TR&28_无菌原料药（BPCs）的工艺模拟---中英文&之一
This document provides guidance relative to the validation of
aseptic processing activities associated with the production of
sterile bulk pharmaceutical chemicals. It draws upon the concepts
and principles developed in PDA's and PhRMA's prior publications on
aseptic processing technology (1, 2, 3). This effort expands upon
those documents to provide assistance for individuals and firms
producing sterile bulk pharmaceutical chemicals. Our goal in this
revision was to update the document to reflect 6 years of industry
experience with it, as well as an acknowledgement of acceptance
criteria limitations that were present in the first edition (4). We
have also endeavored to address some of the issues raised by FDA in
their review of the earlier edition.
本文档提供了无菌原料药生产加工有关的验证指导。它借鉴了FDA和PhRMA以前出版的无菌加工技术（1，2，3）的概念和原则。这使得该文件可以为个人和企业的无菌原料药生产提供帮助。我们在这次修订的目的是更新文件，以归纳6年来的行业经验，以及验收标准的规定，这将在第1版（4）中称述。我们还大量列举一些美国FDA在其早期版本的回顾中提到的一些问题。
The preparation of sterile materials in the quantity and scale used
in the manufacture of bulk pharmaceutical chemicals generally
requires equipment and procedures quite different from those used
in the manufacture of finished pharmaceuticals. The uniqueness of
the production methods for sterile bulks precludes the direct
extrapolation of the process simulation approaches employed for
aseptically produced sterile formulations.
原料药生产中，无菌原料在数量和规模上的准备，一般都需要相当的设备和过程，这与成品药的制造有所不同。无菌原料生产方法的独特，排除了用于无菌制剂的无菌生产上的工艺模拟直接推断方法。
This technical report was disseminated in draft for public review
and comment prior to publication. Many of the submitted comments
have been included in the final document. We believe this approach
accomplished the widest possible review of the document and ensures
its suitability as a valuable guide to industry in the area of
process simulation testing for sterile bulk pharmaceutical
chemicals.
This document should be c it is not intended
to establish any mandatory or implied standard.
这份技术报告以草案形式提前发布供公众审查和评论。大多数提交的意见将被列入最后版本中。我们相信，这种方法实现了对文件最广泛的审查，并确保作为一个针对无菌原料药的工艺模拟试验领域的宝贵的指导性文件的合格性。这份文件应被视为指南，而不是任何强制规定或标准。
INTRODUCTION
Sterile Bulk Pharmaceutical Chemicals.
无菌原料药
Sterile BPC Production Technology
无菌BPC生产技术
Closed Systems
Open Systems &开放系统
1.5 Considerations
需考虑事项
SIMULATION CONCEPTS AND
PRINCIPLES
工艺模拟的概念和原则
Number and Frequency of Tests
测试的数量的频率
Worst Case
3 PROCESS SIMULATION TEST METHODS
工艺模拟测试的方法
Total Process Simulation
总工艺模拟
Unit Operation(s) Simulations&
单元操作模拟
TEST MATERIALS USED IN PROCESS SIMULATION
过程模拟中用到的测试原料
Growth Medium Simulations&
生长介质模拟
Placebo Material Simulation&&
安慰剂原料模拟
Simulation Without Material&&
无原料模拟
Production Material Simulation&
生产原料模拟
EVALUATION OF SIMULATION TEST MATERIALS
模拟测试原料的评估
Evaluation of Entire Test Material&
全体测试原料的评估
Evaluation of Test Material Samples&
测试原料单体的评估
DOCUMENTATION　文件
ENVIRONMENTAL MONITORING&&
ELEMENTS OF PROCESS SIMULATION
工艺模拟测试的评估
Interventions&
Duration of Simulation&
Production Batch Size/Process
Simulation Test
产品的批产量/工艺模拟的批量
Incubation Conditions&
Operating Procedures&
Staffing Considerations&
人员的思考
Campaigns&
Equipment Qualification&
INTERPRETATION OF RESULTS AND ACCEPTANCE CRITERIA
结果的解释和可接受水平
Background&
Approaches for Acceptance Criteria&
可接受水平的判定方法
Quantitative&
Qualitative&
FAILURE INVESTIGATION AND CORRECTIVE ACTION
失败评估和纠正措施
PERIODIC REASSESSMENT&
定期再评估
APPENDIX1,SELECTION
STERILIZATION
TEST MATERIALS
测试原料的选择和灭菌
APPENDIX 2, DEFINITIONS
APPENDIX 3, REFERENCES
1. INTRODUCTION
1.1. Purpose&
The preparation of sterile bulk pharmaceutical chem&icals requires
the combination of classical chemical/ biological production
methods with the well-defined concepts for the preparation of
sterile materials. The integration of these fields entails process
equipment and operating procedures which are often substantially
different from ordinary practice in either discipline. This
document outlines process simulation practices for sterile bulk
pharmaceutical chemicals (sterile BPCs), utilizing concepts drawn
from both bulk phar&maceutical chemical operations and sterile
product manufacturing and adapted to fit the unique nature of these
materials. It presents options for determining the adequacy of
aseptic operations performed during large scale manufacturing while
allowing for realistic acceptance criteria for such
operations.
