The GxP-Lexicon – Definitions around the topics GxP and ......16 Bioburden 16 BMG 16 BP (British Pharmacopoeia) 16 Bracketing 16 British pharmacopeia (BP) ... 38 FMEA (Failure Mode

The GxP-Lexicon

Testo Industrial Services – More assurance, better service

Definitions around the topics GxP and quality assurance

3

PREFACE

Effectiveness, identity and purity are quality

attributes, which are required for the products

of the GMP-regulated environment. With the

term „Good Manufacturing Practice“, the

quality assurance guidelines are summarized

from national and international regulations and

laws. Meanwhile, additional GxP forms have

developed and its scope of application has

expanded to adjacent sectors like medical

devices and life sciences.

The complex requirements of the “GMP-Com-

pliance” bring up various specific terms and

abbreviations.

This GxP lexicon explains most of the terms

around the topics: GxP, qualification, valida-

tion and quality assurance. This lexicon shall

serve as a compact reference book and aid for

all GMP users, whereby no claim regarding the

completeness should be raised.

Your Testo Industrial Services Team

44

Content

Content

A C

B

10 Termsanddefinitions

10 21 CFR 210/211

10 483er

11 Action Limit

11 Active Pharmaceutical Ingredient (API)

11 Admission

11 ADI (acceptable daily intake)

11 AGES

11 Air exchange rate

12 Aide Mémoire (AiM)

12 AMBO

12 AMBV

12 AMG

13 AMWHV

13 Annex

13 Annual Product Review (APR)

13 API

13 APR

14 Audit

14 Audit trail

14 Autoclave

15 Barrier systems

15 Batch Record Review

15 BfArM

16 Bioburden

16 BMG

16 BP (British Pharmacopoeia)

16 Bracketing

16 British pharmacopeia (BP)

17 Bubble-Point-Test

17 Bulk ware

18 Calibration

18 Capacity test

18 CAPA

18 CEP

18 CFR

19 CFU

19 cGMP

19 Challenge Test

19 Change Control

19 Charge

20 Charge documentation

20 CIP

20 Clean Corridor-Principle

20 Cleaning validation

21 Cleanroom

21 Cleanroom-Principal

21 Cleanroom classes

22 Compliance

22 Computer-System-/Softwarevalidation

(CSV)

22 Computer validation

23 Conformity

23 Consecutive process validation

23 Containment (operator protection)

24 Contamination

24 Continued Process Verification (CPV)

24 Continuous validation/verification

24 Corrective- and preventive action

24 Corrective Action/Preventive Action

(CAPA)

G

55

E

FD

24 CPV

25 cRABS

25 Cross Contamination

25 CSV

25 Culture media

25 Culture media filling

26 DAB

26 Data review

26 Definition of medicinal products

27 Deliver

27 Design of Experiments (DoE)

27 Design qualification (DQ)

28 Deviation

28 Deviation Management

28 DIN EN ISO 13485

29 DIN EN ISO 14644

30 Disaster recovery

30 Disinfection

30 Distributing

30 DMS

30 Document management system (DMS)

30 DQ

31 D-value

31 EDMF

31 eDMS

31 EDQM

32 EG-Guideline

32 EG-Regulation

32 EMA/EMEA

32 EMA-guideline

32 Endotoxins

33 EP

33 ETA

33 ETD

33 EU-GMP-guideline

33 European Pharmacopoeia

34 Event Tree Analysis

35 Factory Acceptance Test (FAT)

35 Fault Tree Analysis

35 FDA

36 FDA Guidance for Industry – Process

Validation

36 Federal Food, Drug and Cosmetic Act

36 FFDCA

36 Filter Fan Unit (FFU)

37 Fish bone diagram/-method

37 Flow visualization

38 FMEA (Failure Mode and Effects

Analysis)

38 FMECA (Failure Mode, Effects and

Criticality Analysis)

38 Formulation

39 FTA

39 Functional specification sheet

40 Galenics

40 GAMP

40 GCP

40 GDP

40 GEP

40 GLP

66

IM

N

OJ

LK41 GMP

41 GMP-compliant facility design

41 GSP

41 GxP

42 HACCP

42 Hand disinfection

42 HAZOP

42 HEPA-Filter

43 Hygienic design

43 Hygienic zone concept

44 ICH

44 Infiltrating procedure

44 Information officer

45 In-process control

45 Installation qualification (IQ)

45 IPC

45 IPK

45 IQ

46 Ishikawa-Diagram/-Method

46 ISO 14644

46 ISO 13485

46 Isolator

46 ISPE

48 Japanese pharmacopoeia (JP)

48 JP

49 KBE (colony-forming unit)

50 LAF/LF

50 Laminar (Air) Flows

50 Life-Cycle-Approach

50 LIMS

50 Lock concept

51 Logbook

51 Low turbulence displacement flow (TAV)

52 Major change

52 Manufacturing authorization

53 Material flow

53 Matrixing

53 Media Fill Test

53 Medical product term (according MPG)

54 Method validation (analytical)

54 Metrological Traceability

55 Microbiological monitoring

55 Minor change

55 Monitoring

55 MPG

56 NOAEL

56 NOEL

56 Official calibration

56 OOS

56 OOT

57 Operational qualification (OQ)

H

Content

77

P

Q

R

57 OQ

57 Out-of-Specification (OOS)

57 Out-of-Trend (OOT)

58 Parenteral

58 Particle monitoring

58 PEI

58 Performance qualification (PQ)

59 Personnel flow

59 Ph. Eur.

59 Pharmacology

59 Pharmaceutical excipient

60 PIC/S

60 Postal Audit

60 PPQ

60 PQ

60 PQR

61 Primary packaging material

61 Process

61 Process capability

61 Process capability study

61 Process Performance Qualification

(PPQ)

62 Process validation (PV)

62 Production manager

62 Product Quality Review (PQR)

63 Product specification

63 Prospective Qualification

63 Prospective validation

63 PV (Process Validation)

63 Pyrogenicity/Pyrogens

63 Pressure cascade

65 QA

65 QbD

65 QP

65 Qualification

65 Qualification report

65 Qualification master plan

66 Qualification plan

66 Qualification report

66 Quality control manager

67 Qualified Person (QP)

67 Quality assurance (QS/QA)

67 Quality by Design (QbD)

68 Quality management handbook

68 Quality risk management (QRM)

69 RABS

69 Recovery Test

69 Release

69 Remedy

69 Reproducibility

70 Requalification

70 Reserve samples

70 Restricted Access Barrier System

(RABS)

70 Retoure/return

70 Retrospective qualification

71 Revalidation

71 Risk analysis (RA)

71 Risk assessment

71 Risk based qualification system

72 Risk check/review

72 Risk communication

72 Risk controlling

88

W

T

VU

S

73 Risk management

73 Risk priority number (RPZ)

73 Risk reduction

73 RLT-facility/air conditioning system

74 Robustness

74 Risk monitoring

75 Sanitization

75 Safety workbench (SWB)

75 Secondary contamination

75 Secondary packaging materials

76 Self-inspection

76 Shell model

76 Sinner circle

76 SIP

77 Site Acceptance Test (SAT)

77 Site Master File (SMF)

77 SOP (Standard Operating Procedure)

78 Specialist responsible for technical

matters

78 Specification

78 Specification sheet

79 Step-by-step plan agent

79 Sterility

79 Steril filtration

79 Sterilization

80 Stress test

80 Swissmedic

80 Supplier audits

81 TAMC (Total Aerobic Microbial Count)

81 Target specification sheet

81 Test plan

81 Therapeutic Products Act/

Heilmittelgesetz (HMG)

81 Therapeutic Products Agency (Cantonal

in Switzerland)

82 Third-Party Audits

82 TOC-measurement

83 Traceability

83 Tracematrix/Traceability Matrix

83 Track & Trace

83 Turbulent currents

84 TYMC (Total Yeasts/Moulds Count)

85 URS (User Requirement Specification)

85 USP

86 Validation

86 Validation report

86 Validation master plan (VMP)

87 Validation matrix

87 Validation plan

87 VDI 2083

87 VAV: Agreement for the delimitation of

responsibility

88 V-Modell

89 Warning limit

89 Warning Letter

89 WHO

90 WIP

90 Worst-Case-Szenario

Content

99

91 ZLGZ

100

Terms and definitions


21 CFR 210/211CFR: Code of Federal Regulations–Federal guidelines of the

USA

Title 21: Food and Drugs – includes the regulative provisions in

the area of food and medicinal products.

