Some Equipment In Injection Drug Production

membrane with 0.22 µm filter pores. The sterile filtrate is immediately filled into a sterile tube (vial) and sealed.

- Filling injections: the volume of medicine filled into the tube (bottle) must be checked regularly to make timely adjustments during the filling process, ensuring the required volume is met (see the quality requirements for injections).

Heat sterilization (applied to heat-resistant injectable drugs): injectable drugs after being bottled, viald and sealed will be transferred to the sterilization room. Depending on the injectable drug, the method will be applied.

- Sterilize the oil injection solution by dry heat at 180 o C for 30 minutes.

- Sterilize aqueous injection solutions by moist heat at the temperature and time as shown in Table 4.4.

The next steps are labeling, packaging, testing finished products and warehousing (finished products are only warehoused when testing meets quality standards).

Injection suspension:

Injectable suspension is one of the difficult injectable forms to produce, which is reflected in two aspects: it is necessary to maintain the level of dispersion of the drug in the preparation while ensuring the sterility requirements of the injectable preparation, but the injectable suspension product cannot be sterilized by heat after closing the tube (bottle), because:

- If the injectable suspension is sterilized by heat, high temperature will increase the solubility of the drug in the dispersion medium, the drug particles will be partially or completely dissolved, but when the drug cools, the drug will recrystallize into crystals with very different shapes, sizes and polymorphs that the manufacturer cannot control, changing the bioavailability of the drug.

- High temperatures can also cause changes in the drug, especially when the mixture contains ingredients that are not heat-stable.

Therefore, injectable suspensions must be prepared in sterile environments and equipment and appropriate sterilization methods must be applied for each specific production stage. Injectable suspensions can be prepared by the following two methods:

1) Disperse sterile solid drug into sterile carrier under sterile environmental and equipment conditions through the following steps:

- Prepare a sterile solid drug substance of the specified particle size. The sterile drug substance powder may be obtained by aseptic crystallization or by sterilization by radiation followed by fine division in a suitable blender under aseptic conditions.

- Dissolve the other ingredients in the solvent into a solution or separate solutions, filter if necessary, sterilize these solutions (by filtration or moist heat or dry heat depending on the nature of the solution).

- Create a paste between the sterile pharmaceutical powder and a sufficient amount of the prepared sterile solution (usually using a wetting agent solution).

- Disperse the pharmaceutical paste into the remaining sterile solution and pass the mixture through a homogenizer to obtain a homogeneous mixture.

2) Condensation due to solvent change:

Example of preparing a testosterone injection: prepare the vehicle solution and sterilize it. Dissolve the testosterone in acetone and sterilize this solution by filtering through a 0.22 µm filter (use a filter that is resistant to organic solvents). Add the sterile testosterone solution to the sterile vehicle solution, the testosterone will recrystallize. Dilute the suspension with the vehicle, mix well, let the crystals settle, and aspirate the clear liquid. Add the vehicle and repeat the process several times until all the acetone is removed. Dilute the suspension to the desired volume and bottle under aseptic conditions.

Emulsion injection

Emulsion injection is a microheterogeneous mechanical dispersion system consisting of two immiscible liquid phases conventionally called oil phase and water phase, in which one phase is dispersed into the other phase in the form of droplets with diameter of 0.1 - 0.5 µm thanks to suitable emulsifiers such as lecithin, phospholipid, polysorbate.

To ensure the droplet size of the dispersed phase after dispersing the oil phase into the water phase to form an emulsion, it is necessary to filter the emulsion through a filter membrane with a 0.5 µm filter hole.

During the storage of the drug preparation, the droplet size of the dispersed phase may increase due to the droplets spontaneously aggregating together to form larger droplets, which can easily cause injection accidents, especially D/N emulsions used for intravenous injection.

In general, injectable emulsions are difficult drugs to prepare. In practice, there are some D/N type fatty oil emulsions used for intravenous injection to provide energy to patients.

Dry powder injection

The preparation procedure with the powder for injection may be as follows:

Object

Technical operations	Content control
Recipe	→ Calculate quantity	Check the formula
Pharmaceutical ingredients, Excipients	→ Weigh, grind, pulverize, and sterilize	Check the weight, check
	↓	condition
Single powder	→ Mix and match	Content, copper
	↓	best
Double powder	→Distribution
	↓	Weight
Pharmaceutical bottle	→ Close the lid
	↓
	Labeling
	↓
	→Boxed
	↓
Finished product	→ Isolation	Tested according to standards
	↓	standard
	Import to warehouse

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Many solid pharmaceuticals are physically and chemically unstable when dissolved or dispersed in an aqueous medium in the form of solutions or suspensions. For injectable drugs containing such pharmaceutical ingredients, they are usually prepared in the form of dry powders and only

reconstituted into a solution or suspension immediately before injection. Dry powder injectables may be prepared by freeze-drying or spray-drying.

- Freeze dried:

Freeze-drying is a process of drying a frozen aqueous solution at a temperature below the eutectic temperature of the solution, the solvent is removed directly from the solid phase without passing through the liquid phase under reduced pressure (usually below 100 µm Hg), resulting in a dry product.