无菌原料药的制备需要典型的生化生产方法与无菌原料制备概念的明确理解相结合。这些领域的合并意味着工艺设备和作业流程实质上往往与通常做法不同。本文件概述了无菌原料药（无菌BPCs）的工艺模拟实践，系统采用批量原料药作业和无菌产品制造的概念来适应这些材料的独特性质。报告在允许这些作业的实际验收标准的同时，陈述了在大规模生产中无菌作业的充分性的鉴定观点。
The aseptic procedures utilized in the production of sterile BPCs
can be evaluated using a process simu&lation methodology. However,
in certain instances the use of a microbiological growth medium in
a bulk manufacturing plant can pose significant problems. It is
often necessary to consider other simulation options which pose
less potential risk to the manufacturing area. It is useful to
utilize a narrower definition of a process simulation in these
cases. The following
definitions make a clear distinction between possible
无菌BPCS生产过程中使用的无菌流程可以用工艺模拟方法论来评估。然而，在某些情况下，在批量制造工厂中微生物培养基的使用可能造成重大问题。常常有必要考虑能减少对制造领域构成潜在风险的其他模拟方案。利用这些案件中工艺模拟的狭义定义是非常有意义的。下面的定义为各可行方法作出明确区分：
Process Simulation
(without microbiological growth media)
工艺模拟（无微生物培养基）
Method of evaluating an aseptic process employing methods which
closely approximate those used for sterile materials using an
ap&propriate placebo material.
与使用适当安慰剂原料的无菌原料评估方法相类似的无菌工艺的评价方法，
Process Simulation
(with microbiological growth media)
工艺模拟（有微生物培养基）
Method of evaluating an aseptic process using a microbial growth
medium employing methods which closely approximate those used for
sterile materials (5).
与无菌原料评估方法相类似的使用微生物的生长方法的无菌工艺评价方法。
The process simulation test also provides a way to evaluate changes
made to an aseptic processing operation which might affect the
sterility of the final product. It can be useful in identifying
potential weaknesses in an aseptic processing operation which might
contribute to the microbiological contamination of the
这个过程模拟试验也提供了一种方法来评估可能影响最终产品失败的无菌工艺的变化。它可以有助于鉴定在无菌工艺中的潜在弱点，这些弱点可能导致产品的微生物污染。
Sterile Bulk Pharmaceutical
Chemicals&
无菌原料药
For the purposes of this document, a sterile bulk pharmaceutical
chemical is defined as a sterile material derived from chemical,
fermentation or semi-synthetic sources which is final packaged or
stored in bulk form. The bulk material may be an active
pharmaceutical ingredient (API) or an excipient. Sterile BPCs are
typically solids, but may be solutions or
suspensions.
本文件的目的是定义无菌原料药是由那些最后以批量的形式被包装或存储的化学药品，发酵物或半派生的无菌材料而派生。其中大部分材料可能是一个活性成份（API）或赋形剂。无菌BPCs系统通常是固体，但也可能是溶液或悬浮物。
This document addresses the validation of aseptic processing during
sterile bulk manufacturing activities (referred to as primary
manufacturing in many parts of the world). It describes methods and
procedures for the conduct of process simulation tests, including
crystallization, separation, purification, drying, milling,
blending and bulk packaging of sterile bulk pharmaceutical
chemicals which are aseptically produced. Aseptic operations
required in the preparation of sterile formulations are not a part
of this document and have been addressed by PDA elsewhere
这份文件涉及到无菌原料生产活动（在世界的许多地方也叫作二次生产）的无菌工艺的验证。它描述了管理工艺模拟实验的方法和程序，包括结晶，分离，纯化，干燥，加工，混合与无菌生产的无菌原料药品的无菌包装。有无菌操作要求的无菌原料和生物技术过程不包括在这份文件中，而在PDA（4）中被陈述。
Sterile BPC Production Technology&
无菌BPC生产技术
The preparation of sterile bulk materials entails the completion of
a series of unit operations under aseptic conditions. The equipment
utilized for these aseptic unit operations is sterilized using a
validated procedure prior to the introduction of the sterile BPC.