Part 210: Current Good Manufacturing Practice ( cGMP) in

manufacturing, processing, packing, or holding of drugs; gene-

ral

Part 211: Current Good Manufacturing Practice ( cGMP) for

finished pharmaceuticals

The 21 CFR 210/211 contains the GMP-guidelines for USA in

a very detailed form. Part 210 refers hereby to manufacturing-

and packing process of food and medicinal devices whilst Part

211 contains basically the guidelines for finished pharmacy

products.

483erThe problem report is defined as ‘483’, which is issued by the

FDA-inspectors ( FDA) and where the occurring complaints

during an inspection are documented. The description derives

from form No. 483 which is used for the creation of the short

report. A ‚483’ is generally published, however without menti-

oning the respective company and product names. Depending

on the relevance of the documented defects, a warning letter

will be issued on the basis of the ‚483’ ( Warning Letter).

11A

Action Limit A limit determined by law, guidelines or company-internal poli-

cy which, if exceeded, corrective actions must immediately be

started as well as troubleshooting and correction of the reason.

Active Pharmaceutical Ingredient (API)= Substance: The medical (pharmacological) effective part of a

pharmaceutical.

AdmissionThe admission is the authorization for the market release of

a product. Prerequisite is always the GMP compliance of the

product. In Germany, the admission is given by the BfArM or

PEI; in the US by the FDA.

ADI (acceptable daily intake)= Acceptable Daily Intake (ADI): The ADI defines, which amount

of a certain substance e.g. a drug substance is harmless for the

health, under the assumption that a person is exposed to it for

a lifetime.

AGES= Agency for Health and Food Safety: The AGES is owned by

the republic of Austria. Its tasks arise from the health- and food

security law and the European food security politic.

Air exchange rate

The air exchange rate is the air volume flow related to

the room volume, this means the air exchange rate is

12

the indication how often the air is exchanged per hour

in the turbulent room and is also an important criteri-

on for the performance assessment of a clean room.

Aide Mémoire (AiM)Guidelines-, questions- and recommendations catalogue; pu-

blished by the ZLG ( ZLG) as a handbook for the inspection

of companies in the pharmaceutical and medicine production

sector in Germany. Several AiM’s are accessible online on the

ZLG homepage (www.zlg.de).

AMBO= “Arzneimittelbetriebsordnung“(Austria): Regulation of the

Federal Ministry for Health, Family and Youth for the respective

companies which produce, control or trade medicinal products.

AMBV= “Arzneimittel-Bewilligungsverordnung“: regulation on authori-

zations in the pharmaceutical sector in Switzerland.

AMG= “Arzneimittelgesetz” (Germany). Includes 147 paragraphs

and 18 sections, e.g. about the production and admission of

medicinal products and the protection of a person during the

clinical trial. „§ 1 Purpose of the regulation: It is the purpose of

this law, in the interest of a proper pharmaceutical supply for

human and animal for the safety when working with medicinal

products especially for the quality, effectiveness and harmless-

ness of the medicinal products in accordance with the following

regulations.“A


13

AMWHV= Arzneimittel- und Wirkstoffherstellungsverordnung: (Ordi-

nance on the manufacture of medicinal products and active

ingredients).

Regulation about the usage of good manufacturing practice

at the production of pharmaceuticals and active substances

and about the application of good and professional praxis at

the production of products with human origin. The „AMWHV“

implements the European GMP-requirements for Germany. All

GMP-regulated companies must be aligned according to these

regulations.

AnnexThe “Annexe” are different annexes of the EU-GMP-guideline.

Currently, there is Annex 1 to Annex 19; however there is no

longer an Annex 18. Annex 18 was published in 2005 as an EU-

GMP guideline edition II.

Annual Product Review (APR)APR is a retrospective review of the history of a pharmaceutical

in the scope of one year, as required by the FDA for products

manufactured or imported products in the USA.

API Active Pharmaceutical Ingredient

APR Annual Product Review A

14

AuditInspection or viewing of a locality (e.g. an organization, a pro-

duction facility) for the purpose to audit the equivalent of the

issued requirements and condition (here: Compliance of the

GMP-regulations and its specifications). An Audit can be car-

ried out by various bodies (e.g. by representatives of clients or

representatives of authorities other than the competent super-

visory authority such as FDA). It is conceptually separated from

an inspection which may only be carried out by the competent

supervisory authority (i.e. the inspectors of the regional autho-

rity).

Audit trail(= test trail) serves the complete traceability of all activities,

actions and system states through the recording of traces that

indicate when, by whom or through what a process was affec-

ted. Usually, it concerns recordings of computer- and software

systems and is regulatory required by the 21 CFR Part 11 and

the Annex 11 (EU GMP).

Autoclave In the GMP area an autoclave is a pressure chamber in which

various products can be autoclaved, i.e. sterilized (e.g. clean

room clothes), for a certain period of time under the influence of

water vapor at defined pressure and temperature values.

A


15B

Barrier systems A barrier system serves, for example at aseptic filling proces-

ses, to physically separate personnel and products in order

to protect both the staff against highly active ingredients as

well as the prevention of microbiological contaminations of the

product.

Examples of such barrier systems are workbenches, isolators

and RABS-facilities ( Restricted Access Barrier System).

Batch Record ReviewBatch Record Review describes a system, in which all informa-

tion for the “batch certification” is compiled. This includes e.g.

the “batch production”, test reports as well as all recordings

regarding deviations and OOS reports. This information serves

the QP (qualified person) as a decision basis for the release of a

batch (batch release).

BfArM= Bundesinstitut für Arzneimittel und Medizinprodukte:

Federal authority of the BMG;

Tasks of the BfArM’s:

• Authorization of finished pharmaceutical products based on

the Medicines Law.

• Collection & evaluation of reports regarding unwanted side

effects, which only become known after the authorization.

• Registrations of notifications regarding incidents with

medical products: central recording, evaluation and assess-

ment of the products as well as the coordination of the mea

sures to be taken.

• Federal Opium Agency (part of the BfArM): Permission for

the legal placing on the market of narcotics and respective

base materials.

16B

Bioburden= microbial load: Total number of viable micro-organisms on or

in pharmaceuticals before their sterilization.

BMG= Bundesministerium für Gesundheit (=Federal Ministry of

Health): prepares draft laws, ordinances and administrative pro-

visions. The most relevant task for the GMP area: The design of

the general provisions for the production, clinical trial, admis-

sion, distribution channels and monitoring of pharmaceuticals

and medical devices/products.

BP (British Pharmacopoeia)British pharmacopoeia

BracketingConcept of a validation in which the batches are tested only on

extremes of certain determined and justified design factors. In

the cleaning validation bracketing can be understood as a pro-

duct based implementation. Here lead substances are defined.

Similar products/processes do therefore not have to be valida-

ted individually, but a representative and risk-based spectrum

is sufficient.

British pharmacopeia (BP)= British Pharmacopoeia; the British Pharmacopeia is a collec-

tion of official standards, which are valid for medical products

and pharmaceutical substances within the UK. This rulebook

is issued and annually updated by the „British Pharmacopoeia

Commission Secretariat of the Medicines and Healthcare Pro-

ducts Regulatory Agency“.


17

Bubble-Point-TestWith the Bubble-Point-Test, a filter can be tested on possible

damages or imperfections by drawing a conclusion on the ma-

ximum pore size. For this purpose, the filter will be immersed

into a wetting liquid and impinged with gas pressure which will

be increased slowly. The minimum pressure, which causes the

leakage of the first bubble in the filter, defines the bubble-point.

The lower the pressure, the bigger the maximum pore size of

the filter will be.

