Changes must be made in the form of amendments. Such methods must be validated to ensure that they are adequate for analytical purposes in the control and validation of the BPC manufacturing process. Usually, whether the methods are the same or different, the specifications may be tighter for the in-process tests. There should be an audit trail for changes to data. The methods used for in-process testing may differ from those used for release testings. 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. 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. For the single OOS result the investigation should include the following steps and these inquiries must be conducted before there is a retest of the sample: - the analyst conducting the test should report the OOS result to the supervisor. Review laboratory logs for the sequence of analysis versus the sequence of manufacturing dates. The system must assure that raw data are stored and actually processed. Inspection process of a laboratory involves the assessment of laboratory functions in full operation. The inspection team is expected to review such letters on file at the district office, and they are expected to ask the plant for access to such letters. Complete the inspection even though there has been no response to these letters or when the response is judged inadequate. A significant portion of the CGMP regulations (21 CFR 211) pertain to the quality control laboratory and product testing. List other batches and products possibly affected, the results of investigation of these batches and products, and any corrective action. This information may also be obtained from the supplier of the drug substance. Therefore, all health and safety hazards must be identified and carefully evaluated so that protective measures can be incorporated into the design. There is no substitute for actually seeing the work performed and noting whether good technique is used. 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. 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. Quality control testing of pharmaceutical raw materials is critical to drug development from early-stage through to commercial batch release. These impurities cannot be evaluated without a suitable method and one that has been validated. Determine that a full scale inquiry has been made for multiple OOS results. If there is a computer data base, determine the protocols for making changes to the data. Floor-to-ceiling windows cover two full sides of the building, allowing generous amounts of natural light into the workspace. Context and challenges. This client is a major pharmaceutical player specializing in pharmaceutical synthesis and specialty ingredients. It is highly unlikely that a firm can "accurately and consistently weigh" to the same microgram. Several issues must be addressed when evaluating computerized laboratory systems. Absorbance values and calculations have even been found on desk calendars. These investigations represent a key issue in deciding whether a product may be released or rejected and form the basis for retesting, and resampling. 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. Manufacturers may be required to accelerate or force degradation of a product to demonstrate that the test is stability indicating. Some of these tests are filed in applications and others may be established by the protocols used to manufacture the product. Review laboratory logs for the sequence of analysis and the sequence of manufacturing dates. Provide summation of the process sequences that may have caused the problem, 3. The firm's analyst should follow a written procedure, checking off each step as it is completed during the analytical procedure. The court acknowledged that some retesting may precede a finding of nonprocess or process-based errors. Evaluate the manufacturer's validation report for their stability testing. If a sample larger than the unit must be taken initially, aliquots which resemble the dosage size should be carefully removed for the test, retests, and reserve samples. 4. The inability to identify an error's cause with confidence affects retesting procedures, not the investigation inquiry required for the initial OOS result. To aid in choosing the appropriate mechanical system, an energy analysis was conducted using eQuest , an energy simulation software, to evaluate the buildings energy consumption based on size and location. The initial OOS result was claimed the result of analyst error based on a statistical evaluation of the data. 3. Results should not be changed without explanation. 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. Methods appearing in the USP are considered validated and they are considered validated if part of an approved ANDA. The goal of retesting is to isolate OOS results but retesting cannot continue ad infinitum. Any other practice would blur differences in portions of the blend and defeat the object of the test. Expect to see consistent in-process test results within batches and between batches of the same formulation/process (including development or exhibit batches). Again, review the raw laboratory data and the results of testing at the various stations to determine if the data actually reported matches the data found in on site records. The court ordered the recall of one batch of product after having concluded that a successful resample result alone cannot invalidate an initial OOS result. Cannot use a re-sample to assume a sampling or preparation error, 4. Firms cannot frequently reject results on this basis. 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. Check for the reuse of stock solutions without assuring their stability. The pharmaceutical quality control laboratory serves one of the most important functions in pharmaceutical production and control. One court has ruled that sample size influences ultimate blend test results and that the sample size should resemble the dosage size. Experienced investigators and analysts may contact the review chemist (with appropriate supervisory concurrence) when questions concerning specifications and standards arise. N ovartis Vaccines (Novartis) has applied a structured implementation of - lean principles across Quality Control (QC) laboratories in Europe, India, China, and the United States. When conducting a comprehensive inspection of a laboratory, all aspects of the laboratory operations will be evaluated. 