Depending upon the process, the equipment may be classified as
either a "closed" or an "open" system (see below). While it is
recognized that a "closed" system is generally preferred, there are
process and equipment limitations such that "open" systems are the
only means available for the execution of certain unit operations.
The process train for a sterile BPC may include both "open" and
"closed" portions. The test methods used for
the process simulation must include all portions of the system
whether "open" or "closed" and transitions between them (see
Section 3).
大量无菌原料的制备需要在无菌条件完成一系列的单元作业。这些无菌单元操作所使用的设备预先采用无菌BPC技术进行了灭菌。该设备可以分类为“封闭”或“开放”系统（见下文）。人们认识到，虽然一个“封闭”系统被普遍采用，但由于工艺及设备的限制，“开放”系统对于某些单元操作来说是唯一可以利用的系统。无菌BPC的工艺培养可能既包括“开放”又包括“封闭”部分。在工艺模拟过程中使用的测试方法必须包括系统的所有部分，不论是“开放”或“封闭”，或者是它们之间的过度系统的所有部分（见第3节）。
Closed Systems&
A "closed" system is one that is designed to prevent the ingress of
microorganisms by means of physical separation from the surrounding
environment. A "closed" system:
“封闭”系统是旨在通过物理分离方法来防止周围环境中的微生物的侵入。
“封闭”系统：
Is constructed, installed and qualified in a manner which
demonstrates integrity is maintained throughout the full range of
operating conditions, and over a time period inclusive of the
longest expected usage (i.e., manufacturing campaign). The
qualification is done according to a formal protocol, following
generally accepted engineering principles, and is
documented.
建造，安装的方式保持完整合格的整个运作情况，并且在一段时间内最长的包容性的预期使用（即生产活动）。遵循普遍接受的工程原则、根据正式协议，条约被制定并记录在案。
Is sterilized-in-place or sterilized while closed prior to use
using a validated procedure
就地消毒或在使用验证程序前封闭消毒
Can be utilized for its intended purpose without breach to the
integrity of the system
可以利用其设计而不违反该系统的完整性
Can be adapted for fluid transfers in and/or out while maintaining
保持无菌的状况下适应液体的流进和/或流出。
Is connectable to other closed systems while maintaining integrity
of all closed systems (e.g., Rapid Transfer Port, steamed
connection, etc.)
& 在保持所有封闭系统的完整性的同时可与其他封闭系统连接（例如，快速传输接口，蒸汽连接等）
Is safeguarded from any loss of integrity by sched&uled preventive
maintenance.
是否有防护措施以避免定期预防性维修产生的完整性损失。
Utilizes sterilizing filters for sterilization of process streams
which are integrity tested and traceable to each product
利用除菌过滤器进行工艺线的灭菌，过滤器进行完整性测试并可追溯到每一个产品批次。
By virtue of their design, closed systems provide a substantially
increased measure of protection to the materials processed within.
Where a sterile BPC can be processed in its entirety within closed
systems, the risk of contamination is negligible.
由于他们的设计的优越性，封闭系统提供了内部材料加工保护措施。无菌BPC可以在整个封闭的系统内处理，污染的危险是微不足道的。
Open Systems&
An "open" system lacks one or more of the features of a "closed"
“开放”系统缺乏一个或多个“封闭”系统的功能。
1.5. Considerations&&
要考虑的事项
A holistic approach must be used to adequately validate and control
aseptic processes. A process simulation test is only a
point-in-time representation of the capabilities of an aseptic
processing system, including environment, equipment, procedures and
personnel. &验证和控制无菌加工过程必须充分使用一个全面解决办法。一个工艺模拟试验只是一个无菌处理系统能力的反映，包括环境，设备，程序和人员。
It does not ensure that sterile bulk materials produced at other
times will have the same level of microbiological
它并不能保证在其他时间生产的无菌散装物料将有相同的微生物质量水平。However,
through control and validation of related processes, such as
environmental monitoring, qualification of personnel and validation
of cleaning and sterilization cycles, it is possible to maintain
the level of asepsis demonstrated during the process simulation
但是，通过控制和相关的进程的验证，如环境监测，人员评估和清洗验证以及消毒周期验证，它有可能在这个工艺模拟测试中保持无菌水平。
Therefore, it is important to validate the related sanitization and
sterilization
processes independently, such as sterilization/depyrogenation of
the product, sterilization of the process equipment including
product contact surfaces, sterilization of containers (intermediate
and final packaged bulk), and support systems such as air, water,
or nitrogen (6, 7, 8).
