qc | slide 1 of 83 august 2006 good practices for quality control laboratories who training material...

QC | Slide 1 of 83 August 2006

Good Practices for Quality Control Laboratories

WHO Training material amended by Dr. AJ van Zyl for the training workshop in

Dar Es Salaam, Tanzania, August 2006

Supplementary Training Modules on Good Manufacturing Practice

WHO Technical Report Series, No. 902, 2002. Annex 3


Introduction

This QC training module consists of 4 parts:

Part 1: Management and organization

Part 2: Materials, equipment, instruments and devices

Part 3: Working procedures and documents, and safety in the laboratory

Part 4: Inspecting the laboratory Part One.

Quality ControlQuality Control


Objectives

To discuss Good Practices for Quality Control laboratories including quality systems and infrastructure

To understand the role and importance of the Quality Control laboratory in:

–Sampling and testing–Materials, equipment and systems

To discuss approaches in inspecting a Quality Control laboratory

Part One



Quality Control

Part One. Management and infrastructure

1. Organization and management2. Quality system3. Control of documentation4. Records5. Data processing equipment6. Personnel7. Premises8. Equipment, instruments and other devices


Quality Control

Part Two. Materials and set-up of equipment, instruments and other devices

9. Specifications archive10. Reagents11. Reference materials12. Calibration, validation and verification of

equipment, instruments and other devices13. Traceability


Quality Control

Part Three. Working procedures

14. Incoming sample15. Analytical worksheet16. Testing17. Evaluation of test results18. Retained samples

Part Four. Safety in pharmaceutical control laboratories

19. General rules


Background

Recommendations relevant to quality control testing at the site of the pharmaceutical manufacturer

Laboratory provides a service - like a manufacturing unit

“products” include test results, advice and investigations

Needs–buildings, personnel, resources–equipment, raw materials–quality assurance program Part One.



When starting to review compliance e.g. during inspection:

Preparation with background information

Materials and products

SMF

Product dossier (e.g. specifications, tests)



Assess implementation and compliance with all the recommendations

GMP

GP NCL

Different approaches (systematic, material or product flow)



Start at laboratory, walk through and assessing Organization and management:

Suitable size, construction and location - safety requirements considered in the design

Adequate degree of separation of the activities

Sufficient number of rooms or areas to assure the isolation of test systems.

Suitable testing and safety equipment–E.g. voltage stabilizers should be installed where needed

Storage rooms or areas for supplies and materials with protection against infestation, contamination, and/or deterioration.


Part One. 7.1. – 7.5.


Premises (2)

Separate areas for receipt, storage and sample preparation to prevent contamination or mix-ups

Ensure maintaining identity, concentration, purity, and stability

Safe storage of hazardous substances

Fire regulations

Flammable reagents, fuming and concentrated acids, bases, volatile amines – safe storage separately


Part One. 7.6. – 7.7.


Storage areas and central store

Separate for secure storage of samples, retained samples, reagents, laboratory accessories, reference materials

Appropriate storage conditions e.g. refrigeration where necessary

Restricted access to designated personnel

Organized to accommodate incoming and outgoing samples, reagents, equipment, instruments and other devices


Part One. 7.7.1.1. – 7.7.1.4


Appropriate storage conditions.

Storage area with clean bottles, vials, spoons, funnels, and labels required for dispensing reagents from larger to smaller containers

Store keeper responsibilities:

Store and inventory, expiry dates

Areas for flammable substances, for fuming and concentrated acids etc

Self-igniting materials, such as metallic sodium stored separately. Part Two. 10.7.1. – 10.7.3.



Central store (2)

Safety instructions if toxic or flammable reagents are stored or used.

Poison, narcotic and psychotropic substances–Marked as "Poison", kept separately, in locked cabinets–Register maintained

Archive facilities–documents, samples and specimens–Conditions to protect from deterioration, and access restricted

Handling and disposal of wastes–Facilities for collection, storage and disposal–Decontamination, where applicable, and transportation.


Part One. 7.7.1.4. – 7.10.


PersonnelSufficient number, with necessary education, training, technical knowledge and experience

No conflict of interest or other pressure

Competence ensured for activities, performing tests and/or calibrations, validations or verifications, evaluation of results and signing test reports and calibration certificates

Staff undergoing training - supervised, with formal assessment after training

Personnel must be qualified on the basis of appropriate education, training, experience and/or demonstrated skills


Part One. 6.1 – 6.3.


