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08 GxP > Week 1 good laboratory practice > Flashcards

Week 1 good laboratory practice Flashcards

1
Q

What is GxP the collective term for?

A

Collective term for quality guidelines and regulations used in several different industries including the pharmaceutical industry

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2
Q

What are GxP guidelines designed to ensure?

A
  • Designed to ensuer that products are safe and capable of meeting their intended use in accordance to regulatory standards
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3
Q

List some internationally recognised GxP standards

A
  • Good Laboratory Practice (GLP)
  • Good Clinical Practice (GCP)
  • Good Pharmacovigilance Practice (GPvP)
  • Good Manufacturing Practice (GMP)
  • Good distribution Practice (GDP).
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4
Q

Who checks all licensed medicines before they can be given to patents in the UK and what is their main objective?

A
  • Medicines and Healthcare products regulatory Agency (MHRA) is responsible
  • The main objective of the MHRA is to protect the health of the general public by ensuring the safety and effectiveness of medicines, healthcare products and medical equipment.
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5
Q

Which units does the MHRA monitor?

A
  • GLP
  • GCP
  • GMP
  • GDP
  • GPvP
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6
Q

What it the role of MHRA GLP inspectors?

A
  • target companies that perform non-clinical studies, which submit their data to authorities, to examine the safety of new drugs to the environment, animals, and humans.
  • Assess the credibility of the data submitted.
  • Target facilities that actively test cosmetics, food additives, agrochemicals, human and veterinary pharmaceuticals.
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7
Q

What is the roe of MHRA GCP inspectors?

A
  • Monitor if clinical trials are conducted in compliance with the requirements of European guidelines and regulations.
  • Conduct inspections on a range of sites, including research organisations, clinical and (non-clinical) trial laboratories and pharmaceutical sponsor establishments.
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8
Q

What is the roe of MHRA GMP inspectors?

A
  • Assess whether pharmaceutical manufacturers are compliant with European Commission (EC) guidance on GMP. Applicable to manufacturing sites within the UK and overseas sites that manufacture products for the UK.
  • Certify that medicines available in the UK are continuously delivered to a high standard of safety, quality, and efficacy.
  • Accountable for assessing and authorising NHS manufacturing units, biological products, investigational medicinal products, and blood product establishments.
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9
Q

What is the role of MHRA GDP inspectors?

A
  • Focus on designated sites used by wholesale traders for storing and distributing medicinal products.
  • Inspections are in agreement with the requirements set by the Medicines for Human Use Regulations 2005 and the EC Guide for Good Distribution Practice for Medicinal Products for Human Use.
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10
Q

What is the role of MHRA GPvP inspectors?

A
  • Assess whether marketing authorisation holders are compliant with the European legislations in regards to the process of examining post marketing for safety in clinical practice.
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11
Q

Give a brief overview of the stages of the drug discovery process (diagram)

A
  • Drug disovery process can be separated ino distinct stages
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12
Q

What is the first stage of the drug discovery process?

A
  • Stage 1:
  • Begins with elementary discovery methods, in turn, the results may be used to define efficacy for the prospect drugs.
  • Involves the screening of thousands of new molecular entities (NMEs) to target a particular disease.
  • Not covered by a regulatory standard but there are guidelines in place.
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13
Q

What is the second stage of the drug discovery process?

A
  • Successful NMEs are subsequently examined, by screening-type assays, for potential toxic effects, which cause a further reduction in the number of ‘potential’ drugs taken to the next stage.
  • GLP research within the drug development process occurs within this stage.
  • Toxicology and safety pharmacology research in this stage must be GLP compliant. These studies are ‘non-clinical’ as they are not performed on humans.
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14
Q

What is the third stage of the drug discovery process?

A
  • This is the clinical stage, where GCP is the fundamental requirement for “… quality standards, ethical conduct, and regulatory compliance…”.
  • GCP must be established in all clinical trials including:
    • Phase I: concerning drug tolerance and to investigate human pharmacokinetics
    • Phase II: confirming the dose-effect relationship
    • Phase III: clinical efficacy trials.
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15
Q

What is the fourth stage of the drug disovery process?

A
  • This is the post-approval stage, where the drug must be registered and becomes available on the market.
  • However, even after this stage, the application of the drug is examined by pharmacovigilance procedures.
  • All subsequent clinical trials i.e. Phase IV must be compliant with GCP.
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16
Q

In the drug discovery process where is GMP present?

A
  • Beyond stage 3 GMP applies to all manufactres drug substance (Active Pharmaceutical Ingredients, API) and drug products (formulated medicines).
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17
Q

What is GLP needed and not needed for?

