Preparation of Ampoules and Infusions

Summary

The objectives of this experiment are: 1. to master the handling of empty ampoule and pendant glass filter; 2. to master the basic operation of preparation, filtration, filling and sterilization of injection solution; 3. to familiarize with ampoule leakage check and clarity check; 4. to learn the use of drying box and purification workbench; 5. to master the quality requirements of infusion agent and the process and operation of hand-made production; 6. to practice the pretreatment of infusion vials, rubber stoppers, pre-treatment of isolation film; 7. further familiarize with the requirements and operation methods of clean treatment, air sterilization and aseptic operation in aseptic operation room; 8. familiarize with the selection of microporous filtration membranes, pre-treatment and use of methods.

Operation method

decompression filtration

Principle

1. Treatment of ampoule Fill the ampoule with purified water, heat it at 100 ℃ for 30 minutes, shake off the water while it is hot, then fill the ampoule with filtered purified water and water for injection, shake off the water, and so on for three times, in order to remove the trace free alkali, metal ions, dust, sand and other impurities on the surface of ampoule, and immediately dry it at 120-140 ℃, and reserve it. 2. Treatment of pendant glass filter Rinse the pendant glass filter with purified water, dry it at 120-140 ℃ immediately and reserve it. The cleaned ampoule should be dried at 120~140 ℃ immediately and set aside.2. Treatment of fused glass filter Rinse the fused glass filter with purified water, soak it in 1%~2% sodium nitrate sulfate solution for 12~24 hours, and then rinse it with purified water and water for injection until the rinse solution is neutral and clear, then pump it to dryness and set it aside.3. Liquid Dispensing Liquid dispensing instruments should be cleaned and dried according to the requirements and then be used. There are two general methods of liquid dispensing. (1) dilute method: the raw material is added to the solvent, once the required concentration. (2) Concentrated method: the raw material is added to part of the solvent, formulated into a concentrated solution, heated and filtered, if necessary, can add activated carbon treatment, can also be refrigerated and then filtered, and then diluted to the required concentration. 4. Filtering Filtration methods include pressurized filtration, depressurized filtration, and high hydrostatic filtration, etc. There are also many types of filters. There are also many types of filters for crude, prefiltration and fine filtration. According to the laboratory conditions, install the filtration device. 5. Filling and sealing Immediately fill and seal the filtered drug solution. Requirements for accurate dosage, the liquid does not stain the ampoule neck wall. If the drug is easy to oxidize, inert gas can be passed during the filling process. 6. Sterilization and leakage detection After the ampoule is melted and sealed, sterilize it in time according to the regulations. After sterilization, take out the ampoule while it is hot and put it into cold 1% methylene blue solution for leakage detection. 7. Aqueous solution of injection solution for intravenous drip (infusion agent) should be free of pyrogens, insoluble particles should comply with the regulations and isotonic with blood as far as possible, in addition to meeting the general requirements for injection agent. 8. Intravenous drip emulsion, the dispersed phase particle size of the majority of pure (80%) should be less than 1 μm, there shall be no more than 5 μm particles, should be non-pyrogenic, resistant to autoclave sterilization, stable during storage, and shall not be used for vertebral injection. In addition, the pH value of the injection solution for intravenous drip should be close to the pH value of human blood, no bacteriostatic agent should be added, and it should not cause abnormal changes in the blood after being fed into the human body. The preparation of infusion agent is similar to that of ampoule.