因此，重要的是要独立验证相关的消毒和灭菌过程，例如灭菌/产品的除热原，工艺设备的灭菌，包括产品接触表面，容器的灭菌（中间产品和最终包装），支持系统，如空气，水，或氮（6，7，8）。
Confidence in the sterility of a specific production lot is
gathered through a number of process controls and procedures
including: documented and validated sterilization/sanitization
procedures, in-process controls regulating the production process,
environmental monitoring, comprehensive batch records, extensive
qualification of process equipment, and training of operating
personnel.
对一个具体生产批次的无菌的确信是通过过程控制和程序的序列号来收集，包括：被记载和验证过的杀菌/消毒程序，对生产过程监察的实时过程控制，环境监测，全面记录，工艺设备的全方位条件，和培训操作人员。
2. PROCESS SIMULATION CONCEPTS AND PRINCIPLES
& 工艺模拟的概念和原理
2.1. Number and Frequency of Tests&
实验的次数和频率
For a new facility or production process, process sim&ulations can
be performed as part of the overall vali&dation. Initial process
simulation tests, if performed, are conducted after equipment
qualification, steriliza&tion process validation, and personnel
training have been performed, and environmental monitoring has
demonstrated that the new facility is under the desired state of
control (9, 10, 11). If a process simulation test fails in the
absence of this supportive work, identifi&cation of a possible root
cause will usually be more difficult. Three consecutive successful
process simu&lation tests are performed when evaluating a new
facility or process. Prior to release of the new facility, or new
process for production use, acceptable results from these process
simulation tests should be achieved to demonstrate the
reproducibility of the process.
对应一个新的设施或生产工艺，工艺模拟应该作为所有验证的一部分。最初的工艺验证应该在设备确认、灭菌工艺验证、人员培训已经完成并且环境监测证明新的设施已经在预期的状态中受控之后进行(9,
10, 11)。如果没有作这些支持性的工作，工艺模拟实验失败的话，将很难确定可能的原因。当确认一个新的设施或工艺时，验证一个工艺应该进行三次连续成功的模拟工艺实验。在为生产使用正式批准一个新的设施、新的工艺之前，应该完成这样连续的可接受的结果，以证明工艺的可重复性。
In existing facilities, a process simulation test program should be
considered for each aseptic process. Addi&tional process simulation
tests may be considered to evaluate changes to procedures,
practices or equip&ment configuration (See Section 11—Periodic
Reas&sessment).
在现有设施，过程模拟测试程序应被考虑到每个无菌过程。追加工艺模拟试验可被用来评估程序、实践或设备配置的变更（见第11期再评估表）。
Process simulations for closed systems can be per&formed after
sterilization to confirm the acceptable sterilization of the
systems as well as the appropriate&ness of the procedures employed
within. The duration of campaigns for closed system may be
established through physical monitoring of such aspects as
pres&sure differentials, leak rates, filter integrity tests, etc.
and is further supported by a preventive maintenance program. End
of campaign process simulations are thus not required for the
closed portions of a process system. The duration of campaigns for
open systems may be confirmed through appropriate process
simu&lations conducted at the end of a real or simulated
封闭系统的过程模拟可以在灭菌后实施，以确认该系统的灭菌合格性以及内部程序的适当性。在封闭系统的工作持续时间可能将通过如压力差，泄漏率，过滤器完整性测试等物理等方面的监测来被确定，并进一步被预防性维修计划所支持。工作过程模拟的完成不需要一个工艺系统的封闭部分。开放系统的工作持续时间可能通过真实或模拟的工作结束时进行的适当的工艺模拟来被确认。
2.2. Worst Case　最差条件
One of the more prevalent techniques used in the validation of
pharmaceutical processes is the employ&ment of "worst case"
scenarios.
