Audit – 15 Auditing an Analytical Quality & Stability Testing Laboratory

Goals

When you have completed this unit, you should be able to:

Ø Understand what the GMP requirements are for the analytical quality laboratory and stability testing laboratory

Ø Identify which GMP regulations govern the analytical quality laboratory

Ø Use a range of information tools, from the contents of this training in support of analytical testing and stability testing auditing.

Ø Recognize compliance or non-compliance of analytical quality laboratory and stability testing

Definitions

Acceptance Criteria: The criteria a product must meet to successfully achieve delivery requirements.

Analyte: A substance being analyzed, a single component (compound) of a mixture

Chromatography: The science which studies the separation of molecules based on differences in their structure and/or composition. Chromatography is also a method to separate components of an analyte involving a mobile phase moving through a stationary phase. Types of chromatography are thin layer chromatography, gas chromatography, liquid chromatography and paper chromatography.

Chromatogram: The record of results for the process of chromatography that shows the response of each component as a function of time and concentration of the sample. The record may be the media itself, e.g. the paper or thin layer medium, a piece of paper (e.g. computer print out) or it may be retained in a computer and displayed on video display terminal.

Consistency: The ability of the instrument to test the same sample numerous times under the same conditions and generate the same data within in a very strict range.

Detection limit: The detection limit of an individual analytical procedure is the lowest amount of analyte in a sample which can be detected but not necessarily quantitated as an exact value. This is considered to be 3 times the signal to noise ratio, within PAR&D.

Gas chromatography (GC): A type of chromatography where a liquid sample is vaporized and then injected into a column on a carrier gas. Components of the analyte bind to the column at different rates, with different parts of the analyte passing through the column at different times.

High performance liquid chromatography (HPLC): A type of chromatography using relatively high pressures and small diameter column packings to achieve sharp and highly reproducible elution profiles.

Laboratory Information Management System (LIMS): A system which can be used to schedule and record analytical data.

Linearity: The linearity of an analytical procedure is its ability (within a given range) to obtain test results which are directly proportional to the concentration (amount) of analyte in the sample. For those analytical procedures which are not linear, another mathematical relationship (proportionality) must be demonstrated.

Method Validation: The process by which it is established, by laboratory studies, that the performance characteristics of the analytical methods meet the requirements for the intended application.

New Drug Application (NDA): Application to the US regulatory agency (FDA) to allow the sponsor to market a drug product in the US.

Marketing Authorisation Application (MAA): Application for authorisation to place medicinal products on market. This is a specific term for the EU/EAA markets.

Japanese New Drug Application (JNDA): Application to be submitted for regulatory drug approval to the Japanese Ministry of Health, Labour and Welfare (MHLW).

Clinical Trial Application (CTA): An application to regulatory authority(ies) for the permission to perform a clinical study using an investigational product in subject/patients. Defined in ICH guideline for GCP, May 1996.

Investigation New Drug Application (IND): A new drug that is used in a clinical investigation application.

Out-of-specification (OOS) result: A laboratory test that is outside its regulatory or compendial limits. In some cases, there may be additional tests and/or limits that are used to assess the quality of a material, but are not included in registrations or compendia. In these cases, the general principles described here are useful, but more latitude is allowable in the disposition of the material as long as it meets its legal requirements.

Out-of-trend (OOT) result: A laboratory test that is within its regulatory or compendial limit but is atypical of previous results for the test over a number of batches or earlier time points in a stability study and may provide early indication of a potential OOS result. The importance of OOT results increases as the knowledge of the product increases and more latitude in interpretation of, and response to, an OOT result may be appropriate in early development compared to commercial product.

Figure: Out of Trend Results

Precision: The precision of an analytical procedure expresses the closeness of agreement (degree of scatter) between a series of measurements obtained from multiple sampling of the same homogeneous sample under the prescribed conditions. Precision should be measured using authentic samples. However, if it is not possible to obtain a homogeneous sample it may be measured using artificially prepared samples or a sample solution. The precision of an analytical procedure is usually expressed as the variance, standard deviation of coefficient of variation of a series of measurements.

Quality standard: A set of minimum specifications and testing methods for raw materials, packaging components, chemical intermediates, active substance or drug products as established by official compendia and/or registered requirements.

