Documentation in pharmaceutical industry

It's all about the topic of documentation in pharmaceutical industry. In this the specifications of pharmaceutical quality assurance plays the main role so that it's mainly effective for the people who is in the stream of pharmaceutical quality assurance.

1. UNIVERSITY OF CHEMICAL TECHNOLOGY, CHHATRAPATI SAMBHAJINAGAR. PHARMACEUTICAL QUALITY ASSURANCE DEPARTMENT ~ POOJA HARKAL Documentation in Pharmaceutical Industry

2. Technical Documentation Documentation is the Essential and crucial part in any of the company. In pharma we can say “If it is not documented, it has not done” . Documentation is an evidence to show or to prove that the things have done accordingly. Quality assurance documents are the heart of the company. Technical documents are Master Formula Record (MFR). Batch Manufacturing Record (BMR). Drug Master File (DMF) While registering the Indian product in overseas market RA team should be carefully check, verify all the documents for the genuinity, quality and uniformity from batch to batch and to avoid delay in the approval process.

3. Documentation flow chart

4. Master Formula Record (MFR): MFR is a master document which contains detailed information about the product, process etc. MFR is prepared by the Formulation and Development team which is called technology transfer. By this master document BMR and BPR prepared.

5. MASTER BATCH RECORD Master Batch Record also known as MFR (Master Formula/ Mfg Record). It should be available for each product, batch and pack size. It is a master document for any pharmaceutical product. It contains all information about the manufacturing process for the product. It is prepared by the research and development team of the company. It is used as reference standard for preparing batch manufacturing record (BMR) by manufacturing units. It plays an important in consistency for each batch manufacturing. Responsible Department : Primary Responsibility : Formulation Research and Production Department Secondary Responsibility : QA Department

6. 2. Flow chart: Steps involved in the manufacturing process and flow chart representing the material movement from dispensing to the finished product to packaging and to the store. 3. Equipment: List of equipment required for the manufacture of the product with the capacity 4. Special instructions: Warnings and precautions related to manufacturing process should be clearly mentioned. Quantity to be added should be mentioned. Time interval and overages to be added to be mentioned clearly. Name of the ingredient with tests and specification limit as per IP, BP and USP. 5. Calculations: Quantity to be added to get 100% final product. It can be done by using water content or LOD to get 100% potency.

7. 6. Manufacturing process:  It should include all the steps involved the manufacturing process like sifting, milling, granulation, mixing, blending, lubricating, compression, coating, filling, if necessary filtration with environmental conditions such as temperature, humidity, storage to be maintained with time. 7. Packaging process:  Details of packaging materials used.  Line clearance, batch reconciliation of the packing material. 8. Yield:  It includes theoretical yield, Practical yield and acceptance limit of the batch

8. Master Batch Record Packaging details : There have to be authorized packaging instructions Name. Description of dosage form. Pack sizes- Number, dose volume. A total list of all Packaging materials required for standard batch size with reference to the specifications of the packaging material Specimens of all packaging material. Line clearance instructions. Description of packaging operations. In process controls.

9. BATCH MANUFACTURING RECORD Once the Master formula is prepared, pilot batch will be started to validation and BA/BE studies, upon getting the report from the pilot batch BMR will be prepared which will be used for commercial batch manufacturing. The "Batch Manufacturing Record" is the necessary quality and GMP documentation for tracing the complete cycle of manufacturing batch or lot. The batch manufacturing record should be checked before issuance to assure that it is the correct version and a legible accurate reproduction of the appropriate master production instruction. Before any processing begins, a check should be performed and recorded to ensure that the equipment and workstation are clear of previous products, documents, or materials not required for the planned equipment is clean and suitable for use. These records should be numbered with a unique batch or identification number and dated and signed when issued.

10. Batch Manufacturing Record Content : Name of the product, Batch number, revision number, effective date. Product details like Type of the product, dosage, shape of the drug. Batch size and Total number of tablets or capsules. Pack size and packaging Instructions. Storage instructions. Production batch record issuance. Signed & issued by QA Signed for completion by production Bill of materials: It is a list of all raw material ingredients that are required involving more materials appear in the final product.

11. Reference documents i.e., SOP’s such as Dispensing of the product, temperature and humidity monitoring, material weighing, cleaning procedure, use, operation and cleaning of the equipment. List of raw material along with quantity required. Equipment description, calibration certificate etc. Area clearance- step by step cleaning of the equipment and area. Production procedure- Instruction for each step of the production from dispensing to dispatch. Calculation of yield. Yield = Finished product Yield =  

12. Post production review- Complete batch has been reviewed for the completeness and accuracy in the entries for Good Documentation Practices. Product release- the product should comply with the finished goods specifications and released to market Responsibility : Primary Responsibility : QA/ QC/ Production Officer Secondary Responsibility : QA/ QC/ Production Manager

13. BMR format should contain following parts: Batch record : First page of the BMR has all records about the batch as batch no., batch size, composition MFR, weight of drug, shelf life, storage condition, manufacturing date, expiry date. General instruction for mfg. : Health and safety instruction to the operation and be followed during the mfg. process regarding the material and equipment used during mfg. Equipment cleaning record : Check list of the cleaning of all equipment is prepared. Those are used in manufacturing of the batch including the previous product batch and date of cleaning. Bills of materials : list of the raw materials should have the quantity of the material with that AR number. Weight of the material should be verified by QA.

