Documentation in Pharmaceutical Industry

Documentation in Pharmaceutical Industry - master formula record , DMF ( DRUG MASTER FILE )

1. DOCUMENTATION IN PHARMACEUTICAL INDUSTRY Presented by Navaneethakrishnan P Department of Pharmaceutics Karpagam College of Pharmacy Coimbatore -32 Department Of Pharmaceutics, KCP, CBE-32 1

2. CONTENT MASTER FORMULA RECORD (MFR) DRUG MASTER FILE (DMF ) GENERIC DRUG DEVELOPMENT HATCH-WAXMANN ACT Department Of Pharmaceutics, KCP, CBE-32 2

3. MFR - INTRODUCTION Introduction In the 1997 WHO guidance document: “WHO/VSQ/97.01: A WHO guide to good manufacturing practice (GMP) requirements. Standard operating procedures and master formulae WHO identifies manufacturing instructions as “ Master Formula Other terms used in GMP guidelines and regulations are “ Manufacturing Formula ”, “ Master Production and Control Record ” An approved master document that describes “ The full process of manufacturing for the batch of product with at least cross-reference to the support operations for a batch of a specific product” Department Of Pharmaceutics, KCP, CBE-32 3

4. Definition The following are the extracted definitions from several guidelines: WHO GMP Guidelines: A formally authorized master formula should exist for each product and batch size to be manufactured. Health Canada GMP guidelines: “MASTER FORMULA (formula-type ) – A document or set of documents specifying the raw materials with their quantities and the packaging materials, together with a detailed 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 .” Department Of Pharmaceutics, KCP, CBE-32 4

5. US CFR . To assure uniformity from batch to batch, master production and control records for each drug product, including each batch size there of , shall be prepared , dated, and signed (full signature, handwritten) by one person and independently checked, dated, and signed by a second person. The preparation of master production and control records shall be described in a written procedure and such written procedure shall be followed. Department Of Pharmaceutics, KCP, CBE-32 5

6. Required Content of Master Formula: MASTER FORMULA RECORD as per WHO MASTER FORMULA - PRODUCTION MASTER FORMULA FOR PACKAGING MASTER PRODUCTION AND CONTROL RECORDS REQUIRED BY THE USA Department Of Pharmaceutics, KCP, CBE-32 6

7. MASTER FORMULA (PRODUCTION) as per WHO The master formula should include: Name of the product, with a product reference code relating to its specification. A description of the dosage form , strength of the product and batch size A list of all starting materials to be used with the amount of each. A statement of the expected final yield with the acceptable limits, and of relevant intermediate yields, where applicable. A statement of the processing location and the principal equipment to be used Department Of Pharmaceutics, KCP, CBE-32 7

8. Cont.... The methods, or reference to the methods , to be used for preparing and operating the critical equipment, e.g. cleaning (especially after a change in product ), assembling , calibrating, sterilizing. Detailed step-wise processing instructions ( e.g. checks on materials, pretreatments , sequence for adding materials, mixing times , temperatures ). The instructions for any inprocess controls with their limits. T he requirements for storage of the products , including the container , the labeling, and any special storage conditions. Any special precautions to be observed. Department Of Pharmaceutics, KCP, CBE-32 8

9. MASTER FORMULA - PACKAGING The name of the product A description of its pharmaceutical form , strength and, where applicable , method of application. The pack size expressed in terms of the number, weight or volume. A complete list of all the packaging materials required for a standard batch size, including quantities, sizes and types, with the code or reference number relating to the specifications for each packaging material. Sp ecial precautions to be observed , including a careful examination of the packaging area and equipment in order to ascertain the line clearance before and after packaging operations ; Department Of Pharmaceutics, KCP, CBE-32 9

10. MF and corresponding Batch Records Master Formula give the complete production instructions for a specific batch and batch size of cell banks, virus seed lots, intermediates, final bulks, final formulated bulks or final container product. The batch production record (BPR) is the approved copy of the master document with filled in data entries, signatures, dates, production locations, operators, and lot number, records of all supporting data (autoclave records, cleaning records, equipment identification and calibration dates, in-process test results, and QC results) Department Of Pharmaceutics, KCP, CBE-32 10