A
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18
Q

When was the concept of GLP initiated?

A
  • In the 1970s GLP was initiated in retaliation to the concerns about the validity of non-clinical safety data submitted to the Food and Drug Administration (FDA).
  • Examination of non-clinical studies revealed cases of misconduct such as inadequate documentation of methods and results, insufficient planning and unjustifiable implementation of studies.
  • These inadequacies became public and US FDA’s publication of Proposed Regulations on GLP in 1976.
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19
Q

What did GLP regulations establish?

A
  • A foundation for assurance that all reports for non-clinical studies submitted to FDA would reflect the compliance of the research to the regulations
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20
Q

How did the Organisation for Economic Co-operation and Development (OECD) adopt GLP and more generally what does the OECD seek to achieve?

A
  • Created a specialist group to formulate the first OECD Principles of GLP on an international scale.
  • Enforce mutual acceptance of non-clinical safety test data.
  • All OCED member countries have a commitment to democratic government. They are commonly known for their publication on economic affairs. However, the OECD also has a role in helping governments to responds to main social, economic and scientific issues.
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21
Q

What was the effect of the OECDs publication of Principles of GLP?

A
  • Principles of GLP is mandatory for the mutual acceptance of data (known as the MAD agreement) from different countries.
  • Advantage of this mutual acceptance of conformity is that it eliminates unnecessary duplication of safety test experiments, as it avoids the need to comply with individual regulations enforced by different counties.
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22
Q

Why and how were the OECD Pinrciples of GLP applied to governments around the world?

A
  • All governments are concerned with the quality of non-clinical health studies. This is because non-clinical research indicates whether or not it is safe to proceed with the test item, to clinical trials in humans.
  • OECD GLP Principles were applied to create a standard criteria for the performance of these non-clinical studies.
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23
Q

What is GLP defined as in the OECD Principles? Why wre these principles created?

A
  • “a quality system concerned with the organisational process and the conditions under which non-clinical health and environmental safety studies are planned, performed, monitored, recorded, archived and reported”
  • Developed to promote the quality and validity of test data used for establishing the safety of drugs and chemical products
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24
Q

What do the Principles of GLP provide and what are they required for?

A
  • Provides a standardised approach for ensuring the integrity, quality, and reliability of non-clinical studies
  • Requires that practicing institutions appoint responsibilities to staff in order to certify that effective management is in place for study implementation (planning, monitoring, recording, reporting archiving), in case a reconstruction of the entire study is needed
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25
Q

When ma an institution not proclaim that they are in accordance for the Princpls of GLP?

A
  • When they only partially implement GLP regulations
  • Many laboratories state that they implement good practices on a daily basis, this does not mean that they are compliant to the OECD GLP Principles.
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26
Q

The GLP Principles, in relation to pharmaceutical development, are only applicable to studies that are…

A
  • Non-clinical (animal or in vitro studies)
  • Intended to gather data on the safety of drugs/chemicals in relation to human health and/or the environment
  • Planned to be submitted to a state registration authority with the intention to register the tested drug/chemical
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27
Q

GLP constraints for non-clinical studies implemented to determine drug safety, are applicable to the following types of studies…

A
  • Single and repeated dose toxicity
  • Reproductive toxicity
  • Mutagenic and carcinogenic potential
  • Toxicokinetics and pharmacodynamics studies
  • Tolerance studies
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28
Q

What are some of the simple rules to GLP Principles are to and why is it good to follow these eve if not GLP compliant?

A
  • GLP Principles are beneficial even if you are not required to be adherent to the OCED GLP Principles.
  • Say what you do (operating procedures)
  • Do what you say (implement the procedures)
  • Be able to prove it (efficient record keeping)
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29
Q

What is GLP not concerned with (what determines it instead?) but why may it be beneficial to follow GLP princples anyway?

A
  • GLP is not concerned with scientific methods.
  • The scientific method may be founded upon test guidelines and its scientific importance is determined by the (Drug) Regulatory Authority that issues marketing authorisation.
  • Obedience to GLP Principles will diminish several sources of errors and therefore, improve the credibility of the data.
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30
Q

What do the GLP Principls issue obligations to?

What do they ensure?

What do tey help to do and what are they not concerned with?

A
  • GLP Principles issue the obligations for the management of non-clinical safety studies.
  • Esures that the research to carry out experiments in compliance with a pre-established scientific design.
  • Help to describe and regulate the planning, performance, recording, reporting, and archiving processes within research institutions. The GLP regulations are not concerned with the scientific value of studies
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31
Q

Who is responsible for the scientific value of studies?