14. 5. Manufacturing Process : Should be written step by step in easy language. Milling, Shifting, Drying, Compression, Coating and Packing having all instruction with process time should be written. 6. Yield : Yield of batch should be calculated at the end of every stage to calculate the process loss. Final yield should be calculated at the end of manufacturing that should not be less than 99%. 7. Abbreviations : list of used in document should be made to understand the BMR easily. 8. History of changes : At the end of document should have a list of the changes in the document including the revision no. and date of change.

15. Documentation of Completion of each Significant step in the BMR should include: Specific identification of each batch, including weights, measures, and batch numbers of raw materials, intermediates, or any reprocessed materials used during manufacturing. Signatures of the persons performing and directly supervising or checking each critical step in the operation.

16. In-process and laboratory test results. Actual yield at appropriate phases or times. Any deviation noted, its evaluation, and investigation conducted (if appropriate) or reference to that investigation (if stored separately). Results of release testing. Production and quality control records should be reviewed as part of the approval process of batch release. Any divergence or failure of a batch to meet its specifications should be thoroughly investigated.

17. CONCLUSION Master batch records provide the product's overall description and detailed manufacturing and testing instructions. Batch manufacturing record (BMR) is an important document for chemical and process manufacturers. It tells users how to produce a batch of a given product, then records the entire production process, from start to finish. It is a complete specification for manufacturing a specific batch size in a specific plant at a specific time.

18. Introduction Of Quality Audit :

19. The other names of this type of audit are first party audit or self audit . The auditors and the process or product being audited belongs to same company. Self audit helps to achieve goals of pharmaceutical industry in a professional way by advising them in improvement of any procedure related to the quality of the product. 1.Internal audit

20. Benefits of internal audit : Tells you the health of a quality system. Identify the root of a problem and plan for corrective and preventive actions with timeline. Achieve better allocation of resources. Able to avoid potentially big problem continuous improvement.

21. 2.EXTERNAL AUDIT The another name of this audit is known as Second Party Audit . These audits are usually carried out for any outsourcing operations or suppliers. This is the reason in this audit customer is actually performing audit on supplier or contractor . The organization has to comply may rules and regulations eg. cGMP guidelines and thus audits of the contractors and suppliers is also having important role in regulatory compliance. Third party A customer wants an audit of your company but wants your company to pay for it.

22. 3. Regulatory Audit

23. Audit Plan

24. AUDIT PLANNING: Before Audit Plan well in advance. Decide if there are any products or activites that you want to exclude from the audit. Know your procedures and where they are located. Remove all absolute documentation. Ensure all uncontrolled documentation that you are working with are properly stamped "uncontrolled“. Label all your filing cabinets and files. Ensures all productive material, is identified by number and status. Ensure all materials are stored in authorized areas.

25. Eliminate all unused ,scrap/suspect material from around machine and workstations. Scrap /non-confirming material must be segregated and clearly identified. Do not over communicate and make people nervous, the system is being tested not them. Be prepared for the audit team to spelt up and audit separately. Have an audit communication center set up. DURING AUDIT Make everyone aware that the auditors are likely to ask up to six questions: What is your quality policy. Tell me how do you do your job. Show me where your system it tells you to do this. Can i see some evidences. What action do you take if you have problems. What training have you received to help you to do this job.

26. Be punctual and respectful . Be honest in your answers. Do not brag: they are not customer. You do not have to impress them with the past or future, just what happens now . Do not volunteer additional information. Just answer the question asked and stop. Do not “ramble on”. Do not use terms like “ usually” or “generally”. They invite further questions. Do not fill in space between questions. If there is a gap, let the auditor fill it. Do not rush or divert the auditors. They are responsible for their own schedule. Note any non-compliances observed in as much detail as possible. Do not “point fingers” at someone else in front of the auditors. Do not challenge or argue to excess. Make your point then stop. Do not be panic.

27. AFTER AUDIT Do not argue at the exist meeting.it is too late. Do not rush into hasty corrective action-do it properly. Remain polite, even if you did not do well-it is not the auditor fault; it is your organization that failed.