Bulk ware= Bulk ware is each product which has, except for the final

packaging, gone through all processing stages.

B

18C

CalibrationCalibration is the comparison of a measured value or a measu-

ring standard with the correct value at specified conditions, the

documentation of the deviation, the calculation of the measure

ment uncertainty and the creation of the certificate- or calibra-

tion protocol. One of the most important criteria of a professio-

nal calibration is the complete/gapless traceability to natio-

nal and international standards.

Capacity testThe capacity test is a long-term stress test, which shall show,

whether a (IT-) system is fully functioning in long-term, even un-

der full load. Possible capacity limitations would then become

visible then. For example, a document management system

should also start the correct workflow for the validity of a docu-

ment, as for instance, if hundreds of documents become valid

at the same time.

CAPA Corrective Action/Preventive Action

CEP (certificate of suitability of mono-graphs of the European pharmacopoeia)The certificate, which confirms that a drug substance has been

produced according to the monographs of the European Phar-

macopoeia.

CFR= Code of Federal Regulations: Federal guidelines of the United


19C

States of America. Example: 21 CFR 210 and 211

CFU KBE

cGMP= current Good Manufacturing Practice: As the US American

GMP guidelines are permanently revised, the correct name the-

re is cGMP (c=current). However, in Europa, the guidelines are

only revised upon request, so that the c (current) is not used.

The name is therefore only GMP.

Challenge TestChallenge Test describes a qualification- or validation test

under worst-case conditions. Often, this method is intentionally

complemented through errors to prove that these are disco-

vered, remedied or prevented through those adopted measu-

res.

Change ControlThe change control is a formal system for maintaining the defi-

ned status, e.g. the validation status. A systematic, risk based

assessment, which measures become necessary, through an

intended or actual change will follow in order to maintain the

GMP conformity and e.g. the specification. These measures are

evaluated by qualified representatives of the respective depart-

ment.

ChargeA charge (batch) is one in a single operation or in a series of

20C

operations manufactured, homogenous and defined quantity of

starting material, pharmaceuticals or packaging material.

Charge documentationThe charge (batch) documentation includes instructions and

protocols for the production and packaging procedure as well

as the test protocol. In this way, the entire history of a charge

(batch) can be completely retraced. The charge (batch) docu-

mentation serves as basis for the charge release and is particu-

larly of high importance if quality defects (which were not reco-

gnizable at the time of release) are discovered at a later date.

CIP= Cleaning In Place: Automatized system cleaning within a

closed system, for example by so-called spray balls.

Clean Corridor-Principle The Clean Corridor is a protection concept for the prevention

of cross contamination. Hereby, a spatial arrangement is gi-

ven, in which the corridor (from where different process rooms

go off) is the room with the highest pressure. This causes an

overflow in direction to the production rooms, so that the leaka-

ge of a product in another area can be prevented.

Cleaning validationThe cleaning validation is a documented evidence that with a

cleaning process a plant condition is achieved which is appro-

priate for the production of pharmaceuticals. Hereby, the effec-

tiveness and repro- ducability of the entire cleaning process is

verified. The


21C

four decisive parameters, which affects the success of the

cleaning, are represented in the „Sinner`scher Kreis“ (Sinner

circle): Chemistry, mechanics, temperature and time (cf.

Sinner’s circle). Another requirement for the successful cleaning

is the GMP-conform plant design.

CleanroomA clean room is a room which, due to its concept, is designed

not to exceed a defined particular and microbiological conta-

mination. In accordance with the purity specification, that such

a room constantly fulfills, a purity classification is attributed.

Furthermore, a clean room is equipped with locks and access

protection.

Cleanroom-Principal The Cleanroom principal is a protection concept, which works

through a shell concept with overpressure to adjoining areas

with low air purity. The overflow takes place from the clean

room and thereby prevents the intrusion of polluted air in the

clean room.

( pressure cascade).

Cleanroom classesIn the DIN EN ISO 14644-1 different clean room classes

(ISO 1–9) are classified according the maximum values of the

permitted particle concentration (in particle per cubic meter air).

ISO class 1 is hereby the clean room class with the lowest per-

mitted particle concentration. In the EU GMP guidelines, letters

from A to D are assigned to the clean room classes, additionally

it is differentiated between manufacturing- and resting state.

Testo Industrial Servicescleanroom

22

Classification limits in Annex 1EC Guidelines to Good Manufacturing Practice, Revision to Annex 1

Room classes

Maximumpermittednumberofparticleperm3,equalorbiggerthantabulatedvalue

Resting state 0,5 µm 5,0 µm

Manufacturing 0,5 µm 5,0 µm

A 3.520 20 ISO 5 ISO M(20; ≥ 5 µm)

3.520 20 ISO 5 ISO M(20; ≥ 5 µm)

B 3.520 29 ISO 5 ISO M(29; ≥ 5 µm)

352.000 2.900 ISO 7

C 352.000 2.900 ISO 7

3.520.000 29.000 ISO 8

D 3.520.000 29.000 ISO 8

not specified

Compliance= Compliance of conditions with standards and specifications.

GMP-compliance is therefore the adherence of GMP-regulated,

i. e. the respective laws, guidelines and handbooks (e.g. EU-

GMP handbook).

Computer-System-/Software- validation (CSV) Computer validation

Computer validation= Validation of computer-aided systems: According to the EU-

GMP guidelines, a computer consists of „a compilation of

hardware components and the associated software, which was

designed and assembled to provide a specific function or a

group of functions.” During the computer validation, the suitabi-

lity of this hardware- software concept for achieving the desired

functionality is checked and the results documented.C


23

Concurrent validationThe validation takes place, while the production, for the pro-

ducts which will be sold later, is already running. A start of the

routine production before the end of the validation process

must be explained, documented and approved by authorized

staff. The validation charge will only be released for trade after

successful completed validation.

Conformity Compliance

Consecutive process validationValidation today is no longer considered as a unique and

timely limited activity. It is rather a permanent verification that

accompanies the entire process during the period from the

design phase to the market withdrawal of the product. The new

process validation approach thus follows consequently the life

cycle model. This means that every manufactured batch is – in

a broader sense - a validation batch.

Containment (operator protection) Inclusion of a biologic agent or other substances within a defi-

ned room.

Primarycontainment: Prevents the escape into the immediate

working environment (e.g. through closed containers).

Secondarycontainment:Prevents the escape outwards or

in other work environments (e.g. through rooms with special

ventilation systems/locks). C

24

ContaminationThe unwanted penetration of impurities or contaminates, of

chemical or micro biological nature, in or on a raw material or

an intermediate or finished product at the manufacturing, the

testing, the packaging, the storing or the transportation.

Continued Process Verification (CPV) Consecutive validation

Continuous validation/verification Consecutive validation

Corrective- and preventive action Corrective Action/Preventive Action

Corrective Action/Preventive Action (CAPA)= Systematic approach, which includes correction and preven-

tion measures.

Corrective action: A measure to correct the error cause of a

detected and unwanted situation and to prevent a recurrence in

other areas or in another procedure with high probability.

Preventive action: A measure to avoid a potential new error

proactively. This is often done with the help of risk analyses.

CPV= continued process verificationC


25

cRABS= closed RABS (Restricted Access Barrier System): A closed

RABS is the room opposite of the room where the operator is.

It is completely airtight, whereas the standard- RABS can con-

tain openings, for example for the air flow outlet, (these must

of course be designed in such a way that “no reaching in” is

possible). ( RABS)

Cross Contamination = Contamination of a raw material or product by unwanted

mixing with another substance during the production process.

CSV= Computer-System-validation/Computer- and Software- vali-

dation ( Computer validation)

Culture mediaUsed in the microbiology to cultivate microorganisms. Culture

media exist in liquid and solid form (agar) and they contain the

most important nutrients for microorganisms. Selective nu- tri-

ent media are construed through their ingredients on special

microorganisms. Hereby, the growth of unwanted germ types

can be reduced or avoided.

Culture media filling Media Fill Test

CAgar plates in various versions

26D

DAB= Deutsches Arzneibuch (German Pharmacopoeia): contains

supplementary regulations for the EP (European pharmacopo-

eia) regarding procedures and active substances, which are not

common in all European countries.

