1. Good Laboratory Practice (GLP)
Angela Ng Min Hwei, PhD
Tissue Engineering Centre
Faculty of Medicine, UKM

2. Tissue Engineering Centre (TEC)
Established in 2008 as Centre of Research Excellence in UKMMC
Completed building of a GMP facility for cell and tissue processing in 2011
Obtained certificate of compliance to GMP standards in 2012
Currently, running clinical trial for MyDerm™, a tissue engineered skin
R&D facility has completed ISO9001 and in the midst of ISO audits

4. Medical Product Development Process
*Time line approximately yrs
Non-clinical/ Pre-clinical trial
Clinical TrialPhase I
Discovery
Safety of personnel & facilities
Safety & toxicology in in vitro and animal studies
Safety in human (normal subjects)
CT Phase II
CT Phase III
(Multi-centre)
Marketing
CT Phase IV
Post-marketing
Efficacy in patients
Continuous monitoring of adverse effects

5. Role of Laboratories in Medical Product Development Process
Research Laboratories
Discovery & development of new drugs / device/therapy
Fundamental research/mechanisms of diseases
Animal Laboratories
In vivo studies
Animal models / preclinical studies
Safety and sensitivity testing
Calibration Laboratories
Equipment & device calibration

6. Clinical Testing & Analytical Laboratories
Non clinical Testing & Analytical Laboratories
Toxicology
Mutagenicity
Safety pharmacology
Bioequivalence / bioavailability
pharmacokinetics
Clinical Testing & Analytical Laboratories
Screening & Diagnosis (Enrolment : inclusion criteria exclusion)
Quality control
Trial monitoring : Verify effects of drugs clinical efficacy
Monitoring of adverse effects safety
Data analysis
Verification
Manufacturing Laboratories
Production of drugs, cell-based therapy, plasma products, medical device

7. Why do we need STANDARDS?
Laboratories are required to be Accredited or Compliant to a set of defined STANDARDS
Standards are documented agreements containing technical specifications or other precise criteria used consistently as rules, guidelines and definitions of characteristics to ensure that material, products, process and services are fit for its claimed purpose.

8. Standards required at various stages of medical product development
Good practice
in Lab/ ISO / HIRAC
GLP
GCP
GMP / GTP
GLCP
Non-clinical/ Pre-clinical trial
Clinical Trial Phase I (Safety in human, tolerance of test drugs, define human pharmacokinetics)
Discovery
Safety of personnel & facilities
ISO (International Organisation of Standardisation) is a worldwide federation of national standards from 130 countries
NGO established in 1947 with a mission to promote development of standardisation and related activities in the world with a view to :
- facilitate international exchange of goods
- develop coorperation in spheres of intellectual,
scientific, technological and economic activity
GUIDELINES FOR HAZARD IDENTIFICATION, RISK ASSESSMENT AND RISK CONTROL (HIRARC), 2008 by DOSH (Department of Occupational Safety & Health)
Safety & toxicology in in vitro and animal studies
GCP is the basis for quality standards, ethical conduct and regulatory compliance
GDP
CT Phase II
(Efficacy, dose-effect relationship)
CT Phase III
(full-scale, often multi-centre clinical efficacy trials in patients)
Clinical trial data submit for approval
CT Phase IV
Post-marketing

9. Standards available
International Organisation of Standardisation (ISO)
Good Clinical Practice (GCP)
Good Manufacturing Practice (GMP)
Good Distribution Practice (GDP)
Good Tissue Practice (GTP)
Good Clinical Laboratory Practice (GLCP)
OECD Principle of Good Laboratory Practice (OECD GLP)

10. Good Clinical Practice (ICH-GCP)
Standards must be adhered during Clinical Drugs Trial for design, conduct, performance, monitoring, auditing, recording, analysis and reporting in order to provide assurance that data and reported results are credible and accurate and integrity and confidentiality of trial subjects are protected
Section 2.13
Systems with procedure that assure the quality of every aspect of the trial should be implemented

