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Introduction to QC

GMP Training – Introduction to Quality Control (QC) by www.gmpsop.com


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Training Outcome of the Module:

Testing laboratories provide a vital function with regard to provision of accurate

and reliable test results. Their customers rely upon these results to make

important decisions particularly in the areas of patient health, consumer

protection and the safety or suitability of materials, samples and products.

On completion of this module, you should be able to:

Recognize what comprises a laboratory quality manual.

Relate the safety requirements of the QC laboratory to day-to-day work

practices.

Distinguish between the different types of laboratory documents.

Stale the rules for record keeping and data recording.

Recognize the key features of test methods and specifications.

GLP (GOOD LABORATORY PRACTICES)

GLP generally refers to a system of management controls for laboratories and

research organizations to ensure the consistency and reliability of results as

outlined in the Organization for Economic Co-operation and Development

(OECD) Principles of GLP and national regulations.

GLP applies to non-clinical studies conducted for the assessment of the safety

of chemicals to man, animals and the environment.

According to 21 CFR 58:

" ... Nonclinical laboratory study [(GLP)] means in vivo or in vitro experiments

in which test articles are studied prospectively In test systems under

http://www.gmpsop.com/




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laboratory conditions to determine their safety. The term does not include

studies utilizing human subjects or clinical studies or field trials in animals.

The term does not include basic exploratory studies carried out to determine

whether a test article has any potential utility or to determine physical or

chemical characteristics of a test article."

G(QC)LP: GOOD (QUALITY CONTROL) LABORATORY PRACTICES

Refers to the laboratory practices and procedures within a laboratory that

conducts regulated quality control testing, usually the results are used for

commercial reasons.

It is well-documented that working within a documented quality systems

framework will provide more consistency in laboratory processes, which will in

turn improve the laboratory efficiency through error minimization.

Think of the consequential problems if, through a laboratory error, a batch is

rejected when it is actually satisfactory: the company will lose the income that

would have been generated from that batch. Even worse would be the situation

where QC incorrectly passed a defective batch this may have critical

consequences for the company, through harm to patients, recall of the batch,

and loss of confidence in the company by the regulators and the public. Rather

than simply being an overhead, the QC laboratory is often the last chance to

catch a problem before it becomes much bigger.

What do the GMP rules say?

US FDA CFR 211

Sec. 211.160 General requirements.




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(a) The establishment of any specifications, standards, sampling plans, test

procedures, or other laboratory control mechanisms required by this subpart,

including any change in such specifications, standards, sampling plans, test

procedures, or other laboratory control mechanisms, shall be drafted by the

appropriate organizational unit and reviewed and approved by the quality control

unit.

(b) Laboratory controls shall include the establishment of scientifically sound

and appropriate specifications, standards, sampling plans, and test procedures

designed to assure that components, drug product containers, closures, in-

process materials, labeling, and drug products conform to appropriate standards

of identity, strength, quality, and purity.

International GMPs

Chapter 1 Quality Management

1.3 Quality Control is that part of Good Manufacturing Practice which is

concerned with sampling, specifications and testing, and with the organization,

documentation and release procedures which ensure that the necessary and

relevant tests are actually carried out and that materials are not released for use,

nor products released for sale or supply, until their quality has been judged to

be satisfactory.

Overview

The QC laboratory must have o quality system in place. The primary objective of

the quality system is to assure the accuracy and precision of laboratory results

so that they will be Reliable, Interpretable, Repeatable and Defensible.

This module is based upon the guidance within GMP rules and ISO 17025 -

General requirements for the competence of testing and calibration laboratories.

ISO 17025 can be used by laboratories as a standard to develop and establish a

quality system, and for the assessment by their clients or by third parties. The

standard is also being used as a criterion for laboratory accreditation, but is not



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industry specific and compliance with this standard is not o regulatory

imperative.

A combination of GMP rules and ISO 17025 requirements provide a complete set

of requirements for a regulated pharmaceutical QC laboratory. However, in the

pharmaceutical industry generally laboratory are audited and licensed according

to the GMP rules themselves. ISO 17025 is more of an optional requirement.

ROLE OF THE LABORATORY

QC compliance encompasses many activities

that are documented in the GMP rules.

Sampling

Sampling of starting materials and finished

products is completely governed by GMP

regulations. All sampling procedures and plans

must be documented.

If wrong or insufficient samples are taken or a

poor sampling technique is used, any

subsequent testing may then give misleading

results. As a result, good product may be

rejected, or much worse, defective product may

be released.

Testing

Testing of samples in the laboratory is a

mandatory requirement under GMP regulations.

Its effectiveness, though, is limited because the

entire batch cannot be tested nor can the batch

be tested for all types of potential

contamination.

In fact, QC testing is limited to looking for

defects after they have occurred, so it is not a

QA prevention system but rather a defect

detection system.



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Reporting results

Each product has a specific set of specifications

registered with the government authorities.

Starting materials and finished products are

required to be tested to these specifications, and

the results reported to QA management if there

is a problem.

Batches may not be released to the market if

results do not conform to the approved

specifications.

Laboratory documentation

Laboratory documentation and records must

follow the same rules as manufacturing GMP

documents. The QC lab is required to have

SOPs, test methods, specifications, registers,

logs and testing records in place.

These documents must be current approved,

accurate, provide traceability and be archived

for later review. Government auditors are

particularly interested in the QC testing records

when they conduct GMP audits.

