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FDA清洗过程验证检查指南(中英)(接续)

时间:2010年11月23日 ⁄ 分类: 验证 评论:0

  接上一扩篇。
  2.清洗过程记录
  程序和记录
  2. Cleaning Process Written
  Procedure and Documentation
  检查通过验证的清洗过程的程序的细节和特性,还有要求文件的数量。我们已经明白常规的标准操作规范(SOP),而其他人使用批记录或要求明确记录每个执行步骤的日志系统。执行不同的清洗步骤或程序的必要文件数量因为系统和清洗过程的复杂性、操作员的能力及对操作员的培训培训情况而变化。
  Examine the detail and specificity of the procedure for the (cleaning) process being validated, and the amount of documentation required. We have seen general SOPs, while others use a batch record or log sheet system that requires some type of specific documentation for performing each step. Depending upon the complexity of the system and cleaning process and the ability and training of operators, the amount of documentation necessary for executing various cleaning steps or procedures will vary.
  如果需要更复杂的清洗程序,记录关键清洗步骤(如某种原料药的合成工艺)是很重要的。这种情况下,设备本身的详细记录文档应包括谁清洗的和这些清洗可维持的时间的信息。然而,对于相关简易的清洗操作,执行基本文件的全部清洗过程就足够了。
  When more complex cleaning procedures are required, it is important to document the critical cleaning steps (for example certain bulk drug synthesis processes). In this regard, specific documentation on the equipment itself which includes information about who cleaned it and when is valuable. However, for relatively simple cleaning operations, the mere documentation that the overall cleaning process was performed might be sufficient.
  其它因素,如清洗历史、清洗后发现的残留物级别、和试结果的可变性,也可支配需要文件的数量。例如,如果在清洗后发现了不定的残留物级别,特别是认为可接受的清洗过程,那么就必须确定过程和操作员的执行是否有效。应该做适当的评估,如果认为操作员的执行有问题,就需要更多的文件(指南)和培训。
  Other factors such as history of cleaning, residue levels found after cleaning, and variability of test results may also dictate the amount of documentation required. For example, when variable residue levels are detected following cleaning, particularly for a process that is believed to be acceptable, one must establish the effectiveness of the process and operator performance. Appropriate evaluations must be made and when operator performance is deemed a problem, more extensive documentation (guidance) and training may be required.[separator]
  3.分析方法
  3. Analytical Methods
  应该确定用来检测残留物或污染物的分析方法的特征和灵敏度。用分析技术能检测生产和清洗过程中很低级别的残留物。如果没有发现污染物或残留物级别,并不意味着清洗后不存在残留物污染物。只能说明样品中不存在高于分析方法灵敏度或检测限度的污染物级别。公司应该通过结合从设备表面重新找回残留物及残留物回收率(如50%或者90%)的分析方法,对使用的分析方法进行挑战。这在根据取样结果下结论前是很必要的。不好的取样技术会有相反的测试结果(见下)。
  Determine the specificity and sensitivity of the analytical method used to detect residuals or contaminants. With advances in analytical technology, residues from the manufacturing and cleaning processes can be detected at very low levels. If levels of contamination or residual are not detected, it does not mean that there is no residual contaminant present after cleaning. It only means that levels of contaminant greater than the sensitivity or detection limit of the analytical method are not present in the sample. The firm should challenge the analytical method in combination with the sampling method(s) used to show that contaminants can be recovered from the equipment surface and at what level, i.e. 50% recovery, 90%, etc. This is necessary before any conclusions can be made based on the sample results. A negative test may also be the result of poor sampling technique (see below).
  4.取样
  4. Sampling
  通常有两种可接受的取样方法。最可取得方法是从设备表面直接取样。另一种方法是使用冲洗溶液。
  There are two general types of sampling that have been found acceptable. The most desirable is the direct method of sampling the surface of the equipment. Another method is the use of rinse solutions.
  a. 表面直接取样-确定使用的取样材料类型和对测试数据产生的影响,因为取样材料可以妨碍测试。例如,发现药签上粘合剂的干扰样品的分析。因此,在早期的确认程序中,保证取样媒介和溶剂(用于从媒介中萃取)的满意度和它们可以被使用是很重要的。
  a. Direct Surface Sampling - Determine the type of sampling material used and its impact on the test data since the sampling material may interfere with the test. For example, the adhesive used in swabs has been found to interfere with the analysis of samples. Therefore, early in the validation program, it is important to assure that the sampling medium and solvent (used for extraction from the medium) are satisfactory and can be readily used.

  直接取样的好处是可以评估难以清洗和相当容易接近的区域,使得可确定每个给出的表面区域的污染物或残留物的级别。另外,不能溶解的残留物可以通过物理切除的方法来取样。
  Advantages of direct sampling are that areas hardest to clean and which are reasonably accessible can be evaluated, leading to establishing a level of contamination or residue per given surface area. Additionally, residues that are "dried out" or are insoluble can be sampled by physical removal.
  b.冲洗样品-使用冲洗样品的两个好处是可以大面积的取样,而且可以对人为达不到或常规不能卸解的系统进行取样和评估。
  b. Rinse Samples - Two advantages of using rinse samples are that a larger surface area may be sampled, and inaccessible systems or ones that cannot be routinely disassembled can be sampled and evaluated.
