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GUIDE TO INSPECTIONS OF PHARMACEUTICAL QUALITY CONTROL LABORATORIES(SECOND)

8. RESAMPLING

Firms cannot rely on resampling. 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. to release a product that has failed testing and retesting unless the failure investigation discloses evidence that the original sample is not representative or was improperly prepared.

Evaluate each resampling activity for compliance with this guidance.

9. AVERAGING RESULTS OF ANALYSIS

Averaging can be a rational and valid approach when the object under consideration is total product assay, but as a general rule this practice should be avoided. The court ruled that the firm must recall a batch that was released for content uniformity on the basis of averaged test results. because averages hide the variability among individual test results. This phenomenon is particularly troubling if testing generates both OOS and passing individual results which when averaged are within specification. Here, relying on the average figure without examining and explaining the individual OOS results is highly misleading and unacceptable.

Content uniformity and dissolution results never should be averaged to obtain a passing value.

In the case of microbiological turbidimetric and plate assays an average is preferred by the USP. 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.

10. BLEND SAMPLING AND TESTING

The laboratory serves a vital function in blend testing which is necessary to increase the likelihood of detecting inferior batches. Blend uniformity testing cannot be waived in favor of total reliance on finished product testing because finished product testing is limited.

One court has ruled that sample size influences ultimate blend test results and that the sample size should resemble the dosage size. Any other practice would blur differences in portions of the blend and defeat the object of the test. 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. 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.

Multiple individual blend uniformity samples taken from different areas cannot be composited. However when variation testing is not the object of assay testing, compositing is permitted.

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. This means that the samples must be representative of those sites that might be problems; e.g. weak or hot spots in the blend.

11. MICROBIOLOGICAL

The review of microbiological data on applicable dosage forms is best performed by the microbiologist (analyst). Data that should be reviewed include preservative effectiveness testing, bioburden data, and product specific microbiological testing and methods.

Review bioburden (before filtration and/or sterilization) from both an endotoxin and sterility perspective. For drug substance labs evaluate methods validation and raw data for sterility, endotoxin testing, environmental monitoring, and filter and filtration validation. Also, evaluate the methods used to test and establish bioburdens.

Refer to the Microbiological Inspection Guide for additional information concerning the inspection of microbiological laboratories.

12. SAMPLING

Samples will be collected on pre-approval inspections. Follow the sampling guidelines in CP 7346.832, Part III, pages 5 and 6.

13. LABORATORY RECORDS AND DOCUMENTATION

Review personal analytical notebooks kept by the analysts in the laboratory and compare them with the worksheets and general lab notebooks and records. 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.

Review laboratory logs for the sequence of analysis versus the sequence of manufacturing dates. Test dates should correspond to the dates when the sample should have been in the laboratory. If there is a computer data base, determine the protocols for making changes to the data. There should be an audit trail for changes to data.

We expect raw laboratory data to be maintained in bound, (not loose or scrap sheets of paper), books or on analytical sheets for which there is accountability, such as prenumbered sheets. For most of those manufacturers which had duplicate sets of records or 'raw data', non-numbered loose sheets of paper were employed. Some companies use discs or tapes as raw data and for the storage of data. Such systems have also been accepted provided they have been defined (with raw data identified) and validated.

Carefully examine and evaluate laboratory logs, worksheets and other records containing the raw data such as weighings, dilutions, the condition of instruments, and calculations. Note whether raw data are missing, if records have been rewritten, or if correction fluid has been used to conceal errors. Results should not be changed without explanation. Cross reference the data that has been corrected to authenticate it. 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.

Test results should not have been transcribed without retention of the original records, nor should test results be recorded selectively. For example, investigations have uncovered the use of loose sheets of paper with subsequent selective transcriptions of good data to analyst worksheets and/or workbooks. Absorbance values and calculations have even been found on desk calendars.

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. These practices raise questions about the overall quality of data.

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. Multiple injections recorded should be in consecutive files with consecutive injection times recorded. Expect to see written justification for the deletion of all files.

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. 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. Evaluate the justification for disregarding test results that show the product failed to meet specifications.

14. LABORATORY STANDARD SOLUTIONS

Ascertain that suitable standards are being used (i.e. in-date, stored properly). Check for the reuse of stock solutions without assuring their stability. Stock solutions are frequently stored in the laboratory refrigerator. Examine the laboratory refrigerators for these solutions and when found check for appropriate identification. Review records of standard solution preparation to assure complete and accurate documentation. It is highly unlikely that a firm can 'accurately and consistently weigh' to the same microgram. Therefore data showing this level of standardization or pattern is suspect and should be carefully investigated.

15. METHODS VALIDATION

Information regarding the validation of methods should be carefully evaluated for completeness, accuracy and reliability. In particular, if a compendial method exists, but the firm chooses to use an alternate method instead, they must compare the two and demonstrate that the in-house method is equivalent or superior to the official procedure. For compendial methods firms must demonstrate that the method works under the actual conditions of use.

Methods can be validated in a number of ways. Methods appearing in the USP are considered validated and they are considered validated if part of an approved ANDA. Also a company can conduct a validation study on their method. System suitability data alone is insufficient for and does not constitute method validation.