Sections of ISO 17025

The two main sections of ISO 17025 are Management (Section 4) and Technical

Requirements (Section 5), which are together broken down into the key areas

shown in the diagram below.

Organization, Management and Quality Systems

4.1 Organization

4.2 Management System

4.3 Document Control

4.13 Control of Records



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4.15 Management Reviews

Suppliers, Service and Customer feedback

4.4 Review: Tenders and Contracts

4.5 Sub-contracting

4.6 Purchasing

4.7 Customer Service

4.8 Complaints

Control of Nonconforming Testing

4.9 Control of Non-conforming Testing

4.11 Corrective Action

Improvement, Audit and Reviews

4.10 Improvement

4.12 Preventive Action

4.14 Internal Audits

Technical Requirement

5.2 Personnel

5.3 Accommodation and Environment

5.4 Test Methods, Calibration and Validation

5.5 Equipment

S.6 Measurement traceability

5.7 Sampling

5.8 Handling of Test and Calibration items

5.9 Assuring Results

5.10 Reporting of Results

Understanding and using the laboratory quality manual

ISO 17025 requires that the QC laboratory prepares, publishes, and maintain a

quality manual the laboratory quality manual provides a description of the

quality system describes the responsibilities and authorities of various managers

and contains the policies for each section of ISO 17025.

Generally, the quality manual also references or lists the SOPs that are used to

run the laboratory.



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The manual is used to:

Induct new staff into the tab

provide a reference document for stall and interested third parties

describe the range of lab controls and checks

describe reporting responsibilities

LABORATORY QUALITY MANUALS

Documentation provides personnel with essential

information about relevant QA and GMP rules

through SOPs and excel ways to manufacture and

test products safely through master instructions and

test methods.

(Companies may have slightly different names for

these documents.) Companies cannot have a quality

plan without proper approved documents in place.

It is a GMP requirement that documentation must be

followed exactly. Following documentation also helps

minimize mistakes.

Training is an essential requirement under GMP:

personnel must be trained before they are approved

to perform o job. Untrained personnel will eventually

make errors and mistakes that con cost lives.

It is a GMP rule that staffs are trained to the

approved documents applicable to their work areas,

and they must sign to the effect that they understand

the requirements.

DOCUMENTATION

TRAINING



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Self-inspections or internal audits, are requirements

under GMP. The purpose of a self-inspection is to

independent check that the rules and documents

established by QA management are being followed.

Self-inspections also provide opportunities to

improve procedures and practices in the factory.

Corrective action is required when an internal audit

reveals a problem that might affect the quality of a

product.

Corrective action may also be required when a

problem occurs in production.

Corrective actions must be documented, and

incorrect procedures updated, in order to improve

the company's quality plan.

Contents of a laboratory quality manual

The quality manual should specifically describe or refer to:

the Laboratory Quality Policy, commitment and objectives

the standard of service and governing standards (e.g. ISO 17025, GMP)

laboratory SOPs and technical methods

how independence of judgment is demonstrated

the responsibilities and authority for key personnel

qualifications and job descriptions (organizational structure)

the management elements of ISO 17025

deployment of the procedures and standards and training for personnel

QA program (audit, review & improvement)

AUDIT

CORRECTIVE ACTION



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document control records management and archiving systems

GOOD TO KNOW – LABORATORY QUALITY POLICY

The following are some Items that should be covered in the Laboratory Quality

Policy:

conflict of Interest, ethics and referenced standards

maintained and deployed procedures for laboratory operations, and tests

based upon referenced methods for testing.

sample handling to maintain integrity of the analytical data

maintenance of records to facilitate retrieval

employment of qualified and trained personnel

routine maintenance of laboratory data to support test results

maintenance of an instrument calibration program that provides

measurement traceability to International System of Units (SI units)

change control for management systems and test methods

Importance of document change control

The laboratory relies on multiple documents to ensure that the right tests are

conducted, only current test methods are used, and the results ore compared

against the current and approved specifications.



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The laboratory WPs, tests, methods and specifications are under version control.

In order to update any one of these documents, a change request should be

raised and approved by management.

A written process is also needed for changing the internal document to match

the latest industry standards or official regulatory documents and/or

pharmacopoeias.

Important laboratory SOPs

The laboratory manual and written procedures should reflect the requirements

of ISO 17025. Even if a laboratory does not intend to be certified to this standard,

there are some essential procedures that are needed, these include:

Laboratory management and organization

Records, documentation and archiving

Reagent and standard quality control

Test method validation and control

Instrument calibration and maintenance programs



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Material and product specifications

Quality, integrity and authenticity of data

Sampling procedures

Personnel training

Trend analysis, audits and reviews

Common key SOPs for QC Laboratory

QC staff should be familiar with the following key SOPs:

Management structure, responsibility and authority

Apparatus and instrument use and maintenance procedures [per instrument)

Record keeping, reporting, storage, archiving retrieval systems

Completion of laboratory records, workbooks, logs, and registers

Handling out-of-specification (OOS) conditions

Release of results from the laboratory

Sample receipt identification, labelling, handling, traceability and protection

Analytical method validation and change/updates

Computer security restrictions and data entry

Reference standards control

Laboratory calibration and performance check program

Retention samples control

Training programs

Training of personnel

Under ISO 17025, a key element for personnel is appropriate training and

documentation of all training activities. For example, operators of a



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chromatographic system need to get trained before they operate the instrument,

and internal auditors will have to be trained prior to conducting internal audits.