The DAB is available through the „Deutschen Apotheker Verlag“

(German pharmacist publisher) and consists of the three phar-

macopoeias: European Pharmacopoeia, German Pharmacopo-

eia and Homeopathic Pharmacopoeia.

Data reviewA data review can replace a practical revalidation, in case no

critical changes have been made on the process since the

validation. Then it is sufficient to evaluate the process- and pro-

duct data of the previous period. An inspection of the validated

status of batches, especially designed for this purpose, is no

longer necessary.

Definition of medicinal products – according AMG, § 2:

(1) Medicinal products are intended for preparations of

substances,

1. Which are for the use in or on the human or animal body and

are remedies with features determined for the healing or alle-

viation, for the prevention of human or animal diseases or the

prevention of pathological complaints or

2. which are used in or on human or animal bodies, or which

can be given to a human or an animal in order to:

a) restore, correct or influence the physiological functions

through a pharmacologic, immunologic or metabolic effect or

b) create a medical diagnosis.

– according HMG; Art. 4 Abs. 1a:


27D

Products with chemical or biological origin, which are determi-

ned and advertised for the medical exposure on the human or

animal organism, especially for the recognition, protection or

treatment of diseases, injuries and handicaps; part of the medi-

cinal products are also blood and blood products.

DeliverThe paid or unpaid transfer or surrender of a pharmaceutical or

remedy for the purchaser’s use as well as for the use on third

persons or animals. (HMG; Art. 4f).

Design of Experiments (DoE)= statistical design of experiment; method to determine the

correlation between influencing factors and results of a pro-

cess. By changing the influencing factors and measuring the

resulting results, the correlations should be described accor-

ding its coefficients in a model. The correlation between control

and disturbance variables in a process and in the resulting

product and process properties will be determined.

Design qualification (DQ)= Design Qualification: A documented proof, that the designa-

ted design for facilities and equipment is suitable for the inten-

ded use. The DQ, which takes place before the purchase of the

equipment, includes the documentation of the planning phase

plus the decision making for the purchase of a facility.

The requirements for the planned facility should be defined and

specified. The elements of the DQ are usually:

• the design qualification plan,

• the User Requirement Specification,

• the specification sheet (= requirements of the customer

28

regarding scope of delivery- and of service)

• tthe performance specification (execution of the contractor

for the implementation of the facility, respectively the imple-

mentation of the project), as well as:

• the design qualification report

The DQ is the documentation of the comparison between the

specification- and requirement sheet as well as the underlying

laws, regulations and standards.

DeviationIn general, a deviation can be described as a result or a si- tu-

ation within a process, which does not correspond with the

planning respectively expectations or also with very concrete

related regulations. Examples for this are deviations within the

scope of quality control, of the monitoring or product specifica-

tions.

Deviation ManagementDeviation management is the standardized and controlled

handling of a deviation. This includes the recognition, analysis

respectively monitoring as well as the correction of a deviation.

Both the causes of a deviation as well as the related implica-

tions must be registered and classified. This procedure ensures

an efficient correction of errors and their consequences and

enables an early recognition of critical situations in the future as

well as the initiation of appropriate countermeasures.

DIN EN ISO 13485DIN EN ISO: A standard defined by the German institute for

Standardization on the basis of an ISO and/or CEN developed

international norm.D


29

ISO 13485 defines the quality management system and its

structure for medical products, which is used for the design

and development, production and installation as well as the

maintenance of medical products. This derives from ISO 9001

and extends this regarding specific requirements for medical

products.

DIN EN ISO 14644ISO 14644 deals with the topics clean room and contami-

nation control. The products and processes, which profit from

controlled airborne contaminations, includes those which are

used in the aerospace, micro electronic-, pharmaceutical-, and

food industry as well as in the medicine technology and the

health care. Besides the particle purity in the air, many additi-

onal aspects in planning, determination in the operation and

in the control of clean rooms and other related areas are to be

considered. The norm is therefore divided into different parts:

(Status: 11/2014):

• 14644-1: Classification of the air purity based on the

particle concentration

• 14644-2: Monitoring to verify the clean room performance

regarding air purity based on the particle concentration

• 14644-3: Test procedure

• 14644-4: Planning, execution and commissioning

• 14644-5: Operation

• 14644-6: Terms/terminology

• 14644-7: SD-Modules (Clean air hoods, hand glove boxes,

isolators and minienvironments)

• 14644-8: Classification of the air purity based on the

chemical concentration (ACC)

• 14644-9: Classification of the particulate surface cleanliness

• 14644-10: Classification of the chemical surface purity

• 14644-12*: Classification of the air purity based on the D

30

nanoparticle concentration

• 14644-14: Evaluation of the clean room appropriateness

with devices through the particle concentration in the air.

Disaster recovery= Disaster recovery after an IT-blackout; this includes the reco-

very of important data as well as the repair or replacement of

destroyed hardware components.

DisinfectionDuring the disinfection, a targeted germ reduction of certain

undesirable germ spectra takes place with the aim to avoid

further proliferation.

Distributing= The transfer or surrender – either against payment or free

of charge – of a remedy with the exception of the dispensing

(HMG; Art. 4e).

DMS Document management system

Document management system (DMS) Electronical document management system (therefore often

called eDMS) in the form of an IT-solution.

DQ Design qualificationD


31E

D-valueThe D-value indicates a dose or a period of time by which a

certain germ (test microorganism) is reduced by one log level or

90% during defined conditions and by dying out (inactivation).

The D-vaue is an important parameter for sterilisation procedu-

res (e.g. thermal sterilisation).

EDMF= European Drug Master File: A Drug Master File documents

the pharmaceutical production & quality assurance of phar-

maceuticals. This document serves as a template to the res-

ponsible agency for the admission of a pharmaceutical. An

EDMF is mostly then used, when the manufacturer of the phar-

maceutical is not identical with the manufacturer of the finished

product. In this way, the manufacturer can ensure its product

secret by only describing the synthesis pathways and the pro-

cess development in the confidential part of the Drug Master

File. This part is available to the responsible authority, however

not to the pharmaceutical producer.

eDMS Document management system

EDQM= European Directorate for the Quality of Medicines and Health-

Care. The EDQM is responsible for the development and publi-

cation of the European pharmacopeia, coordinates the regular

investigation of drug samples by the respective investigative

bodies of the member states and releases standard substances

for the quality control. The contact point of the EDQM for the

sampling from the German market is the ZLG.

32E

EG-Guideline= Legislation of the European community: Member states have

a certain scope for the implementation of national law (imple-

mentation in law or regulation).

EG-Regulation= Legal act of the European community: has an overall validity,

is binding in all its parts and is valid in all member states – this

means it is not necessary to implement it into national law,

which also means that no modifications are possible.

EMA/EMEA= European Medicines Agency: The EMA is a decentralized

agency of the EU with base in London. Since 1995 the EMA

is responsible for the scientific evaluation of pharmaceuticals,

which are developed by pharma companies for the use within

the European Union. The EMA has a central role in the drug

approval within the EU and the EEA-states, as the European

Commission issues the notices for admission on the basis of its

evaluations.

EMA-guideline Guideline issued by the European Medicines Agency e.g. for

the topics human- und veterinary medicinal products as well as

health protection and GDP (Good Distribution Practice).

Endotoxins= Pyrogens, which exist in terms of lipopolysaccharide in the

bacterial cell wall in gram-negative bacteria. Endotoxins can

cause reactions from fever to death for patients through paren-


33E

teral administration. Endotoxins can be detected by the rabbit

pyrogen test or by the so-called LAL test.

EP= European Pharmacopoeia: published by the European

Directorate for the Quality of Medicines & Health Care (EDQM);

contains the official standards and methods, which are valid for

medical products and pharmaceutical substances within the

EU.

ETA Event Tree Analysis

ETD= acceptable daily intake ADI

EU-GMP-guideline= Guideline for the Good Manufacturing Praxis: The first

version, in which the European guidelines are implemented in

detail, was published in 1989. Meanwhile it consists of 3 parts

as well as the annexes 1–19 (Annexes).

