October 05, 2010

3. Audit Preparation & Compliance  Quality Assurance Medicinal products must be certified by Qualified Person for each production batch accordance with the requirements of the Marketing Authorization. The medicinal products are stored, distributed and subsequently handled so that quality is maintained throughout their shelf life. Manufacturing processes are clearly defined, systematically reviewed and shown to be capable of consistently manufacturing medicinal products of the required quality and complying with their specifications. Ensuring all necessary facilities for GMP.

4. Audit Preparation & Compliance Quality Control Adequate facilities, trained personnel and approved procedures. Sampling, inspecting and testing starting materials, packaging materials, intermediate, bulk, and finished products, and where appropriate for monitoring environmental conditions for GMP purposes. Product Quality Review.

5. Audit Preparation & Compliance Data from environmental monitoring. Validation records of test methods, where applicable. Procedures for and records of the calibration of instruments and maintenance of equipment.

6. Personnel, Training & Hygiene . Responsibilities of the head of the Production Department & QC Besides the basic training on the theory and practice of Good Manufacturing Practice. Personnel working in areas where contamination is a hazard. Visitors or untrained personnel should, preferably, not be taken into the Production and Quality Control areas. Audit Preparation & Compliance 

7. Audit Preparation & Compliance  Premises & Equipment Premises should be designed to protect the manufacture, presents minimal risk of causing contamination of materials or products. �Premises should not be any hazard to the quality of products. They should be cleaned, disinfected. Lighting, temperature, humidity and ventilation should be appropriate and such that they do not adversely affect.�

8. Audit Preparation & Compliance Premises should be designed and equipped so as to afford maximum protection against the entry of insects or other animals. Provision to prevent the entry of unauthorized people. Production, storage and quality control areas should not be used as a right of way.

9. Audit Preparation & Compliance Production Area Premises should preferably be laid out in a logical order & cleanliness levels. Orderly positioning of equipment and materials so as to minimize the risk of confusion. Cross-contamination and to minimize the risk .

10. Audit Preparation & Compliance Pipe work, light fittings , Drains. Production areas should be effectively ventilated, with air control facilities . Premises for the packaging of medicinal products should be specifically designed and laid out so as to avoid mix-ups or cross-contamination. In-process controls .

11. Audit Preparation & Compliance  Storage Areas Storage areas for products, packaging materials, intermediate, bulk and finished products, products in quarantine, released, rejected, returned or recalled. Receiving and dispatch bays should protect materials and products from the weather. Where quarantine status is ensured by storage in separate areas, these areas must be clearly marked and their access restricted to authorized personnel.

12. Audit Preparation & Compliance  Highly active materials or products should be stored in safe and secure areas. Printed packaging materials are considered critical to the conformity of the medicinal product and special attention should be paid to the safe and secure storage of these materials. Special requirements are needed in laboratories handling particular substances, such as biological or radioactive samples

13. Audit Preparation & Compliance  Equipment Manufacturing equipment should be designed, located and maintained to suit its intended purpose. Repair and maintenance operations should not present any hazard to the quality of the products. Washing and cleaning equipment should be chosen and used in order not to be a source of contamination.

14. Audit Preparation & Compliance  Equipment should be installed in such a way as to prevent any risk of error or of contamination. Measuring, weighing, recording and control equipment should be calibrated and checked at defined intervals by appropriate methods. Adequate records of such tests should be maintained. Production equipment should not present any hazard to the products. The parts of the production equipment that come into contact with the product must not be reactive.

15. Audit Preparation & Compliance  Documents Required Specifications for Starting and Packaging Materials. Specifications for Intermediate and Bulk Products. Specifications for Finished Products. Manufacturing Formula & Processing Instructions Packaging Instructions Batch Processing Records Batch Packaging Records Sampling Plan Testing

16. Audit Preparation & Compliance  Design qualification Installation qualification Operational qualification Performance qualification. Qualification of established (in-use) facilities, systems and equipment.

17. Audit Preparation & Compliance Process Validation. �Prospective validation. �Concurrent validation. �Retrospective validation. �Cleaning Validation. �Revalidation.

18. Audit Preparation & Compliance Contract Manufacture Analysis The Contract Giver. The Contract. The Contract Acceptor.

19. Audit Preparation & Compliance  Complaints & Product Recall. Self Inspection.

20. Audit Preparation & Compliance  Annex 1: Manufacture of Sterile Medicinal Products Isolator Technology Blow/Fill/Seal Technology Terminally Sterilized Aseptic Processing Sanitation Processing Sterilization

21. Audit Preparation & Compliance Moist Heat. �Dry Heat. Sterilization by Radiation. Sterilization with Ethylene Oxide.

22. Audit Preparation & Compliance Filtration of Medicinal Products that cannot be Sterilized in Final Container. Finishing of Sterile Products.

