|
ICH Q7要点
1. Introduction The Guide as a whole does not cover safety aspects for the personnel engaged in the manufacture, nor aspects of protection of the environment. These controls are inherent responsibilities of the manufacturer and are governed by national laws. 2. Quality Management 2.1 Principles The system for managing quality should encompass the organisational structure, procedures, processes and resources, as well as activities necessary to ensure confidence that the API will meet its intended specifications for quality and purity. All quality related activities should be defined and documented. 2.2 Internal Audits (Self Inspection) Audit findings and corrective actions should be documented and brought to the attention of responsible management of the firm. Agreed corrective actions should be completed in a timely and effective manner. 2.3 Product Quality Review Regular quality reviews of APIs should be conducted with the objective of verifying the consistency of the process. Such reviews should normally be conducted and documented annually and should include at least: l A review of critical in-process control and critical API test results; l A review of all batches that failed to meet established specification(s); l A review of all critical deviations or non-conformances and related investigations; l A review of any changes carried out to the processes or analytical methods; l A review of results of the stability monitoring program; l A review of all quality-related returns, complaints and recalls; and l A review of adequacy of corrective actions. The results of this review should be evaluated and an assessment made of whether corrective action or any revalidation should be undertaken. Reasons for such corrective action should be documented. Agreed corrective actions should be completed in a timely and effective manner. 3. Buildings and Facilities 3.1 Water Where the manufacturer of a non-sterile API either intends or claims that it is suitable for use in further processing to produce a sterile drug (medicinal) product, water used in the final isolation and purification steps should be monitored and controlled for total microbial counts, objectionable organisms, and endotoxins. 4. Process Equipment 4.1 Design and Construction Major equipment (e.g., reactors, storage containers) and permanently installed processing lines used during the production of an intermediate or API should be appropriately identified. A set of current drawings should be maintained for equipment and critical installations (e.g., instrumentation and utility systems). 4.2 Equipment Maintenance and Cleaning Where equipment is assigned to continuous production or campaign production of successive batches of the same intermediate or API, equipment should be cleaned at appropriate intervals to prevent build-up and carry-over of contaminants (e.g. degradants or objectionable levels of micro-organisms). Non-dedicated equipment should be cleaned between production of different materials to prevent cross-contamination. 4.3 Computerized Systems If system breakdowns or failures would result in the permanent loss of records, a back-up system should be provided. A means of ensuring data protection should be established for all computerized systems. Data can be recorded by a second means in addition to the computer system. 5. Documentations and Records 5.1 Documentation System and Specifications All production, control, and distribution records should be retained for at least 1 year after the expiry date of the batch. For APIs with retest dates, records should be retained for at least 3 years after the batch is completely distributed. 5.2 Equipment Cleaning and Use Record If equipment is dedicated to manufacturing one intermediate or API, then individual equipment records are not necessary if batches of the intermediate or API follow in traceable sequence. In cases where dedicated equipment is employed, the records of cleaning, maintenance, and use can be part of the batch record or maintained separately. 5.3 Records of Raw Materials, Intermediates, API Labelling and Packaging Materials Master (approved) labels should be maintained for comparison to issued labels. 6. Materials Management 6.1 Sampling and Testing of Incoming Production Materials At least one test to verify the identity of each batch of material should be conducted, with the exception of the materials described below in 7.32. A supplier's Certificate of Analysis can be used in place of performing other tests, provided that the manufacturer has a system in place to evaluate suppliers. Supplier approval should include an evaluation that provides adequate evidence (e.g., past quality history) that the manufacturer can consistently provide material meeting specifications. Full analyses should be conducted on at least three batches before reducing in-house testing. However, as a minimum, a full analysis should be performed at appropriate intervals and compared with the Certificates of Analysis. Reliability of Certificates of Analysis should be checked at regular intervals. Processing aids, hazardous or highly toxic raw materials, other special materials, or materials transferred to another unit within the company’s control do not need to be tested if the manufacturer’s Certificate of Analysis is obtained, showing that these raw materials conform to established specifications. Visual examination of containers, labels, and recording of batch numbers should help in establishing the identity of these materials. The lack of on-site testing for these materials should be justified and documented. 6.2 Storage Materials stored in fiber drums, bags, or boxes should be stored off the floor and, when appropriate, suitably spaced to permit cleaning and inspection. 7. Production and In-process Controls 7.1 Production Operations Actual yields should be compared with expected yields at designated steps in the production process. Expected yields with appropriate ranges should be established based on previous laboratory, pilot scale, or manufacturing data. Deviations in yield associated with critical process steps should be investigated to determine their impact or potential impact on the resulting quality of affected batches. 