4.0 Acceptance Criteria 可接受标准
4.1. Introduction 概述
Companies must demonstrate during validation that the cleaning procedure routinely employed for a piece of equipment limits potential carryover to an acceptable level. That limit established must be calculated based on sound scientific rational.
公司在验证时要证明各设备日常所用的清洁程序能将带入下一产品的潜在残留限制在一个可以接受的水平。所建立的限度必须进行科学合理的计算。
This section provides practical guidance as to how those acceptance criteria can be calculated. It is important that companies evaluate all cases individually. There may be specific instances where the product mix in the equipment requires further consideration.
本部分提供实用的指南，指导如何计算这些可接受标准。公司对各案进行各案评估是非常重要的。有时还需要考虑产品从哪步开始混入设备中。
The acceptance criteria preferably should be based on the Acceptable Daily Exposure (ADE) calculations whenever this data is available. The Acceptable Daily Exposure defines a limit at which a patient may be exposed every day for a lifetime with acceptable risks related to adverse health effects. Calculations of Acceptable Daily Exposures of API’s and intermediates are usually done with involvement of industrial hygienists and toxicologists, who review all available toxicology and clinical data to set the limits. The justification of the calculation should be documented.
如果可以获得可接受日暴露（ADE）值，最好依据其计算可接受标准。可接受日暴露限度定义的是患者终身每天暴露于该浓度，但对健康的不良影响仍处于可接受风险水平。原料药和中间体的ADE一般由企业的卫生学家和毒理学家来制订，他们会审核各种可以获得的毒性和临床数据来设定限度。计算的合理性要进行记录。
In many cases Occupational Exposure Limits (OEL) will be defined for API’s, Intermediates and Industrial Chemicals by Industrial Hygienists and toxicologists and the OEL data is then used to define containment measures such that operators are adequately protected while working with the chemicals.
在很多情况下，会由行业卫生学家和毒理学家对原料药、中间体和工业级化学品的职业暴露限度（OEL）值进行界定，这时应使用OEL数据来制订限制措施，例如，操作人员在操作化学物质时需要受到充分保护。
The OEL data can also be used to calculate the ADE for cleaning of equipment.
OEL数据也可以用于计算设备清洁的ADE值。
In certain cases where availability of pharmacological or toxicological data is limited, for example for chemicals, raw materials, intermediates or API’s in early phase clinical trials, cleaning limits based on fraction of clinical doses, LD50 or general cleaning limits may be calculated. In these cases, carcinogenic, genotoxic and potency effect of these structures should be evaluated by toxicologists.
在特定情况下，如果药性或毒性数据有限，例如，化学物质、原料、中间体或处于早期临床试验的原料药，其清洁限度可以基于临床剂量、半数致死量或一般清洁限度来计算。在这种情形下，需要有毒理学家对其结构的致癌性、基因毒性和效价影响进行评估。
The acceptance criteria for equipment cleaning should be based on visually clean in dry conditions and an analytical limit.
设备清洁的可接受标准应依据干燥状态下目视清洁及分析限度。
Unlike in pharmaceutical production, where residues on the surface of equipment may be 100 % carried over to the next product, in API production the carry-over risk is much lower for technical and chemical manufacturing reasons. Therefore all the following examples for calculating the limits can be adapted to the suitable situation by using different factors. A competent chemist with detailed knowledge about the equipment and the chemical processes and the properties of the chemicals involved such as solubility should justify this factor by evaluating the specific situation.
在制剂生产中，设备表面残留会100%被带入下一产品，而在原料药生产中，由于技术和化学生产原因，带入风险要低很多。因此，以下限度计算举例可以采用不同安全因子后用于适当的情形。应有一名具备设备和化学工艺知识，知晓所涉及化学品特性，如溶解度的化学家对特定情形下应使用的安全系统进行评估。
4.2. Methods of Calculating Acceptance Criteria 计算可接受标准的方法
4.2.1 Acceptance criteria using health-based data 采用健康基础数据的可接受标准
The Maximum Allowable Carryover (MACO) should be based upon the Acceptable Daily Exposure (ADE) when this data is available. The principle of MACO calculation is that you calculate your acceptable carry-over of your previous product, based upon the ADE, into your next product.
