日期：2018-02-11 / 人气： / 来源：http://www.rzfanyi.com/ 作者：译声翻译公司
10. STORAGE AND DISTRIBUTION 10.储存和分发
10.1 Warehousing Procedures 10.1 入库程序
10.10 Facilities should be available for the storage of all materials under appropriate conditions (e.g., controlled temperature and humidity when necessary). Records should be maintained of these conditions if they are critical for the maintenance of material characteristics.
10.11 Unless there is an alternative system to prevent the unintentional or unauthorized use of quarantined, rejected, returned, or recalled materials, separate storage areas should be assigned for their temporary storage until the decision as to their future use has been made.
10.2 Distribution Procedures 10.2 分发程序
10.20 APIs and intermediates should only be released for distribution to third parties after they have been released by the quality unit(s). APIs and intermediates can be transferred under quarantine to another unit under the company’s control when authorized by the quality unit(s) and if appropriate controls and documentation are in place.
10.21 APIs and intermediates should be transported in a manner that does not adversely affect their quality.
10.22 Special transport or storage conditions for an API or intermediate should be stated on the label.
10.23 The manufacturer should ensure that the contract acceptor (contractor) for transportation of the API or intermediate knows and follows the appropriate transport and storage conditions.
10.24 A system should be in place by which the distribution of each batch of intermediate and/or API can be readily determined to permit its recall.
11. LABORATORY CONTROLS 11.实验室控制
11.1 General Controls 11.1 控制通则
11.10 The independent quality unit(s) should have at its disposal adequate laboratory facilities.
11.11 There should be documented procedures describing sampling, testing, approval, or rejection of materials and recording and storage of laboratory data. Laboratory records should be maintained in accordance with Section 6.6.
11.12 All specifications, sampling plans, and test procedures should be scientifically sound and appropriate to ensure that raw materials, intermediates, APIs, and labels and packaging materials conform to established standards of quality and/or purity. Specifications and test procedures should be consistent with those included in the registration/filing. There can be specifications in addition to those in the registration/filing. Specifications, sampling plans, and test procedures, including changes to them, should be drafted by the appropriate organizational unit and reviewed and approved by the quality unit(s).
11.13 Appropriate specifications should be established for APIs in accordance with accepted standards and consistent with the manufacturing process. The specifications should include control of impurities (e.g., organic impurities, inorganic impurities, and residual solvents). If the API has a specification for microbiological purity, appropriate action limits for total microbial counts and objectionable organisms should be established and met. If the API has a specification for endotoxins, appropriate action limits should be established and met.
11.14 Laboratory controls should be followed and documented at the time of performance. Any departures from the above-described procedures should be documented and explained.
11.15 Any out-of-specification result obtained should be investigated and documented according to a procedure. This procedure should include analysis of the data, assessment of whether a significant problem exists, allocation of the tasks for corrective actions, and conclusions. Any resampling and/or retesting after OOS results should be performed according to a documented procedure.
11.16 Reagents and standard solutions should be prepared and labeled following written procedures. Use by dates should be applied, as appropriate, for analytical reagents or standard solutions.
11.17 Primary reference standards should be obtained, as appropriate, for the manufacture of APIs. The source of each primary reference standard should be documented. Records should be maintained of each primary reference standard’s storage and use in accordance with the supplier’s recommendations. Primary reference standards obtained from an officially recognized source are normally used without testing if stored under conditions consistent with the supplier’s recommendations.
11.18 Where a primary reference standard is not available from an officially recognized source, an in-house primary standard should be established. Appropriate testing should be performed to establish fully the identity and purity of the primary reference standard. Appropriate documentation of this testing should be maintained.
11.19 Secondary reference standards should be appropriately prepared, identified, tested, approved, and stored. The suitability of each batch of secondary reference standard should be determined prior to first use by comparing against a primary reference standard. Each batch of secondary reference standard should be periodically requalified in accordance with a written protocol.
11.2 Testing of Intermediates and APIs 11.2 中间体和原料药的测试
11.20 For each batch of intermediate and API, appropriate laboratory tests should be conducted to determine conformance to specifications.
11.21 An impurity profile describing the identified and unidentified impurities present in a typical batch produced by a specific controlled production process should normally be established for each API. The impurity profile should include the identity or some qualitative analytical designation (e.g., retention time), the range of each impurity observed, and classification of each identified impurity (e.g., inorganic, organic, solvent). The impurity profile is normally dependent upon the production process and origin of the API. Impurity profiles are normally not necessary for APIs from herbal or animal tissue origin. Biotechnology considerations are covered in ICH guidance Q6B.
