2. 体现了FDA项目整合和机构改革的变化，明确了工艺和设施办公室（Office of Process and Facilities, OPF）和药品质量办公室（Office of Pharmaceutical Quality, OPQ）等新机构的在批准前检查中的职能，及其和监管事务办公室（Office of Regulatory Affairs, ORA）的新工作机制。
Objective 1: Readiness for Commercial Manufacturing
目标1：为商业化生产准备就绪
Determine whether the establishment has a quality system that is designed to achieve sufficient control over the facility and commercial manufacturing operations.
(a) Objective 1a: Manufacturing and laboratory changes, deviations, and trends relating to the development of drug substance and drug product manufacturing have been adequately evaluated.
Assess whether investigations relevant to the proposed commercial manufacturing process have been appropriately evaluated, including related laboratory, equipment maintenance, and manufacturing (e.g., development batch) investigations. Investigative reports or resultant change control reports for development issues may not always be as comprehensive as required for marketed drugs. Nonetheless, the firm should appropriately document, record, and objectively assess all development data and information, including but not limited to data submitted in or generated after the filing of an application or DMF. Examples of deviations related to the application include:
Laboratory issues that occurred during or after method validation, such as:
o Unexpected laboratory events—including results that fall outside of the specifications or acceptance criteria—identified during stability, in-process, and release testing for the exhibit batches, biobatches, or process validation batches.
o Discrepancies found while conducting the method validation (particularly issues that may have occurred in its final stages) or technical transfer.
o Changes in an analytical method after completing the method validation or technical transfer because of an inability to use the method as written.
Related equipment maintenance and performance issues, which could affect the proposed commercial manufacturing process, such as:
o Calibration failures associated with commercial equipment planned for use in the proposed commercial batch record.
o CGMP investigations and trending associated with the performance and capability of the commercial equipment planned for use in the proposed commercial batch record.
o CGMP manufacturing investigations (e.g., significant deviations, rejects, complaints/returns) and trending associated with similarly manufactured marketed drug products at the establishment.
o 对该企业已上市药品类似生产中相关的 CGMP 生产调查（比如，重大偏差，拒收，投诉/退货），以及趋势分析。
o 严重的设备故障。
Evaluate these investigations to determine if the establishment is prepared for the proposed commercial manufacturing process at commercial scale, including that there are appropriate controls in place to detect and mitigate the most likely and significant problems.
Related regulations for finished pharmaceuticals: 21 CFR 211.67(a) addresses equipment maintenance, cleaning, and sanitization. For the validation/verification of analytical methods, refer to CFR 211.160–211.167 and 211.194. Refer to 21 CFR 211.100, 211.192, and 211.198 for regulations relating to product deviations and investigations.
Related guidance for APIs: For preventative maintenance, cleaning, and sanitization of equipment, refer to International Council for Harmonisation (ICH) guidance for industry Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients, section V.B, Equipment Maintenance and Cleaning. For the validation of analytical methods, refer to ICH Q7, section XII.H, Validation of Analytical Methods. For guidance relating to product investigations, refer to ICH Q7, sections VI.E, Batch Production Records, VI.G, Batch Production Record Review, VIII.A, Production Operations, and XV, Complaints and Recalls.
(b) Objective 1b: A sound and appropriate program for sampling, testing, and evaluating components (including APIs), in-process materials, finished products, containers, and closures for purposes of releasing materials or products has been established, including a robust supplier qualification program.
Review sampling plans and procedures, including those described in batch records, to evaluate the establishment’s intended approach to sampling components, in-process materials, and finished product. Sampling plans must ensure that representative samples are collected and tested/examined as verification of product quality. The method of selecting samples, number of samples taken, statistical criteria for the number of samples taken, and acceptable and unacceptable quality limits should be scientifically based and appropriate. Consider the extent of experiences with the proposed commercial process when determining adequacy of sampling plans. Also, areas of criticality or process vulnerability should receive special attention because these points in a process generally require more extensive sampling. For example, a firm may consider the use of process analytical technology (PAT).
For finished dosage establishments purchasing multiple lots of components from an external supplier, evaluate the suppliers’ variability and the specification criteria. For finished dosage and API establishments, the firm should establish statistical criteria for component, in-process, and finished product variability in comparison with the specification criteria. If the division believes that it is warranted, a for-cause sample of the component can be collected. Contact the laboratory for instructions before collection.
