著者

三川 正明

出版者

一般社団法人日本PDA製薬学会

雑誌

日本PDA学術誌 GMPとバリデーション (ISSN:13444891)

巻号頁・発行日

vol.2, no.2, pp.93-98, 2000 (Released:2006-07-29)

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GMP for imported drugs (GMPI) has been issued in June and effective from August 1st in the last year. One of the most noteworthy issues is that the quality agreement with the foreign manufacturer has become a legal requirement. It is increasing to use the Third Party Manufacturer (TPM), in order to reduce business risks and total lifetime costs. All new TPM shall be assessed for GMP conformance and monitored for QA performance, in order to guarantee the product quality to be supplied. Quality agreement should be made as a part of business agreement, so that to guarantee the manufacturer's GMP conformance and mutual quality assurance on the product. As a sound business, the products and components or materials should be purchased from certified manufacturers and/or suppliers at the lowest life cycle cost. The lowest unit cost is not always necessary. The supplier should be reliable on their quality system, capable in supplying enough amount at the right time. Sound procurement system and TPM management will be required to assure the product quality and maintain a good supply chain. Quality agreement and continuous assessment on GMP compliance and QA performance of the manufacturers and/or suppliers should be a critical part of the procurement system and TPM management in the pharmaceutical companies.

著者

志村 靖二 李 仁義

出版者

一般社団法人日本PDA製薬学会

雑誌

日本PDA学術誌 GMPとバリデーション (ISSN:13444891)

巻号頁・発行日

vol.2, no.2, pp.81-91, 2000 (Released:2006-07-29)

参考文献数

10

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For both liquid and gas filters in aseptic processing, it has been stressed on the importance of integrity confirmation in site, before and after filtration. With newly developed water intrusion test (WI), only using water and gas, it is convenient to perform the test for hydrophobic air filters in site. In order to establish the WI procedure in site, here we pointed out on the followings: influential factors for WI results, test procedure, points to consider WI in site, and the case study with vacuum break filters of freeze dryer, especially installed in machine room. With regard to the influential factors for WI results, the changes in the temperature of test fluid and environment, test gas and water, and their introduction, filter cleanliness, filter types and size, air leakage in the upstream, test instrument and the stabilization time during the test etc. were described. According to WI, it is simple and different from the other kinds of test methods, especially on the wetting and drying procedure. Finally, from the test results using vacuum break filter installed in the machine room, it was convinced the importance of the temperature control between water and environment. In addition, in order to obtain high reproducible test results, and to do the effective trouble-shooting, it is important to be understood the influential factors and preliminary checking procedure, by the operators.

著者

鷲見 昭典 奥山 孝三 小林 薫 大谷 渡 大村 孝男

出版者

一般社団法人日本PDA製薬学会

雑誌

日本PDA学術誌 GMPとバリデーション (ISSN:13444891)

巻号頁・発行日

vol.2, no.1, pp.28-33, 2000 (Released:2006-08-01)

