欧盟GMP无菌药品附录征求意见稿,翻译出炉!

发布日期:2017-12-29

附录1

无菌药品的生产(征求意见稿)

翻译:黄云柯 何乐 常达 李德齐 宋云泽 魏巍 张磊

校对&排版:黄云柯 王孝东 李兴


Document map 文件结构

Section Number 章节号

General overview 总览

1.Scope

范围

Additional areas (other than sterile medicinal products) where the general principles of the annex can be applied.

额外部分(除无菌药品以外的部分)指适用于附录总则的部分

2.Principle

总则

General principles as applied to the manufacture of medicinal products.

作为适用于药品生产的原则。

3.Pharmaceutical Quality System (PQS)

制药质量体系(PQS)

Highlights the specific requirements of the PQS when applied to sterile medicinal products.

强调了当适用于无菌药品时的PQS的具体要求。

4.Personnel

人员

Guidance on the requirements for specific training, knowledge and skills. Also gives guidance to the qualification of personnel.

对于具体培训,知识及技能的要求的指导。同时也对人员资质提出了指导。

5.Premises

厂房

General guidance regarding the specific needs for premises design and also guidance on the qualification of premises including the use of barrier technology.

有关厂房设计的具体需求的总体指导以及包括隔离技术使用的厂房确认的指导。

6.Equipment

设备

General guidance on the design and operation of equipment.

设备设计和操作的总体指导。

7.Utilities

公用系统

Guidance with regards to the special requirements of utilities such as water, air and vacuum.

有关诸如水系统,空气系统以及真空系统的公用工程系统的特殊要求的指导。

8. Production and specific technologies

生产与具体技术

Discusses the approaches to be taken with regards to aseptic and terminal sterilisation processes. Also discusses different technologies such as lyophilization and Blow Fill Seal (BFS) where specific requirements may be required. Discusses approaches to sterilization of products, equipment and packaging components.

讨论所采用的与非最终灭菌工艺和最终灭菌工艺相关的方法。还讨论可能存在具体要求的不同技术,例如冻干和吹灌封(BFS)。讨论用于产品,设备及包装部件的灭菌方法。

9.Viable and non-viable environmental and process monitoring

常规的和非常规的环境及工艺监测

This section differs from guidance given in section 5 in that the guidance here applies to ongoing routine monitoring with regards to the setting of alert limits and reviewing trend data.

常规的和非常规的环境及工艺监测:该部分不同于本指南第五章节部分的内容,本处适用于警戒限的设置以及趋势数据审核的持续的常规监测。

The section also gives guidance on the requirements of Aseptic Process Simulation.

本部分同样对无菌工艺的模拟提供了指导。

10.Quality control (QC)

质量控制(QC)

Gives guidance on some of the specific Quality Control requirements relating to sterile medicinal products.

对具体的有关无菌药品的质量控制要求提供了指导。

11.Glossary

术语

Explanation of specific terminology.

具体专业名词的解释。

1 Scope 范围

The manufacture of sterile medicinalproducts covers a wide range of product types, (sterile active substancethrough to finished dosage form), batch sizes (single unit to multiple units),processes (from highly automated systems to manual processes), primarypackaging materials and technologies (e.g. biotechnology, classical smallmolecule manufacturing and closed systems). This Annex provides generalguidance that should be used for all sterile medicinal products and sterileactive substances, via adaption, using the principles of Quality RiskManagement (QRM), to ensure that microbial, particulate and pyrogencontamination associated with microbes is prevented in the final product.
无菌药品的生产涵盖了一个广泛的产品类型,(从无菌活性成分至最终的制剂成品),批量(从单个单位到多个单位),工艺(从高度自动化系统到人工操作),内包装材料及技术(例如,生物技术,经典小分子生产以及密闭系统)。本附录为所有无菌药品和无菌活性成分提供了一个总的指导原则,经过适用,使用质量风险管理(QRM)的原则,以确保能够阻止最终产品中与微生物有关的微生物污染,尘埃粒子污染和热原污染。

