辅料审计关注点

beiwei5du

APPENDIX A AUDITING CONSIDERATIONS
A1. Introduction
Many excipients are used in food, cosmetic or industrial products as well as in pharmaceuticals. Thus environmental conditions, equipment and operational techniques employed in excipient manufacture are often those of the chemical industry as opposed to the pharmaceutical industry. Chemical processes can produce impurities from side reactions. Careful process control is therefore essential to minimise levels of impurities and contamination.
Excipients are often manufactured on a large scale utilising continuous processing and automated process controls. Production equipment and processes vary depending on the type of excipient being produced, the scale of production and the type of operation (for example batch versus continuous process).
This appendix is intended to aid in the preparation by an excipient manufacturer for an audit. Both external and internal auditors (see also 8.2.2) will find this appendix useful in identifying the significant issues with respect to GMP and quality that require examination. This section will assist excipient manufacturers in identifying the key deliverables when adopting the GMP standards listed in the other sections of this Guide and help in planning an audit to verify the quality of the excipient manufacturing process and the manufacturer’s quality management system.
For additional information on auditing refer to the IPEC-Americas Good Manufacturing Practices Audit Guideline for Bulk Pharmaceutical Excipients. Also for guidance on the auditing process refer to the IQA PQG Monograph No 5 Pharmaceutical Auditing.
A2. GMP Principles
A2.1 Control of impurities and contamination
In general, the pharmaceutical customer does not perform further chemistry or purification steps on the excipient and it is used as purchased. Consequently, impurities present in the excipient are likely to be present in the drug product. Although dosage form manufacturers have some control over excipient quality through specifications, the excipient manufacturer has greater control over the physical characteristics, quality and the presence of impurities in the excipient they produce.
External contamination of the excipient can arise from the manufacturing environment. However, chemical processes used to manufacture excipients are often performed in closed systems that afford protection against such contamination, even when the reaction vessels are not located in buildings. The external environment may require suitable controls to avoid potential contamination wherever the excipient or in-process material is exposed.
A2.2 Excipient properties and functionality
Excipients are frequently used in different types of drug products where physical characteristics, such as particle size, may be important. While the finished dosage form manufacturer is primarily responsible for identifying the particular physical characteristics needed, it is also the responsibility of the excipient manufacturer to control excipient manufacturing processes adequately to ensure consistent conformance to excipient specifications. Wherever possible, consideration should be given to the end use of the excipient. This is particularly important if the excipient is a direct component of a sterile drug product or one that is claimed to be pyrogen-free.
A2.3 Consistency of manufacture and change control
A thorough understanding of the manufacturing process and effective control of change can best assure consistency of excipient quality from batch to batch. Implementation of changes may also have consequences for registration filings with regulatory agencies.
Changes in excipient manufacturing processes may result in changed physical or chemical properties of the excipient that are only evident during subsequent processing or in the finished dosage form. This is particularly important in the context of the pharmaceutical product approval process where bioequivalence comparisons are made between pivotal, clinical trial batch ("bio batch") production and commercial scale-up batches. Changes made to the excipient supplied for the commercial product from the excipient supplied for the bio batch should be such that they do not impact the quality and performance of the commercial drug product. Scale-up of excipients to commercial production may involve several stages and data may be required to demonstrate consistency between batches through the scale-up process.
A2.4 Traceability
Traceability of batch-related records to facilitate investigations and retrieval of product is also a key requirement of GMP.
A3. Application of GMP Principles
It is the responsibility of the excipient manufacturer to designate and document the rationale for the point in the manufacturing process at which appropriate GMP is to be applied. From this point on appropriate GMP should be applied. The manufacturer should apply a level of GMP to each manufacturing stage commensurate with the importance of that step in assuring product integrity. This may be demonstrated by means of the use of a risk assessment procedure (for example HACCP, FMEA).
The stringency of GMP in excipient production should increase as the process proceeds from early manufacturing to final stages, purification and packaging. Physical processing (for example granulation, coating or physical manipulation of particle size such as milling, micronising) as well as chemical processing of excipients should be conducted at least to the standards suggested by this Guide.
It should be recognised that all intermediates might not require testing. An excipient manufacturer should, however, be able to identify critical or key points in the manufacturing process where selective intermediate sampling and testing is necessary in order to monitor process performance.
A4. General Auditing Considerations
Audits of an excipient operation will be influenced by the purpose of the audit and the intended use of the excipient. The key stages of a production process should be examined to determine whether the manufacturer adequately controls these steps so the process performs consistently. Overall, an audit should assess the excipient manufacturer's capability to deliver a product that consistently meets established specifications.
The audit team may consist of engineers, laboratory analysts, purchasing agents, computer experts, maintenance or other appropriate personnel as appropriate to the scope and purpose of the audit. External auditors must respect confidentiality of the manufacturer’s processes and other disclosures.