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. 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. The analytical performance parameters listed in the USP XXII, <1225>, 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.) needed to validate the method.

16. EQUIPMENT

Laboratory equipment usage, maintenance, calibration logs, repair records, and maintenance SOPs also should be examined. The existence of the equipment specified in the analytical methods should be confirmed and its condition noted. Verify that the equipment was present and in good working order at the time the batches were analyzed. Determine whether equipment is being used properly.

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. One would have to suspect the data that are generated from a piece of equipment that is known to be defective. Therefore, continuing to use and release product on the basis of such equipment represents a serious violation of CGMP's.

17. RAW MATERIAL TESTING

Some inspections include the coverage of the manufacturer of the drug substance. The safety and efficacy of the finished dosage form is largely dependent on the purity and quality of the bulk active drug substance. Examine the raw data reflecting the analysis of the drug substance including purity tests, charts, etc.

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. 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. Report findings where there is substantial difference in impurity profiles and other test 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. Such methods must be validated to ensure that they are adequate for analytical purposes in the control and validation of the BPC manufacturing process. The drug substance manufacturer must have complete knowledge of the manufacturing process and the potential impurities that may appear in the drug substance. These impurities cannot be evaluated without a suitable method and one that has been validated.

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. Some of these tests are filed in applications and others may be established by the protocols used to manufacture the product. The validation of methods for such tests are as important as the test for chemical attributes.

Physical properties tests often require the use of unique equipment and protocols. These tests may not be reproducible in other laboratories, therefore, on site evaluation is essential.

18. IN PROCESS CONTROLS AND SPECIFICATIONS

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. For example, evaluate the tests for weight variation, hardness, and friability. These tests may be performed every fifteen or thirty minutes during tableting or encapsulating procedures. All testing must comply with CGMP's.

The drug application may contain some of the in-process testing plan, including methods and specifications. The inspection must confirm that the in-process tests were done, as described in the plan, and ascertain that the results were within specifications. The laboratory work for the lengthier tests should also be reviewed.

The methods used for in-process testing may differ from those used for release testings. Usually, whether the methods are the same or different, the specifications may be tighter for the in-process tests. A product with a 90.0%-110.0% assay release specification may have a limit of 95.%-105.0% for the in-process blend. Some of the tests done may differ from those done at release. For example, a firm may perform disintegration testing as an in-process test but dissolution testing as a release test.

Expect to see consistent in-process test results within batches and between batches of the same formulation/process (including development or exhibit batches). If this is not the case, expect to see scientific data to justify the variation.

19. STABILITY

A stability-indicating method must be used to test the samples of the batch. If there is no stability-indicating assay additional assay procedures such as TLC should be used to supplement the general assay method. Evidence that the method is stability indicating must be presented, even for compendial methods.

Manufacturers may be required to accelerate or force degradation of a product to demonstrate that the test is stability indicating. 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. This information may also be obtained from the supplier of the drug substance. Validation would then be relatively straightforward, with the typical parameters listed in the USP in chapter <1225> on validation of compendial methods addressed as applicable.

Evaluate the manufacturer's validation report for their stability testing. 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.

Evaluate the raw data used to generate the data filed documenting that the method is stability indicating and the level of impurities.

20. COMPUTERIZED LABORATORY DATA ACQUISITION SYSTEMS

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.

- Compliance Policy Guide 7132a.08 Computerized Drug Processing: Identification of 'Persons' on Batch Production and Control Records.

- 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

- Guide to Inspection of Computerized Systems in Drug Processing.

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. Equally important are the procedure to audit data and programs and the process for correcting errors. Several issues must be addressed when evaluating computerized laboratory systems. These include data collection, processing, data integrity, and security.

Procedures should only be judged adequate when data are secure, raw data are not accidentally lost, and data cannot be tampered with. The system must assure that raw data are stored and actually processed.

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.

- Data entries may not be deleted. Changes must be made in the form of amendments.

- The data base must be made as tamperproof as possible.

- The Standard Operating Procedures must describe the procedures for ensuring the validity of the data.

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. 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.

21. LABORATORY MANAGEMENT

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. 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. Individually or collectively, these factors are the basis for an objection only when they are shown to result in inadequate performance of responsibilities required by the CGMPs.

Review laboratory logs for the sequence of analysis and the sequence of manufacturing dates. Examine laboratory records and logs for vital information about the technical competence of the staff and the quality control procedures used in the laboratory.

Observe analysts performing the operations described in the application. There is no substitute for actually seeing the work performed and noting whether good technique is used. You should not stand over the analysts, but watch from a distance and evaluate their actions.

Sometimes the company's employees have insufficient training or time to recognize situations that require further investigation and explanation. Instead they accept unexplained peaks in chromatograms with no effort to identify them. They may accept stability test results showing an apparent increase in the assay of the drug with the passage of time with no apparent question about the result. Also, diminishing reproducibility in HPLC chromatograms appearing several hours after system suitability is established is accepted without question.

Good manufacturing practice regulations require an active training program and the documented evaluation of the training of analysts.

The authority to delete files and override computer systems should be thoroughly examined. Evaluate the history of changes to programs used for calculations. Certain changes may require management to re-examine the data for products already released.