11. FORMATS of MF Generally MF should be a single documents of that provide step by step production instruction raw material equipment's used location production data etc., Department Of Pharmaceutics, KCP, CBE-32 11

12. Issuing of MF Master formulae are almost stored in the computer The official signed form is a paper copy When a production order is made , QA is responsible to generate a copy usually adds the lot number and stamps each page of the reproduced MF The MF should make a reference to in process tests, QC tests, production parameter that are computer recorded, environmental monitoring autoclave run charts etc., The batch records include the all production records and support records . Master formula once approved and signed should remain under the control of QA. Copies don’t stored in production area . When revision are made (if any change) then a new version is assigned a revision number, the approval signature and effective dates are added, the previous is achieved. MF, copies are distributed to relevant department and in a production run should be distributed along with stamped by QA. 12 Department Of Pharmaceutics, KCP, CBE-32 12

13. Example of MF Department Of Pharmaceutics, KCP, CBE-32 13

14. Example of MF Department Of Pharmaceutics, KCP, CBE-32 14

15. DRUG MASTER FILE (DMF) Department Of Pharmaceutics, KCP, CBE-32 15

16. DRUG MASTER FILE (DMF) INTRODUCTION: A Drug Master File (DMF) is a submission to the Food and Drug Administration (FDA) that may be used to provide confidential detailed information about facilities, processes, or articles used in the manufacturing, processing, packaging, and storing of one or more human drugs . The submission of a DMF is not required by law or FDA regulation . The information contained in the DMF may be used to support an Investigational New Drug Application (IND), a New Drug Application (NDA), an Abbreviated New Drug Application (ANDA), another DMF, an Export Application, or amendments and supplements to any of these. Department Of Pharmaceutics, KCP, CBE-32 16

17. SUBMISSION OF DMF Each DMF submission should contain a transmittal letter , administrative information about the submission, and the specific information to be included in the DMF as described in this section. The DMF must be in the English language . Whenever a submission contains information in another language, an accurate certified English translation must also be included. Each page of each copy of the DMF should be dated and consecutively numbered. An updated table of contents should be included with each submission . Department Of Pharmaceutics, KCP, CBE-32 17

18. SUBMISSION OF DMF Department Of Pharmaceutics, KCP, CBE-32 18

19. Types of DMF Department Of Pharmaceutics, KCP, CBE-32 19

20. TYPE 1 : Manufacturing Site, Facilities, Operating Procedures, and Personnel A Type I DMF is recommended for a person outside of the United States to assist FDA in conducting on site inspections of their manufacturing facilities.  The DMF should describe the manufacturing site, equipment capabilities, and operational layout . A Type I DMF is normally not needed to describe domestic facilities, except in special cases, such as when a person is not registered and not routinely inspected . The description of the site should include acreage, actual site address, and a map showing its location with respect to the nearest city. An aerial photograph and a diagram of the site may be helpful . A diagram of major production and processing areas is helpful for understanding the operational layout.  Department Of Pharmaceutics, KCP, CBE-32 20

21. TYPE 2 : Drug Substance, Drug Substance Intermediate, and Material Used in Their Preparation, or Drug Product Type II DMF should, in general, be limited to a single drug intermediate, drug substance, drug product, or type of material used in their preparation 1) Drug Substance Intermediates, Drug Substances, and Material Used in Their Preparation Summarize all significant steps in the manufacturing and controls of the drug intermediate or substance. Detailed guidance on what should be included in a Type II DMF for drug substances and intermediates may be found in the following guidelines: Guideline for Submitting Supporting Documentation in Drug Applications for the Manufacture of Drug Substances. Guideline for the Format and Content of the Chemistry, Manufacturing, and Controls Section of an Application . Department Of Pharmaceutics, KCP, CBE-32 21