28. Report the successful Audit can be achieved through a formal report that has been generated by the leader of the Audit Team and reviewed by that individual's manager the essential elements of the audit report should include Distribution List. Dates Of Audit. Scope Of Audit. Name Of Team Leader. Name Of Other Team Members With Positions In Team Eg. Auditor, Expert, Auditor In Training, Guest And So On. AUDIT REPORT

29. 6. Standards of reference used in audit. 7. Date of opening meeting with list of attendees and position titles. 8. Date of closing meeting with list of attendees and position title. 9. General strengths. 10. General weakness. 11. Specific observations requiring corrective and or preventive actions. 12. Request for corrective and preventive action plans for each observation. 13. Due date for the response to the audit report.

30. Information of audit report is highly confidential therefore copies of the audit report should be controlled. Many companies use unique codes or numbering methods to control the copies. It is necessary to follow and track the corrective and preventive actions. Audit is not really completely closed out until all observations have been verified as effectively corrected. Monitoring of effectiveness may take very long time (a year or more) some auditors elect to close out the audit once the corrective and preventive actions have been verified correctly.

31. Introduction of Distribution Record Distribution record are written data related to distribution of drug product from the manufacturer to the distributor. It include wide range of document like invoice bill of lading, customer receipt’s, internal warehouse storage and inventory record it etc. Maintenance of records is important to facilitate complete recall of batch, if necessary.

32. DISTRIBUTION RECORDS The distribution record should be contain: Name ,strength of the product, distribution of the doses form. Name an address of the consignee. Data and quantity shipped and lot of control number of the drug product. The distribution record shall we maintain in a manner. So as to facilitate prompt and complete recall of the batch if necessary. Prior to distribution or dispatch of batch of a drug it should be insure that the batch has been tested, approved and release by quality control personnel.

33. DISTRIBUTION PROCEDURE Written procedure shall be established and followed, describe in the distribution of drug products. A procedure where by the oldest approved stock and product is distribution first. A system by which the distribution of each lot of drug product can be the readily determine to facilitate it’s recall if necessary. Distribution record must be constructed and procedure established to facillate recall of defective product. Manufacturer must maintain record of the distribution transaction involving in the process of finishing goods.

34. All record should be indexed by either manufacturing batch number of the packaging control number as the mean of accountability until the shipment passes from the direct control of manufacturer. The distribution process also include other consideration it must be arrange so that a first in /first out of moment of product occur. APIs should only the release for distribution to third party after they have the been released by the quality unit. API should be transported in the manner that does not adversely affect their quality. A system should be in place by which the distribution of each batch of intermediate and API can be readily determine to permit its recall.

35. ELECTRONIC DATA HANDLING: According to 21 CFR part 11 the electronic record can be electronics signature must control the electronic data record security, integrity, traceability and the proper use of electronics signature. A document management system consists of hardware and software that convert paper document into the electronic documents, manages and achieve those electronic document and they index and store them according to company policy.

36. Objective for the implementing and EDC system in clinical trial Real time data access. Efficient data transfer and faster impact on marketing of drug. Overcoming the shipping of paper CRFs (case report form) from remote areas. Synergy between the serious adverse effect reporting and the data base.

37. ADVANTAGES DISADVANTAGES

38. CONTROLLED DOCUMENT UNCONTROLLED DOCUMENT Documents shall be periodically reviewed (recommended once/year). QA & Document control Centre are responsible to ensure that issued documents are controlled, effective and implemented. Use of electronic signatures as well as electronic maintenance and submission, is an acceptable substitution for paper, when practical. Documents that is not subjected to amendments, changes or revisions and not traceable. OR The photocopy of master copy of controlled documents or written procedure which shall be given to any department or person for reference purpose only.

39. Drug Master File (DMF) DMF is a confidential document for API (Active Pharmaceutical Ingredient) submitted to the regulatory body for the approval process. In fact there is no regulations to file a DMF. It is not reviewed on receipt as like dossier and DMF’s are neither approved nor disapproved.

40. Type I DMF It contains information about the plant information like Manufacturing site. Equipment capabilities. Operational layout. Corporate headquarters. Site Address.

41. Type II DMF It includes information about all the significant steps in manufacturing and control of drug substance and intermediates Manufacturing sections Quality control Inputs Intermediates and In-process Finished drug substance Raw Materials Packing Materials Validations. Stability data. Impurities. Packaging and labelling

42. Type III DMF It contains detailed information of the packaging material used. i.e., Intended use of the packing material Composition of the packing material. Name of the suppliers. Specifications. Toxicological data on the packing material Type IV DMF Excipients used in the manufacture of the product. Compendia excipients usually not reviewed so DMF is not required

43. Differences between the Application (Dossier) and DMF Sr.No APPLICATION (DOSSIER) DMF 1 Must be filed by applicant Not mandatory to file DMF 2 Comes under regulatory status No such regulations 3 Each applications and their supplements are entered in common database DMF’s are entered in separate database as per the type 4 Submitted to intended review division Submitted to Regulatory body 5 Review procedure is different than that of DMF Reviewed only when referenced with NDA/ ANDA applications 6 Approval timeline is there No approval timeline

44. DMF Filing System

45. DMF Reviewing System

46. Important points to be noted in DMF Holder: The person who submits a DMF. Agent: The person or company who represents the DMF holder. Applicant: The person or company who use the DMF for referencing in the NDA or ANDA submission. Agent will be appointed by the DMF holder to file DMF and to communicate with the regulatory body. Major contents of DMF are, Transmittal letter, Administrative information of DMF holder, Technical information of the product. Reason to file DMF: DMF filed for API’s which acts as supportive document while submitting NDA or ANDA.

