weak or hot spots in the blend. Periodic data comparisons would be sufficient only when such comparisons have been made over a sufficient period of time to assure that the computerized system produces consistent and valid results. Also, diminishing reproducibility in HPLC chromatograms appearing several hours after system suitability is established is accepted without question. For example, Compliance Program 7346.832 requiring pre-approval NDA/ANDA inspections contains general instructions to conduct product specific NDA/ANDA inspection audits to measure compliance with the applications and CGMP requirements. Review laboratory logs for the sequence of analysis and the sequence of manufacturing dates. Procedures should only be judged adequate when data are secure, raw data are not accidentally lost, and data cannot be tampered with. Documents relating to the formulation of the product, synthesis of the bulk drug substance, product specifications, analysis of the product, and others are examined during the review process in headquarters. In addition to the general approach utilized in a drug CGMP inspection, the inspection of a laboratory requires the use of observations of the laboratory in operation and of the raw laboratory data to evaluate compliance with CGMP's and to specifically carry out the commitments in an application or DMF. The team should evaluate the replies to these letters to assure that the data are accurate and authentic. When a diagnostic test is performed in the medical laboratory, the outcome of the test is a result. As a minimum, each pharmaceutical quality control laboratory should receive a comprehensive GMP evaluation each two years as part of the statutory inspection obligation. The review of microbiological data on applicable dosage forms is best performed by the microbiologist (analyst). This includes the preparation of the FDA 483. Separate areas shall be provided each for physico-chemical, biological, microbiological or radio-isotope analysis. General Safety Rules of Quality Control Laboratory Quality Control General and specific safety Rules & instructions reflecting identified risk, should be made available to each staff member and supplemented regularly as appropriate. An alternative means to invalidate an initial OOS result, provided the failure investigation proves inconclusive, is the "outlier" test. Pharmaceutical quality control testing is usually a matter of repetitive testing of samples of APIs or of a limited number of pharmaceutical products, whereas national quality control laboratories have to be able to deal with a much wider range of pharmaceutical substances and products and, therefore, have to apply a wider variety of test methods. The Center for Drug Evaluation and Research (CDER) may have issued deficiency letters listing problems that the sponsor must correct prior to the approval of NDA/ANDA's and supplements. These common sense measures enhance the accuracy and integrity of data. The test cannot be used for chemical testing results. The three-level laboratory building was designed with the same open-space concept as the entire facility. GMP Pharmaceutical quality control (QC) testing programs for raw materials, APIs and intermediates to pharmacopoeia specifications supported by troubleshooting and specialist QC methods, delivered by experts . Sponsors are not required to file all the test data because such action would require voluminous submissions and would often result in filing redundant information. March3rd,2014 These tests may be performed every fifteen or thirty minutes during tableting or encapsulating procedures. Test results should not have been transcribed without retention of the original records, nor should test results be recorded selectively. Data that should be reviewed include preservative effectiveness testing, bioburden data, and product specific microbiological testing and methods. Senior managers in the drug industry are responsible for the effectiveness of this system, which is known as the Pharmaceutical Quality System (PQS). is not a product failure. Observe analysts performing the operations described in the application. Context and challenges. Instead they accept unexplained peaks in chromatograms with no effort to identify them. If there is a computer data base, determine the protocols for making changes to the data. Testing areas should accommodate raw materials active phar… As part of the investigation firms should consider the record of previous batches, since similar or related failures on different batches would be a cause of concern. The firm's analyst should follow a written procedure, checking off each step as it is completed during the analytical procedure. The quality control (QC) laboratory plays a critical role in pharmaceutical production, for both in-process and finished product testing. However, non-process and process related errors resulting from operators making mistakes, equipment (other than laboratory equipment) malfunctions, or a manufacturing process that is fundamentally deficient, such as an improper mixing time, represent product failures. FAILURE (OUT-OF-SPECIFICATION) LABORATORY RESULTS. The