22. TYPE 2 : Drug Substance, Drug Substance Intermediate, and Material Used in Their Preparation, or Drug Product 2) Drug Product Manufacturing procedures and controls for finished dosage forms should ordinarily be submitted in an IND, NDA, ANDA, or Export Application. If this information cannot be submitted in an IND, NDA, ANDA, or Export Application, it should be submitted in a DMF. When a Type II DMF is submitted for a drug product, the applicant/sponsor should follow the guidance provided in the following guidelines: Guideline for the Format and Content of the Chemistry, Manufacturing, and Controls Section of an Application. Guideline for Submitting Documentation for the Manufacture and Controls for Drug Products Guideline for Submitting Samples and Analytical Data for Methods Validation Department Of Pharmaceutics, KCP, CBE-32 22

23. TYPE 3 : Packaging Material Each packaging material should be identified by the intended use , components , composition , and controls for its release . The names of the suppliers or fabricators of the components used in preparing the packaging material and the acceptance specifications should also be given . Data supporting the acceptability of the packaging material for its intended use should also be submitted as outlined in the " Guideline for Submitting Documentation for Packaging for Human Drugs and Biologics ." Toxicological data on these materials would be included under this type of DMF , if not otherwise available by cross reference to another document . Department Of Pharmaceutics, KCP, CBE-32 23

24. TYPE 4 : Excipient, Colorant, Flavor, Essence, or Material Used in Their Preparation Each additive should be identified and characterized by its method of manufacture, release specifications, and testing methods. Toxicological data on these materials would be included under this type of DMF, if not otherwise available by cross reference to another document. Usually, the official compendia and FDA regulations for color additives, direct food additives, indirect food additives, and food substances, may be used as sources for release tests, specifications, and safety. Guidelines suggested for a Type II DMF may be helpful for preparing a Type IV DMF. The DMF should include any other supporting information and data that are not available by cross reference to another document. Department Of Pharmaceutics, KCP, CBE-32 24

25. TYPE 5: FDA Accepted Reference Information FDA discourages the use of Type V DMF's for miscellaneous information, duplicate information, or information that should be included in one of the other types of DMF's. If any holder wishes to submit information and supporting data in a DMF that is not covered by Types I through IV, a holder must first submit a letter of intent to the Drug Master File Staff FDA will then contact the holder to discuss the proposed submission . Department Of Pharmaceutics, KCP, CBE-32 25

26. Format, Assembly, and Delivery of DMF An original and duplicate are to be submitted for all DMF submissions. Drug Master File holders and their agents/representatives should retain a complete reference copy that is identical to, and maintained in the same chronological order as, their submissions to FDA . The original and duplicate copies must be collated, fully assembled, and individually jacketed. Each volume of a DMF should, in general, be no more than 2 inches thick. For multivolume submissions, number each volume. For example , for a 3 volume submission, the volumes would be numbered 1 of 3, 2 of 3, and 3 of 3. Department Of Pharmaceutics, KCP, CBE-32 26

27. Cont … U.S . standard paper size (8-1/2 by 11 inches) is preferred. Paper length should not be less than 10 inches not more than 12 inches . However, it may occasionally be necessary to use individual pages larger than standard paper size to present a floor plan, synthesis diagram, batch formula, or manufacturing instructions. Those pages should be folded and mounted to allow the page to be opened for review without disassembling the jacket and refolded without damage when the volume is shelved . Department Of Pharmaceutics, KCP, CBE-32 27

28. Cont … Delivery to FDA Drug Master File submissions and correspondence should be addressed as follows: Drug Master File Staff Food and Drug Administration 5901-B Ammendale Rd. Beltsville, MD 20705-1266 Department Of Pharmaceutics, KCP, CBE-32 28

29. Generic Drug Development A   G eneric drug  is a pharmaceutical drug that has the same chemical substance as the drug that was originally developed , patented and innovated . Generic drugs are allowed for sale after the expiry of the patent  of the original drugs . Because the active chemical substance is the same, the medical profile of generics is believed to be equivalent in performance. The generic drug has the same active pharmaceutical ingredient (API) as the original , but it may differ in characteristics such as manufacturing process, formulation, excipients, color, taste, and packaging. Department Of Pharmaceutics, KCP, CBE-32 29