Quantitation limit: The lowest amount of a given substance in a sample that can be quantified with suitable accuracy and precision with the selected analysis procedure

Reference standard: Sample of substance used as benchmark during chemical analysis of a product.

Regulatory analytical procedure: An analytical procedure used to evaluate a defined characteristic of the drug substance or drug product.

Relative standard deviation (RSD): The internal correlation of the standard deviation of a set of specific numbers. The RSD is the sample SD divided by the sample Mean. The RSD is usually expressed as a percentage. The higher the percentage is, the worse the correlation. The RSD is also known as 100 times the Coefficient of Variation (CV).

Reserve/ Reference samples: Term used for samples taken for retention.

Specification: An approved quantitative value or requirement that raw materials, in-process materials, products, equipment and systems must conform to or contain. The documents that contain the specification information are sometimes referred to as “specs” or specifications.

ALSO The quality standards (i.e., tests, analytical procedures, and acceptance criteria) provided in an approved application to confirm the quality of the drug substances, drug products, intermediates, raw materials, reagents, and other components including container closure systems, and in-process materials.

Specificity: The ability of a test method to measure an analyte without interference from other sample components (e.g. excipients, known impurities, and degradation products).

Stability-indicating assay: A validated quantitative analytical procedure that can detect the changes with time in the pertinent properties of the drug substance and drug product.

Standard Deviation (SD): A measure of the dispersion of a series of results around their average, expressed as the square root of the variance.

System suitability testing: The evaluation of the components of an analytical system to show that the performance of a system meets the standards required by the method.

Type or Class A glassware: Glassware that conforms to applicable construction and accuracy requirements as certified by the American Society of Standards and Testing. This glassware is marked with the letter “A” on it.

Explanation of Topic

Introduction

The purpose of this training module is to provide information on what to include in an audit of an analytical quality laboratory. Since the analytical laboratory performs many sophisticated and complex tests, this training module will contain detailed information about some of the tests that can be performed in a laboratory to increase the auditor’s understanding of the analytical laboratory environment. Topics included in this section of the training unit are:

Ø Importance of laboratory audits

Ø Laboratory administration, organization and personnel training

Ø General condition of laboratory

Ø Sample receipt and tracking

Ø Analytical testing concepts and methods validation

Ø Reference standards/reagents/volumetric solutions

Ø Documentation-procedures, SOPs, records and reports

Ø Instrumentation and equipment-

Ø OOS investigations

Ø Quality standards

Ø Change control program

Ø Stability testing

Ø Reserve/Retained sample testing

Ø Certificate of Analysis

The Importance of the Laboratory Audit

An audit of the quality analytical laboratory is important for a number of reasons.

Testing is performed to assure that the drug product meets acceptance criteria throughout the drug manufacturing process and its shelf life.  Shown below are the types of testing the analytical laboratory performs and the benefits of the testing.

Because testing is so important, analytical laboratory techniques and instrumentation must perform within their specified limits continually. Documentation must be accurate and complete.

To assure this, there must be laboratory controls in place, including:

Ø Specifications, test methods and sampling plans in place that are approved.

Ø Deviations and changes must be documented and justified

Ø Tests must be conducted to determine conformance to specifications

Ø Laboratory equipment and instrumentation must be calibrated using an established written program that must also be uniquely identified and in the plant/site system.

Ø There must be a written testing plan for testing and sampling final product which must include the method of sampling and number of units per batch

Ø Test methods must be validated

Ø Acceptance criteria for release testing must be adequate.

Ø Batches not meeting acceptance criteria must be rejected

Ø There must be an established written stability program in place

Ø An adequate number of batches must be tested to determine and/or maintain expiry life.

Ø An appropriate identified reserve sample that is representative of each lot (e.g. active ingredient, finished product) needs to be retained

To determine if the controls are in place, an audit of the analytical quality laboratory must be performed. This audit should be well organized, thorough, and focused. A good place to start is to find about the laboratory personnel and the organization of the lab.