The intent of the Annex is to provideguidance for sterile medicinal products. However some of the principles andguidance, such as contamination control strategy, room qualification,classification, monitoring and gowning, may be used to support the manufactureof other products that are not intended to be sterile (such as certain liquids,creams, ointments and low bioburden biological intermediates) but where the controlof microbial, particulate and pyrogen contamination, to reduce it as far aspossible, is considered important.
本附录的目的是为无菌药品提供一个指导。尽管如此,有些原则和指导,例如污染控制策略,房间确认,洁净级别,监测和更衣,可能被用于支持其他非无菌用途的产品的生产(例如某种液体制剂,膏剂,软膏剂以及低微生物负载的生物中间体)。所以,对所存在的微生物污染,尘埃粒子污染和热原污染进行控制,并尽可能的降低,被认为是非常重要的。

2 Principle 原则

The manufacture of sterile products issubject to special requirements in order to minimize risks of microbiological,particulate and pyrogen contamination. The following key areas should beconsidered:
无菌药品的生产需符合特殊的要求以降低微生物,尘埃粒子及热原的污染风险。应考虑以下关键区域:

a)Facility, equipment and processdesign must be optimized qualified and validated according to Annex 11 andAnnex15 of EU GMP. The use of appropriate current technologies should beimplemented to ensure protection and control of the product from potentialextraneous sources of particulate and microbial contamination such aspersonnel, materials and the surrounding environment. 
设施,设备及工艺的设计须基于EU GMP附录11和附录15中的要求被最优化确认和验证。适当的当前技术的使用应被实施以确保产品能够从潜在的外部来源的微粒和微生物污染中得到保护和控制,例如人员,物料及周边环境。

b)Personnel must have appropriateskills, training and attitudes with a specific focus on the principles involvedin the protection of sterile product during the manufacturing, packaging anddistribution processes.
人员须具备在生产、包装及发运过程中与保护无菌药品的原则相适应的技能,培训及态度。

c)Processes and monitoringsystems for sterile product manufacture must be designed, commissioned,qualified and monitored by personnel with appropriate process, engineering andmicrobiological knowledge.
无菌药品的生产过程及监控系统须由具有合适的工艺、工程以及微生物知识的人员进行设计、运行并确认。

Processes, equipment, facilities andmanufacturing activities should be managed in accordance with QRM principlesthat provide a proactive means of identifying, scientifically evaluating andcontrolling potential risks to quality. Risk assessments should be used tojustify alternative approaches to those specified in this Annex only if thesealternative approaches meet or surpass the intent of this Annex.
工艺、设备、设施及生产活动应基于QRM的原则进行管理,该原则提出了一个前瞻性的方法用于识别、科学评估及控制潜在的质量风险。只有当这些可选择的方法满足或超出本附录的目的时,风险评估方可被用于判断本附录中所明确的那些可选择的方法。

Quality Assurance is particularlyimportant, and manufacture of sterile products must strictly follow carefullyestablished and validated methods of manufacture and control. A contaminationcontrol strategy should be implemented across the facility in order to assessthe effectiveness of all the control and monitoring measures employed. Thisassessment should lead to corrective and preventative actions being taken asnecessary.
质量保证尤其重要,无菌药品的生产必须严格遵循仔细建立的以及经过验证的生产和控制方法。一个污染控制策略应在整个设施内被实施以便评估所有采用的控制以及监测方法的有效性。该评估应能在必要时引入纠正和预防措施。

The strategy should consider all aspects ofcontamination control and its life cycle with ongoing and periodic review andupdate of the strategy as appropriate.
该策略应考虑所有污染控制的因素,在其生命周期内应具有持续性和周期性的审核,并在必要时更新该策略。

Contamination control and steps taken tominimise the risk of contamination from microbial and particulate sources are aseries of successively linked events or measures.  These are typically assessed, controlled andmonitored individually but these many sources should be consideredholistically.
所采取的用于降低来自微生物和微粒来源的污染风险的污染控制和步骤是一系列连续关联的事件或措施。这些事件或措施应被单独地进行评估、控制和监测,但有些来源可进行整体考虑。

