300047 VO Prozesse und Methoden in der Life Science

300047 VO Prozesse und Methoden in der Life Science Industrie
Ausgearbeitete Prüfungsfragen und Verständnisfragen (September 2014)
Anmerkung:
Die Abkürzungsliste und die alten Prüfungsfragen – die sich oft wiederholen - sollten zum Bestehen der Prüfung ausreichend sein.
Es kommt so gut wie in jeder gestellten Frage eine Abkürzung vor – meistens reicht es aus hinzuschreiben was die Abkürzung bedeutet.
Es gibt viele Seiten zur Prüfung (etwa 7-8), aber die meisten Fragen sind kurz beantwortbar. Pro Frage gibt es 1-3 Punkte.
Ich habe sowohl neuere Fragen als auch das .pdf Dokument mit den Abkürzungen (siehe den letzten Teil hier) integriert – als Vorbereitung zur Prüfung
habe ich selbst kurze Merkzettelchen / eine Stichwortliste verwendet und diese dann auswendig gelernt. Die Tabelle der Abkürzungen befindet sich wie
erwähnt am Ende dieser Ausarbeitung hier.
Fragen deren Nummer unterstrichen wurde sollten ausreichend beantwortet sein – das bedeutet aber auch umgekehrt das Fragen, die nicht unterstrichen
wurden, eben nicht gut ausgearbeitet sind bzw. ganz fehlen.
(1) IVDD:
In Vitro Diagnostic Medical Devices. Diese Direktive nennt sich auch 98/79/EC – siehe → http://www.tuv-sud.com/industry/healthcare-medicaldevice/market-approval-certification-for-medical-devices/ce-marking/ivdd.
Aus dem Foliensatz – der wichtigste Teil ist dick hervorgehoben:
Directive 98/79/EC, article 1 (b):
'in vitro diagnostic medical device` means any medical device which is a reagent, reagent product, calibrator, control material, kit, instrument, apparatus,
equipment, or system, whether used alone or in combination, intended by the manufacturer to be used in vitro for the examination of specimens,
including blood and tissue donations, derived from the human body, solely or principally for the purpose of providing information:
- concerning a physiological or pathological state, or
- concerning a congenital abnormality, or
- to determine the safety and compatibility with potential recipients, or
- to monitor therapeutic measures.
Mit anderen Worten: das sind diagnostische Gerätschaften die Proben von Menschen untersuchen können, also Blut, Gewebeteile und so weiter.
Specimen receptacles are considered to be in vitro diagnostic medical devices. 'Specimen receptacles` are those devices, whether vacuum-type or not,
specifically intended by their manufacturers for the primary containment and preservation of specimens derived from the human body for the purpose of in
vitro diagnostic examination.
Products for general laboratory use are not in vitro diagnostic medical devices unless such products, in view of their characteristics, are specifically
intended by their manufacturer to be used for in vitro diagnostic examination.
Konkrete Beispiele für IVDD Testsysteme:
→ Hepatitis und HIV tests
→ Coagulations Testsysteme
→ Urin Teststreifen
→ Schwangerschaftstests
→ Blutzucker-Überwachungssysteme für Diabetiker
(2) FDA:
Die 1906 gegründete FDA ist die in den USA heimische Gesundheitsbehörde; die sogenannte “Food and Drug Administration”.
→ http://en.wikipedia.org/wiki/Food_and_Drug_Administration
The Food and Drug Administration (FDA) is an agency within the U.S. Department of Health and Human Services.
It consists of the Office of the Commissioner and four directorates overseeing the core functions of the agency: Medical Products and Tobacco, Foods and
Veterinary Medicine, Global Regulatory Operations and Policy, and Operations.
The FDA is responsible for protecting the public health by assuring the safety, effectiveness, quality, and security of human and veterinary drugs,
vaccines and other biological products, and medical devices.
The FDA is also responsible for the safety and security of most of the US nation’s food supply, all cosmetics, dietary supplements and products that give
off radiation.
Siehe auch dieses Video in bezug auf Influenza-Vaccines und die Rolle der FDA → http://www.fda.gov/AboutFDA/Transparency/Basics/ucm195661.htm
(3) NCE:
NCE ist New Chemical Entity.
