Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_101_библиотеки_им_акад_М_И_Перельмана

the quality system, and the desired work culture (e.g., team building, communication, change, behavior). Under a quality framework, education should emphasize employees’ essential job duties and relevant cGMP regulatory criteria.

cGMP regulations necessitate that equipment be qualied, calibrated, cleaned, and maintained to prevent contamination and mix- ups. In terms of calibration and maintenance, most standard quality device types require standards higher than those outlined in cGMP requirements. While cGMP rules give equal importance to both process and testing equipment, most quality programs primarily focus on testing equipment.

When a producer outsources, they enlist a third party to handle operational processes that are inherently their responsibility. For instance, a manufacturer might outsource packaging and labeling tasks or cGMP compliance training. Quality systems involve contracts (termed quality agreements) that outline materials or services, quality prerequisites, obligations, and communi­cation protocols. The producer ensures that the contracted company is accredited under a quality scheme. Personnel from both the contracting rm and the contracting manufacturer should be appropriately qualied and managed for performance in accordance with the contracting rm’s quality framework. The quality standards of the contracting rm and contracting manufacturer should align. It’s crucial within a quality scheme that ofcers of the contracting manufacturer are well- versed in the contract’s precise specications. Concurrently, the QCU holds the respon­sibility of authorizing or rejecting goods or services provided under the agreement, adhering to cGMP requirements.

The elements of a quality framework and cGMP regulation standards for manufacturing operations share many similarities. It’s important to reiterate that FDA compliance and inspection systems pri­marily focus on cGMP regulations.

Manufacturers and contractors are mandated to scrutinize the components and services they pro­vide under the quality systems model; however, the testing framework differs from cGMP rules.

Under the quality systems plan, suppliers must undergo regular audits. The manufacturer may observe the supplier’s tests or inspections during the audit to evaluate the reliability of the supplier’s COAs. An audit should comprehensively assess the supplier’s quality system to ensure consistent reliability. The FDA suggests a hybrid approach (reviewing suppliers’ COAs and conducting sup­plier audits). Even if comprehensive analytical testing isn’t conducted, the audit may cover the supplier’s analysis, but a clear identity test remains necessary.

In a quality system, written protocols are followed, and any deviations are justied and documented. This enables the manufacturer to monitor the product’s history in terms of personnel, goods, facilities, and chronology as necessary. It ensures that the processes for product release are comprehensive and well- documented.

Identied components within a quality framework signicantly aid manufacturers in man­aging change and executing continuous improvement in their production processes. As an integral part of this framework, it’s crucial to establish procedures ensuring the accuracy of test results. Any out- of- specication test results should undergo thorough scrutiny, as they might stem from research or production issues. Utilizing empirical and statistical data is recommended to justify invalidating test results. Upon completing production, it’s advisable for manufacturers to align shipping specications with special handling needs to maintain consistency, such as refrigeration in biopharmaceuticals.

Regular denition and review of trends serve as essential elements within a quality manage­ment framework. One effective method to achieve this is through statistical process management. Analyzing trends enables continuous monitoring of quality, early detection of potential deviations before they escalate into problems, supplements the data collected for annual reviews, and aids pro­gress throughout the product lifecycle. Assessing process capabilities helps determine necessary changes, thereby contributing signicantly to process performance and development.

The validation master plan (VMP) is a comprehensive document within the quality assurance system. It initiates with process creation and evolves over time, reducing the risk of overlooking crucial components in the CMC section and ensuring batch compliance through effective validation techniques. Process validation, a key part of the VMP, encompasses various aspects such as:

The protocol for any validation study includes a declaration of experimental purpose, speci­cation of what is to be qualied or validated, experimental plans, sampling plans, test plans with approval requirements, and a summary of statistical tests to be applied.

Identifying essential raw materials and ensuring identity, purity, suitability, and traceability are needed.

Information about the target protein, the chosen expression strategy, and specic post- translational modication requirements (like glycosylation, acylation, phosphorylation, or pegylation) serve as justications for the process. The process plan should cover aspects such as product safety, pro­cess robustness, scaling up, cGMP production, and cost considerations. This plan should allow for updates in the process, aligning it with evolving stages from phase 1 to the mature phase 3. A visual ow chart detailing all process unit actions, including the entry and exit points of key raw materials or adventitious agents, is provided. The chart encompasses impurities from the host cell, the drug, and procedural elements. A solid foundation in process awareness and comprehension forms the basis for designing an effective process management strategy for each unit activity and the overall process. Management solutions can be devised to reduce input variance, adjust during production to limit its impact on output, or a combination of both.

Quality Assurance (QA) systems ensure the reliability and suitability of analytical processes for their intended tasks. Evaluating the quality of raw materials, personnel, facilities, and manufacturers is essential, along with thorough validation of the analytical methods in compliance with Good Manufacturing Practice (GMP) criteria. The extent of validation varies based on the development stage; during initial phases, techniques are still evolving, focusing primarily on effectiveness and toxicity testing. However, procedures must be fully validated before creating clinical test batches. Critical validation factors encompass specicity, linearity, range, accuracy, precision, detection limit, quantication limit, robustness, and system suitability testing. These requirements align with other CMC (Chemistry, Manufacturing, and Controls) testing methods. More detailed information can be found in the ICH harmonized tripartite guideline Q2B (www.ich.org/ Medi aSer ver.jser?@ ID= 418&@ MODE= GLB). Revalidation might be necessary if there are changes in the manufacturing process, drug product structure, or analytical method. The extent of revalidation required depends on the nature of the changes. The empirical validation plan outlines the steps for completing empir­ical validation, included within the master validation plan. A formal report on analytical technique description encompasses sample preparation instructions, raw material lists, process descriptions, data collection procedures, results, data interpretation, and a systematic validation process with relevant sample and control replication analytical sequences, validation features, data analysis, and reporting methodologies.

A manufacturer must ensure a high level of condence in the performance of the manufac­turing process before commercially distributing any batch for consumer use. This ensures that both active pharmaceutical ingredients (APIs) or active biological drugs, and the resultant drug products,

adhere to critical attributes such as identity, strength, quality, purity, and potency. Objective evidence and data from laboratory, pilot, and commercial- scale investigations are utilized to provide this assurance. Statistical information can demonstrate the consistent production of satisfactory quality goods under commercial manufacturing settings.

An effective validation program relies on information and expertise gained during product and process development. This knowledge serves as the basis for developing a manufacturing process control strategy that ensures goods meet specied quality attributes. Manufacturers must acknow­ledge various sources of variance by:

Stage 1 process design produces cGMP documentation for industrial manufacturing (i.e., the ini­tial commercial masterbatch development and control record (211.186) and supporting procedures). Firms should draw up a process ow diagram for the full- scale process.