参考文献数

7

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Two major problems are expected to arise in the future in connection with plasma proteins. The first problem is the lack of source materials. The second problem is the risk of transmission of viral disease such as hepatitis, HIV or other yet-to-be identified viruses. Genetic engineering is the best approach to solve these problems. Plasma derived human serum albumin (pHSA) is one of the most useful plasma proteins. However, producing recombinant human serum albumin (rHSA) commercially via genetic engineering is not entirely straightforward. Two hurdles must be cleared in order to develop rHSA. One is cost and the other is quality. Albumin is typically administered in tens of gram quantities. At a purity level of 99.999% (a level considered sufficient for other recombinant protein preparations such as vaccine and cytokine), rHSA impurities on the order of one mg will still be injected into patients. So impurities from the host organism, in this case yeast, must be reduced to a minimum. Furthermore, purified rHSA must be identical to pHSA. Despite these stringent requirements, cost must be kept in check. One gram of pHSA costs a few dollars. Our goal is to produce rHSA at least as economically as pHSA. Thus to rein in rHSA costs, maximum quantities of albumin must be produced from minimum volumes of culture, and highly efficient, high-yield purification methods are required. Because of these special issues about rHSA development, purification methods were designed under conception described below. 1. Easy automatic control, 2. Easy scale up, 3. Use of no special materials, 4. Use of no complicated methods. The item No.1 is necessary for cost cutting and uniformity of quality. The item No. 2 is essential by the reason mentioned below. In the first stage of rHSA development, we examined purification methods based on 3 to 10 l fermentation scale. In the next stage of rHSA development, we confirmed and optimized purification methods established at the first stage using 1000 l fermentation scale. The final stage of rHSA development is commercial scale. We have the plan of fermentation scale being 50 m3. The purification methods of rHSA must be identical throughout these three stages. Easy scale up is a very important factor for process development. Column chromatography is the best approach to solve these problems. So we used a lot of column chromatography techniques in rHSA purification. The items No.3 and No.4 are necessary for the reason mentioned below. Affinity chromatography is usually a very efficient method. But in the case of rHSA, affinity chromatography is not efficient considering cost and capacity. Furthermore, gradient elution is a very efficient method for small size chromatography, but in rHSA purification, chromatography column is very large. Gel packing into large columns is much more difficult than in small ones, and also, chromatography patterns in large columns are often different from those of small ones. In other words, though impurities can be separated in small scale, separation efficiency becomes very low in large scale and thus the results of chromatography is different between large and small scales. Because of the reasons mentioned above, the media used in our process are very popular ones such as ion exchange, hydrophobic and gel filtration. The methods of chromatography we used are very simple, i.e., rHSA is adsorbed on the media, impurities are washed out, and then rHSA is eluted at a stretch. Or contrariwise, rHSA is flowed through the media while the impurities are adsorbed. In this way, scale up of chromatography is very simple. Same bed height and same linear flow give same results independent of gel volume.

著者

鈴木 治 井上 幹夫

出版者

一般社団法人日本PDA製薬学会

雑誌

日本PDA学術誌 GMPとバリデーション (ISSN:13444891)

巻号頁・発行日

vol.2, no.1, pp.34-39, 2000 (Released:2006-08-01)

参考文献数

9

被引用文献数

1

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The previous study has shown that stainless steel surfaces on piping could greatly be subject to rouging during the operation of high-purity water systems (Suzuki O et al.: Pharm Tech 22: 66-82, 1998). The follow-up study has hereupon been carried on to fed out what will potentially develop into such rouging on stainless steel, because the fouling-like rouging has always been an anxious matter to pharmaceutical engineers. The name of rouging is now given to a corrosive discoloration developed with various contaminants in the high-purity water treatment process, which will also occur in WFI (Water for Injection) systems or pure steam generators. Stainless steel elbow-piping sections, which surfaces were finished at such a high mill finish as mechanical polish and electropolish, were exposed to pure steam generated at 2 kg/cm2-g. The steam was also fed into the near-horizontal piping section not stagnant with distillate and the intentionally arranged section stagnant with distillate for 30 days. The inner surface after pure steam fed was visually inspected and analyzed by a physical technique of Auger electron spectroscopy so that rouging discoloration was detected to be mostly due to its surface oxidization of stainless steel. The oxidization is divided into two groups: namely, (1) reddish discoloration results from the vapor attack, and (2) blackish discoloration comes from long contact with condensate on stainless steel surfaces. The latter discoloration is further divided into two types in the chemical respect; namely, with carbon and without carbon. Although these kinds of discoloration may provide no deterioration for water quality because of very low solubility of metal oxides, a further study of this rouging mechanism should be made to acquire clear grounds for the final conclusion.

著者

谷野 忠嗣 青木 義広 吉田 達守 鷲見 裕 水田 泰一

出版者

一般社団法人日本PDA製薬学会

雑誌

日本PDA学術誌 GMPとバリデーション (ISSN:13444891)

巻号頁・発行日

vol.2, no.1, pp.19-27, 2000 (Released:2006-08-01)

参考文献数

8

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Fluidized-bed granulation has many operational parameters to be optimized in comparison with other simple wet granulation such as kneading or agitating. In addition, these parameters are not independent of each other: a change in one parameter often influences other parameters. Therefore, difficulties are sometime experienced with scale-up study of fluidized-bed granulation. It is a fact, however, that this granulation method has considerable merits to prepare highly compressible granules which can prevent capping incidents. It is experimentally known that tablets prepared by fluidized-bed granulation have usually higher hardness than those prepared by any other granulation methods. In this study, the authors discussed a scale-up and granule size control strategy on fluidized-bed granulation focusing on the moisture in granulation.