- Spray drying :

Principle: first, mix the drug solution (according to the established formula), sterilize this solution by filtering through a membrane with a 0.22 µm filter, the sterile filtrate is pumped into the spray dryer and sprayed into the drying chamber of the machine through a nozzle under appropriate spray pressure (generated from an air compressor), the high spray pressure will turn into aerosol form, this aerosol stream is in direct contact with the sterile hot air flow blowing in the same direction, the solvent from the aerosol droplets will evaporate very quickly due to the large contact and leave dry drug powder. The drug powder is then bottled using a suitable powder filling machine. The entire process must be carried out under aseptic conditions.

Spray drying is more economical than freeze-drying, but it is also a technique for producing sterile powdered injectable drugs that is very difficult to implement because this technique requires sterile filtration of a very large amount of air and ensuring the sterility of the entire spray-drying equipment as well as the powder mass after spray-drying from the spray dryer to the powder packaging machine is not simple.

3.3. Some equipment in the production of injectable drugs

- Water Distiller

- Vacuum pipe cleaning and sealing system

- Pill packing and tube welding machine

- Steamer

Figure 4.7. Diagram of water distillation machine

Figure 4.8 Principle of closing each tube

Figure 4.9. Diagram of syringe filling machine

Figure 4.10 Steam sterilizer diagram

(a) Main pressure gauge; b) Separator, c) Pressure reducing valve, d) Air supply pipe for the outer shell, e) Air supply pipe for the sterilization chamber; f) Air filter, g) Pressure gauge for measuring the pressure in the shell, h) Pressure gauge for measuring the sterilization chamber pressure, i) Air vent for the shell, j) Vacuum pump, k) Exhaust pipe communicating with the shell, l) Exhaust pipe for the sterilization chamber, m) Thermometer hole, n) Direct reading thermometer, o) Temperature recording device, p) Filter, q) Check valve, r) Temperature regulator, s) Branch pipe, t) Steam outlet pipe, u) Water shut-off valve).

4. Quality requirements of injectable drugs

Injections are one of the sterile pharmaceutical preparations with very high quality requirements. To ensure the overall quality of an injectable preparation, in addition to strictly controlling all stages in the technical process of injectable production, the injectable preparation must also meet the following quality control requirements and must maintain that quality until the drug is used.

4.1. Sensory indicators

- Colorless or has the color of the drug

- Injectable suspensions are suspensions that may settle but must disperse immediately upon gentle shaking and must maintain a homogeneous dispersion for a sufficient time to draw the correct dose into the syringe. Injectable suspensions contain dispersed particles smaller than 15µm in size, no more than 10% of particles between 15µm and 20µm in size and virtually no particles between 20µm and 50µm in size.

- The emulsion injection must not show any signs of separation.

4.2. Transparency

- Injectable solutions must be clear and free of insoluble particles when examined visually under specified conditions. DĐVN IV (Appendix 11.8, Section B).

4.3. Volume or mass

- Unless otherwise directed, Single-dose Injections must meet the following requirements:

+ Injections with a volume not greater than 5ml meet the requirements of method 1.

+ Injections with a volume greater than 5ml meet the test requirements of method 2. The two test methods are clearly stated in DĐVN IV (Appendix 1, page PL - 28).

- Multi-dose injectable drugs have a prescribed volume limit of:

+ The volume stated on the label is not greater than 50ml, the allowable limit is 10%.

+ The volume stated on the label is greater than 50ml, the allowable limit is 5%.

- Mass uniformity (applicable to single powder drugs): for powder drugs with mass greater than 40 mg, the concentration difference is 10%. When the average mass is equal to or less than 40 mg, the preparation does not have to be tested for mass uniformity, but must be tested for content uniformity.

4.4. Aseptic

Injections must be sterile. If the injections are not sterile, they can cause very serious consequences such as infection at the injection site, blood infection, etc.

To test the sterility of injectable drugs, we often have two commonly used tests: the filtration method or the direct inoculation method. These two methods are clearly stated in DĐVN IV (Appendix 13, page PL - 266).

4.5. Pyrogenic substances

Injections must not contain pyrogens. Pyrogen testing is performed in the following cases:

- For single-dose injectables containing 15 ml or more and for which endotoxin testing is not required, unless otherwise indicated.

- For single-dose injectables with a volume of less than 15ml if the label states “no pyrogen” and there is no requirement for endotoxin testing.

Details on the testing method can be found in DĐVN IV (Appendix 13, page PL – 256).

4.6. Bacterial endotoxins

Bacterial endotoxin testing is performed in cases specified in the monograph or according to specific requirements to detect or quantify bacterial endotoxins in injectable drugs. Details of the test are recorded in DĐVN IV (Appendix 13, page PL - 250).

When bacterial endotoxin testing is required, pyrogen testing is not required, unless otherwise specified.