GOOD TO KNOW – ISO 17025 : PERSONNEL

The ISO 17025 chapter on personnel covers:

Competence through appropriate education, training, experience and/or

demonstrated skills. This may include relevant knowledge of the technology

and legislation/standards and to understand significance of deviations.

A laboratory policy to identify training needs and goals or objectives for

education, training and skills.

That the laboratory ensures its people are supervised and competent

Development and maintenance of job descriptions with responsibilities

The laboratory shall authorize people for specific tasks



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TRAINING OF PERSONNEL

An effective training system requires that staff have

a working knowledge of the principles of running a

QC laboratory. This also includes the understanding

of GMP as its applied to the laboratory (This forms

the knowledge base for more technical training.

All laboratory staff, including managers, supervisors,

and analysis, should understand the intention and

content of the SOPs that apply to them. They should

be able to follow the SOPs and interpret them

accurately.

A fundamental requirement for laboratory analysis is

to be able to accurately and repeatedly understand

and interpret the requirements within specific test

methods. Test methods should be written

unambiguously, and analysts should be trained in

the application of each specific test method.

The competency of analysts to execute test methods

using appropriate analytical techniques is on

essential success factor for running a QC laboratory.

Analysis must be able to operate complex

instrumentation, prepare samples, and interpret the

data. And calculate the results without error. The

application requires competency assessment.

KNOWLEDGE OF QC PRINCIPLES

UNDERSTANDING

OF SOPS

INTERPRETATION

OF TEST

METHODS

APPLICATION OF

ANALYTICAL

TECHNIQUES



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Laboratory personnel sample and test all chemicals that pass through the

factory, and as such may be exposed to potential hazards.

It's vital that all chemicals, and particularly potent materials, are handled

according to the MSDS and sampled according to the specific sampling

procedures for that material. This often means wearing masks, gloves, and in

some cases respirators, as well as sampling in a biological hazards safety

cabinet.


US FDA CFR 211

GMP does not address safety and environmental issues. There is other legislation

and industry codes of practice that management and supervisors must be aware

of in the laboratory.

International GMPs

GMP does not address safety and environmental issues. There is other legislation

and industry codes of practice that management and supervisors must be aware

of in the laboratory.

Overview

An essential part of induction for new laboratory employees is familiarization

with laboratory safety rules and requirements: in particular, the handling of

corrosive substances, the wearing of protective garments, eye protection, and

familiarity with the MSDS.

Many laboratories include particular safely requirements relating to an

instrument or a test method within the test method document itself. Before

commencing any test, the analyst should be familiar with these safely

requirements.




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There are quite a few hazards in a laboratory, including, but certainly not limited

to, the following:

unprotected use of solvents

equipment not being stored correctly

chemical exposure or spillage

broken or exploding gloss

untidy physical environment

repetitive strain injuries

GOOD TO KNOW – TYPES OF DANGEROUS CHEMICALS

Classes of dangerous chemicals include:

explosives and gases

active materials, e.g. cytotoxics

flammable materials

peroxides and oxidizing agents

poisons and infectious substances

radioactive materials

corrosives

What is a Material Solely Data Sheet (MSDS)?

An MSDS provided by the supplier is designed to provide both workers and

emergency personnel with the proper procedures for handling or working with a

particular substance or when on accident occurs.

The MSDS includes information such as:



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Physical data on safe handling

Toxicity limits

Health effects on exposure

First aid on exposure

Reactivity with other chemicals

Safe storage

Sole disposal

Use of personnel protective equipment

Recommended spillage and leakage procedures

Basic laboratory safety rules

Here are some basic safety rules for working in a QC laboratory:

If in doubt don't proceed! Ask a supervisor.

Always read any caution statements before commencing any procedure or

test method.

Read warning labels and check the MSDS for information on handling.

Always use and wear protective equipment when handling chemicals.



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Always check the laboratory manual. SOPs and test methods for safe

handling details.

Never handle chemicals by hand.

Do not pipette any chemicals by mouth.

Immediately clean up spillages.

"A place for everything and everything in its place."

The laboratory is generally a safe place to work, but most laboratories are busy,

have complicated instruments, and handle corrosive or poisonous chemicals.

One of the basic rules in any workplace is to practice good housekeeping. While

this is a fundamental requirement for manufacturing GMP, it is also applicable

to the laboratory, not only for safety reasons, but also for efficiency reasons.

Good housekeeping practices means that everything has a designated place and

when instruments and chemicals are not in use they should be returned to their

designated location.

Critical aspects of a safe and efficient workplace include:

Regular and proper housekeeping

Storing dangerous reagents and chemicals in designated places

Observing rules for safe-handling



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Important housekeeping rules

These are some of the more important housekeeping rules applicable to a

laboratory:

The golden rule in any laboratory is if you're unsure about any technique or

practice, do not proceed. Ask for advice from supervision.

Never handle chemicals or instruments if you don't understand the safety

implications.

At the end of each day, clean down workbenches, reseal solvents and

reagents, and dispose of surplus materials.

Clear out all expired reagents and standards regularly.

Certain solvents and acids must be stored in corrosive-proof safety cabinets,

and must be transported in safety containers.

Ensure dress is according to lab dress codes. This includes gowns, footwear,

eye protection, and gloves when handling corrosive chemicals.

Complete records and documents in real time, and file them away from the

workbench.