A
  • Initially the responsibility of the senior scientists working on the research project, followed by the Regulation Authorities and finally for the international scientific community
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32
Q

GLP emphasises the importance of the following main points…

A
  • Resources
  • Characterisation
  • Rules
  • Results
  • Quality Assurance
33
Q

WHat do the GLP prnciples state with regards resources: organisation and personel?

What tool can be used to enable this?

A
  • GLP regulations states that the structure of the research organisation and the responsibilities of the research personnel to be clearly distinguished.
  • Organisational chart should provide a true reflection of the institution and should be regularly kept up to date.
  • Organisational charts and job descriptions are useful because they provide an indication of the way in which the laboratory operates and the connections between the different departments.
34
Q
  • What are the GLP Principles requirements with regards resources: organisation and personnel?
A
  • It is essential that the number of personnel available must be adequate to carry out the tasks required in a time-efficient way.
  • Another major point in GLP regulations is the position of the Study Director who is the central point of control for the study
35
Q

Who appoints the study director, what is their role and what is it their duty to do?

A
  • Facility management that appoints the suitable person to be the Study Director, which will be fully responsible for the GLP compliance of all activities within the study. Study Director signs the GLP Compliance Statement.
  • Duty to assess the impact of events that may influence the integrity of the study and to implement suitable corrective procedures when needed.
  • In a multi-site study, the Study Director is responsible for the phases delegated to test sites, i.e. sites where specific phases of the study are conducted.
36
Q

Who supervises the delegated phase at the test site?

Who is this person under the instruction of?

A
  • Principal Investigator (PI) who supervises the delegated phase on the test sites.
  • The PI is under instruction by the Study Director.
37
Q

What is the main source of GLP non-compliance and whos role is it to ensure this doesn’t happen?

A
  • Managerial aspects of a non-clinical study accounts for approximately 15% of GLP regulations but this is often seen as the main source of non-compliance.
  • The manager of the test facility is accountable for GLP-compliance and the application of both good science and good organisation.
38
Q

Besides the application of both good science and good organisation what else is the managerial team responsible for?

A
  • Management team is also responsible for ensuring that adequate resources are assigned to specific studies and support areas.
  • The master schedule is a document that records the planning/resource allocation system required by GLP.
39
Q

What does the master schedule contain and what must each master schedule ensure?

A
  • Documents vital information on all studies within the institution and their current status
  • Ensure that:
    • All studies are included.
    • Protocol review.
    • Report preparation.
    • The system in an approved standardised (SOP) format.
    • Main responsibilities identified.
  • Schedule continuously updated and approved, versions of the master schedule will be archived.
40
Q

With regards Resources: Facilities and Equipment what does the term “test facility” refer to?

A
  • Person(s), premises and operational units that are needed to conduct the non-clinical health and environmental safety study.
  • May also include several test sites, at one or more locations.
41
Q

How should the test facility be designed?

A
  • Should be an appropriate size and location to address the requirements of the study
  • Be designed cautiously to ensure that the validation results are obtained confidently and to provide a sufficient amount of separation of the different components of the study.
  • Laboratory zones such as the pharmacy area and the animal facility that should be carefully considered.
42
Q

Why are the enforcements regarding test facilities in place?

A
  • Ensure that the research is not negotiated based on insufficiencies in the test facilities.
  • Doesn’t necessarily mean that the most advanced level of technology is required.
  • More importantly, test facility management ensures that the aims of the study can be achieved using the test facilities available.
43
Q

What does separating the different elements of the study ensure?

How can it be accomplished?

A
  • Ensures that different experiments do not hinder each other or unfavourably affect the results of the study. This can be accomplished by:
    • Physical separation (doors, walls or isolators)
    • Organisational Separation (using the same area to perform different experiments at different times)
    • Designated areas (animal facilities and dose mixing areas)
44
Q

With regards test facility, how should the animal facility be created, what measures should be put in place and how?

A
  • Created to limit environmental effects on the animals.
  • Measures should be in place to avert animals from contracting diseases or come into contact with substances that may affect the results.
  • Introducing a barrier system (restricting staff and substances from entering the animals room) can be used to reduce the risks of contamination.
  • The environment will also need to be closely regulated
45
Q

An efficient animal house would provide distinct areas for…

A
  • Different species
  • Quarantine
  • Necropsy
  • Storage
  • Laboratory procedures
46
Q

What does the dose mixing area manage and what must it accomodate?

