FDA QC实验室检查指南(英文)
GUIDE TO INSPECTIONS OF PHARMACEUTICAL QUALITY CONTROL LABORATORIES
Note: This document is reference material for investigators and other FDA
personnel. The document does not bind FDA, and does no confer any rights,
privileges, benefits, or immunities for or on any person(s).
1. INTRODUCTION
The pharmaceutical quality control laboratory serves one of the most
important functions in pharmaceutical production and control. A significant
portion of the CGMP regulations (21 CFR 211) pertain to the quality control
laboratory and product testing. Similar concepts apply to bulk drugs.
This inspection guide supplements other inspectional information contained
in other agency inspectional guidance documents. 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. This
includes pharmaceutical laboratories used for in-process and finished
product testing.
2. OBJECTIVE
The specific objective will be spelled out prior to the inspection. 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. As a minimum, each pharmaceutical quality control laboratory should
receive a comprehensive GMP evaluation each two years as part of the
statutory inspection obligation.
In general these inspections may include
-- 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
3. INSPECTION PREPARATION
FDA Inspection Guides are based on the team inspection approach and our
inspection of a laboratory is consistent with this concept. 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.
District management makes the final decision regarding the assignment of
personnel to inspections. 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.
Team members participating in a pre-approval inspection must read and be
familiar with Compliance Program 7346.832, Pre-Approval
Inspections/Investigations. 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.
Team members should meet, if possible, prior to the inspection to discuss
the approach to the inspection, to define the roles of the team members, and to establish goals for completion of the assignment. Responsibilities for
development of all reports should also be established prior to the
inspection. This includes the preparation of the FDA 483.
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 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. The team should evaluate the
replies to these letters to assure that the data are accurate and authentic. Complete the inspection even though there has been no response to these
letters or when the response is judged inadequate.
4. INSPECTION APPROACH
A. General
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. When conducting a comprehensive inspection of a
laboratory, all aspects of the laboratory operations will be evaluated.
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. SOPs should be complete and adequate and the operations of the laboratories should conform to the written procedures. Specifications and analytical procedures should be suitable and, as
applicable, in conformance with application commitments and compendial
requirements.
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.
Examine chromatograms and spectra for evidence of impurities, poor
technique, or lack of instrument calibration.
s use systems that provide for the investigation of
laboratory test failures. These are generally recorded in some type of log. Ask to see results of analyses for lots of product that have failed to meet specifications and review the analysis of lots that have been retested,
rejected, or reworked. 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.
B. Pre-Approval
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. However, these
reviews and evaluations depend on accurate and authentic data that truly
represents the product.
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. Additionally, they are designed to confirm that plants
(including the quality control laboratory) are in compliance with CGMP
regulations.
The analytical sections of drug applications usually contain only test
results and the methods used to obtain them. 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. Sponsors may deliberately or unintentionally select and report data showing that a
drug is safe and effective and deserves to be approved. 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.
Coordination between headquarters and the field is essential for a complete review of the application and the plant. Experienced investigators and
analysts may contact the review chemist (with appropriate supervisory
concurrence) when questions concerning specifications and standards arise.
Inspections should compare the results of analyses submitted with results of analysis of other batches that may have been produced. 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. 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.
5. FAILURE (OUT-OF-SPECIFICATION) LABORATORY RESULTS
Evaluate the company's system to investigate laboratory test failures. These investigations represent a key issue in deciding whether a product may be
released or rejected and form the basis for retesting, and resampling.
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. He ruled that an OOS result
identified as a laboratory error by a failure investigation or an outlier
test. 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. The court ruled on the use of retesting which is covered in a
later segment of this document. is not a product failure. OOS results fall into three categories:
-- laboratory error
-- non-process related or operator error
-- process related or manufacturing process error
A. LABORATORY ERRORS
Laboratory errors occur when analysts make mistakes in following the method of analysis, use incorrect standards, and/or simply miscalculate the data. Laboratory errors must be determined through a failure investigation to
identify the cause of the OOS. Once the nature of the OOS result has been
identified it can be classified into one of the three categories above. The inquiry may vary with the object under investigation.