Part I: GMP- principles for the manufacture of pharmaceuticals

Part II: Good manufacturing praxis for active substances

Part III: GMP-related documents (incl. quality risk management)

European Pharmacopoeia EP

34E

Event Tree AnalysisThe „Event Tree Analysis“ is a method for determining the

possible consequences, which are triggered by an error.

Starting from an initial error, with the help of different paths

which show the individual system components, an event

tree diagram will be created at which end all possible error

consequences and effects are listed.


Conse-

quence 1.11

Conse-

quence 1.0

Conse-

quence 1.12

Conse-

quence 2.11

Conse-

quence 2.0

Conse-

quence 2.12

Undesiredincidence

35F

Factory Acceptance Test (FAT) Acceptance/control of ordered devices and facilities directly at

the supplier on site. Usually, after the delivery and installation

the

Site Acceptance Test (SAT) takes place.

Fault Tree AnalysisContrary to the Event Tree Analysis, the Fault Tree Analysis is

developed from the error to the cause. This means, the most

likely cause or cause combination will be searched for an error.

Basicincidence

Undesiredincidence

Basicincidence

Basicincidence

Basicincidence

FDA= U. S. Food and Drug Administration; The FDA is the highest

health authority in the US and responsible for the drug appro-

val. In order to ensure the compliance of standards, also of

the numerous imported medicals into the US, the FDA is

internationally active and conduct audits at the exporting

manufacturers outside the US.

36

Laminar-Flow-Unit with FFU (picture: Franz Ziel GmbH)

F

FDA Guidance for Industry – Process Validation= Guideline for the process validation in the industry: contains

non-binding recommendations for the implementation of the

process validation, based on the current perception of the US-

authority FDA. It is explicitly pointed out that an orientation to

another guideline is possible, provided that the compliance of

all GMP-regulations is ensured.

Federal Food, Drug and Cosmetic ActFFDCA is the legal basis for all activities and the existence

of the FDA. The compliance of this law is ensured through

inspections of plants and products, test analysis and consumer

information.

FFDCA Federal Food, Drug and Cosmetic Act

Filter Fan Unit (FFU)Filter Fan Unit describes a combined component of ventilator

and filter, which absorbs air on one side and emits air on the

other side through a filter in a closed (clean) room.

Besides this room-in-room solution, a FFU can also be supplied

with air via a supply network. Whilst a local circulating air-

FFU can merely increase the air change depletion of particulate

loads and is used for local protection concepts, additional fresh

air in the clean room and the required amount of air for the

maintenance of the pressure cascade can be supplied through

a centrally supplied FFU.


37F

Fish bone diagram/-methodThe fish bone method (also called Ishikawa-Diagram) is a

graphical method for displaying errors/causes and the resulting

effects (error sequence). The name is derived from the visual

similarity with a fish bone. Often it is also named after its

founder, Kaoru Ishikawa. Due to the type of presentation,

which leads towards a clear target, the method provides a clear

process understanding.

Flow visualizationWithin the framework of the clean room qualification, the

flow visualization serves to visualize the air flows to test a

TAV-flow or overflows at pressure cascades. Through a so-

called „Flow markers“ or fog generator, fog is brought into

the airflow. The flow visualization is carried out at all critical

overcurrent locations, e.g. on door gaps, hatches and locks.

The documentation is done with the aid of photo and/or video

recordings.

problem

milieumachine

cause effect

human

material

maincause

secondarycause

method measurement

38F

FMEA (Failure Mode and Effects Analy-sis)= Failure-Mode- and Effects analysis or also named failure-

condition type- and impact analysis: FMEA is a risk analysis

procedure, which is used for the analysis of individual failures

and error sequences and error causes. The FMEA is especially

used in industries with high requirements on the product and

process reliability. FMEA is currently the most utilized method

for systematic risk analysis in the pharmaceutical industry

and can also display very complex observations. Depending

on the type of FMEA, the interaction of components of a

complex system (System FMEA), the construction of products

or construction units (Construction FMEA) or the steps of a

manufacturing- or performance process (Process-FMEA) are

observed. At the FMEA, a risk priority number ( Risk priority

number) will be determined for each single partial step. If this

exceeds a previously determined limit value, it is necessary to

take risk reducing measures.

FMECA (Failure Mode, Effects and Criti-cality Analysis)= FMECA is an extension of the FMEA by the factor „criticality“

or „extent of failure consequences”. FMEA

FormulationThe formulation of a pharmaceutical includes the preparation

with the respective components, as well as its design (dosage

form). After completing the formulation process of a product, it

is considered as bulk product.


39G

FTA Fault Tree Analysis

Functional specification sheetThe functional specification sheet consists of contractor

statements for the realization and processing of a project (e.g.

plant construction). It is the detailed description of the supplier

for the implementation strategy of the specification sheet and

should therefore include all listed obligatory requirements.

Often no separate functional specification sheet will be

created. Instead it will be replaced by a respective offer of

the contractor, provided that it is prepared in a detailed and

appropriate way

40G

Galenics=The science of drug manufacturing. This includes the design

and the technological testing of pharmaceuticals.

GAMP= Good Automated Manufacturing Practice; refers to the vali-

dation of computer aided systems.

GCP= Good Clinical Practice; valid for the area of clinical studies:

Quality requirements for the planning and implementation of

clinical studies.

GDP= Good Distribution Practice; Good Sales Practice; controlled,

safe sales channel of the pharmaceuticals from the time leaving

the manufacturer to the end consumer.

GEP= Good Engineering Practice; relevant for the area of

engineering: Good and effective planning of the facility.

GLP= Good Laboratory Practice; relevant for the laboratory sector:

=Validation of non-clinical safety tests and procedures.


41G

GMP= Good Manufacturing Practice; Good manufacturing practice

for pharmaceuticals: Entirety of national and international rules

for the production of pharmaceuticals and quality assurance,

which ensure the health of the population and protect the

consumer from dubious products.

GMP-compliant facility designA facility planning and construction, which is based on the

GMP-regulations and already has the aim for the optimization

of the future GMP-compliant operation, for example easy

accessible and cleanable machine parts (cf. hygiene design).

GSP= Good Storage Practice; relevant for the area of storage:

Storage under controlled, constant conditions (temperature,

humidity, light).

GxP= Good x Practice; Umbrella term for specified GMP-regulated

sub-areas, examples: GAMP, GCP, GEP, GLP, GDP, GSP.

42H

HACCP= Hazard Analysis of Critical Control Points; danger and/or

risk analysis of critical control and steering points. One critical

control point is hereby a step or phase in which a danger

is identified and through precise and controlled measures

eliminated or reduced to an acceptable level. HACCP is a

preventive risk analysis procedure, which is mainly used in

the food industry and can be considered as a kind of GMP

preliminary stage.

Hand disinfectionAs germs spread permanently and pass on microorganisms by

every touch, the number of germs can only be reduced through

periodic hand disinfection. For this reason, before any activity

or the resumption of an activity in a cleanroom or hygienic

zone, hands/ gloves must be disinfected. The hand disinfection

will reduce the number of germs by 5-log steps (99,999%).

HAZOP= Hazard and operability studies; Method for the systematic

identification of possible errors through brainstorming on the

basis of relevant key words (e.g. none, more, except), which are

used on relevant parameters (e.g. contamination, temperature).

Potential risks and hazards will be detected here.

HEPA-Filter= High Efficiency Particulate Air Filter: HEPA-Filter are

particular air filters with an extremely high capture efficiency.

Classification and testing of the HEPA-filter are standardized in

the DIN EN 1822 (part 1–5).


43H

Hygienic designThe term hygienic design refers to the hygiene-optimized cons-

truction and planning of components, rooms and production

facilities. The goals of the hygienic design are for example to

avoid dead spaces, free access to all areas for the purpose of

cleaning and disinfection as well as minimizing the machine

surface (avoidance of deposit areas).