Materials and Instruments

Procaine hydrochloride Panax quinquefolium Vitamin C Glucose Sodium chloride Blood
Procaine hydrochloride Sodium chloride Water Panax quinquefolium Polysorbate-80 Vitamin C Sodium bicarbonate Sodium metabisulfite Sodium edetate Glucose Sodium citrate Citrate
Ampoules Fillers Sterilization kettles Brushes Infusion bottles Gel caps

Move

(i) Ampoule preparation
1. Preparation of procaine hydrochloride injection
[Prescription]. Procaine hydrochloride 10 g Sodium chloride 7 g Adequate amount of water for injection Total 1000 ml Prepare 2 ml ampoules per person.
[Preparation method] (1) Liquid preparation: take about 800 ml of water for injection, add sodium chloride and stir to dissolve, add procaine hydrochloride, and add acid to adjust the PH to 4.0-4.5, then add solvent to the full amount, stir well, and then filter to get clear liquid. (Note the addition and connection of the filtration device and the principle). (2) Wash the empty ampoule: first fill with 0.1% hydrochloric acid solution, rinse and then boil with water, dry. (3) Filling and sealing of injection: pay attention to the exhaustion of the filling and sealing device, to adjust the position, and before dissolving and sealing, you can use the waste ampoule to practice the technique in order to reduce the loss. (4) Sterilization and leakage detection of ampoule: Sterilize the ampoule by circulating steam at 100 ℃ for 30 minutes, and put it into colored solution for leakage detection while it is hot. (5) Quality check of ampoule: PH value and clarification waste check. (6) Printing and packaging of ampoule.
[Note] (1) procaine hydrochloride is a weak base combined with strong acid salt, easy to hydrolyze, decarboxylation to generate aniline, for this reason, the first adjustment of PH to 4.2-5.0, because this time is the most stable, some with hot pressure 115.5 ℃ for half an hour to the bacteria (generally believe that 100 ℃ for half an hour is good). (2) sodium chloride regulates osmotic pressure, and can increase the stability of the solution, inhibit hydrolysis. (3) Oxygen, light, metal, etc. can also affect the decomposition, so in the preparation and storage should be avoided.
2. Preparation of Banlangen Injection
[Prescription] Panax quinquefolium 550 g Benzyl alcohol 10 ml Polysorbate-80 10 ml Adequate amount of water for injection Total 1000 ml Prepare 2 ml ampoule per person.
[Method of Preparation] (1) Leaching: Take Panax quinquefolium, add 6-7 times of water and soak for half an hour, decoct twice, half an hour each time, filter, combine the filtrate, and concentrate it to 600-700 ml in a straight fire, and then concentrate it to 300-350 ml in a water bath. (2) Refinement ① alcohol treatment: take the concentrate, stir and add alcohol, so that the alcohol content of 60%, refrigerated for more than 24 hours, the refrigerated liquid filtration, filtrate with 60% alcohol wash 1-2 times, filtrate heating de-alcohol to no alcohol flavor. ② ammonia treatment: take the filtrate, stirring ammonia so that the PH value of 8.5-9, refrigerated for 24 hours, filtered, water bath heating to remove ammonia to no ammonia odor, PH value of 5.5-6, and its liquid with fresh water for injection diluted to 1,000 ml, 24 hours of refrigeration, filtration, filtrate with Tween-80, benzyl alcohol, plus water for injection to 1,000 ml, filtered with a No. 3 pendant fusion funnel, that is, the clarified injection solution. (3) The process of handling, filling and sealing, sterilization, quality inspection, printing and packaging of empty ampoule is the same as the preparation of procaine hydrochloride injection.
[Note]. (1) Panax quinquefolium contains 10% water, so cast 10% more when casting. (2) The root contains sugar, starch, etc., and should be stirred frequently when concentrated to prevent coking. (3) Add alcohol treatment, mainly remove protein, gum, plant mucus, inorganic salts and other impurities. (4) The antimicrobial components of Panax quinquefolium are not heat-resistant, and the decoction or sterilization is generally not more than 100 ℃ for 1 hour. (5) Lose all the activity at PH8, but can still be restored after neutralization, and the removal of ammonia is to reduce the PH to below 7 to restore its antibacterial activity.
3. Vitamin C injection preparation
[Prescription] Vitamin C 105 g Sodium bicarbonate 49 g Sodium metabisulfite 3 g Disodium edetate 0.05 g Add 1000 ml of water for injection.