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Testing records and laboratory document retention procedures ore required

because it is a GMP and legal requirement to retain critical documents for

prescribed periods. there are many instances where access to historical

documents and records beyond the minimum GMP requirement are needed, for

example, with product safety investigations, pharmacovigilance reviews,

complaint investigation, and legal enquiries. Any SOP or policy should reflect

these business needs as well.


US FDA CFR 211


(a) Any production, control, or distribution record that is required to be

maintained in compliance with this part and is specifically associated with a

batch of a drug product shall be retained for at least 1 year after the expiration

date of the batch or, in the case of certain OTC drug products lacking expiration

dating because they meet the criteria for exemption under 211.137, 3 years after

distribution of the batch.

International GMPs

Chapter 4 Documentation

4.8 The records should be made or completed at the time each action is taken

and in such a way that all significant activities concerning the manufacture of




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medicinal products are traceable. They should be retained for at least one year

after the expiry date of the finished product.

Laboratory documentation overview

The laboratory documents are designed to ensure there is linkage between the

standard procedures and test methods (what is required to do) and the

laboratory records (what was actually done). This forms the laboratory records

quality system

LABORATORY DOCUMENTATION OVERVIEW

The laboratory quality manual and laboratory

policies are top level documents describing the

overall management and organization of the

laboratory. These documents should reflect the

requirements under GMP rules.

LABORATORY QUALITY MANUALS



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Standard operating procedures provide more detailed

and specific requirements for each of the laboratory

quality elements. For example, SOPs describe how to

handle a sample, how to conduct an audit, how to

release a result from the laboratory and how to

manage a complaint. SOPs are generally not specific

to test methods.

Test methods provide specific step-wise direction on

how to properly execute a test procedure in a

standardized manner. A test method is specific to on

analysis and for on instrumental technique such as

HPLC. Specifications generally accompany test

methods and provide pass/fail criteria and

acceptance criteria for a test method, such as system

suitability or control limits.

Sample and reagent preparation sheets are used to

document the instructions for preparing laboratory

solutions, standards, and working reagents. It is

important in a laboratory to provide accurate

instructions and records of these preparations.

Usually these sheets are linked to specific test

methods. Equally important are the instructions for

calibrating standard solutions.

Records of testing include laboratory analyst note

books, specific testing sheets, and analytical

printouts, electronic records such as

chromatographs, and ancillary records that support

the compliance of the laboratory. Ancillary records

would include calibration reports, training records,

and monitoring of the environment.

STANDARD

OPERATING

PROCEDURES

TEST METHODS

AND

SPECIFICATIONS

SAMPLE AND

REAGENT

PREPARATION

SHEETS

LABORATORY

DOCUMENTS



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Typical laboratory documentation

The QC laboratory would be expected to have the classes of documents indicated

on the filing cabinet below. These documents would be subject to regulatory

audit.

TYPICAL LABORATORY DOCUMENTATION

Method validation protocols provide documented

evidence that a given test method con and will

consistently generate reliable results.

Validation of an analytical method is the process of

formally establishing that the method will meet the

intended analytical application, e.g. to identify a

specific impurity.

Protocols ore used to formally describe how a test

method is validated. The protocol includes a range of

experiments or tests used to verify the validity of the

method. Some of these tests include precision,

accuracy, linearity, range, selectivity, sensitivity,

ruggedness, robustness, and system suitability.

Calibration records should include the following:

name of the instrument

unique instrument identification

limits for calibration - measurement uncertainly

date of calibration

due date for next calibration

details of maintenance. adjustment. or repair (pre

and post calibration)

PROTOCOLS

CALIBRATION

RECORDS



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reference to the calibration procedure

results of the calibration

statement of compliance, or otherwise to a

reference standard

signature of the person performing the

calibration

traceability to the ISO standard, if applicable

SOPs are usually written according to the company

structure and template. This is a typical table of

contents for regulated SOPs:

Scope and Application

Responsibility

Materials and Equipment

Definitions and Precautions

Detailed Procedure

Change History

Approval

Related documents and references

Laboratory test methods are critical documents that

must be followed exactly when performing a test. Test

methods usually have the following features:

names of those who authored, reviewed, and

approved the test method

document and version number

scope and application

STANDARD

OPERATING

PROCEDURES

TEST

METHODS



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materials, standards, and equipment needed

necessary safety precautions

detailed method (description of test, sample

preparation, instrument setup/conditions, test

run, and instrument shut down)

calculations and system suitability

change history

Structure of typical test methods

Laboratory test methods are critical documents that must be exactly followed

when performing a test, and are controlled and approved by management. Test

methods usually have the following features:

'Written By:" (test expert)

"Reviewed By:" (laboratory supervisor)

"Approved By:" (laboratory manager)

unique document number and revision code

document scope

safety notices

instruments and materials

system suitability limits

details of the method steps

how the results are calculated and recorded



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Laboratory notebooks

Laboratory notebooks are usually issued by the laboratory supervisor.

The analyst should record all testing information and protect the notebooks from

unauthorized change, loss, reagent spillage, or deterioration.

Ideally, notebooks should:

be issued to a person or location

be document-controlled

be uniquely numbered

be sequentially page numbered

have spaces for signatures and second checks

be held for the life of the product

Since notebooks provide official records, analysts are required to record and sign

for testing-related activities within these documents. The laboratory notebooks

must be archived for later review, if required.



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Analytical method validation protocols

Method validation provides documented evidence that a given test method can

and will consistently generate reliable results.

Validation of an analytical method is the process of formally establishing that

the method will meet the intended analytical application, e.g. to identify a specific

impurity.

