Regulatory affairs PPT api, biologics, novel, therapies obtaining nda.pptx

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1. Regulatory Requirement for Product Approval: API, Biologics, Novel Therapies obtaining NDA PRESENTED TO- DR. VIJAYAKUMAR M.R. ASSISTANT PROFESSOR DEPT. OF PHARMACEUTICAL SCIENCES BBAU LUCKNOW PRESENTED BY- AJAY PRATAP MANI M.PHARM 1 ST SEM(PHARAMCEUTICS) DEPT. OF PHARMACEUTICAL SCIENCES BBAU LUCKNOW

2. TABLE OF CONTENT API and its regulatory requirements for approval NDA and ANDA applications DMF and its types Filing of DMF Biologics and its regulatory authority Sources and types of biologics Biologics license application (BLA ) Novel drugs with its regulatory requirements Rules for approval of novel drugs New approaches- fast testing and approval CDSCO rules for novel drug marketing

3. Introduction to Regulatory Landscape in India 1 Central Drugs Standard Control Organization (CDSCO) CDSCO is India's national regulatory body for pharmaceuticals and medical devices. It oversees drug approval processes and ensures compliance with regulations. 2 Drugs and Cosmetics Act, 1940 This act forms the foundation of pharmaceutical regulations in India. It governs the import, manufacture, distribution, and sale of drugs and cosmetics. 3 New Drugs and Clinical Trials Rules, 2019 These rules streamline the approval process for new drugs. They provide guidelines for conducting clinical trials and submitting applications.

4. ACTIVE PHARMACEUTICAL INGREDIENT (API) Any substance or mixture of substance interred to be used in the manufacture of drug product and that, when used in the production of a drug, because an active ingredient of the product . Such substance are intended to furnish pharmacological activity or other direct effect in the diagnosis, care, mitigation, treatment or prevention of disease or to affect the structure and function of the body . API materials that are the active for new drugs are covered by NDA documentation . Innovator companies would use their IND or NDA filings to provide the expected details covering an API, while all others would establish and submit a DMF with the FDA or other appropriate country authority, such as EMA in Europe.

5. REGULATORY GUIDELINES FOR APIs . In order to obtain marketing Authorization for a drug product the applicant has to show evidence of efficacy, safety and Quality of the drug product . Different countries have different procedure for regulatory filing for API, in US it has done as per the DMF procedure of the FDA while in Europe it is done by ASMF procedure . The order and off-patent APIs have an alternative assesment system called the " Certification of Suitability" (CEP). It is used in the country that have signed the European pharmacopoeia convention.

6. NEW DRUG APPLICATION (NDA ) The NDA application is the vehicle through which drug sponsor formally propose that the FDA approve a new Pharmaceutical for sale and marketing in the U.S . The US Food and Drug administration (USFDA) already for several decades has had an extensive and complex set of API requirements in place covering the areas of drug registration, Current Good Manufacturing Practice ( cGMP ) and new FDA registrations.

7. Navigating the New Drug Application (NDA) Process Pre-Submission Meeting Schedule a meeting with CDSCO to discuss the NDA strategy. Clarify regulatory requirements and expectations. Dossier Preparation Compile a comprehensive dossier following CTD format. Include all required modules with detailed data and analyses. NDA Submission Submit the NDA electronically through SUGAM portal. Pay the required fees and track the application status. Review and Approval Respond promptly to any queries from CDSCO. Prepare for potential GMP inspections and expert committee presentations.

8. ABBREVIATED NEW DRUG APPLICATION (ANDA) An abbreviated new drug application ANDA contains data which is submitted to FDA for the review and potential approval of a generic drug product. Once approved, an applicant may manufacture and market the generic drug product to provide a safe, effective, lower cost alternative to the brand name drug it reference . A generic drug product is one that is comparable to an innovator drug product in dosage from, strength, route of administration, quality, performance characteristics and intended use. All approved product, both innovator and generic, are listed in FDA's approved drug products with therapeutic Equivalence Evaluations ( Orange Book)

9. DRUG MASTER FILE FOR API A drug master file (DMF) is a confidential, detailed document submitted by Active Pharmaceutical Ingredient (API) manufacturers to the U.S. Food and Drug Administration (FDA) Recently USFDA has issued Completeness Assessments for Type II ΑΡΙ DMFs under Generic Drug User Fee Amendment (GDUFA) It is also called as Active Substance Master File (ASMF)

10. TYPES OF DRUG MASTER FILE FOR API TYPE I : Manufacturing Site, Facilities, Operating Procedures, and Personnel (no longer applicable ). TYPE II : Drug Substance, Drug Substance Intermediate, and Material Used in Their Preparation, or Drug Product . TYPE III: Packaging Material TYPE IV: Excipient, Colorant, Flavor, Essence, or Material Used in their Preparation . TYPE V: FDA Accepted Reference Information.