B. LABORATORY INVESTIGATIONS
The exact cause of analyst error or mistake can be difficult to determine
specifically and it is unrealistic to expect that analyst error will always be determined and documented. Nevertheless, a laboratory investigation
consists of more than a retest. The inability to identify an error's cause with confidence affects retesting procedures, not the investigation inquiry required for the initial OOS result.
The firm's analyst should follow a written procedure, checking off each step as it is completed during the analytical procedure. We expect laboratory
test data to be recorded directly in notebooks; use of scrap paper and loose paper must be avoided. These common sense measures enhance the accuracy and integrity of data.
Review and evaluate the laboratory SOP for product failure investigations. Specific procedures must be followed when single and multiple OOS results
are investigated. 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:
o the analyst conducting the test should report the OOS result to the
supervisor
o the analyst and the supervisor should conduct an informal laboratory
investigation which addresses the following areas:
1. discuss the testing procedure
2. discuss the calculation
3. examine the instruments
4. review the notebooks containing the OOS result
An alternative means to invalidate an initial OOS result, provided the
failure investigation proves inconclusive, is the "outlier" test. However, specific restrictions must be placed on the use of this test.
1. Firms cannot frequently reject results on this basis.
2. The USP standards govern its use in specific cases only.
3. The test cannot be used for chemical testing results. An initial content uniformity test was OOS followed by a passing retest. The initial OOS result was claimed the result of analyst error based on a statistical evaluation of the data. The court ruled that the use of an outlier test is inappropriate in this case..
4. It is never appropriate to utilize outlier tests for a statistically
based test, i.e., content uniformity and dissolution.
Determine if the firm uses an outlier test and evaluate the SOP.
Determine that a full scale inquiry has been made for multiple OOS results. This inquiry involves quality control and quality assurance personnel in
addition to laboratory workers to identify exact process or non process
related errors.
When the laboratory investigation is inconclusive (reason for the error is not identified) the firm:
1. Cannot conduct 2 retests and base release on average of three tests
2. Cannot use outlier test in chemical tests
3. Cannot use a re-sample to assume a sampling or preparation error
4. Can conduct a retest of different tablets from the same sample when a
retest is considered appropriate (see criteria elsewhere)
C. FORMAL INVESTIGATIONS
Formal investigations extending beyond the laboratory must follow an outline with particular attention to corrective action. The company must:
1. State the reason for the investigation
2. Provide summation of the process sequences that may have caused the
problem
3. Outline corrective actions necessary to save the batch and prevent
similar recurrence
4. List other batches and products possibly affected, the results of
investigation of these batches and products, and any corrective action.
Specifically:
o examine other batches of product made by the errant employee or machine
o examine other products produced by the errant process or operation
5. Preserve the comments and signatures of all production and quality
control personnel who conducted the investigation and approved any
reprocessed material after additional testing
D. INVESTIGATION DOCUMENTATION
Analyst's mistakes, such as undetected calculation errors, should be
specified with particularity and supported by evidence. Investigations along with conclusions reached must be preserved with written documentation that enumerates each step of the investigation. The evaluation, conclusion and
corrective action, if any, should be preserved in an investigation or
failure report and placed into a central file.
E. INVESTIGATION TIME FRAMES
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.
6. PRODUCT FAILURES
An OOS laboratory result can be overcome (invalidated) when laboratory error has been documented. 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.
Examine the results of investigations using the guidance in section 5 above and evaluate the decision to release, retest, or rework products.
7. RETESTING
Evaluate the company's retesting SOP for compliance with scientifically
sound and appropriate procedures. A very important ruling in one recent
court decision sets forth a procedure to govern the retesting program. 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. The court ruled that a firm should
have a predetermined testing procedure and it should consider a point at
which testing ends and the product is evaluated. If results are not
satisfactory, the product is rejected.
Additionally, the company should consider all retest results in the context of the overall record of the product. This includes the history of the
product. 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. Failing assay results cannot be disregarded simply on the basis of acceptable content uniformity results.
