JPH0252507B2 - - Google Patents

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Publication number
JPH0252507B2
JPH0252507B2 JP58220729A JP22072983A JPH0252507B2 JP H0252507 B2 JPH0252507 B2 JP H0252507B2 JP 58220729 A JP58220729 A JP 58220729A JP 22072983 A JP22072983 A JP 22072983A JP H0252507 B2 JPH0252507 B2 JP H0252507B2
Authority
JP
Japan
Prior art keywords
water
pyrogenic
bacteria
substances
membrane separation
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
JP58220729A
Other languages
Japanese (ja)
Other versions
JPS60114265A (en
Inventor
Akyoshi Kamida
Tatsuo Goto
Naotake Motoi
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Daicel Corp
Original Assignee
Daicel Chemical Industries Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Daicel Chemical Industries Ltd filed Critical Daicel Chemical Industries Ltd
Priority to JP22072983A priority Critical patent/JPS60114265A/en
Publication of JPS60114265A publication Critical patent/JPS60114265A/en
Publication of JPH0252507B2 publication Critical patent/JPH0252507B2/ja
Granted legal-status Critical Current

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  • Physical Water Treatments (AREA)

Description

【発明の詳細な説明】 本発明は医薬用および製薬工業用などで用いら
れる精製水、注射用水、輪液などの中に存在する
発熱性物質を分解して、不活性化する方法に関す
る。
DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for decomposing and inactivating pyrogens present in purified water, water for injection, ring fluid, etc. used in medicine and the pharmaceutical industry.

さらに詳しくは従来、生菌の殺菌方法の補助的
な一手段として用いられていた紫外線照射法を用
いて水または水溶液中の発熱性物質を分解または
不活性化する方法に関する。
More specifically, the present invention relates to a method of decomposing or inactivating pyrogenic substances in water or an aqueous solution using ultraviolet irradiation, which has conventionally been used as an auxiliary method for sterilizing viable bacteria.

一般に医薬、製薬用の精製水、注射用水、輪液
などは有害物質含有量などが局方で厳しく規定さ
れており、これを除去するための各種の方法が用
いられている。
In general, pharmaceuticals, purified water for pharmaceutical use, water for injection, ring fluid, etc., have strict regulations regarding the amount of harmful substances they contain, and various methods are used to remove these substances.

これらの有害物質の中で完全な除去法が難しい
ことなどで特に問題となつているのは細菌類およ
び発熱性物質と称されているものである。その中
でも細菌類は完全にゼロにしない限りは増植する
ものであり、発熱性物質の主なものは生菌、死
菌、菌の代謝物など細菌に由来するものが多い。
細菌の中でも特にグラム陰性菌に由来する内毒素
が最も代表的な発熱性物質として知られている。
Among these harmful substances, bacteria and pyrogens are particularly problematic because it is difficult to completely remove them. Among them, bacteria will continue to grow unless they are completely eliminated, and the main pyrogens are derived from bacteria, such as live bacteria, dead bacteria, and bacterial metabolites.
Among bacteria, endotoxins derived from Gram-negative bacteria are known as the most typical pyrogenic substances.

したがつて水または輸液などを無菌にするとい
うことは発熱性物質を増加させない方法の一つに
はなる。しかしながら除去または不活性化するこ
とにはならない。
Therefore, making water or infusions sterile is one way to prevent the increase in pyrogenic substances. However, it does not result in removal or inactivation.

この細菌、なかでも特に生菌を殺菌する方法と
しては対象物の形状にもよるが、加熱法、薬剤に
よる殺滅菌法、γ線照射法などが用いられてき
た。対象物が注射用水の場合には蒸留法によるこ
とが局方でも定められており広く用いられている
が、紫外線照射よる殺菌は補助的な手段として用
いられてきたに過ぎない。
Methods for sterilizing these bacteria, especially viable bacteria, have been methods such as heating, sterilization using chemicals, and gamma ray irradiation, depending on the shape of the object. When the target substance is water for injection, the distillation method is stipulated in the Japanese Pharmacopoeia and is widely used, but sterilization by ultraviolet irradiation has only been used as an auxiliary method.

一方熱や薬品に対して安定で、局方に規定され
ている蒸気滅菌によつても分解しない発熱性物質
を除去する方法としては蒸留法とともに最近では
限外過法や逆浸透法などのような半透膜を用い
た膜分離法が注目されてきている。
On the other hand, methods for removing pyrogenic substances that are stable against heat and chemicals and do not decompose even with steam sterilization as prescribed in the pharmacopoeia include distillation, as well as ultrafiltration and reverse osmosis. Membrane separation methods using semipermeable membranes have been attracting attention.