Laboratory Administration, Organization and Personnel

When auditing the laboratory, determine if there have been any recent changes in the laboratory. These could range from introduction of new analysts or supervisors into the laboratory, changing the organization from a structured, hierarchical system to a team environment, or the implementation of new or different types of testing.

The laboratory should be organized to ensure that there are adequate numbers of analysts available on all shifts to perform the workload and adequate supervision for out of normal hours working. Discuss with the laboratory manager or responsible person any corrective actions from regulatory inspections or internal audits. Determine the status of these corrective actions and if they were corrected within the agreed time period.

Training

All personnel working in the laboratory should be trained in both GMP and the technical skills required for their job function. GMP training should be continuous at intervals specified in a site SOP.

Personnel should also be formally trained and qualified, according to site procedure, on operation of specific instruments, use of specific methods and techniques. Personnel should be qualified on each test and/or technique prior to executing them on their own. This training should be documented and competency based.

General laboratory conditions

The laboratory should be uncluttered. There should be no miscellaneous pieces of paper sitting on laboratory benches. All reagents should be labeled with an expiration date.

If glassware is washed in the lab there should be an SOP explaining what glassware is washed and instructions on how to perform the washing and rinsing. Equipment should be within its calibration date as indicated by either a sticker on the machine, calibration logbook or electronic calibration management system.

If the laboratory uses storage devices such as cold rooms and freezers, the chart indicating the temperature should be current with previous charts available for review.

Where possible temperature storage facilities should be alarmed to indicate when the temperature has deviated from the set range and a documented procedure in actions to be taken in the event of a temperature deviation.

After reviewing the lab, a good way to understand the lab procedures and flow of materials is to follow a sample through the laboratory.

Sample Receipt and Tracking

The laboratory should have a procedure and system in place to manage samples. When receiving samples, the laboratory should record the name or identification of the sample as indicated in the site’s SOP, type of sample, date received, type of storage needed (i.e. refrigeration, protected from light, etc.), and signature of person who received it.

The sample may be entered into a validated computer system (e.g. LIMS) or manually into a logbook if it is controlled. The laboratory should account for all samples coming into the laboratory (i.e. each sample that is received in the laboratory should undergo testing). Once the sample has been received it needs to be tested within an established time frame.

Analytical Testing Concepts and Methods Validation

Analytical testing is performed to:

Ø Identify what components are in the drug product, raw materials and active substance.

Ø Determine if the correct components are present

Ø Determine if the components are present in the correct concentration/amount

Ø Determine the quality of the product whose chemical constitution is critical

Ø Determine if there are any chemicals present that should not be

To do this, the test methods must meet certain analytical parameters.  The basic validation parameters for test methods are:

Ø  Precision

Ø  Accuracy

Ø  Specificity

Ø  Detection limit

Ø Quantification limit

Ø Linearity

Ø Range

Ø System suitability

Ø Robustness

Ø Ruggedness

Precision is reproducibility, repeatability or consistency.  An example is an arrow hitting a target.  The number of arrows that hit the same area or near the same area give a value for precision.

Figure: Precision and Accuracy

Accuracy is getting results that are within the specifications. In the case of an arrow hitting the target, the goal is to have all the arrows hit the center of the target. Linearity is another analytical parameter. A sample should be able to be diluted and assayed with the assay results directly proportional to the concentration of the analyte in the sample.

If the test has good linearity, the plot of the results should yield a straight line The specificity of a method defines the ability of the method to measure the analyte of interest to the exclusion of other relevant components.

The test should be specific enough that even if there are other components in the sample, only one component is measured. Each method will have a range. The range of the method is the area between the lower and the upper limits of quantitation.

The range should be linear. The detection limit, also known as the Limit of Detection, allows the laboratory analyst to determine if a particular analyte is present but may not provide a quantity of the analyte. If an analytical instrument is used, it is usually the smallest concentration of analyte the instrument is able to “see”. Quantification limit, also known as the Limit of Quantification, is the smallest amount (lowest concentration) that an analyte can be measured accurately and precisely.

The detection limit and the quantification limit may be different for the same instrument being used.

Ruggedness refers to the degree of reproducibility of test results obtained by the analysis of the same samples under a variety of normal test conditions. Some examples of these include testing in different laboratories, using different analysts, conducting the tests on different instruments, using different lots of reagents, using different elapsed times, performing assays on different days.

