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Good Laboratory Practice

Mr. Vijay Kulahalli

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Bicycle

What is missing ?
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Pharmaceuticals are not bicycles

What is missing ?

You can not tell


something is wrong
just by looking at it !

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Good Manufacturing Practice

• GMP is concerned with


 Quality
 Safety
 Purity
 Strength
 Identity
of Pharmaceutical products

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GMP and GLP
 cGMP in laboratory is not different from cGMP in
plant
 There are several regulatory requirements on
cGMP in laboratory
 An efficient and effective laboratory only could
be audit proof

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Good Laboratory Practice
 Scope of this presentation is limited to Quality Control /
Analytical Services Laboratories
 Chemical
 Instrumental
 Microbiological
 Packaging material testing
 In principle it may be applicable to R&D Laboratories,
Public Testing Laboratories and State Owned
Laboratories

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Good Laboratory Practice
 What is GLP
 Not just good practices in a Laboratory !!
 Good Laboratory Practice is a quality system concerned with the
organizational process and the conditions under which laboratory
studies are –
 Planned

 Performed

 Monitored

 Recorded

 Archived

 Reported

Thus GLP covers the whole gamut of


Laboratory Processes
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Good Laboratory Practice

GLP in the laboratory, with GMP in


manufacturing and related functions,
gives assurance of product quality
up to the time of administration
to the patient

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Good Laboratory Practice
 The purpose of GLP is to -
 Promote the development of quality test data
 Ensure sound laboratory management
 Ensure robust conductance of laboratory testing
 Ensure accurate reporting of test findings
 Ensure safe archival of laboratory data

All for assuring Product Quality and thus Patient Safety

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Laboratory Data Integrity

 Regulators consider data integrity critical


 Analytical results should
 Accurately describe the properties of the samples
assessed
 Permit correct conclusions to be drawn about the
quality of the samples
 Form the basis for any subsequent administrative and
legal actions
 Form the basis for any customer responses

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Laboratory Data
Global Acceptance

• Laboratory data integrity has an important


international dimension

• Global acceptance of C of A
• Duplicative testing can be avoided
• Costs saved to nation and industry
• Faster disposal of registration submissions

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Why Laboratory Testing

 Input material controls


 Identity of each items
 Purity of each items
 Freedom from impurities
 Freedom from contamination
 Regulatory compliance
 Also helps in identifying
 Trend of supplies during product reviews
 Uniformity in supplies
 Supplier performance reviews

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Why Laboratory Testing

 In Process Controls
 Process progress
 Reaction completion
 Regulatory compliance
 Also helps in
 Early warnings on process progress
 Manufacturing trends
 Process capability studies
 Validation reviews

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Why Laboratory Testing

 Finished products controls


 Compliance to registered specifications
 Purity and identity established
 Stability assured till end of life
 Assurance to customer on quality and efficacy
 Mandated regulatory compliance
 Also helps in
 Manufacturing trends
 Product reviews
 Process capability studies, validation reviews

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Good Laboratory Practice
Compliance requirements

 21 CFR Part 211, US FDA cGMP


 Subpart I – stipulates detailed laboratory controls to be followed
 Orange Guide of the UK
 Chapter 6 – Quality Control, mentions Good QC Laboratory
Practice, stipulates detailed control measures
 WHO GMP Guidelines
 GLP stipulated in several Technical Reports
 Others like ICH Q7A, OECD (Organization of Economic Co-
operation and Development in Europe) etc.

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Good Laboratory Practice
Compliance requirements
 The Drugs and Cosmetics Act, 1940
 Schedule M - Section 14 on Quality Assurance
mentions about GLP without much details
 Schedule M - Section 16 on Quality Control Unit
covers several points that are part of GLP
 Schedule U Part III – Particulars to be recorded in
Analytical Records
 New Schedule I on GLP being incorporated soon,
draft circulated in October 2006

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Good Laboratory Practice
Compliance requirements

 Thus compliance is mandated


 Compliance is essential for -
 Patient safety primarily
 Meeting regulatory expectations
 High level of customer confidence

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Good Laboratory Practice
Main elements
 Resources
 Organization
 Personnel and training
 Facilities
 Equipment
 Chemicals and reagents
 Documentation
 Procedures (MOAs and SOPs)
 Specifications
 Raw test data
 Log books
 Final reports and C of A
 Archival
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Good Laboratory Practice
Main elements

 Systems
 Analytical Equipment Validation

 Equipment Calibration

 Analytical Method Validation

 Out of Specification Investigations

 Internal audits

 Good housekeeping & Laboratory Safety

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Organization
 Management responsibility
 Define Laboratory manager’s role and responsibilities
 Authority and responsibility in line with other line managers
 Independence of laboratory function (QC & QA)
 GLP compliance must be referred to in the Quality Manual
 Appropriate budgets must be provided
 Identify internal and external customers

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Personnel and training
 Adequate in number
 Suitably qualified and experienced
 Approved by the regulatory bodies (expert staff, QP etc.)
 Responsibilities defined, communicated and
documented
 Role templates available