この膜分離法を使用すれば発熱性物質とともに
生菌、死菌なども蒸留法と同じ程度まで同時に除
去することが可能で、局方規定の試験にも充分合
格することがその普及のスピードからも一般に認
められてきていることが明らかである。
Using this membrane separation method, it is possible to simultaneously remove pyrogenic substances as well as live and dead bacteria to the same extent as the distillation method, and due to the speed with which it has become popular, it has been shown to be able to fully pass the pharmacopoeia-regulated tests. It is clear that this is also becoming generally accepted.

ところで、この発熱性物質試験法として局方に
規定されているうさぎを使用する方法は言わば定
性的な試験法であり、また時間とコストのかかる
方法であるため、それに代る定量的な方法として
リムラステストと称される試験法が既に広く普及
してきており、特に最近ではリムラステストの中
でも比色法が開発され、高感度で、しかも判定の
客観性においても優れていることが注目されてい
る。
By the way, the method using rabbits, which is prescribed in the Japanese Pharmacopoeia as a pyrogenic substance test method, is a qualitative test method and is time-consuming and costly, so it is recommended to use a quantitative method instead. A test method called the limulus test has already been widely used, and recently, a colorimetric method has been developed among the limulus tests, and it has attracted attention for its high sensitivity and excellent objectivity of judgment.

リムラステストの感度は一般に局方に規定され
ている発熱性物質試験法の10〜100倍と言われて
いるため逆に新たな問題がクローズアツプされて
きた。
The sensitivity of the Limulus test is generally said to be 10 to 100 times that of the pyrogenic substance test method specified in the pharmacopoeia, and new problems have been brought to the fore.

それは従来、局方で規定された試験法で合格と
判定されていた場合でも高感度なリムラステスト
によるとかなりの量の発熱性物質が検出されるこ
とがわかつてきたことである。
The reason for this is that it has become clear that even if a drug has been judged to pass by the conventional pharmacopoeia-specified test method, a considerable amount of pyrogenic substances can be detected by the highly sensitive Limulus test.

これは蒸留法、膜分離法のどちらの方法で調整
されたものでも同じ程度であり、例えば原水とし
て1〜10ng/mlの発熱性物質を含有するイオン
交換水を処理した場合、発熱性物質濃度で0.01〜
0.1ng/ml(ng/ml=10-9g/ml)程度は検出
されるのが一般的である。
This is the same whether it is prepared by distillation or membrane separation. For example, when ion-exchanged water containing 1 to 10 ng/ml of pyrogenic substances is treated as raw water, the pyrogenic substance concentration is from 0.01
It is generally detected at around 0.1 ng/ml (ng/ml = 10 -9 g/ml).

このリムラステストと局方に規定されているテ
ストとの相関性についてはリムラステストで0.2n
g/ml以下であれば局方に規定されている方法で
も陰性になると言われている。
Regarding the correlation between this Limulus test and the test prescribed by the pharmacopoeia, the Limulus test has a correlation of 0.2n.
It is said that if it is less than g/ml, it will be negative even by the method specified in the pharmacopoeia.

したがつて、このように局方の規定では合格す
る程度であつてもリムラステストで定量的に検出
されるわづかな量の発熱性物質を除去するための
努力が医薬品に関するGMP令の施行とともにな
されるようになつてきた。
Therefore, efforts are being made to eliminate the small amount of pyrogenic substances that are quantitatively detected by the Limulus test, even if they pass the pharmacopeia regulations, along with the enforcement of the GMP ordinance regarding pharmaceuticals. It's starting to feel like this.

例えば膜分離法と蒸留法との組合せシステム、
膜分離法、蒸留法を夫々2段システムで使用する
方法などがその代表的な例である。
For example, a combination system of membrane separation method and distillation method,
Typical examples include a method using a membrane separation method and a distillation method in a two-stage system.

しかしながらこれらの方法はシステムが複雑
で、設備コストランニングコストとも莫大なもの
となり、実用的ではない。
However, these methods are not practical because the systems are complicated and the equipment costs and running costs are enormous.

そこで本発明者なら鋭意検討した結果、簡単な
システムで、且つ、安価に、より高品質の注射用
水、輸液などを製造することができる方法を発見
し、本発明を完成させるに至つた。
As a result of intensive study, the inventors of the present invention have discovered a method of producing higher quality water for injection, infusions, etc. using a simple system and at low cost, and have completed the present invention.

