Checklist for Laboratory in Pharma Industry

Laboratories should be audited regularly and at least once per year.

Auditing is an independent activity and separate from self-inspection.

Auditing activities could include reviewing SOPs, worksheets, laboratory notebooks, balance
calibration records, working control data, pipette calibration records, equipment monitoring
logs and other related items for producing test results.

The auditor should use a checklist to determine the auditing scope and content (and example
of such a checklist is detailed below).

The audit results then initiate corrective and/or preventive action to ensure continuous
improvement of the quality system.

Based on past results and a review of laboratory performance (such as the number of
deviations or out-of-specification reports), the auditor may elect to focus on specific areas
(such as a test method) or a more general review of the laboratory, such as tracking the path of
a sample from receipt through testing and to final reporting.

These different approaches will often rest upon risk and a risk-based approach to
auditing.

It is important that the person tasked with auditing the laboratory has an understanding
of laboratories is general and Ideally of the specific function of the laboratory.

During the audit the auditor should observe, check the documentation, and also listen to
what is being said (interestingly, the word audit is derived from a Latin word “audire”
which means “to hear”).

*The laboratory itself should prepare for the audit in advance, such as by:
Planning thoroughly and carefully

Organizing everything ahead of time, including documents and records, to save valuable time
during the audit.

Making sure all staff aware of the audit and arranging schedules so that all staff needed for the
audit will be available.
*Laboratory Management*
The laboratory must be managed correctly, with the appropriate trained and qualified people in
place. In addition, there must be a clear management function, with personnel and different
levels of responsibility and seniority.

Management should have a focus on laboratory process control, which should include quality
control for testing, appropriate management of the sample, including collection and handling,
and method verification and validation.

The laboratory should establish, implement and maintain a management system appropriate to
the scope of its activities.

The laboratory must document its policies, systems, programs, procedures and
instructions to the extent necessary to assure the quality of the test and/or calibration
results.

The system’s documentation needs to be communicated to, understood by, available to, and
implemented by the appropriate personnel.

With management, the laboratory should have managerial and technical personnel who have
the authority and resources needed to carry out their duties including the implementation,
maintenance and improvement of the management system and to identify the occurrence of
departures from the management system or from the procedures for performing tests and/or
calibrations, and to initiate actions to prevent or minimize such departures.

Furthermore, laboratory management should provide adequate supervision of testing and

calibration staff, including trainees, by persons familiar with methods and procedures, purpose
of each test and/or calibration, and with the assessment of the test or calibration results.

In addition, they should have technical management which has overall responsibility for the
technical operations and the provision of the resources needed to ensure the required quality
of laboratory operations.
*Good Laboratory Design*
The laboratory must be appropriately designed laboratory to enable appropriate workflow and
to avoid cross-contamination or mix-up of samples.

This will include dedicated work areas and materials of construction, such as workbenches
being built of materials that are durable and easy to disinfect.

Furthermore, access to rooms where manipulation or analysis of samples takes place, or

where hazardous chemicals or other materials are stored.

As part of good design principles, the laboratory must have systems to monitor, control,
and record environmental conditions as required by the relevant specifications, methods
and procedures or where they influence the quality of the results.

Due attention should be paid, for example, to biological sterility, dust, electromagnetic
disturbances, radiation, humidity, electrical supply, temperature, and sound and
vibration levels, as appropriate to the technical activities concerned.

Management needs to ensure that tests and calibrations are stopped when the environmental
conditions jeopardize the results of the tests and/or calibrations.

There should be effective separation between neighboring areas in which there are
incompatible activities. Measures must be taken to prevent cross-contamination and access to
and from laboratory areas dealing with the tests and/or calibrations need to be controlled.

The laboratory must determine the extent of control based on its particular circumstances.
Further, measures need be taken to ensure good housekeeping in the laboratory.
*Laboratory Personnel*
The laboratory management should have mechanisms in place to ensure the competence of all
who operate specific equipment, perform tests and/or calibrations, evaluate results, and sign
test reports and calibration certificates.

When using staff who are undergoing training, appropriate supervision needs to be provided.

Personnel performing specific tasks are to be qualified on the basis of appropriate education,
training, experience, and/or demonstrated skills, as required.

*Instrumentation*
Well-operated equipment and instruments reduce variation in test results and improve the
laboratory’s confidence in the accuracy of testing results.

Hence, it is important that laboratory results are of required quality and this will often rest
upon the suitability of the instrumentation, and whether instrument calibration has been
conducted. In addition to
calibration, regular verifications are required to ensure that measurements are accurate, such
as verification of balances or pipettors.

To support these requirements, an equipment management program should be in place to

address equipment selection, preventive maintenance, and procedures for troubleshooting and
repair.

*Sample Management*
Sample management is a key part of process control. Importantly, the quality of the work a
laboratory produces is only as good as the quality of the samples it uses for testing. The
laboratory needs to be proactive in ensuring that the samples it receives meet all of the
requirements for producing accurate test results.

This means there need to be sample records that show chain-of-custody.

