Regulatory Requirements [PDF]

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Generic drug regulatory approval process in the USA, Europe, and India G. Sai Bhavani, M. P. Venkatesh*, T. M. Pramod Kumar ABSTRACT Regulatory involvement in the generic drug development hastens the drug approval process which directly/indirectly accelerated the launching of drug into the market. The regulatory documents whether in-house of documents to be submitted to regulatory authorities should be carefully reviewed by the skilled personnel to minimize the queries raised by the regulatory agencies and speed up the approval process. These are few differences in the dossier submission requirements among the three regions, i.e., the USA, Europe, and India which has been clearly represented through succinct comparisons third part of this work. Generic manufacturers may file an abbreviated new drug application that incorporates the safety/effectiveness data submitted by original innovator drug manufacturer and adds only bioequivalence studies. Therefore, it is very difficult and challenging task to approve a drug by the manufacturing companies, simultaneously submitted in all the regulatory authorities. The literature work, the comparison parameters, and difference in generic drug approval requirements have been delineated in this work, which gives clear depict where India lies in its generic drug approval process and the challenges that Indian regulatory authority has to overcome in the near future. KEY WORDS: Europe, India, Process approval, Regulatory affairs, USA

INTRODUCTION The pharmaceutical trade is one of the extremely synchronized industries, with a lot of rules and system enforced by the administration to protect the health and well-being of the public. Therefore, the aim of the pharmaceutical trade is to recognize and expand a generic drug product meet the varied market desires. As per global market trend, it is estimated that about $150 billion worth of drugs will be off-patented throughout the period 2010–2019, which will serve up as a stage for pharmaceutical companies to develop generic drugs. The pharmaceutical industry in India has exposed an extraordinary enlargement which in twist has risen the wealth of India. Somewhat parallel with the harmonization incomplete group toward creating an ordinary promote for medicines within the EU for require of wider harmonization. A new drug is clear as one that is not usually recognizable as safe and effective for the future Access this article online Website: jprsolutions.info

ISSN: 0975-7619

indications. And also, this definition has much greater reach than simply a “new” chemical entity.[1] The term “new drug” also refers to a drug product already in existence that never approved by the Food and Drug Administration (FDA) for marketing in the United States; new therapeutic indications for an approved drug, a new dosage form, a new route of administration, a new dosing schedule, or any other significant clinical differences than those approved. A generic drug product is one that is comparable to an innovator drug product in dosage form, strength, route of management, quality, and future use.[1,2]

INDIA In India, drugs are regulated both at central and state level. At the state level, state drug regulatory authorities issue licenses to manufacture approved drugs to monitor the quality of the drugs along with Central Drugs Standard Control Organization (CDSCO). At the central level, CDSCO under the Ministry of Health and Family Welfare is responsible for approving of new drugs, clinical trials,

Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysuru, Karnataka, India *Corresponding author: Dr. M. P. Venkatesh, Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Sri Shivarathreeshwara Nagara, Mysuru - 570 015, Karnataka, India. Phone: +91-9886506306. E-mail: [email protected] Received on: 14-01-2020; Revised on: 25-02-2020; Accepted on: 27-03-2020

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and licensing of drugs[3] in India; the regulation of drug, r-DNA, medical devices, and biological products is distributed within various ministries.

USFDA In the United States, FDA is the drug regulatory authority for approving food, human and veterinary drug products that are to be marketed in the USA.[3]

EMA In Europe, European Medicines Agency is the regulatory agency for approving human and veterinary drug products centrally to market the drugs in European Union (EU). There is also entity National Competent Authorities for favorable the drug products in EU individual states. The objective of this study is to figure out the determinants for selecting a generic application and the rigid aspects concerned in generic drug development. Understanding the differences between three countries and highlighting the generic drug approval process in the US, EU, and India. Each and every study has some follows certain pathways and patterns to attain the goal.

DISCUSSION USA Generic drug approval process in the USA Hatch-Waxman Act intended to balance interests of consumers, the brand name pharmaceutical industry (innovator), and the generic drug industry to “make available more low-cost generic drugs and to create a new incentive for increased expenditures for research and development of certain products which are subject to pre-market approval”.[4] Title I of Hatch-Waxman Act authorized marketing of generic drugs on approval of abbreviated new drug application (ANDA). Under this ANDA can be approved on submission of evidence that the active ingredient of the generic drug is the “bioequivalent” of a drug previously approved by the USFDA Title II of Hatch-Waxman Act, this section provided specific extensions of patents covering drugs and other products subject to “regulatory review” by the FDA and government agencies.[5] Under section 505 (j) of Hatch-Waxman Act, an ANDA may be filed for a generic version of any “listed drug.” Listed drug any drug for which an NDA has previously been approved is deemed to be a listed drug and is listed by FDA in the orange book. Drugs previously approved under ANDAs and antibiotics are also regarded as listed drugs. An ANDA must include all information required in an NDA except full reports of Drug Invention Today | Vol 14 • Issue 3 • 2020