Hygienic zone concept= Activity-specific arrangement of different air cleanliness-/

clean room classes. Example: Aseptic preparations; the aseptic

preparation and filling takes place in a room with the air cleanli-

ness class A. The surrounding area of A equals the cleanliness

class B. The preparation of solutions which are sterile filtered

before the filling, takes place in cleanliness class C. In the air

cleanliness class D, the handling of facility components is car-

ried out after cleaning or before the autoclaving.

44

ICH= International Conference on Harmonization of Technical

Requirements for Registration of Pharmaceuticals for Human

Use; The ICH pursues the goal of unifying the criteria for the

approval of a pharmaceutical in Europe, the USA and Japan.

Members are the European Commission, the FDA as well as

the Japanese Ministry of Health Labour and Welfare (MHLW).

Infiltrating procedure The infiltration procedure consists of precisely defined dressing

regulations for the process- or product specific work clothes

in a clean room; e.g. in order to avoid the contamination of the

outside of the clean room clothes during the dressing.

In general, when changing clothes it should be from the top to

bottom. With the entry of a clean room into a higher classified

clean room area, an additional clothes changing procedure

is necessary. At the infiltrating of employees, additional hand

hygiene measures are essential.

Information officerThe legal requirements for the information officer are compara-

ble to those that are demanded from a qualified person.

The information officer is responsible for the publication of

the scientific information about the pharmaceuticals and is

in this context responsible for the adherence of the general

prohibition of misleading. The information officer must ensure

that the labeling, package insert, prescribing information

and advertising confers with the content of the authorization

and registration. His work is therefore part of the preventive

consumer protection. The information officer can simultaneous

have the position of the expert person and the phased plan

representative.I


45

In-process controlInspections which are carried out during the ongoing

production are called in-process controls. Aim is the monitoring

and, if necessary, the adaption of processes to the given

specifications. By extension, the control of the environment and

the equipment can be considered as part of the in-process

control.

Installation qualification (IQ)The installation qualification documents the correct imple-

mentation of the previously defined requirements for the

installation and modification of the facility. The IQ is primarily

based on the compiled specifications in the DQ. The res-

pective documents are tested on its completeness and correct-

ness and, if necessary, updated and supplemented. Moreover,

with the IQ-documents a proof is provided that all equipment

parts are professionally and lawfully delivered and installed.

Classical IQ-tests are among other things the control of the

acceptance, the testing of the electronic installation and MSR-

points tests and the input/output test (I/0-test).

IPC In-process control

IPK In-process control

IQ Installation qualification I

46I

Ishikawa-Diagram/-Method Fish bone diagram/-method

ISO 14644 DIN EN ISO 14644

ISO 13485 DIN EN ISO 13485

Isolator= Safety workbench class III; spatially limited, decontaminated

element usually with air quality of the purity class ISO 5 or

higher, which is used for a continuous insulation of the

interior towards the environment (e.g. towards personnel). Two

insolator types are differentiated:

• Closed isolator systems

By sealing – during the entire working process, the

contamination from outside of the interior will be avoided. The

material flow takes place solely via aseptic locks.

• Open isolator systems

The system has openings which, however are constructed in

such a way that the contamination is excluded. This is achieved

for example through the constant overpressure in the interior.

Many isolators are operated under negative pressure for the

purpose of employee protection.

ISPE= International Society for Pharmaceutical Engineering;

ISPE is an international Non-Profit-Organization with currently

20.000 members in more than 90 countries worldwide and


47I

deals with trainings and the information exchange of employees

in the pharmaceutical industry. Members are involved in

the rulebook creation of FDA and EMA and publish various

own ISPE-guides. These ISPE- Guides are very detailed and

represent the current state of technology for the pharmaceutical

industry.

48J

Japanese pharmacopoeia (JP)The Japanese pharmacopoeia, created by the Pharmaceuticals

and Medical Devices Agency (PMDA), a sub-organization of

the Japanese Ministry of Health Labour and Welfare (MHLW),

comprises four parts:

• General determinations regarding raw materials and

preparations

• General tests and inspections

• Monographs

• General information

Every five years a completely revised version is published.

JP Japanese pharmacopoeia


49

KBE (colony-forming unit)Colony forming unit (CFU): serves the qualification of

microorganism/germs in the microbiology. For example, du-

ring a „direct contact test“ a culture medium will be applied on

a surface for a certain time (e.g. 10 sec). After the incubation of

the culture medium, the microorganism multiplies and becomes

visible as a colony (= CFU).

K

KBE on a agar plate

50L

LAF/LF Laminar (Air) Flows

Laminar (Air) FlowsLaminar Airflows are enclosures with terminal HEPA- filters, to

protect machines and work areas; mostly implemented with

FFUs (Fan Filter Units). It is a low turbulence displacement

flow (laminar flow). The air flow moves solely in one direction

and in parallel levels with a constant pace. According to Annex

1 (EU-GMP-guideline) a benchmark of 0,36–0,54 m/s should

be achieved if it concerns an aseptic production. Otherwise,

deviating paces, designed for the process, are possible (e. g. in

weighing cabins).

Life-Cycle-Approach Understanding of quality assurance, which is orientated that all

QS-measures (risk management, qualification, validation etc.)

display the entire life cycle of a facility or a process. The entire

concept must be designed for the life cycle of a process or a

product.

LIMS= laboratory information- and management system; IT-System

for the administration and processing of data which are obtai-

ned in the laboratory.

Lock conceptLock concepts consists of several rooms, consequently one

room after another, which enable a passage of persons and

material from one clean room area into a clean room area with


51L

a higher or lower purity level, without contamination one of the

areas.

LogbookA log book serves as the continuous documentation of critical

equipment. This includes general machines, facilities, devices

and in particular ventilation systems, water systems and rooms.

In the log book all validations, calibrations, maintenance

works and repairs, cleanings and sterilization as well as all

modifications, reconstruction measures and, if necessary, other

processes are noted.

Low turbulence displacement flow (TAV)TAV is the periodical and spatial directed flow profiles. They are

mainly used in pharmaceutical sterile rooms (filling) (clean room

class A).

52

Major changeMajor changes are considered as changes which require ins-

pections on the process/of a facility that influence the product

quality and/or process reliability. Examples are tchanges in the

manufacturing/production, relocation in the sense of a change

of location of the company or a change in the compilation/

process parameters.

Manufacturing authorizationWhoever produces the following requires a manufacturing

authorization according to AMG § 13:

1. Pharmaceuticals within the meaning of § 2 section 1 or

section 2 number 1,

2. Testsera or test antigens,

3. Active substances, which have human, animally or a

microbial origin or which are produced in genetic ways or

4. Other for the drug manufacturing specific substances with

a human origin

Such authorization is issued by the respective federal state

authority. In case of genetically produced pharmaceuticals

and active ingredients and other substances intended for the

pharmaceutical production with human, animally or microbial

origin or which are produced by genetic engineering etc. the

decision about the permission takes place after consultation

with the relevant supreme state authority. According to

§ 14 section 1 no 6a AMG, the holder of a manufacturing

authorization must ensure that the production and testing

takes place in accordance with the current state of science and

technology. To do this, a GMP-conform quality management

system must be operated.

M


53M

Material flowThe material flow is the coordinated sequence of the individual

production and storage steps from the raw materials to the

final products. The material flow is intended to preclude an

accidental exclusion of a quality determining production or

control step. Furthermore, mix -ups are avoided and the

compatibility with other manufacturing processes is ensured.

MatrixingMatrixing is a cleaning validation method with the aim to reduce

the overall validation scope. The approach is the equipment-

based implementation.

Media Fill TestThe Media Fill Test is a method for the validation of the aseptic

implementations of filling processes. For this process simula-

tion, the filling is carried out with culture media in order to test if

they are aseptic/sterile. Often, the media fill is conducted under

worst- case conditions.

Medical product term (according MPG)According to medicine product law § 3:

Medical devices are […] Instruments, devices, technical

devices, software, substances and preparations derived

from substances or other objects […], which are used by the

producer, due to their functions, for humans for the purposes

a. detection, prevention, monitoring, treatment or disease relief,

b. detection, monitoring, treatment, relief or compensation for

injuries or disabilities,

c. examination, replacement or modification of the anatomic

construction or of a psychologic procedure

54M

d. regulation of conception

The intended main effect in or on the the human body is not

caused neither through pharmacological or immunological

active substances, nor is achieved through metabolism,

however which mode of action can be supported by such

means.