在制药工艺验证中最常采用的技术之一是采用“最差条件”。The
use of "worst case" situations is intended to provide a greater
challenge to the process, system or equipment being validated than
that experienced under routine processing
conditions.采用
“最差条件”
是有意对工艺、系统、设备在更高的挑战条件下进行验证。If, under
the circumstances of the "worst case" challenge, acceptable results
are achieved, then there is greater confidence in the reliability
of the system under more normal situations.
如果在“最差条件”的挑战下，仍能够达到预期的可接受标准，那么在正常条件下，对系统的可靠性将有更高的信心。Process
simulation tests readily lend themselves to "worst case"
challenges. Some of the types of challenges which may be employed
where possible are:
工艺模拟实验很容易进行“最差条件”的挑战。下面提供了一些类型的挑战：
using materials, equipment, utensils and other items which have
remained in the aseptic process&ing area for extended periods after
sterilization。使用的原料、设备、器具等在灭菌后于无菌工艺区保留时间超出期限。
using the maximum number of personnel necessary to process the
使用人员数超过灌装工艺所需。
increasing the time period between the completion of equipment
sterilization and the start of the process
simulation。
设备消毒的完成与开始模拟之间时间间隔过长
using a growth promoting medium or placebo material in the process
simulation test rather than an inhibitory
material。
& 在工艺模拟实验中使用促生长培养基或安慰剂，而不是使用有抑制性的处方。
performing a process simulation test after completion of the last
lot in a production campaign。
& 在最后的生产完成后进行工艺模拟实验。
The conduct of a process simulation for a sterile bulk typically
includes activities and manipulations that are specific for its
execution.
对于无菌原料的工艺模拟的进行通常包括大量特定的活动和操作。These
added steps introduce a higher potential for contamination than is
inherent in the routine process and pose an increased risk for
process simulation failure.
相比固有的常规工艺，这些额外的步骤导致了更高的潜在污染，增加了过程模拟失败的风险。
In the development of protocols or procedures used for the
definition of process simulation tests, the use of "worst case"
challenges such as those described above is an essential element of
a well-founded program.
在建议用于定义工艺模拟试验的方案或过程时，一个有良好根据的程序会使用上面提到的“最差条件”的挑战。The
"worst case" challenges selected may vary based upon the specific
type of process simulation utilized (see Sections 3 and
对“最坏条件”的挑战的选择可能会根据运用的工艺模拟的类型特点有所不同（见第3和4章）。Risk
assessment approaches such as hazard analysis and critical control
point (HACCP), failure effects mode analysis (FEMA) or fault tree
analysis (FTA) may be used to determine appropriate
challenges.正式的风险评估方法，例如HACCP、FEMA或FTA可以用于确定合适的挑战。
3. PROCESS SIMULATION TEST METHODS&
工艺模拟试验方法
The application of these general procedures to any specific aseptic
procedure may require modification of the methods described herein.
These adaptations should be accomplished in a manner which will not
improve the results of the simulation, relative to routine
operations.
这些一般程序在用于其他特定的无菌过程时可能需要对本文所诉的方法进行修改。但修改需要注意不改变模拟结果以及相关惯例操作。
The conduct of process simulation tests for sterile bulk
pharmaceuticals entails simulation of the process from the point of
sterilization through to the completion of bulk packaging. Sterile
bulk processes generally consist of a series of unit operations
which in total comprise the production processes.
对无菌原料药的工艺模拟试验，必须从灭菌开始到完全灌装结束全过程的模拟。无菌原料工艺的总生产工艺一般由一系列的单元工艺构成。For
the purposes of process simulation it may be appropriate to conduct
evaluations around either a single operation or a group of
operations. Provided that all of the unit
operations utilized in the production of a sterile BPC have been
evaluated in an appropriate manner, the segmented approach to
simulation can be as suitable as a comprehensive test involving all
of the unit operations in a single simulation.