(4) PK:
(5) CTD: Was ist das? Was sind die wichtigsten 3 Punkte davon?
CTD steht für Common Technical Documentation.
The Common Technical Document (CTD) is a set of specification for application dossier for the registration of Medicines and designed to be used across
Europe, Japan and the United States.
It is an internationally agreed format for the preparation of applications regarding new drugs intended to be submitted to regional regulatory authorities
in participating countries.
It was developed by the European Medicines Agency (EMA, Europe), the Food and Drug Administration (FDA, US) and the Ministry of Health, Labour
and Welfare (Japan).
The CTD is maintained by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use
(ICH).
The Common Technical Document is divided into five modules:
(a) Administrative and prescribing information
(b) Overview and summary of modules 3 to 5
(c) Quality (pharmaceutical documentation)
(d) Preclinical (Pharmacology/Toxicology)
(e) Clinical - efficacy (Clinical Trials)
Siehe auch → http://en.wikipedia.org/wiki/Common_Technical_Document
(6) AUC: Definition, Relevanz für Generika.
AUC bezeichnet die “area under the curve”.
Siehe Wikipedia → http://en.wikipedia.org/wiki/Area_under_the_curve_%28pharmacokinetics%29
“In the field of pharmacokinetics, the area under the curve (AUC) is the area under the curve (mathematically known as integral) in a plot of
concentration of drug in blood plasma against time. Typically, the area is computed starting at the time the drug is administered and ending when the
concentration in plasma is negligible. In practice, the drug concentration is measured at certain discrete points in time and the trapezoidal rule is used to
estimate AUC.”
Mit anderen Worten, AUC gibt die Blutplasma-Konzentration eines Arzneiwirkstoffes wieder.
Hier ein Bild zur “area under the curve”:
(7) MTD: What is MTD?
MTD is the maximum tolerable dose for chemotherapeuticals.
(8) GLP:
(9) QP: Wer ist das, welche Qualifikationen sind relevant?
QP ist eine “Qualified Person”.
(10) SAE+SAR:
(11) CRF:
(12) IMPD:
(13) ITT:
(14) PPT:
(15) CHMP:
(16) MRP:
Dies ist die “mutual recognition procedure”.
(17) NDA:
(18) FMEA:
(19) ALARP: Was heisst das, wozu wird es benutzt? [DONE]
ALARP steht für “as low as reasonably possible”; alternativ auch “as low as reasonably practible”. Es handelt sich hier also um “risk acceptance”.
Das ALRAP-Prinzip wird im Risikomanagement angewandt und besagt, dass das Risiko möglichst gering gehalten werden soll, ohne jedoch die
Durchführung von Prozessen zu gefährden.
In der Praxis wird das ALARP-Prinzip an einem Risikographen festgelegt. Dieser zeigt auf, welche operativen und strategischen Risken für ein
Unternehmen akzeptabel sind und welche es nicht sind.
Warum benötigt man das ganze?
→ Manche Arbeitsbereiche haben ein hohes Risiko, wie zum Beispiel in der Ölindustrie/Bohrinsel oder das Arbeiten in AKWs – für letzteres gibt es
zum Beispiel ein stark erhöhtes Strahlenrisiko. Die Risken sind hier nicht immer leicht abzuschätzen, ALARP soll hier also aushelfen die Risken korrekt
einzuschätzen.
Folgendes Diagramm zeigt so einen allgemeinen Risikographen:
Weiterführende Links:
→ http://www.hse.gov.uk/risk/expert.htm
(20) OOS:
(21) PDCA: Was ist das? Was macht man in jeder einzelnen Phase? [DONE]
Plan → Do → Check → Act
Siehe auch Wikipedia → http://en.wikipedia.org/wiki/PDCA
Dieser 4-Stufen Plan wird zur Kontrolle und kontinuierlichen Verbesserung von Prozessen und Produkten eingesetzt.
Diese 4 Stunden bedeuten folgendes:
(a) PLAN: Establish the objectives and processes necessary to deliver results in accordance with the expected output (the target or goals). By establishing
output expectations, the completeness and accuracy of the spec is also a part of the targeted improvement. When possible start on a small scale to test
possible effects.
(b) DO: Implement the plan, execute the process, make the product. Collect data for charting and analysis in the following "CHECK" and "ACT" steps.