次に本発明の構成を詳しく説明する。 Next, the configuration of the present invention will be explained in detail.

本発明は従来から生菌の殺菌法として広範囲に
使用されてきた紫外線殺菌器を発熱性物質の分解
または不活性化のために使用することである。
The present invention uses an ultraviolet sterilizer, which has been widely used as a method of sterilizing viable bacteria, for decomposing or inactivating pyrogenic substances.

従来、紫外線殺菌器は生菌を殺菌する方法とし
て液体または気体物質に適用されており、それな
りの有効性は認められていたが、これだけでは不
完全であり、先に述べた膜分離法などを後段に組
合せて使用されるケースが多かつた。
Conventionally, ultraviolet sterilizers have been applied to liquid or gaseous substances as a method of sterilizing living bacteria, and although they have been recognized to be somewhat effective, this alone is insufficient, and methods such as the membrane separation method mentioned earlier have been used. There were many cases where it was used in combination with the latter stage.

その理由は紫外線殺菌器は明らかに生菌に対す
る殺菌力は非常に優れており、条件次第では完全
無菌を達成することができるが、殺菌によつて生
じた死菌および菌の代謝物などを除去することが
できないので、これらが発熱性物質として残存
し、これを除去するための手段として膜分離法を
使用するという考え方が一般的な常識であつた。
The reason for this is that ultraviolet sterilizers obviously have very good sterilizing power against living bacteria, and depending on the conditions, they can achieve complete sterilization, but they also remove dead bacteria and bacterial metabolites produced by sterilization. Therefore, it was common knowledge that these remained as pyrogenic substances, and that membrane separation was used as a means to remove them.

また紫外線殺菌器の生菌に対する殺菌効果は認
められていたものの、発熱性物質に対しては全く
効果がないものと考えられていた(中外医学社発
行、玉熊正悦、石山賢共著「エンドトキシンシヨ
ツク」、頁26など参照)。したがつて紫外線殺菌器
を発熱性物質の分解または不活性化のために使用
するということは言わば当業者間でも盲点となつ
ていた。
Furthermore, although it was recognized that ultraviolet sterilizers had a sterilizing effect on viable bacteria, they were thought to be completely ineffective against pyrogens ("Endotoxin Shock", published by Chugai Igakusha, co-authored by Masayoshi Tamakuma and Ken Ishiyama). ”, p. 26, etc.). Therefore, the use of ultraviolet sterilizers to decompose or inactivate pyrogenic substances has been a blind spot, so to speak, even among those skilled in the art.

しかしながら、本発明者らは適用する対象液中
の発熱性物質の濃度および紫外線強度次第では紫
外線照射法だけでも発熱性物質を分解または不活
性化することができることを見出し、本発明に到
達した。
However, the present inventors have discovered that depending on the concentration of the pyrogenic substance in the applied target liquid and the intensity of the ultraviolet rays, it is possible to decompose or inactivate the pyrogenic substance by ultraviolet irradiation alone, and have arrived at the present invention.

本発明の方法は紫外線照射法単独でも有効であ
るが、蒸留装置や膜分離装置で処理して局方に定
められた規定では合格するが、高感度なリムラス
テストで検出されるような比較的低濃度の発熱性
物質を含む液に対して適用するのが特に有効であ
る。発熱性物質含有量が比較的少い場合は紫外線
照射を前段にしても、単独で使用してもよい。ま
た蒸留装置や膜分離装置に供給する原水はイオン
交換水、井戸水、水道水などいづれでも良い。
Although the method of the present invention is effective with ultraviolet irradiation alone, it passes the pharmacopoeia regulations when treated with a distillation device or membrane separation device, but the relatively low It is particularly effective to apply to liquids containing high concentrations of pyrogenic substances. If the content of the pyrogenic substance is relatively small, ultraviolet irradiation may be used as a first step or may be used alone. The raw water supplied to the distillation device or membrane separation device may be ion-exchanged water, well water, tap water, or the like.