在可以获得可接受日暴露水平（ADE）值时，最大允许残留（MACO）应基于ADE计算。MACO计算的原则是基于ADE值，计算你允许从你的上一个产品带入下一个产品中的残留量。
Procedure 程序
Calculate the ADE (Acceptable Daily Exposure) according to the following equation and use the result for the calculation of the MACO.
根据以下公式计算ADE值，将结果用于MACO值的计算：
MACO = | NOAEL × BW |
UFc × MF × PK |
From the ADE number, a MACO can be calculated according to:
根据以下公式从ADE值计算MACO值：
MACO = | ADE previous × MBSnext |
TDDnext |
MACO = | ADE上一产品 × MBS下一产品 |
TDD下一产品 |
MACO | Maximum Allowable Carryover: acceptable transferred amount from the previous product into your next product (mg) | 允许最大残留：从上一产品带入下一产品的最大可接受量 |
ADE | Acceptable Daily Exposure (mg/day) | 可接受日暴露水平 |
NOAEL | No Observed Adverse Effect Level (mg/kg/day) | 未观察到副反应的水平 |
BW | Is the weight of an average adult (e.g. 70 kg) | 平均成人体重 |
UFc | Composite Uncertainty Factor: combination of factors which reflects the inter- individual variability, interspecies differences, sub-chronic-to-chronic extrapolation, LOEL-to-NOEL extrapolation, database completeness. | 组分不确定因子：反映单个变量之间、不同品种差异、亚急性折算为急性外推、LOEL折算为NOEL外推、数据完整性等补偿因素的综合系数 |
MF | Modifying Factor: a factor to address uncertainties not covered by the other factors | 修正因子：用于表达未被其它因子覆盖的不确定因素 |
PK | Pharmacokinetic Adjustments | 药动学调整 |
TDDnext | Standard Therapeutic Daily Dose for the next product (mg/day) | 下一产品的标准治疗日服用剂量 |
MBSnext | Minimum batch size for the next product(s) (where MACO can end up) (mg) | 下一产品的最小批量（MACO全部带入其中） |
The draft EMA/CHMP/CVMP/SWP/19430/2012 makes reference to the Permitted Daily Exposure (PDE). The PDE uses the no observed effect level (NOEL) instead of the no observed adverse effect level (NOAEL) used in the ADE calculation. The PDE may also be used as alternative to the ADE to calculate the MACO.
EMA/CHMP/CVMP/SWP/19430/2012草案中引用了允许日暴露（PDE）值。PDE采用了无可见影响水平（NOEL）代替无可见不良反应水平（NOAEL）用于ADE的计算。PDE值也可以用于代替ADE值来计算MACO值。
Instead of calculating each potential product change situation, the worst case scenario can be chosen. Then a case with most active API (lowest ADE) is chosen to end up in the following API with the smallest ratio of batch size divided with TDD (MBS/TDD ratio).
可以选择最差情况方案来替代对每个可能的产品更换情况下的残留计算。这时，可以选择活性最强的原料药（ADE最低）作为上一产品，选择批量TDD比值（MBS/TDD比值）最小的原料药作为后续产品。
If OEL data is available, the ADE can be derived from the OEL.
如果可以获得OEL值，则可以从OEL值计算ADE值。
4.2.2. Acceptance criteria based on Therapeutic Daily Dose 基于日治疗剂量的可接受标准
When limited toxicity data is available and the Therapeutic Daily Dose (TDD) is known, this calculation may be used. It is used for final product changeover API Process —A to API Process —B.
如果可以获得有限毒性数据和日治疗剂量（TDD）值，可以采用本计算方式。它可以用在原料药生产工艺A更换到原料药生产工艺B。
Procedure 程序
Establish the limit for Maximum Allowable Carryover (MACO) according to the following equation.