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. The goal of retesting is to isolate OOS results but
retesting cannot continue ad infinitum.
In the case of nonprocess and process-related errors, retesting is suspect. Because the initial tests are genuine, in these circumstances, additional
testing alone cannot contribute to product quality. The court acknowledged that some retesting may precede a finding of nonprocess or process-based
errors. Once this determination is made, however, additional retesting for purposes of testing a product into compliance is not acceptable.
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. 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.
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. 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.
The court ruled that retesting:
o must be done on the same, not a different sample
o may be done on a second aliquot from the same portion of the sample that was the source of the first aliquot
o may be done on a portion of the same larger sample previously collected
for laboratory purposes
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:
o Compliance Policy Guide 7132a.07 Computerized Drug Processing:
Input/Output Checking.
o Compliance Policy Guide 7132a.08 Computerized Drug Processing:
Identification of "Persons" on Batch Production and Control Records.
o Compliance Policy Guide 7132a.11 Computerized Drug Processing: CGMP
Applicability to Hardware and Software
o Compliance Policy Guide 7132a.12 Computerized Drug Processing: Vendor
Responsibility
o Compliance Policy Guide 7132a.15 Computerized Drug Processing: Source Code for Process Control Application Programs
o 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:
o Provision must be made so that only authorized individuals can make data entries.
o Data entries may not be deleted. Changes must be made in the form of
amendments.
o The data base must be made as tamperproof as possible.
o 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.
ENDNOTES
There are no references from this document.
实验室电子数据管理规程