11.22 The impurity profile should be compared at appropriate intervals against the impurity profile in the regulatory submission or compared against historical data to detect changes to the API resulting from modifications in raw materials, equipment operating parameters, or the production process.
11.23 Appropriate microbiological tests should be conducted on each batch of intermediate and API where microbial quality is specified.
11.3 Validation of Analytical Procedures 11.3 分析方法的验证
See Section 12. 见第12章
11.4 Certificates of Analysis 11.4 分析报告单
11.40 Authentic certificates of analysis should be issued for each batch of intermediate or API on request.
11.41 Information on the name of the intermediate or API including, where appropriate, its grade, the batch number, and the date of release should be provided on the certificate of analysis. For intermediates or APIs with an expiry date, the expiry date should be provided on the label and certificate of analysis. For intermediates or APIs with a retest date, the retest date should be indicated on the label and/or certificate of analysis.
11.42 The certificate should list each test performed in accordance with compendial or customer requirements, including the acceptance limits, and the numerical results obtained (if test results are numerical).
11.43 Certificates should be dated and signed by authorized personnel of the quality unit(s) and should show the name, address, and telephone number of the original manufacturer. Where the analysis has been carried out by a repacker or reprocessor, the certificate of analysis should show the name, address, and telephone number of the repacker/reprocessor and reference the name of the original manufacturer.
11.44 If new certificates are issued by or on behalf of repackers/reprocessors, agents or brokers, these certificates should show the name, address, and telephone number of the laboratory that performed the analysis. They should also contain a reference to the name and address of the original manufacturer and to the original batch certificate, a copy of which should be attached.
11.5 Stability Monitoring of APIs 11.5 原料药的稳定性监测
11.50 A documented, on-going testing program should be established to monitor the stability characteristics of APIs, and the results should be used to confirm appropriate storage conditions and retest or expiry dates.
11.51 The test procedures used in stability testing should be validated and be stability indicating.
11.52 Stability samples should be stored in containers that simulate the market container. For example, if the API is marketed in bags within fiber drums, stability samples can be packaged in bags of the same material and in small-scale drums of similar or identical material composition to the market drums.
11.53 Normally, the first three commercial production batches should be placed on the stability monitoring program to confirm the retest or expiry date. However, where data from previous studies show that the API is expected to remain stable for at least 2 years, fewer than three batches can be used.
11.54 Thereafter, at least one batch per year of API manufactured (unless none is produced that year) should be added to the stability monitoring program and tested at least annually to confirm the stability.
11.55 For APIs with short shelf-lives, testing should be done more frequently. For example, for those biotechnological/biologic and other APIs with shelf-lives of one year or less, stability samples should be obtained and should be tested monthly for the first three months, and at 3-month intervals after that. When data exist that confirm that the stability of the API is not compromised, elimination of specific test intervals (e.g., 9-month testing) can be considered.
11.56 Where appropriate, the stability storage conditions should be consistent with the ICH guidances on stability.
11.6 Expiry and Retest Dating 11.6 有效期和复验期
11.60 When an intermediate is intended to be transferred outside the control of the manufacturer’s material management system and an expiry or retest date is assigned, supporting stability information should be available (e.g., published data, test results).
11.61 An API expiry or retest date should be based on an evaluation of data derived from stability studies. Common practice is to use a retest date, not an expiration date.
11.62 Preliminary API expiry or retest dates can be based on pilot scale batches if (1) the pilot batches employ a method of manufacture and procedure that simulates the final process to be used on a commercial manufacturing scale and (2) the quality of the API represents the material to be made on a commercial scale.
11.63 A representative sample should be taken for the purpose of performing a retest.
11.7 Reserve/Retention Samples 11.7 留样
11.70 The packaging and holding of reserve samples is for the purpose of potential future evaluation of the quality of batches of API and not for future stability testing purposes.
11.71 Appropriately identified reserve samples of each API batch should be retained for 1 year after the expiry date of the batch assigned by the manufacturer, or for 3 years after distribution of the batch, whichever is longer. For APIs with retest dates, similar reserve samples should be retained for 3 years after the batch is completely distributed by the manufacturer.
11.72 The reserve sample should be stored in the same packaging system in which the API is stored or in one that is equivalent to or more protective than the marketed packaging system. Sufficient quantities should be retained to conduct at least two full compendial analyses or, when there is no pharmacopoeial monograph, two full specification analyses.