5. Some injectable drug formulas

5.1. Alteplase, lyophilized powder for injection in vials with 3 strengths (Genentech):

Alteplase 20mg 50mg 100mg

L-Arginine 0.7g 1.7g 3.5g

Phosphoric acid 0.2g 0.5g 1g Polysorbate 80 < 1.6mg < 1.4mg < 11g

The drug is mixed with 0.9% sodium chloride injection solution or 5% glucose at a ratio of 1 mg/ml and infused immediately after mixing.

5.2. Amikacin sulfate 50mg/ml, 2ml vial (Elkins – Sinn, USP 24):

Amikacin sulfate 100ng

Sodium bisulfite 0.13%

Sodium citrate 0.5%

Sulfuric acid to adjust pH = 3.5 – 5.5 (best 4.5) Sterile water for injection to 2ml

5.3. Digoxin 0.25mg/ml, 2ml tube (Glaxo Wellcome):

Digoxin 0.50mg

Propylene glycol 40%

Ethanol 10%

Sodium phosphate 0.17%

Citric acid 0.08%

Sterile water for injection v.s. 2ml Solution has pH = 6.8 - 7.2.

5.4. Ergonovine maleate, 1ml syringe (Lilly):

Ergonovine maleate 0.2mg

Ethyl lactate 0.1%

Lactic acid 0.1%

Phenol 0.25%

Sterile water for injection for 1ml Injection has pH = 2.7 - 3.5.

II. INJECTIONAL MEDICATIONS

1. Definition

Intravenous drug is a sterile aqueous solution or oil-in-water emulsion, free of pyrogens, free of bacterial endotoxins, free of antiseptics, isotonic with blood, used for intravenous infusion in large volumes and at slow speeds.

Figure 4.11. Some forms of intravenous drugs

2. Characteristics of intravenous drugs

Intravenous drugs are a type of injectable drug, so first of all, the preparation must meet the general quality standards of injectable drugs. However, infusion drugs are used in large doses (hundreds of ml for one infusion), so infusion drugs have some characteristics that are different from injectable drugs in general.

- Intravenous drugs do not contain strong active ingredients.

- Injectable drugs are liquid drugs with distilled water as solvent to mix the injection, in which the active ingredient is completely dissolved into a real solution, colloidal solution or dispersed in water to create a D/N emulsion.

- Intravenous drugs are usually solutions that are isotonic with blood and body fluids. If the solution is hypertonic, it must be infused at an extremely slow rate.

- Injectable drugs must not contain bacterial endotoxins and must not contain pyrogens. To ensure this quality requirement, the drug must be sterilized by heat in an autoclave immediately after preparation.

- Infusion solutions must not contain particles detectable by the naked eye and are only allowed to have a certain number of invisible particles (each country's Pharmacopoeia has its own regulations), determined by an automatic particle counter or by filtration and counting under a microscope.

3. Clinical application

Intravenous drugs are used in treatment for many different purposes:

- Provides water and electrolytes when the body is dehydrated and loses electrolytes.

- Provide nutritional needs for the body when the patient cannot eat or drink. In these cases, glucose and fructose solutions can be infused.

Amino acid solutions, D/N type fatty oil emulsions combined with vitamins, minerals and trace elements

- Neutralize and re-establish acid-base balance in case of acidosis or alkalosis due to metabolic or functional disorders.

- Diuretic when the body is in a state of water retention.

- Anticoagulant and blood preservative used in storing fresh blood.

- Used as an intermediate medium or “carrier” for many other injectable drugs, the injectable drug will be combined with a suitable intravenous drug solution immediately before being administered to the patient. The combination of injectable drugs with intravenous drugs is quite commonly used in treatment because it is very convenient, especially when it is necessary to maintain a constant concentration of the drug in the blood at a therapeutically effective level for a long period of time. However, if the drug combination is not compatible with each other, it can cause dangerous complications in treatment.

Incompatibility when combining injectable drugs with infusion drugs can be due to changes in solution pH, solubility of the drug or chemical interactions.

Incompatibility when combining injectable drugs with certain infusion drugs can be recognized by the appearance of precipitation, turbidity, gas formation or discoloration of the solution; but sometimes it is not visible such as changes in pH or drug concentration in the solution due to hydrolysis, oxidation or complexation, which can only be detected by appropriate analytical methods; in addition, there may be incompatibility in terms of pharmacological effects.

In some cases, incompatibilities can be predicted based on the chemical properties of the drug involved. For example, Phenobarbital sodium will precipitate as free acid if Phenobarbital injection is combined with an infusion solution having an acidic pH. Calcium chloride infusion will precipitate when combined with Sodium bicarbonate infusion solution.

To minimize incompatibility when using intravenous drugs as an intermediate medium to introduce drugs into the body, it is necessary to follow some principles:

- Only combine immediately before infusion and only infuse when no changes in the sensory appearance of the drug are detected.

- Do not combine different injectable drugs in the same infusion solution.

- Absolutely do not combine incompatible drugs as indicated in the monographs.

- It is best to combine only when there are research results on compatibility.

4. Quality standards

4.1. Transparency

Infusion solutions must meet the requirements for visual clarity of injectables (Appendix 11.8, Section B) and must meet the requirements for the number and size limits of particles not visible to the naked eye (Appendix 11.8, Section A).

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