根据以下公式建立允许最大残留（MACO）值：
MACO = | TDD previous × MBSnext |
SF × TDDnext |
MACO = | TDD上一产品 × MBS下一产品 |
SF × TDD下一产品 |
MACO | Maximum Allowance Carryover: acceptable transferred amount from the previous product into your next product (mg) | 允许最大残留：从上一产品中可以接受转入下一产品的数量(mg) |
TDDprevious | Standard Therapeutic Daily Dose of the investigated product (in the same dosage from as TDDnext) (mg/day) | 所讨论的产品的日标准治疗剂量（以下一产品TDD计的同样剂量）(mg/day) |
TDDnext | Standard Therapeutic Daily Dose for the next product (mg/day) | 下一产品的日标准治疗剂量(mg/day) |
MBSnext | Minimum batch size for the next product(s) (where MACO can end up (mg) | 下一产品的最小批量（MACO会携入的产品）(mg) |
SF | Safety factor (normally 1000 is used in calculations based on TDD). | 安全系数（一般基于TDD值采用1000来计算） |
4.2.3. Acceptance criteria based on LD50 基于半致死量的可接受标准
In cases where no other data is available (e.g. ADE, OEL, TDD,…) and only LD50 data is available (e.g. chemicals, intermediates, detergents, …), the MACO can be based upon LD50 data.
如果没办法获得其它数据（例如，ADE、OEL、TDD等值），只能获得半数致死量数据（例如化学物质、中间体、清洁剂……），MACO可以基于半数致死量数据来计算。
Procedure 程序
Calculate the so called NOEL number (No Observable Effect Level) according to the following equation and use the result for the establishment of MACO (See [3] oe page 53 - for reference).
根据以下公式，计算NOEL值（无可见影响水平），用于建立MACO值（参见第53页的【3】部分，供参考）
From the NOEL number a MACO can be calculated according to:
从NOEL值，用以下公式计算MACO值：
MACO = | NOELprevious × MBSnext |
SFnext × TDD next |
MACO = | NOEL上一产品 × MBS下一产品 |
SF下一产品 × TDD 下一产品 |
MACO | Maximum Allowance Carryover: acceptable transferred amount from the previous product into your next product (mg) | 允许最大残留：从上一产品中可以接受转入下一产品的数量(mg) |
NOELprevious | No Observed Effect Level (mg/day) | 无可见影响水平(mg/day) |
LD50 | Lethal Dose 50 in mg/kg animal. The identification of the animal (mouse, rat etc.) and the way of entry (IV, oral etc.) is important (mg/kg) | 50%的动物致死量，单位mg/kg。动物种类（大鼠、小鼠等）和摄入途径（注射、口服等）也很重要(mg/kg) |
BW | Is the weight of an average adult (e.g. 70 kg) (kg) | 成年人平均体重（例如70kg）(kg) |
2000 | 2000 is an empirical constant | 经验常数 |
TDDnext | Standard Therapeutic Daily Dose for the next product (mg/day) | 下一产品的日标准治疗剂量(mg/day) |
MBSnext | Minimum batch size for the next product (s) (where MACO can end up) | 下一产品的最小批量（MACO会携入的产品）(mg) |
SFnext | Safety factor | 安全系数 |
The safety factor (SF) varies depending on the route of administration (see below). Generally a factor of 200 is employed when manufacturing APIs to be administered in oral dosage forms.
安全系数（SF）根据摄入途径不同而不同（见下）。一般系数200用于口服剂型原料药生产。
Safety factors: 安全系数
Topicals 10 – 100 局部给药
Oral products 100 – 1000 口服给药
Parenterals 1000 – 10 000 注射给药
4.2.4 General Limit as acceptance criteria 可接受标准的一般限度
If MACO calculations result in unacceptably high or irrelevant carryover figures, or toxicological data for intermediates are not known, the approach of a general limit may be suitable. Companies may choose to have such an upper limit as a policy. The general limit is often set as an upper limit for the maximum concentration (MAXCONC) of a contaminating substance in a subsequent batch.