  冲洗样品的一个缺点是,残留物或污染物可能不溶解或堵塞在设备中。用到的一种类似物是“赃罐”。在评价对不干净的药罐的清洗时,特别是那种有干结残留物的,不应该只看冲洗水是否干净,而应该看药罐是否干净。
  A disadvantage of rinse samples is that the residue or contaminant may not be soluble or may be physically occluded in the equipment. An analogy that can be used is the "dirty pot." In the evaluation of cleaning of a dirty pot, particularly with dried out residue, one does not look at the rinse water to see that it is clean; one looks at the pot.
  在验证清洗过程时,要核实确保对冲洗水中的残留物或污染物进行直接测量。例如,只是简单检测冲洗水的质量(它是否符合测试纲要)而不检测潜在的污染物的做法是不被认可的。
  Check to see that a direct measurement of the residue or contaminant has been made for the rinse water when it is used to validate the cleaning process. For example, it is not acceptable to simply test rinse water for water quality (does it meet the compendia tests) rather than test it for potential contaminates.
  C.常规的生产过程控制
  c. Routine Production In-Process Control
  监控,即间接检测,如导电率测试,在清洗过程取得验证之后,就可作为常规监控的数值。尤其对那些原料药生产商来说,反应物,反应堆或设备间的管道系统可以只是用冲洗溶液样品取样,这样做就很正确了。任何间接测试方法必须表明与设备的状况有关。在验证期间,公司必须对检测未清洗的设备的间接测试的结果不被认可进行记录存档。
  Monitoring - Indirect testing, such as conductivity testing, may be of some value for routine monitoring once a cleaning process has been validated. This would be particularly true for the bulk drug substance manufacturer where reactors and centrifuges and piping between such large equipment can be sampled only using rinse solution samples. Any indirect test method must have been shown to correlate with the condition of the equipment. During validation, the firm should document that testing the uncleaned equipment gives a not acceptable result for the indirect test.
  V.确立限度
  V. ESTABLISHMENT OF LIMITS
  FDA并不想设定决定清洗过程是否有效的认可参数或方法。因为原料药和成品剂型生产工业中使用设备和产品中的巨大差异,FDA这么做不太可行。公司确定残留物限度的根据应当合理基于生产商对涉及的原料的了解,而且应当是做的到并可证实的。为了确立合理的限度,明确分析方法的敏感性是很重要的。行业代表在著作或陈述中提到的一些限度包括分析检测级别如10ppM,生物活性级别如1/1000的正常治疗剂量,器官感觉级别如无可见残留物。
  FDA does not intend to set acceptance specifications or methods for determining whether a cleaning process is validated. It is impractical for FDA to do so due to the wide variation in equipment and products used throughout the bulk and finished dosage form industries. The firm's rationale for the residue limits established should be logical based on the manufacturer's knowledge of the materials involved and be practical, achievable, and verifiable. It is important to define the sensitivity of the analytical methods in order to set reasonable limits. Some limits that have been mentioned by industry representatives in the literature or in presentations include analytical detection levels such as 10 PPM, biological activity levels such as 1/1000 of the normal therapeutic dose, and organoleptic levels such as no visible residue.
  检查限度确立的方式。不像化学残留物(如活性成分,非活性成分和清洁剂)已经被清楚鉴定的成品药物,原料药生产工艺中也许还有没有进行化学鉴定的部分反应物和多余的副产品。在确定残留物限度时,也许只是集中注意主要的反应物做得并不够,因为也许有别的化学变异产物更难以除去。有的情况下,除了进行化学分析,薄层色谱分析(TLC)也是必要的。在原料药生产工艺中,特别是某些如类固醇的高效化学制品生产中,如果设备不是专用的,必须考虑副产品的问题。检查的目的就是要保证任何限度的根据都有科学道理。
  Check the manner in which limits are established. Unlike finished pharmaceuticals where the chemical identity of residuals are known (i.e., from actives, inactives, detergents) bulk processes may have partial reactants and unwanted by-products which may never have been chemically identified. In establishing residual limits, it may not be adequate to focus only on the principal reactant since other chemical variations may be more difficult to remove. There are circumstances where TLC screening, in addition to chemical analyses, may be needed. In a bulk process, particularly for very potent chemicals such as some steroids, the issue of by-products needs to be considered if equipment is not dedicated. The objective of the inspection is to ensure that the basis for any limits is scientifically justifiable.
  VI.其它问题
  VI. OTHER ISSUES
  a.无效对照药品
  a. Placebo Product
  为了评估和验证清洗过程,有的生产商在设备中按照与加工成品完全相同的操作参数进行无效对照药批次生产。然后检测无效对照药批次的样品的残留物。然而,我们的文件可以证明在使用无效药验证清洗过程时需要阐明的几个重要问题。
  In order to evaluate and validate cleaning processes some manufacturers have processed a placebo batch in the equipment under essentially the same operating parameters used for processing product. A sample of the placebo batch is then tested for residual contamination. However, we have documented several significant issues that need to be addressed when using placebo product to validate cleaning processes.