Ruggedness is normally expressed as the lack of influence of operational and environmental variables of the analytical method on test results. Robustness is the capacity to remain unaffected by small, but deliberate variations in the method parameters and provide an indication of its reliability.

Most analytical laboratory test methods are validated using some of these parameters.

Test method validation

All analytical procedures, which are used to generate data that could be included in a regulatory submission, must be validated to the degree appropriate for the phase of development before use. Full validation should be performed during phase III of the development. Analytical procedures that are used to test a commercial finished product, active ingredient, raw material or packaging component, must be validated before use.

Records should be in place to show what was done during the validation testing. Methods can be validated in a number of ways. If a site uses a method that appears in the USP (or other official compendia) it is considered validated, but the method must be shown to work under the actual conditions that it will be used (method qualification).

A method is also considered validated if it is part of an approved NDA. A site can also conduct a validation study on their method. However, system suitability data alone is not sufficient to validate a method. Method validation data must be consistent and conform to acceptance criteria. Validation results from a number of different tests, conducted under the same conditions, must demonstrate repeatability.

When using varying concentrations of test solutions, the results must be linear. Many assay and impurity tests now use HPLC. It is expected that the precision of these assays be equal or less than the RSD’s for system suitability testing.

Analytical performance parameters listed in the USP/NF (current version), <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.

To perform the test, reference standards, reagents and volumetric solutions are needed as part of the assay. They must be prepared correctly and meet their specifications.

Reference Standards, Volumetric Solutions and Reagents

Procedures for working with reference standards, volumetric solutions, and reagents used in the analytical quality laboratory should be approved and in place. These procedures should include:

Ø Which reference standards are used first if there is more than one lot of standard

Ø How to qualify the standard, whether through in house testing or Certificate of

Analysis from the manufacturer,

Ø When and how reference standards and volumetric solutions should be recertified, and the documentation requirements for recertification

Ø How the reference standards and volumetric solutions should be stored and monitored

Ø How reference standards should be used (i.e. “as is” or “dry before use”)

Reagents should have their expiration date clearly marked on the container.  Storage instructions and lot number should not be obscured if a label is attached by the laboratory. If a reagent is used in a preparation its lot number should be recorded.

Documentation

It is expected that all procedures, records and reports accurately represent both the actual in- use testing process and accurate data. Documents that should be reviewed, as applicable, during a laboratory audit should include information about the laboratory itself and its systems, as well as test results. These documents include:

Ø An Out of Specification (OOS) or Out of Trend (OOT) Investigation

Ø Raw material testing specifications, methods, and results

Ø In-process testing specifications, methods and results

Ø Cleaning verification

Ø Method validation data

Ø Equipment qualification

Ø Final release testing specifications, methods, and results for a drug product

Ø Release testing specifications for intermediates

Ø Personnel training records

Ø Analysts’ laboratory notebooks

Ø Log books for equipment maintenance and calibration

Ø Log books for reference standards and preparations

Data review

All data should be recorded in controlled notebooks, controlled worksheets, controlled files and/or validated computer systems (LIMS). Notebooks and/or worksheets should be properly signed and dated and concurrent with the tests being performed. If the laboratory has decided to keep print outs of data in a file or notebook for storage purposes, the file or notebook should be controlled and referenced in the analyst’s notebook.

All data and calculations should be reviewed by a second person, usually a supervisor or a member of the quality group, to determine completeness and accuracy. Some analytical tests to determine composition of the drug product will require chromatography, either GC, HPLC, or another type of chromatography.

If using GC or HPLC, there should be a run sequence list for each run. The chromatography conditions or parameters (flow, injection volume, serial number, etc.) should be approved and established and indicated for each run.

The laboratory should have a system in place to review all chromatograms. There should be a requirement that all chromatograms in a run sequence are reported. System suitability should be documented and correctly calculated.

If extra peaks representing impurities or other discrepancies are found when reviewing chromatograms, the auditor should determine if there is a site procedure and program in place that requires investigations to be completed within a short time and notification of management.

