Documentation In Pharmaceutical Industry

Master formula record, DMF (Drug Master File), Distribution records. Generic drugs product development Introduction , Hatch-Waxman act and Amendments, CFR (CODE OF FEDERAL REGULATION) ,Drug product performance, In-vitro, ANDA regulatory approval process, NDA approval process, BE and drug product assessment, in –vivo, Scale up process approval changes, Post marketing surveillance, Outsourcing BA and BE to CRO

1. Regulatory affairs I Silambarasan M pharm(pharmaceutics) MTPG &RIHS

2. WHAT IS REGULATORY AFFAIRS? A regulatory affairs is a profession which act as interface between pharmaceutical industry and drug regulatory authority around the world.

3. GOAL’S OF RA Protection of Human health Ensuring safety ,efficacy and quality of drugs Ensuring accuracy of product information

4. MAJOR REGULATORY AUTHORITY Country Regulatory Authority India Central Drugs Standard Control Organization(CDSCO) US Food and Drug Administration (US FDA) UK Medicines and Health care products regulatory Agency (MHRA) Australia Therapeutic Goods Administration (TGA) Japan Japanese Ministry of health, Labour and Welfare (MHLW) Canada Health Canada Europe European Directorate for Quality of Medicines (EDQM)

5. ROLE OF REGULATORY AFFAIRS Registration document to regulatory Agency To keep Track in every change in legislation To give strategic & technical advice to R&D,QC, PRODUCTION

6. Master formula record

7. MASTER FORMULA RECORD Master Formula Record (MFR) is a master document for any pharmaceutical product. MFR contains all information about the manufacturing process for the product. MFR is prepared by the research and development team of the company. MFR is used as reference standard for preparing batch manufacturing record (BMR) by manufacturing units. MFR is also called Master Manufacturing Record, Master Production Record .

8. DEFINITION “A document or set of documents specifying the starting materials with their quantities and the packaging materials , together with a description of the procedures and precautions required to produce a specified quantity of a finished product as well as the processing instructions , including the in-process controls”

9. MASTER FORMULA RECORD CONTAIN’S Product Details Name, logo and address of the manufacturing company Dosage form name Brand name Product code Product description Batch size Pack size and packing style Shelf life Storage conditions MFR number and date Authorization by the production and quality assurance head

10. MFR SAMPLE

11. DRUG MASTER FILE

12. DRUG MASTER FILE It is a submission to USFDA or to concerned regulatory authority, that may be used to provide confidential and detailed information about manufacturing ,processing ,packaging or storing of one or more human drugs. DMF is not mandatory by law or FDA regulation. DMF is submitted by API manufacturers. The information in DMF is used to support NDA,ANDA,IND . It is a submission that indicates that product of one company is a quality product and meet the required standards .

13. TYPES OF DRUG MASTER FILES

14. REVIEWER When reviewer receives an application (IND/NDA/ANDA) that references DMF Requests the DMF from the CDR (central document room) After getting DMF, the Reviewer starts the review procedure If Reviewer found any deficiency in the content of DMF, The APPLICANT is notified for deficiencies DETAILED DEFICIENCIES are communicated to the holder. HOLDER should submit the REQUESTED INFORMATION to the DMF REVIEW OF DMF

15. DISTRIBUTION RECORD

16. DISTRIBUTION RECORDS Distribution : The division and the movement of pharmaceuticals products from the premises of the manufacturer to the end user or to an intermediate point by means of various transport methods. Distribution records : Are written data related to distribution of drug products from manufacturer to the distributor.

17. DISTRIBUTION PROCEDURE A procedure whereby the oldest approved stock of a drug product is distributed first. It must be constructed and procedures established to facilitate recall of defective product . The manufacturer must maintain records of all distribution transactions involving in process or finished goods. Computerized tracking systems are most common.

18. DISTRIBUTION RECORDS SHOULD CONTAIN Name Strength of the product Name and address of consignee Date and quantity shipped Control number of drug product

19. GENERIC DRUG PRODUCT DEVELOPMENT

20. GENERIC DRUG A generic drug is “ a drug product that is comparable to/ bioequivalent to brand/innovator drug in dosage form, strength, route of administration, quality & performance characteristics ”. After the expiry of the patent or marketing rights of the patent drug , generic drugs are marketed.

21. PRODUCT DEVELOPMENT PRODUCT : A product is something sold by an enterprise to its customers. PRODUCT DEVELOPMENT : Product development is the set of activities beginning with the perception of a market opportunity and ending in the production , sale and delivery of a product.