Personnel (2)Permanently employed, or under contract

Contracted personnel to be supervised and sufficiently competent, motivated – work complying good practice of the laboratory.

Current job descriptions for managerial, technical and key support personnel

Records of competence, educational and professional qualifications, training, skills and experience

–Readily available, and include date of confirmation of competence, plus criteria for confirmation and name of the confirming authority.


Part One. 6.4 – 6.5


Managerial and technical personnel:

Head of laboratory (supervisor)

Head of central registry

Analysts

Technical staff

Head of central store

Quality Manager


Part One. 6.6


Quality system:

Management to establish, implement and maintain quality system that covers policies, systems, programmes, procedures and instructions

Communicated, available, understood and implemented

Documented in a quality manual–available to the laboratory personnel–maintained and updated by a responsible person


Part One. 2.1.


The quality manual should contain at least:

Organizational chart; operational and functional activities;

General and specific quality assurance procedures;

Proficiency testing schemes;

Use of reference materials;

Feedback and corrective action (for testing discrepancies)

Procedure for dealing with complaints;

A flow chart for samples;

Details of audit and quality system review;

Qualification of personnel;

Training and maintaining competence of staff; and

A quality policy statement.


Part One. 2.1.


The quality policy should include at least:

A statement of the standard of service it will provide

The purpose of the quality system

Management's commitment to:–Good professional practice and quality of testing, calibration, validation and verification, as a service to its clients–Compliance with Good Practices

All personnel to familiarize themselves with the documentation concerning quality, implementation of the policies and procedures


Part One. 2.1.


The quality system must be reviewed systematically and periodically

–E.g. internal and external audits with reports and details of any corrective action taken.

Laboratory quality manager appointed with:–Defined responsibilities and authority for ensuring that the quality system is implemented and followed at all times.–Direct access to the highest level of management at which decisions are taken on laboratory policies or resources


Part One. 2.2. - 2.3.


Control of documents

Documentation (essential part of QA)

Procedures to control and review all documents

The laboratory must establish and maintain procedures for:

–identification, collection, indexing, access, storage, maintenance and disposal of quality documentation and technical records.


Part One. 3.1.


SOPs: Written and authorized

For administrative and technical operations, such as:

Purchase and receipt of consignment of materials–e.g. samples, reference material, reagents

Internal labelling, quarantine, and storage of materials

Appropriate installation of each instrument and equipment

Sampling and inspection

Testing materials, describing the methods and equipment used


Part One. 4.4.


Other SOPs. . .

Qualification, analytical apparatus

Calibration, maintenance, cleaning, sanitation

Safety measures

Personnel matters including–qualification, training, clothing, and hygiene

Environmental monitoring

Preparation and control of reference materials.


Part One. 4.4.


Verify compliance (in practice)

From register, select a batch of API, excipient and finished product

Request specifications and test methods

Retention samples

Verify information in register against sampling sheet, PO, delivery note, incoming goods register, analytical report, sampling SOP etc



Specifications archive

Current versions of all specifications

Pharmacopoeia compendia or in manufacturers' registration documents.

Archive must contain:

List of all pharmacopoeias in the laboratory– all updates and corrections must be noted;– adequate numbers of supplements and addenda.

File of non-pharmacopoeia quality specifications– numbered and dated, latest version;– information relevant to the status of the quality specifications;– corrections or changes appropriately handled, including producing a revised document as soon as possible.

Part Two. 9.1. – 9.2.



Specifications archive

Use of the master copy– photocopies accounted for and controlled for use

Confidentiality of specifications

Responsibility defined for:

Updating all pharmacopoeias - including supplements, addenda, and corrective measures used in the laboratory;

Maintaining a specifications file

Part Two. 9.3. – 9.5.



E.g. Artesunate

What should you look for initially?



Incoming samples (Sampling plan and procedures)

Sample size sufficient for:– the tests to be performed– replicate tests– retained / retention sample

The laboratory must have a sampling plan and internal procedure for sampling, available to all analysts and technicians within the laboratory

Part Three. 14.1.1. – 14.4.3.



Test request can be filled out during sampling - accompany each sample submitted to the laboratory, and should contain the following information e.g.:

source of the material

full description including its International Nonproprietary Name, concentration or strength, manufacturer, and batch number (if available), size of the sample

reason for requesting the analysis

date on which the sample was collected

Part Three. 14.2.1. – 14.4.2.2.