Protocols are used as planning tools to describe the different tests and the

acceptable results applied to demonstrate the validity of the method. Different

methods will have different validation criteria: standard methods must be

demonstrated as "fit for purpose" in the laboratory; adapted and non-standard

methods must be validated.

Performance parameters required for assay validation

ICH guidance and pharmacopoeial monographs recommend that a number of

test method performance parameters be evaluated during analytical method

validation. The performance parameters evaluated depend on the use of the

method. For example, tests for impurities require either Limit of Detection (LOD)

or Limit of Quantitation (LOQ).

(adopted from USP 25 <1225> and ICH Q2(Rl))



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Analytical

Performance

Parameters

Identity

Test

Assay

Activities

Assay (Detergents and

Impurities)

Assay

Dissolution

Content /

potency Quantitative Limit Test

Precision NO YES YES NO YES

Accuracy NO YES YES NO YES

Limit of

Detection NO NO NO YES NO

Limit of

Quantitation NO NO YES NO NO

Specificity NO YES YES YES YES

Range NO YES YES NO *

Linearity NO YES YES NO *

Robustness NO YES YES NO YES

* Maybe required depending on the nature of the specific test

TYPICAL LABORATORY DOCUMENTATION

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 may be considered at three levels:

repeatability, intermediate precision and

reproducibility.

The accuracy of an analytical procedure expresses

the closeness of agreement between the value which

is accepted either as a conventional true value or an

accepted reference value and the value found.

PRECISION

ACCURACY



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This is sometimes termed trueness.

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.

The Quantitation limit of an individual analytical

procedure is the lowest amount of analyte in a

sample which can be quantitatively determined with

suitable precision and accuracy. The quantitation

limit is a parameter of quantitative assays for low

levels of compounds in sample matrices, and is used

particularly for the determination of impurities

and/or degradation products.

Specificity is the ability to assess unequivocally the

analyte in the presence of components which may be

expected to be present. Typically, these might include

impurities, degradants, matrix, etc.

Lack of specificity of an Individual analytical

procedure may be compensated by other supporting

analytical procedure(s).

The range of an analytical procedure is the interval

between the upper and lower concentration

(amounts) of analyte in the sample (including these

concentrations) for which It has been demonstrated

that the analytical procedure has a suitable level of

precision, accuracy and linearity.

LIMIT OF

DETECTION

LIMIT OF

QUANTITATION

SPECIFICITY

RANGE



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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

The robustness of an analytical procedure is a

measure of its capacity to remain unaffected by

small, but deliberate variations in method

parameters and provides an indication of its

reliability during normal usage

Managing laboratory instruments

One of the pre-requisites for a reliable and validated method is to ensure that

laboratory instruments are themselves properly qualified. For example, they

must be within calibration, properly maintained and serviced and be compatible

with the laboratory environmental conditions.

The following documents are required for each major laboratory instrument:

instrument history files

calibration certificates

vendor manuals and associated drawings

maintenance and calibration programs and schedules

operating procedures, including safety instructions

software verification and security of electronic data

qualification and validation protocols and reports

If instruments are unreliable, then the test methods themselves are unreliable.

LINEARITY

ROBUSTNESS



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Accurate and traceable laboratory records are vital for a number of reasons. They

are used to verify that all test results are accurate, and that no errors have been

made in calculating results at the lime of batch release. They are used in the

event of a complaint or marketplace problem to confirm that the batch under

review was tested reliably. In some cases, this information may also be used

legally to verify that the laboratory did not make any errors.

Laboratory records are also often audited by regulatory agencies during GMP

inspections or investigations. The official must be satisfied that the right results

have been calculated and entered. Without a fully traceable record, this is very

difficult to prove.

Many laboratories use computer systems to process test data because, if properly

validated and secure, this approach can reduce potential errors in calculations.

The computer system cannot safeguard against incorrectly entered data, so

traceable records including initial observations are also needed.


US FDA CFR 211




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Sec. 211.194 Laboratory records.

(a) Laboratory records shall include complete data derived from all tests

necessary to assure compliance with established specifications and standards,

including examinations and assays, as follows:

(1) A description of the sample received for testing with Identification of source

(that is, location from where sample was obtained), quantity, lot number or other

distinctive code, date sample was taken, and date sample was received for

testing.

(4) A complete record of all data secured in the course of each test, including all

graphs, charts, and spectra from laboratory instrumentation, properly identified

to show the specific component, drug product container, closure, in-process

material, or drug product, and lot tested.

Sec. 58.3 Good Laboratory Practices regulations.

(k) Raw data means any laboratory worksheets, records, memoranda, notes, or

exact copies there of, that are the result of original observations and activities of

a nonclinical laboratory study and are necessary for the reconstruction and

evaluation of the report of that study. In the event that exact transcripts of raw

data have been prepared (e.g., tapes which have been transcribed verbatim,

dated, and verified accurate by signature), the exact copy or exact transcript may

be substituted for the original source as raw data. Raw data may include

photographs, microfilm or microfiche copies, computer printouts, magnetic

media, including dictated observations, and recorded data from automated

instruments.

International GMPs

Chapter 6 Quality Control

6.9 For some kinds of data (e.g. analytical tests results, yields, environmental

controls,..) it is recommended that records in a manner permitting trend

evaluation be kept.

6.10 In addition to the information which is part of the batch record, other

original data such as laboratory notebooks and/or records should be retained

and readily available.