investigations demonstrating that the drug is safe and effective in use.[6] ANDA additionally information Labeling of the drug for which ANDA is required is similar as the accepted labeling for the listed drug. Its route of administration, dosage form, and strength are the same as the listed drug and also status of orange book listed patents on the approved drug. Types of certifications An applicant for ANDA must certify to FDA that in its opinion and to the best of its knowledge, with respect to each listed patent that claims the drug or use of the drug for which the applicant seeking approvals are: “Paragraph Notifications” the Hatch-Waxman Act has undertaken necessary considerations to prevent litigations between generics and NDA applicants.[6] The pathway for approval of generics by the HatchWaxman begins with the certification procedures. Hatch-Waxman proposed four options for the application for generic approval.[7,8] ANDA review process in the USA The ANDA review process is detailed in Figures 1 and 2. Withdrawal of approval of an ANDA FDA may withdraw (or) suspend approval of an ANDA while the agreement of the listed drug on which the ANDA relies is also reserved or pendant. Further, an approval of an ANDA or 505 (b) (2) “application may be withdrawn on the basis of evidence showing that the drug is unsafe for use or ineffective or that the ANDA” or 505 (b) (2) application contains any untrue statement of material fact.[9,10] Major requirements for ANDA review process 1. Bioequivalence data 2. QC specifications 3. CMC controls. Bioequivalence definition Bioequivalence is a word in pharmacokinetic used to consider the usual in vivo biological similarity of two proprietary preparations of a drug. •

Bioequivalence project manager accesses the list and assigns to individual reviewers on “first-in, first-reviewed” policy.

Quality control definition Quality control is a system maintaining standards in manufactured products by testing sample of the output against the specification. CMC controls (review) CMC section of DMF, ANDA, SANDA’s, and annual reports. 136

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Applicant

ANDA

Acceptance& Complete file

Refuse to file NO

YES B.E Review

Chemistry Review

Plant Inspection

Labelling Review

B.E Review Acceptable

Chemistry Review Acceptable

NO

NO

YES

B.E Letter Deficiency

Pre Approval Acceptance

Not Applicable Letter

NO Approval Pending Results YES ANDA Approved

Figure 1: Abbreviated new drug application review process FDA checks the ANDA application in the checklist for completeness

• •

Submit ANDA to OGD Entire review of chemistry, Micro,Labeling and Bioequivalence

Generic Development

FDA Find no issues

Generic launch

Approval of ANDA by FDA

Figure 2: Steps for launching of generic drugs

Regulations for ANDA review process Code of Federal Regulations (CFR): These are the set of laws that are applicable toward ANDA Review process: 21 CFR Part 320 – Bioequivalence and bioavailability requirements. 21CFR Part 314 – Applications for FDA approval to market a new drug. Forms • Form FDA 356h (Form 356 h) – Application to market a new or abbreviated new drug or biologic 137

for human use, which ANDA applicants must fully complete and sign for their submissions Form FDA 3794 – Generic drug user fee cover sheet Form FDA 3674 – Certifications to accompany drug, biological product, and device applications/ submissions [Table 1].

Europe The EU has one of the most highly regarded regulatory systems in the world. The system comprises European Parliament, the Council of Ministers, and the European Commission. EU consists of 27 member states, the European Medicines Agency is a decentralized agency of the European Union, located in London.[7,8] Legal basis for applications in Europe The eligibility and the desires are set in the Commission Regulation (EC) No. 726/2004 and clearly mentioned in the articles 8 and 10 are of the directive 2001/83/EC. Types of submission procedure To market a generic medicinal product in European Economic Area which consists of 27 member states and 3 EFTA countries, a marketing authorization has to be issued. EMA regulates the medicinal products marketing authorization through various committees. Different types of submissions for receiving marketing authorization in Europe are given below in the table. In case of generic drug products, generally, Drug Invention Today | Vol 14 • Issue 3 • 2020

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Table 1: Types of paragraph certifications Paragraph I Paragraph II Paragraph III Paragraph IV

That the patent information relating to innovator patent has not been filed That relevant patent has already expired That the generic will not market the drug until after the patent expires The generic manufacturer should certify that an applicable patent is invalid or will not be infringed by the generic product

Table 2: Brief review on Europe procedure and summary Agencies Procedure responsible type