(c) CHECK: Study the actual results (measured and collected in "DO" above) and compare against the expected results (targets or goals from the "PLAN")
to ascertain any differences. Look for deviation in implementation from the plan and also look for the appropriateness and completeness of the plan to
enable the execution, i.e., "Do". Charting data can make this much easier to see trends over several PDCA cycles and in order to convert the collected
data into information. Information is what you need for the next step "ACT".
(d) ACT: Request corrective actions on significant differences between actual and planned results. Analyze the differences to determine their root causes.
Determine where to apply changes that will include improvement of the process or product.
When a pass through these four steps does not result in the need to improve, the scope to which PDCA is applied may be refined to plan and improve with
more detail in the next iteration of the cycle, or attention needs to be placed in a different stage of the process.
(22) CAPA:
(23) IQ:
(24) OQ:
(25) URS: Was ist das? Wer erstellt die URS?
URS ist die User Requirement Specification.
“The User Requirements Specification describes the business needs for what users require from the system. User Requirements Specifications are written
early in the validation process, typically before the system is created. They are written by the system owner and end-users, with input from Quality
Assurance. Requirements outlined in the URS are usually tested in the Performance Qualification or User Acceptance Testing. User Requirements
Specifications are not intended to be a technical document; readers with only a general knowledge of the system should be able to understand the
requirements outlined in the URS.”
“The URS is generally a planning document, created when a business is planning on acquiring a system and is trying to determine specific needs. When a
system has already been created or acquired, or for less complex systems, the user requirement specification can be combined with the functional
requirements document.”
Siehe auch diese Webseite: → http://www.ofnisystems.com/services/validation/user-requirement-specifications/
(26) Pareto chart:
Wikipedia: → http://en.wikipedia.org/wiki/Pareto_chart
A Pareto chart, named after Vilfredo Pareto, is a type of chart that contains both bars and a line graph, where individual values are represented in
descending order by bars, and the cumulative total is represented by the line.
The left vertical axis is the frequency of occurrence, but it can alternatively represent cost or another important unit of measure. The right vertical axis is
the cumulative percentage of the total number of occurrences, total cost, or total of the particular unit of measure. Because the reasons are in decreasing
order, the cumulative function is a concave function. To take the example above, in order to lower the amount of late arrivals by 78%, it is sufficient to
solve the first three issues.
The purpose of the Pareto chart is to highlight the most important among a (typically large) set of factors. In quality control, it often represents the
most common sources of defects, the highest occurring type of defect, or the most frequent reasons for customer complaints, and so on. Wilkinson (2006)
devised an algorithm for producing statistically based acceptance limits (similar to confidence intervals) for each bar in the Pareto chart.
These charts can be generated by simple spreadsheet programs, such as OpenOffice.org Calc and Microsoft Excel and specialized statistical software
tools as well as online quality charts generators.
The Pareto chart is one of the seven basic tools of quality control.
Also have a look at the following picture:
(27) therapeutic window:
(28) qd:
(29) 21 CFR part 11:
(30) Odds ratio:
(31) Drug discovery: Was ist das?
Beim Vorgang des “drug discovery” zielt man primär auf Rezeptoren im menschlichen Körper ab.
(32) MPG:
Dies ist das Medizinproduktgesetz. In Österreich ist es seit 1996 wirksam.
(33) MDD:
Dies ist “Medical Device Directive”.
Diese Direktive ist ziemlich lang – hier der Inhalt:
Directive (2007/47/EC): article
(a) "medical device" means any instrument, apparatus, appliance, software, material or other article, whether used alone or in combination, together
with any accessories, including the software intended by its manufacturer to be used specifically for diagnostic and/or therapeutic purposes and
necessary for its proper application, intended by the manufacturer to be used for human beings for the purpose of:
- diagnosis, prevention, monitoring, treatment or alleviation of disease,
- diagnosis, monitoring, treatment, alleviation of or compensation for an injury or handicap,
- investigation, replacement or modification of the anatomy or of a physiological process,
- control of conception, and which does not achieve its principal intended action in or on the human body
by pharmacological, immunological or metabolic means, but which may be assisted in its function by such means;”
Mit anderen Worten, es geht hier einfach um medizinisch-technische Instrumente.