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. Review records of standard solution preparation to assure complete and accurate documentation. Top 10 ERP selection criteria to consider when starting the ERP software selection process, GMP Documentation for the Cannabis Industry. Evaluate the company's retesting SOP for compliance with scientifically sound and appropriate procedures. All testing must comply with CGMP's. Test dates should correspond to the dates when the sample should have been in the laboratory. All failure investigations should be performed within 20 business days of the problem's occurrence and recorded and written into a failure or investigation report. adopted in 2009 a revised version of the Good practices for pharmaceutical quality control laboratories (1). Examine the laboratory refrigerators for these solutions and when found check for appropriate identification. Coordination between headquarters and the field is essential for a complete review of the application and the plant. Evaluate the company's system to investigate laboratory test failures. 5. In this case, it is good practice to include OOS results in the average unless an outlier test (microbiological assays) suggests the OOS is an anomaly. Pre-approval inspections are designed to determine if the data submitted in an application are authentic and accurate and if the procedures listed in the application were actually used to produce the data contained in the application. This includes pharmaceutical laboratories used for in-process and finished product testing. One basic aspect of validation of laboratory computerized data acquisition requires a comparison of data from the specific instrument with that same data electronically transmitted through the system and emanating on a printer. 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. 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. 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 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. principles into pharmaceutical quality control laboratory design. A new model of laboratory design is emerging, one that creates lab environments that are responsive to present needs and capable of accommodating future demands. Specifications and analytical procedures should be suitable and, as applicable, in conformance with application commitments and compendial requirements. Specifically: - examine other batches of product made by the errant employee or machine, - examine other products produced by the errant process or operation, 5. System suitability data alone is insufficient for and does not constitute method validation. Evaluate the justification for disregarding test results that show the product failed to meet specifications. - The Standard Operating Procedures must describe the procedures for ensuring the validity of the data. 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. Methods can be validated in a number of ways. The court ordered a recall of one batch of product on the basis of an initial content uniformity failure and no basis to invalidate the test result and on a history of content uniformity problems with the product., type of test performed, and in-process test results. Procedures should only be judged adequate when data are secure, raw data are not accidentally lost, and data cannot be tampered with. An alternative means to invalidate an initial OOS result, provided the failure investigation proves inconclusive, is the "outlier" test. weak or hot spots in the blend. Test results should not have been transcribed without retention of the original records, nor should test results be recorded selectively. 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. 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 agency has provided some basic guidance on security and authenticity issues for computerized systems: - Provision must be made so that only authorized individuals can make data entries. We expect laboratory test data to be recorded directly in notebooks; use of scrap paper and loose paper must be avoided. During the inspections carried out when prequalifying laboratories, the inspectors had noticed that some of the texts of these guidelines might benefit from additional guidance, with a special focus on microbiology. - the analyst and the supervisor should conduct an informal laboratory investigation which addresses the following areas: 4. review the notebooks containing the OOS result. Follow the sampling guidelines in CP 7346.832, Part III, pages 5 and 6. Review personal analytical notebooks kept by the analysts in the laboratory and compare them with the worksheets and general lab notebooks and records. 1. It is important, for computerized and non computerized systems, to define the universe of data that will be collected, the procedures to collect it, and the means to verify its accuracy. Team members participating in a pre-approval inspection must read and be familiar with Compliance Program 7346.832, Pre-Approval Inspections/Investigations. 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. 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. Separate instrument room with adequate area shall be provided for sensitive and sophisticated instruments employed for analysis. Preserve the comments and signatures of all production and quality control personnel who conducted the investigation and approved any reprocessed material after additional testing. Retesting following an OOS result is ruled appropriate only after the failure investigation is underway and the failure investigation determines in part whether retesting is appropriate. Evaluate the decision to release lots of product when the laboratory results indicate that the lot failed to meet specifications and determine who released them. The court ruled on the use of retesting which is covered in a later segment of this document. It is appropriate when analyst error is documented or the review of analyst's work is "inconclusive" , but it is not appropriate for known and undisputed non-process or process related errors. - Guide to Inspection of Computerized Systems in Drug Processing. Examine the results of investigations using the guidance in section 5 above and evaluate the decision to release, retest, or rework products. The inspection team must decide if there is valid and scientific justification for the failure to report data which demonstrates the product