Related regulations for finished pharmaceuticals: 21 CFR 211.160 requires sampling plans (and specifications) to be scientifically based and appropriate; 21 CFR 211.165 requires sampling plans for finished product to be in writing and to meet appropriate statistical quality control criteria before batch release; 21 CFR 211.110, 211.134, and 211.166 address sampling in the context of in-process materials, labeling, and stability, respectively; and 21 CFR 211.84 requires that sampling of components, drug product containers, and closures be representative.
Related guidance for APIs: Refer to ICH Q7, section XI.A, General Controls, which recommends sampling plans to be scientifically sound and appropriate and sampling procedures to be in writing. This section also addresses sampling in the context of raw materials, intermediates, APIs, and labels and packaging materials. ICH Q7, section VII.C, Sampling and Testing of Incoming Production Materials, recommends that samples should be representative of the batch of material from which they are taken. ICH Q7, section XI.F, Expiry and Retest Dating, addresses sampling in the context of performing a retest.
Coverage of this element is warranted for new construction or facility design, new uses of existing equipment that pose potential risks (e.g., addition of a highly potent product), or equipment operations unique to the application under review. Observe the firm’s operations as you inspect the facility and after reviewing blueprints, floor plans, or as-built diagrams of utility systems (such as the purified water system piping and air handling systems). Verify that the establishment has facility, equipment cleaning, maintenance, and utility system controls in place (or planned) that are designed to prevent contamination that could be deleterious to the specific application product, and ensure that controls are in place to prevent cross-contamination of and by the application product.
Inspect new construction intended for the application product, as well as the installation of new equipment, and other significant changes to the existing facility or practices relating to material/personnel flow. Evaluate the establishment’s proposed compliance with related CGMP requirements. Pay special attention to the new product or marketed products that are highly potent or potentially sensitizing in humans to ensure that the product is not liable to contaminate existing products in the facility.
Related regulations for finished pharmaceuticals: 21 CFR 211.42–211.67 require facility and equipment controls to prevent contamination and to ensure well-organized operations.
Related guidance for APIs: Refer to ICH Q7, sections IV.A (Design and Construction) through V.B (Equipment Maintenance and Cleaning), which recommend facility and equipment controls to prevent contamination and to ensure well-organized operations.
(d) Objective 1d: Adequate procedures exist for batch release, change control, and investigating failures, deviations, complaints, and adverse events, and for reporting this information to FDA (e.g., through FARs).
Review the establishment’s quality and change procedures and audit the establishment’s compliance to its procedures for already marketed product, as appropriate (e.g., selecting actual failures, deviations, and complaint investigations; related adverse drug experience reports, including submissions to FDA if required). Note that the regulations for adverse drug experience (ADE) reporting only cover prescription and application products. If significant problems are found with the establishment’s existing complaint handling and reporting procedures, the division should consider recommending a directed inspection of the ADE reporting system under compliance program 7353.001—Postmarketing Adverse Drug Experience (PADE) Reporting Inspections.
Related regulations for finished pharmaceuticals: 21 CFR 211.192 and 211.198 address failure and complaint investigations; 21 CFR 211.100 addresses deviations from written manufacturing procedures; 21 CFR 314.81(b)(1) is the requirement for submitting a FAR to FDA; 21 CFR 314.80 addresses ADE reporting requirements for application products; and 21 CFR 310.305 addresses ADE reporting requirements for marketed prescription drugs for human use without approved NDAs.
Related guidance for APIs: Refer to ICH Q7, sections VI.E, Batch Production Records, VI.G, Batch Production Record Review, VIII.A, Production Operations, and XV, Complaints and Recalls, for guidance relating to failure and complaint investigations and deviations from written manufacturing procedures.
(e) Objective 1e: The proposed commercial process and manufacturing batch record, including instructions, processing parameters, and process control measures, are feasible and scientifically and objectively justified. This objective is linked to the firm’s process validation program across the product lifecycle.
An essential part of the inspection is evaluating the justification for the proposed commercial process and the manufacturing batch record. The extent of process validation activities that have been completed at the time of application submission can vary, but, at a minimum, data from Stage I process validation should be available. To establish process feasibility, evaluate Stage I process validation development studies and knowledge gained about manufacturing operation vulnerabilities, including the influence of raw material variability, and determine the purpose of each study performed by the firm. For example, review studies conducted to establish process controls or process parameters directly related to the CQAs of the drug product in the application. These may include studies of worst-case or boundary conditions to establish proven acceptable ranges or more sophisticated studies involving design of experiment or multivariate analysis modeling. Assess the protocols and their execution and the reliability of the data and conclusions. Include the inadequacy of data to support the filed processing approach, or the proposed master batch record provided during inspection, on Form FDA 483.