23. Audit Preparation & Compliance Typical Example of Audit Observation Point:- Autoclave �Thermocouples were not introduced into area which would be considered worst case for steam penetration e.g. lengths of tubing thermocouples or Biological Indicators shall be introduced into this tubing. Placement of thermocouples during the initial performance qualification must be adequately noted so that they can be placed in the exact same locations during the Requalification studies. �

24. Audit Preparation & Compliance No criteria were specified with regard to equilibration time for the temperature probes in the autoclave. Which is dependent upon the size of the Autoclave? Sublethal cycles or independent D value verification shall be performed on each lot of biological indicators received on site. In the autoclave load position of the item must be uniform during the qualification and autoclave operation. �In a fluid load a minimum of one thermocouple in the mid of the load must be placed.

25. Audit Preparation & Compliance Each cycle run must be able to reference pre and post run calibration data which verifies that the thermocouples are within a tolerance of � 0.5 DegC. Load pattern details with photograph should be match with BMR, SOP & Qualification protocol. Prior to autoclave qualification, steam quality testing must be performed from the respective autoclave sampling. .

26. Audit Preparation & Compliance F0 Determination must be performed especially in Liquid Load. Air detector shall be available on Autoclave to detect air pockets in Autoclave chamber. Can you demonstrate comparison studies are being conducted between the Performance Qualification and the following Requalification studies? (Are they documented?) Vent Filter Sterilization:- Is the sterilization of the air vent filter fitted to the autoclave treated as a Porous load.

27. Audit Preparation & Compliance Depyrogenation Tunnel:- �Speed of the conveyer should be performed & It shall be not more than the set limit. �Nonviable particle count should be conducted in 1 m3 volume sampling for each which complies with class 100 (Grade �A�) areas. �A minimum temperature of 300 � C. for ? 3 min. & 3-log reduction shall be maintained in Depyrogenation Zone.

28. Audit Preparation & Compliance Area Qualification The air changes per hour should be maintained as per different grade area. �Filter integrity should be executed twice in a year for critical area. �If the leakage is in more than 5% of surface area, then filter shall be replaced and test shall be repeated. �This testing is performed to verify that the clean zone can achieve the air cleanliness This test is conducted under at-rest conditions & It must be meet the 1 m3 sampling in Grade A & Grade B area. �

29. Audit Preparation & Compliance Non viable particle count result should be consistent among the different location taken in a single room. Filter replacement record should be available for tracking the filter integrity checked. �Area recovery study must be performed for grade �B� area & it should be recovered by 20 min. �Air Flow parrelism test \ smoke visualization test must be performed in every year & Air should be moves downwards from the HEPA Filters, over the operating area, away from the operator and is drawn out at the bottom rear of the room.

30. Audit Preparation & Compliance  Media Fill Validation �Prior to Media Fill Area Qualification shall be within the qualification due period, Routine Microbial Monitoring shall be within the limit; Routine Water Monitoring (PW, WFI, and CS) shall be within the limit. All critical Equipment like Autoclave, Depyrogenation Tunnel are within the qualification due period. �Environmental & Personnel Monitoring �All viable organisms monitoring activity shall be done like routine product filling activity. In addition to that during media fill microbial monitoring shall be done as follows and contaminant shall be identified to genus level. �

31. Audit Preparation & Compliance  Finger dab test all the involved personnel in media fill (during exit), Surface swab of gown (Chest, Forehead & Forearm) of operating personnel (during exit).,Surface swabbing of equipment (after filling). , Active Air Monitoring by using air sampler (during media fill).,Passive air monitoring by Settle plate method (throughout media fill).

32. Audit Preparation & Compliance  Media sterilization must be done by performed especially by filtration method by using 0.2? sterile filters. Pre integrity is ensuring by COA & Post filter integrity test should comply with requirement Growth promotion test should be carried out on the media (post incubation) after 14 days of incubation. A minimum of 5000 units must be filled in Media Fill run where batch size intended is less than 5000 then equivalent number of units shall be filled. �

33. Audit Preparation & Compliance Soybean casein digest medium (Veg. SCDM) must be used. Media (30gm/lit) shall be prepared as per manufacturer instructions. In process simulation trails will entail the filling of the largest and smallest containers on a given filling line The process simulation test should represent a �worst case� situation and include all manipulations and interventions likely to be represented during a shift.

34. Audit Preparation & Compliance Ensure that an effective maintenance and refurbishing system is in place. Ensure proper status labeling of equipment and tools. Ensure that the structure of the OOS procedure is based on logical process flow. Ensure that an SOP for investigation of contaminations in the production area is established � �

35. Audit Preparation & Compliance Ensure proper electronic archiving of data. Ensure that correct vendor/supplier is qualified

36. Audit Preparation & Compliance Risk analysis report not prepared for EMN, sampling locations in clean rooms. �Water sample are not taken from the hose pipe as hose pipes are used by production personnel during manufacturing for taking water. Sterility testing by membrane filtration was not validated Media used for environmental monitoring did not contain inactivators for sanitizing agents.

37. Audit Preparation & Compliance Training �Training matrix not prepared for production personnel It was stated that an operator could only perform visual inspection for a maximum period of four consecutive hours. Vial and PFS defects were not classified with respect to criticality nor were alert and action limits in place for the various categories of defects.

38. Audit Preparation & Compliance There was no specific training in relation to visual identification and differentiation of defects for lyophilized product. Certification not performed under worst case conditions of operator fatigue. A minimum of 95% rejection of defects was required for certification; however, an evaluation of the types of defects not rejected was not required.