Process validation of the sterilization process.

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The manufacturing process validation is to be covered with following aspect in case of sterile injectable formulation

MICROBIOLOGICAL STERILIZATION VALIDATION

This section provides information and data in support of the efficacy of sterilization processes in drug applications,

The following information is provided in this section:

1. Validation of Sterilizing Grade Filters/ Filter Validations

The Prepared bulk solution in pressure vessel is filtered as per the instruction in the batch manufacturing record. The solution is aseptically filtered by first sterilizing grade pre-sterilized filter.

-Compatibility study:

The compatibility study is performed on filter which includes the testing of Integrity Test (Pre-and Post-Product Exposure), Product Exposure and Filter Visual Inspection after Production and laboratory process parameters

-Viability Study:

The viability study test results demonstrate that the test organism, B.diminuta was not viable in injection. The test filter and recovery filter flushes were within the acceptance criteria.

The aim of the bacterial challenge validation study was to have documented evidence demonstrating that the filtration process will consistently remove a high level of a standard bacterium or relevant bio-burden isolate.

-Filter Adsorption Study:

Adsorption is the binding of formula components onto the filter (primarily the membrane). It may cause product to fall below specifications for these ingredients. There are complicating factors, however, in that flow rate, drug concentration, preservative concentration, temperature, pH and ionic strength can affect adsorption.

This test involves the filtration of injection through a sterilized filter capsule under simulated process conditions. The adsorption of active components by the filter is evaluated by comparison of the product composition pre and post filtration.

It is important to ensure that the filter does not adversely affect the process stream. Extractables are chemical compounds that can be extracted from product contacting surfaces when exposed to an appropriate solvent under exaggerated conditions (i.e, time and temperature). Pre-treatment of the product contacting surface, such as gamma irradiation or steam sterilisation, may also increase the levels of extractables present.

2. Validation of Sterilization and Depyrogenation of Product Containers and Closures and Validation of Sterilization of Sterile Bulk Drug OR Product Contact Equipment.

This involves with the following parameters.

-Bulk Drug Solution Components that are Sterilized Separately

Sterilization of the container/closure system, equipment and accessories used for manufacturing and filtration (including pressure vessels used for manufacturing, holding, filtration and filling) and equipment, accessories used for filling is conducted by a validated sterilization process. Vials are sterilized and depyrogenated in a Tunnel Sterilizer. Aluminum seals, Equipment and accessories used for manufacturing and filtration.

-Validation of Sterilization Process for Rubber Stoppers:

Validation of Sterilization Process for Pre-sterilized capsule filters:

1) Tunnel Sterilization Validation:

The Validation of the Tunnel Sterilizer evaluates Heat Distribution with at least thirty (30) temperature probes that are tied to the outside of vials and these vials are arranged linearly across the width of the tunnel conveyor belt.

2) Steam Sterilization Validation using Autoclave

This section provides a description of the studies conducted to validate the sterilization process for Aluminium seals, Equipment, accessories used for manufacturing and filtration (including pressure vessels used for manufacturing, holding, filtration and filling) and Equipment and accessories used for filling by summarizing the methods and results of heat distribution, heat penetration, and biological indicator studies conducted in the steam sterilizer and to provide evidence that the process is capable of achieving a minimum Sterility Assurance Level (SAL) of 10-6

The component/equipment/accessories are loaded in autoclave as per the validated load pattern. After completion of sterilization cycle the load is unloaded in the cooling zone under LAF (class 100), by opening the door of sterile side.

3 Procedures and Specifications for Media Fills (Media Fill Validation) & Investigation and Action to be Taken in Case of Media Fill Failure

The critical stages of bulk solution manufacturing, sterile filtration, aseptic filling and sealing during the manufacture of sterile injection have been validated with a media fill procedure. The media fill runs were performed using the same rooms and equipment used during the manufacturing process. Simulations are made to ensure that the regular process for commercial batches consistently and reliably produces the finished product of the desired quality. Details on the aseptic process validation are found in the validation report and summary provided in this section.

4 Container-Closure and Package Integrity

Container-Closure Integrity Test:

Container-closure integrity testing in microbiological stress conditions is performed for validation purposes.

Container Closure Integrity Testing by Leak Test:

Leak testing by physical method using methylene blue solution has been performed on ANDA batch to test the container closure integrity.

The container closure integrity testing is conducted at the start, middle and end of sealing operation using Leak testing apparatus during batch manufacturing. In the Leak Test, packaging integrity of the product is tested by subjecting it to vacuum test while immersed in dye solution.

Container Closure Integrity Validation:

The procedure followed for performing container closure integrity validation under microbiological stress conditions is included in the container closure integrity Validation Protocol.

Summary of Container Closure Integrity Validation Procedure:

Samples for container closure integrity should be collected after 14 days incubation of media filled vials. Vials are collected from the initial, middle and end of the media fill run so, as to have representative samples from entire run.