[Preparation] Take 80% of the total amount of water for injection, saturated with carbon dioxide (or nitrogen), add vitamin C to dissolve, slowly add sodium bicarbonate in stages, stirring to make soluble; the other will be sodium metabisulfite and disodium edetate dissolved in the appropriate amount of water for injection; the two liquids are combined, stirred, adjust the pH value of 6.0-6.2, add carbon dioxide (or nitrogen) saturated water for injection to the full amount of samples to determine the content of the qualified After that, filtered to clear, potted under carbon dioxide (or nitrogen) airflow, 100 ℃ circulating steam sterilization for 15 minutes, can be.
[Role and use] Vitamin drugs. Used in the prevention and treatment of scurvy, also used in acute and chronic infectious diseases and purpura and other auxiliary treatment.
[Usage and dosage] Intravenous or intramuscular injection, 0.1-0.25 g, 0.25-0.5 g a day.
[Note] (1) Vitamin C has an enediol structure in its molecule and is easily oxidized. Its aqueous solution in contact with air, automatically oxidized into dehydroascorbic acid, the latter is then hydrolyzed to generate 2,3-diketone L-gulose that is the loss of therapeutic effect, this compound is then oxidized into oxalic acid and L-butyric acid. The finished product is yellow after decomposition. Factors affecting the stability of this product are mainly oxygen in the air, solution pH and metal ions, so the production of inert gas, adjusting the pH value of the solution, adding antioxidants and metal ion chelating agent and other measures. (2) The stability of the product is related to temperature. Some experiments have proved that with 100 ℃ sterilization for 30 minutes, the content decreased by 3%, while 100 ℃ sterilization for 15 minutes to reduce only 2%, so 100 ℃ sterilization for 15 minutes is good. (3) Vitamin C is highly acidic and irritating when injected, so it is added with sodium bicarbonate to neutralize the salt to reduce injection pain. At the same time, sodium bicarbonate plays a role in regulating pH value.
4. Quality check (1) Air leakage check Put the sterilized ampoule into the colored solution while it is hot, take it out when it is cold, rinse it with water, remove the stained ampoule and record the number of air leakage. (2) Clarity check Wipe the outer wall of the ampoule clean, take 6 ampoules of 1~2 ml each time, at the edge of the umbrella, hold the neck of the ampoule to make the liquid gently turn over, and check it by eye. 18 seconds each time. 50 ml of ampoule should be checked. Each time check 18 seconds. 50 ml or more than 50 ml of injection solution according to the upright, inverted, plain view of the three-step method of rotary inspection. According to the above devices and methods of inspection, in addition to the special provisions of the varieties, not found to have a foreign body or only with a trace of white spots as a qualification. (3) Inspection results Record the inspection results in the table. [Note] White lumps: refers to the use of prescribed inspection methods, can be seen to have a clear plane or angle of the white material.
White spots: White spots are counted if the plane or corners cannot be recognized. However, some white substances are not easy to see the plane, angles (such as spherical), but the same size or larger with the above white blocks, should be treated as white blocks. Microscopic substances that appear to be absent or faintly visible during the examination are not counted as white spots.
Trace white spots: for injection solution of 50 ml or less than 50 ml, if only 3 or less white spots are seen within the specified inspection time, it shall be regarded as trace white spots; for injection solution of 100 ml or more than 100 ml, if only 5 or less white spots are seen within the specified inspection time, it shall be regarded as trace white spots.
Small amount of white spots: the liquid is clear, the number of white spots is more than micro white spots, and it is difficult to count accurately in the specified examination time.
Trace deposits: refers to certain biochemical preparations or polymer compounds preparations, there are tiny deposits after standing, gently inverted with a smoke-like fine line floating, gently shaken to be dispersed.
Foreign matter: including glass shavings, fibers, color dots, color blocks and other foreign matter.
Special foreign matter: metal shavings and obviously visible glass shavings, glass block, glass sand, hard hair or coarse fiber and other foreign matter. Metal shavings with one side of the flash that is, glass shavings with flickering or angular transparent material that is.
(ii) Infusion preparation
