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Form-Fill-Seal Technology or Blow, Fill-Seal Technology: 10.1 Form-Fill-Seal units are specially built automated machines in which through one continuous operation, containers are formed from thermoplastic granules, filled and then sealed. Blow, fill-seal units are machines in which containers are moulded / blown (pre- formed) in separate clean rooms, by non-continuous operations. Note: (i) These shall be installed in at least Grade C environment. (ii) These shall comply with the limits as recommended in Table at Item 4.2. 10.2. Form-Fill-Seal/Blow, Fill-Seal machines used for the manufacture of products for terminal sterilization shall be installed in at least Grade C environment and the filling zone within the machine shall fulfil Grade A requirements. 10.3. Terminally sterilized products.– 10.3.1. Preparation of primary packaging material such as glass bottles, ampoules and rubber stoppers shall be done in at least Grade D environment. Where there is unusual risk to the product from microbial contamination, the above operation shall be done in Grade C environment. All the processes used for component preparation shall be validt.. 10.3.2. Filling of products requiring terminal sterilization shall be done under Grade A environment with a Grade C background. 10.4 Preparation of solutions, which are to be sterilized by filtration, shall be done in Grade C environment, and if not to be filtered, the preparation of materials and products shall be in a Grade A environment with Grade B in background. Drugs and Cosmetics Rules, 1945 414 10.5 Filtration (Membrane).- (i) Solutions for Large Volume Parenterals shall be filtered through a non-fibre releasing, sterilizing grade cartridge/membrane filter of nominal pore size of 0.22 µ for aseptic filling whereas 0.45 µ porosity shall be used for terminally sterilized products. (ii) A second filtration using another 0.22 µ sterilizing grade cartridge / membrane filter shall be performed immediately prior to filling. Process specifications shall indicate the maximum time during which a filtration system may be used with a view to precluding microbial build-up to levels that may affect the microbiological quality of the Large Volume Parenterals. (iii) The integrity of the sterilized filter shall be verified and confirmed immediately after use by an appropriate method such as Bubble Point, Diffusive Flow or Pressure Hold Test. 10.6 Sterilization (Autoclaving).– 10.6.1. Before any sterilization process is adopted, its suitability for the product and its efficacy in achieving the desired sterilizing conditions in all parts of each type of load pattern to be processed, shall be demonstrated by physical measurements and by biological indicators, where appropriate. 10.6.2 All the sterilization process shall be appropriately validt.. The validity of the process shall be verified at regular intervals, but at least annually. Whenever significant modifications have been made to the equipment and product, records shall be maintained thereof. 10.6.3 The sterilizer shall be double ended to prevent mix-ups. 10.6.4 Periodic bio-burden monitoring of products before terminal sterilization shall be carried out and controlled to limits specified for the product in the Master Formula. 10.6.5 The use of biological indicators shall be considered as an additional method of monitoring the sterilization. These shall be stored and used according to the manufacturer’s instructions. Their quality shall be checked by positive controls. If biological indicators used, strict precautions shall be taken to avoid transferring microbial contamination from them. 10.6.6 There shall be clear means of differentiating ‘ sterilized’ and ‘un-sterilized’ products. Each basket, tray or other carrier of products or components shall be clearly labelled with the name of the material, its batch number, and sterilization status. Indicators shall be used, where appropriate, to indicate whether a batch (or sub-batch) has passed through the sterilization process. 10.6.7 Sterilization records shall be available for each sterilization-run and may also include thermographs and sterilization monitoring strips. They shall be maintained as part of the batch release procedure. 10.7. Sterilization (By dry heat).– 10.7.1 Each heat sterilization cycle shall be recorded on a time/temperature chart of a suitable size by appropriate equipment of the required accuracy and precision. The position of temperature probes used for controlling and/or recording shall be determined during the validation and, where applicable, shall also be checked against a second independent temperature probe located in the same position. The chart shall form a part of the Drugs and Cosmetics Rules, 1945 415 batch record. Container mapping may also be carried out in the case of Large Volume Parenterals. 10.7.2 Chemical or biological indicators may also be used, but shall not take the place of physical validation. 10.7.3. Sufficient time shall be allowed for the load to reach the required temperature before measurement of sterilization time commences. This time shall be separately determined for each type of load to be processed. 10.7.4. After the high temperature phase of a heat sterilization cycle, precautions shall be taken against contamination of sterilized load during cooling. Any cooling fluid or gas in contact with the product shall be sterilized unless it can be shown that any leaking container would not be approved for use. Air inlet and outlets shall be provided with bacterial retaining filters. 10.7.5. The process used for sterilization by dry heat shall include air-circulation within the chamber and the maintenance of a positive pressure to prevent the entry of non- sterile air. Air inlets and outlets should be provided with micro-organism retaining filters. Where this process of sterilization by dry heat is also intended to remove pyrogens, challenge tests using endotoxins would be required as part of the validation process. 10.8. Sterilization (By Moist Heat).- 10.8.1 Both the temperature and pressure shall be used to monitor the process. Control instrumentation shall normally be independent of monitoring instrumentation and recording charts. Where automated control and monitoring systems are used for these applications, these shall be validt. to ensure that critical process requirements are met. System and cycle faults shall be registered by the system and observed by the operator. The reading of the independent temperature indicator shall be routinely checked against the chart-recorder during the sterilization period. For sterilizers fitted with a drain at the bottom of the chamber, it may also be necessary to record the temperature at this position throughout the sterilization period. There shall be frequent leak tests done on the chamber during the vacuum phase of the cycle. 10.8.2 The items to be sterilized, other than products in sealed containers, shall be wrapped in a material which allows removal of air and penetration of steam but which prevents re-contamination after sterilization. All parts of the load shall be in contact with the sterilizing agent at the required temperature for the required time. 10.8.3. No Large Volume Parenteral shall be subjected to steam sterilization cycle until it has been filled and sealed. 10.8.4 Care shall be taken to ensure that the steam used for sterilization is of a suitable quality and does not contain additives at a level which could cause contamination of the product or equipment. 10.9. Completion/finalisation of sterile products– 10.9.1. All unit operations and processes in the manufacture of a batch shall have a minimum time specified and the shortest validt. time shall be used from the start of a batch to its ultimate release for distribution. Drugs and Cosmetics Rules, 1945 416 10.9.2. Containers shall be closed by appropriately validt. methods. Containers closed by fusion e.g. glass or plastic ampoules shall be subjected to 100% integrity testing. Samples of other containers shall be checked for integrity according to appropriate procedures. 10.9.3 Containers sealed under vacuum shall be tested for required vacuum conditions. 10.9.4 Filled containers of parenteral products shall be inspected individually for extraneous contamination or other defects. When inspection is done visually, it shall be done under suitably controlled conditions of illumination and background. Operators doing the inspection shall pass regular eye-sight checks with spectacles, if worn, and be allowed frequent rest from inspection. Where other methods of inspection are used, the process shall be validt. and the performance of the equipment checked at suitable intervals. Results shall be recorded.