Specifications concerning Holding Periods

Holding time study is to be performed for manufactured bulk and filtered bulk.

Sterility Testing Methods and Release Criteria

The membrane filtration sterility test for injectable have been validated on the submission batches.

Bacterial Endotoxins Test and Method

Generally performed with the Gel Clot Test

Fish Disease Treatment Strategies

1.Treatment strategy of bacterial diseases

There are two kinds of bacterial diseases: bacterial hemorrhagic disease and bacterial Gill disease. Bacterial hemorrhagic disease is a common disease of freshwater fishes, in the early stage, mild bleeding symptoms will appear in both sides of the fish body and mouth, as well as the fin base and the upper and lower cheek, later it will find the bleeding in the fish body, some fish scales will appear erect phenomenon, fish belly will appear swollen phenomenon, this needs to be treated with drugs, can use the aerator to put chlorine such dags into water. Bacterial Gill disease, under normal circumstances, you can use Calcium lime to clear the pond, or add drag into fish feed.

2.Treatment strategies for parasitic diseases

For Ichthyophthirius disease, need to use special drag, and continuous to use 3 to 7 courses before they can completely eliminate. A mixture of pepper and ginger can also be poured into pond. Myxosporidiosis often occurrence in common carp, once get the disease, it will appear gray white cysts in gill, pectoral, ventral, caudal and other parts. In severe cases, tumor like cyst will appear in mine eyes, intestine and brain, can use Calcium lime or bleacher to clear the fish pond. For already sick fish, you can use the Junduke and iodine and other drag to cure.

3.Treatment strategies for viral diseases

In freshwater fish, grass carp is the most susceptible to viral hemorrhagic disease, once grass carp infected with viral hemorrhagic disease, its eyes, head and gill and other parts appear congestion, the whole body is dark black. For viral hemorrhagic disease, now it has not developed effective drugs, can only use lime and bleaching powder to disinfect fishpond and remove the pond sludge.

Fish Disease Preventive Measure & Control

Scientific stocking, raising the disease resistance of the fish body, control of the pathogen and the use of drugs and other measures.

Scientific stocking: the water should be adequate, clean, free from pollution, the physical and chemical characteristics of water should be suitable for fish habits. Therefore, water should be from the independent intake channels, fill the new water regularly, the water must not discharged into other ponds, to prevent the spread of fish diseases. A variety of fish polyculture can reduce the incidence of parasitic disease; dense stocking but not make the density too high can not only ensure the yield per unit area, but also prevent excessive contact with the fish from causing a highly contagious disease. Feed should be qualitative, quantitative, positioning, timing, periodically check the season, eliminate weeds, bait, dead and parasite intermediate hosts, to prevent disease occurrence and spread. If you produce feed pellets yourself, please choose suitable feed formulation, and High Quality Feed Machines.

Improving the disease resistance: Vaccine for fish, or immersing the fish body into vaccine liquid can make the fish body get immunity. Vaccine generally isolated from the diseased fish, pathogens was made after culture, inactivation and other processes. Sometimes methylene blue usp grade grinding disease fish viscera, filter to the residue, inactivate filtrate. Through artificial selection or hybrid method to cultivate fish varieties with strong resistance to disease, it is a positive means of preventing fish diseases.

Control pathogen: Before stocking, farmers should drain the water, remove the bottom surface of the sun and remove the pool sludge, weeds etc., to eliminate pathogens and parasite oviposition sites. Can also sprinkle lime, bleaching powder, tea cake into fish pond for drug cleaning, disinfect the water weeds, manure, feed, farming tools and other places before use them. In order to prevent the spread of the international spread of pathogens, the import and export of fish to be quarantine. Regulations of the people's Republic of China on import and export of animal and plant quarantine and Interim Provisions on Quarantine of freshwater fish at the port Determined scope, object, method and processing method of quarantine, any of the pathogens causing serious harm to the fish but lack of effective methods of prevention and control, such as the infectious pancreatic necrosis virus from salmon and trout of, the Myxosoma cerebralis could cause rotation disease, etc. are listed as the main object of quarantine.

Administration of drugs: For the prevention and treatment of fish diseases are the main types of halogen(Bleaching powder, sodium chloride, iodine,etc.), Heavy metal salt(copper sulfate and ferrous sulfate, cupric chloride, potassium dichromate, etc.), sulfonamides (sulfadiazine, sulfathiazole, sulfonamides, etc.), furan (nitrofurazone, furan ketones, disable fishery drugs), organic phosphorus insecticide trichlorfon, etc.), antibiotics (penicillin, streptomycin, chloramphenicol, chlortetracycline, oxytetracycline, erythromycin, etc.), Chinese herbal medicine (Sapium sebiferum, rhubarb, garlic, Euphorbia humifusa, iron, etc.), As well as other bactericidal effects(Malachite green and methylene blue dye, lime, sulfur, borax, Potassium Permanganate etc.).