10.5. Ó¦µ±¶ÔÇå½à¹¤ÒÕÓÐÄÄЩӰÏìÇå½àЧ¹ûºÍÇå½àÐÔÄܵıäÁ¿½øÐÐÆÀ¹À£¬ÀýÈç²Ù×÷Ô±¡¢³ÌÐòÖеÄϸ½ÚÏñÁÜϴʱ¼äµÈ£¬Èô±äÁ¿¾¹ý֤ʵ£¬ÄÇôӦ¿¼Âǽ«×î²îÌõ¼þ×÷ΪÇå½àÑéÖ¤Ñо¿µÄ»ù´¡¡£
10.6. Limits for the carryover of product residues should be based on a toxicological evaluation. The justification for the selected limits should be documented in a risk assessment which includes all the supporting references. Limits should be established for the removal of any cleaning agents used. Acceptance criteria should consider the potential cumulative effect of multiple items of equipment in the process equipment train.
10.6. ²úÆ·²ÐÁôµÄЯ´øÏÞ¶ÈÓ¦¸ù¾Ý¶¾ÀíѧÆÀ¼Û£¬ÏÞ¶ÈÑ¡ÔñµÄÒÀ¾ÝÓ¦ÔÚ°üº¬²Î¿¼ÎļþµÄ·çÏÕÆÀ¹ÀÖÐдÃ÷£¬»¹Ó¦µ±¸ø³öËùʹÓÃÇå½à¼Á²ÐÁôµÄÏÞ¶È£¬¿É½ÓÊܱê×¼ÖÆ¶¨Ê±»¹Ó¦µ±¿¼Âǹ¤ÒÕÉ豸Çåµ¥Öжà¸öÉ豸DZÔÚµÄÀÛ»ýЧӦ¡£
10.6.1.Therapeutic macromolecules and peptides are known to degrade and denature when exposed to pH extremes and/or heat, and may become pharmacologically inactive. A toxicological evaluation may therefore not be applicable in these circumstances.
10.6.1. ÒÑÖªÖÎÁÆÐÔ´ó·Ö×ÓºÍëÄÁ´ÔÚpH³¬¹ýÏÞÖÆ»ò¼ÓÈȵÄÇé¿öÏ»ᷢÉú½µ½âºÍ±äÐÔ£¬ÓпÉÄÜʧȥҩÀíѧ»îÐÔ£¬»ùÓÚ¶¾ÀíѧµÄÆÀ¼ÛÔÚÕâÖÖÇé¿öÏÂÓпÉÄܲ»ÊÊÓᣠ10.6.2.If it is not feasible to test for specific product residues, other
representative parameters may be selected, e.g. total organic carbon (TOC) and conductivity.
10.6.2. Èç¹ûûÓа취¿ÉÒÔ¼ì²âÌØ¶¨µÄ²úÆ·²ÐÁô£¬¿ÉÒÔʹÓÃÆäËû´ú±íÐÔ²ÎÊý£¬±ÈÈç×ÜÓлú̼£¨TOC£©ºÍµçµ¼ÂÊ¡£
10.7. The risk presented by microbial and endotoxin contamination should be considered during the development of cleaning validation protocols. 10.7.
ÔÚÖÆ¶¨Çå½àÑéÖ¤·½°¸Ê±£¬Ó¦¿¼ÂÇ¿ÉÄܳöÏÖµÄ΢ÉúÎïºÍϸ¾úÄÚ¶¾ËØ·çÏÕ¡£
10.8. The influence of the time between manufacture and cleaning and the time between cleaning and use should be taken into account to define dirty and clean hold times for the cleaning process.
10.8. Çå½à¹¤ÒÕÖУ¬Ó¦¿¼ÂÇÉú²úÍê³ÉÖÁÇå½à¿ªÊ¼ÒÔ¼°Çå½àºóÖÁÔÙ´ÎʹÓõÄʱ¼ä¼ä¸ô£¬ÒÔÃ÷È·ÔàÉ豸ºÍ¸É¾»É豸µÄ´æ·Åʱ¼ä¡£
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10.9. Where campaign manufacture is carried out, the impact on the ease of cleaning at the end of the campaign should be considered and the maximum length of a campaign (in time and/or number of batches) should be the basis for cleaning validation exercises.
10.9. ²ÉÓÃÁ¬ÐøÐÔÉú²úʱ£¬Ó¦¿¼ÂÇÔÚÉú²ú½áÊøºó½øÐÐÇå½àµÄÄÑÒ׳̶ȣ¬²¢½«×Á¬ÐøÉú²úµÄʱ¼ä£¨ÒÔʱ¼äºÍ/»òÉú²úÅú´Î¼Æ£©×÷ΪÇå½àÑéÖ¤µÄ»ù´¡¡£ 10.10. Where a worst case product approach is used as a cleaning validation model, a scientific rationale should be provided for the selection of the worst case product and the impact of new products to the site assessed. Criteria for determining the worst case may include solubility, cleanability, toxicity and potency.