An audit should focus on the quality-critical processing steps that are necessary to produce an excipient that meets the established physical and chemical criteria. These steps should be identified and controlled by the excipient manufacturer. Quality-critical processing steps can involve a number of unit operations or unit processes.
Quality-critical steps can include, but are not limited to, the following:
• phase changes involving the desired molecule, solvent, inert carrier or vehicle (for example dissolution, crystallisation, evaporation, drying, sublimation, distillation or absorption),
• phase separation (for example filtration or centrifugation),
• chemical changes involving the desired molecule (for example removal or addition of water of hydration, acetylation or formation of a salt),
• adjustments of the solution containing the molecule (for example pH adjustment),
• precise measurement of added excipient components, in-process solutions, recycled materials (for example weighing or volumetric measurements),
• mixing of multiple components,
• changes that occur in surface area, particle size or batch uniformity (for example milling, agglomeration or blending).
A5. Audit Check Points
A good approach for an excipient plant audit is a review of the following areas:
• nonconformances, such as the rejection of a batch that did not meet specifications, customer complaints, return of a product by a customer or retrieval of a product. The manufacturer should have determined the cause of the non-conformance, a report of the investigation prepared and subsequent corrective action initiated and documented. Records and documents should be reviewed to ensure that nonconformances are not the result of a poorly developed or inconsistent process,
• customer complaint files, such as reports that some aspect of the product is not entirely suitable for use, since these may be caused by impurities or inconsistencies in the excipient manufacturing process,
• change control logs to ascertain whether the company evaluates their significant changes to decide if the customer and/or regulatory authority should be notified,
• nonconforming products meeting or Material Review Board documents and/or equivalent records that demonstrate that the disposition of nonconforming product is handled in an appropriate manner by responsible individuals,
• master formula and production records for frequent revisions that may reveal problems in the excipient production process,
• evidence for the presence of unreacted intermediates and solvent residues in the finished excipient,
• materials management systems to ensure adequate control over nonconforming materials so they cannot be sold to customers or used in manufacturing without authorisation,
• review of a process flow diagram to aid understanding of the various processing stages. The critical stages and sampling points should be identified as part of the review of the processing records,
• review of contamination control measures.
In evaluating the adequacy of measures taken to prevent contamination and cross-contamination of materials in the process, it is appropriate to consider the following risk factors:
• the type of system (for example open or closed). Enclosed systems in chemical plants often are not closed when they are being charged and/or when the final product is being emptied. In addition, the same reaction vessels are sometimes used for different reactions,
• the form of the material (for example wet or dry),
• the stage of processing and use of the equipment and/or area (for example multi-purpose or dedicated),
• continuous versus batch production.
A6. Documentation and Record Review
Documentation required for the early steps in the process need not be as comprehensive as in the latter stages of the process. It is important that a chain of documentation exists and that this is complete when:
• the excipient can be identified and quantified for those processes where the molecule is produced during the course of the process. For batch production a theoretical mass balance may also be established with appropriate limits, as deviations from tolerance are a good indicator of a loss of control,
• an impurity or other substance likely to adversely affect the impurity profile or form of the molecule is identified and subsequent attempts are made to remove it.
As chemical-processing proceeds, a chain of documentation should be established which includes:
• a documented process,
• the identification of critical processing steps,
• appropriate production records,
• records of initial and subsequent batch numbers,
• records of raw materials used,
• comparison of test results against meaningful standards.
If significant deviations from the normal manufacturing process are recorded there should be evidence of suitable investigations and a review of the quality of the excipient.
Complete documentation should be continued throughout the remainder of the process for quality-critical processing steps until the excipient is packaged and delivered to the end user. The batch should be homogenous within the manufacturer’s specifications. This does not necessitate the final blending of continuous process material if process controls can demonstrate compliance to specifications throughout the batch.
In order to promote uniformity in excipient GMP inspections the following basic requirements should be established:
• that a unique batch number is assigned to the excipient which enables it to be traced through manufacture to release and certification,
• that suitable controls are in place for the preparation of a batch record for batch processing and/or a production record, log sheet or other appropriate documentation for continuous processing,
• demonstration that the batch has been prepared using GMP guidelines from the processing point at which excipient GMP has been determined to apply,
• confirmation that the batch is not combined with material from other batches for the purpose of either hiding or diluting an adulterated batch,
• records showing that the batch has been sampled in accordance with a sampling plan that ensures a representative sample of the batch,
• records that the batch has been analysed using scientifically established test methods designed to assure that the product meets the established standards, specifications and characteristics,
• adequate stability data to support the intended period of use of the excipient. These data can be obtained from historical data, actual studies on the specific excipient or from applicable “model product” studies that can reasonably be expected to simulate the performance of the specific excipient.