Data printouts, at a minimum, should include the following information:

Ø Date

Ø Person performing the test

Ø Sample identification (i.e. name of product, strength, lot number, batch number, time (if appropriate) etc.

Ø Piece of equipment used (unique identification number)

Ø Person who reviewed the chromatogram, if required in the site’s SOP

Ø Method and parameters used to run the test

All laboratory preparation of samples, reagents, and standards, must be recorded in controlled laboratory notebooks and/or controlled worksheets or specific logbooks. Included in the preparation should be calculations, dilutions, and concentrations as directed by the site’s SOPs.

Equipment and instrumentation

All operating pieces of laboratory equipment and instrumentation should be in calibration and meet operating specifications established for that instrument. When equipment is introduced into the laboratory, it should be qualified, meeting both the manufacturer’s and site’s specifications.

The qualification should be completed prior to use following the established procedure(s) for equipment qualification. Equipment qualification may include manufacturer’s specifications, system requirements, operating range, drawings, parts list, user’s manual, recommended preventative maintenance and calibration schedules and methods, applicable SOPs, and functional testing across operating and/or working range.

There should be a record or log of when a specific piece of equipment was used and for what samples. Equipment should also be routinely calibrated.

This can be achieved by having the equipment assigned to a preventive or routine maintenance schedule, sending the equipment out to a certified vendor who performs calibrations, or having calibrations performed by laboratory personnel.

Whichever path is taken, there should be an established acceptance criteria. Documentation should include both the “as found” result (prior to calibration being performed) and the result after calibration. Appropriate testing should be conducted to ensure that the equipment is ready for use. There should be a defined procedure for actions to be taken in the event of a calibration failure, including impact on any testing completed using the piece of equipment.

SOPs should be established for maintenance and calibration of equipment. Laboratory equipment should be scheduled for preventative maintenance based on the manufacturer’s suggested maintenance schedule and/or previous experience with the equipment. SOPs for calibration and maintenance should be reviewed to determine if they contain enough detail to ensure that equipment is operating with reliability and accuracy.

The requirement for a calibration and maintenance schedule should be indicated in an SOP. If equipment is broken or needs repair it should be marked as “Out of Service”, “DO NOT USE-repair needed” or other words that indicate the equipment should not be used. Calibrated equipment or instruments should have a visible sticker that indicates who performed the calibration, when it was performed and when the next calibration should be performed. Computers or electronic Laboratory Management Information Systems (LIMS) used in the laboratory for databases, recording raw data and preparing reports, need to be validated. These same computers need to be fully compliant with Electronic records and electronic signatures requirements.

Access to the computer and access to various types of information should be tightly controlled with the system available only to authorized personnel. Spreadsheets used to perform result calculations or data interpretation need to be adequately controlled and validated. If there are any changes made to the hardware and/or software, changes must be made according to the change control system established at the site.

As an auditor, you will see many types of laboratory equipment and instrumentation. Some will be used to separate and quantify the components of the analyte or drug sample. Others will provide information about the chemical structure. Still others will be used to determine the physical properties of the drug product. A few of the more common methods and instruments will be shown below.

Methods

High Pressure Liquid Chromatography (HPLC)

HPLC works by pumping the mobile phase, composed of a solvent, through a column (the stationary phase) under very high pressure. The analyte is injected into the moving phase or solvent, and carried through the column.

In HPLC, all analytes travel the same distance (the length of the column), so compounds are characterized by retention time (i.e. the time that an analyte remains in the column).  Once the analyte is eluted, it passes through a detector where data is integrated.  This data is then transformed into a chromatogram.

Figure: HPLC

Gas chromatography

Gas chromatography is also a separation method for mixtures of chemicals. The carrier gas acts as the moving phase.  The sample, usually a liquid, is injected into the gas, and then carried through the column.  A detector is attached to the end of the column.

Figure: GC

Spectroscopy

Other tests that may be performed in the analytical laboratory are those that can identify functional groups on molecules. It is not unusual to take a sample from a separation method and then use another method to provide further characterization. Other instruments used are Fourier Transform Infrared (FTIR), IR, atomic absorption, mass spectroscopy and others. The results are printed as spectrum or spectra. In most instances the spectra will be plotted with the wavelength on the x-axis and the absorbance on the y-axis. Pictures of instruments with their spectra are shown.