(cont):

size of the consignment from which it was taken, when appropriate

expiry date (pharmaceutical product) retest date, (starting material, pharmaceutical excipients)

pharmacopoeia specifications or other official specifications to be used for testing

record of further comments (e.g. discrepancies found)

required storage conditions Part Three. 14.2.1. – 14.4.2.2.



Registration and labelling

All samples should be assigned a registration number

Separate registration numbers - different batches

A label with appropriate information on each container of the sample

Part Three. 14.3.1. – 14.3.2.



Central register

The following information should be recorded:

registration number

date of receipt

specific unit to which the sample was forwarded.

Sample received should be inspected:

the findings must be recorded, dated and initialled

discrepancies and damage recorded

queries referred back to the provider of the sample

Part Three. 14.4.1. – 14.5.1.



Storage

The sample prior to testing, the retained sample and any remaining portions of the sample after performance of all required tests must be stored safely (storage conditions)

Analysis is determined by the head

The sample must be stored until all relevant documentation has been received

Request for analysis may be accepted verbally only in case of emergencies

Data recorded on the analytical worksheet

Copies or duplicates of all documentation must accompany each numbered sample when sent to the specific unit.

Part Three. 14.6.1. -14.9.



Specification as per dossier

Version and reference number

Reference to test methods/procedures

Test parameters and acceptance limits

Verify tests done



Identification on sample from each container

Verify spectrum and or chromatogram (number of containers)

Traceability to instrument used, reference standard used, analyst, date, source data (preparation of sample e.g. logbook or worksheets)

Refer to the test method for materials required



4. Records

All original observations, calculations and derived data, calibration, validation and verification records etc. and final results must be retained on record for an appropriate period of time e.g.

– whole length of time the drug is on the market

Records to contain sufficient information to permit repetition of tests and include e.g.:

–identity of the personnel involved in sampling, preparation and testing of the samples–Instruments, equipment etc.


Part One. 4.1 – 4.2.


Records must be:

Legible and readily retrievable

Stored and retained in a manner that prevents modification, damage or deterioration and/or loss

Held secure and in confidence

Includes reports from internal audits and management reviews and records from possible corrective and preventive actions


Part One. 4.3.


Analytical worksheet

An internal document in a printed form for recording information

Complemented by the raw data obtained in the analysis

One used for each numbered sample

A further set of analytical worksheets in duplicate can be used for a collaborating unit (after testing, all results are assembled in one analytical worksheet, using the data from all collaborating units).

Part Three. 15.1. – 15.3.2.



The analytical worksheet must provide or leave space for the following information:

registration number of the sample

page numbering including total number of pages (including annexes)

date of the test request

date of analysis performed

name and signature of analyst

description of the sample received

reference to the specifications to which the sample was tested including limits (adding any or special methods employed) - reference number of the specifications, if available (e.g. pharmacopoeia monograph)Part Three. 15.4.1.



The analytical worksheet must provide or leave space for the following information (cont):

results obtained of tested sample

the interpretation of the results and the final conclusions, signed by each of the analysts involved and initialled by

the supervisor

the identity of the test equipment used

further comments, for example, for internal information

Part Three. 15.4.1.



The above information may be complemented by:

detailed notes on the specifications selected and the methods of assessment used

whether and when portions of the sample were forwarded to other units for special tests (for example, mass spectrometry, x-ray diffraction), and the date when the results were received

identification number of any reference material

if applicable, data to be attached of an instrument verification

if applicable, data to be attached of a reagent verification.

Part Three. 15.4.1.



The completed analytical worksheet must be signed by the responsible analyst/s and initialled by the supervisor.

Specifications necessary to assess the sample:

Particular pharmacopoeia monograph

Manufacturer’s specifications

National pharmacopoeia to be used

Specifications contained in the product licence, and should be the current version Part Three. 15.4.2. – 15.5.2.



Verification of data:

Reference standard (library?), batch number

Primary/official standard or working standard

Procedure for preparation (who, how, where, container, labelling, records, tests, expiry date, storage condition)

Use log – and information file



Reference materials have assigned values of a quantity. Hierarchy for reference materials:

Primary chemical substance– has appropriate qualities within a specified context, and whose value is accepted without requiring comparison to another chemical substance

Secondary chemical reference substance–- characteristics are assigned and/or calibrated by comparison with a primary chemical reference substance. The extent of characterization and testing of a secondary chemical reference substance may be less than for a primary chemical reference substance. This definition may apply inter alia to some substances termed “working standards.