北重楼

有中文版吗

Maria2015

谢谢分享，好好学习！

beiwei5du

北重楼 发表于 2016-11-8 12:30
有中文版吗

暂没有，该段落是选自IPEC的辅料GMP

wanggui_929

楼主翻译下再上传最好

Maria2015

楼主请问一下，这个是哪个官方出的？在哪里可以找到呢？谢谢

beiwei5du

Maria2015 发表于 2016-11-9 11:17
楼主请问一下，这个是哪个官方出的？在哪里可以找到呢？谢谢

IPEC 官网上The Joint IPEC – PQG Good Manufacturing Practices Guide FOR PHARMACEUTICAL EXCIPIENTS

王雪1993

This does not necessitate the final blending of continuous process material if process controls can demonstrate compliance to specifications throughout the batch.这句话是什么意思啊？

Maria2015

beiwei5du 发表于 2016-11-9 11:56
IPEC 官网上The Joint IPEC – PQG Good Manufacturing Practices Guide FOR PHARMACEUTICAL EXCIPIENTS

好的，谢谢！

涛哥

附录 A 审计注意事项
A1. 简介
许多赋形剂用于食品、化妆品或工业产品以及药物中。因此，赋形剂制造中采用的环境条件、设备和操作技术通常是化学工业的，而不是制药工业的。化学过程会从副反应中产生杂质。因此，仔细的过程控制对于最大限度地减少杂质和污染水平至关重要。
辅料通常利用连续加工和自动化过程控制进行大规模生产。生产设备和工艺因生产辅料的类型、生产规模和操作类​​型（例如分批与连续工艺）而异。
本附录旨在帮助辅料制造商准备审核。外部和内部审核员（另见 8.2.2）都会发现本附录有助于识别需要检查的与GMP和质量有关的重大问题。本部分将帮助辅料制造商在采用本指南其他部分中列出的 GMP 标准时确定关键可交付成果，并帮助规划审核以验证辅料制造过程的质量和制造商的质量管理体系。
有关审核的更多信息，请参阅 IPEC-美洲散装药用辅料的良好生产规范审核指南。有关审核过程的指导，请参阅 IQA PQG 专着 No 5 Pharmaceutical Auditing。
A2。GMP 原则
A2.1 杂质和污染的控制
一般来说，制药客户不会对赋形剂进行进一步的化学或纯化步骤，而是按购买的方式使用。因此，赋形剂中存在的杂质很可能存在于药品中。尽管剂型制造商通过规格对辅料质量有一定的控制，但辅料制造商对其生产的辅料的物理特性、质量和杂质的存在有更大的控制。
辅料的外部污染可能来自生产环境。然而，用于制造赋形剂的化学过程通常在封闭系统中进行，即使反应容器不在建筑物中，也能防止此类污染。外部环境可能需要适当的控制，以避免在赋形剂或加工材料暴露于任何地方的潜在污染。
A2.2 辅料特性和功能