laboratory serves a vital function in blend testing which is necessary to increase the likelihood of detecting inferior batches. OOS results fall into three categories: - process related or manufacturing process error. This includes the history of the product. The analytical performance parameters listed in the USP XXII, , under the heading of Validation of Compendial Methods, can be used as a guide for determining the analytical parameters (e.g., accuracy, precision, linearity, ruggedness, etc.) An official website of the United States government, Recalls, Market Withdrawals and Safety Alerts, Pharmaceutical Quality Control Labs (7/93). The inability to identify an error's cause with confidence affects retesting procedures, not the investigation inquiry required for the initial OOS result. Large countries may require several pharmaceutical … In some cases the sponsor of ANDA's may be able to search the literature and find background data for the specificity of a particular method. The analytical sections of drug applications usually contain only test results and the methods used to obtain them. 2009 a revised version of the Good practices for pharmaceutical quality control laboratories (1). Obviously, the initial larger sample should not be subjected to any additional mixing or manipulation prior to removing test aliquots as this may obscure non-homogeneity. These tests may not be reproducible in other laboratories, therefore, on site evaluation is essential. A significant portion of the CGMP regulations (21 CFR 211) pertain to the quality control laboratory and product testing. Examine laboratory records and logs for vital information about the technical competence of the staff and the quality control procedures used in the laboratory. - the specific methodology which will be used to test a new product, - a complete assessment of laboratory's conformance with GMP's, - a specific aspect of laboratory operations. Some companies use discs or tapes as raw data and for the storage of data. However, specific restrictions must be placed on the use of this test. It is highly unlikely that a firm can "accurately and consistently weigh" to the same microgram. This district court ruling provides an excellent guide to use in evaluating some aspects of a pharmaceutical laboratory, but should not be considered as law, regulation or binding legal precedent. in-date, stored properly). Evaluate raw laboratory data, laboratory procedures and methods, laboratory equipment,including maintenance and calibration, and methods validation data to determine the overall quality of the laboratory operation and the ability to comply with CGMP regulations. Top 10 ERP selection criteria to consider when starting the ERP software selection process, GMP Documentation for the Cannabis Industry. We expect laboratory test data to be recorded directly in notebooks; use of scrap paper and loose paper must be avoided. A stability-indicating method must be used to test the samples of the batch. - must be done on the same, not a different sample, - may be done on a second aliquot from the same portion of the sample that was the source of the first aliquot, - may be done on a portion of the same larger sample previously collected for laboratory purposes. Formal investigations extending beyond the laboratory must follow an outline with particular attention to corrective action. If there is no stability-indicating assay additional assay procedures such as TLC should be used to supplement the general assay method. However when variation testing is not the object of assay testing, compositing is permitted. Test dates should correspond to the dates when the sample should have been in the laboratory. Quality by Design (QbD) refers to the strategies developed and advanced by the US Food and Drug Administration, the International Conference on Harmonisation (ICH), and the United States Pharmacopeia (USP), 1-5 based on scientific principles and risk assessment and focused on product and process understanding. He ruled that an OOS result identified as a laboratory error by a failure investigation or an outlier test. IN PROCESS CONTROLS AND SPECIFICATIONS. Once this determination is made, however, additional retesting for purposes of testing a product into compliance is not acceptable. Methods can be validated in a number of ways. Cannot conduct 2 retests and base release on average of three tests, 2. Check for the reuse of stock solutions without assuring their stability. Results should not be changed without explanation. A product with a 90.0%-110.0% assay release specification may have a limit of 95.%-105.0% for the in-process blend. Click to share on Twitter (Opens in new window), Click to share on Facebook (Opens in new window), VWR Laboratory-Online-Planning – Free online application. Validation would then be relatively straightforward, with the typical parameters listed in the USP in chapter on validation of compendial methods addressed as applicable. because averages hide the variability among individual test results. This client is a major pharmaceutical player specializing in pharmaceutical synthesis and specialty ingredients. - Compliance Policy Guide 7132a.08 Computerized Drug Processing: Identification of "Persons" on Batch Production and Control Records. Quality Control Laboratories shall be designed … Several issues must be addressed when evaluating computerized laboratory systems. Coordination between headquarters and the field is essential for a complete review of the application and the plant. All testing must comply with CGMP's. The goal of retesting is to isolate OOS results but retesting cannot continue ad infinitum. The inquiry may vary with the object under investigation. 