(34) AIMDD:
Active Implantable Medical Devices Directive.
Aus dem Foliensatz:
‘active implantable medical device’ means any active medical device which is intended to be totally or partially introduced, surgically or medically, into
the human body or by medical intervention into a natural orifice, and which is intended to remain after the procedure.
Also mit anderen Worten – ein Cyborg! ;-)
Realistischer geht es hier eher um Schrittmacher für das Herz und ähnliche Medical Devices die man in den Körper stopfen muss.
(35) AMC: What is this?
AMC is an active medical device. This refers to any medical device relying for ist functioning on a source of electrical energy or any source of power other
than that directly generated by the human body or gravity.
(36) ATMP: Wofür steht das? Nenne Beispiele hierzu.
ATMP steht für “Advanced Therapy Medicinal Product”.
Siehe zum Beispiel hier:
→ http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000296.jsp
“Companies can apply to the European Medicines Agency to determine whether a medicine they are developing is an advanced-therapy medicinal
product (ATMP). The procedure allows them to receive certification that a medicine, based on genes, cells or tissues, meets the scientific criteria that
define ATMPs.”
Aus dem Foliensatz:
Directive 2002/98/EC: Blood and Blood components: amended by → • Regulation EC/1394/2007: Advanced Therapy Medicinal Products
sowie
Directive 2004/23/EC: human tissues and cells
Directive 2004/23/EC: human tissues and cells sets standards of quality and safety for the donation, procurement, testing, processing, preservation, storage
and distribution of human tissues and cells.
Directive 2002/98/EC: setting standards of quality and safety for the collection, testing, processing, storage and distribution of human blood and blood
components.
Scope:
- Tissues
- Cells
- Sperms, Oocytes
if „substantially“ altered.
Beispiele für Advanced Therapies:
• Cutting
• Separation, concentration, filtering
• Sterilisation
• Radiation
• Lyophilisation
• Kryo-conservation
• Storage in antibiotic solution .....
of cells and tissues are no „substantial“ changes → covered by 2004/23/EC and 2002/98/EC.
Covered:
- Gene Therapy
- Cell Therapy
- Tissue Engineering
→ Combination Products (e. g. with medical devices)
(37) Generika: Definition. Was ist wichtig? Wer registriert Generikr bzw. ist für sie zuständig?
Generika sind “Nachahmerpräparat” - es sind dies Arzneimittele, die eine wirkstoffgleiche Kopie eines bereits unter einem Markennamen auf dem
Markt befindlichen Medikamentes sind (letzteres bezeichnet man auch als Originalpräparat).
Das Generikum (Singular von Generika) unterscheidet sich oft bezüglich der Herstellungstechnologie, aber mag sich auch in bezug auf die enthaltenen
Hilfsstoffe unterscheiden.
Generika werden zumeist unter dem internationalen Freinamen (INN) des Wirkstoffes mit dem Zusatz des Herstellernamens angeboten.
Ein Generikum soll dem Originalprodukt in dessen beanspruchten Indikationen therapeutisch äquivalent sein – es muss ihm somit in Wirksamkeit und
Sicherheit entsprechen (= therapeutische Äquivalenz).
Diese therapeutische Äquivalenz wird für niedermolekulare Wirkstoffe dann angenommen, wenn der statistische Vertrauensbereich der Bioverfügbarkeit
eines Generikums innerhalb von 80 % bis 125 % der Bioverfügbarkeit des Originalpräparats liegt (=Bioäquivalenz).
→ http://de.wikipedia.org/wiki/Generikum
(38) INN:
Dies ist der “internationale Freiname”, sprich der generische Name für eine pharmazeutische Substanz. Im englischen Original heisst dies “International
Non-proprietary Name”.
Ein Beispiel dazu ist:
Aspirin → die Substanz von Aspirin ist “acetyl salicylic acid” → http://www.drugs.com/ppa/aspirin-acetylsalicylic-acid-asa.html.
Ein weiteres Beispiel gibt es für “monoclonal antibodies”. Die enden alle auf -mab, wie zum Beispiel Rituximab. Ein anderes Beispiel hierzu ist
„bevacizumab“ (Avastatin®) → a monoclonal antibody directed against VEGF, thereby inhibiting angiogenesis.