10.10. µ±²ÉÓÃ×î²îÌõ¼þ²úÆ·µÄ·½·¨×÷ΪÇå½àÑé֤ģʽʱ£¬Ó¦´ÓÈܽâÐÔ¡¢¿ÉÇå½àÐÔ¡¢¶¾ÐÔºÍЧ¼ÛµÈ·½Ãæ¿ÆÑ§ºÏÀíµÄ½âÊÍΪʲôѡÔñ¸Ã²úÆ·×÷Ϊ×î²îÌõ¼þµÄ²úÆ·£¬²¢ÔÚÓÐвúÆ·ÒýÈëʱӦÆÀ¹ÀÆäÓ°Ïì¡£
10.11. Cleaning validation protocols should specify or reference the locations to be sampled, the rationale for the selection of these locations and define the acceptance criteria.
10.11. Çå½àÑéÖ¤·½°¸ÖÐÓ¦Ö¸Ã÷»òÒýÓÃÈ¡ÑùλÖã¬Ñ¡ÔñÕâЩλÖõÄÀíÓÉ£¬Ã÷È·¿É½ÓÊܱê×¼¡£
10.12. Sampling should be carried out by swabbing and/or rinsing or by other means depending on the production equipment. The sampling materials and method should not influence the result. Recovery should be shown to be possible from all product contact materials sampled in the equipment with all the sampling methods used.
10.12. ¿ÉÒÔ¸ù¾ÝÉú²úÉ豸ѡÔñ²ÁÊá¢ÁÜÏ´»òÆäËû·½·¨½øÐÐÈ¡Ñù£¬µ«È¡Ñù²ÄÁϺͷ½·¨Ó¦²»Ó°Ïì¼ì²â½á¹û£¬Ó¦Ö¤Ã÷ËùʹÓõÄÈ¡Ñù·½·¨´ÓÓë²úÆ·½Ó´¥µÄ²»Í¬²ÄÖʵÄÉ豸±íÃæÉÏÈ¡ÑùµÄ»ØÊÕÂʶ¼ÊÇÊÊÓõġ£
10.13. The cleaning procedure should be performed an appropriate number of times based on a risk assessment and meet the acceptance criteria in order to prove that the cleaning method is validated.
10.13. Ó¦»ùÓÚ·çÏÕÆÀ¹À¾ö¶¨Çå½à³ÌÐòÓ¦ÖØ¸´Ö´ÐеĴÎÊý£¬ÇÒÇå½à³ÌÐòÓ¦·ûºÏ¿É½ÓÊܱê×¼£¬ÒÔ´ËÖ¤Ã÷Çå½à·½·¨ÊǾ¹ýÑéÖ¤µÄ¡£
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10.14. Where a cleaning process is ineffective or is not appropriate for some equipment, dedicated equipment or other appropriate measures should be used for each product as indicated in chapters 3 and 5 of EudraLex, Volume 4, Part I.
10.14. ÈçµÚËľíµÚÒ»²¿·ÖµÚ3Õº͵Ú5ÕÂËùÊö£¬ÈôÇå½à¹¤ÒÕÊÇÎÞЧµÄ»ò²»ÊʺÏijÀàÉ豸£¬ÄÇô¶Ôÿ¸ö²úƷӦʹÓÃרÓÃÉ豸»òÆäËûÊÊÒ˵ķ½·¨¡£
10.15. Where manual cleaning of equipment is performed, it is especially important that the effectiveness of the manual process should be confirmed at a justified frequency.
10.15. µ±Ê¹ÓÃÊÖ¹¤Çå½àÉ豸ʱ£¬ÐëÈ·¶¨Ò»¸öºÏÊÊµÄÆµÂÊÒÔÈ·ÈÏÈ˹¤Çå½àµÄÓÐЧÐÔÊǷdz£ÖØÒªµÄ¡£ 11. CHANGE CONTROL 11. ±ä¸ü¿ØÖÆ
11.1. The control of change is an important part of knowledge management and should be handled within the pharmaceutical quality system.
11.1. ±ä¸ü¿ØÖÆÊÇ֪ʶ¹ÜÀíÖÐÖØÒªµÄÒ»²¿·Ö£¬Ó¦µ±ÔÚÒ©Æ·ÖÊÁ¿¹ÜÀíÌåϵÖеõ½Ó¦Óá£
11.2. Written procedures should be in place to describe the actions to be taken if a planned change is proposed to a starting material, product component, process, equipment, premises, product range, method of production or testing, batch size, design space or any other change during the lifecycle that may affect product quality or reproducibility.