The development of such strategies requiresthorough technical and process knowledge. Potential sources of contaminationare attributable to microbiological and cellular debris (e.g.pyrogens/endotoxins) as well as particulate matter (glass and other visible andsub-visible particles).
该策略的开发需要通过技术和工艺知识。潜在的污染源被归结于微生物及细胞残骸(例如热原/内毒素)以及微粒(玻璃及其他可见和不可见微粒)。

Elements to be considered within such a documentedcontamination control strategy should include (but not be limited to): 
文件中需记录的污染控制策略应考虑的要素有(但不限于):

a)Design of both the plant andprocess.
工厂及工艺的设计。
b)Equipment and facilities.
设备和设施。
c)Personnel.
人员。
d)Utilities.
公用系统。
e)Raw Materials Control –including in-process controls.
原料控制-包括过程控制。
f)Product containers andclosures.
产品容器及密闭。
g)Vendor approval – such as keycomponent suppliers, sterilization of components and single use systems, andservices. 
供应商的批准-例如关键成分的供应商、组分的灭菌及一次性系统和服务。
h)For outsourced services, suchas sterilization, sufficient evidence should be provided to the contract giverto ensure the process is operating correctly. 
对于外部提供的服务,例如灭菌,应将充分的证据提供给合同的委托方,以确保工艺被正确地操作。
i)Process risk assessment.
工艺风险评估。
j)Process validation.
工艺验证。
k)Preventative maintenance –maintaining equipment and premises (planned and unplanned maintenance) to astandard that will not add significant risk of contamination.
预防性维护保养-设备及设施的维护保养(计划性及非计划性维护保养)应有一个标准,使之不会带来重大的污染风险。
l)Cleaning and disinfection.
清洁和消毒。
m)Monitoring systems - includingan assessment of the feasibility of the introduction of scientifically sound,modern methods that optimize the detection of environmental contamination.
监测系统-包括对引入科学合理、现代方法的可行性评估,该方法用于优化环境污染的检测。
n)Prevention – Trending,investigations, corrective and preventive actions (CAPA), root causedetermination and the need for more robust investigational tools.
预防-趋势化、调查、纠正和预防措施、根本原因的确定以及对更有利的调查工具的需要。
o)Continuous improvement based oninformation from the above systems.
基于来自上述系统信息的持续改进。

The manufacturer should take all steps andprecautions necessary to assure the sterility of the products manufacturedwithin its facilities. Sole reliance for sterility or other quality aspectsmust not be placed on any terminal process or finished product test.
生产者应采取所有必要的步骤及防范措施以确保在其设施内所生产产品的无菌性。无菌性或其他质量因素不能仅仅依靠任何一个最终工艺步骤或成品检测。

Note 1: This guidance does not lay downdetailed methods for determining the microbiological and particulatecleanliness of air, surfaces etc. Reference should be made to other documentssuch as the EN/ISO Standards and Pharmacopoeial monographs for more detailedguidance.
注释1:不建议用本指导方法来确定空气、表面等的微生物及微粒洁净度。更具体的指导应参照其他标准,例如EN/ISO标准以及药典中各论的相关要求。

Note 2: Where national legislation permits,additional guidance regarding the preparation of unlicensed sterile medicinalproducts normally performed by healthcare establishments for direct supply topatients, reference may be made to the Annex 1: “Guidelines on the standardsrequired for the sterile preparation of medicinal products” of the PIC/S guideto good practices for the preparation of medicinal products in healthcareestablishments, PE 010.
注释2:如国家立法许可,由医疗机构建立的用于直接供患者使用的非上市的无菌药品的制备其他指导标准可参见PIC/S《良好的医疗机构药品制备管理规范》,PE010附录1:《药品无菌制备标准指南》.