47. Obligations of DMF Holder Should submit any changes as amendments. Should notify regulatory body of change in holder name or address. Should notify regulatory body of change in agent or representative. Issue LOA to each applicant who intends to use that API. Should submit annual report to regulatory body on the anniversary date of DMF filing. Symbols used in finding the status of DMF “A” : Active, (DMF is acceptable and up to date) “I” : Inactive “N” : Not assigned DMF number “P” : Pending filing review

48. DMF for OTC drugs and compendia excipients are never reviewed. DMF cannot be registered or approved, it just entered in DMF database. Letter of Authorization (LOA) shall be send by DMF holder to regulatory body (2 copies) and NDA/ANDA applicant (1 copy). DMF number will be assigned only when the regulatory body receives 2 copies of DMF along with the cover letter. If any deficiencies found in DMF it shall be communicated with the holder and the applicant will be just notified. DMF shall be registered immediately but not reviewed.

49. Regulatory body will issue termination letter to DMF holder when there is no communication for 3 consecutive years (i.e., no annual report) regarding the DMF. If annual report is not send, it causes delay in the review process of the filed NDA and ANDA. Regulatory body shall send a reminder letter called overdue notice letter (ONL) to DMF holder, if there is no response from the holder within 90 days, one copy will be send to federal center and the other will be destroyed. Now a days DMF filing also become electronic submission and can convert existing Paper MF’s to eCTD

50. COMMON TECHNICAL DOCUMENT (CTD) It is an essential document to be submitted to regulatory body as a supportive list of leaflets attached with the registration applications for pharmaceuticals to get market authorization. Mainly CTD tells about the format for the data. The Common Technical Document (CTD) guidance’s have been developed for Japan, European Union and United States. Most countries have adopted the CTD format. Hence, CDSCO has also decided to adopt CTD format for technical requirements for registration of pharmaceutical products for human use. This guidance is developed by CDSCO based on: The ICH Harmonized Tripartite Guideline on “Organization of the Common Technical Document for the Registration of Pharmaceuticals for Human Use”. M4, Step 4 version dated January 13, 2004, and Drugs & Cosmetics Act 1940 and Rules made thereunder. The CTD is only a format for submission of information to CDSCO.

51. CTD: OVERVIEW The CTD is organized into five modules (Module 1, 2, 3, 4, and 5) and a diagrammatic representation of organization of the CTD is provided in Annexure I.

52. ELECTRONIC COMMON TECHNICAL DOCUMENT ( eCTD ) eCTD is electronic Common Technical Document, an electronic format where the information and document is submitted to regulatory body electronically by using a software. Some of the eCTD software are Pharm ready, Edios etc. Requirements of eCTD : 1. Copy and paste. 2. Verifying and printing documents. 3. Document Annotation. 4. Export of information to databases.

53. Sr. No. Common Technical Document (CTD) Electronic Common Technical Document (eCTD) 1 Paper submission Electronic (Using Software) 2 Tedious and Difficult Review process Faster review process 3 Bulk and Large documents XML files storage will be in GB 4 Cross references include CTD section number Cross references include hyperlink and book mark 5 CTD navigation through TOC and Volumes eCTD navigation by XML backbone 6 Paper volume- A4 Layout shall be A4 or US letter size 7 Submitted in Binders or boxes Submitted on CD or DVD or e-mail or Portal. 8 Compiled electronically with volumes, tabs and slip sheets and then printed to paper. Compiled electronically with documents in folders

54. Regulated Market Non- Regulated Market These countries have well-defined procedures for marketing and distribution of pharmaceuticals both for human and veterinary use. MAHs should file applications to market their drugs with all the supportive and required data. eg. Major big countries with specific authorities / monitoring bodies to look after health of its citizens - US, JAPAN, AUSTRALIA, CANADA, INDIA, Etc. Regulated Pharma markets require submission of dossier in CTD format which has to provide clinical trial and bioequivalence studies. Small to very countries which do not have any specific authorities which controls the supply of medicine. One can consider newly formed countries, small population countries and under developed countries. AFRICAN countries, some Asian countries. Being said since these countries do not have specific monitoring authorities, they depend on other regulated countries.

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