A
  • Manages test item workflow including storage, dispensing, weighing, mixing and dispatching the pharmaceutical compound.
  • Area needs to be suitable to accommodate the capacity of workflow, permitting the staff to work efficiently.
47
Q
  • With regards Resources: Equipments what do the GLP Principles require and why?
A
  • To ensure that the equipment is adequate, validation programmes, calibration, and maintenance checks should be implemented to ensure reliable and accurate performance.
  • Recording the use and maintenance is crucial for monitoring the current status of the equipment and its history. Recall that the purpose of these GLP regulations is to minimise invalidation of results due to inadequate or faulty equipment.
48
Q

According to the GLP Principles how can you check the suitability of the equipment?

A
  • The suitability of the equipment can only be determined by taking into account the task that the equipment will be used for. SOPs generally determine the suitability of the equipment.
49
Q

Provide examples of methods used to calibrate equipment

A
  • A weighing balance can be calibrated using a set of standard weights.
50
Q

Why does equipment need to be maintained and what are the different sorts of maintenance?

A
  • Ensure that it continues to provide a consistent degree of performance, thereby reducing the chances of malfunction.
  • There are two main types of maintenance:
    • Preventive maintenance: occurs when components of the equipment are replaced based on their expected lifespan.
    • Curative maintenance: refers to repairs that occur due to a fault being detected.
51
Q

According to the GLP Principles, why is characterisation important?

A
  • Crucial that sufficient knowledge of the test item and the test system has been obtained by the key investigators of the study, before assessing the safety properties of the compound.
52
Q

Define the term “test item” regarding characterisation

A
  • The test item can be an active component for a medicine, a vaccine, a food additive, a pesticide etc.
  • GLP regulations state that the test facility implements the same procedures for formulation of the test item so that the same exact method can be repeatedly used to obtain the same concentrations each time.
53
Q

What are the characteristics of the test item that needs to be considered prior to assessing the safety properties of the compound?

A
  • The importance of recording the usage of the test item which enables the experimenter to have ultimate traceability of the quantity of the test item used i.e. compare actual use against the expected use.
  • The manufacturer/ study sponsor supplies the test item.
54
Q

With regards to a test item, what standardised procedure must be in place?

A
  • Standardised procedure must be in place for test item receipt, documenting the handling instructions and storage conditions.
  • For traceability purposes, it is important that once the test item has been received, to record this information immediately and to show that it has not been kept in conditions that may compromise its chemical activity.
55
Q

Documentation with regards to the arrival of the test item generally includes…

A
  • Name of the test item
  • Name of supplier
  • Batch number
  • Description of the test item
  • Weight/ volume of the test item
  • Date of arrival
  • Storage conditions
  • Name of the person who received the test item
56
Q

Discuss the characteristic of storage regarding a test item

A
  • The test items must be stored under regulated environmental conditions.
  • To minimise the risk of cross contamination and confusing the test item with a similar test item, the storage of the compound should be carefully considered.
  • Only assigned staff members should have access to the test item.
57
Q

With regards a test item, why is preparation important and what documentation is generated to support this?

A
  • If the incorrect dose of the test item is administered to the test system, this will compromise the experiment.
  • Crucial that well-defined procedures are in place and that each stage involved in dose formulation is documented.
  • The documentation must refer to the method of preparation of the dose (including the trial preparation) and the stability and/or suitability of the test item in the chosen vehicle.
58
Q

With regards test item preparation, what documents are generated? Give an example of GLP regulations stressing the importance of accountability

A
  • Analyses of the results are often based on the evidence that the test system received the correct concentration of the test item, at the specified time points.
  • Information is obtained by accurate documentation of each step in the study.
  • Important to document the nature and the quality of the test item e.g. has the compound degraded over time.
  • This is an example of how GLP regulations stresses the importance of accountability and traceability of the test item.
59
Q

With regards characterisation what does “disposal” refer to and how is it documented?

A
  • Typically there will be copious amounts of the test item remaining, which needs to be disposed of in an environmentally acceptable approach.
    • Disposal of the test item needs to be recorded so that the amount of test item consumed is accountable.
60
Q

With regards characterisation of a test item, what is a “test system”?

A
  • Animals are commonly used as test systems however, they can also be plants, bacteria, organs, cells and specialist equipment.
  • A test system can be referred to as any system subjected to a test item during a safety experiment.
61
Q

How is responsible for determining the test system?

What points are considered?

A
  • The Study Director and management team determine the appropriateness of the test system by considering the following points:
    • Suitability of the model
    • Study objectives
    • Data presented by previous researchers
62
Q

With regards the tests system what points need to be documented?