3 Pharmaceutical Quality System (PQS) 制药质量体系(PQS)

3.1 The manufacture of sterile medicinalproducts is a complex activity that requires additional controls and measuresto ensure the quality of products manufactured. Accordingly, the manufacturer’sPharmaceutical Quality System (PQS) should encompass and address the specificrequirements of sterile product manufacture and ensure that all activities areeffectively controlled so that all final products are free from microbial andother contamination. In addition to the PQS requirements detailed in chapter 1of the EU GMPs, the PQS for sterile product manufacturers should also ensurethat:
无菌药品的生产是一个复杂的活动,该活动需要额外的控制和措施以确保所生产的产品质量。通常,生产者的制药质量体系(PQS)应包括或强调无菌药品生产的具体要求以确保所有的活动均得到了有效地控制,以便使所有的最终产品没有微生物或其他的污染。此外,在EU GMP第一章关于PQS的描述中,无菌产品生产者的PQS应能确保:

a)There is an effective risk management system integrated into theproduct life cycle to minimise microbial contamination to ensure the safety,quality and efficacy of sterile manufactured product, including assurance ofsterility. 
应有一个有效的风险管理系统与产品的生命周期相结合以降低微生物污染,确保无菌生产的药品的安全、质量及效力,包括无菌保证。

b)The manufacturer has sufficient knowledge and expertise inrelation to the products manufactured and the manufacturing methods employed.
生产者应具有足够的与产品生产及所开发的生产方法相关的知识和经验。

c)Root cause analysis of procedural, process or equipment failureis key to ensure that the risk to product is correctly understood and suitablecorrective and preventative actions are implemented.
程序上的、工艺或设备失败的根本原因的分析是保证正确地理解产品风险,实施恰当的纠正和预防措施的关键。

d)Risk assessment is performed to identify, assess, eliminate (whereapplicable) and control contamination risks to prevent contamination, tomonitor and detect contamination, and to establish process requirements andacceptance criteria for all elements of a sterile manufacturing process. Therisk assessment should be documented and should include the rationale fordecisions taken in relation to mitigating risks, discounting of potential risksand residual risk. The risk assessment should be reviewed regularly as part ofon-going quality management, during change control and during the periodicproduct quality review. 
实施风险评估是为了识别、评价、排除(如适用)及控制污染风险以防止污染,监测和检测污染,并为所有无菌生产工艺要素建立工艺要求和接受标准。风险评估应被记录并包括所采取的用于减轻风险、降低潜在风险和剩余风险的合理决定。风险评估应被作为持续质量管理的一部分在变更控制以及产品周期质量回顾时进行定期审核。

e)Processes associated with the finishing and transport of sterileproducts should not compromise the finished sterile product in terms ofcontainer integrity or pose a risk of contamination and ensure that medicinalproducts are stored and maintained in accordance with registered storageconditions.
与无菌产品的结束和运输相关的过程不应对无菌产品的容器密闭性造成危害或形成一个污染风险以确保药品按照其注册的储存条件被储存和维护。

f)Persons responsible the quality release of sterile medicinesshould have appropriate access to manufacturing and quality information andpossess adequate knowledge and experience in the manufacture of sterile dosageforms and their critical quality attributes in order to be able to ascertainthat the medicines have been manufactured in accordance with the registeredspecification and are of the required safety, quality and efficacy.
负责无菌产品质量放行的人员应能获得足够的生产及质量信息,并具备足够的无菌剂型生产和关键质量属性的知识和经验以便能够确定药品是按照注册的质量标准被生产出来并符合所要求的安全、质量及效力。

3.2 Investigations should be performed intonon-conformities, such as sterility test failures or environmental monitoringexcursions or deviations from established procedures, with a specific focusregarding the potential impact to sterility, to not only the specific batchconcerned but also any other potentially impacted batch. The reasons forincluding or excluding product from the scope of the investigation should beclearly recorded and justified within the investigation.
应对不符合项进行调查,例如无菌性检验失败或环境监控超标或与已建立的程序存在偏差。调查可通过对无菌性的潜在影响进行具体关注,不仅涉及到某一具体批次,还涉及到其他存在潜在影响的批次。对于在调查范围内涵盖或排除产品的原因,应在调查时被明确地记录并证明。

4 Personnel 人员

4.1 The manufacturer should ensure thatthere are sufficient appropriate personnel, suitably qualified and experiencedin the manufacture and testing of sterile medicines and any of the specificmanufacturing technologies used in the site’s manufacturing operations, toensure compliance with Good Manufacturing Practice applicable to themanufacture of sterile medicinal products.
生产商应确保有足够的符合条件的人员,这些人员有对无菌药品生产和检测的资质和经验,以及在生产现场所使用的任何一种具体生产技术,以确保无菌药品的生产符合良好药品生产质量管理规范的要求。