出版者

一般社団法人日本PDA製薬学会

雑誌

日本PDA学術誌 GMPとバリデーション (ISSN:13444891)

巻号頁・発行日

vol.1, no.2, pp.110-117, 1999 (Released:2006-08-03)

著者

町原 英 白旗 慎吾

出版者

一般社団法人日本PDA製薬学会

雑誌

日本PDA学術誌 GMPとバリデーション (ISSN:13444891)

巻号頁・発行日

vol.1, no.2, pp.77-81, 1999 (Released:2006-08-03)

参考文献数

4

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100% inspection can not completely eliminate all of defect qualities from the lot, because of the limitation of detection rate. Three models of 100% inspection methods, which have different stopping rules, have been statistically compared by taking the detection rate into consideration. The three models of inspection methods are defined as follows. (A) Stop when we detect no defects for the first time. (B) Stop when we detect no defects for the second time. (C) Stop when we meet the first successive two no-detections of defects. It is found that, in view of the average number of total insepction times, the rule A is the best whereas in view of the average number of undetected defects the rule C is the best. The rule B stands between the rules A and C and is close to rule C. If we also consider the costs of inspection and undefected defects, the rule B is robust and when the probability to detect the defects is high then the rule A is excellent. The rule C is found to be too conservative.

出版者

一般社団法人日本PDA製薬学会

雑誌

日本PDA学術誌 GMPとバリデーション (ISSN:13444891)

巻号頁・発行日

vol.1, no.2, pp.97-109, 1999 (Released:2006-08-03)

著者

稲津 邦平

出版者

Parenteral Drug Association Japan Chapter

雑誌

日本PDA学術誌 GMPとバリデーション (ISSN:13444891)

巻号頁・発行日

vol.1, no.2, pp.95-96, 1999 (Released:2006-08-03)

著者

田中 喜久夫

出版者

一般社団法人日本PDA製薬学会

雑誌

日本PDA学術誌 GMPとバリデーション (ISSN:13444891)

巻号頁・発行日

vol.1, no.2, pp.83-93, 1999 (Released:2006-08-03)

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Shizuoka Prefecture is the second largest prefecture of pharmaceutical production on the valve basis in Japan. Guidance Office of Pharmaceutical Affairs, Department of Health and Welfare has various functions such as inspection guidance and training program for industries. Concerning the GMP issues, there are two groups of field inspection consisting of 2 inspectors each in Shizuoka Prefectural Government. They spent 175 days in a year for field inspections as a rule. There are 59 pharmaceutical manufacturing facilities to which GMP is applied in Shizuoka Prefecture, among which 18 facilities are for manufacturing sterile products, 18 facilities are for manufacturing active pharmaceutical ingredients only, and other manufacturing facilities are for other dosage forms such as solid dosage form and external use. In the year of 1998, 266 cases were observed as objectionable, although some of which were minor ones or only recommendations. Among these 266 observations, 246 (92.5%) were concerning manufacturing control and management including the implementation of validation, and 19 were concerning equipments and construction features. These observations have been analyzed in details to show in what parts of GMP were week and should be improved hereafter. Followings are major parts which were observed as to be improved; (1) responsible persons should perform their job by themselves, (2) keen attention should be paid to the consistency among SOP, actual practice and manufacturing records, (3) change and/or omission of the written procedure should be performed only after official authorized approval, of the written procedure, (4) deficiencies were observed in lack of such records as cleaning, calibration, comparison between the standard yield and actual yield, trend analysis of % of rejected product by process inspection, and storage of raw data, (5) retest rule should be established in every case, (6) some deviations were observed in storage condition of products, raw materials and reference standards for laboratory test use, (7) complaint handling procedure and training procedure should be more clearly established to facilitate and secure the practice, (8) some inadequacies were observed in operation room condition, preparation vessel, and laboratory equipments.