このように本発明の方法を蒸留装置または膜分
離装置と組み合わせて使用するときのもう一つの
利点は蒸留装置と膜分離装置との組合せ、または
それぞれの装置の2段組合せなどでは供給した原
液量に対して2段目で得られる発性熱物質を除去
した液の回収率が80〜90%であるのに対して殆ん
ど100%に近いことである。また一旦溶液にして
しまつた輸液などの場合は蒸留装置を使用するこ
とができず、また膜分離装置の場合は発熱性物質
は除去されても組成が変わることも起こり得る。
Another advantage when using the method of the present invention in combination with a distillation device or a membrane separation device is that the amount of raw liquid supplied is In contrast, the recovery rate of the liquid obtained in the second stage from which exothermic substances have been removed is 80 to 90%, whereas it is almost 100%. Further, in the case of an infusion that has been made into a solution, a distillation device cannot be used, and in the case of a membrane separation device, even if the pyrogen is removed, the composition may change.

それに対して紫外線照射による方法であれば循
環するだけで組成の変化を起こさずに発熱性物質
を分解または不活性化することができる。
On the other hand, if the method uses ultraviolet irradiation, the exothermic substance can be decomposed or inactivated by simply circulating it without causing any change in composition.

また本発明のように発熱性物質の分解または不
活性化のために紫外線照射法を用いれば、従来蒸
留装置や膜分離装置で一旦発熱性物質を除去した
水を80℃以上の加熱をすることなしにタンク中に
貯留することは良くないとされていた考え方も覆
えすことができる。即ち上記装置で一旦処理した
水をタンク中に加熱せずに貯留しておき、循環回
路中で紫外線を照射しておけば菌の増殖を防止で
きるとともに発熱性物質を分解または不活性化す
ることが可能である。したがつて従来の夜間また
は休日中の運転管理に関する問題を解決すること
ができる。
Furthermore, if ultraviolet irradiation is used to decompose or inactivate pyrogens as in the present invention, water from which pyrogens have been removed using conventional distillation equipment or membrane separation equipment can be heated to 80°C or higher. This can also overturn the idea that it was bad to store water in tanks without water. In other words, by storing the water that has been treated with the above device in a tank without heating it and irradiating it with ultraviolet rays in the circulation circuit, it is possible to prevent the growth of bacteria and to decompose or inactivate pyrogenic substances. is possible. Therefore, problems related to conventional operation management during nighttime or holidays can be solved.

次に本発明の効果を実施例に基いて説明する。 Next, the effects of the present invention will be explained based on examples.

実施例 1 原水:市水を陽イオン交換樹脂塔と陰イオン交換
樹脂塔に通水して得た電気電導度μ(m)/cmのイ
オン交換水 水温:20℃ 発熱性物質分析法:(比色法リムラステスト法=
パイロデイツク法により分析) 原水発熱性物質濃度:2ng/ml 原水供給量:250/時間 紫外線照射量:250/時間 紫外線発生器出力:14.6ワツト 紫外線照射水の発熱性物質濃度:0.2ng/ml 実施例 2 実施例1における原水を外過膜処理した水を
原水とした以外は実施例1と同様に行ない以下の
結果を得た。
Example 1 Raw water: Ion exchange water with electrical conductivity μ(m)/cm obtained by passing city water through a cation exchange resin tower and an anion exchange resin tower Water temperature: 20°C Pyrogen analysis method: ( Colorimetric method Limulus test method=
Analyzed by pyrodic method) Raw water pyrogenic substance concentration: 2ng/ml Raw water supply amount: 250/hour UV irradiation amount: 250/hour UV generator output: 14.6 Watts Pyrogenic substance concentration of ultraviolet irradiated water: 0.2ng/ml Example 2 The following results were obtained in the same manner as in Example 1, except that the raw water in Example 1 was treated with an outer filtration membrane.

限外過膜処理水の発熱性物質濃度:0.1ng/
ml 限外過膜処理水に紫外線照射した水の発熱性
物質濃度:0.02ng/ml 実施例 3 Difco社製リポポリサツカライドE.Coli0127B
−8を10ng/mlの濃度になるように調整したブ
ドウ糖10%水溶液を50作成し、実施例1と同じ
紫外線照射量の下で液温を20℃に保ちながらポン
プによる循環運転を行ない、各経過時間毎の発熱
性物質濃度を測定し、得られた結果を図1に示し
た。図1において横軸は経過時間(時間)、縦軸
はパイロデイツク法により測定した発熱性物質の
濃度(ng/ml)、1−1は本実施例3、2−2
は次記比較例1の結果である。
Pyrogenic substance concentration in ultrafiltration membrane treated water: 0.1ng/
ml Concentration of pyrogenic substances in ultrafiltration membrane-treated water irradiated with ultraviolet light: 0.02 ng/ml Example 3 Lipopolysaccharide E.Coli0127B manufactured by Difco
-8 was adjusted to a concentration of 10 ng/ml to prepare 50 10% aqueous glucose solutions, and under the same amount of ultraviolet irradiation as in Example 1, a pump was used to circulate the solution while keeping the liquid temperature at 20°C. The pyrogenic substance concentration was measured at each elapsed time, and the obtained results are shown in FIG. In Figure 1, the horizontal axis is the elapsed time (hours), the vertical axis is the concentration of pyrogenic substances (ng/ml) measured by the pyrodic method, and 1-1 is the present Example 3, 2-2
are the results of Comparative Example 1 below.