11. ISO Standards for laboratories
For Accreditation of Competence of Testing and Calibration Laboratories
ISO/IEC Guide 25 (1990) – replaced by ISO/IEC 17025
ISO/IEC (2005) new standards which meets those of ISO 9001 and covering both technical and management requirements. In general, more mandatory in nature compared to the recommendations if ISO 25
ISO/IEC (2002) - expanded, requirements for quality and competence of Medical Laboratories e.g.
JPMD, UMBI

12. Good Manufacturing Practice (WHO-GMP)
A standard that should be followed by manufacturers of registered pharmaceutical / traditional products and cosmetics to ensure that the product manufactured is safe, efficacious and of quality.
Satisfactory GMP compliance is one of the requirements for product registration, as well as to apply for a manufacturing license with the Drug Control Authority (DCA).
Uncontrolled manufacturing operations may be detrimental to consumer health.

13. Good Tissue Practice (GTP )
Guideline developed by FDA specifically to establishments that manufacture Human Cell and Tissue Products (HCT/Ps). Not implemented in M’sia yet.
Similar to GMP but taking into considerations that the nature of the product is very different (biologics vs drugs)
Additional guidelines e.g.:
All donor eligibility requirements
Prevention of the introduction, transmission, or spread of communicable diseases,
Ship in quarantine

14. Good Distribution Practice (GDP)
Defined as important steps that should be considered in the storage, transportation and distribution (cold chain, integrity of labels & everyone involved in the distribution channel, etc) of registered products / notified cosmetics, including associated materials in order to preserve its characteristics and quality until it reaches the consumer.
Generally, GDP is included into the scope of a GMP inspection.

15. Good Clinical Laboratory Practice (WHO- GCLP)
Applies those principles established under GLP for data generation used in regulatory submissions relevant to the analysis of samples from a clinical trial.
Ensures the reliability and integrity of data generated by analytical laboratories.
Ensures that the objectives of the GCP principles are carried out.

16. Good Laboratory Practice (OECD GLP)
GLP applies to nonclinical studies conducted for the assessment of the safety or efficacy of chemicals (including pharmaceuticals).
GLP helps assure regulatory authorities that the data submitted are a true reflection of the results obtained during the study and can therefore be relied upon when making risk/safety assessments.

17. OECD Principles of GLP
Define and describe a quality system concerned with the organisational processes and conditions under which a non-clinical health and environmental safety study is conducted
Non-clinical laboratory study means in vivo (in experimental animals) or in vitro experiments in which test articles are studied prospectively in test systems under laboratory conditions to determine their safety

18. Origin of Good laboratory Practice (GLP)
1st evolved in USA, 1970s as a result of concerns about validity of preclinical safety data submitted to FDA for new drug applications
1950s s : 40% toxicology testing were carried out by Industrial Biotest Laboratories (IBT)
, FDA imposed requirements for manufacturers to prove drug effectiveness and responsible in determining if benefits outweigh risks

19. History of GLP
GLP was first introduced in New Zealand and Denmark in 1972.
Most notably, the lab that ran tests for big companies such as Procter and Gamble called Industrial Bio Test.
It was discovered that mice that they had used to test lotion and deodorants had developed cancer and died.
867 audits of IBT performed by FDA (1962 Law of Drug Amendments) : 518 were found to be invalid due to numerous discrepancies between study and data
or were so poor that police investigators could not piece together what work had been done...even though IBT superficially delivered the test results their contracts with the manufacturers specified.

20. Industrial Bio Test lab threw the dead mice and covered results deeming the products good for human use.
FDA found 4 IBT managers guilty of frauds
Those involved in production, distribution and sales for the IBT lab eventually served jail time.
GLP was instituted in US following these cases of fraud generated by toxicology labs in data submitted to the FDA by pharmaceutical companies.

21. International Harmonisation
The Organisation for Economic Cooperation and Development (OECD ) formulated the first worldwide OECD Principles of GLP ( revised in 1997)
- to avoid non-tariff barriers to trade
- to promote mutual acceptance to non-clinical safety test
to eliminate unneccessary duplication of experiments
International harmonisation of tests
Adherence of member countries to these OECD standards permits international acceptability of safety testing from different countries (1981). Malaysia became a provisional member in 1998.