(39) Erkläre “Validation vs. Qualification” sowie “Validation & Distribution”:
(40) CDER: Was ist das?
CDER ist das Center for Drug Evaluation and Research.
Sie teilt die Arzneimittelstoffe (“drugs”) in drei Kategorien ein:
(1) new drugs
(2) generic drugs
(3) over-the-counter drugs
Ein Arzneimittelstoff wird “neu” genannt wenn er entweder von einem anderen Hersteller produziert wird, oder für einen anderen Zweck, oder einer
sonstigen grossen Veränderung unterzogen wird.
Am strengsten werden die sogenannten "new molecular entities" vom CDER bewertet – dies sind Arzneiwirkstoffe die wirklich ganz neu sind.
(41) CBER: Was ist das?
CBER ist das Center for Biologics Evaluation and Research. Siehe hier →
http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CBER/default.htm.
Aus dem Original:
“CBER is the Center within FDA that regulates biological products for human use under applicable federal laws, including the Public Health Service
Act and the Federal Food, Drug and Cosmetic Act. CBER protects and advances the public health by ensuring that biological products are safe and
effective and available to those who need them. CBER also provides the public with information to promote the safe and appropriate use of biological
products. “
(42) Was ist der “primary endpoint”?
In a clinical research trial, a clinical endpoint generally refers to occurrence of a disease or a symptom constitutes one of the target outcomes of the trial,
but may also refer to any such disease or sign that strongly motivates the withdrawal of that individual or entity from the trial, then often termed humane
(clinical) endpoint.
A clinical trial will usually define or specify a primary endpoint as a measure that will be considered success of the therapy being trialled (e.g. in
justifying a marketing approval). The primary endpoint might be a statistically significant improvement in overall survival (OS). A trial might also
define one or more secondary endpoints such as progression-free-survival (PFS) that will be measured and are expected to be met. A trial might also define
exploratory endpoints that are less likely to be met.
(43) Was bezeichnet die Abkürzung “SOP”?
(44) Was bezeichnet die Abkürzung “Pop”?
Dies bezeichnet ein Proof of Principle (demonstrate feasibility in model systems).
(45) IVD: Explain its specificityIVD steht für In-Vitro Diagnostics.
(46) Was sind Orphan Drugs? Wo werden sie in der EU registriert?
(47) What is “Risk”?
Risk is the combination of the probability of harm and the severity of that harm.
(48) NME: Wofür steht diese Abkürzung und was ist das ganze? [DONE]
New Molecular Entities.
A new chemical entity (NCE) is a drug that contains no active moiety that has been approved by the FDA in any other application yet.
A new molecular entity (NME) is a drug that contains an active moiety that has never been approved by the FDA or marketed in the US.
(49) What is a “notified body”?
(50) Route of administration: p.o. ausschreiben. Was bedeutet es?
per oral → Aufnahme über den Mund.
(51) AMG
AMG ist das Arzneimittelgesetz; seit 1993 in Österreich.
(52) Was ist der “therapeutic index”?
75% LD /25% ED50 50
(53) ITT vs. PPT, Relevanz für Studien?
ITT heisst: Intention To Treat
PPT heisst: Per Protocol Treatment
PPT:
“Assessing per-protocol treatment effcacy on a time-to-event endpoint is a common objective of randomized clinical trials.”
→ http://www.ncbi.nlm.nih.gov/pubmed/24187408
(54) What are “Medicinal Products”? (Definition of medicinal products)
→ A medicinal product is any substance or combination of substances presented as having properties for treating or preventing disease in human
beings.
or
→ Any substance or combination of substances which may be used in or administered to human beings either with a view to restoring, correcting or
modifying physiological functions by exerting a pharmacological, immunological or metabolic action, or to making a medical diagnosis.’
(55) What is “Quality”?
(56) Was sind Phase 3 Studien? Welche Charakterisika haben sie? Welches Design wird bei Phase 3 Studien verwendet?
(57) Was ist der Unterschied zwischen MD und MP?
(58) Was ist die clinical trial phase I? Was ist “study design” hierbei?
Legislation: 2001/20/EC = clinical trials directive
Prior to approval:
– Phase I (dose finding, adverse reactions)
– Phase II (safety & efficacy, PK/PD)
– Phase III (safety & efficacy in a randomized/controlled study)
Post approval:
– Phase IV (post market surveillance study)
(59) Was bedeutet “hit-to-lead”?