著者

Kazuya YOSHIDA S.L. IRISHI J. A. BOOSE

出版者

Parenteral Drug Association Japan Chapter

雑誌

日本PDA学術誌 GMPとバリデーション (ISSN:13444891)

巻号頁・発行日

vol.1, no.2, pp.71-76, 1999 (Released:2006-08-03)

参考文献数

7

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Viral spiking studies were used to validate the capacity of our manufacturing process of a biological product derived from animal origin to inactivate or eliminate potential viral contaminants. Since the present study was intended for early Phase I & II clinical trials, two model viruses, Xenotropic Murine Leukemia Virus and polio virus, type 1, which represent a range of physical, chemical, and biological properties were selected for examination. It is generally recommended to take at least two different viral inactivation removed procedures for the robustness of the manufacturing process. We therefore selected a heat treatment and an ethanol purification step, two steps which held the potential for inactivation through independent mechanisms (i.e., physical and chemical inactivation, respectively). Finally, with the design of the experiment taken into consideration, the manufacturing steps were scaled-down and validated. Further, based upon the data collected during validation, the step parameters used for the present study were considered worst-cases. The result of the present spiking study for the two steps was a combined reduction of > 11 logs for polio virus and > 8 logs for X-MuLV which was the maximum attainable clearance given the spiking titer and dilution level for both viruses and both manufacturing steps.

著者

井上 冨士夫 樫山 薫明 泉 雅満

出版者

一般社団法人日本PDA製薬学会

雑誌

日本PDA学術誌 GMPとバリデーション (ISSN:13444891)

巻号頁・発行日

vol.1, no.1, pp.37-43, 1999 (Released:2006-08-04)

参考文献数

13

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A novel dual-chamber Bag (O-IN-Bag) was designed using a film which is a blend of polyethylene and polypropylene. The Bag is divided into by welding two chambers by an easy-to-peel seal (EPS). The upper chamber is filled with an injectable powder or lyophilized drug and the lower chamber is filled with 100 ml of diluent such as 0.9% sodium chloride. In the present report, we describe the characteristics of this O-IN-Bag product. The generation of particulate matter at the breakage of the EPS, stability of cefazolin sodium (CEZ), strength of the Bag container, and sterility of the inside of the container were studied. The results were compared with those of a conventional injectable system wherein antibiotics in glass vials are reconstituted with diluent using a double-ended transfer needle or a syringe. Reportedly, the O-IN-Bag system significantly reduces the time required to reconstitute drugs and storage space, and is easy to dispose. The system could retain the sterility and stability of its contents, and generated less particulate matter than the conventional system. In addition, the Bag proved physically strong enough as a container.

著者

小嶋 茂雄

出版者

一般社団法人日本PDA製薬学会

雑誌

日本PDA学術誌 GMPとバリデーション (ISSN:13444891)

巻号頁・発行日

vol.1, no.1, pp.18-35, 1999 (Released:2006-08-04)

参考文献数

5

被引用文献数

1

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Harmonization of requirements for the regulation of drugs in the world is essential in order to make newly developed pharmaceuticals available all over the world as quickly as possible. For such purpose, ICH (International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use) has been organized and actively promoted by 6 parties from three regions (Japan: MHW & JPMA, USA: FAD & PhRMA, EU: CPMP & EFPIA). Quality topics on “Stability Testing, ” “Validation of Analytical Procedures” and “Impurities Testing” has already been finalized among three regions and implemented as the domestic guidelines by the regulatory authority of each member country. Other quality topics on “Specifications,” “GMP on Active Pharmaceutical Ingredients” and “Common Technical Documents” are now under discussion in ICH. In Japan, Revision of General Notices in Japanese Pharmacopoeia is proposed to cope with the concepts of “periodical/skip testing, ” in-process testing” and “parametric release” included in the Step 2 Draft of ICH Speicification Guideline. This article describes the concepts of ICH quality guidelines and their impacts on the regulation for drugs in Japan.

著者

高木 和則

出版者

一般社団法人日本PDA製薬学会

雑誌

日本PDA学術誌 GMPとバリデーション (ISSN:13444891)

巻号頁・発行日

vol.13, no.1, pp.35-39, 2011 (Released:2011-11-25)

著者

日本 PDA 製薬学会 無菌製品 GMP 委員会

出版者

一般社団法人日本PDA製薬学会

雑誌

日本PDA学術誌 GMPとバリデーション (ISSN:13444891)

巻号頁・発行日

vol.17, no.2, pp.151-155, 2015 (Released:2016-01-16)

参考文献数

10

著者

Henderson Jr. John W. Long William J.

