Sterile drugs should be manufactured using aseptic processing only when terminal sterilization is not feasible. However, some final packaging may afford some unique and substantial advantage (e.g., some dual-chamber syringes) that would not be possible if terminal sterilization were employed. In such cases, a manufacturer can explore the option of adding adjunct processing steps to increase the level of sterility assurance.
Product Requirements
在可能的情况下，FDA已经陈述了终端灭菌的使用应在制造无菌产物时，当没有对达到最终产物的不利影响时。
因此，建立加工条件的第一步，因此是制造设施的设计，是确定是否需要终端灭菌。
In some cases, an additional method e.g. heat treatment, can be added to aseptic processing to better assure product safety.
决策树选择灭菌方法
- Those products intended to be sterile should be terminally sterilized in their final container as clearly stated in the European Pharmacopoeia, and in the CPMP Notes for Guidance.
- 在不可能由于制剂不稳定性而通过热量进行末端灭菌，应采用末端灭菌，过滤和/或无菌处理的替代方法。
- It is recognized that the new terminal sterilization process other than those described in the pharmacopoeia may be developed to provide sterility assurance levels equivalent to present official methods, and such processes when properly validated may offer alternative approaches.
- 不恰当的使用heat-labile包装material cannot in itself be the sole reason for adoption of aseptic processing. However, it may be that the choice of a packaging material for a given product has to take into account factors other than the method of sterilization.
- Conventionally, it has been accepted that other factors such as the type of container, route of administration and patient benefit have contributed to the choice of a particular container type, which will not withstand terminal heat sterilization (e.g. certain ophthalmic products) and such products are therefore manufactured by validated aseptic processing.
Sterilization Choices for Aqueous Products
非水液体，半固体或干粉的灭菌选择
For the purpose of ensuring sterility, all aqueous-based sterile products are subject to terminal moist heat sterilization, with the following exceptions:
- 终端潮热灭菌的情况不实用，例如，产品劣化。此类实例完全评估和记录。
- For aseptic processes that exclude human intervention e.g., robotics, form-fill-seal and barrier system, may be employed in lieu of terminal moist heat sterilization providing that validation data demonstrated equivalence.
采用两种基本方法为潮湿的热过程开发灭菌循环：
- 矫枉过正
当产品可以承受过多的热处理时，使用这一点0≥ 12 without adverse effects. Bio burden and resistance data are not required to determine the required “F0“values. Cycle parameters are adjusted to assure that the coldest point within the load receives an “F0“that will provide at least a 12-log reduction of microorganisms having a D121value of at least one minute.
- 生存概率
This approach is used primarily for heat labile products. In this approach, the process for the terminal sterilization of a sealed container is validated to achieve the destruction of pre-sterilization bio burden to a level of 100, with a minimum safety factor of an additional six-log reduction (1x10-6). The probability that any one unit is contaminated is therefore no more than one in a million; this is considered to be an acceptable level of sterility assurance.
The probability of survival is determined using a semi-logarithmic microbial death curve, where a plot of the log of the number of survivor versus time at a fixed temperature yields a straight line.
The determination of the minimum “F0“存活方法概率的价值基于给定产物中发现的微生物（生物负担）的数量及其耐热性。
Types of Terminal Sterilization
Sterilization by heat
Each heat-sterilization cycle should be recorded by means of appropriate equipment of suitable accuracy and precision, e.g. on a time/temperature chart with a suitably large scale. The temperature should be recorded by a probe at the coolest part of the load or loaded chamber, this point having been determined during the validation; the temperature should preferably be checked against a second independent temperature probe located at the same position. The chart, or a photocopy of it, should form part of the batch record. Chemical or biological indicators may also be used but should not take the place of physical controls.
Sufficient time must be allowed for the whole of the load to reach the required temperature before measurement of the sterilizing time is started. This time must be determined for each type of load to be processed.