Method validation (analytical) Proof, that an analysis method (as specified in the test instruc-

tion) provides correct and reliable results. Text and methodolo-

gy are harmonized in the ICH Q2 for EU, Japan and the USA.

Metrological Traceability Property of a measurement result or the value of a standard,

through an uninterrupted chain of comparison measurements

with specified measurement uncertainties on suitable standards

-usually base on national or international standards. Traceability

is therefore ensured by measurement results obtained through

a continuous chain of calibrations based on international or

national standards.

Calibration hierarchy Germany

National Standard

Referencestandard

Workingstandard/Factorystandard

Internalcalibrationlaboratory

Accreditedcalibra-tionlaboratory

PTB

Technicalresources


55M

Microbiological monitoring Investigation of the (clean room) contamination sources air,

media, surfaces and personnel exposed to microbial burden

e.g. KBE/m3 or KBE/25 cm2.

Minor changeMinor change is considered as a change that requires control

and which affects a unit in need of control. This includes, for

example, the replacement of a part of equipment, the change of

a cleaning agent or also the exchange of a laundry for working

clothes.

MonitoringMonitoring compliance of specified parameters e.g. in clean

rooms the control of air purity or the monitoring of the room

climate.

MPG= Medical Devices Act; The „MPG“ regulates the trade of

medical products and provides assurance, suitability and per-

formance of the medical products as well as the health and

the required protection of patients, users and third parties. The

MPG does not apply to pharmaceuticals.

56N

NOAEL= no observed adverse effect level: Highest dose of a subs-

tance without a negatively observed effect.

NOEL= no observed effect level: Highest dose of a substance without

observable or critical effect.

Official calibrationThe official calibration is the verification of the compliance of

the calibration error limits. Official calibrations are solely carried

out by the (Landeseichamt) National Calibration Office. The

official calibration can only be carried out for the measuring

instruments and measuring standards which have a type

approval. In contrast to the normal calibration, the test object

deviation compared with the reference will not be determined at

the official calibration. Obligatory official calibration is primarily

compulsory for those devices which serve the consumer

protection and legal certainty (e.g. water meter, counter scales

or traffic radar equipment).

OOS Out-of-specification

OOT Out-of-Trend


57O

Operational qualification (OQ)= Documented proof, that facilities, installations and equipment

are properly functioning as installed or modified within the

provided operating areas. The OQ documents, that all facilities,

including all associated equipment parts, can be operated

according to the specifications. Additionally, the controlling

of the operating parameters must confer with the previously

defined definitions.s.

OQ Operational qualification

Out-of-Specification (OOS)A result which does not meet the specification

Out-of-Trend (OOT)= A result which is still within the specifications, but due to the

fact tha it does not correspond to the trend observed, over a

longer period of time, it shows a certain abnormality.

58

ParenteralParenteral means „bypassing the digestive tract“. The Euro-

pean Pharmacopeia therefore defines parenteral as „sterile

preperations, intended for the injection, infusion or implantation

in the human or animal body“. The enteral resorption and

therefore the unspecified immune system (saliva, gastro-

intestinal tract) are bypassed. Hence, the impurities in

parenteral are associated with high health risks.s.

Particle monitoringThe particle monitoring serves the monitoring of particulate air

purity. Too high a particle load can lead to an excessive con-

tamination of the respective product with particles but also with

microbiologic organisms.

PEI= Paul Ehrlich-Institut: Federal Institute for Vaccines and Bio-

medical Pharmaceuticals belongs to the Federal Ministry for

Health. It is responsible for the admission of clinical tests as

well as for the approval of certain groups of pharmaceuticals

(biomedical pharmaceuticals: vaccines for human and animal,

antibodies comprising pharmaceuticals, allergens for therapy

and diagnostic, blood and blood products).

Performance qualification (PQ)Proof of the permanent specification conformity of a facility in

operating status. Hereby, the interaction and/or compilation of

all facility components will be checked and the performance

limits tested. Thereby, the differentiation of performance

qualification and process validation is not always clear. The

performance qualification can be delimited to this effect that a


P

59P

product related proof of the effectivity and reproducibility of the

device/facility should be provided.

Personnel flowA well thought-out and coordinated personnel flow is a

requirement according to GMP-compliant production. It is part

of the implementation of the hygienic zone concept and thus

prevents the cross-contamination. Additionally, it serves the

product and personnel protection. The term “personnel flow”

comprises the requirements for the access to pharmaceutical

areas only via locks and changing rooms, only to employ

trained personnel and to determine at all times how many

people are required for operating, monitoring and maintaining

the facilities.

Ph. Eur. EP

PharmacologyPharmacology is the science of interactions between drug sub-

stances and living beings..

Pharmaceutical excipient Pharmaceutical excipients are substances, which are part of

a pharmaceutical; however they are not active substances

themselves. They are added in order to influence, for example,

the pharmaceutical design or its release into the organism.

60

PIC/S= Pharmaceutical Inspection Cooperation Scheme; Union of

many member countries from all over the world, which has set

itself the goal of further development of GMP together and to

harmonize the resulting regulations.

Furthermore, in order to avoid multiple inspections, the

mutual recognition of inspections should be improved and the

movement of pharmaceutical should be simplified by reducing

trade barriers. The PIC/S provides PIC/S guides and PIC/S-

recommendations.

Postal AuditA postal audit is carried out without actually visiting the

company to be audited. Instead, a more comprehensive

questionnaire will be sent by the auditor to the supplier, who

fills it independently with the respective information and

relevant references. A verification of this information can take

place at a later time during an appointment on location.

PPQ Process Performance Qualification

PQ Performance Qualification

PQR Product Quality Review


P

61P

Primary packaging materialThe primary packaging material is the part of the packaging,

which surrounds the product directly. This means there is a

direct contact. Therefore, primary packaging is often made of

aluminum, glass or plastic as those materials are inert or hardly

cause any abrasion.

ProcessEach defined organizational procedure or step of a sequence

cascade which is connected with procurement, the production,

the handling and the distribution of pharmaceuticals.

Processes are clearly defined and unambiguous in terms of

responsibilities.

Process capabilityProcess capability means that a process is controllable,

stable and compliant with the specifications. This is then

given, if the critical parameters are subject to a purely random

diversification (normal distribution) and the respective values

are within the upper or lower interference tolerances/tolerance

limits.

Process capability study =Statistical method to compare the process information with

the permissible tolerances to derive a statement about the

process capability.

Process Performance Qualification (PPQ)The PPQ is part of the new Life-Cycle-Approach and replaces =

Primary packaging material of pharmaceuticals

62P

Statistical method to compare the process information with the

permissible tolerances to derive a statement about the process

capability.

Process validation (PV)Process validation is the documented proof that the process

within certain parameters can produce a new medical product

in an effective and reproducible way which fulfils in advance

defined specifications and quality attributes. Hereby, it shall be

proved, that even critical process steps, which are difficult to

control, follow a predefined procedure and the entire process

is completely reproducible – for a consistent quality and

specification compliant. The scope of the PV is determined by

the risk management.

Production manager The production manager is responsible for ensuring that the

correct production, the validation of the production procedure

and the training of the personnel for the area production (§

12 AMWHV). The production manager must have sufficient

specialized qualification. A respective proof of qualification

and reliability (Certificate of good conduct) must be available

to the supervisory authority. The production manager must be

independent of the Quality control manager

Product Quality Review (PQR)= Periodic product quality review; regular quality reviews of

medical products, with the aim to confirm the consistency

of the current process and appropriateness of the current

specifications for the source materials as well as for the final

products in order to emphasize trends and to identify product


63P

and process improvements. The PQR should be conducted

annually under consideration of previous review results.

Product specificationA product specification should contain all information which is

necessary to prepare the exact written instructions for the

process, packaging, quality control, batch release and

shipment of a product.