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Personnel and training
 Suitably trained and re-trained periodically
 Training needs identified
 Schedules drawn up
 Training materials made
 Assessment done
 Records maintained
 Right attitude and team spirit
 Rotated in all sections for flexibility
 Succession plans in place

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Laboratory Facilities

 Should be conveniently located, segregated from


production
 Minimum internal and external traffic to ensure quiet
environment
 Adequately spaced – sample receiving areas, testing areas,
utility areas like water, steam and gases, office areas,
sample storage areas, document storage areas etc.
 Logical workflow to avoid crisscross movements

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Laboratory Facilities

 Instrument rooms separated from chemical lab


 Incubations rooms and cold rooms
 Microbiology laboratory should be separate
 Packaging material testing lab near warehouse
 Bulk chemical and solvent storage areas separate from
lab
 Flame proof areas for bulk storage of solvents
 Hot rooms for gas burners and furnaces
 Glassware washing areas
 Meeting rooms, library
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Laboratory Facilities
 Adequate lighting and ventilation
 Air-conditioning of instrument rooms
 Floors, walls and ceiling smooth, easy to clean
 Table tops resistant to acids, alkalis and solvents e.g. ss,
glass, melamine etc.
 Service lines to be colour coded
 Fumes extraction systems should be provided
 Animal house should be separate
 Safe storage areas for poisonous substances

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Laboratory Equipment

 Ideally all needed equipment should be available


 Outsourcing any tests should be justified
 Instruments and other equipment serviced periodically
and calibrated as per schedules
 Replacement policy available
 Budgets available for replacement and maintenance

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Laboratory Equipment
 All equipment identified, status labelled
 Instrument Operations Procedures and Calibration
procedures in place
 Log books for each instrument in place
 All Volumetric wares must be calibrated or mfr’s
certificate obtained

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Chemicals and reagents

 All chemical and reagents must be labelled


 Volumetric & other standard solutions must have
 Date of preparation
 Use before date
 Initials of the person who made
 Batch number
 Do not return unused volumetric solutions to bulk
 Use only distilled water or water meeting IP
requirements for reagent preparation
 Date of receipt of chemicals should be indicated on
containers

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Chemicals and reagents
 Reference standards, microbiological cultures and
culture media handled with special care
 Traceability for all standards and reagents
 Availability of cold cabinets, refrigerators with
temperature monitors
 Material Safety Data Sheets (MSDA) for all chemicals

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Documentation
Specifications and Procedures
 Documentation cell preferred
 Manual system or LIMS
 Periodically updated, circulation controlled
 Specifications
 Methods of testing for RM, PM and FP
 Sampling procedures
 Sample logs
 Standard Operating Procedures
 Instrument Operating Procedures
 Instrument logs

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Documentation
Specifications and Procedures
 Procedures should be in place for
 Receipt of samples
 Testing of samples
 Qualification of instruments
 Validating equipment and methods
 Failure investigations
 Training of staff
 Generating and maintaining records

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Documentation
Specifications and Procedures
 Analytical equipment validation documents
 Analytical method validation documents
 Method transfer documents from R&D
 Test reports and Certificates of Analysis
 Meet Schedule U requirements
 Meet customer country regulatory requirements
 Traceability and cross references as required
 Explicit comments by the Lab In-charge

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Documentation
Raw Test Data
 Raw test data means
 All original test records like weights, calculations etc.
 Handwritten notes if any
 Computer and other printouts
 Chromatograms, spectra, photographs
 Recorded data from other automated instruments
 Importance of raw test data
 Integrity of test assured and verifiable
 Documented proof for conclusions drawn
 Traceability assured
 Regulatory requirement

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Documentation
Log Books
 Bound workbooks or controlled worksheets
 Sequential numbering of pages
 Indexing if required
 Issue, use and archival controlled
 User traceable, acknowledge receipt
 Concurrent entries in log books / sheets
 Pages not detached, blank pages signed off
 Attachments easily identifiable and traceable

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Documentation
Final Reports and C of A
 Both customer and regulatory requirement
 Must include complete data of the item tested
 Must have protocol reference
 Must be dated
 Must refer to the specifications or specs included
 Initials or signature of the person who tested
 Initials or signature of a second person who verified the
original records
 Clear statement of sentencing

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Documentation
Archival
 Must have a company policy of document retention, that
should meet minimum regulatory requirements
 Wherever possible original records to be retained
 Photographs, photocopies and microfilms acceptable
 Electronic data should have regular back-ups (robust
validation required)
 Secure storage, preferably flame proof areas
 Restricted and controlled access to archived records
 Destruction of old records as per schedules

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Analytical Equipment Validation
 All analytical equipment impacting product quality must
be validated
 It makes business sense to do so
 AEV must be a part of Site Validation Master Plan
 Individual equipments must form part of a separate
detailed laboratory plan
 Both new equipment and any major improvements to
existing equipment must be covered