A
  • The selected test item will need to be justified in the protocol.
  • The identification of the animals must be documented throughout the study.
  • Animals must be allocated to groups before they are given the test item. If animals are randomised, the method of randomisation should be documented.
63
Q

With regards GLP rules what is a “protocol”?

A
  • Protocol outlines the study design, which provides evidence that the study has been sufficiently planned.
  • The GLP Principles list the fundamental points to be included in a study protocol. Before a GLP study can begin, the protocol must first be approved
64
Q

How can the study protocol be adjusted and how are ammendments recorded? Give some elements of ammendments to be recorded

A
  • Study protocol can be adjusted to permit the Study Director to respond to results or variables during the course of the study.
  • All amendments must be documented and the most important elements to record include the following:
    • The reason for the amendments.
    • The study being amended.
    • The new instructions.
65
Q

What should the experimental design of the study protocol include?

A
  • The dose of the test item
  • The dosing route of the test item administered to the test system
  • Regularity of dosing
  • Vehicles used
  • Dosing preparation methods
  • Storage conditions
  • Quality control
  • Modifications to the SOPs
66
Q

With regards GLP rules what are written procedures?

A
  • Routine procedures are described in Standard Operating Procedures (SOPs).
  • Establishing a complete set of SOPs is required for GLP compliance.
  • SOPs help reduce bias in studies by standardising commonly used techniques. However, techniques are continually being improved so the procedures will need to be adapted accordingly.
67
Q

Who is responsible for ensuring that SOPs are generated and maintained?

A
  • The management team is responsible for ensuring that SOPs are generated and maintained.
68
Q

What do the experiments of a study generate, who reports it, what does it form the basis of and why is it important?

A
  • The experiments performed in the study generate data.
  • Study Director reports the experimental data in the discussion and conclusion sections of the study report.
  • The study report and the experimental data form the basis of understanding of the results to the general public through publication.
  • Considering the importance of the knowledge generated from non-clinical studies, it is vital that the data is of high quality and genuine.
69
Q

With regards study results, what does raw data refer to? What is it fundemental to?

A
  • Original data generated during the study.
  • Also records the procedures that were used in the study.
  • Collection of the raw data is fundamental for the reconstruction of studies and enables the researcher to retrace the events of a study (such as what was done, how it was performed, when the work was carried out, who carried out the experiments).
  • Results and the interpretation of the results, provided by the experimenters, must be an accurate mirror image of the raw data.
70
Q

With regards study results, who is accountable for the study report and what specifically are they accountable for?

A
  • Study Director is accountable for scientific interpretation of the results included in the study report and he/she must state to what degree the study was conducted in compliance with the GLP Principles
71
Q

With regards study results, what is archiving? How is safekeeping enforced and who is responsible for it?

A
  • The records of the experiments must be stored for safekeeping because the study may need to be reconstructed at a later date.
  • In most cases, to ensure safekeeping of the data, restricted access to archive facilities, may be enforced.
  • The Study Director is responsible for ensuring safekeeping of experimental data.
72
Q

With regards study results, what is archived?

A
  • Includes all raw experimental data, experimental results, environmental conditions, maintenance records, protocols and amendments, specimens and quality assurance documentations.
73
Q

What is an alternative term for Quality Assurance (QA) and what is the GLP definition of QA?

A
  • AKA the Quality Assurance Unit (QAU)
  • QA defined as an allocated team of people responsible for assuring management that GLP compliance has been upheld in the test facility.

“…QA acts as an “independent” quality control service…”

74
Q

How is the subjectivity of QA enabled?

A
  • QA must be distinct from the operational activities of the studies, thereby, serving as a spectator of the entire preclinical research process
75
Q

What does QA oversee?

A
  • In obedience to GLP Principles, QA oversee all states of preclinical studies, from planning the study to archiving of the documentation
76
Q

What does the QA statement document and why is the QA statement not a GLP-compliant document?

A
  • Documents the dates on which the study was inspected and the dates the results were reported to the management team and the Study Director.
  • QA statement is not a GLP- compliance statement, as this is the duty for the Study Director
77
Q

What should the QA statement indicate?

A
  • should indicate that the study report accurately reflects the study data
78
Q

What/how and why does QA inspect?

A
  • Random QA inspections of test facilities and experimental activities ensure that the study is continually undergoing GLP.
  • Inspections focus on the stages of the study that are crucial for the validity and integrity of the data.

08 GxP (5 decks)

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