  任何人都不能保证,污染物在整个系统中均匀分布。例如,如果流出阀或掺和器的斜槽被污染,污染物就不可能均匀分布在无效药上,而是很可能集中在最初产出的批次上。另外,如果污染物或残留物上较大的颗粒,它也不可能均匀分布在无效药上。
  One cannot assure that the contaminate will be uniformly distributed throughout the system. For example, if the discharge valve or chute of a blender are contaminated, the contaminant would probably not be uniformly dispersed in the placebo; it would most likely be concentrated in the initial discharge portion of the batch. Additionally, if the contaminant or residue is of a larger particle size, it may not be uniformly dispersed in the placebo.
  有的公司假定,残留物的污染物会均一的从设备表面消失;这也不是一个有效的结论。最终,分析效果会被污染物的稀释而大大削弱。基于这些问题的存在,在冲洗,擦拭样品时要结合使用无效药方法。
  Some firms have made the assumption that a residual contaminant would be worn off the equipment surface uniformly; this is also an invalid conclusion. Finally, the analytical power may be greatly reduced by dilution of the contaminate. Because of such problems, rinse and/or swab samples should be used in conjunction with the placebo method.
  b.清洁剂
  b. Detergent
  如果在清洗中使用了清洁剂或肥皂,应该确定和考虑试图检测残留物时带来的难度。使用清洁剂的普遍问题就是其成分。许多清洁剂供应商并没有说明清洁剂的成分,这使生产商难以评估残留物。和产品残留物一样,生产商评估除去残留物的清洗过程的效用也是必要的和重要的。然而,与产品残留物不同的是,在清洗后不希望有清洁剂存在(或者超敏感检测的量很低)。清洁剂并不是生产工艺中的成分,加进去只是为了便于清洗。这样,它们就容易清除。另一方面,还要选择使用不同的清洁剂。
  If a detergent or soap is used for cleaning, determine and consider the difficulty that may arise when attempting to test for residues. A common problem associated with detergent use is its composition. Many detergent suppliers will not provide specific composition, which makes it difficult for the user to evaluate residues. As with product residues, it is important and it is expected that the manufacturer evaluate the efficiency of the cleaning process for the removal of residues. However, unlike product residues, it is expected that no (or for ultra sensitive analytical test methods - very low) detergent levels remain after cleaning. Detergents are not part of the manufacturing process and are only added to facilitate cleaning during the cleaning process. Thus, they should be easily removable. Otherwise, a different detergent should be selected.
  c.清洗前的检测
  c. Test Until Clean
  因为有的生产商在清洗前就进行检测,所以应当考察和评估检测和重测的结果。他们要检测,重新取样,重新检测设备或系统,直到达到被认可的残留物级别。因为系统或者设备经过被验证的清洗过程,所以不必进行重新取样,用的话也只适于很少的情况。持续的重新取样和重新检测只能说明,清洗过程没有达到验证要求,因为重新检测事实上证明了无效的清洗后仍然存在不被接受的残留物和污染物。
  Examine and evaluate the level of testing and the retest results since testing until clean is a concept utilized by some manufacturers. They test, resample, and retest equipment or systems until an "acceptable" residue level is attained. For the system or equipment with a validated cleaning process, this practice of resampling should not be utilized and is acceptable only in rare cases. Constant retesting and resampling can show that the cleaning process is not validated since these retests actually document the presence of unacceptable residue and contaminants from an ineffective cleaning process.
  VII.参考文献
  VII. REFERENCES
  1) J. Rodehamel, "Cleaning and Maintenance," Pgs 82-87, University of Wisconsin's Control Procedures in Drug Production Seminar, July 17-22, 1966, William Blockstein, Editor, Published by the University of Wisconsin, L.O.C.#66-64234.
  2) J.A. Constance, "Why Some Dust Control Exhaust Systems Don't Work," Pharm. Eng., January-February, 24-26 (1983).
  3) S.W. Harder, "The Validation of Cleaning Procedures," Pharm. Technol. 8 (5), 29-34 (1984)
  4) W.J. Mead, "Maintenance: Its Interrelationship with Drug Quality," Pharm. Eng. 7(3), 29-33 (1987).
  5) J.A. Smith, "A Modified Swabbing Technique for Validation of Detergent Residues in Clean-in-Place Systems," Pharm. Technol. 16(1), 60-66 (1992).
  6) Fourman, G.L. and Mullen, M.V., "Determining Cleaning Validation Acceptance Limits for Pharmaceutical Manufacturing Operations," Pharm. Technol. 17(4), 54-60 (1993).
  7) McCormick, P.Y. and Cullen, L.F., in Pharmaceutical Process Validation, 2nd Ed., edited by I.R. Berry and R.A. Nash, 319-349 (1993)


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