaceutical Ingredient (API). The API Supply is managed worldwide by India and China. In recent decades, manufacturers have moved their production lines to Asia in order to cut API production costs in Western Europe and the United States. Everywhere an API is created, the safety and quality standards of the country in which end users are situated must be met. This means that drugs sold within the EU must meet the strict safety and quality requirements of the European Medicines Agency. An API fabrication company, the construction of the capsule and the packing of the medicine are no longer complete. In order to ensure that the drug products fulfil the quality standards and away from any defect, the governing bodies which are responsible for patient or public safety have established strict screenings. If these standards are not respected by manufacturers, the product may result in fines or reminders. Among all the regulatory authorities, the European Union has one of the strict regulations. Like other drug products the quality and efficacy of the API manufactured is taken very seriously by EMA (European Medicines Agency). Therefore, when placed on the European market, even the API has a lot to follow. The Regulations laid down by the EMA pertaining to Active Pharmaceutical Ingredients ensure that the API either manufactured in European Union or Imported into European meets the quality requirements and there would be no doubts regarding the efficacy of the product. The process of obtaining a marketing authorization thus is an extensive process as the regulatory ensure the data regarding the API provided is adequate to consider that the product is safe to be used in the formulation of a drug product and will not deter the efficacy of the drug product.

REFERENCES:

1. Nandini N. Marketing Authorization and strategies for the promotion of Drugs in India, Europe and USA. World J Pharm Pharm Sci. 2019; 8(8): 1-17.

2. Final Guideline Active Substance Master File: Available from: URL:https://www.ema.europa.eu/en/human-regulatory/active-pharmceutical-ingredient/guidance-document (accessed on 17th September 2019).

3. Narla SK. Marketing Authorization of Human Medicinal Products to European Union/European Economic Area. Int J Pharm Sci Rev Res. 2011; 10(1): 1-9.

4. Panfilova H, Olesia N, Liusine S, Oksana T. The Analysis of Organizational Approaches in Drug Registration in the EU, Ukraine, Tajikistan, Turkmenistan and Uzbekistan. Res J Pharm Tech. 2018; 11(5):1894-1900.

5. Nuthalakanti N, Priyanka B. Marketing Authorization and Strategies for the Promotion of drugs in India, Europe and USA. World J Pharm Pharm Sci. 2019; 8(8): 336-52.

6. Kekare A, PC J, Janodia M et al. Drug product registration and marketing authorization procedures in EU-A perspective. Marmara Pharmaceutical Journal. 2013; 17(1): 1-6.

7. Skrnjug I, Uzeirbegovic S, Romcevic ML, Tomic S et al. Mutual Recognition in European System: A blueprint for increasing access to medicines. Regulatory Toxicology and Pharmacology. 2019; 106(1): 270-77.

8. Makvana P, Maheshwari D. Regulatory Requirements for Marketing Authorization of Generic Product in European Countries by Decentralised Procedure. J Pharm Sci Bioscient Res. 2014; 4(2): 145-49.

9. Jayalakshmi B, Seetharaman R, Kamaraj R. Registration and Regulatory Requirements of Generic Drugs Marketing Authorization in “BRICS” Countries. Res J Pharm Tech. 2019; 12(3): 1403-1408.

10. Jawahar. N, Shrivastava N, Ramachandran. A, Priyadharshini BR. Procedures and Applications for Marketing Authorization of Medicinal Products in European Union. J Pharm Sci and Res. 2015; 7(4): 219-25.

11. Sathya Narayanan AS, Lakshmi KS, Raju K. An Overview on Good Pharmacovigilance Practices and New Operational Plan Milestones of Eudravigilance in European Union. Res J Pharm Tech. 2020; 13(4):1793-1798.

12. Todi M. Dossier for Marketing Authorization in European Union. Bos J Basic Med Sci. 2002; 2(2): 56-60.

13. Prathyusha DS, Ngabhushanam BBMV, Reddy DN. Marketing Authorization Process of New Drug Substances in U.S and Europe. Indo Ame J Pharm Sci. 2017; 4(6): 1690-98.

14. Elias S, Yaser B, Saleh T. Quality control of the active Pharmaceutical ingredients of some Pharmaceutical products prior the termination of their shelf life. Res J Pharm Tech. 2019; 12(12): 6111-6118.

15. Pawan KP, Nidhi J, Pathak AK, Panigrah MK, Arun KI. Fixed Dose Combination Product: Current Status Among Regulatory Agencies. Res J Pharm Tech.2009; 2(3);433-438.

16. Bhargava NS, Shah DB, Maheshwari DG. Registration Process of API in U.S and Europe along with comparison of USDMF and EUDMF. Int J Pharm Sci Res. 2015; 6(3): 486-94.

17. Mithun EG, Puranik SB, Hasija N. An Overview of Registration of API in Regulated Markets (USFDA, Canada, EU and EDQM). Int Journal of Pharm Pharm Res. 2016; 8(1): 216-31.

18. Srilakshmi C. Regulatory Requirements for Registration of API in US and EU. Int J Pharm Chem Res. 2017; 3(2): 312-28.

19. Active Pharmaceutical Ingredient Guidance Document: Available from: URL:https://www.ema.europa.eu/en/human-regulatory/active-pharmceutical-ingredient/guidance-document (accessed on 5th September 2019).

20. European Drug Master File for Active Substance:Available from: URL:https://www.ema.europa.eu/en/human-regulatory/active-pharmceutical-ingredient/guidance-document/Directive-75/318/EEC (accessed on 2nd December 2019)

21. Guidelines Active Substance Master File Procedure Available from: URL:https://www.ema.europa.eu/en/human-regulatory/active-pharmceutical-ingredient/guidance-document-active-substance-master-file-procedure (accessed on 2nd December 2019).

Received on 15.12.2020 Modified on 10.05.2021

Research J. Pharm. and Tech. 2022; 15(5):2070-2076.

DOI: 10.52711/0974-360X.2022.00342