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6.16 The results obtained should be recorded and checked to make sure that

they are consistent with each other. Any calculations should be critically

examined.

Overview

Laboratory records are essential documents within any regulated laboratory, and

are generally checked during a regulatory audit. Records may be in hard copy,

in electronic formal, or a combination of the two.

Laboratory records:

provide evidence that tests were actually conducted

allow a second analyst to check results

allow traceability of standards and samples

allow tor out-of-specification (OOS) events to be investigated

assist in troubleshooting problems

Lab records may in some cases provide legal evidence of compliance.

Records should be archived in line with company-specified time periods.



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Key supporting records

Records are logged on a daily basis by analysts and are put into notebooks or

logbooks. Examples of key records include:

Sample receipt register for tracking samples through the laboratory

Instrument calibration records

Instrument and equipment maintenance logs

Standards register and inventory lists

Analyst training records

Records of preparation of reagents and standards

Retention sample storage lists

Incubator temperature records in a microbiology laboratory

Chromatograms and instrument printouts

GOOD TO KNOW – RECORD RETENTION

Nominated archive periods for record retention is usually a legal requirement.

Archiving should include:

SOPs

Specifications



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Validation protocols and reports

Lab notebooks

Raw data

Chromatograms

Electronic files

Testing summaries and reports

Maintenance and calibration records

Training records

Job descriptions

Employment records

Completing notebooks and sheets

The following list shows some common rules for filling out notebooks and

laboratory worksheets.

Date and sequentially number each page.

Record the standard reference or lot number, and the strength/activity.

Record the sample lot number.

Reference the test method document (e.g. TM-1204 Ver D).

Reference the instrument the test was performed on (e.g. HPLC #24).

Record all observations and measurements and/or references to

chromatograms.

Record calculations neatly.

The person conducting the second check of the calculations should be identified

as well.



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To change records:

Never use whiteout or erasers

To correct data, cross out the incorrect data with one line, enter the new

information, and initial and date it.

Summarizing data records

One of the most important aspects of laboratory testing is to be able to easily

and quickly review historical results.

This becomes important when investigating problems, reviewing annual product

trends and deciding when to change the frequency of testing.

Records of test results should be maintained in a tabulated, chronological form,

so that formal reviews and trend analysis can be undertaken.

Example of a control chart for trending results over time



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Checking and reviewing records

A critical part of quality control is ensuring the reliability of results.

One way to ensure that the results are error-free is to conduct a second,

independent check of calculations and raw data, by a different analyst or

supervisor.

The following should be checked:

record has been completed to quality control standards

current approved test method and specifications were used

accurate recording or summary of results from chromatograms

calculations are accurate

replicate results are internally consistent

no deviations from approved test method

results reported are consistent with previous trends

Pharmacopoeial monographs provide general conditions for performing test

methods. Pharmacopoeial methods are considered robust that is, they have been

validated in multiple laboratories, but each laboratory will use unique

instrumentation, different analysts and probably prepare samples differently.

This means that pharmacopoeial methods must be verified as suitable for each

laboratory in which they are used: this is a form of validation. Port of the

verification and transfer to the laboratory involves preparing a specific test

method that is validated and used for initial analyst training. It is expected that

companies publish specific in-house methods.





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US FDA CFR 211


(a) The establishment of any specifications, standards, sampling plans, test

procedures, or other laboratory control mechanisms required by this subpart,

including any change in such specifications, standards, sampling plans, test

procedures, or other laboratory control mechanisms, shall be drafted by the

appropriate organizational unit and reviewed and approved by the quality control

unit. The requirements in this subpart shall be followed and shall be

documented at the time of performance. Any deviation from the written

specifications, standards, sampling plans, test procedures or other laboratory

control mechanisms shall be recorded and justified.

International GMPs

Chapter 6 Quality Control

6.15 Analytical methods should be validated. All testing operations described in

the marketing authorization should be carried out according to the approved

methods.

Overview

Test methods and specifications are at the heart of any well-run laboratory.

Well-written test methods drive good analytical techniques, effective training,

analyst competency, method validations, and minimize laboratory errors. Well-

written specifications provide unambiguous acceptance criteria for each test,

and demonstrate that test results are in compliance with product registration

details and pharmacopoeial monographs.



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Maintaining these methods as current is one of the key success factors for any

regulated laboratory.

Test methods

Laboratory test methods have a well-defined lifecycle, from origin to publication,

through to update and retirement. GMP and QC rules determine these pathways.

TEST METHOD LIFE CYCLE

Test methods generally originate from one of three

sources. These include official pharmacopoeias, new

methods from a development laboratory, and/or adopted

from literature.

During development, methods are tested for suitability

according to the product they are being used for, and the

analytical validation performance parameters.

1. Source methods

2. Method development

3. Published method

4. Validation5. Transfer to QC Lab

6. Verify suitability

7. Use method in testing

8. Update method

9. Archieve old version

SOURCE

METHODS

METHOD DEVELOPMENT



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Once a method has been suitably developed, it is

published in a formal that should be unambiguous and

easy to follow far an analyst. The published method

should also reference any instrumentation and

corresponding settings.

Once a method is published, it must be validated

according to ICH Q2(R1), or equivalent criteria. This

method validation package should confirm the suitability

of the method. The validation report is generally

submitted to a regulatory agency as proof that the

method is lit for use and validated.

When a test method is suitably validated, it is transferred

to the QC laboratory for commercial use. At this point,

QC analysts become responsible for the test method.