International Biological Standards–a category of biological reference material having World Health Organisation (WHO) status

Part Two. 13.5.1. – 13.5.3.



Reference materials

Used for testing and/or calibration, validation or verification of a sample or equipment, instruments or other devices

Responsibility must be assigned to a specific person

Registration and labelling with an identification number assigned

–A new identification number to each new batch–Number marked on each vial–Quoted on the analytical worksheet at every use

Part Two. 11.1. – 11.2.4.



Central register for reference materials containing information:

identification number of the material

precise description of the material

source

date of receipt

batch designation or other identification code

intended use of the material (e.g. as an infrared reference material, as an impurity reference material for thin-layer chromatography, etc.)

location of storage in the laboratory, and any special storage conditions

further indications (e.g. results of inspections). Part Two. 11.3.1 – 11.3.2.



Information file for reference materials containing information:

In addition to the central register - a file containing information on the properties of each reference material

Working standards - include the results of all tests and verifications

Inspection

Inspected at regular intervals, no deterioration, appropriate storage conditions

Inspections must be recorded in the central register and/or the information file

See also "The general guideline on the establishment, maintenance and distribution of reference materials"

Part Two. 11.4.1. – 11.6.



5. Data processing equipment

Includes computers, automated tests or calibration equipment; used for collection, processing, recording, reporting, storage or retrieval of test- and/or calibration-data

Where used, requires systematic verifications of calculations and data transfers

For computer software developed by the user:– this documented in detail– validated or verified as being adequate for use


Part One. 5.1.


5. Data processing equipment

Located in suitable environmental supporting operating conditions

Maintenance of computers and automated equipment

Procedures established and implemented for protecting data integrity– Include e.g. integrity and confidentiality of data entry or collection, data storage, transmission and processing

Procedures in place to describe how:– Changes are made, documented, and controlled for information maintained– To protect and keep back-up data at all times– To prevent unauthorized access or amendments to the data.


Part One. 5.1.


Reagents

Reagents, chemicals, including solvents and materials used in tests and assays - of appropriate quality and supplied with COA

List of pre-qualified suppliers

Clear responsibility in job descriptions for the preparation of reagents in the laboratory

SOPs according to pharmacopoeia or other standards

Records for the preparation, and standardization of volumetric solutions


Part Two. 10.1. – 10.3.


Reagent labels must clearly specify:– the contents, the manufacturer, the date received, and as appropriate, the concentration, standardization factor, shelf-life and storage conditions (purchased)– date of preparation, name and initials of person (if prepared in the laboratory)

Volumetric solutions:– the name of the manufacturer of the original reagent (where diluted), the date of preparation, the date of standardization and factor, and identify the responsible technician

Reagents must not be moved unnecessarily from unit to unit

Whenever possible, transportation in original containers

Subdivided in scrupulously clean, fully labelled containers Part Two. 10.4-10.5.3.



Inspect reagent containers when delivered (e.g. seals intact)

Inspection recorded on the label giving the date, name and initials

If tampered with, rejected, unless identity and purity can be confirmed

Distilled water and deionized water

Water should be considered as a reagent.

Precautions to avoid contamination during:–supply, storage and distribution.

To comply with pharmacopoeia and other official requirements for quality. Part Two. 10.6.1. - 10.6.4.3



Calibration, validation and verification of equipment, instruments and other devices

Regular calibration, validation and verification of all equipment, instruments and other devices used to measure the physical properties of substances must be performed

Specific procedures for each type of equipment, instrument and other devices must be established, having regard to the extent of which they are used, verified and calibrated at regular intervals according to SOP

Part Two. 12 -12.2.



The records must include at least the following:

name of equipment, instrument and other devices

manufacturer's name, type identification, serial number or other unique identification

verification/calibration to comply with the specifications

current location, where appropriate

the manufacturer's instructions, if available, or reference to their location

Part Two. 12.5.



The records must include at least the following (2):

dates, results and copies of reports, verifications and certificates of all calibrations, adjustments, acceptance criteria, and due date of next verification/calibration

maintenance carried out to date and the maintenance plan

history of any damage, malfunction, modification or repair. It is also recommended to keep records and additional observations of the time, the equipment, instruments or devices were used

Part Two. 12.5.