出版者

一般社団法人日本PDA製薬学会

雑誌

日本PDA学術誌 GMPとバリデーション (ISSN:13444891)

巻号頁・発行日

vol.9, no.2, pp.90-95, 2007

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窒素を含有する数種の心臓病治療薬について,ZORBAX Rapid Resolution (RR) 3.5 μm カラムと,Rapid resolution HT (RRHT) 1.8 μm カラムで,分離検討を行いました。分析メソッド開発の上で重要なポイントは分析時間,分離,感度ですが,RR カラム,RRHT カラムを使用してメソッド開発することで,これら 3 項目について最も満足できるメソッドを,素早く構築することができます。このアプリケーションノートでは,RR カラムと RRHT カラムを使い,分析時間,分離,感度の比較を行いました。更に,3 項目で最善の結果が得られた条件について,カラム温度を変更して分析することで,分離がシビアな成分の選択性の変更,分離の改善が行えるかを検討しました。<br>

著者

日本 PDA 製薬学会技術教育委員会 小島 威 須賀 尚 綱島 大介 橋本 葭人 檜山 行雄 前田 仁 2009-2011 日本 PDA 製薬学会 技術教育委員会メンバー 上田 龍 榎本 将雄 奥村 剛宏 柿木 宏一 鎌田 謙次 紀井 良明 黒田 弘文

出版者

一般社団法人日本PDA製薬学会

雑誌

日本PDA学術誌 GMPとバリデーション (ISSN:13444891)

巻号頁・発行日

vol.18, no.1, pp.1-24, 2016

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QbD¹⁾開発を経ていない医薬品を ICH²⁾ビジョンに基づき各社のシステムに取り込むためには,それぞれの製品に QbD による製品・工程理解が必要となる。そのためには,利害関係者間での必要性の共通認識,会社内の連携,経営資源の配分など運営的な課題と具体的な手法の提示,薬事手続きに関する不安という課題がある。これらの課題に取り組み,既存品の置かれている現状解析から,品質・生産におけるリスクのみならず,行政動向を踏まえると薬事的なリスクも抱えることとなることを指摘し,既存品に対する QbD 適用の必要性を考察した。上市後 16 年経過した経口錠剤の溶出性低下をトリガーとした QbD 適用事例を示した。この事例は開発情報・実生産情報を基にした CQA³⁾確認,データマイニング⁴⁾,追加実験,改善検討,管理戦略の再構築という流れになっている。続いて,変更管理の全体的流れを整理した上で,前出の事例をもとに複数の管理戦略選択肢を上げ,それぞれに対する薬事手続きを考察した。さらに,既存薬に Q8⁵⁾適用する場合の社内体制とデータの扱いを検討した。変更提案をきっかけとした短期的な取り組みと継続的改善を達成する長期的な取り組みに分け検討を進め,リスクアセスメントのベースとなるデータの種類・所在をまとめた上で必要な社内機能を考察した。検討した既存品 QbD をまとめ,新規開発における QbD との比較検討を行ったところ,双方に共通したベストプラクティスがあることが認識された。その上で,『商用生産 QbD の推進』を総括的な結論とした。<br> 本検討は 2009 年から 2011 年にかけ行われ,2011 年 10 月 4 日に成果発表会を開催した。<br>

著者

川村 邦夫

出版者

一般社団法人日本PDA製薬学会

雑誌

日本PDA学術誌 GMPとバリデーション (ISSN:13444891)

巻号頁・発行日

vol.1, no.1, pp.9-17, 1999 (Released:2006-08-04)