Summary

EMA

Centralized procedure

Reference member state

Decentralized procedure

Reference member state

Mutual recognition procedure

Member states

National authorization

It is for single application, single evaluation, and authorization allowing direct access to the single market of the member countries Application is submitted to all member states where intended and choose one of them as reference member state. The assessment report is prepared by RMS including the concerned member states and based on both comments, MA is granted It is followed where an applicant having MA in one member state, wishes to obtain the same in other member states. It is based on mutual recognition of concerned member states, granted by the reference member states MA is granted by member states and hence an application must be submitted to the particular member state

the decentralized procedure is followed, whereas in case of the new drug products, the application for marketing authorization is always submitted through a centralized procedure [Table 2].[9,10] India Drugs are regulated in India both central and state level through the CDSCO under the Ministry of Health and Family Welfare which is responsible for approval new drugs, clinical trials, and licensing of drugs. Drug regulatory authorities issue the licenses at the state level. The regulation of drugs, medical devices, and biological products in India is distributed with in various ministries. There are mainly two regulatory Drug Invention Today | Vol 14 • Issue 3 • 2020

bodies which regulate the drug approval, marketing, production, quality, and drug price in India.[11,12] The National Pharmaceutical Pricing Authority (NPPA) The department of petrochemicals and chemicals controls the function of NPPA. NPPA fixes or revises the price of bunch drugs and formulations. NNPA updates the record under price control through addition and elimination of drugs in line with prescribed guidelines. NPPA also maintains data on production, “exports and imports and market share of pharmaceutical firms.” NPPA monitors the shortage of medicines in addition to provide inputs to issues pertaining to drug pricing. 1. Generic drug require form 44 for approval in India 2. A treasury challan of INR 15,000 is required all the active ingredients for more than 1 year and INR 50,000 of the active ingredients is approved for less than 1 year in India 3. Manufacturing of bulk drugs and raw materials the applicant has a manufacturing license for bulk drugs, a copy of the same is needs to be submitted 4. Chemical and pharmaceutical information including: Information on active ingredients. a. Brief chemical and pharmaceutical data on formulation b. Master manufacturing formula. Future challenges for generics manufacturers in India The generic drug companies in India have minor road technical and diversify market requirements. And also more patents expire, the common portion of the pharmaceutical advertise is usual to prolong to have enlarged sales. The technical ability for manufacturing and supplying generic drugs of these companies’ determination global generics market. However, their potential sustainable enlargement depends on filling in spirited markets of developed world. The future prospects of generic product regulation in India and the US are of huge significance as they will make a decision for the track of enlargement of Indian Pharmaceutical Industries. Based on the current cases and incidents that have occurred in India and the US related to the generic product utilization, the new critical roles will be implemented.[9,10] Comparison of generic drug filling in different countries Worldwide, the FDA in the United States, European Medicine Agency (EU) in Europe, CDSCO in India, Ministry of Health labor the regulatory requirements, and filling procedure of drug product of different countries in the world are different from each other [Tables 3-5].[9-11] 138

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Registration requirements and comparison between regulated and emerging markets Table 3: Comparison of generic approval process in EU, India, and the US Regional needs

EU

India

US

Review organization

Drug Control General of India

USFDA

Single step

Single step

BSE/TSE data

In EU, they have multiple agencies CHMP EMEA Various health national agencies Centralized Decentralized Mutual recognition It is required for EU

Code Total copies Timeline for approval Requests Purpose Presentation

Applicable for EU 1 12 months EU MAA eCTD and paper along with Nees

It is required for India agency Not applicable for India 1 2–18 months India MAA Paper

It is not applicable for the US agency Not applicable for the US 3 18 months US ANDA/NDA eCTD

Drug registration process

Table 4: Finished product QC regional needs Regional needs

EU

India

US

Process as per ICH guide lines Analyze Disintegration Color identification Water content

ICH-Q6A 100% Applicable Applicable Not necessary

ICH-Q6A 100% Applicable Applicable Necessary

ICH-Q6A 110% Not applicable Not applicable Necessary

Table 5: Manufacturing and CMC control requirements Regional needs

EU

India

US

Total batches Validation Packaging Size of the batch

3 Not applicable for process validation In EU, it is not required Pilot scale and one lab batch

1 In India, it is not addressed In India, it is applicable Pilot scale required

1 Not applicable in the US Required 100,000 units 1 lakh units and one pilot scale

CONCLUSION

ACKNOWLEDGMENT

Generic drug developed is a major part of the pharmaceutical industry and grow fast because to the copyright end of the branded drugs. Generic manufacturers might database an ANDA that incorporates the safety/effectiveness information submitted by unique innovator drug manufacturer and adds only bioequivalence studies. I have selected three different countries, the US, Europe, and India, and although there is a continuous process of harmonization. It is concluded that the United Sates has the toughest drug approval standard in the world. To sold a new a drug, the Pharma manufacturer has to give the proof of safety and effectiveness of drug required by the law. In EU, pharmaceutical industries follow three approval procedures centralize, decentralize, and mutual recognition procedure. The CDSCO is the major medical regulatory organization in India.

The authors thank JSS College of Pharmacy and JSS Academy of Higher Education and Research, Mysuru, and for providing necessary facilities to carry out this work.

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Source of support: Nil; Conflicts of interest: None Declared

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