7.2 In-process Sampling and Controls Out-of-specification (OOS) investigations are not normally needed for in-process tests that are performed for the purpose of monitoring and/or adjusting the process. 7.3 Blending Batches of Intermediates or APIs For the purpose of this document, blending is defined as the process of combining materials within the same specification to produce a homogeneous intermediate or API. In-process mixing of fractions from single batches (e.g., collecting several centrifuge loads from a single crystallization batch) or combining fractions from several batches for further processing is considered to be part of the production process and is not considered to be blending. The expiry or retest date of the blended batch should be based on the manufacturing date of the oldest tailings or batch in the blend. 8. Packaging and Identification Labeling of APIs and Intermediates 8.1 Label Issuance and Control Access to the label storage areas should be limited to authorized personnel. All excess labels bearing batch numbers or other batch-related printing should be destroyed. Returned labels should be maintained and stored in a manner that prevents mix-ups and provides proper identification. Obsolete and out-dated labels should be destroyed. Printing devices used to print labels for packaging operations should be controlled to ensure that all imprinting conforms to the print specified in the batch production record. 8.2 Packaging and Labeling Operations Intermediate or API containers that are transported outside of the manufacturer's control should be sealed in a manner such that, if the seal is breached or missing, the recipient will be alerted to the possibility that the contents may have been altered. 9. Laboratory Controls 9.1 General Controls 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. 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. 9.2 Certificates of Analysis Authentic Certificates of Analysis should be issued for each batch of intermediate or API on request. 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 repacked or preprocessor, the Certificate of Analysis should show the name, address and telephone number of the repacker/reprocessor and a reference to the name of the original manufacturer. 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. 9.3 Reserve/Retention Samples 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. Appropriately identified reserve samples of each API batch should be retained for one year after the expiry date of the batch assigned by the manufacturer, or for three years after distribution of the batch, whichever is the longer. For APIs with retest dates, similar reserve samples should be retained for three years after the batch is completely distributed by the manufacturer. Sufficient quantities should be retained to conduct at least two full compendia analyses or, when there is no pharmacopoeia monograph, two full specification analyses. 10. Validation 10.1 Validation Policy The critical parameters/attributes should normally be identified during the development stage or from historical data, and the ranges necessary for the reproducible operation should be defined. Any variations from the validation protocol should be documented with appropriate justification. 10.2 Qualification Before starting process validation activities, appropriate qualification of critical equipment and ancillary systems should be completed. 10.3 Approaches to Process Validation Prospective validation performed on an API process should be completed before the commercial distribution of the final drug product manufactured from that API. 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. 10.4 Process Validation Program 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 ten to thirty consecutive batches should be examined to assess process consistency, but fewer batches can be examined if justified. 10.5 Periodic Review of Validated Systems 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. 10.6 Validation of Analytical Methods 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. 11. Change Control After the change has been implemented, there should be an evaluation of the first batches produced or tested under the change. The potential for critical changes to affect established retest or expiry dates should be evaluated. If necessary, samples of the intermediate or API produced by the modified process can be placed on an accelerated stability program and/or can be added to the stability monitoring program. 12. Rejection and Re-use of Materials 12.1 Reprocessing Continuation of a process step after an in-process control test has shown that the step is incomplete is considered to be part of the normal process. This is not considered to be reprocessing. 12.2 Reworking Before a decision is taken to rework batches that do not conform to established standards or specifications, an investigation into the reason for non-conformance should be performed. Batches that have been reworked should be subjected to appropriate evaluation, testing, stability testing if warranted, and documentation to show that the reworked product is of equivalent quality to that produced by the original process. Concurrent validation is often the appropriate validation approach for rework procedures. This allows a protocol to define the rework procedure, how it will be carried out, and the expected results. If there is only one batch to be reworked, then a report can be written and the batch released once it is found to be acceptable. Procedures should provide for comparing the impurity profile of each reworked batch against batches manufactured by the established process. Where routine analytical methods are inadequate to characterize the reworked batch, additional methods should be used. |
|
|
