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Nitrogen Preparation Methods and Quality Standards and Verification Requirements for Pharmaceutical Use

Author:Nitrogen Preparation Methods and Quality Standards and Verification Requirements for Pharmaceutical Use  Browse:1024  Time:2019-05-07

1. Conventional methods of nitrogen production

1.1 Deep cooling air separation nitrogen production

        Cryogenic air separation nitrogen is a traditional nitrogen production method that has been in recent decades. It uses air as a raw material, compresses and purifies it, and then uses heat exchange to liquefy the air into liquid air. Liquid air is mainly a mixture of liquid oxygen and liquid nitrogen.

The boiling points of liquid oxygen and liquid nitrogen are different (the boiling point of the former is -183 ° C at 1 atm, and the latter is -196 ° C), and they are separated by liquid-liquid rectification to obtain nitrogen.

1.2 Membrane air separation and nitrogen production

        Air is used as a raw material, and under different pressure conditions, gases of different properties such as oxygen and nitrogen have different permeation rates in the membrane to separate oxygen and nitrogen. Compared with other nitrogen-making equipment, it has the advantages of simpler structure, smaller volume, no switching valve, less maintenance, faster gas production (≤3 minutes), convenient capacity increase, etc. It is especially suitable for medium and small nitrogen users whose nitrogen purity is less than 98%, and has the best function-price ratio. When the purity of nitrogen is above 98%, the price of PSA nitrogen machine is 15% higher than that of PSA nitrogen machine of the same specification.

1.3 PSA pressure swing adsorption nitrogen production

        Pressure swing adsorption (PSA) is a new gas separation technology that uses a molecular sieve to separate the gas mixture by differentiating the "adsorption" properties of different gas molecules.

At present, carbon molecular sieves or zeolite molecular sieves are widely used in the field of nitrogen and oxygen production. The separation of oxygen and nitrogen by molecular sieves is mainly based on the different diffusion rates of these two gases on the surface of molecular sieves. Carbon molecular sieves are carbon-based adsorbents with some characteristics of activated carbon and molecular sieves. Carbon molecular sieves have very small microporous composition, with pore size ranging from 0.3 to 1 nm. The gas with smaller diameter (oxygen) diffuses faster and enters the solid phase of molecular sieve more frequently, so the nitrogen enrichment component can be obtained in the gas phase. After a period of time, the adsorption of oxygen on molecular sieves reaches equilibrium. According to the different characteristics of adsorption capacity of carbon molecular sieves to adsorbed gases under different pressures, reducing pressure makes carbon molecular sieves desorb oxygen. This process is called regeneration. Pressure swing adsorption (PSA) usually uses two towers in parallel, alternating pressure adsorption and decompression regeneration to obtain continuous nitrogen flow.

2. Nitrogen and pharmaceutical production

2.1 Function

(1) The nitrogen filling protection of the storage tank keeps the oxygen and carbon dioxide in the water at a low level;

(2) Anti-oxidation during the injection process, such as prevention of oxidation during the production of compound amino acids;

(3) Nitrogen-filling protection of finished products.

2.2 Quality Requirements and Test Standards

NO.

Test Items

China GMP Standard

Standard(USP)

Standard(EP)

Remarks

1

Odor

No odor and stench

No odor and stench

No odor and stench

GMP/T13277-91General use of compressed air quality standards
≥ GMP implementation guide drug production verification guide

 

Pharmacopoeia USP32

 

Pharmacopoeia EP60

 

2

Moisture test (related to dew point temperature)

<100mg/ m3

 

No liquid

≤67mmp

 

3

Oil test

<1mg/ m3

No oil

≤0.1mg/ m3

4

Dust test

——

——

——

5

Bacterial test

<1CFU/ m3

——

——

6

Nitrogen and oxygen ratio test

20%-22%

19.5%-23.5%

20.4%-21.4%

7

Carbon monoxide test

<11mg/ m3

≤5.0*10-4

 

≤5ppm

8

Carbon dioxide test

<1400mg/ m3

≤1.0*10-5

 

≤500ppm

9

Nitric oxide and nitrogen dioxide test

——

≤2.5ppm

≤2ppm

10

Sulfur dioxide

——

≤5ppm

≤1ppm

11

Reference

GMP/T13277-91General use of compressed air quality standards
≥ GMP implementation guide drug production verification guide

 

Pharmacopoeia USP32

Pharmacopoeia EP60

Note: GMP nitrogen is not regulated as a drug in China, but the United States and the European Union incorporate nitrogen into the pharmacopoeia.

 

3. Validation of nitrogen system

3.1. IQ

1. Equipment inspection

2. Component installation inspection

3. Instrument calibration and inspection

4. Inspection of media supply

5. Installation and inspection of equipment

6. Material inspection of contact products

7. Installation and inspection of control system

8. Inspection of spare parts

9. Filter inspection

3.2 OQ

3.2.1. Pre-confirmation requirements

SOP examination

Inspection of testing instrument

3.2.2 Operation Confirmation Check

Inspection of mechanical function

Auto-control function test

Operation parameter confirmation

Noise Testing and EHS confirmation

3.3 PQ (according to QS, TS)

1. Microorganisms, granules, moisture and others

2. Purity (non-oxygen content, oxygen content)

3. Pressure and pressure stability test

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