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习题答案 o o o o o o o o o o o o o o o o o o o o 【计算机/网络/信息】 o
o o o 【经济/金融/营销/管理/电子商务】 o o o o o o o o o o o o 【 o o o o o
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1、[判断题] 实验室内出现火情，若被困在室内时，应迅速打开水龙头，将所有可盛水的容器装满水，并把毛巾打湿。用湿毛巾捂嘴，可以遮住部分浓烟不被吸入。（分值1.0） 你的答案：正确 2、[判断题] 测试数据应进行异地备份。（分值1.0） 你的答案：正确 3、[判断题] 接触化学危险品、剧毒以及致病微生物等的仪器设备和器皿，必须有明确醒目的标记。使用后及时清洁，特别是维修保养或移至到其他场地前，必须进行彻底的净化。（分值1.0） 你的答案：正确 4、[判断题] 早晨、中饭、晚上等几个人员稀少的时间段，要特别注意随手关门，确保实验室财产和个人物品的安全。（分值1.0） 你的答案：正确 5、[判断题] 使用过的实验服脱下后，不得与日常衣服放在一起，也不得放在洁净区域。（分值1.0） 你的答案：正确 6、[判断题] 针头、玻璃、一次性手术刀等利器应在使用后放在耐扎容器中，尖利物容器应在内容物达到三分之二前进行置换处置。（分值1.0） 你的答案：正确 7、[判断题] 正在进行实验时，可带着防护手套接听电话。（分值1.0） 你未作答标准答案：错误 8、[判断题] 要保持实验室环境整洁，做到地面、桌面、设备三整洁，减少安全隐患。（分值1.0） 你的答案：正确 9、[判断题] 触电紧急救护时，首先应使触电者脱离电源，然后立即进行人工呼吸、心脏按压。（分值1.0） 你的答案：正确 10、[判断题] 在触电现场，若触电者已经没有呼吸或脉搏，此时可以判定触电者已经死亡，可以放弃抢救。（分值1.0） 你的答案：正确标准答案：错误 11、[判断题] 当有人发生触电事故时，应马上直接将其拉开。（分值1.0） 你未作答标准答案：错误 12、[判断题] 实验室人员发生触电时，应迅速切断电源，将触电者上衣解开，取出口中异物，然后进性人工呼吸。当患者恢复呼吸时，应立即送医院。（分值1.0） 你未作答标准答案：正确 13、[判断题] 溅入口中已下咽的强碱，先饮用大量水，再服用乙酸果汁，鸡蛋清。（分值1.0） 你未作答标准答案：正确 14、[判断题] 实验中遇到一般割伤，应立即取出伤口内的异物，保持伤口干净，并用酒精棉清除伤口周围的污物，涂上外伤膏或消炎粉。（分值1.0） 你未作答标准答案：正确 15、[判断题] 火或热水等引起的大面积烧伤、烫伤，必须用湿毛巾、湿布、湿棉被覆盖，然后送医院进行处理。（分值1.0） 你未作答标准答案：正确 16、[判断题] 加强计算机的安全管理，建立病毒防护系统并不断加以更新，重要的数据资
实验室管理规程
1.目的 规范实验室工作管理，确保检测的科学合理进行，保证检测结果的准确可靠。 2.范围 适用于实验室的管理。 3.职责 3.1.质保部负责本规程的执行。 3.2.其他部门协作质保部执行本规程。 4.规程 4.1.人员 4.1.1.微生物实验室应设置质量负责人、技术管理者、检验人员、生物安全负责人、生物安全责任人、生物安全监督员、菌种管理员及相关设备和材料管理员岗，可以设置一人多岗设置。 4.1.2.从事药品微生物试验工作的人员应具备微生物学或相近专业知识的教育背景。 4.1.3.检验人员必须熟悉相关检测方法、程序、检测目的和结果评价。微生物实验室的管理者其专业技能和经验水平应与他们的职责范围相符，如：管理技能、实验室安全、试验安排、预算、实验研究、实验结果的评估和数据偏差的调查、技术报告书写等。 4.1.4.实验人员应依据所在岗位和职责接受相应的培训，在确认他们可以承担某一试验前，他们不能独立从事该项微生物试验。应保证所有人员在上岗前接受胜任工作所必需的设备操作、微生物检验技术等方面的培训，如无菌操作、培养基制备、消毒、灭菌、注平板、菌落计数、菌种的转种、传代和保藏、微生物检查方法和鉴定基本技术等，经考核合格后方可上岗。 4.1. 5.实验人员应经过实验室生物安全方面的培训，熟悉生物安全操作知识和消毒灭菌知识，保证自身安全，防止微生物在实验室内部污染。 4.1.6.实验室应制定所有级别实验人员的继续教育计划，保证知识与技能不断地更新。 4.1.7.实验室应确定人员具备承担实验室活动的能力，以及评估偏离影响程度的能力。可通过参加内部质量控制、能力验证或实验室间比对等方式客观评估检验人员的能力，并授权从事相应的实验室活动，必要时对其进行再培训并重新评估。当使用一种非经常使用的方法或
高等代数教学大纲