基于工艺模拟的目的，围绕一个操作或一组操作来进行评估可能比较适当。如果一个无菌BPC生产中所使用的所有操作单元都以适当的方式进行评估，那么分段模拟方法作为一个全面的、在一次单独模拟中涉所有操作单元的测试是非常合适的。
The decision whether to perform the process simulation as a single
integrated test or in trials based upon one or more unit operations
must consider the pros and cons of each approach. It should be
recognized that the decision to conduct an overall simulation or
step-wise simulation approach is independent of the use of
microbiological growth media or other materials in the
simulation. 　决定是否执行作为一个单一的综合过程模拟测试还是执行一个或多个操作单元为基础的过程模拟测试必须考虑每种方法的利弊。
应当承认，决定进行整体模拟或分步模拟方法于对微生物生长介质或其他材料在模拟中的使用是独立的。
3.1. Total Process Simulation　总工艺模拟
In this type of simulation, the entire aseptic process is evaluated
in a trial which follows the process from where the materials are
first made sterile, through subdivision into containers for
在这种模拟方式中，整个无菌过程的评价是遵循从材料首次被无菌化到装运集装箱的整个过程来评价的。
Advantages&
The simulation may be able to follow the process more closely than
a series of smaller simulations.
相比一系列的小型模拟测试，该模拟测试更加贴近下列工艺。
Requires less time to complete than a series of smaller
simulations.
相比一系列的小型模拟测试，该模拟测试更加节省时间。
Disadvantages
If contamination is detected the identification and correction of
sources is more difficult than in a unit operation
simulation.
如果发现污染，污染源的识别和纠正比一系列单元操作模拟更加困难。
In the event of failure, the entire simulation must be repeated
after corrective measures have been taken.
在发生故障时，整个模拟必须纠正后再次采取措施。
Will generally require the use of a single test material (either
liquid or solid) throughout the entire simulation which may
introduce significant differences in the simulation and in how
contam&ination might occur when compared to the routine production
通常会要求在整个模拟测试中使用单个测试材料（或液体或固体），和传统的生产工艺相比，这有可能引起明显的差异和污染。
3.2. Unit Operation(s) Simulations&
单元操作模拟
In this form of simulation, a series of individual trials are
conducted covering all of the steps in the aseptic process. Where
the simulation is performed in several steps, the establishment of
an acceptance criterion must address the cumulative contribution
from each of the unit operations. Thus the total numbers of
organisms detected over the entire process must be
considered.
在这个模拟的方式中，对个别进行的一系列试验涵盖了无菌过程的所有步骤。在进行模拟的几个步骤中，一个验收标准的建立，必须来自各单元操作的经验累积。因此，在整个过程中发现的生物总数必须予以考虑。
Advantages
If contamination is detected, the corrective measures can focus on
a smaller portion of the overall process.
如果发现污染，纠正措施可以侧重于整个进程的一小部分。
^ Evaluation of the effects of changes to a specific part of the
process can be restricted to a limited number of
对一个过程的特定部分变化的影响的评价，可以限制在有限数量的步骤。
In the event of failure of a portion of an individual simulation,
only that simulation which failed may need to be repeated after
corrective action has been taken.
在个别模拟发生故障时，仅仅只是失败的那个模拟需要采取纠正措施
In some aseptic processes, this approach may resemble the actual
process more closely.
在一些无菌加工过程，这种做法可能于实际的工艺更为密切。
Allows for the use of either liquid or solid test materials in
different parts of the overall simulation, which may more closely
resemble actual production.
允许使用液体或固体材料在整个模拟中的不同部分，这可能更接近实际生产。
Disadvantages
Requires more time to perform than a total process
simulation.
相比总工艺模拟该方法需要更长时间。
May require some degree of overlap to evaluate the overall
可能对整个过程的评价需要一些重复。
The methods required to evaluate individual unit operations may
require more handling of sterile materials to accommodate a
segmented process simulation.
个别单元操作的评价方法可能需要对更多的灭菌材料进行处理，以适应细分过程的模拟方法。
A larger number of environmental monitoring samples must be taken
during each of the individual process
simulations.