Records can be manual, e.g., forms or logbooks, or electronic, e.g., LIMS (laboratory
information management system).

In addition, samples need to be stored in an area that maintains their quality.

This includes areas that are properly identified, clean and orderly, and is adequate to prevent
mix-up and contamination from other samples, from chemicals and reagents, and from
spillage.

An important area is with sample labeling.

Each sample should be clearly labeled with:

* Unique identification numbers

* The test that has been requested
* The time and date of collection
* The sample expiry time
* Sample storage conditions
* Identification of the person who collected the sample

*This leads into sample receipt: *

Verifying the sample is properly labeled, adequate in quantity, in good condition, and
appropriate for the test requested.

The test request must be complete and include all necessary information.

Recording sample information into a register or log.

Enforce procedures for storing the sample prior to the test (location, time, temperature,
ensuring sample segregation etc.) And then logging in the sample, recording either manually
or electronically:

* Date and time of collection,

* Date and time the sample was received in the laboratory,
* Sample type,
* Tests to be performed.

With storage:

* Description of what samples should be stored;

* Retention time;
* Location;
* Conditions for storage, such as atmospheric and temperature requirements;

System for storage organization—one method is to store samples by day of receipt or

accession number.

The laboratory must have a system in place to allow for tracking a sample throughout
the laboratory from the time it is received until results are reported.

There should also be a process in place for rejecting samples.

Samples could be rejected, for instance, due to:

* An unlabeled sample Broken or leaking tube/container

* Insufficient information
* Sample label and accompanying record do not match
* Sample collected in wrong tube/container
* Sample stored incorrectly
* Sample time expired
* Inadequate volume poor handling during transport

Traceability, Uncertainty, and Proficiency Testing Traceability, uncertainty and proficiency

testing are the three important areas to be addressed in an audit.

Traceability is about gaining the assurance that the measurement results can be related
to a reference through a documented, unbroken chain of comparisons. For example, the
bias, precision, and accuracy of testing can be determined by testing a certified reference
material and comparing the laboratory results with the certified value.

The certified value of the reference material is generally reported with uncertainty such that
the comparison is of statistical significance.

Proficiency tests serve as the external quality assurance, assuming the laboratory
participates in a proficiency sample test program organized outside of the laboratory.

Proficiency testing is an interlaboratory comparison, in which a number of laboratories

conduct testing methods within their own lab on the same material and report the results
to the organizing party.

Each individual laboratory is then evaluated for performance based on statistical calculations.

To establish required proficiency, the laboratory needs to maintain an appropriate schedule to

participate in a proficiency test program.
*Reference Standards and Controls*
The laboratory must establish a quality control program for all quantitative tests.
Evaluating each test run in this way allows the laboratory to determine if patient results
are accurate and reliable.

This will be achieved using appropriate reference standards, and the suitability and
verification of reference standards should be assessed as part of an audit.

The audit should also consider the controls run with each test. Controls are substances that
contain an established amount of the substance being tested—the analyte.

Controls are tested at the same time and in the same way as test samples.

The purpose of the control is to validate the reliability of the test system and evaluate the
operator’s performance and environmental conditions that might impact results.

*The auditor should consider:

If controls are appropriate for the targeted diagnostic test—the substance being measured in
the test must be present in the control in a measurable form.

The amount of the analyte present in the controls should be close to the decision points of the
test; this means that controls should check both low values and high values.

Controls should have the same matrix as the test sample.

For quantitative testing, statistical analysis is often used for the monitoring process, such as
the use of Levey–Jennings charts.

The source of the control material should be considered: control materials may be purchased,
obtained from a central or reference laboratory, or made in-house.

Purchasing and Supplier Approval The laboratory should have a policy and procedure(s) for
the selection and purchasing of services and supplies it uses that affect the quality of the tests
and/or calibrations.

Procedures should exist for the purchase, reception and storage of reagents and laboratory
consumable materials relevant for the tests and calibrations.

The laboratory needs to ensure that purchased supplies and reagents and consumable materials
that affect the quality of tests and/or calibrations are not used until they have been inspected or
otherwise verified as complying with standard specifications or requirements
defined in the methods for the tests and/or calibrations concerned.
These services and supplies used need to comply with specified requirements and records of
actions taken to check compliance are to be maintained.

*Documentation*
An efficient laboratory requires good quality records and procedures. In this context
“document” could be policy statements, procedures, specifications, calibration tables, charts,
text books, posters,
notices, memoranda, software, drawings, plans, etc.

These may be on various media, whether hard copy or electronic, and they may be
digital, analog, photographic or written.

All documents issued to personnel in the laboratory as part of the management system
should have been reviewed and approved for use by authorized personnel prior to issue.

With standard operating procedures these must be clear instructions as to ensure consistency:

everyone should perform the tests exactly the same way so that the same result can be
expected from all staff.

Such procedures should also ensure accuracy, since following written procedures help
laboratory staff produce more accurate results than relying on memory alone because they will
not forget steps in the process.