failed to meet its predetermined specifications. In general these inspections may include. State the reason for the investigation, 2. If there is no stability-indicating assay additional assay procedures such as TLC should be used to supplement the general assay method. The test cannot be used for chemical testing results. Design – construction of a pharmaceutical laboratory and a control room Design / Project management Life Sciences France. The drug substance manufacturer must have complete knowledge of the manufacturing process and the potential impurities that may appear in the drug substance. For example, in the case of content uniformity testing designed to detect variability in the blend or tablets, failing and non-failing results are not inherently inconsistent and passing results on limited retesting do not rule out the possibility that the batch is not uniform. The three-level laboratory building was designed with the same open-space concept as the entire facility. 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. a complete assessment of laboratory’s conformance with GMP’s. The .gov means it’s official.Federal government websites often end in .gov or .mil. Analyst's mistakes, such as undetected calculation errors, should be specified with particularity and supported by evidence. 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. Nevertheless, we expect investigators, analysts and others to work as teams and to advise management when additional expertise is required to complete a meaningful inspection. 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. These inspections may include a complete assessment of laboratory’s conformance with the code of GMP or they may be limited to specific methodology or aspects of the laboratory. 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. Span of supervisory control, personnel qualifications, turnover of analysts, and scope of the laboratory's responsibility are important issues to examine when determining the quality of overall management and supervision of work. 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. Cannot conduct 2 retests and base release on average of three tests, 2. needed to validate the method. An OOS laboratory result can be overcome (invalidated) when laboratory error has been documented. Inspections should compare the results of analyses submitted with results of analysis of other batches that may have been produced. 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. Separate areas shall be provided each for physico-chemical, biological, microbiological or radio-isotope analysis. Relevant sections of the NDA or ANDA should be reviewed prior to the inspection; but if the application is not available from any other source, this review will have to be conducted using the company's copy of the application. Evaluate the methods and note any exceptions to the procedures or equipment actually used from those listed in the application and confirm that it is the same method listed in the application. Nevertheless, a laboratory investigation consists of more than a retest. Multiple individual blend uniformity samples taken from different areas cannot be composited. For most of those manufacturers which had duplicate sets of records or "raw data", non-numbered loose sheets of paper were employed. You should not stand over the analysts, but watch from a distance and evaluate their actions. Note whether raw data are missing, if records have been rewritten, or if correction fluid has been used to conceal errors. 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 use of computerized laboratory data acquisition systems is not new and is addressed in the following CGMP guidance documents: - Compliance Policy Guide 7132a.07 Computerized Drug Processing: Input/Output Checking. An initial content uniformity test was OOS followed by a passing retest. because averages hide the variability among individual test results. - Compliance Policy Guide 7132a.08 Computerized Drug Processing: Identification of "Persons" on Batch Production and Control Records. Find bellow some examples of Pharmaceutical Quality Control Lab: Your email address will not be published. Cannot use outlier test in chemical tests, 3. Responsibilities for development of all reports should also be established prior to the inspection. Your email address will not be published. Samples will be collected on pre-approval inspections. This includes the preparation of the FDA 483. Some of the tests done may differ from those done at release. Good manufacturing practice regulations require an active training program and the documented evaluation of the training of analysts. Also a company can conduct a validation study on their method. The laboratory work for the lengthier tests should also be reviewed. 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.) These are generally recorded in some type of log. Specific procedures must be followed when single and multiple OOS results are investigated. Cut charts with injections missing, deletion of files in direct data entry systems, indirect data entry without verification, and changes to computerized programs to override program features should be carefully examined. This inspection guide supplements other inspectional information contained in other agency inspectional guidance documents. These tests may not be reproducible in other laboratories, therefore, on site evaluation is essential. Quality control begins with sample collection and ends with the reporting of data. 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. Some older compendial methods may not be capable of detecting impurities as necessary to enable the control of the manufacturing process, and newer methods have been developed to test these products. When the laboratory investigation is inconclusive (reason for the error is not identified) the firm: 1. However when variation testing is not the object of assay testing, compositing is permitted. Content uniformity and dissolution results never should be averaged to obtain a passing value. Evaluate the test results from in-process tests performed in the production areas or laboratory for conformance with established sampling and testing protocols, analytical methods, and specifications. Once this determination is made, however, additional retesting for purposes of testing a product into compliance is not acceptable. Most manufacturers use systems that provide for the investigation of laboratory test failures. Laboratory records and logs represent a vital source of information that allows a complete overview of the technical ability of the staff and of overall quality control procedures. 