Figure: Infrared Spectrophotometer

Physical test methods

The analytical laboratory may also have to perform physical tests on drug products. One of the pieces of equipment that an auditor will see if the site tests tablets is a dissolution tester. Dissolution tests are used to determine the rate that tablets dissolve andthe amount of active ingredients released.

Figure

Out-of-Specification

Specifications for laboratory testing should be based on sound scientific reasoning and established during validation of the test method during product development.

They should also be specific for the drug product or sample being tested. Sometimes the laboratory results will not be within specifications. These results are considered out of specification (OOS).

Out of specification results refer to all suspect laboratory results that are outside of the specifications, acceptance criteria, or in-process control limits established in new drug applications, official compendia or by the manufacturer.

Investigations should be conducted for those test results that are OOS for the acceptance criteria of the test performed. The site should have an approved SOP or testing protocol that includes details of the OOS and OOT elements to be investigated. If there are automated systems for documenting tracking and trending OOS, they should be validated.

Change Control Program

All laboratory equipment, methods, and procedures should be part of a site change control program.  This program should be outlined in an approved SOP.

All changes to both equipment, including software and hardware changes, and analytical methods, need to be:

Ø Documented with a description of the work performed

Ø Evaluated for impact on qualification

Ø Approved prior to implementation

Change control procedures should also include directions for incorporating changes based on pharmacopoeia requirements and requires that the incorporation is timely.

Stability Testing

The purpose of stability testing is to provide evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors such as temperature, humidity, and light.

Stability testing permits the establishment of recommended storage conditions, retest periods, and shelf lives. When a laboratory performs stability testing it must have an SOP managing all parts of the stability program. The SOP should include:

Ø Approved stability protocols specifying, at a minimum, sample size, test intervals, test storage, storage conditions as contained in the regulatory submission.

Ø A system for monitoring stability chambers

Ø A system for sampling stability inventory including specific times to remove and test stability sample.

Ø A procedure for reviewing stability data for trends

Ø An procedure for notifying management and performing investigations

Since monitoring of stability chambers is a high priority with regulatory agencies, the laboratory should use qualified chambers. These chambers should be assigned to a calibration and maintenance schedule.

Temperature and humidity requirements should be established in an approved SOP. The chambers should have an alarm system and a procedure in place to manage both alarms and deviations.

If there are any changes made to the chambers, the changes must be subject to the change control system established at the site. Testing of the product should be performed in the equivalent container as clinical or market product, for development or commercial studies respectively. An adequate number of batches should be tested with stability indicating assays.

The site should also be monitoring laboratory results of stability test samples to determine if there is an OOT result. Trends may indicate a process drift and should be investigated and the cause determined. An approved SOP for defining what constitutes a trend and how to manage OOT results should be in place.

Reserve/Retained Sample Testing

Samples of each lot in each shipment should be retained and stored in the same container- closure system under label conditions. The reserve sample consists of at least twice the amount required for full testing. Temperature logs should be maintained and available for review.

For API clinical trial material there should be system that ensures sufficient quantity of each reserved sample is retained for an appropriate length of time after approval, termination or discontinuation of an application.

Every year until discard, reserve samples or batches selected by acceptable statistical standards should be examined visually for evidence of deterioration.

Certificate of Analysis

A Certificate of Analysis should be produced where appropriate to detail the testing completed on a batch. There should be processes in place to ensure the accuracy of the certificate.

Summary

Since the analytical quality laboratory provides information that is used for release of our drug product, it is important that the laboratory follows GMP. The goal of the laboratory should be that the correct samples have the required testing performed. To accomplish this,

Ø Analytical methods must be validated and appropriately used to test the samples

Ø Laboratory personnel must be trained

Ø Equipment and instrumentation must be qualified, calibrated and maintained

Ø Documentation must be complete and accurate.

Ø Appropriate systems must be in place to manage OOS and OOT results, investigations, routine preventative maintenance, and change control

Key Parameters in Auditing Analytical Quality Laboratories

Prior to the audit

Ø Find out which products are tested and the test methods used

Ø Choose at least one product with specifications and test methods as detailed in the

Ø Marketing Authorization/NDA/CTA/IND/JNDA to follow during the audit.