This evaluation includes a review of the firm’s scale-up studies (e.g., the scale-up from the biobatch, or pivotal batches, to a larger (interim or full) scale batch). The firm may need to change its proposed commercial process as scale-up studies are completed and knowledge is gained. Such changes alone are not a violation and should not be cited as a deficiency. However, if feasible, discuss these findings with the OPF manufacturing assessor to determine the impact of such changes on the objectives of this compliance program.
Determine and report the firm's projected timeline for completion of additional process validation activities and additional planned studies and their purpose. Though not required at the time of the PAI, completion of certain planned studies, including Stage 2 of process validation, may demonstrate that the product can be reliably manufactured at commercial scale. If the firm states that it has completed the process validation activities necessary to distribute the finished drug product (i.e., completion of Stage 2, Process Performance Qualification), fully audit and assess these studies and conclusions. These include studies and experiments to scientifically optimize processing parameters and other manufacturing instructions for significant processing steps. Additional studies typically include commercial-scale batches (conformance batches) that are manufactured at the site in accordance with the master batch and production control record using qualified commercial-scale equipment and utilities and trained production personnel. These commercial-scale studies are typically conducted in accordance with a formal protocol and are intended to confirm the process design before commercial launch. They also establish a level of reproducibility and consistency at nominal processing conditions. One of the firm’s conclusions from these Stage 2 process validation studies must be that a high level of assurance was achieved in that the commercial process is capable of consistently delivering quality product meeting its CQAs. Though not required at the time of the PAI, the manufacturer is expected to plan for sufficient ongoing evaluation (Stage 3, Continued Process Verification) of the manufacturing process once marketing approval has been granted by CDER.
Thoroughly examine results and data of manufactured batches to determine if unresolved issues exist with the commercial control strategy. Listed below are examples of situations requiring follow-up:
The drug product or API does not meet its CQAs, and root cause has not been determined.
Batch records, in-process data, or process monitoring records reveal an unexpected highly variable process and the reason is unknown.
Inconsistent execution of the batch record and manufacturing instructions or operator workarounds (possible indication of poor process design or training).
Control measures do not appear to align with raw development data (e.g., important parameters or material attributes that impact CQAs are not being monitored or measured at the appropriate frequency).
Sampling and monitoring plans for Stage 2 process validation (e.g., process qualification) are not justified or are insufficient based on raw development data.
The data justifying critical process parameters are inadequate.
Review completed studies in the process validation lifecycle for related drugs to evaluate the firm’s capabilities and procedures. Interviewing key employees, such as the lead validation engineer, may be helpful in assessing a firm's ability to implement a sound process and control strategy. List deficiencies in these studies on Form FDA 483, and advise the firm that appropriate corrections must be completed before commercial distribution of the first batch.
If unable to provide sufficient process validation lifecycle coverage, state as such in the inspection report. Divisions should cover these processes during the next surveillance or postapproval inspection.
ORA and CDER review of information may overlap because applicants are being encouraged to share more product and process development information with CDER in accordance with FDA guidance. The investigator should incorporate CDER insights into the inspectional evaluation of the proposed commercial process and should discuss inspectional findings regarding the adequacy of the establishment’s Stage 2 process validation plans (i.e., process performance qualification plans) with OPF. The investigator should discuss process performance qualification plan issues with the firm, document the discussion in the EIR for CDER review, and, when applicable, document pertinent observations on Form FDA 483.
OPQ requires that certain data be filed to demonstrate that aseptic filling and sterilization processes are validated before approval is granted. OPF’s review of this summary information is complemented by FDA’s on-site inspection of these operations. Evaluating the adequacy of process validation at a facility is critical to ensure implementation of reproducible processes.
The investigator may find that the inspected establishment was not responsible for performing some of the process development activities and studies, and that reports for development studies are not available for inspection. The investigator should collect information about each establishment involved in process development (e.g., name, address, responsible person, work performed). This information should be included in the EIR. The OPF manufacturing assessor will then determine if additional facilities need to be evaluated or inspected.
Related regulations for finished pharmaceuticals: 21 CFR 211.100(a) and 211.110 require developing a well-designed and reproducible process, and 21 CFR 211.22 covers the quality unit’s responsibilities. Aseptic and sterilization processes are required to be validated by 21 CFR 211.113(b) and 211.42.
Related guidance for APIs: Refer to ICH Q7, sections XII.A (Validation Policy) through XII.E (Process Validation Program) for guidance regarding process validation.