参考文献数

6

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There are various academic associations related to pharmaceutical sciences and technology, most of which are dealing with pharmaceuticals themselves. The focussed areas are to synthesize new chemical entities, to find new pharmacological or therapeutic effects, and to develop new dosage forms. Relatively few researches have been reported on the area of manufacturing process, although there have been various researches and studies have been performed, particularly since the time of introduction of the concept of validation. This would be attributed to the lack of appropriate JOURNAL which enables the active information exchange possible. The journal newly published by Japan PDA would encourage persons who are engaging manufacturing plant, development engineering, quality laboratory and also who are engaging in regulatory inspections. As some examples of subjects which are expected to be contributed to the Japan PDA Journal relating to the future concept of manufacturing plant and manufacturing control, several topics are introduced. In the future manufacturing plant, 1) environment controlled area would become limited area which is as small as necessary, which becomes possible by applying isolator system or barrier system. Even the classification of cleanliness would become different one in future, along with the study of air flow dynamics as well as the application of isolator system. 2) Application of Luciferin-Luciferase-Chemo-luminance, method of microbial control would make the current air borne microbes control method different one and to make more quick in getting result and feed back to the process. 3) Continuous and automatic monitoring of air borne particulate would make more strict control and more quick action possible. 4) Systematic analysis of various data obtained from the monitoring of water would make correlation among various specifications more clear. As the results, continuous automatic in-line monitoring of water system by using conductivity, TOC, pH, and particulate matter might be enough to assure the quality of water, after the accumulation of quality data. As an example, it might be revealed that TOC value of 25 ppb or less shows endotoxin of 0.25 EU/ml or less. UF membrane would be used more frequently, since it endures high pressure steam sterilization. 5) Hydrogen peroxide sterilization would be more frequently be used according to the development and application of gas monitoring system. Submission of such papers and active discussion would make the pharmaceutical industry active and regulatory agencies would be able to have sound scientific basis on each operation.

著者

小林 通有

出版者

一般社団法人日本PDA製薬学会

雑誌

日本PDA学術誌 GMPとバリデーション (ISSN:13444891)

巻号頁・発行日

vol.3, no.1, pp.20-27, 2001

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Spray drying is used as a very convenient means for drying liquid into powder instantly, continuously and economically in laboratory use and large production, but at high temperature, e.g. over 100°C as inlet air temperature. Freeze-drying is a typical drying technology for drying heat-sensitive products at 20-50°C during desorption drying, but for several hours. Due to invention of Four Fluid Nozzle (patented in USA, Europe and Japan), spray drying at low temperature closer to atmospheric temperature below 80°C as hot air temperature is possible and therefore a new drying technology as low temperature spray drying has been realized based on the principle of quicker drying speed by huge heating surface area of droplets minimized below abt. 10 μm by the new nozzle. The Four Fluid Nozzle, which was developed by the design concept of minimization and uniformity of droplet size for quicker drying speed and elimination of wet deposits on chamber wall, has a special acceleration zone on it for forming thin film of liquid just before atomization in addition to a focusing point of compressed air as a newly designed structure for removing loss of atomization energy. Thus, the droplet size distribution is in a very narrow range resulting in the uniform particle size distribution of dry powder all in a single micron. The smaller and uniform droplet size makes heating surface area bigger by abt. 10 times compared with conventional atomization systems and so such smaller droplets are dried quickly and completely before reaching chamber wall even at low temperature without wet deposits on chamber wall. The geometry of the new nozzle is quite the same even in smaller or larger types of the nozzles and so the quality of dried product is also the same even in case of the so-called circle nozzle for larger production scale, for example having the atomization capacity of max. 1000 Itr/h. There is a possibility that conventional low temperature drying technology like freeze-drying, vacuum drying, etc. can probably be replaced by the low temperature spray drying technology. Drying of parenteral drugs will also be possible by the new drying technology with Four Fluid Nozzle using CIP/SIP systems, powder recovery system with metal mesh cartridge filter and isolation technology as a validatable system in the near future.<br>

著者

小松 俊彦

出版者

一般社団法人日本PDA製薬学会

雑誌

日本PDA学術誌 GMPとバリデーション (ISSN:13444891)

巻号頁・発行日

vol.3, no.1, pp.8-12, 2001

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In recent years, in Japanese society, Medical practice, medicines, foods, and environmental accidents and natural disasters have been happening. The importance of "Danger management" has been realized, and its system has been strongly sought. On the other hand, even about contagious diseases, treatment with sulfa drugs and/or antibiotics, and inoculation with vaccines have advanced in development. In the developed countries, contagious disease had been thought to be almost conquered. Nevertheless, in the past 20 years about 30 new infectious diseases have appeared, and the previous diseases also have gained immunity to medicines by changing character and virology, reappearing as new diseases and are looked upon as problems. Especially concerning infectious diseases, the importance of controlling dangers such as HIV infected blood plasma goes without saying. With this background, concerning the increasingly sought biosafely, biological production facilities biohazards counterplans sighted as basic lectures are to be conducted. The lecture content is dealing with biohazards, and biosafety principles and practices, and biosafety guideline in bioproduction facilities.<br>