The objective is to achieve a consistent (reliable) and accurate result.

Records should be available for all aspects of the laboratory function.

These can be manual or computerized and they will contain are the collected information
produced by the laboratory in the process of performing and reporting a laboratory test.

Characteristics of records are that they need to be easily retrieved or accessed and that they
contain information that is permanent and does not require updating.

*Examples include: *

* Sample logbooks
* Sample registers
* Laboratory workbooks or worksheets
* Instrument printouts
* Equipment maintenance records
* Quality control data
* External quality assessment or proficiency testing records
 * Training records
* Results of internal and external audits
* Out-of-specification reports
* Incident reports

*Test records must contain key information, such as: *

* Identification of the test

* Identification of laboratory
* Unique identification and location of the sample
* Date and time of collection, and time of receipt in laboratory
* Date and time of release of report
* Primary sample type

*Results reported in SI units or units traceable to SI units, where applicable*

Reference materials, where applicable the test result, reported in appropriate units of
measurement Interpretation of results, where appropriate Applicable comments relating
to quality or adequacy of sample, methodology limitations, or other issues that affect
interpretation.

Identification and signature of the person authorizing release of the report If relevant, notation
of original and corrected results If the record is a copy, that it is a certified copy of the original
With
manual forms these should be authorized in advance and serialized, so that each test record
had a unique identifier.

All laboratory documents need to be controlled. A system must be established for managing
them so that current versions are always available.

A document control system provides procedures for formatting and maintaining documents.

The auditor should assess whether there are outdated documents in circulation if there are any
document distribution problems and if there are any external documents that are not being
properly controlled.
Control also extends to storage and archiving.

*Data and Computerized Systems in Pharma Industry*

Data integrity is an important area, applying both to paper records and automated systems.

Information systems include the management of data and records contained in both computer
and non-computerized systems.
Laboratory management must ensure that documented procedures for sample collection,
indexing, access, storage, maintenance, amendment and safe disposal of quality and technical
records is in place, among other more specific test activities.

Such procedures must guarantee that the laboratory has access to the data and information
necessary to provide a service which meets the needs and requirements of the user.

*Electronic systems should also have:

*Permanence—*backup systems are essential in case the main system fails.

Additionally, regular maintenance of the computer system will help to reduce system failures
and loss of data
*Security— *password protection with multiple user levels of access.

*Traceability— *electronic record systems should be designed in a way that allows for
tracing the sample throughout the entire process in the laboratory Audit trails.

*Trending and Controls*

Much of quality control is concerned with measurements or at least an assessment of a result

against predetermined limits.

Where discrete results are produced, the laboratory should be undertaken trend analysis (such
as by using statistical process control). Such approaches involve the application of statistical
methods to evaluate variability in the laboratory testing.

Control charts provide the best means by which to monitor the testing procedures. In
analytical laboratories, control charts are produced by calculating the long-term mean
and range by averaging multiple sets of experimental duplicates over time.

Through this, the laboratory can put in place a system to establish an expected average and
variation for future comparison.

Control charts thus provide a standard against which the stability of the laboratory
performance can be evaluated, and they should feature within the audit.
*Laboratory Non-Conformances in Pharma Industry*

The laboratory must have a policy and procedures that that is be implemented when any
aspect of its testing and/or calibration work, or the results of this work, do not conform to its
own procedures or the agreed requirements of the customer. The policy and procedures must
ensure that:
The responsibilities and authorities for the management of nonconforming work is designated
and actions (including halting of work and withholding of test reports and calibration
certificates, as necessary) are defined and taken when nonconforming work is identified.

An evaluation of the significance of the nonconforming work is made correction is taken

immediately, together with any decision about the acceptability of the nonconforming work

Where necessary, the customer is notified, and work is recalled.

The responsibility for authorizing the resumption of work is defined.

In addition, the laboratory would have needed to establish a policy and procedure and should
designate appropriate authorities for implementing corrective action when nonconforming
work or departures from the policies and procedures in the management system or technical
operations have been identified.

A problem with the management system or with the technical operations of the laboratory can
be identified through a variety of activities, such as control of nonconforming work,
internal or external audits, management reviews, feedback from customers and from staff
observations. Furthermore, when improvement opportunities are identified or if preventive
action is required, action plans should be developed implemented and monitored to reduce the
likelihood of the occurrence of such nonconformities and to take advantage of the
opportunities for improvement.
*Self-Inspection / Self-Audit in Pharma Industry*

The laboratory should periodically, and in accordance with a predetermined schedule and
procedure, conduct internal audits of its activities to verify that its operations continue to
comply with the requirements of the management system. The internal audit program should
address all elements of the management system, including the testing and/or calibration
activities. It is the responsibility of the quality manager to plan and organize audits as required
by the schedule and requested by management. Such audits need to be carried out by trained
and qualified personnel who are, wherever resources permit, independent of the activity to be
audited.
Other Considerations
Other important considerations for the audit include the use of reference materials, repeated
analyses, and sample and reagent blank analyses.