30. cont., According to WHO, “ A generic drug is a pharmaceutical product , usually intended to be interchangeable with an innovator product that is manufactured without a license from the innovator company and marketed after the expiry date of the patent or other exclusive rights ” The English dictionary defines the word GENERIC as: “ Not protected by trademark registration; Nonproprietary or any product, as a food, drug , or cosmetic that can be sold without a brand name ” Department Of Pharmaceutics, KCP, CBE-32 30

31. cont., Department Of Pharmaceutics, KCP, CBE-32 31 Example for Generic drug and Branded drug

32. cont., Department Of Pharmaceutics, KCP, CBE-32 32 Difference between Generic drug and Branded drug

33. Approval for Generic Drugs Department Of Pharmaceutics, KCP, CBE-32 33 The expiry of patent drug for innovator, it can be manufactured and marketed by any pharmaceutical company . Before marketing the drug, generic manufacturers need to obtain permission from relevant drug regulatory authorities . 1. A ny drug manufactured should follow good manufacturing practices guidelines , the enforcement of which is the responsibility of drug regulators. 2. There is a requirement for  in-vitro dissolution and  in-vivo bio-availability and bio-equivalence (BA-BE) testing of new brand ( i.e generic manufacturer) which compares the release of active pharmaceutical ingredient (API) on certain dissolution and liberation characteristics and pharmacokinetic parameters ( C max ,  T max , and area-under-the-curve) with those from reference standard .

34. Hatch Waxman Act Department Of Pharmaceutics, KCP, CBE-32 34 The Hatch-Waxman Amendments is also known as the " Drug Price Competition and Patent Term Restoration Act of 1984”. This act allow the approval pathway for generic drug products , within short period of time. In simple words  “Hatch-Waxman act is the amendment to Federal, Food, Drug and Cosmetics act which established the modern system of approval of generics through Abbreviated New Drug Applications (ANDAs)”

35. Cont., Department Of Pharmaceutics, KCP, CBE-32 35 Significant of Hatch-Waxman act: Prior to the Hatch and Waxman act the generic drug manufacturer had to do the entire clinical trials. After the passage of Hatch and Waxman act the generic drug manufacturer had to only prove bioequivalence of generic drug to the innovator drug by showing that the generic drug is 80-125% bioequivalent to the innovator drug. The time and cost involved for getting the generic drug into the market was significantly reduced . Low cost quality, safe and effective generic drugs were available to the patients. Since 1984, over 10,000 generic drugs have entered the market, and generics accounted for close to 50 percent of prescriptions filled (as on august 1, 2003). Billions of dollars in health care costs are being saved annually .

36. Cont., Department Of Pharmaceutics, KCP, CBE-32 36 A true Hatch-Waxman system has three components , which work together to bring generic pharmaceuticals to market quickly , all the while encouraging innovation:    The first component lightens the burden of regulatory review for generic products , by creating an Abbreviated New Drug Application (ANDA) for generic producers to file with the U.S. Food and Drug Administration (FDA ). It allows generic firms to begin testing, but not to undertake commercial activities , before the expiration of the innovator's patent.

37. Cont., Department Of Pharmaceutics, KCP, CBE-32 37 The second component , Patent Term Restoration (PTR) restores some of the effective patent life that is lost in the increasingly complex clinical trial and FDA review process for innovative pharmaceutical products. Pharmaceutical inventions receive the same standard term of 20 years from the date that the patent application is filed , as do all other patented products, but, after completion of clinical research and regulatory approval, the effective patent life for a new pharmaceutical product is approximately 11 years . PTR creates the possibility of patent term extensions to compensate innovators for a portion of the patent exclusivity period that is lost due to lengthy FDA regulatory review periods upto 14 years

38. Cont., Department Of Pharmaceutics, KCP, CBE-32 38 The third component , The creation of finite periods of protection for commercially valuable and confidential data in the clinical dossier, known as DATA EXCLUSIVITY . Prior to Hatch-Waxman, the clinical dossier for an innovative product was treated as permanently proprietary information. Data Exclusivity represents a benefit provided to the generic industry, which is now allowed to rely on the results of the clinical data after the expiration of a period that should be no less than five years.

39. Reference Department Of Pharmaceutics, KCP, CBE-32 39

40. Thank You Department Of Pharmaceutics, KCP, CBE-32 40