22. GENERIC PRODUCT DEVELOPMENT PROCESS The input of the process is a mission statement and the output of the process is the product launch . MISSION STATEMENT : Identifies the target market for the product , provides a basic functional description of the product , and specifies the business goals of the effort ; results from well executed product planning phase. PRODUCT LAUNCH : Occurs when the product becomes available for purchase in the market place.

23. HATCH WAXMAN ACT It is otherwise called as “ Drug Price competition & Patent term Restoration Act” . Established in 1984. The main objective is - to reduce the cost - to make available more low cost generic drugs - Motivating the generic drug Manufacturer Generic drug manufacturers files ANDA that incorporates safety and effectiveness data submitted by original pioneer drug manufacturer and adds only bioequivalence study .

24. PROVISIONS OF THE ACT Paragraph I : that such patent information has not been filed Paragraph II : that such patent has expired Paragraph III : of the date on which such patent will expire Paragraph IV : that such patent is invalid or will not be infringed by the manufacture, use, or sale of the new drug for which the application is submitted

25. ORANGE BOOK Contains the list of all FDA approved Drug products It is updated monthly.

26. CODE OF FEDERAL REGULATIONS (CFR)

27. CODE OF FEDERAL REGULATIONS (CFR) CFR is the codification of the general & permanent rules and regulations (also called as Administrative law) published in the federal register by the executive departments & agencies of the federal government of the united states. It is divided into 50 titles that represent broad areas. Each title is further divided into chapters, subchapters, parts, and sections. A regulation is cited by title, part, and section, e.g. 14 CFR 121.313 (Title 14, Part 121, Section 313). Title 21 of the CFR is reserved for rules of the Food and Drug Administration. In all, 21 CFR consists of 1499 parts. There are a number of electronic sources for accessing CFR.

28. NOTABLE SECTIONS 11 Electronic records and electronic signature related. 50 Protection of human subjects in clinical trials. 54 Financial Disclosure by Clinical Investigators. 56 Institutional Review Boards that oversee clinical trials. 58 Good Laboratory Practices (GLP) for nonclinical studies.

29. DRUG PRODUCT PERFORMANCE (DPP)

30. DRUG PRODUCT PERFORMANCE (DPP) DPP is defined as the release of the drug substance leading to bioavailability of the Drug substance. Assessment of DPP is important since bioavailability is related both to the pharmacodynamics response and to adverse effects . DPP – determined by In-vivo Bioequivalence studies or in-vitro by comparative drug dissolution studies.

31. DRUG PRODUCT PERFORMANCE DRUG PRODUCT PERFORMANCE FOR NEW DRUG FOR GENERIC DRUG

32. METHOD FOR ASSESSING BIOAVAILABILITY & BIOEQUIVALENCE

33. NDA REGULATORY APPROVAL PROCESS

34. NDA (NEW DRUG APPLICATION) The vehicle through which drug sponsors formally propose that the regulatory body approve a new pharmaceutical for sale and marketing. The data gathered during the animal studies and human clinical trials of an Investigational new product become part of the NDA.

35. FUNDAMENTALS OF NDA SUBMISSION Index Summary Chemistry, Manufacturing, and Control Samples, Method Validation Package, and Labeling Nonclinical Pharmacology and Toxicology Human Pharmacokinetics and Bioavailability Microbiology (for anti-microbial drugs only) Clinical Data Safety Update Report (typically submitted 120 days after the NDA's submission) Statistical Case Report Tabulations Case Report Forms Patent Information

36. ANDA REGULATORY APPROVAL PROCESS

37. ANDA(ABBREVIATED NEW DRUG APPLICATION ) Abbreviated new drug application (ANDA) is an application for a U.S. generic drug approval for an existing licensed medication or approved drugs. A generic drug product is one that is comparable to an innovator drug product in its dosage form , strength , quality etc. 42

38. CONTENT AND FORMAT OF AN ABBREVIATED APPLICATION Application form Table of contents Basis for abbreviated new drug application submission Conditions of use Active ingredients Route of administration, dosage form and strength Bioequivalence Labeling Chemistry, manufacturing and controls. Samples Patent certification. 44

39. BE AND DRUG PRODUCT ASSESSMENT

40. BIOEQUIVALENCE AND DRUG PRODUCT ASSESSMENT By World Health Organization (WHO): Two pharmaceutical products are bioequivalent if they are pharmaceutically equivalent , and their bioavailabilities, in terms of rate ( Cmax and tmax ) and extent of absorption (area under the curve), after administration of the same molar dose under the same conditions, are similar to such a degree that their effects can be expected to be essentially the same.

