Analysis Of The Problems Of Packaging Materials In The Production Process Of Freeze-Dried Powder Injection

Aiming at the problems encountered by packaging materials in the bottle washing process, filling process, freeze-drying process, and capping process of freeze-dried powder injections, the process analysis of packaging materials in the production of powder injections was carried out. Freeze-dried powder preparations are non-terminal sterilized products, which have strict standards for sterility and production process control, and because they are intravenous injection products, problems in quality control may cause some adverse reactions such as pyrogen allergies and thrombosis, which directly affect to patient safety. The inner packaging materials used in lyophilized powder injections are in direct contact with the liquid medicine, which is an important factor affecting product quality. Therefore, the importance of lyophilized powder injection packaging materials for drug quality and production process is self-evident.

The inner packaging materials used in freeze-dried powder injections include three categories: glass bottles, butyl rubber stoppers, and aluminum caps: barrier properties, corrosion resistance, and acid resistance in the process of direct contact between glass bottles and liquid medicines; Liquid compatibility, puncture debris, insoluble particles, self-sealing, volatile sulfide, etc.; the aluminum material, opening force, and fit of the aluminum cap directly affect the quality of the drug. Moreover, the packaging materials used for freeze-dried powder injections must withstand high-temperature sterilization and low-temperature freezing. From the perspective of ensuring the quality of drugs, comprehensive consideration and evaluation of the above-mentioned packaging materials should be carried out. At the same time, attention should also be paid to whether the packaging materials meet The production process requirements and the problems applicable to production equipment, the influence of different inner packaging materials on the production process of freeze-dried powder injection drugs will be discussed below in combination with the actual situation.

Part 1 The Impact Of Glass Bottles On The Production Process

On November 8, 2012, the Office of the State Food and Drug Administration issued the “Notice on Strengthening the Supervision and Administration of Drugs for Pharmaceutical Glass Packaging Injections”, which put forward stricter and higher standards for the packaging material glass bottles used by drug manufacturers. The purpose of the requirements is to speed up the upgrading of glass bottles for pharmaceutical packaging materials in my country, improve the quality of various injection types of drugs, ensure the safety of patients while reducing the impact of the production process on the quality of drugs.

Pharmaceutical packaging glass is divided into borosilicate pharmaceutical glass and sodium calcium silicate pharmaceutical glass, soda lime glass is used for disposable infusion bottles, oral liquid, etc., borosilicate glass is used for freeze-dried powder injection, Blood products, biological products and other injections. Borosilicate pharmaceutical glass includes high borosilicate glass, neutral borosilicate glass, and low borosilicate glass, which are used for freeze-dried powder injections with different characteristics according to the comprehensive evaluation of alkali resistance, acid resistance and risk of precipitates.

At present, low-borosilicate glass and soda-lime silicate glass are the most widely used in domestic freeze-dried powder injections, but the chemical stability of these two kinds of medicinal glass bottles is poor, and it is easy to appear for alkaline and acidic drugs:

The liquid medicine has a corrosive effect on the glass, and the glass is prone to peeling off;

Glass bottles contain a small amount of impurities such as magnesium and calcium, and are prone to small white spots and foggy particles. High borosilicate glass is suitable for preparations sensitive to aluminum, barium, and strontium, has strong acid and alkali resistance, and has good chemical stability.

The structure of the linkage equipment on my country’s freeze-drying production line is basically similar to that of the international ones. The international linkage equipment is exquisite in workmanship, stable in performance, reasonable in structure, and high in purification devices. The manufacturing technology of production line linkage equipment in my country has also made great progress in recent years. Equipment automation, equipment precision, and equipment operation performance have all been greatly improved. The improvement of the overall advantages of the production linkage line has higher requirements for the matching degree and overall quality of packaging glass bottles and equipment. There will be some impact on the production process.

The bottle washing process on the linkage line is to clean the packaging glass bottles with purified water and water for injection. After cleaning, the packaging material glass bottles need to check whether the insoluble particles are qualified to judge the degree of cleaning. The removal of the outer packaging of the packaging material glass bottle before washing and loading the bottle is also a key link. If the glass bottle absorbs foreign matter such as film and paper, the dust generated when passing through the tunnel oven will affect the clarity of the drug. The quality and size of the packaging material glass bottle and the matching between the packaging material and the production equipment directly affect the quality of the drug in the entire drug production process.

Packaging material glass bottles whose quality does not meet the production standards will have broken bottles and broken bottle heads during bottle washing and drying procedures, resulting in substandard drug clarity. When there is a size difference in the glass bottle of the packaging material, it will cause the phenomenon of bottle jamming and bottle inversion during the operation of the bottle conveying track of the production equipment, and the operator will interfere with the quality of the drug when troubleshooting; , The mismatch of the aluminum cap will result in poor sealing of the medicine and unqualified capping quality. In addition, the uneven quality of glass bottles will cause bottle bursting and cracking during the freeze-drying process.

Part 2 The Impact Of Rubber Stoppers On The Production Process

Rubber plugs are generally divided into natural rubber plugs and butyl rubber plugs. Natural rubber plugs are mainly made of latex, which contains 92% to 95% rubber hydrocarbons and 5% to 8% non-rubber hydrocarbons.

Natural rubber is prone to the following problems during use:

(1) Generally, the surface is not smooth, and has strong adsorption to some microorganisms, heat sources and highly polluting substances;

(2) It is not easy to rub, and it is easy to produce more insoluble particles when mechanically stirred;

(3) The chemical properties are unstable, and it is easy to react with the liquid medicine;

(4) The price of natural rubber is cheap, the production process is simple, and the preparation process will cause pollution to the atmosphere.