12. VALIDATION 12.验证
12.1 Validation Policy 12.1 验证方针
12.10 The company’s overall policy, intentions, and approach to validation, including the validation of production processes, cleaning procedures, analytical methods, in-process control test procedures, computerized systems, and persons responsible for design, review, approval, and documentation of each validation phase, should be documented.
12.11 The critical parameters/attributes should normally be identified during the development stage or from historical data, and the necessary ranges for the reproducible operation should be defined. This should include:
Defining the API in terms of its critical product attributes
Identifying process parameters that could affect the critical quality attributes of the API
Determining the range for each critical process parameter expected to be used during routine manufacturing and process control
12.12 Validation should extend to those operations determined to be critical to the quality and purity of the API.
12.2 Validation Documentation 12.2 验证文件
12.20 A written validation protocol should be established that specifies how validation of a particular process will be conducted. The protocol should be reviewed and approved by the quality unit(s) and other designated units.
12.21 The validation protocol should specify critical process steps and acceptance criteria as well as the type of validation to be conducted (e.g., retrospective, prospective, concurrent) and the number of process runs.
12.22 A validation report that cross-references the validation protocol should be prepared, summarizing the results obtained, commenting on any deviations observed, and drawing the appropriate conclusions, including recommending changes to correct deficiencies.
12.23 Any variations from the validation protocol should be documented with appropriate justification.
12.3 Qualification 12.3 确认
12.30 Before initiating process validation activities, appropriate qualification of critical equipment and ancillary systems should be completed. Qualification is usually carried out by conducting the following activities, individually or combined:
Design Qualification (DQ): documented verification that the proposed design of the facilities, equipment, or systems is suitable for the intended purpose
Installation Qualification (IQ): documented verification that the equipment or systems, as installed or modified, comply with the approved design, the manufacturer’s recommendations and/or user requirements
Operational Qualification (OQ): documented verification that the equipment or systems, as installed or modified, perform as intended throughout the anticipated operating ranges
Performance Qualification (PQ): documented verification that the equipment and ancillary systems, as connected together, can perform effectively and reproducibly based on the approved process method and specifications
12.4 Approaches to Process Validation 12.4 工艺验证的方法
12.40 Process Validation (PV) is the documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce an intermediate or API meeting its predetermined specifications and quality attributes.
12.41 There are three approaches to validation. Prospective validation is the preferred approach, but there are situations where the other approaches can be used. These approaches and their applicability are discussed here.
12.42 Prospective validation should normally be performed for all API processes as defined in 12.1. Prospective validation for an API process should be completed before the commercial distribution of the final drug product manufactured from that API.
12.43 Concurrent validation can be conducted when data from replicate production runs are unavailable because only a limited number of API batches have been produced, API batches are produced infrequently, or API batches are produced by a validated process that has been modified. Prior to the completion of concurrent validation, batches can be released and used in final drug product for commercial distribution based on thorough monitoring and testing of the API batches. 12.43 有时由于原料药生产批号有限，原料药批号不是经常生产，或原料药是用验证过的，但已变更的工艺生产的，无法从连续生产中得到数据，可进行同步验证。同步验证完成之前，只要对原料药批号进行了充分的监控和测试，这些批号可以放行并用于最终制剂药的商业销售。
12.44 An exception can be made for retrospective validation well-established processes that have been used without significant changes to API quality due to changes in raw materials, equipment, systems, facilities, or the production process. This validation approach may be used where:
1. Critical quality attributes and critical process parameters have been identified
2. Appropriate in-process acceptance criteria and controls have been established
3. There have not been significant process/product failures attributable to causes other than operator error or equipment failures unrelated to equipment suitability
4. Impurity profiles have been established for the existing API
12.45 Batches selected for retrospective validation should be representative of all batches produced during the review period, including any batches that failed to meet specifications, and should be sufficient in number to demonstrate process consistency. Retained samples can be tested to obtain data to retrospectively validate the process.
12.5 Process Validation Program 12.5 工艺验证的程序
12.50 The number of process runs for validation should depend on the complexity of the process or the magnitude of the process change being considered. For prospective and concurrent validation, three consecutive successful production batches should be used as a guide, but there may be situations where additional process runs are warranted to prove consistency of the process (e.g., complex API processes or API processes with prolonged completion times). For retrospective validation, generally data from 10 to 30 consecutive batches should be examined to assess process consistency, but fewer batches can be examined if justified.