41. NEED OF BIOEQUIVALENCE The need of bioequivalence studies is increasing due to the large growth of the production and consumption of generic product Bioequivalence studies are conducted if there is : A risk of bio inequivalence or A risk of pharmacotherapeutic failure No clinical studies have been performed in patient with the generic product to support its efficacy and safety

42. TYPES OF EQUIVALENCE 1. Chemical equivalence Two or more drug product contain same labelled chemical in a same amount. 2. Pharmaceutical equivalence Two or more drug are identical in strength, quality, purity, content uniformity , disintegration and dissolution. 3. Therapeutic equivalence Indicate that two or more drug product that contain the same therapeutically active ingredient elicit identical pharmacological effect and control the disease to the same extent. 4. Bioequivalence It is a relative term which denotes that the drug substance in two or more identical dosage form, reaches the systemic circulation at the same relative rate and relative extent.

43. DESIGN AND EVALUATION OF BIOEQUIVALENCE STUDIES

44. TYPE OF DESIGN 1. Complete randomized design All treatment are randomly allocated among all experimental subject . example: if there is 20 subjects, number them from 1 to20. Random select non repeating number 2. Randomized block designs Subjects are sorted into homogenous group called blocks. Method Subjects having similar background characteristics are formed as blocks

45. EVALUATION OF DATA Analytical data - Analytical method for measurement of drug must be validated for accuracy, precision, sensitivity and specificity. - More then one method during bioequivalence study may not be valid because different methods may yield different values.

46. Dos a ge Form Drug in sol u ti o n Gut wall Blo o d Site of a c ti v ity T h e r ap e ut i c effect Pharmacokinetic measurements

47. BIOWAIVERS The term Biowaiver is applied to a drug regulatory approval process when a dossier (application) is approved based on the evidence of Bioequivalence. The biowaiver means that the in vivo bioavailability and bioequivalence studies may be waived (i.e not necessary for the product approval) In 1995 , US department of Health and Human Services , and US-FDA started the Biopharmaceutical Classification System , with the aim of granting so called Biowaivers for SUPAC. Applicant can request biowaiver for immediate release product based on an approach termed the biopharmaceutics classification system BCS (32).

48. The BCS is a framework for classifying drug substances based on solubility and intestinal permeability. The BCS classifes drug substances as:

49. SCALE-UP PROCESS APPROVAL CHANGES The scale-up process approval changes made after approval in the composition, Manufacturing process, mfg. equipment & change of site have become known as Scale-up and Post Approval Changes . Abbreviated as SUPAC. NDA → Larger Batch Size ANDA → Larger Batch Size

50. SCALE-UP POST APPROVAL CHANGES The FDA has issued various guidance for SUPAC. They are SUPAC – IR (For Immediate-release solid oral dosage form) SUPAC – MR (For Modified-release Solid oral dosage form) SUPAC – SS (For Non-sterile semisolid dosage form such as creams, ointments, gels & lotions)

51. POST MARKETING SURVEILLANCE (PMS) PMS is the practice of monitoring the safety of a pharmaceutical drug or medical device after it has been released on the market. It is an important part of the science of Pharmacovigilance. Objective: To develop information about drug effects under customary condition of drug use. To assess a known serious risk related to the use of drug Advantages: Helps to detect rare ADR’s Drug interaction

52. METHODS OF SURVEILLANCE: Four types of studies are generally are used to identify drug effects Controlled clinical trials Spontaneous & Voluntary recording Cohort studies Case Control studies

53. SOURCES OF PMS Customer surveys Literature reviews Expert user groups Customer complaints The media

54. OUTSOURCING BA AND BE TO CRO Definition Contract research organisation (CRO) is an entity that extends support to pharmaceutical, biotechnology and medical devices industry in the form of research services outsourced on a contract basis. A CRO may offer such services like: Biopharmaceutical development Clinical & preclinical research Clinical trial Biological assay development Pharmacovigilance

55. OUTSOURCING BA AND BE TO CRO Outsourcing is the business practice & hiring a party outside a company to perform services & create goods that traditionally were performed in-house by the company’s own employee & staff. It is generally done to To reduce the costs and Improving the efficient resources within a company Eg : Outsourcing is Bioavailability, Bioequivalence, Research & Development Department etc.

56. THANK U