一个更大的环境监测样本必须在每个过程模拟中被采用。
4. TEST MATERIALS USED IN PROCESS
SIMULATION&
工艺模拟使用的测试物料
Independent of the decision on whether the aseptic process is to be
simulated in total or in unit operation fashion, consideration must
be given to the selection of a material to be utilized in the
simulation. The choices are: a microbiological growth promoting
media, placebo material, simulation without material or actual
product material (generally an excipient). With each choice there
are of course certain advantages and disadvantages. Materials that
inhibit microbiological growth should not be used. If a test
material is utilized, a further decision between a liquid or powder
material is also required. Those firms that have chosen to segment
the process simulation according to the various unit operations may
elect to make different selections for the test material in
different parts of their overall program. For example, in sterile
BPC simulations with a crystallization step, a liquid material may
be used during simulation of the early steps, and a powder material
in those steps which follow the crystallization
不管决定是模拟整个无菌工艺或部分单元操作的形式，应考虑模拟使用的物料的选择。选择是：促进微生物生长的培养基，安慰剂物料，无物料模拟或实际产品物料（通常为辅料）。每种选择都有一定的优点和缺点。不能使用抑制微生物生长的物料。如果选择了一种测试物料，进一步需要决定选择液体或粉末物料。那些决定按照不同的单元操作将工艺模拟分开的公司，可能需要在整个方案中的不同部分选择不同的测试物料。例如，带有结晶工序的无菌原料药模拟，在早期步骤模拟阶段可能需要液体物料，而结晶工序后的步骤需要粉末物料。
Inherent in
the selection of a test material, and the decision to use a test
material at all are considerations of potential adverse affects
implicit in the use of a material.
As a general rule, nothing should be introduced into the system,
whether media or placebo, which may present a problem in subsequent
processing. The material (if used) must be able to be easily
removed from the equipment in order to prevent an increased
potential for contamination of production materials that would
later enter the system.
在选择测试物料时的一个内在问题，决定究竟使用哪种测试物料，需要考虑物料使用时的潜在副作用。一般原则，不能在系统中引入任何物质，不管是培养基或安慰剂，可能在随后的加工中带来问题。为防止增加随后进入系统的产品物料的潜在污染，使用的物料必须能从设备上容易移除。
See Appendix
1 for information on the selection, sterilization and use of test
materials.
见附录1测试物料选择、灭菌和使用的信息。
4.1. Growth Medium Simulations&
培养基模拟
A microbial growth medium in either liquid or solid state is
processed in lieu of the production materials. The microbiological
growth media may be tested for microbial count or sterility
depending upon the acceptance criteria requirements in the
使用液体或固体状态的微生物培养基来代替生产物料。微生物生长培养基可进行微生物计数或无菌测试，由方案中要求的可接受标准决定。
Advantages&&
Allows for the direct evaluation of the aseptic processing
procedures.
允许无菌加工程序的直接评价。
Less reliance on environmental conditions in the evaluation of the
在工艺评价时较少依赖于环境条件。
Disadvantages&&
The microbiological growth media may be overly sensitive to
antibiotic materials and other innately inhibitory materials. The
use of deactivating enzymes may be necessary, however their utility
in large systems may be severely limited.
微生物培养基可能对抗菌性物料和其他先天性抑菌物料过于敏感。可能需要使用灭活酶，但是他们在大系统中的使用可能严格受限。
Cleaning of the process equipment after exposure to the
microbiological growth media may represent a new cleaning procedure
which must be developed and validated.
工艺设备在暴露于微生物培养基后进行清洗，可能提出了一个必须开发和验证的新的清洗程序。
It adds increased risk of microbiological contamination of the
facility by providing a major nutrient source when normal materials
used may be innocuous or bactericidal.
另外，由于提供了一个营养来源，增加了设施微生物污染的风险，而正常使用的物料可能是无害的或杀菌的。
Detection of contamination in large containers may be
difficult.
在大容器中检测污染可能比较困难。
Quantities of microbiological growth media required may be
excessive.
可能需要大量的微生物培养基数量。
Process simulation may have little resemblance to the actual
process because of concerns regarding the media's growth promotion
capability under routine operating conditions within the
equipment.
由于关系到设备内在正常操作条件下的培养基的促生长能力，工艺模拟与实际工艺可能很少有类似之处。
Process gases should be replaced with air to enhance microbial
工艺气体由能促进微生物回收率的空气代替。
Placebo Material Simulation&&
安慰剂物料模拟
A placebo material is substituted for the production materials and
handled in a representative manner. The placebo material can be
sampled for microbial count or sterility testing depending upon the
acceptance criteria requirements of the protocol.
使用安慰剂物料来代替生产物料，以一种特定的方式处理。安慰剂物料可取样用来进行微生物计数或无菌测试，由方案中要求的可接受标准决定。
Advantages
Can use materials which are able to tolerate the actual processing
conditions utilized in the aseptic process.