11.2. µ±³öÏÖÆðʼÎïÁÏ¡¢Ô¸¨ÁÏ¡¢¹¤ÒÕ¡¢É豸¡¢ÉèÊ©¡¢²úÆ··¶Î§¡¢Éú²ú»ò¼ìÑé·½·¨¡¢ÅúÁ¿¡¢Éè¼Æ¿Õ¼ä»ò¿ÉÄÜÔÚ²úÆ·ÉúÃüÖÜÆÚÖÐÓ°Ïì²úÆ·ÖÊÁ¿»òÖØÏÖÐÔµÄÆäËû±ä¸üµÈ×÷Ϊ¼Æ»®ÐÔ±ä¸ü±»Ìá³öʱ£¬Ó¦ÓÐÊéÃæµÄ³ÌÐòÀ´ÃèÊö¼Æ»®ÐÔ±ä¸ü³öÏÖʱӦ²ÉÈ¡µÄÐж¯¡£
11.3. Where design space is used, the impact on changes to the design space should be considered against the registered design space within the marketing authorization and the need for any regulatory actions assessed.
11.3. µ±Éæ¼°µ½Éè¼Æ¿Õ¼äʱ£¬Ó¦¶ÔÕÕÉÏÊÐÅú×¼µÄ×¢²áÉè¼Æ¿Õ¼ä£¬¿¼ÂDZä¸ü¶ÔÉè¼Æ¿Õ¼äµÄÓ°ÏìÒÔ¼°ÊÇ·ñÐèÒª²ÉȡһЩ·¨¹æÐж¯¡£
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11.4. Quality risk management should be used to evaluate planned changes to determine the potential impact on product quality, pharmaceutical quality systems, documentation, validation, regulatory status, calibration,
maintenance and on any other system to avoid unintended consequences and to plan for any necessary process validation, verification or requalification efforts.
11.4. Ó¦µ±Ê¹ÓÃÖÊÁ¿·çÏÕ¹ÜÀíÀ´ÆÀ¹À¼Æ»®ÐÔ±ä¸ü¶Ô²úÆ·ÖÊÁ¿¡¢Ò©Æ·ÖÊÁ¿ÏµÍ³¡¢Îļþ¡¢ÑéÖ¤¡¢·¨¹æ×´Ì¬¡¢Ð£×¼¡¢Î¬»¤ºÍÆäËûϵͳ´øÀ´µÄDZÔÚÐÔÓ°Ï죬ÒÔ±ÜÃâ²»¿ÉÔ¤Áϵĺó¹ûºÍ²ÉÈ¡¹¤ÒÕÑéÖ¤¡¢È·ÈÏ»òÔÙÈ·ÈϵıØÒªÐÔ¡£
11.5. Changes should be authorised and approved by the responsible persons or relevant functional personnel in accordance with the pharmaceutical quality system.
11.5. ±ä¸üÐèÒª±»ÊÚȨ£¬²¢¾¹ý¸ºÔðÈË»òÖÊÁ¿¹ÜÀíÌåϵÖй涨ÓÐÏàÓ¦Ö°ÄܵÄÈËÔ±½øÐÐÅú×¼¡£
11.6. Supporting data, e.g. copies of documents, should be reviewed to confirm that the impact of the change has been demonstrated prior to final approval.
11.6. Ö§³ÖÐÔÊý¾Ý£¨ÈçÎļþµÄ¸´Ó¡£©Ó¦½øÐÐÉóºË£¬ÒÔÈ·±£±ä¸üµÄÓ°ÏìÔÚ±ä¸ü×îÖÕÉóÅúǰµÃµ½Ö¤Êµ¡£
11.7. Following implementation, and, where appropriate, an evaluation of the effectiveness of change should be carried out to confirm that the change has been successful.
11.7. ºóÐøÖ´Ðм°±ØÒªÊ±ºò£¬Ó¦µ±¶Ô±ä¸üµÄÓÐЧÐÔ½øÐÐÆÀ¹À£¬ÒÔÖ¤Ã÷±ä¸üÊdzɹ¦µÄ¡£
12. GLOSSARY 12. ´Ê»ã±í
Definitions of terms relating to qualification and validation which are not given in other sections of the current EudraLex, Volume 4, are given below. ÏÖÐÐGMPµÚËľíÆäËû²¿·Ö¹ØÓÚÈ·ÈϺÍÑé֤ûÓгöÏÖµÄÊõÓﶨÒåÈçÏ£º Bracketing approach.
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