11. FILING OF DMF Recent update regarding USFDA DMF is now we can submit e-CTD via ESG (Electronic Submission Gateway ). The deadline for the conversion of Paper format to e- CTD is beginning May 5, 2017, all submission types NDA, ANDA, BLA and Master Files must be submitted in eCTD format . FY 2024 and FY 2025 User Fee Rates User Fee Type   FY 2024 FY 2025 ANDA   $ 252,453 $ 321,920 DMF   $ 94,682 $ 95,084 Program Large Size $ 1,729,629 $ 1,891,664   Medium Size $ 691,852 $ 756,666   Small Size $ 172,963 $ 189,166 Facility Domestic API $ 40,464 $ 41,580   Foreign API $ 55,464 $ 56,580

12. BIOLOGICS Biologics are the products manufactured, extracted from or semi synthesized from a biological source which are regulated by FDA and are used to prevent cure and treat diseases and medical conditions . These are generally large, complex molecules produced through biotechnology in a living system such as a microorganism, plant cell or animal cell. These could be made of sugars, proteins, nucleic acids or complex combinations of these substances or may be living entities . These are complex mixtures that are not easily identifiable and characterized these tend to be heat sensitive and susceptible to microbial contamination hence, it is necessary to use aseptic principles from initial manufacturing process . EXAMPLES : Botox, Herceptin, Vaccines, Enbrel.

13. SOURCE AND TYPES OF BIOLOGICS Types Blood derivatives Vaccines Allergenic extracts Whole blood Blood components Proteins Human tissues Cellular and gene therapies Xenotransplantation products SOURCES Mammalian cell culture Bacteria Insect cell culture Plant cell culture Yeast Transgenics Avian cell culture Humans

14. REGULATORY AUTHORITY FOR BIOLOGICS Centre for biologics evaluation and research (CBER) is the centre within FDA that regulates biological products for human use under applicable Federal laws including the Public Health Services Act (PHS) and the Federal, Food, Drug and Cosmetics Act CBER protects and advances the public health by ensuring that biological products are safe and effective . FDA's regulatory authority for the approval of biologics resides in (PHS) Act. Biologics are subjected to regulation under Federal, Food, Drug And Cosmetics act (FD&C) Act . Some medical devices which are used to produce biologics are regulated by CBER under FD&C Act's medical device amendments of 1976 . FDA also reviews new biological products and new indications and usage for already approved products on the market for the treatment of known diseases . It , protects against threats of emerging infectious diseases . It provides the public with information to promote safe and appropriate use

15. BIOLOGICS LICENSE APPLICATION (BLA) The Biologics License Application (BLA) is a request for permission introduce or deliver for introduction a Biologic product into the market. It is mainly regulated by 21 CFR 600-800 . It is submitted by any legal person or entity, who engaged in manufacture or an applicant for a license who takes responsibility for compliance with product and establishment of standards . A Biologic License application generally applies to vaccines and other Allergenic drug products and cellular and genetic therapies.

16. A cover letter should always accompany any FDA submission. Addressed below are the Form FDA 356(h), the cover letter, and all 20 sections of the BLA application . Before each section is addressed individually, it is worth emphasizing the importance of the application form [Form FDA 356(h)], the cover letter, and the first three sections. Cover Letter: It consists of basic administrative information requested about the BLA application (e.g., sponsor name and address, etc .). The cover letter should provide at least seven types of information: Name and address of sponsor and others Product name Reason for submission(e.g. original submission, supplement, amendment, etc.). Information contained in the submission Agreements with the FDA. Other documents relating to submission. Special circumstances. Fast track review .

17. SUMMARY FORMAT INCLUDES 1.Description of drug and formulation 2. Annotated draft insert 3. Product pharmacological class 4. Scientific rationale for use of product 5. Clinical benefits 6. Foreign marketing history 7. CMC summary a. Drug substance b. Drug product. c. Stability d. Investigational summary (listing of batches used in the clinical studies) 8 . Nonclinical summary 1 . Pharmacology 2 . Toxicology 9. Human pharmacokinetics and bioavailability 10. Microbiological summary 11. Clinical summary 12. Benefit/risk relationship

18. BLA REVIEW PROCESS Then current CBER BLA review process is developed to meet requirements of Prescription Drug User Fee Act(PDUFA) of 1996. According to this act FDA agreed to institute standards and timelines in exchange for user fees paid by BLA sponsors. The goal is to standardize both review process and review content. CBER issued no. of guidance documents which provide type of information to be included in BLA for each biologic product class

19. AMENDING THE LICENSE APPLICATION During the review of the BLA, FDA's request to address unresolved issues regarding the original submission and a response to such a request is generally referred to as an amendment. Or A change to any unapproved application is called an Amendment (IND, BLA, and NDA ).