“Hit” bedeutet eine Aktivität in einer künstlichen Umgebung (“activity in vitro”).
Siehe auch Wikipedia → http://en.wikipedia.org/wiki/Hit_to_lead
“Hit to lead (H2L) also known as lead generation is a stage in early drug discovery where small molecule hits from a high throughput screen (HTS) are
evaluated and undergo limited optimization to identify promising lead compounds.”
(60) Was bedeutet “NOAEL”?
No Observed Adverse Effect Level (basis for defining starting dose in clinical phase I trails)
(61) Was ist “Rx”?
Rx = prescription drug only (advertisements targeting layman are not allowed)
(62) Was heisst “OTC”?
OTC = over the counter; approved drugs, that however can be sold without prescription.
(63) If we are to start with a format for drug discovery (e. g. we wish to create a new drug), what should we keep in mind about the different compounds?
Small molecule:
+ easy to manufacture and analyse, cheap, stable, good to control, versatility
Peptide:
+ ease of manufacture, specificity, low toxicity
- stability, bioavailability, membrane permeability
Antibody:
+ specificity, potency, stability (in plasma)
- bioavailability, membrane/tissue permeability, expensive to manufacture
Vaccines:
+ long lasting, cheap, convenient
+ prevention of disease (e. g. virus, bacteria)
+ therapeutic vaccines (e.g. allergies, cancer, Alzheimer) → immunotherapy: challenges
- efficacy, overcome tolerance, specificity, lack of suitable animal models, delivery of antigen
Antisense, siRNA:
+ easy to manufacture, cheap, specificity, potency, low toxicity
- stability, bioavailability, membrane permeability
(64) What is “HTS”?
HTS means “high trough-put screening”. It is applied for small molecules and peptides, fragment based screening and antibody maturation.
(65) Was heisst “SAR”?
SAR = structure-activity relationship.
(66) Was heisst “ADME”?
Absorption, Distribution, Metabolism and Excretion (describes the deposition of a drug within an organism)
Wichtige Parameter (aus dem Foliensatz der Vorlesung übernommen):
→ Microsomal stability
→ Hepatocyte stability
→ P450 substrate
→ P450 Inhibitor
→ Permeability
→ Transporter efflux (Pgp)
→ Protein binding
(67) Was bedeutet “Lead optimization”?
Dies ist der Fall wenn wir die Eigenschaften eines Arzneiwirkstoffes verbessern (“increase drug-like properties”).
(68) Wie können wir die “Druglikeness” messen?
Mittels der “Lepinski's Rule of Five”:
• Not more than 5 hydrogen donors (NH, OH, ..)
• Not more than 10 hydrogen bond acceptors (N, O)
• Molecular weight under 500 g/mol
• Partition coefficient (octanol/water) log P less than 5
→ But: This is only applicable for orally active small molecules.
(69) Was ist die EMA bzw. EMEA?
EMA: European Medicines Agency
(70) Was ist CPMP?
Committee for Proprietory Medicinal Products.
(71) Was ist “ICH”?
The International Conference on Harmonization.
(72) Was bedeutet “MoA”?
MoA ist Mode of action: it usually includes mention of the specific molecular targets to which the drug binds, such as an enzyme or receptor.
For instance, the mechanism of action of aspirin involves irreversible inhibition of the enzyme cyclooxygenase, which suppresses the production of
prostaglandins and thromboxanes thereby reducing pain and inflammation.
(73) Welche 4 “main drug actions” existieren?
(a) Depressing
(b) Stimulating
(c) Destroying cells
(d) Replacing substances
(73) What means “potency”?
Potency is the dose required to generate an effect.
(74) What means “Bioavailability”?
Bioavailability is the fraction of an administered dose of unchanged drug that reaches the systemic circulation.
(75) What does “Extrapolation to patients” mean?
Significance for clinical trials:
– Roughly 70% of effects in animal models predictable
– Animal models bad predictor e. g. in skin, cardiovascular system or for subjective conditions (e. g. depression)
– Relatively good predictor e. g. for haematological, gastrointestinal, renal or hepatic indications
(76) Examples for in-vitro “Toxicological Studies” and why are they relevant?