As part of the transfer, validated test methods must be

verified as to their suitability in the QC laboratory. This

generally involves partial validation to confirm that the

transferred method remains in a validated slate and is

still lit tor use, using the QC laboratory using the

instruments and analysts.

The test method is used for the routine testing of target

products, and if properly validated and transferred,

should be reliable and robust.

From time to time, methods will require updating under

document and change control. Some reasons for

updating include regular updates to pharmacopoeias or

improvements to the method itself. Updated methods

generally require partial revalidation. The old method

should then be archived in case it needs to be referred to

at a later date.

PUBLISHED

METHODS

VALIDATION

TRANSFER

TO QC LAB

VERIFY

SUITABILITY

USE METHOD

IN TESTING

UPDATE

METHODS



Page 41 of 52

GOOD TO KNOW – A TYPICAL TEST METHOD LAYOUT

1.0 Policy and Definitions

2.0 Equipment and Materials

2.1 Equipment

2.2 Materials

3.0 Procedure

4.0 General Requirements

5.0 Test Method -Contents

5.1 Principal of the method

5.2 Materials list

5.2.1 Materials and reagents

5.2.2 Instrument description (including instrument settings)

5.3 Test Procedures

5.3.1 Preparation of standard solution

5.3.2 Preparation of sample and # of replicates required

5.3.3 Preparation of positive and negative controls

5.3.4 Test procedure and instrument settings

5.3.4.1 Instrument setting and preparation

5.3.4.1.1 Start up

5.3.4.1.2 Shut down

5.3.4.1.3 General operation

5.3.4.1.4 Data entry standards

5.3.4.1.5 Computer controls

5.3.4.2 Step-by-step procedure description

5.4 Reading the test endpoint

6.0 Calculations -include an example where warranted

7.0 Test acceptance criteria

7.1 Validity of the test -list system suitability criteria

7.2 Repeat testing

7.2.1 Invalid Test

7.2.2 Samples which fail specification



Page 42 of 52

8.0 References and attachments

Integrity and accuracy of a test method

The accuracy, precision, and selectivity of test methods is critical to the reliability

of test results.

To ensure the integrity and accuracy of a test method, the following pre-

requisites are recommended:

accurate and unambiguous interpretation of the written method

proper training of the analysts on the method

properly calibrated and maintained equipment

in-built performance checks per run

clear instruction on how to prepare samples

Typical sample processing in the laboratory

The QC lab fallows a series of documented steps to test a sample. Each of these

steps is supported by a current and validated test method, a qualified

instrument, a calibrated reference standard and an approved specification.



Page 43 of 52

DOCUMENTED STEPS TO TEST A SAMPLE

The laboratory maintains a Sample Receiving

Register. This register logs the botch and sample

number, number of samples provided and the lime

and date the sample first entered the laboratory.

This is the commencement of sample tracking.

Many test methods require sample preparation

before the test is run. The test method should

describe exactly how the sample is prepared. This



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may involve simple dilution or more complex

extraction and manipulation. Always refer to the

current test method before setting up the sample.

Once the sample is prepared, it is included in the

test run. Care must be taken to ensure that the

sample is not degraded, e.g. by spillage, exposure

to atmosphere, or temperature degradation on the

bench. Always refer to the current test method for

instructions and how to protect the sample during

testing. Concurrent with testing the sample,

analysts should ensure that the instrument or a

logbook records the sample number, and it traced

exactly to the test result.

For instrumental runs such as HPLC/GC, the test

method usually includes a verification that the

entire instrumental system is performing

satisfactorily on the day of the run. This is called

"system suitability testing" (SST). Non-

instrumental methods may also include control or

equivalent verification systems. The test methods

should describe how the integrity of particular test

runs is verified.

Once the sample has been run, either the

instrument or the analyst will perform a

calculation to arrive of a result. It is essential to

double check all calculations before finalizing

sample results.

All QC laboratories have written procedures for

handling and investigating only result that

appears to be OOS. The analyst should ensure

that as soon as an OOS event occurs, supervision



Page 45 of 52

is notified, the sample is retained, and a

documented investigation is commenced.

Once the sample has been run, either the

instrument or the analyst will perform a

calculation to arrive of a result. It is essential to

double check all calculations before finalizing

sample results.

Before commencing any assay, the analyst should

refer to the current version of the test method. The

test method should be available at the worksite.

Samples must be processed through qualified and

calibrated instruments. The analyst should be

aware of the status of the instrument before

conducting the test. In particular, the analyst

should pay attention to the instrument calibration

status. If an instrument is out of calibration, do

not proceed with the test. All laboratory

instruments, upon introduction to the laboratory,

should undergo formal qualification.

Many tests require comparison of the sample to an

official reference standard. The some core should

be taken in preparing the reference standard as is

taken when preparing the sample for test. The

analyst should ensure that only the current

approved reference standard should be used. The

reference standard number must be recorded in

the test record.

In all QC testing laboratories, there will be a set al

published and approved specifications for each



Page 46 of 52

starting material and finished product. When

calculating and checking results, the analyst

should refer to the current specification to decide

the status of the sample. These specifications are

often registered with the regulatory agency and

cannot be changed.

Importance of specifications

Specification documents define official tests, test methods, and limits, and relate

to starting materials, packaging materials, components, bulk products and

finished products, but may also apply to critical steps of manufacture.

QC specifications should conform to statutory standards (e.g. pharmacopoeias)

and any specifications accepted by regulatory bodies for approval of the product

or in connection with its registration.