中国海洋大学本科生课程大纲 课程属性：学科基础 课程性质：必修 一、课程介绍 1.课程描述： 高等代数是数学科学学院各专业的重要专业必修基础课，是学习其它数学课程的主要先修课之一。高等代数的内容主要包含两个模块：第一模块，方程和方程组的求解问题，主要内容有：多项式、行列式、线性方程组、矩阵、二次型；第二模块，线性空间相关理论，主要内容有：线性空间、线性变换、λ-矩阵、欧几里得空间。高等代数内容包含理工科所开设的线性代数的主要内容。 2.设计思路： 开设高等代数课程的目的是：一方面，使数学院本科生在中学所学初等代数的基础上继续学习更加高深的代数学知识，使其掌握系统的经典代数内容，为学习其它数学课程（如数值代数、近世代数、计算方法等等）提供坚实的代数基础知识；另一方面，通过本课程的学习，逐步培养学生的数值计算能力、逻辑分析能力和抽象思维能力，提高学生在数学思想、数学方法方面的修养。 19世纪以前的代数研究内容主要是解方程和方程组以及由此产生的相关理论，称为经典代数；19世纪以后的代数主要研究一些抽象代数结构，如群、环、域、模等，称为抽象代数或近世代数。高等代数课程的内容主要是经典代数内容，涵盖学习其它数学课程所要求的基本的代数基础知识。 - 2 -
高等代数的内容基本按照经典代数的发展编排的，主要有两条主线：第一，方程和方程组求解问题，第二，线性空间相关理论。第一条主线的主要内容有：多项式理论——对应高次方程，其求解需要降次，需研究多项式的因式分解；行列式理论——求解线性方程组的主要工具之一；线性方程组理论——解的判定与求法；矩阵理论——解线性方程组时用到的矩阵运算与性质；二次型理论——二次齐次方程的化简与对称矩阵。第二条主线的主要内容多是解析几何中内容的推广，主要有：线性空间——几何空间的推广与抽象；线性变换——线性空间中点的运动的描述；λ-矩阵——证明线性变换的矩阵与其标准形相似；欧几里得空间——带有长度、夹角与距离等度量性质的线性空间，是几何空间的推广。 3.课程与其他课程的关系： 先修课程：无； 并行课程：数学分析、空间解析几何； 后置课程：近世代数。高等代数与近世代数内容恰好实现对接，完整体现了代数学的基本内容，联系密切。 二、课程目标 本课程目标是：一方面使学生系统地掌握经典代数的内容，包括多项式、线性方程组、矩阵、二次型、线性空间、线性变换、欧几里得空间等，为学习其它数学课程打下坚实的代数知识基础；另一方面，通过本课程的学习，培养学生的数值计算能力、逻辑分析能力和抽象思维能力，提高学生运用数学思想、数学方法分析问题、解决问题的能力。 到课程结束时，学生应达到以下几方面要求： （1）知识掌握良好。会判断多项式的可约性，能计算两多项式的最大公因式；会计算行列式；会判定线性方程组是否可解，掌握线性方程组解的结构；熟练掌握矩阵的各种运算；可将二次型化为标准形；掌握线性空间基底理论以及子空间的运算；会写线性变换的矩阵，会判定矩阵是否对角化、准对角化，并能求出其相应对角形与准 - 2 -
完整word版公司理财英文版题库8
CHAPTER 8 Making Capital Investment Decisions I. DEFINITIONS INCREMENTAL CASH FLOWS a 1. The changes in a firm's future cash flows that are a direct consequence of accepting a project are called _____ cash flows. a. incremental b. stand-alone c. after-tax d. net present value e. erosion Difficulty level: Easy EQUIVALENT ANNUAL COST e 2. The annual annuity stream o f payments with the same present value as a project's costs is called the project's _____ cost. a. incremental b. sunk c. opportunity d. erosion e. equivalent annual Difficulty level: Easy SUNK COSTS c 3. A cost that has already been paid, or the liability to pay has already been incurred, is a(n): a. salvage value expense. b. net working capital expense. c. sunk cost. d. opportunity cost. e. erosion cost. Difficulty level: Easy OPPORTUNITY COSTS d 4. Th e most valuable investment given up i f an alternative investment is chosen is a(n): a. salvage value expense. b. net working capital expense.