比較例 1 紫外線照射を行なわずに、実施例3と同様に行
ない、得られた結果を図−1に併記した。
Comparative Example 1 The same procedure as in Example 3 was carried out without UV irradiation, and the obtained results are also shown in Figure 1.

【図面の簡単な説明】[Brief explanation of drawings]

第1図は実施例3および比較例1のテスト結果
で、縦軸は発熱性物質濃度、横軸は運転経過時間
である。
FIG. 1 shows the test results of Example 3 and Comparative Example 1, where the vertical axis is the pyrogen concentration and the horizontal axis is the elapsed operation time.

Claims (1)

【特許請求の範囲】 1 比色法リムラステストによる発熱性物質の含
有量が10ng/ml以下の液体に紫外線を照射する
ことにより比色法リムラステストによる発熱性物
質の含有量を0.2ng/ml以下にすることを特徴と
する発熱性物質不活性化方法。 2 発熱性物質含有液が限外濾過処理した水であ
る特許請求の範囲第1項記載の方法。 3 発熱性物質含有液がブドウ糖水溶液である特
許請求の範囲第1項記載の方法。
[Claims] 1. By irradiating ultraviolet light to a liquid whose pyrogenic substance content is 10 ng/ml or less as determined by the colorimetric limulus test, the content of the pyrogenic substance as determined by the colorimetric limulus test is reduced to 0.2 ng/ml or less. A pyrogenic substance inactivation method characterized by: 2. The method according to claim 1, wherein the pyrogen-containing liquid is ultrafiltered water. 3. The method according to claim 1, wherein the pyrogen-containing liquid is an aqueous glucose solution.
JP22072983A 1983-11-25 1983-11-25 Inactivation of heat generating substance Granted JPS60114265A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP22072983A JPS60114265A (en) 1983-11-25 1983-11-25 Inactivation of heat generating substance

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
JP22072983A JPS60114265A (en) 1983-11-25 1983-11-25 Inactivation of heat generating substance

Publications (2)

Publication Number Publication Date
JPS60114265A JPS60114265A (en) 1985-06-20
JPH0252507B2 true JPH0252507B2 (en) 1990-11-13

Family

ID=16755604

Family Applications (1)

Application Number Title Priority Date Filing Date
JP22072983A Granted JPS60114265A (en) 1983-11-25 1983-11-25 Inactivation of heat generating substance

Country Status (1)

Country Link
JP (1) JPS60114265A (en)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB8807380D0 (en) * 1988-03-29 1988-05-05 Gunn A Blood processing apparatus
JP7184683B2 (en) * 2019-03-18 2022-12-06 ウシオ電機株式会社 Decontamination method

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5364948A (en) * 1976-11-24 1978-06-09 Kurita Water Ind Ltd Method of producing refined water not containing heat generating substance
JPS55132603A (en) * 1979-04-04 1980-10-15 Kuraray Co Ltd Purifying method of water for dialysis
JPS56141811A (en) * 1980-04-03 1981-11-05 Asahi Chem Ind Co Ltd Ultrafiltration method
JPS57147405A (en) * 1981-03-10 1982-09-11 Nikkiso Co Ltd Method for treating water by reverse osmotic membrane

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5364948A (en) * 1976-11-24 1978-06-09 Kurita Water Ind Ltd Method of producing refined water not containing heat generating substance
JPS55132603A (en) * 1979-04-04 1980-10-15 Kuraray Co Ltd Purifying method of water for dialysis
JPS56141811A (en) * 1980-04-03 1981-11-05 Asahi Chem Ind Co Ltd Ultrafiltration method
JPS57147405A (en) * 1981-03-10 1982-09-11 Nikkiso Co Ltd Method for treating water by reverse osmotic membrane

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