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. Because the initial tests are genuine, in these circumstances, additional testing alone cannot contribute to product quality. It is achieved through laboratory control of analytical performance. Data that should be reviewed include preservative effectiveness testing, bioburden data, and product specific microbiological testing and methods. Determine if the manufacturer has a program to audit the certificate of analysis of the BPC, and, if so, check the results of these tests. - 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. Carefully examine and evaluate laboratory logs, worksheets and other records containing the raw data such as weighings, dilutions, the condition of instruments, and calculations. The evaluation, conclusion and corrective action, if any, should be preserved in an investigation or failure report and placed into a central file. Additionally, they are designed to confirm that plants (including the quality control laboratory) are in compliance with CGMP regulations. Certain changes may require management to re-examine the data for products already released. Refer to the Microbiological Inspection Guide for additional information concerning the inspection of microbiological laboratories. FDA Inspection Guides are based on the team inspection approach and our inspection of a laboratory is consistent with this concept. The existence of the equipment specified in the analytical methods should be confirmed and its condition noted. Observe analysts performing the operations described in the application. The laboratory inspection may be limited to specific issues, or the inspection may encompass a comprehensive evaluation of the laboratory's compliance with CGMP's. If results are not satisfactory, the product is rejected. Pharmaceutical Quality Control Testing. These common sense measures enhance the accuracy and integrity of data. 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. The analytical sections of drug applications usually contain only test results and the methods used to obtain them. SOPs should be complete and adequate and the operations of the laboratories should conform to the written procedures. A very important ruling in one recent court decision sets forth a procedure to govern the retesting program. Review bioburden (before filtration and/or sterilization) from both an endotoxin and sterility perspective. This phenomenon is particularly troubling if testing generates both OOS and passing individual results which when averaged are within specification. Multiple injections recorded should be in consecutive files with consecutive injection times recorded. Evaluate each resampling activity for compliance with this guidance. He ruled that an OOS result identified as a laboratory error by a failure investigation or an outlier test. Expect to see written justification for the deletion of all files. 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. For example, evaluate the tests for weight variation, hardness, and friability. The team should evaluate the replies to these letters to assure that the data are accurate and authentic. For compendial methods firms must demonstrate that the method works under the actual conditions of use. The review of microbiological data on applicable dosage forms is best performed by the microbiologist (analyst). Also, diminishing reproducibility in HPLC chromatograms appearing several hours after system suitability is established is accepted without question. OOS results fall into three categories: - process related or manufacturing process error. 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. Examine chromatograms and spectra for evidence of impurities, poor technique, or lack of instrument calibration. Laboratory errors occur when analysts make mistakes in following the method of analysis, use incorrect standards, and/or simply miscalculate the data. An official website of the United States government, Recalls, Market Withdrawals and Safety Alerts, Pharmaceutical Quality Control Labs (7/93). Information regarding the validation of methods should be carefully evaluated for completeness, accuracy and reliability. Stock solutions are frequently stored in the laboratory refrigerator. Designing a quality control laboratory requires a design process similar to that of production facilities: listening and gathering information, examining and optimizing sample analysis flows, integrating bench equipment servicing, designing for ergonomics and environmental conditions, as well as envisioning strategies for lab storage and solvent management. Additionally, the company should consider all retest results in the context of the overall record of the product. Evaluate the raw data used to generate the data filed documenting that the method is stability indicating and the level of impurities. For example, a firm may perform disintegration testing as an in-process test but dissolution testing as a release test. 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. Therefore data showing this level of standardization or pattern is suspect and should be carefully investigated. FAILURE (OUT-OF-SPECIFICATION) LABORATORY RESULTS. Notify me of follow-up comments by email. Investigations along with conclusions reached must be preserved with written documentation that enumerates each step of the investigation. Latest: » Have you heard that we're supporting Wockhardt to get the Covid-19 vaccine to market? Control personnel who conducted the investigation type of log product quality forms is best performed by protocols... Testing facilities once the nature of the best HVAC system that was most suitable for a complete assessment laboratory. Deletion of all production and control firm: 1 changes to data of! Review records of standard solution preparation to assure complete and accurate documentation stability testing testing, compositing is.... Assays an average is preferred by the USP websites often end in.gov.mil. 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Generates both OOS and passing individual results which when averaged are within specification undetected calculation errors should!