12.51 Critical process parameters should be controlled and monitored during process validation studies. Process parameters unrelated to quality, such as variables controlled to minimize energy consumption or equipment use, need not be included in the process validation.
12.52 Process validation should confirm that the impurity profile for each API is within the limits specified. The impurity profile should be comparable to, or better than, historical data and, where applicable, the profile determined during process development or for batches used for pivotal clinical and toxicological studies.
12.6 Periodic Review of Validated Systems 12.6验证系统的定期审核
12.60 Systems and processes should be periodically evaluated to verify that they are still operating in a valid manner. Where no significant changes have been made to the system or process, and a quality review confirms that the system or process is consistently producing material meeting its specifications, there is normally no need for revalidation.
12.7 Cleaning Validation 12.7 清洗验证
12.70 Cleaning procedures should normally be validated. In general, cleaning validation should be directed to situations or process steps where contamination or carryover of materials poses the greatest risk to API quality. For example, in early production it may be unnecessary to validate equipment cleaning procedures where residues are removed by subsequent purification steps. 12.70 通常应当验证清洗程序。一般来说，清洗验证应当针对那些如果受到污染或偶然带入异物就会对原料药的质量带来极大危险的情况或工序。例如，在生产的前期阶段，可能就无需验证设备的清洗程序，那里的残留物会被后面的纯化步骤除去。
12.71 Validation of cleaning procedures should reflect actual equipment usage patterns. If various APIs or intermediates are manufactured in the same equipment and the equipment is cleaned by the same process, a representative intermediate or API can be selected for cleaning validation. This selection should be based on the solubility and difficulty of cleaning and the calculation of residue limits based on potency, toxicity, and stability.
12.72 The cleaning validation protocol should describe the equipment to be cleaned, procedures, materials, acceptable cleaning levels, parameters to be monitored and controlled, and analytical methods. The protocol should also indicate the type of samples to be obtained and how they are collected and labeled.
12.73 Sampling should include swabbing, rinsing, or alternative methods (e.g., direct extraction), as appropriate, to detect both insoluble and soluble residues. The sampling methods used should be capable of quantitatively measuring levels of residues remaining on the equipment surfaces after cleaning. Swab sampling may be impractical when product contact surfaces are not easily accessible due to equipment design and/or process limitations (e.g., inner surfaces of hoses, transfer pipes, reactor tanks with small ports or handling toxic materials, and small intricate equipment such as micronizers and microfluidizers).
12.74 Validated analytical methods having sensitivity to detect residues or contaminants should be used. The detection limit for each analytical method should be sufficiently sensitive to detect the established acceptable level of the residue or contaminant. The method’s attainable recovery level should be established. Residue limits should be practical, achievable, verifiable, and based on the most deleterious residue. Limits can be established based on the minimum known pharmacological, toxicological, or physiological activity of the API or its most deleterious component.
12.75 Equipment cleaning/sanitation studies should address microbiological and endotoxin contamination for those processes where there is a need to reduce total microbiological count or endotoxins in the API, or other processes where such contamination could be of concern (e.g., non-sterile APIs used to manufacture sterile products).
12.76 Cleaning procedures should be monitored at appropriate intervals after validation to ensure that these procedures are effective when used during routine production. Equipment cleanliness can be monitored by analytical testing and visual examination, where feasible. Visual inspection can allow detection of gross contamination concentrated in small areas that could otherwise go undetected by sampling and/or analysis.
12.8 Validation of Analytical Methods 12.8 分析方法的验证
12.80 Analytical methods should be validated unless the method employed is included in the relevant pharmacopoeia or other recognized standard reference. The suitability of all testing methods used should nonetheless be verified under actual conditions of use and documented. 12.80 分析方法应当进行验证，除非采用的方法列在相关的药典或其它公认的参照标准中。然而，所有测试方法的适应性应当在实际使用条件下加以证实，并归档备查。
12.81 Methods should be validated to include consideration of characteristics included within the ICH guidances on validation of analytical methods. The degree of analytical validation performed should reflect the purpose of the analysis and the stage of the API production process.
12.82 Appropriate qualification of analytical equipment should be considered before initiating validation of analytical methods.
12.83 Complete records should be maintained of any modification of a validated analytical method. Such records should include the reason for the modification and appropriate data to verify that the modification produces results that are as accurate and reliable as the established method. 12.83已验证过的分析方法的任何修改都应当保存完整的记录。这类记录应当包括修改的理由和合适的数据，以证实该修改所产生的结果和规定的方法同样准确、可靠。