&可使用能忍受无菌工艺使用的实际加工条件的物料。
Placebo materials can be chosen such that their removal from the
processing equipment after the simulation can be readily
accomplished.
可选择安慰剂物料，容易实现在模拟后从加工设备上移除。
Placebo materials can be substantially less expensive than product
or microbiological
growth media, which can be a significant concern in large process
equipment.
&&安慰剂物料的成本远低于产品或微生物生长培养基，在较大的工艺设备中是显著关注点。
Some of the actual materials utilized in the aseptic process may be
& 可使用在无菌工艺中实际使用的某些物料。
Disadvantages
Sterility or microbial count testing must be performed in order to
assess whether any microorganisms are present.
必须执行无菌或微生物计数测试，以评估是否存在微生物。
Cleaning of the process equipment after exposure to the placebo may
represent a new cleaning procedure which must be developed and
validated.
生产设备在暴露给安慰剂后的清洁表明，必须进行新清洁程序的执行和验证。
The placebo material must be evaluated for lack of inhibitory
effects on microorganisms.
安慰剂原料必须进行对微生物无抑制效应的评估。
The sterilization of powder placebos must be
validated.
粉末安慰剂的灭菌必须验证。
Testing of large quantities of material may be
可能需要对大量的原料进行测试。
Simulation Without Material&&
无物料模拟
This is a simulation performed in the absence of materials. This
approach has been used to evaluate operating procedures and
personnel performing discrete aseptic manipulations, e.g.,
subdivision into final containers. The aseptic production processes
are simulated using the procedures, personnel, equipment and
components ordinarily utilized in the aseptic process. Immediately
after completion of the simulation, extensive microbial sampling of
product contact surfaces and personnel is performed. Alternatively
or in addition, a flush of the process train with a suitable medium
can be employed. The surface sampling results are utilized to
determine microbial count or sterility depending upon the
acceptance criteria requirements of the protocol.
这是一种无物料状态下进行模拟。利用该方法来评价操作程序和进行间歇式无菌操作的人员，例如再次分装进最终容器。使用无菌工艺平常使用的程序、人员、设备和部件来模拟无菌生产工艺。完成模拟后，立刻进行产品接触表面和人员的大量的取样。可选择的或额外的，使用合适的介质冲洗工艺链。利用表面取样结果来确定微生物计数或无菌测试，由方案中要求的可接受标准决定。
Advantage&
The absence of materials eliminates cleaning (except for sampling
residues, if any), microbial count or sterility testing, inhibition
and recovery studies associated with the use of either a growth
media or a placebo material.
物料的缺席，排除了清洗（除了淋洗取样之外，如有）、与生长培养基或安慰剂物料相关的微生物计数或无菌测试、抑菌性和回收率试验。
Disadvantages&
The ability to detect microorganisms may be limited due to
uncertainty in sampling methods and recovery
efficiency.
& 由于取样方法和回收率的不确定性，检测微生物的能力受到限制。
Conducting accurate and successful recovery validation may be
difficult.
& 进行准确的和成功的回收率验证可能困难。
Relies on the microbial evaluation of product contact
依赖于产品接触表面的微生物评价。
4.4. Production Material Simulation&
产品物料模拟
This is a simulation that is performed using actual production
materials (generally an
excipient). The material can be sampled for microbial count or
sterility testing depending upon the acceptance criteria
requirements of the protocol.
使用实际生产物料(一般是辅料)进行模拟。该物料能取样后进行微生物计数或无菌测试，由方案中的可接受标准决定。
Advantages&
The process being simulated may utilize identical processing
conditions as those used in production.
& 模拟工艺可使用等同于生产中使用的加工条件。
The materials used for the simulation are known to be compatible
with the processing equipment.
模拟使用的物料与工艺设备相容。
No specialized cleaning of the equipment is necessary, the routine
methods used after the production can be employed with
confidence.
设备不需要特殊的清洁，确信可以利用生产后使用的常规方法。
Disadvantages&
Sterility testing or microbial count determination must be
performed.
必须进行无菌测试或微生物计数测定。
The production material must be evaluated for lack of inhibitory
effects on microorganisms, or a neutralizing agent must be
必须评价生产物料对微生物没有抑制作用，或必须添加中和剂。
The production materials may be extremely costly.
生产物料可能很昂贵。
Testing of large quantities of material may be
& 需要测试大量的物料。
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