赋形剂经常用于不同类型的药物产品中，其中物理特性（如粒径）可能很重要。虽然成品剂型制造商主要负责确定所需的特定物理特性，但辅料制造商也有责任充分控制辅料制造过程以确保始终符合辅料规格。在可能的情况下，应考虑辅料的最终用途。如果赋形剂是无菌药品的直接成分或声称无热原的成分，这一点尤其重要。
A2.3 制造和变更控制的一致性
对生产过程的透彻了解和对变更的有效控制可以最好地确保不同批次的辅料质量的一致性。变更的实施也可能对监管机构的注册申请产生影响。
辅料制造工艺的变化可能会导致辅料的物理或化学性质发生变化，这些变化仅在后续加工过程中或成品剂型中才会显现。这在医药产品批准过程中尤为重要，在该过程中，在关键的临床试验批次（“生物批次”）生产和商业放大批次之间进行生物等效性比较。从为生物批次提供的赋形剂对商业产品提供的赋形剂所做的更改应不影响商业药物产品的质量和性能。将辅料放大到商业生产可能涉及几个阶段，并且可能需要数据来证明通过放大过程批次之间的一致性。
A2。
批次相关记录的可追溯性以方便产品的调查和检索也是 GMP 的关键要求。
A3。GMP 原则
的应用 辅料制造商有责任指定并记录生产过程中应用适当 GMP 的点的基本原理。从这一点开始，应该应用适当的 GMP。制造商应在每个制造阶段应用与确保产品完整性的重要性相称的 GMP 水平。这可以通过使用风险评估程序（例如 HACCP、FMEA）来证明。
随着工艺从早期制造到最后阶段、纯化和包装，辅料生产中 GMP 的严格性应提高。辅料的物理加工（例如制粒、包衣或物理处理，如研磨、微粉化）以及化学加工应至少按照本指南建议的标准进行。
应该认识到，所有中间体可能不需要测试。然而，辅料制造商应该能够识别制造过程中的关键点或关键点，其中需要选择性的中间取样和测试以监控过程性能。
A4。一般审计注意事项
辅料操作的审核将受到审核目的和辅料预期用途的影响。应检查生产过程的关键阶段，以确定制造商是否充分控制这些步骤，以使过程始终如一地执行。总体而言，审核应评估辅料制造商提供始终符合既定规格的产品的能力。
审核小组可能由工程师、实验室分析员、采购代理、计算机专家、维护人员或其他适合审核范围和目的的适当人员组成。外部审计师必须尊重制造商流程和其他披露的机密性。
审核应侧重于生产符合既定物理和化学标准的辅料所必需的质量关键加工步骤。这些步骤应由辅料制造商确定和控制。质量关键的处理步骤可能涉及许多单元操作或单元过程。
质量关键步骤可以包括但不限于以下内容：
• 涉及所需分子、溶剂、惰性载体或载体的相变（例如溶解、结晶、蒸发、干燥、升华、蒸馏或吸收），
• 相分离（例如过滤或离心），
• 涉及所需分子的化学变化（例如去除或添加水合水、乙酰化或形成盐），
• 调整含有分子的溶液（例如调整 pH 值），
• 精确测量添加的辅料成分、过程中的溶液、回收材料（例如称重或体积测量），
• 多种成分的混合，
• 表面积、粒度或批次均匀性（例如研磨、团聚或混合）发生的变化。
A5。审核检查点
辅料工厂审核的一个好方法是审查以下领域：
• 不合格品，例如拒收不符合规格的批次、客户投诉、客户退回产品或收回产品。制造商应确定不符合项的原因，准备调查报告，并启动随后的纠正措施并记录在案。应审查记录和文件，以确保不符合项不是由于流程开发不善或不一致造成的，
• 客户投诉文件，例如报告产品的某些方面不完全适合使用，因为这些可能是由辅料制造过程中的杂质或不一致引起的，
• 变更控制日志以确定公司是否评估其重大变更，以决定是否应通知客户和/或监管机构，