18 LABORATORY QUALITY CONTROL 18.1 Introduction This chapter addresses internal laboratory quality control (QC), the purpose of which is to monitor performance, identify problems, and initiate corrective action. Analyst's mistakes, such as undetected calculation errors, should be specified with particularity and supported by evidence. For drug substance labs evaluate methods validation and raw data for sterility, endotoxin testing, environmental monitoring, and filter and filtration validation. During the inspections carried out when prequalifying laboratories, the inspectors had noticed that some of the texts of these guidelines might beneﬁ t from additional guidance, with a special focus on microbiology. Examine the raw data reflecting the analysis of the drug substance including purity tests, charts, etc. Review records of standard solution preparation to assure complete and accurate documentation. Specific procedures must be followed when single and multiple OOS results are investigated. Specifications and analytical procedures should be suitable and, as applicable, in conformance with application commitments and compendial requirements. One would have to suspect the data that are generated from a piece of equipment that is known to be defective. Evaluate the company's system to investigate laboratory test failures. Usually, whether the methods are the same or different, the specifications may be tighter for the in-process tests. Expect to see consistent in-process test results within batches and between batches of the same formulation/process (including development or exhibit batches). Multiple injections recorded should be in consecutive files with consecutive injection times recorded. The firm should have a written explanation when injections, particularly from a series are missing from the official work-sheets or from files and are included among the raw data. National pharmaceutical quality control laboratories The government, normally through the national medicines regulatory authority (NMRA), may establish and maintain a pharmaceutical quality control laboratory to carry out the required tests and assays to verify that APIs, excipients and pharmaceutical products meet the prescribed speciﬁ cations. Laboratory logs and documents when cross referenced may show that data has been discarded by company officials who decided to release the product without a satisfactory explanation of the results showing the product fails to meet the specifications. 5. Determine the adequacy of the firm's procedures to ensure that all valid laboratory data are considered by the firm in their determination of acceptability of components, in-process, finished product, and retained stability samples. The inspection must confirm that the in-process tests were done, as described in the plan, and ascertain that the results were within specifications. Evaluate the company's retesting SOP for compliance with scientifically sound and appropriate procedures. Verify that the equipment was present and in good working order at the time the batches were analyzed. Some of these tests are filed in applications and others may be established by the protocols used to manufacture the product. Also, evaluate the methods used to test and establish bioburdens. The methods used for in-process testing may differ from those used for release testings. However, these reviews and evaluations depend on accurate and authentic data that truly represents the product. The number of retests performed before a firm concludes that an unexplained OOS result is invalid or that a product is unacceptable is a matter of scientific judgment. Analytical quality control refers to all those processes and procedures designed to ensure that the results of laboratory analysis are consistent, comparable, accurate and within specified limits. For compendial methods firms must demonstrate that the method works under the actual conditions of use. If firms sample product from sites other than the blender, they must demonstrate through validation that their sampling technique is representative of all portions and concentrations of the blend. Be prepared to examine all records and worksheets for accuracy and authenticity and to verify that raw data are retained to support the conclusions found in laboratory results. Find bellow some examples of Pharmaceutical Quality Control Lab: Your email address will not be published. 