22. OECD Definition of GLP
Good Laboratory Practice (GLP) embodies a set of principles that provides a framework within which laboratory studies are planned, performed, monitored, recorded, reported and archived. These studies are undertaken to generate data by which the hazards and risks to users, consumers and third parties, including the environment, can be assessed for pharmaceuticals (only preclinical studies), agrochemicals, cosmetics, food additives, feed additives and contaminants, novel foods, biocides, detergents etc....

23. GLP regulations (in US)
Deficiencies made public in the Kennedy Hearings of the US Congress. FDA decide to regulate laboratory testing. GLP is an FDA regulation.
Political outcome led to the publication by FDA of Proposed Regulations on Good Laboratory Practice in 1976, Final Rule , June 1979
This forms the regulatory basis for assurance that reports on studies submitted to FDA would reflect faithfully and completely the experimental work carried out.

24. GLP regulations (in Malaysia)
Effective from 29th March 2013, Malaysia is officially a non-member with full adherent to the Organisation for Economic Cooperation and Development (OECD) Council Acts related to Mutual Acceptance of Data (MAD) in the Assessment of Chemicals on Good Laboratory Practice (GLP)
GLP compliance is not mandatory but voluntary in Malaysia - certification by NPCB
In countries in OECD group such as US, it is required by law that any non-clinical studies must to be conducted in compliance with the OECD Principles of GLP for products to be registered in their countries.

25. OBJECTIVES OF GLP
GLP makes sure that the data submitted are a true reflection of the results that are obtained during the study.
GLP also makes sure that data is traceable.
Promotes international acceptance of tests.
It does not concern with the technical validity of the studies
GLP is sometimes confused with the standards of laboratory safety like wearing safety goggles (Good Laboratory Practices).

27. GLP Regulations: Rules and Tools
Chemical and sample inventory, expiration dates
TEST, CONTROL, AND REFERENCE SUBSTANCES
Timely reporting, storage of raw data and reports
RECORDS AND REPORTS
Standard operating procedures
FACILITY OPERATION
Calibration, logbooks of use, repair, and maintenance
EQUIPMENT
Maintain adequate space/separation of chemicals from office areas
FACILITIES
Training records, CVs, GLP training
ORGANIZATION AND PERSONNEL
Documentation (Tools)‏
GLP Regulations (Rules)‏

28. Fundamental points of GLP
Good Laboratory Practice applied in whatever industry targeted, stresses the importance of the following main points
Resources : Organisation, personnel, facilities,
equipment
Rules : Protocols, Standard Operating Procedures,
concept of Study Director
Characterization : Test items, test systems
Documentation : Raw data, final report, archives
Quality Assurance : Independence from study conduct

29. Resources Organization & Personnel
Structure of org and Org chart must reflect realities and up-to date
Responsbilities of all personnel clearly defined; job description, qualifications & competence defined in training and education records.
Study Director
Full responsibility of GLP compliance of all activities within study, signed compliance statement
Aware of all occurrences, judge impact and institute corrective action

30. Facilities and Equipment
Adequate and sufficient to perform the studies
Suitable size, construction and location causing minimize disturbances that would interfere with validity of study.
Avoid problem of overcrowding, cross contamination, confusion between projects and cramped working condition.
Utilities ( water, electricity etc) must be adequate and stable

31. Facilities and Equipment
Separation physically and by organization ensures that different functions or activities do not interfere with one another
Important in:
Pharmacy and dose mixing areas
Histopathology or analytical laboratories – sample mixed up
Animal facility- minimize the effects of environmental variables on the animals, facility designed and operated to prevent animals coming in contact with the disease or with a test item other than the one under investigation

32. Facilities and Equipment
Equipment : strict programme of validation, qualification, calibration and maintenance. Records of procedures maintained
Reagents: labeled appropriately to indicate source, identity, concentration and stability information, earliest expiratory date (in a kit) and specific storage instructions
Separate facilities for handling and storage of test and reference material to prevent contamination and ensure safe storage for hazardous substances

33. Facilities and Equipment
Handling and disposal of waste should be carried out in such a manner so as not to influence the integrity of the study in progress and consistent with regulatory requirements
Appropriate collection, storage, disposal facilities, decontamination, transportation and destruction procedures
Archive facilities should be provided for storage and retrieval of raw data, samples and specimens. Access to archive should be limited to personnel authorized by management

34. Rules
Protocols
The principle steps of studies have to be described in a Study Protocol or Study Plan
The Protocol has to be adopted by the Study Director through dated signature before study starts and alterations to the study design cannot be made unless by formal amendment procedures.