Maintenance procedures and records

Prevent contamination or deterioration - perform systematic verifications

Defective instruments - taken out of service, and clearly labelled or marked

Status of calibration and the date when recalibration is due, indicated

Instruments to be satisfactory before being returned to service

Part Two. 12.6. – 12.10.



Performing the tests

Official pharmacopoeia requirements - see general notices and the specific monographs of the pharmacopoeia

System suitability done as relevant

All values obtained from each test, including blank results, must immediately be entered on the worksheet, and all graphical data, whether obtained from recording instruments or hand-plotted must be attached to the analytical worksheet

Part Three. 16.3.1. – 16.4.



Evaluation of test results

Results must be reviewed and evaluated – do they meet specifications

Consider the results of all tests

Doubtful results should be investigated (Internal quality system, OOS investigation etc)

Doubtful results can be rejected only if they are clearly due to error, which has been identified.

All conclusions entered on the analytical worksheet by the analyst and initialled by the supervisor Part Three. 17.1. – 17.2.



Analytical test report must provide the following information: registration number

name and address of laboratory testing the sample

name and address of originator requesting analysis

name and description and batch number of the sample, where appropriate

reference to the specification(s) used for testing the sample including limits

results of all tests performed, numerical results of all tests performed (if applicable)

conclusion whether or not the sample was found to meet the limits of specifications

Part Three. 17.3.2.



Analytical test report must provide the following information (cont):

date of test performed

signature of the head of the laboratory or authorized person

name and address of repacker/trader, if applicable

name and address of original manufacturer

compliance to requirements

date received

expiry date.Part Three. 17.3.2.



Traceability

Analytical specificities of each measurement procedure and reference material that is used to ascertain traceability, must be known.

Traceability chain, including measurement procedures and reference materials at all levels, must be prepared

Laboratory investigations - applies to measurement procedures as well as to reference materials used

Part Two. 13.1. – 13.3.



Filing

Analytical worksheet filed for safe keeping together with any attachments, including calculations and tracings of instrumental analyses

Analytical test report must be prepared on the basis of the worksheet

Mistakes, amended data or text - old information may be deleted by a single line (not erased nor made illegible) and the new information added alongside, initialled or signed, and an explanation for the change given

Part Three. 15.6. – 15.8.



Other checks

Water system

Compressed air

Steam

Environmental monitoring

Waste

Inspecting the QC laboratory


Safety in the laboratory

–General aspects to consider. . .

Part Four.



General and specific safety instructions must be:

available to each staff member and

supplemented regularly as appropriate (e.g. written material, poster displays, audio-visual material, and occasional seminars)

General rules and SOPs should include:

availability of safety data sheets to staff prior to testing being carried out

prohibition of smoking, eating, and drinking in the laboratory

familiarity with the use of fire-fighting equipment, including fire extinguishers, fire blankets, and gas masks

the use of laboratory coats or other protective clothing including eye protection

Part Four. 19.1. – 19.2.



special handling as required for example for highly potent, infectious, or volatile substances

full labelling of all containers of chemicals, including prominent warnings (e.g. "Poison", "Flammable", "Radiation", etc.) whenever appropriate

adequate insulation and spark-proofing of electrical wiring and equipment, including refrigerators

observation of safety rules in handling cylinders of compressed gases and familiarity with their colour identification codes

awareness of avoiding solitary work in the laboratory

provision of first-aid materials and instruction in first-aid techniques, emergency care, and use of antidotes

Part Four. 19.2.



Protective clothing must be available, including eye protection, masks and gloves

Water showers should be installed

Rubber suction bulbs used on manual pipettes and siphons

Staff must be instructed in the safe handling of glassware, corrosive reagents, and solvents, and particularly in the use of safety containers or baskets to avoid spillage from containers

Warnings, precautions and instructions must be given

Safe disposal of unwanted corrosive or dangerous products by neutralization or deactivation

Safe and complete disposal of mercury and its saltsPart Four. 19.3.



Poisonous or hazardous products

Singled out and labelled appropriately

Unnecessary contacts with reagents, especially solvents and their vapours, must be avoided

The use of known carcinogens and mutagens must be limited or totally excluded if required by local regulations

Replacement of toxic solvents and reagents by less toxic materials or reduction of their use Part Four. 19.4



Thank you

Group sessions

Inspecting the QC laboratory

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