如果MACO计算结果太高，不能接受，或者与带入数字不相关，或中间体毒性数据未知，则适用通用限度方法。公司可以选择例如一个最高限度作为原则。通用限度一般设定为一种污染物质在后续批次中最大浓度上限（MAXCONC）。
Procedure 程序
Establish MACOppm, based on a general limit, using the following equations.
利用以下公式，基于一个通用限度建立MACO限度，ppm为单位。
MACOppm = MAXCONC x MBS
MACOppm | Maximum Allowable Carryover: acceptable transferred amount from the investigated product (“previous”). Calculated from general ppm limit. | 允许最大残留：所讨论的产品（上一产品）被带入下一产品的可接受值，一般表达为ppm限度 |
MAXCONC | General limit for maximum allowed concentration (kg/kg or ppm) of “previous” substance in the next batch. | 允许上一产品在下一产品中的最大浓度通用限度（kg/kg或ppm） |
MBS | Minimum batch size for the next product(s) (where MACO can end up) | 下一产品的最小批量 |
E.g. for a general limit of 100 ppm: MACO = 0.01% of the minimum batch size (MBS), and for a general limit of 10 ppm: MACO = 0.001% of the minimum batch size (MBS).
例如，对于通用限度为100ppm：MACO = 最小批量（MBS）的0.01%，对于通用限度为10ppm：MACO = 最小批量（MBS）的0.001%。
Remarks: The ICH impurity document (Q 3) indicates that up to 0.1% of an individual unknown or 0.5% total unknowns may be present in the product being tested.
注：ICH杂质文件（Q3）指出，在被测试的产品中，单个未知杂质可以达0.1%，总未知杂质可以达到0.5%。
A general upper limit for the maximum concentration of a contaminating substance in a subsequent batch (MAXCONC) is often set to 5-500 ppm (100 ppm in APIs is very frequent) of the previous product into the next product depending on the nature of products produced from the individual company (e.g. toxicity, pharmacological activity …).
根据各公司所生产产品的属性不同（例如，毒性、药物活性等），从上一产品带入下一产品中的污染物质最大浓度通用上限通常设定为5-500ppm（原料药中100ppm是很常见的）。
The Threshold of Toxicological Concern (TTC) concept could be applied to intermediates or API’s with no clinical (e.g. early development) or toxicological data. This concept includes three categories of products with limited or no data:
毒性关注阈值（TTC）概念可以应用于没有临床（例如早期研发阶段）或毒性数据的中间体或原料药。这个概念将数据有限或没有数据的产品分为3个类别
l Products that are likely to be carcinogenic;
l 可能致癌的产品
l Products that are likely to be potent or highly toxic;
l 可能具有效价或高毒性的产品
l Products that are not likely to be carcinogenic, potent or highly toxic.
l 可能致癌、具有效价或高毒性的产品
The corresponding ADE’s recommended for these three categories are 1, 10, 100 μg/day, respectively.
对应此三类所推荐的ADE值分别为1、10和100μg/天。
Another possibility to calculate your ADE for intermediates or API’s, with no clinical or toxicological data (e.g. early development), is based upon the exposure duration of your next product. The values of the CHMP guideline on the Limits of Genotoxic Impurities (ref. EMEA/CHMP/SWP/431994/2007) can be used for your ADE.
在没有临床或毒性数据（例如研发早期）时，计算中间体或API的ADE还有另一个办法，就是基于下一产品的暴露时长。可以将CHMP指南“基因毒性杂质”（参见EMEA/CHMP/SWP/431994/2007）限度值可以用于ADE计算。
Note - If you decide to employ the concept of levels of cleaning (ref. section 5), then different safety factors (ppm limits) may be used for different levels. Especially if the product cleaned out is within the same synthetic chain and covered by the specification of the API, much higher (qualified) levels are acceptable.
