Documentation in pharmaceutical industry, by dr. umesh kumar sharma and anu mathew

DOCUMENTATION IN PHARMACEUTICAL INDUSTRY, BY Dr. UMESH KUMAR SHARMA

1. Documentation in Pharmaceutical Industry Documentation in Pharmaceutical Industry , By : Dr. Umesh Kumar Sharma and Anu Mathew By : Dr. U mesh K umar Sharma And Anu Mathew, Department of Pharmaceutics, Mar Dioscorus College of Pharmacy, Thiruvananthapuram, Kerala, India

2. Documentation in pharmaceutical industry Method of preparing a written material, which describes the process in terms of specifications, instructions etc. The D & C Act under conditions of granting license and schedule M require manufacturer of drugs to maintain various records. Importance of documentation Provides necessary working details, Reduces the risk of mistake, Helps in decreasing batch to batch variation, Considered as the history of batch operations,

3. Types of documents Commitment document: Relationship between industry and the regulatory authorities. Directive document : R elationship between management and employee. Record document : R elationship between the employee and the work they perform.

4. SPECIFICITY

5. Master Formula Records (MFR): Written procedure that give the complete description of all aspects of manufacture, packing and control with an inspection to ensure purity, identity, quality and strength of each dosage unit through its shelf life. Includes all the materials used in any batch manufacturing and step by step process of manufacturing. The master formula must include: The name of the product together with product reference code relating to its specifications. The patent or proprietary name of the product along with the generic name, a description of dosage form, strength, composition of the product and batch size.

6. c) A statement of the processing location and the principal equipment to be used . d) Name , quantity and reference number of all starting materials to be used . e) A statement of expected final yield with the acceptable limits and of relevant intermediate yields, where applicable. f) The methods or reference of the methods to be used for preparing the critical equipment including cleaning, assembling, calibrating, sterilizing. g) Detailed stepwise processing instructions and the time taken for each step. Master Formula Records (MFR): cont …

7. Types of Master Formula Records (MFR): The master formula records gives proportion of ingredients in the formulation. Master batch formula records which specify absolute amounts of specific potent ingredients and excipients in a batch.

8. Master production and control records: Detailed written instructions including all operations starting from dispensing of raw materials till finishing of bulk products and packaging operation of the particular product. It includes batch size, date of manufacture and full signature by 1 st person and further independently checked, dated and signed by 2 nd person.

9. Preparation of master formula : Master formula can be prepared by competent technical staff. It should be reviewed by the head of production, QC department and R & D department.

10. Drug Master File (DMF): Document prepared by a pharmaceutical manufacturer and submitted solely at its description to the appropriate regulatory authority in the intended drug market. There is no regulatory requirement to file a DMF. The DMF provides confidential, detailed information about facilities, process or articles used in the manufacturing, packaging, storing etc. to the regulatory authority. DMF is filed when two or more firms work in a partnership or developing or manufacturing a drug product.

11. Drug Master F ile (DMF) Includes: A) General information General properties. Structure. Nomenclature. B) Manufacture Manufactures. Description of manufacturing process and process control. Flow chart of manufacturing process, Synthetic route of manufacturing process, Manufacturing method,

12. 3. Control of Material List of materials Specification and routine test of the raw material 4.Control of critical steps and intermediates Critical steps, Process validation, 5.Specifications and test method for the intermediates, 6.Manufacturing process development Drug Master File (DMF) Includes: Cont …..

13. C) Characterization 1.Elucidation of structure and other characteristics- Elemental analysis IR spectrum of drug substance NMR spectrum of drug substance Mass spectrum of drug substance UV spectrum of drug substance X-ray diffraction Thermal analysis Comprehensive illustration Drug Master File (DMF) Includes: Cont …..

14. 2) Impurities Sources of potential impurities Types of impurities Test procedure for determining impurities D) Control of drug substances Specifications Analytical procedure Validation of analytical procedure Batch analysis Justification of specification Drug Master File (DMF) Includes: Cont …..

15. E) Reference standards of material F) Container closure system G) Stability H) Material data safety sheet APPENDICES Facilities and E quipment’s. Equipment’s design and location. Adventitious agents safety evaluations statement of comment. Drug Master File (DMF) Includes: cont …..

16. Types of Drug Master File (DMF) : Type 1: Manufacturing site, facilities, operating procedures and personnel. Type 2: Drug substance, drug substance intermediate and material used in their production or drug product. Type 3: Packaging material. Type 4: Excipient ,colorant, flavor. Type 5: FDA accepted reference information.

17. Types of Drug Master File (DMF) : Cont … Type 1 : Manufacturing site, facilities ,operating procedures and personnel No longer used, once used to describe facilities. Recommended for a person outside of the United states to assist FDA in conducting on site inspections of their manufacturing facilities. Should describe manufacturing site, operational layout, equipment capabilities, processing layout.

18. Types of Drug Master File (DMF) : Cont … Type 2 : Drug substance ,drug substance intermediate and material used in their preparation or drug product required for drug substance – active ingredient. A separate DMF is filed for each active ingredient. Brief description of the manufacturing facilities, the address, a contact, phone number and fax number. Manufacturing procedures and control for finished dosage forms s ubmitted in an IND, NDA , ANDA or export application.

19. Types of Drug Master File (DMF) : Cont … Type 3 : Packaging material, Its components and composition, Packaging material intended for use, Name of the suppliers or fabrications of the components used in preparing the packaging material. Acceptance specifications, Eg: - Products that would be classified as type 3 DMFs include bottles, seals, dispensers etc.