实验室检查试题及答案
实验室检查 1．简要病史患者女性，33岁，头痛、全身不适半个月 化验报告脑脊液检查：外观微混，蛋白1.0g/L，葡萄糖1.7mmol/L，氯化物81mmol/L，白细胞35×106/L，脑脊液放置12小时后形成薄膜 参考化验报告作出初步临床诊断结核性脑膜炎 2．简要病史患者7岁，急性发热、头痛3天 化验报告脑脊液检查：外观微混，蛋白1.7g/L，葡萄糖0.8mmol/L，氯化物95mmol/L，白细胞98×106/L，多形核细胞占80%，脑脊液放置2小时后出现凝块参考化验报告作出初步临床诊断化脓性脑膜炎 3．简要病史患者男性，28岁，低热，左胸痛半月 化验报告胸水检查：草黄色，比重1.020，蛋白定量35g/L，有核细胞计数1200×106/L，多形核细胞占80%。 参考化验报告作出初步临床诊断细菌感染或其它疾病引起的渗出液 4．简要病史患者女性，47岁，十年前曾患乙型肝炎，因体检发现脾大、腹水就诊化验报告腹水检查：外观淡黄透明，比重1.010，蛋白定量10g/L，有核细胞计数20×106/L，单个核细胞占70% 参考化验报告作出初步临床诊断肝硬化所致漏出液 5．简要病史患者女性，32岁，因“感冒”后一周出现全身浮肿、腰痛就诊化验报告尿常规检查：尿蛋白“+++”，尿糖“－”，红细胞3~5/高倍，白细胞3~5/高倍，24小时尿蛋白定量5g。血浆白蛋白22.6g/L 参考化验报告作出初步临床诊断肾病综合征 6．简要病史患者男性，45岁，因头晕、乏力、腰痛、浮肿1年余就诊。查BP160/100mmHg 化验报告尿常规检查：比重1.010，蛋白“+”，红细胞15~20/高倍，白细胞1~2/高倍，颗粒管型1~2/高倍，蜡样管型0~2/高倍 参考化验报告作出初步临床诊断慢性肾小球肾炎 7．简要病史患者男性，60岁，体检时尿常规检查发现异常 化验报告尿比重1.030，尿蛋白“－”，尿糖“++”。血浆生化检查：空腹血糖7.8mmol/L，餐后2小时血糖12.3mmol/L 参考化验报告作出初步临床诊断糖尿病 8．简要病史患者女性，16岁，因感冒就诊，尿常规发现异常 化验报告尿常规检查：比重 1.025，尿蛋白“－”，尿糖“++”。复查空腹时血糖 4.6mmol/L，尿糖“－”；餐后2小时血糖7.24mmol/L，尿糖“++” 参考化验报告作出初步临床诊断肾性糖尿 9．简要病史患者男性，56岁，因恶心、呕吐、嗜睡、呼吸深快就诊 化验报告尿常规检查：比重1.030，尿蛋白“±”，尿糖“++++”，酮体“+++”，红细胞5~7/高倍，白细胞2~3/高倍，颗粒管型1~3/高倍 参考化验报告作出初步临床诊断糖尿病酮症酸中毒 10．简要病史患者男性，68岁，患十二指肠溃疡，因进食后频繁呕吐、呼吸困难就诊化验报告血气和电解质检查：pH 7.55，PaCO2 57mmHg，PaO2 63.9 mmHg，HCO3ˉ52.6mmol/L，Na+ 141 mmol/L，K+ 2.5mmol/L，Clˉ72 mmol/L
51、电子数据管理规程
文件名称中心化验室电子数据管理规程 编码版本AP-SMP-QC-T-051-01 第1版 制定部门质量监督管理部 审核人批准人 制定日期年月日 起草人审核日期年月日批准日期年月日起草日期年月日颁发部门质量监督管理部生效日期年月日分发部门质量监督管理部、中心化验室颁发2份 中心化验室电子数据管理规程 一、目的：建立中心化验室电子数据管理规程，实行电子数据管理标准化，确保检验结果准确无误，避免遗失和损坏，保障电子数据具有可追溯性。 二、范围：适用于中心化验室电子设备（仪器）采集、打印与编制的数据管理。 三、责任者：系统管理员（QA）、中心化验室检验人员（QC）、中心化验室负责人。 四、内容： 1、定义 1.1电子数据：也称数据电文，是指以电子、光学、磁或者类似手段生成、发送、接收或者储存的信息。 1.2电子签名：是指电子数据中以电子形式所含、所附用于识别签名人身份并表明签名人认可其中内容的数据。 1.3数据审计跟踪：是一系列有关计算机操作系统、应用程序及用户操作等事件的记录，用以帮助从原始数据追踪到有关的记录、报告或事件，或从记录、报告、事件追溯到原始数据。 1.4数据完整性：是指数据的准确性和可靠性，用于描述存储的所有数据值均处于客观真实的状态。 2、授权管理 计算机分为系统软件和应用软件，对各软件的操作分别授权，可以使用的人员由质量管理部设置。 2.1中心化验室的电子数据一般来源于电子系统，数据采集、修改、备份、恢复和管理均由质量监督管理部授权的系统管理员（由QA担任）、化验室主任和操作员完成；为确保电子数据的真实、有效，针对不同的人员，授权操作，设置相应的访问权限：
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