注：如果你决定采用清洁水平概念（参见第5部分），则对于不同水平可以采用不同的安全系数（ppm限度）。特别是如果被清洁的产品是在同一条合成链中，且其限度包括在原料药的质量标准中，则残留水平较高（确认过的）时也是可以接受的。
4.2.5 Swab Limits 擦拭限度
If homogeneous distribution is assumed on all surfaces, a recommended value can be set for the content in a swab. The maximum allowable carry over from one batch to another can be established based on e.g. ADE, NOEL or TDD (see above). If the total direct contact surface is known, the target value for contamination per square meter can be calculated according equation 4.2.5-I. This can be used as basic information for preparation of a method of analysis and detection limit.
如果假定所有表面上残留的分布是均匀的，可以给擦拭样品设定一个推荐值。可以根据例如ADE值、NOEL或TDD（见上）设定一批到另一批的最大允许残留值。如果知道直接接触产品的总面积，则可以根据4.2.5-I公式计算单位面积上的污染目标值，该值可以在制订方法验证方案和检测限值时参考。
Equation 4.2.5-I Target value [μg/dm2] = | MACO[μg] |
Total surface [dm2] |
公式 4.2.5-I 目标值 [μg/dm2] = | MACO[μg] |
总表面积 [dm2] |
Also other methods with different swab limits for different surfaces in a piece of equipment and/or equipment train can be used. If the equipment can be divided in several parts, different swab limits may be taken for the different parts building up the equipment train. If the result of one part is exceeding the target value, the whole equipment train may still be within the MACO limit. The Carry Over is then calculated according equation 4.2.5-II (see below).
也可以对同一设备和/或设备链不同的表面使用不同的擦拭限度。如果设备被分为几个部分，对可以针对设备链不同部分采用不同的擦拭限度。如果一个部件的结果超出了目标值，整个设备链的残留值仍可能是在MACO的限度以内。这时，可以按公式4.2.5-II（见下）计算残留量。
During equipment qualification and cleaning validation hard to clean parts can be determined. Rather than declaring the hard to clean part as the worst case swab limit for the whole equipment train, it could be separated and dealt with as mentioned above. It should be noted that different types of surfaces (e.g. stainless steel, glass lined, Teflon) may show different recoveries during swabbing. In those cases it may be beneficial to divide the equipment train in several parts, and combine the results in a table or matrix. The total calculated amount should be below the MACO, and the individual swab results should not exceed the maximum expected residues established during cleaning validation / equipment qualification. Recovery studies and method validation are necessary when applying swabbing as a method to determine residues.
在设备确认和清洁验证中，可以确定哪个部件是难以清洁的。其实可以采用上述的方法来将难以清洁的部件分开来，而不需要采用最难清洁的部件作为最差擦拭情况的限度用于整个设备链。要注意不同材质表面（例如，不锈钢、搪玻璃、聚四氟乙烯）可能有不同的擦拭回收率。在这种情况下，如果把设备链划分为几个部分，将结果在一份表或类别中合并可能会比较好。合计数量应低于MACO值，单个擦拭结果不应超过在清洁验证/设备确认中所设立的最大高期望值。在使用擦拭方法测定残留量时，要进行回收率研究和方法验证。
Equation 公式 4.2.5-II
CO [μg] = Σ(Ai[dm2] × mi[μg/dm2]) |
|
|
CO | True (measured) total quantity of substance (possible carryover) on the cleaned surface in contact with the product, calculated from results of swab tests. | 采用擦拭检测结果计算出的与产品直接接触的已清洁表面实际总残留量 |
Ai | Area for the tested piece of equipment # i. | 所测试的 i 设备的面积 |
mi | Quantity in μg/dm2, for each swab per area of swabbed surface (normally 1 dm2) | 单位擦拭面积的残留数量 |
|手机版|药群论坛
( 蜀ICP备15007902号 )
收藏
支持
反对