Failure to meet specification should result in an out-of-specification (OOS) notice

and investigation. If the OOS is confirmed, the sample will be rejected, and a

nonconformance report issued.

IMPORTANCE OF SPECIFICATIONS

Starting Materials:

In the pharmaceutical industry, the requirements

for starting materials must be well-defined and

documented to ensure that you get the material

specified or ordered, and that there are no mixups.

Starting materials are defined by a standard name,

the supplier's/manufacturer's code, and a unique

item code.

Specifications for starting materials should

include:

inspections and/or tests required



Page 47 of 52

reference to test methods and acceptance

criteria

material storage conditions

a retest or expiry date

reference to pharmacopoeial method (if

available)

approved supplier and manufacturer (if

available)

sampling instruction or reference

any precautions

Intermediate Products:

In the pharmaceutical industry, specifications for

intermediate and bulk products should be

available if these are received or dispatched, or if

data obtained from tests on intermediate or bulk

products are used for the evaluation of the finished

product or further processing.

The specifications should be similar to

specifications for starting materials or for finished

products, as appropriate.

Packaging Materials:

In the pharmaceutical industry, the requirements

for pre-printed packaging materials must be well-

defined and documented to ensure that you get the

items you specified or ordered and that there are

no mixups.

Packaging materials are defined by a standard

name, and a unique item code.



Page 48 of 52

Specifications for packaging materials should

include:

a detailed description of the item

inspections and/or tests required

acceptance criteria

an approved label copy

approved supplier and manufacturer (if

available)

sampling instruction or reference

storage conditions

any precautions

Finished Materials:

Specifications for products typically include:

an exact statement of the active material

the product code (if any)

the dosage form and/or strength

physical appearance and identity

all tests and their limits

details of, or reference to, the test methods

sampling instructions

the shelf life and storage conditions

designated name

package details

formula (or reference to a formula)



Page 49 of 52

any precautions

Pharmacopoeias

Pharmacopoeias are published standards often recognized by regulatory

agencies as official standards. Many countries make compliance to

pharmacopoeias a condition of release to market for each batch. Any official or

legal methods will prevail in any dispute situation.

The main sections included in pharmacopoeias are:

general notices for dose forms (e.g. tablets, liquids, sterile products)

monographs for raw materials and products, covering the official tests, test

methods, and information on how to conduct particular tests

guidance on conducting general tests

preparation of standard reagents

Products and raw materials that are compliant to pharmacopoeias must

continue to comply during the entire lifetime of the goods.

Where a pharmacopoeia is applicable to a starting material, this is a minimum

specification, and the QC specifications used should at least conform to it.

Reference standards

A primary reference standard is a substance that has been shown by an

extensive set of analytic tests to be authentic material that should be of high

purity. Primary standards are recognized by the pharmacopoeias and regulatory

agencies as the official industry standards for particular tests.

Primary standards can be:

obtained from an officially recognized source

prepared by independent synthesis



Page 50 of 52

obtained from existing production material of high purity ifthere is no other

external primary standard available

prepared by further purification of existing production material

Secondary reference standards are also substances of established quality and

purity, usually prepared in-house. These standards can only be used if they are

standardized against primary standards using definitive methods that are

published in pharmacopoeias, and national and international standards.

Wherever economically possible, primary standards should be used.

GOOD TO KNOW – REAGENTS AND STANDARD SOLUTIONS

Reagents made up in the laboratory should be prepared following standard

procedures. As applicable, labelling should indicate the concentration,

standardization factor, shelf life, and storage conditions. The label should be

dated and signed or initialed by the person preparing the reagent.

Where relevant, a date for re-standardization should be recorded. In certain

cases, it may be necessary to carry out tests to confirm that the reagent Is

suitable for the purpose for which it is to be used. A record of these tests should

be maintained. Where appropriate, purchased reagent solutions should be

dated upon receipt.

The accuracy and precision of tests results and test methods is dependent on

the reliability, authenticity, and control over reference standards, reagents,

and stock solutions.

Similarly, the retrospective testing of materials and product is dependent on

the protection and storage of retention samples.



Page 51 of 52

Summary

This module has introduced the basic concepts and requirements of

pharmaceutical quality control.

The pharmaceutical QC laboratory operates within o regulatory framework. its

day-to-day operations are governed and outlined in a quality manual, which,

among other things, will list all the SOPs necessary for the smooth running of

the laboratory.

As with any responsible workplace, the QC laboratory has certain solely and

housekeeping requirements by which personnel must abide. MSDSs are

instrumental for helping personnel work with chemicals. A very basic rule to

follow is if personnel are in doubt as to how to proceed, they should be

encouraged to ask a supervisor for assistance.

Maintaining documentation is pivotal for success, not only tor SOPs but also for

documents such as laboratory records and notebooks. GMP rules and common

sense govern how records should be completed (e.g. recording all calculations,

conducting second checks, never using whiteout or erasers). Documents and

records also provide available and traceable evidence to interested parties such

as regulators that the laboratory has conducted testing within a quality system

framework.



Page 52 of 52

TAKE THE

TEST NOW

Number of questions: 10

No time limit

Allow you save and finish at a later date

Allow you to go back and change your answer

Attempting each question is mandatory

Pass mark at and above 70%

Print results and certificates

http://www.gmpsop.com/GMP_Training/INTRODUCTION-TO-QC-QUIZZ.html

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