Examples of in-vitro studies conducted were:
• hERG
• Ames test
• mouse lymphoma L5178Y cell tk gene (mutation assay)
• In vitro micronucleus assay
• Hemolysis
Toxicological studies are relevant for clinical studies, for instance in order to determine NOAEL (no observed adverse effect level). NOAEL can serve as
the basis for defining starting dose in clinical Phase I trials.
(77) What does “GMP” mean?
Good Manufacturing Practice. GMP (EU guideline)
(vii) records of manufacture including distribution which enable the complete history of a batch to be traced, are retained in a comprehensible and
accessible form;
(viii) the distribution (wholesaling) of the products minimises any risk to their quality;
(ix) a system is available to recall any batch of product, from sale or supply;
(x) complaints about marketed products are examined, the causes of quality defects investigated and appropriate measures taken in respect of the defective
products and to prevent reoccurrence.
(78) What does “GDP” mean?
GDP ist „Good documentation practice“.
Features of a good “quality relevant document” should include:
- SOPs
- Specifications
- Manufacturing instructions
Release of document occurs in three stages by:
- Author
- Reviewer
- Quality assurance
Provisions to control:
- Revisions (no ambiguity which document is when valid)
- Changes (change control, audit trail)
- Circulation of document
(79) What ist the “PDCO”?
PDCO is the “Paediatric Committee” (→ http://www.ema.europa.eu/ema/index.jsp?curl=pages/about_us/general/general_content_000265.jsp).
The Paediatric Committee (PDCO) is the committee at the European Medicines Agency that is responsible for assessing the content of paediatric
investigation plans and adopting opinions on them.
This includes assessing applications for full or partial waivers and assessing applications for deferrals.
The PDCO was established in accordance with the Paediatric Regulation (Regulation (EC) 1901/2006 as amended).
Slogans und Merkphrasen:
→ Drugs are medicinal products.
→ Drug development is highly risky.
→ Worldwide there are more than 4.000 Biotech companies.
→ The EU legislation distinguishes medicinal products and medical devices.
→ “Value creation in drug discovery”.
→ Drug Discovery comes before product development.
→ The bench model has these steps: (1) Target Identification → (2) Target Validation → (3) Hit Identification → (4) Hit Validation → (5) Lead
Development → (6) Lead Optimization → (7) Screening (und danach in-vitro und in-vivo Systeme)
Abkürzungstabelle←→Bedeutung:
AMG
Arzneimittelgesetz (1993 in Austria)
MPG
Medizinproduktegesetz
MDD
Medical Device Directive
AIMDD
Active Implantable Medical Devices Directive
IVDD bzw. IVDMD
In Vitro Diagnostic Medical Devices
ATMP
Advanced Therapy Medicinal Product
FDA
Food and Drug Administration
CDER
Center for Drug Evaluation and Research
CBER
Center for Biologics Evaluation and Research
CDRH
Center for Devices and Radiological Health (Link to the CDRH)
PoP
Proof of Principle (= demonstrate feasibility in model systems)
PoC
Proof of Concept (→ the efficacy in patients)
NCE
New Chemical Entity
NME
New Molecular Entities
NBE
New Biologics Entity
HTS
High Through-put Scanning
EMEA
European Medicines Agency
CPMP
Committee for Proprietory Medicinal Products
ICH
International Conference on Harmonization
PD
Pharmacodynamics (= describes what a drug does to the body)
Pk
Pharmacokinetics (= describes what the body does to the drug)
MoA
Mode of Action → usually includes mention of the specific molecular targets to which the drug binds (enzymes,
receptors).