Butyl rubber stopper is mainly composed of isobutylene and (≤3%) isoprene polymerized at -90°C ultra-low temperature. It is the lowest gas-permeable hydrocarbon polymer material at present. Its main component is raw rubber ( Butyl rubber stoppers), vulcanizing agents, vulcanization accelerators, activators, plasticizers, fillers and colorants. Advantages and disadvantages of butyl rubber stoppers during use: Active chlorine and bromine atoms are introduced into the structure of butyl rubber stoppers to form halogenated rubber stoppers. It not only has excellent performance, but also has the advantages of reducing antioxidant pollution, stable quality, and single composition. , high safety, strong inertness and other advantages, but butyl rubber stoppers have the disadvantages of increasing production costs, high prices, and mainly relying on imports of raw materials. In view of the advantages and disadvantages of natural rubber stoppers and butyl rubber stoppers, the State Food and Drug Administration issued the “Notice on Eliminating Ordinary Natural Rubber Stoppers” in 2005, and stipulated that the use of natural rubber should be completely stopped from January 1, 2006. stuffed.

The cleaning and sterilization of packaging material butyl rubber stoppers is related to the entire pharmaceutical production process. The main purpose of cleaning and sterilization is to prevent insoluble particles from being produced during the transportation and transfer of cleaned rubber stoppers, and to achieve the effect of sterilization and heat removal. As for cleaning, the more times the better, generally it can only be cleaned once. Too many times of cleaning will cause the rubber plug to become astringent, resulting in the rubber plug not moving in the upper plug track and being pressed during the filling and plugging link of the production process. Failure to put on the plug or drop the plug, and the astringent rubber plug will also cause the plug to not be tight during the plugging process of the freeze-dried powder injection, resulting in poor air-tightness of the drug. The quality of capping is greatly reduced, seriously affecting the quality of medicines.

Some companies will add “siliconization” during the cleaning process of butyl rubber stoppers to increase the smoothness of the rubber stoppers. A small amount of silicone oil itself is harmless to the human body, but the silicone oil may fall off during the inspection, which will affect the detection of insoluble particles , Too much silicone oil will also cause plug jumping during the freeze-drying process. Some companies only carry out “siliconization” when the rubber stopper leaves the factory, and no longer carry out “siliconization” during cleaning to reduce the impact of silicone oil on the drug. In addition, the high-temperature drying time during the cleaning and sterilization process of the rubber stopper will increase the number of punctured and fallen off particles. .

Part 3 The Impact Of Aluminum-plastic Combined Caps On The Production Process

With the development of the pharmaceutical industry, pharmaceutical companies have higher and higher requirements for pharmaceutical packaging materials. The aluminum-plastic composite cover is a substitute for ordinary aluminum covers. A new type of aluminum-plastic combined cap formed together is mainly used for sealing freeze-dried powder injections, powder injections, oral liquid dosage forms, injection liquid dosage forms and other dosage forms.

The aluminum-plastic composite cap is a one-time use packaging material that does not directly contact the liquid medicine, and has the following advantages:

(1) The aluminum-plastic composite cover has strong resistance to external tension and can withstand climate change;

(2) The structure of the aluminum-plastic composite cover is simple, low in cost, good in sealing performance, and easy to twist off;

(3) The coating protects aluminum, and has the functions of strong adhesion, high temperature resistance, sanitation and environmental protection;

(4) There are various appearance forms, which can increase product identification, increase anti-counterfeiting, and reflect aesthetics.

Although the aluminum-plastic composite cap does not directly contact the liquid medicine, it is still classified as an inner packaging material in the Good Manufacturing Practice (GMP), which illustrates the importance of the aluminum-plastic composite cap for the quality of the drug. The impact of the aluminum-plastic combination cap on the quality of the drug during the production process is mainly reflected in the following aspects:

For the cleaning of aluminum-plastic combined caps, GMP does not require sterility inspection for the cleaning of aluminum-plastic combined caps, but the sterility inspection of aluminum-plastic composite caps is carried out during equipment cleaning verification;

The aluminum chips generated during the capping process will affect the quality of the drug. The 2010 version of GMP has required that the capping equipment should be equipped with a chip removal device to reduce the impact of aluminum chips;

Whether the aluminum-plastic combination cap damages the rubber stopper during the capping process will also affect the quality of the drug. Some aluminum-plastic combination caps are unreasonably designed, and the rubber stopper will be damaged during capping, which will damage the airtightness of the product and cause serious problems. affect product quality;

The degree of matching of glass bottles, rubber stoppers, and aluminum caps also has a certain correlation with the airtightness of medicines.

Part 4 Summary

To sum up, glass bottles, butyl rubber stoppers, and aluminum-plastic combination caps for freeze-dried powder injections affect all aspects of drug quality. How can we avoid these risks? First of all, we should strictly examine the qualifications of packaging material suppliers, put forward product requirements and select packaging materials suitable for the products, conduct entry inspections on purchased packaging materials, and conduct testing of packaging materials after passing the inspection to ensure that packaging materials such as glass bottles, Rubber stoppers and aluminum-plastic composite covers can adapt to the corresponding production equipment, and at the same time, the supporting packaging materials must match each other. Through the test machine, the packaging materials can meet the technical requirements of the product. In order to solve the problems, timely feedback the use requirements of packaging materials to packaging material suppliers, and carry out periodic revisions and reviews, and establish an inner loop of quality control for pharmaceutical packaging materials. Make packaging materials in a controllable state throughout the drug life cycle, and reduce the impact of packaging materials on drug quality.