• 不合格品会议或材料审查委员会文件和/或等效记录，证明负责人以适当的方式处理不合格品，
• 主配方和生产记录，用于频繁修改可能揭示辅料生产过程中的问题，
• 成品赋形剂中存在未反应中间体和溶剂残留物的证据，
• 材料管理系统，以确保对不合格材料进行充分控制，使它们不能在未经授权的情况下出售给客户或用于制造，
• 审查工艺流程图以帮助理解各个处理阶段。关键阶段和采样点应确定为处理记录审查的一部分，
• 审查污染控制措施。
在评估为防止过程中材料污染和交叉污染而采取的措施的充分性时，应考虑以下风险因素：
• 系统类型（例如开放式或封闭式）。化工厂中的封闭系统在充电和/或清空最终产品时通常不会关闭。此外，相同的反应容器有时用于不同的反应，
• 材料的形式（例如湿的或干的），
• 设备和/或区域（例如多用途或专用）的处理和使用阶段，
• 连续生产与批量生产。
A6。文档和记录审查
流程早期步骤所需的文档不需要像流程后期阶段那样全面。重要的是存在一个文档链，并且在以下情况下这是完整的：
• 对于在过程过程中产生分子的那些过程，可以识别和量化赋形剂。对于批量生产，还可以建立具有适当限制的理论质量平衡，因为与公差的偏差是失控的良好指标，
• 识别可能对杂质分布或分子形式产生不利影响的杂质或其他物质，并随后尝试将其去除。
随着化学处理的进行，应建立一个文件链，其中包括：
• 一个记录的过程，
• 关键处理步骤的识别，
• 适当的生产记录，
• 初始和后续批号的记录，
• 所用原材料的记录，
• 将测试结果与有意义的标准进行比较。
如果记录了与正常生产过程的重大偏差，则应有适当调查的证据和对辅料质量的审查。
对于质量关键的加工步骤，应在整个过程的剩余过程中继续完整的文档记录，直到赋形剂被包装并交付给最终用户。批次应该在制造商的规格范围内是同质的。如果过程控制可以证明整个批次符合规范，则不需要对连续过程材料进行最终混合。
为了促进辅料 GMP 检查的一致性，应建立以下基本要求：
• 为辅料分配一个唯一的批号，使其能够从制造到发布和认证进行追踪，
• 有适当的控制措施来准备批处理的批处理记录和/或生产记录、日志表或其他适当的连续处理文件，
• 证明该批次是从确定适用辅料 GMP 的加工点开始使用 GMP 指南制备的，
• 确认该批次未与其他批次的材料混合以隐藏或稀释掺假批次，
• 显示该批次已按照确保该批次具有代表性样本的抽样计划进行抽样的记录，
• 记录该批次已使用科学确定的测试方法进行分析，旨在确保产品符合既定标准、规格和特性，
• 足够的稳定性数据来支持赋形剂的预期使用期限。这些数据可以从历史数据、特定辅料的实际研究或可合理预期模拟特定辅料性能的适用“模型产品”研究中获得。

电脑翻译了，手机看

lumang

王雪1993 发表于 2016-11-9 16:51
This does not necessitate the final blending of continuous process material if process controls can  ...

necessitate是使成为必要的意思，这句意思是如果工艺控制能够确保整批产品都符合要求的话，也不一定需要进行连续生产物料的最终混合。

wenzhao10

学习，学习 ！谢谢分享

小金库

感谢分享，先收藏