1. Treatment of infusion containers and packaging materials: (1) selected qualified infusion bottles, wash off the dust, dripping good cleaning solution placed for 24 hours, normal water wash to neutral, such as opaque brush brush, and finally with filtered water for injection rinse three times, drying. (2) new rubber cap with 3% sodium carbonate solution boiled for about 1 hour, normal water to wash away the lye, and then 1% hydrochloric acid boiled for about 1 hour, normal water to wash away the acid, boiled with water for injection for about 1 hour, and then rinsed with water for injection to pass. (3) polyester wheel diaphragm, can first be immersed in 0.3% of the synthetic detergent rinsed below 50 ℃, and then normal water, distilled water, filtered water for injection repeatedly rinsed and clarified without foreign matter, immersed in filtered water for injection standby.
2. Preparation of glucose injection
[Prescription] Glucose 50 g Appropriate amount of water for injection Total volume 1000 ml
[Preparation method] Take appropriate amount of water for injection, heat and boil, add glucose in stages, stir constantly to form a concentrated solution of 50-70%, use 1% hydrochloric acid solution to adjust the pH value to 3.8-4.0, add 0.1-1.0% of the amount of activated carbon for injection, boil under stirring for 30 minutes, cool to 45-50 ℃ when the activated carbon is filtered out, the filtrate is added with water for injection to the full amount of water for injection to determine the pH value and content, fine filtration until clear, filling and sealing, hot press sterilization at 110 ℃ for 30 minutes. The pH value and content were measured, and then filtered to be clear, potted, and sterilized at 110 ℃ for 30 minutes.
[Note] (1) Select the raw materials in accordance with the specifications for injection. (2) Control the solution PH, sterilization temperature and time to prevent the product from turning yellow.
3. Preparation of sodium chloride injection (sterilized saline)
[Prescription]. Sodium chloride 9 g Water for injection Full volume 1000 ml
[Preparation method] Take sodium chloride and appropriate amount of water for injection, make 20-30% concentrated solution, add 0.1-0.5% activated carbon for injection, boil for 20-30 minutes, filter out the activated carbon, add water for injection to 1000 ml, measure the PH value, if necessary, use 0.1mlo/L sodium hydroxide solution or dilute hydrochloric acid solution to adjust the PH value to 5.4-5.6, and then measure the content of the qualified fine filtration to the amount of clarification, potting, sterilized by hot press at 115.5 ℃ for 30 minutes. 115.5 ℃ hot pressure sterilization for 30 minutes.
[Note] This product has a corrosive effect on glass, if the quality of glass is poor or the storage time is too long, the solution will appear siliceous flakes or other precipitates. It can be treated with dilute hydrochloric acid first when washing the bottle.
4. blood maintenance solution
[Prescription]. Sodium citrate 13.3 g Citrate 4.7 g glucose 30 g Water for injection 1000 ml
[Method of Preparation] Take sodium citrate, citric acid and glucose dissolved in newly boiled and cooled water for injection, and add to the full amount, mix well, adjust the PH value to 4.5-5.5 with citric acid, fine filtration, potting and sealing in 110 ℃ hot pressure sterilization for 30 minutes.
5. Quality inspection of injection solution for intravenous drip Intravenous drip injection is the same as general injection, its content, pH value, clarity, sterility inspection and special inspection items should be in line with the drug standard. In addition, the 2000 edition of Chinese Pharmacopoeia stipulates that the injection solution for intravenous drip with a loading capacity of more than 100 ml must be checked for pyrogen and insoluble particles.
For clarity, sterility and pyrogen check, please refer to section III and section V of this chapter. In the process of clarity inspection, the finished products with chipped cap, crooked cap, loose cap, air leakage and detached isolation film should be picked out.
The inspection method of insoluble particles can be found in the Appendix of Part II of the 2000 edition of the Chinese Pharmacopoeia. Intravenous drip injection unless otherwise specified, each 1 ml of particles containing more than 10 μm shall not be more than 20, containing more than 25 μm particles shall not be more than 2.
After the product quality inspection, it can be labeled, packaged and put into storage.

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