2. Evaluate the history of changes to programs used for calculations. SOPs should be complete and adequate and the operations of the laboratories should conform to the written procedures. Good manufacturing practice regulations require an active training program and the documented evaluation of the training of analysts. Products cannot be "tested into compliance" by arbitrarily labeling out-of-specification lab results as "laboratory errors" without an investigation resulting in scientifically valid criteria. The court ruled on the use of retesting which is covered in a later segment of this document. The pharmaceutical quality control laboratory serves one of the most important functions in pharmaceutical production and control. Such systems have also been accepted provided they have been defined (with raw data identified) and validated. - The Standard Operating Procedures must describe the procedures for ensuring the validity of the data. Separate instrument room with adequate area shall be provided for sensitive and sophisticated instruments employed for analysis. Can conduct a retest of different tablets from the same sample when a retest is considered appropriate (see criteria elsewhere). In the review of method validation data, it is expected that data for repetitive testing be consistent and that the varying concentrations of test solutions provide linear results. Physical tests such as particle size for raw materials, adhesion tests for patches, and extrusion tests for syringes are essential tests to assure consistent operation of the production and control system and to assure quality and efficacy. One court has ruled that sample size influences ultimate blend test results and that the sample size should resemble the dosage size. Many assay and impurity tests are now HPLC, and it is expected that the precision of these assays be equal or less than the RSD's for system suitability testing. Quality Control Area.-(as per schedule M) Quality Control Laboratories shall be independent of the production areas. 1. 4. Any other practice would blur differences in portions of the blend and defeat the object of the test. Examine chromatograms and spectra for evidence of impurities, poor technique, or lack of instrument calibration. Check the impurity profiles of the BPC used in the biobatch and clinical production batches to determine if it is the same as that being used to manufacture full scale production batches. - Compliance Policy Guide 7132a.11 Computerized Drug Processing: CGMP Applicability to Hardware and Software, - Compliance Policy Guide 7132a.12 Computerized Drug Processing: Vendor Responsibility, - Compliance Policy Guide 7132a.15 Computerized Drug Processing: Source Code for Process Control Application Programs. COMPUTERIZED LABORATORY DATA ACQUISITION SYSTEMS. If this is not the case, expect to see scientific data to justify the variation. In a recent court decision the judge used the term "out-of-specification" (OOS) laboratory result rather than the term "product failure" which is more common to FDA investigators and analysts. 20. The laboratory work for the lengthier tests should also be reviewed. Overall management of the laboratory work, its staff, and the evaluation of the results of analysis are important elements in the evaluation of a control laboratory. In addition, verify that the equipment in any application was in good working order when it was listed as used to produce clinical or biobatches. For example, evaluate the tests for weight variation, hardness, and friability. The analyst is expected to evaluate raw laboratory data for tests performed on the test batches (biobatches and clinical batches) and to compare this raw data to the data filed in the application. As part of our effort to achieve uniformity and consistency in laboratory inspections, we expect that complex, highly technical and specialized testing equipment, procedures and data manipulations, as well as scientific laboratory operations will be evaluated by an experienced laboratory analyst with specialized knowledge in such matters. This information may also be obtained from the supplier of the drug substance. Cannot use a re-sample to assume a sampling or preparation error, 4. The court provided explicit limitations on the use of outlier tests and these are discussed in a later segment of this document., or overcome by retesting. It is never appropriate to utilize outlier tests for a statistically based test, i.e., content uniformity and dissolution. As a minimum, each pharmaceutical quality control laboratory should receive a comprehensive GMP evaluation each two years as part of the statutory inspection obligation. Therefore, all health and safety hazards must be identified and carefully evaluated so that protective measures can be incorporated into the design. The authority to delete files and override computer systems should be thoroughly examined. Quality control begins with sample collection and ends with the reporting of data. Pharmaceutical Quality by Design: A Practical Approach outlines a new and proven approach to pharmaceutical product development which is now being rolled out across the pharmaceutical industry internationally. The primary objective in laboratory design is to provide a safe environment for laboratory personnel to conduct their work. 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