35. Rules Written Procedures
Routine procedures described in Standard Operating Procedures (SOP)
Standardization of certain techniques to facilitate comparisons of results
Procedures must be reviewed regularly and modified if necessary to reflect the actual state of the art
SOPs must be available at the work place and in current version

36. Rules
Study Director
Concept of SD as the pivotal point of study control
The single most important individual in a GLP study as he/she represents the pivotal point of study control.
is the person fully responsible the adequacy of the protocol and the GLP compliant conduct of the study.
has to formally accept responsibility for GLP compliance by signing the compliance statement

37. Characterisation
Preclinical safety testing of pharmaceutical compunds requires detail knowledge about the properties of the test items and of the test system (often animal ) to which it is administered.
Identity, purity, composition, stability, impurity profile should be known for the test item, for the vehicle and for the reference material.
If the test system is an animal, it is essential to know such details as its strain, health status and normal biological values

38. Documentation Raw Data
Results of investigations, documentation of procedures and circumstances (temperature, pressure, etc) under which study was conducted
Results and their interpretation must be a true reflection of the raw data
Study Report
Responsibility of Study Director
Ensures contents of report describe the study accurately
Study Director responsible for scientific interpretation of the results

39. Raw Data Examples of raw data
If anyone scribble some notes on a scrap of paper, are those notes considered raw data?
Examples of raw data
Logbooks (to record temperatures or equipment use, repair, and maintenance)‏
Field or laboratory notebooks
Forms (for field or laboratory observations, chain-of-custody, sample or chemical receipt)‏
Training reports
Computer printouts
Recorded data from automated instruments
Question:
What happens if you make a mistake?
Do not obscure original data!! Instead, draw a single strikeout, then add reason code, initials, and date of change.

40. Documentation Archives / Retention of records & materials
For reasons of reconstruction & traceability many years later (usually 7 years; medical records: 20years)
Safekeeping of all records, kept in integral state and can neither be lost nor altered
Restrict access to archives to a limited number of people and maintain records of log-in and log-out for both documents and people

41. Quality Assurance
The test facility should have a documented Quality Assurance Programme to assure that studies performed are in compliance with these Principles of GLP.
The Quality Assurance Programme should be carried out by an individual or by individuals designated by and directly responsible to management and who are familiar with the test procedures.
QA personnel has to be independent of the operational conduct of the studies and it functions as witness to the whole preclinical research process

42. ISO Accreditation vs GLP / GMP compliance
Fundamental requirement of the GLP Principles not covered in ISO/IEC : the use of study plans and Study Director as a concept
More stringent under GLP
- Recording and reporting of data
- Management of data retained in archive to
allow complete reconstruction of study
- A program of independent QA including
internal audits of every study

43. ISO Accrediting Bodies for Malaysia
ISO compliance:
technical assessment
by Accrediting Body
Standards Malaysia – ISO 15189, 17025
SIRIM QAS Internation – ISO 9001
Registration Authorities looks for GMP & GLP compliances
Drug Control Authority or National Pharmaceutical Control Bureau

44. OECD GLP Compliance Monitoring Authorities for Malaysia
Pharmaceutical products
Cosmetics
Food additive products
Veterinary
Pesticides
Industrial products
Feed Additive products
Biotechnology (non- pharmaceutical) products
National Pharmaceutical Control Bureau (NPCB) MoH
STANDARDS MALAYSIA, MOSTI

45. Thank You Say what you do, do what you say, prove it and improve it
Janet Woodcook, M.D.
Director, Center for Drug Evaluation and Research, FDA
Record what you do, not recorded not done
"If it's not written down, it didn't happen”
Thank You