20. SUPPLEMENT TO THE ORIGINAL BLA: Amendments are submitted to update or modify an unapproved BLA, supplements are modify approved license applications . The holder of an approved BLA may seek to change its manufacturing methods, expand the product's indication, or make other changes that reflect new technology or make its product or processes more competitive. ASSEMBLING AND SUBMITTING THE BLA Submission of BLAs in electronic format would speed the review process and also eliminates handling of vast amount of paper. Many guidance documents have been published providing information about filing of the BLA in electronic format with either the conventional 356h format or the new CTD format.

21. Novel Drugs With Its Regulatory Requirements Novel drugs are often innovative products that serve previously unmated medical needs and significantly help to advance patient treatments. Novel drugs can represent important new therapies for advancing patient care. In 2017 CDER gave approval to many noval drugs includes as; Dupixent : to treat adult with moderate-to severe eczema (atopic dermatitis).

22. Rules for approval of a novel drug: FDA approval of a drug means that data on the drug's effects have been reviewed by CDER. The drug is determined to provide benefits that outweigh its known and potential risks for the intended population. These approaches can includes more interaction between CDER staff and drug developers, and shortened timelines for review of application. The drug approval process takes place within a structured framework that includes

23. Analysis of the target condition and available treatments- FDA reviewers analyze the condition or illness for which the drug is intended and evaluate the current treatment landscape, which provide the context for weighing the drug's risks and benefits. Assessment of benefits and risks from clinical data- FDA reviewers evaluate clinical benefit and risk information submitted by the drug maker , Strategies for managing risks- All drugs have risks. Risk management strategies include on FDA- approved drug label, which clearly describes the drug's benefits and risks, and how the risks can be detected and managed .

24. Newer Approach- Faster Testing & Approval The mechanisms speed up the approval process, and apply a degree of flexibility with respect to the evidence requirements for the approval of certain medicines. In the U.S., accelerated pathways (APs) include Fast Track (FT), Breakthrough Therapy Designation (BTD), Accelerated Approval (AA), and Priority Review (PR).

25. Fast Track (FT): Fast track is a process designed to facilitate the development of drugs to treat serious or prevent a condition. If there are available therapies, a fast track drug must show some advantage over available therapy. Showing the effectiveness, effect on serious outcomes. Decreasing a clinical significant toxicity of an available therapy that is common and causes discontinuation of treatment. Avoiding serious side effects of an available therapy Improving the diagnosis of a serious condition.

26. Breakthrough Therapy (BT ): Breakthrough Therapy designation, clinically significant endpoint generally refers to an endpoint that measures an effect on irreversible morbidity or mortality (IMM) or on symptoms that represent serious consequences of the disease. A clinically significant endpoint can also refer to findings that suggest an effect on IMM or serious symptoms. An effect on an established surrogate endpoint. A significantly improved safety profile compared to available therapy ( eg :- less dose-limiting toxicity for an oncology agent)

27. Priority Review (PR): Prior to approval, each drug marketed in the United States must go through a detailed FDA review process. Under the Prescription Drug User Act (PDUFA), FDA agreed to specific goals for improving the drug review time and created a two-tiered system of review times Standard Review and Priority Review. A Priority Review designation means FDA's goal is to take action on an application within 6 months (compared to 10 months under standard review).

28. Accelerated Approval (AA): In 2012, Congress passed the Food and Drug Administration Safety Innovations Act (FDASIA ). These accelerated approval endpoints may includes ones that shows benefits over a shorter duration of treatments. Accelerated approval brings drug that can provides important advances to patients sooner than with traditional approvals.

29. CDSCO rules for novel drug marketing The new drug approval process are divided into three phases for simplification in application- The first phase is premarketing meant for discovery, development and clinical studies, second phase for marketing authorization of drug and third is post marketing. Firstly preclinical studies of a drug are completed to ensure efficacy and safety, and then application for conduct of clinical trials can be conduct (phase I to phase IV) These studies are performed to ensure the efficacy, safety and optimizing the dose of drug in human beings. After the completion of clinical studies of the drug, then an application to the competent authority of India for the approval of drug marketing is submitted. The competent authority review the application and approve the drug for marketing only if the drug is found to be safe and effective in human being or the drug have more desirable effect as compare to the risk.

30. Drug Approval Process: Key Stages and Timelines 1 Pre-Clinical Studies Conduct laboratory and animal studies to assess safety and efficacy. This stage typically takes 3-4 years to complete. 2 Clinical Trials Perform human trials in phases I, II, and III. This crucial stage can last 5-7 years on average. 3 NDA Submission and Review Submit comprehensive data to CDSCO for review. The review process usually takes 12-18 months. 4 Post-Marketing Surveillance Monitor drug safety and efficacy after market approval. This is an ongoing process throughout the drug's lifecycle.

31. REFERENCES The Pharmaceutical Regulatory Process, By Ira R. Berry Robert P. Martin, 2 nd edition. Biologics, Timothy A. Keutzer , Cubist Pharmceuticals , Inc , Lexington, Massachusetts, USA A Text Book of Regulatory Affairs by Mayur S Jain et. al. PeeVee publication. Slide share and internet source.

32. Thank Y ou