在热灭菌循环的高温阶段之后，应在冷却过程中针对灭菌负载的污染来进行预防措施。应灭菌与产品接触的任何冷却液或气体。
潮湿的灭菌
潮湿的灭菌(heating in an autoclave) is suitable only for water-wettable materials and aqueous formulations. Both temperature and pressure should be used to monitor the process. The temperature recorder should normally be independent of the controller, and there should be an independent temperature indicator, the reading from which should be routinely checked against the chart recorder during the sterilization period. For sterilizers fitted with a drain at the bottom of the chamber, it may also be necessary to record the temperature at this position throughout the sterilization period. There should be regular leak tests on the chamber when a vacuum phase is part of the cycle.
除了密封容器中的产品之外，将灭菌的物品应以允许除去空气和蒸汽的渗透物的材料包裹，但防止灭菌后的再污染。载荷的所有部件应在所需时间的温度下与水或饱和蒸汽接触。
Care should be taken to ensure that the steam used for sterilization is of suitable quality and does not contain additives at a level that could cause contamination of the product or equipment.
Sterilization by dry heat
Sterilization by dry heat may be suitable for non-aqueous liquids or dry powder products. The process used should include air circulation within the chamber and the maintenance of a positive pressure to prevent the entry of non-sterile air. If air is supplied, it should be passed through a microorganism-retaining filter (e.g. an HEPA filter). Where sterilization by dry heat is also intended to remove pyrogens, challenge tests using endotoxins will be required as part of the validation.
Sterilization by radiation
Sterilization by radiation is used mainly for the sterilization of heat-sensitive materials and products. Many pharmaceutical products and some packaging materials are radiation-sensitive, so this method is permissible only when the absence of deleterious effects on the product has been confirmed experimentally. Ultraviolet irradiation is not an acceptable method for terminal sterilization.
如果通过外部承包商进行辐射灭菌，制造商负责确保第6.8节的要求，并验证了灭菌过程。还应指定辐射植物操作员（例如使用正确剂量）的职责。
During the sterilization procedure, the radiation dose should be measured. For this purpose, the dosimeters used must be independent of the dose rate and must provide a quantitative measurement of the dose received by the product itself. Dosimeters should be inserted in the load in sufficient number, and close enough together to ensure that there is always a dosimeter in the chamber. Where plastic dosimeters are employed, they should be used within the time-limit of their calibration. Dosimeter absorbances should be read shortly after exposure to radiation. Biological indicators may be used only as an additional control. Radiation-sensitive colour discs may be used to differentiate between packages that have been subjected to irradiation and those that have not; they are not indicators of successful sterilization. The information obtained should constitute part of the batch record.
验证程序应确保考虑封装密度变化的影响。
Handling procedures should prevent any misidentification of irradiated and non-irradiated materials. Each package should carry a radiation-sensitive indicator to show whether or not it has been subjected to radiation treatment.
The total radiation dose should be administered within a predetermined period of time.
Sterilization by gases and fumigants
This method of sterilization should only be used for products where there is no suitable alternative.
Various gases and fumigants may be used for sterilization (e.g. ethylene oxide, hydrogen peroxide vapour). Ethylene oxide should be used only when no other method is practicable. During process validation it should be shown that the gas has no damaging effect on the product and that the conditions and time allowed for degassing are such as to reduce any residual gas and reaction products to defined acceptable limits for the type of product or material concerned. These limits should be incorporated in the specifications.
Direct contact between gas and microorganisms is essential; precautions should therefore be taken to avoid the presence of organisms likely to be enclosed in materials such as crystals or dried protein. The nature and quantity of packaging materials can significantly affect the process.
Before exposure to the gas, materials should be brought into equilibrium with the humidity and temperature required by the process. This requirement should be balanced against the need to minimize the waiting time before sterilization.
每一个灭菌周期应该是密苏里州nitored with suitable biological indicators, using the appropriate number of test pieces distributed throughout the load. The information so obtained should form part of the batch record.
应根据制造商的说明书储存和使用生物指标，并通过积极控制检查其性能。
对于每个灭菌循环，应记录在过程中完成循环所花费的时间，在该过程期间腔室内的压力，温度和湿度以及气体浓度。应在整个循环中记录压力和温度。记录应构成批量记录的一部分。
灭菌后，应在通风条件下以受控的方式储存负荷，以允许浓度残留的气体和反应产物下降到其规定的水平。该过程应验证。