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Analytical Equipment Validation
 User requirement specifications (URS)
 Say what system is required
 Need to be documented
 Should say what is ‘must’ and what is ‘desirable’
 Should be generic and not supplier specific
 Realistic requirements, not over-specified
 Design Qualification
 GMP compliant design
 URS satisfactorily met
 Look at supplier provided details
 Add internal details if required

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Analytical Equipment Validation
 Installation Qualification
 Assures correct installation of the equipment
 Supplier certification received
 Environment checks
 Safety checks
 Operational Qualification
 Confirm that the equipment operates as expected
 Test for all parameters including software
 Test under all ranges, challenge the set parameters
 Training of operators
 SOPs developed

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Analytical Equipment Validation
 Performance Qualification
 Establishes that the equipment performs as per URS
 Establish by routine checks and trial runs
 Validation documentation
 Document at each stage
 URS, Qualification Protocols, Observations, stage wise reports
 Final validation report
 Summary report
 To be approved by QA
 Justifies use of equipment
 Documented justification required for use of equipment with
outstanding actions

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Equipment calibration

 All testing & measuring instruments influencing test


results must be calibrated
 Assures test correctness and dependence
 Ensures regulatory compliance
 Frequency to be risk based and justified
 Calibration procedures in place
 Acceptance criteria defined
 Reference standards traceable
 Each instrument uniquely identified
 Calibration status displayed
 Calibration done by trained operators
 All records maintained
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Analytical Method Validation
 An important aspect of GLP
 ICH Guidelines available
 Documented validation plans for
 Specificity
 Linearity
 Accuracy
 Precision
 Repeatability
 Reproducibility
 Detection Limit
 Quantitation Limit
 Robustness
 Stability in solution
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Out of Specification Investigations
 What is OOS
 A result not meeting specified criteria
 Atypical is not an OOS, but need to be investigated
 OOS and atypical results could be due to
 Laboratory error
 Operator error (non-process related)
 Process related error (usually in mfg)
 Material related errors
 Environment related factors

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Out of Specification Investigations

 Investigations
 Laboratory investigation by laboratory staff
 Expanded laboratory investigation lead by QA
 Outside laboratory investigations (production, warehouse,
engineering etc.)
 Any retesting, resampling must be justified
 Root cause need to be established
 Investigation details must be documented
 Corrective And Preventive Actions (CAPA) agreed
 Should be reviewed during batch releases

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Internal Audit (Self Inspection)
 It is a management responsibility
 Must be a part of the Quality Plan
 SOP available and scope defined
 Schedules drawn up (typically at least quarterly)
 Team for audit identified and trained
 Checklist approach preferred but not the only means
 Cover all laboratory areas and systems
 Issue report as soon as possible
 Get CAPA commitments
 CAPA tracking system put in place
 Findings discussed in management review meetings

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Good housekeeping & Laboratory Safety
 Housekeeping and safety go hand in hand
 Work areas maintained clean and tidy
 Do not permit eating, drinking and smoking in
laboratory
 Laboratory garment regime in place. Special care for
sites handling
 Potent drugs like beta-lactams, hormones, biologicals
 Both natural products and synthetic drugs
 Aseptic products

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Good housekeeping & Laboratory Safety
 Personnel Protective Equipment
 Safety glasses
 Gloves
 Nose masks
 Safety shoes and helmets (for samplers)
 First aid box, eye wash fountains
 Fire extinguishers, fire alarms
 Fire escape routes identified and displayed
 Waste disposal procedures
 Cut off arrangements for ovens and incubators

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Good housekeeping & Laboratory Safety
 Safety procedures must be known to all staff
 Provide awareness on laboratory safety
 Fire hazards (e.g.: use of naked flame, flammable solvents)
 Handling of corrosive chemicals (e.g.: Acids, Bromine)
 Explosive hazards (e.g.: Hydrogen gas cylinder)
 Poisons (e.g.: Potassium cyanide, lead salts, mercury)
 Pressure vessels (e.g.: autoclaves, pressure cooker)
 Electrical safety (e.g.: cable connections, switches)
 Cuts and wounds (e.g.: glassware)
 Biohazards (e.g.: cultures and media)
 Provide Laboratory Safety Manual to all staff

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Productivity in Laboratory

 Timely customer support


 Better space utilization
 Simplified & logical workflow
 Rationalization of testing
 Automation
 Right first time results
 Simplified documents & document flow
 Elimination of non-value adding activities
 Improved visibility of lab operations

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Benefits of Lab Productivity
 Capacity increase in laboratory
 Reduced cost of testing
 Regulatory compliance assured
 Patient safety assured
 Improved morale of staff

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Message
 Patient safety and regulatory compliance are two
parameters of paramount importance for any pharma
laboratory operations
 Laboratory is a place for key decision making
 Without robust laboratory controls, the business will
suffer
 Laboratory efficiency is critical to business success like
any other functional efficiency.
 As a part of laboratory team, you need to focus on that

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