Ø Request a list of laboratory SOPs

Ø Review relevant Quality agreement.

Ø Request a list of laboratory equipment

Ø Request a list of laboratory deviations/OOS/OOT investigations from the previous 12 months

Ø Review previous audits and regulatory audits to determine if there are pending actions

During the audit

Conduct a walk through of the laboratory by following the path of a sample to be tested. Include sample storage areas and chambers.

Ø Receiving and tracking samples

–  Ensure samples are labeled properly and uniquely identified.

–  Ensure that there is a system in place that assures samples are stored under correct conditions.

–  If samples are subdivided for multiple tests, ensure that the subdivision is recorded.

–  If samples are pooled for analysis, ensure that the pooling is recorded.

–  Ensure that the sample is signed in using a well documented and established procedure.

–  Ensure that there is a documented procedure for logging samples out of the laboratory.

–  Ensure that site requirements for sample handling and storage are included in a laboratory SOP.

–  Ensure that samples are managed and stored based on their storage and handling instructions.

–  Check how the laboratory handles ‘non routine samples’ e.g. for experimental work. How these are controlled, logged into the laboratory and results recorded.

Ø SOPs/Quality Standards

–  Ensure that the current approved version is being used.

–  Ensure the analyst knows the correct test to run based on a Quality Standard.

–  Ensure that no uncontrolled documents or extract from SOPs or test methods are used.

–  Ensure all relevant procedures are available to lab personnel

–  Ensure that both test methods and specifications are available to laboratory personnel.

– While observing an analyst, compare the test method being performed to the written version of the procedure.

–  Ensure that there is an approved change control procedure and a reasonable time frame for reviewing SOPs.

–  Ensure pharmacopoeia methods are verified for use in the laboratory.

–  Ensure that methods used are validated for their intended purpose.

–  Ensure that there are validation reports on file for the test methods.

–  Ensure that release methods include stability indicating assays.

Ø Reference standards

–  Ensure that a assigned purity is stated, where required and Certificate of Analysis for the standard is available in the laboratory.

–  Ensure that reference standards are stored under correct storage conditions.

–  Ensure that storage conditions are monitored.

–  Ensure that reference standards are within expiration date.

–  Ensure that standard preparations are labeled and stored correctly.

–  Ensure that storage time for standard preparations is valid.

–  Ensure that there are SOPs available for direction on handling and storing reference standards.

–  Review reference standard logbooks to confirm that the standards are being held under proper conditions.

–  Ensure there is a system in place for the traceability of reference standards.

Ø Reagents

–  Ensure that the grade of reagent is the same as specified in the regulatory submission.

–  Ensure that the reagent is properly labeled, stored, and has an assigned expiration/or re-assay date.

–  Ensure that the water used to prepare the reagent is of the purity required in the site SOP for preparation of the reagent.

–  Ensure that the lot number is recorded when a reagent is prepared.

–  Ensure that if water is held before preparing the reagent that there are scientific studies to justify the hold time.

–  Review reagent preparation logbooks.

Ø Volumetric Solutions

–  Ensure there is an approved preparation procedure in place.

–  Ensure that the data is recorded and easily accessible.

–  Determine what the expiration and re-standardization dates are.

–  Determine if they agree with the Pharmacopoeia

Ø Glassware

–  Ensure that Type A glassware is used for quantitative work.

–  Ensure that there are standard procedures in place for cleaning laboratory equipment and components (i.e. pipettes, volumetric flasks, etc.)

–   Ensure there are storage instructions for clean glassware in place.

–  Ensure that if detergent is used in cleaning the glassware, justification or data verifying its absence is available.

Ø Data and reports

–  Ensure that data is checked by a second person.

–  Ensure that there is an approved SOP on the topic of second person review.

–  Ensure that data is secure with only authorized personnel able to access it.

–  Ensure that raw data is recorded in a notebook or on controlled sheets of paper, not on loose paper.

–  Ensure that data is reported correctly according to approved procedure, i.e. each data point is recorded, as specified in the SOP, versus an average taken.