4.2 Only the minimum number of personnelrequired should be present in cleanrooms. The maximum number of operators incritical areas should be determined based on QRM principles, documented in thecontamination control strategy, and validated during activities such as initialqualification and aseptic process simulations, so as not to compromisesterility assurance. This is particularly important during aseptic processing.Inspections and controls should be conducted outside the clean areas as far aspossible.
应规定洁净室内允许进入的最小人员数量。关键区域内允许进入的操作人员的最大数量的确定应基于QRM原则,并记录在污染控制策略中,然后在生产活动时进行验证,例如首次确认和无菌工艺模拟,以确保不会对无菌保证带来危害。这对于无菌工艺过程尤其重要。检查和控制应尽可能的在洁净区域外进行。

4.3 All personnel (including thoseperforming cleaning and maintenance) employed in such areas should receiveregular training, qualification (including sampling of the operators bioburden,using methods such as contact plates, at key locations e.g. hands arms andchest) and assessment in disciplines relevant to the correct manufacture ofsterile products. This training should include reference to hygiene, cleanroompractices, contamination control, aseptic techniques, and potential safetyimplications to the patient of a loss of product sterility and in the basicelements of microbiology.
工作在这一区域的所有人员(包括那些从事清洁和维护保养的人员)应经常接受培训,确认(包括操作人员微生物负荷的取样;使用方法,例如接触碟;关键位置,例如手部,手臂及胸部)以及与无菌药品正确生产相关的纪律的评估。该培训应包括关于卫生,洁净室实践,污染控制,无菌技术以及由于产品无菌性及微生物基本要素的缺失而对患者造成的的潜在安全影响。

4.4 The personnel working in a grade A/Bcleanroom should be trained for aseptic gowning and aseptic practices.Compliance with aseptic gowning procedures should be assessed and confirmed andthis should be periodically reassessed at least annually and should involveboth visual and microbiological assessment (using additional locations such asarms and chest). Only trained personnel who have passed the gowning assessmentand have participated in a successful aseptic process simulation (APS) test,during which they performed their normal duties, should be authorized to enterany grade A/B area, in which aseptic operations will be conducted, or are beingconducted, whilst unsupervised. The microbial monitoring of personnel in thegrade A/B area should be performed to assess their aseptic behaviour. Thismonitoring should take place immediately after completion of a criticalintervention and upon each exit from the cleanroom. It should be noted thatthere should also be an ongoing continuous monitoring program for personnelincluding some consideration of periodic monitoring under the supervision ofthe quality unit.
在A/B级洁净室工作的人员应接受无菌更衣以及无菌实践的培训。应对无菌更衣程序的符合性进行评估和确认,并且应当至少每年进行周期性再评价,包括目测及微生物的评估(使用额外的位置,例如手臂及胸不)。只有经过培训并通过更衣的评估,并且成功地参与了一次按照其日常任务执行的无菌工艺模拟试验(APS)的人员方可被授权进入A/B级区域,该区域将要从事无菌操作或正在进行,即使没有监督。应通过对A/B级区域的人员的微生物监测来评估其无菌行为。该监测应在关键干扰结束后以及每次退出洁净室前立即进行。值得注意的是,应有一个对人员的持续的连续监测计划,包括考虑在质量部门监督下的一些周期性监测。

4.5 There should be systems in place fordisqualification of personnel from entry into cleanrooms, based on aspectsincluding ongoing assessment and/or the identification of an adverse trend fromthe personnel monitoring program. Once disqualified, retraining andrequalification is required before permitting the operator to have any furtherinvolvement in aseptic practices. This should include consideration ofparticipation in a successful Aseptic Process Simulation (APS).
现场应有取消人员进入洁净室资质的体系,该体系基于来自人员监测计划的负面趋势的持续评估和/或的识别。一旦取消资质,需要在允许该操作人员重新获得任何再次参与无菌实践之前被再次培训并重新获得资质。这应当包括其成功参与一次无菌工艺模拟(APS)的考虑。