ED50
Effective Dose
LD50
Lethal Dose (Link)
Therapeutic Window
ED50 / LD50 50
Therapeutic Index
75% LD /25% ED50 50
ADME
Absorption, Distribution, Metabolism and Excretion (describes the deposition of a drug within an organism)
MTD
Maximum Tolerable Dose or Maximum Tolerated Dose
CRO
Contract Research Organisation
GMP
Good Manufacturing Practice
GLP
Good Laboratory Practice
NOAEL
No Observed Adverse Effect Level (basis for defining starting dose in clinical phase I trails)
QP
Qualified Person
GSP
Good Storage Practice
GDP
Good Distribution Practice
SAE
Serious Adverse Event (toxicity)
AE
Adverse Event (toxicity)
INN
International Nonproprietory Names
GCP
Good Clinical Practice
GDP
Good Documentation Practice
SOP
Standard Operating Procedure
CRF
Case Report Form
IMPD
Investigational Medicinal Product Dossier
ITT
Intention To Treat
PPT
Per Protocol Treatment
CHMP
Committee for Medicinal Products for Humans
CVMP
Committee for Veterinary Medicinal Products
COMP
Committee for Orphan Medicinal Products
HMPC
Committee for Herbal Medicinal Products (Link)
PDCO
Paediatric Committee
CAT
Committee for Advanced Therapies
API
Active Pharmaceutical Ingredient
MRP
Mutual Recognition Procedure (through national health authorities)
Centralized Procedure
occurs through EMEA
CTD
Common Technical Documentation
RMS
Referance Member State (authority that receives and reviews files and leads the process)
CMS
Concerned Member State (additional countries for which marketing authorisation is requested)
IND
Investigational New Drug
NDA
New Drug Application (by CDER)
BLA
Biologics License Application (by CBER)
ANDA
Abbreviated New Drug Application (generic application by CDER)
CAP
Conformity Assessment Procedure (basis on which medicinal products are developed, manufactured and distributed)
DoC
Declaration of Conformity (ensuring that essential requirements are fullfilled)
CEN
European Committee for Standardization
IVD
In Vitro Diagnostics
Harm
damage to health
Hazard
potential source of harm
Risk
Risk is the combination of the probability of harm and the severity of that harm.
Risk
probability x impact
FMEA
Failure Mode and Effect Analysis
HACCP
Hazard Analysis and Critical Control Point
HAZOP
Hazard Operability Analysis
FTA
Fault Tree Analysis
ALARP
As Low As Reasonable Practicable (Possible)
RPN
Risk Priority Number
OOS
Out Of Specification
QA
Quality Assurance
QC
Quality Control
TQM
Total Quality Management
PDCA Cycle
Plan- Do- Check- Act Cycle
CAPA
Corrective Action and Perventive Action system
UCL
Upper Control Limit
LCL
Lower Control Limit
URS
User Requirement Specification
FAT
Factory Acceptance Testing
SAT
Site Acceptance Testing
PAT
Process Analytical Technology (variable process to get a constant product quality)
CQA
Critical Quality Attributes
CPP
Critical Process Parameters
LOD
Limit of Detection Signal/Noise 3:1
LOQ
Limit of Quantitation Signal/noise 10:1
LOL
Limit of Linearity
SAL
Sterilisation Assurance Level
DQ
Design Qualification
IQ
Installation Qualification
OQ
Operational Qualification
PQ
Performance Qualification
IPC
In Process Control
(Q)SAR
(Quantitive) Structure Activity Relationship
(Q)SPR
(Quantitive) Structure Property Relationship
BoM
Bill of Materials
FPC
Final Product Control
CI
Continoous Improvement (Process) KAIZEN → the goal to improve and optimize all processes, all the time
SPC
Statistical Process Control
BPR
Business Process Reengineering
QFD
Quality Function Deployment
CMC
Certified Management Consultant
USP
United States Pharmacopeia
TPM
Total Productive Maintenance
Rx
A prescription drug
OTC
Over The Counter
CTCAE
Common Terminology Criteria for Adverse Events
QoL
Quality of Life (clinical trial endpoint)
21 CFR Part 11
Richtlinie für die Zulassung eines pharmazeutischen Präperats für den US amerikanischen Markt
GAMP
Good Automated Manufacturing Practice
NANDO
New Approach Notified and Designated Organisations
6 sigma
Quality Management Method which uses statistical methods
GHTF
Global Harmonization Task Force
LoQ
List of Questions
Vd
the apparent volume of distribution
GMP
Good Management Practice (wobei wohl die “Good Manufacturing Process” populärer ist als Begriff)
AQC
Analytical Quality Control
AUC
Area under the plasma-time Curve (“area under the curve”)
BE
Bioequivalence
CFR
Code of Federal regulations
R&D
Research and Development
R&S
Relative Standard Deviation