–  Ensure that any data reported includes its units of measurement.

o  If loose sheets of paper or computer printouts are used to record additional data, ensure that each page includes the number of the notebook and notebook page it should be attached to.

–  Ensure that automatic raw data capture with computerized systems follows the same requirements as for paper based data collection.

–  Review data for the chosen product and ensure that correct specifications and methods are used

–  Ensure that relevant system suitability tests are run as appropriate.

–  Ensure that reagents, solutions, standards and instruments used are traceable.

–  Ensure that analytical data is being trended and the collected data evaluated.

Ø Analyst’s Notebook

–  Ensure that all written raw data is recorded in notebooks or controlled worksheets.

–  Ensure that the number and version/date of the method is recorded.

–  Ensure that the exact method as described in the SOP has been followed.

–  If there is deviation from the procedure, ensure that the supervisor or authorized person according to SOP has approved the deviation.

–  Ensure equipment is identified including serial numbers of columns.

–  If applicable, ensure that standard and sample weights are recorded according to established procedure.

–  If applicable, ensure that standard concentration calculations are documented.

–  Ensure that notebooks are controlled.

–  Ensure that notebooks are reviewed by a second person for accuracy and completeness.

–  Ensure that the analyst signs and dates each day data are recorded.

–  Ensure that all entries that are crossed out are initialed and dated according to an approved SOP.

–  Ensure systems for archiving of electronic data or notebooks are present.

Ø Out-of-Specification

–  Ensure that the site has an SOP in place.

–  Ensure that the site is following the SOP through review of OOS investigations.

–  Ensure that once an OOS is discovered, the rationale for the subsequent steps is based on sound scientific reasoning.

–  Ensure that (in the case of a contract laboratory) the site practice is aligned with site requirements.

Ø Change Control Program

–  Ensure that methods, equipment, software and instrumentation are part of the change control program.

–  Ensure that appropriate approvals and levels of approval are in place.

–  Ensure that testing after the modification or change is performed.

–  Ensure the results are within the acceptance criteria.

Ø Personnel Training

–  Ensure that new employees, experienced employees and supervisors are fully trained/qualified.

–  Ensure that any contract employees (laboratory analysts, calibration and PM personnel) are fully trained and qualified to perform the assigned tasks.

–  Ensure that training requirements are defined in an approved SOP.

–  Ensure that laboratory personnel are receiving both GMP and job skills training and that it is documented.

Ø Equipment and Instrumentation

–  Ensure that equipment and instrumentation (including software) are qualified.

–  Ensure that equipment and instrumentation (including software) is part of a preventive maintenance schedule.

–  Ensure that stickers indicating maintenance dates or repair are current and that instruments not to be used are appropriately labeled

–  Ensure, upon completion of repair work, appropriate testing is performed as outlined in an approved change control program.

–  Ensure that the equipment list is accurate based on audit observations.

–  Ensure that all calibration procedures, whether internally or externally performed, have been approved by appropriate site personnel.

–  Ensure that calibration and maintenance is performed with sufficient frequency to assure optimal operating conditions of each piece or equipment or instrumentation.

–  Ensure that there are approved and followed SOPs for maintenance, calibration and change control.

–  Ensure stickers or systems are available to verify maintenance/calibration dates.

–  Ensure that all repair and maintenance work has been documented.

–  Ensure that reference weights used for control of balances are checked against national/international standards as appropriate.

Ø Test method validation

–  Ensure that test methods have been validated.

–  Ensure that there are SOPs directing the validation procedure/method.

Ø Stability testing

–  Ensure that there is an approved formal stability testing program in place.

–  Ensure the site is in compliance with pull dates from the stability testing program.

–  Ensure that stability test chambers and conditions have been validated.

–  Ensure that the testing performed for stability is appropriate and adequate.

–  Determine if the site has a procedure for identifying OOT stability results.

–  Ensure that once an OOT is discovered, the rationale for the subsequent steps is based on sound scientific reason.

Ø Reserve samples

–  Ensure reserve samples are held under conditions specified on their label or as stated in approved retention period documentation.

–  Ensure reserve samples use the same container/closure system as others in the same lot.

–  Ensure that reserve samples are retained as appropriate.