20. Types of Drug Master File (DMF) : Cont… Type 4 : E xcipient , colorant, flavor, essence used in their preparation. Each additive should be identified by this method of manufacture, release specification and testing methods . Toxicological data would be included. The official compendia and FDA regulation for color additives, direct food additives and food substances may be used as sources for release tests and safety.

21. Types of Drug Master File (DMF) : Cont … Type 5: FDA accepted reference information. FDA discourages the use of type 5 DMFs for miscellaneous information, duplicate information. To submit the data which is not covered in type 1 to type 4 DMF. A holder must first submit a letter of intent to the drug master file staff. FDA will contact the holder to discuss the proposed submission.

22. Distribution records Written procedures shall be established and followed, describing the distribution of drug products Include: A procedure where by the oldest approved stock of a drug product is distributed first A system by which the distribution of each lot of drug product can be readily determined to facilitate its recall if necessary.

23. Distribution records Distribution records must be constructed and procedures established to facilitate recall of defective product. All records should be indexed by either the manufacturing batch-lot number of the packaging control number as a means of accountability. It shall contains: Name and strength of the product- Description of dosage form- Name and address of the consigner- Date and qty shipped- Lot and control number of the drug-

24. WHO guidelines for distribution records: Written instruments and records should be available. Procedure should be established and maintained. The title, name and purpose of each document should be clearly stated. All documents should be completed, approved ,signed ad dated by an appropriate authorized persons. In the case of temperature-sensitivity pharmaceutical products, records of investigations and actions should be retained for at least one year after the expiry date of the product.

25. Generic drug product development: Product development is the set of activities beginning with the perception of a market opportunity and ending in production, sale and delivery of a product. The 1 st generic drug product filed and approved by FDA has several financial incentives. As per Hatch-Waxman Act, a 180 day exclusively is awarded to generic manufacturer who first files. During this 6 month period the FDA does not approve any second product of the same generic version.

26. The following general aspects are considered:- Selection of a drug product for manufacture. Patents and exclusivity. Resources for ANDA submission. Selection of a drug product for generic version Previous experience in the selected areas become an advantage to the manufacturer to introduce generic products. The manufacturer may be already making a variety of dosage forms, including the immediate and modified release products. The products such as transdermal drug product may be difficult to make and also riskier but have a greater financial reward due to less competition from generic drug forms.

27. Generic drug product development : Cont …… The market research data and technological advantages influences the selection of generic drug product. Estimated current sales volume of the innovator product. Estimated market share for the generic product, if introduced into the market. The cost of acquiring the technology is important to manufacture the product. Lead time required to make the product and submission of ANDA to the FDA for the approval.

28. Patents and exclusivity: The patent holder may obtain the exclusivity, which prevents the approval of ANDAs. When period of patent or exclusivity expires other manufactures apply to FDA to get permission for the manufacture and sale of generic versions. Orange book is a register in which all the approved products of innovator and generic products are maintained. Orange book updated monthly is made available in the website.

29. Patents and exclusivity : Cont …. Patents that claim the active ingredients or other ingredients. Drug product patents including formulation. Approved polymorphic form , particle size of API. Drugs qualified for Orphan drugs exclusivity. Exclusivity information for other categories with their expiry periods.

30. Hatch –Waxman act: The amendment to federal, food, D&C act which established the modern system of approval of generics through abbreviated new drug applications (ANDA). The Drug P rice Competition and Patent T erm R estoration Act informally known as the Hatch-Waxman Act is a 1984 United States federal law which encourages the manufacture of generic drugs by pharmaceutical industry and established the modern system of government generic drug regulation in the US.

31. Significant results due to 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 this act, the generic drug manufacturer had to only prove bioequivalence of generic drug to the innovator 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. Billions of dollars in health care costs are being saved annually.

32. Patent certifications: As per Hatch and Waxman act, generic drug and 505(b) applicants include certifications in their applications for each patent listed in the orange book for innovator drug. The certification must state one of the following: That the required patent information relating to such patent has not been filled ( para I certification). That such patent has expired ( para II certification). That the patent will expire on a particular date( para III certification).

33. Patent certifications : Cont …. That such patent is invalid or will not be infringed by the drug for which approval is being sought ( para IV certification). The certification under paragraph 1 or II permits the ANDA to be approved immediately, if it is otherwise eligible. A certification under paragraph III indicates that the ANDA may be approved when the patents expires.

34. 180 day exclusivity: The Hatch Waxman Amendments provide an incentive of 180 days of market exclusivity to the 1 st generic applicant who challenges a listed patent by filing a paragraph IV certification and thereby runs the risk of having to defend a patent infringement suit. The statue provides that the first applicant to file a substantially complete ANDA containing a paragraph IV certification to a listed patent will be eligible for a 180-day period of exclusivity beginning either from the date it begins commercial marketing to the generic drug product. 180 day exclusivity could be granted to more than one applicant. Eg.: 180 day exclusivity was granted to Ranbaxy and Watson Laboratories for marketing generic version of Lipitor.

35. Hatch-Waxman bill: The Hatch-Waxman bill officially as the drug price competition and patent term restoration act , brought about the following changes: Generic medicine no longer need to prove their safety and efficacy. Under the bill, generic drug manufactures need only submit an ANDA to prove their product’s bioequivalence to the original branded drug. Generic drug are granted a 180 day period of exclusivity. Manufacturers filling ANDAs can only do so for drugs that have not been patented. ANDAs can only be filled when a branded drug’s patent has expired. Generic drugs cannot go on to market until the branded patent has expired.

36. References: Generic drug product development, solid oral dosage forms, Leon Shargel and Isaderkaufer , vol.143 FDA regulatory affairs: A guide prescription drugs and biologics by Douglas J pisano , David Mantus . Wikipedia.com

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