Prospective Qualification Qualification of a new system before start of the production.

Prospective validationValidation of production start/distribution of a pharmaceutical.

PV (Process Validation) Process validation

Pyrogenicity/PyrogensPyrogens are substances, which can cause fever at parenteral

administration. This can be molecular connections like „Lipopo-

lysaccharide (Bacterias-Endotoxine; decomposition products of

a bacteria) or also particle, e.g. abrasion of injection bottle and

microscopic plastic parts.

Pressure cascadeThe pressure difference between different rooms and working

areas is called pressure cascade. In clean room areas there

64

is, in relation to the environment with lower air purity, an

overpressure in order to control the overflow in one direction

and to minimize the intrusion of impurities (= Clean-Room

Principle). In contrast to this, there are also working areas

in the pharmacy, for example the handling of cytostatics or

viruses in which negative pressure is present in relation to their

environment (=Clean Corridor-Principle). In this way, a leakage

of dangerous substances can be prevented.

P


65Q

QA Quality assurance

QbD Quality by Design

QP Qualified Person

QualificationQualification is the documented proof that a device/plant is

suitable for the intended purpose, fulfill the specified functions

or to produce products and that these are in compliance with

the regulations and norms (= GMP-compliant).

Qualification report Qualification report

Qualification master planThe qualification master plan is a higher-level document,

which describes the qualification strategy and the organization

structure in general. The individual qualification objects are

defined and the necessary qualification steps, with type and

scope of the qualification activities, are described. Thus, it

serves as an overview of devices and plants in relation to the

time planning and defines the corresponding responsibilities for

the completion of the qualification activities.

66Q

Qualification plan=Contents of the qualification plan are the aim, object and

scope of the qualification, the nomination of the persons and

responsibilities in the qualification team and the description of

the qualification strategy. The most important components are

the detailed designation of the individual tests, the description

of their implementation as well as the respective acceptance

cri- terias (also called test plans; can be excluded from the

qualification plan if necessary). Furthermore, the plan should

contain the description of the qualification object and if

applicable, the description of the process, the named critical

system parameter and a document list. The document must be

released at final.

Qualification reportThe qualification report always is always at the end of a

qualification. Here, all results are summarized. Changes in

the test plans as well as any deviations must be documented

accordingly. It must be taken into account that at this point

all critical deviations have to be corrected. Only non-critical

deviations can be accepted upon adequate justification.

Additionally, the report must include the maintenance

programs, recalibration data, operating instructions, SOPs and

the qualification status of the plant. The qualification report is

required for the release to use the facility or for the validation.

Quality control managerThe area of responsibility of the quality control manager

includes, amongst other things, the testing of the source

materials, intermediate and final products, the authorization

of specifications, the validation of the test procedure and the

assurance of staff trainings in his area.


67Q

The legal requirements for the quality control manager are the

required reliability for the performance of tasks and activities as

well as the familiarity with the products and procedures.

Qualified Person (QP)The qualified person must provide proof of the required expert

knowledge according to § 15 AMG (approbated pharmacist

or medical/ scientific studies with additional qualification).

Additional requirements are the respective reliability to carry

out tasks and activities as well as sufficient familiarity with

the products and procedures (§ 16 AMWHV). The qualified

person is responsible for the compliance of the respective

pharmaceutical regulations regarding production, testing and

release before placing the product on the market (§ 19 AMG).

The scope of duties of the qualified person includes:

• The release of batches for placing on the market

• The assurance of reserve samples

• The control whether a quality management system is

maintained in the company

• The responsibility for the gapless documentation to proof

the compliance with all regulations.

Quality assurance (QS/QA) Quality assurance is a wide-ranging concept, which covers all

aspects that either individual or collectively leads the quality of

the product. It represents the entirety of all provided measures,

which are taken to ensure that medical products have the

required quality standards for the intended use.

Quality by Design (QbD)Quality by Design is a holistic, risk-based approach in the

68Q

development and production of pharmaceuticals which aim to

develop a process in which critical, quality relevant

steps are identified and their influence will be measured and

determined within a specified „design space“ (development

framework).

Quality management handbookThe quality management handbook is a higher-level and

binding document, which represents the quality politic and

guidelines of a company. As an essential element for the long-

term implementation of the quality management system it

comprises the description of the organizational and operational

structure and refers to the respective process instructions,

standards and regulations.

Quality risk management (QRM) Quality risk management is the systematic process for the

assessment, control, communication and review of risks for the

quality of the medical products throughout the entire product

life cycle. The quality risk assessment should, according to

ICH Q9, be based on scientific findings and always used

for the purpose of consumer protection. For this purpose, a

comprehensive knowledge of the process as well as clearly

defined framework conditions is necessary. Parts of the quality

risk management are the risk control, the risk assessment

as well as the risk communication (cf. risk evaluation, risk

communication, risk controlling).


69R

RABS Restricted Access Barrier System

Recovery TestMeasurement of the time required for a turbulent clean room,

in order to reduce the particle concentration/contamination by

a specific factor. During the Recovery Test 1:1000 the recovery

time (period) is determined in cleanrooms, which is required for

the depletion of the initial concentration of particles to 1%.

ReleaseThe release can only take place through a qualified person

according § 14 AMG and is the last step before placing the

batch on the market. The release only happens under the

precondition that the production and test procedure is made

according to the regulations and specifications and it is docu-

mented correctly.

RemedyRemedy is a common term for pharmaceuticals and medicinal

products in Switzerland (HMG; Art. 2a).

ReproducibilityWith reproducibility, the consistent product quality and

constant production process is meant. A process is only then

GMP-conform when the result is reproducible. Only like this it

is ensured that, for example in the case of at random sample

examination of a batch, the resultant cognitions also apply to

all the individual products of this charge.

70RRABS(picture: Franz Ziel GmbH)

Requalification=Qualification after modifications or recurring, cyclical review of

critical parameters in order to guarantee that the facility/device

remains in a qualified condition.

Reserve samplesA reserve sample is a sample e.g. of a fully packed unit from

a finished product batch, which is stored for identification

purposes.

Restricted Access Barrier System (RABS)RABS is a concept for the encapsulation of a machine, often

used in aseptic production or as a personal protection for

highly active substances. As a mixture of conventional clean

room technology and isolator technology, an active intervention

is only possible with gloves; the process itself is hereby separa-

ted from the user.

Retoure/return=Returning of a medical product to the manufacturer or

distributor independent whether there is a quality defect or not

Retrospective qualificationA retrospective qualification is considered as a qualification of

systems that have already been implemented or a qualification

based on historical data. A retrospective qualification can

only take place if sufficient data is available for a subsequent

evaluation and monitoring of the critical parameters. From the

GMP point of view, a retrospective qualification is no longer


71R

accepted.

Revalidation=A recurring, cyclic review or repetition of a validation to ensure

that changes, made in the process or equipment, are done in

accordance with certain change control procedures and which

do not affect the process properties and the product quality.

Risk analysis (RA)The risk analysis is part of the risk assessment. In the risk

analysis, the assessment or the weighting of the identified risk/

possible error takes place, determined in the course of the risk

assessment. In the GMP-regulated area, the risk analysis is

often carried out with the FMEA method ( FMEA).

Risk assessmentAim of the risk analysis is the detection of dangers as well as

the analysis and assessment of the risks arising from these

dangers. For this purpose, the problem and questioning – after

the risk –and within the framework of the risk assessment must

be clearly defined. Firstly, possible dangers are identified (risk

identification), whereupon the risk analysis takes place (How

high is the probability of occurrence and the discovery of the

error?). Finally, the risk assessment is carried out (what are the

consequences? How big is the extent?)

Risk based qualification system The aim of the risk-based qualification system is the assurance

of the GMP conformity throughout the entire life cycle of a

facility/ device. Hereby, the risk analysis, i.e. the determination

72R

of the influencing factors, that influence the product quality

negatively, is the fundament for the qualification measures

and for the determination of their extent. The effort and the

documentation of the qualification is based on the severity and

significance of the risks.

Risk check/reviewDue to the fact that the measures taken in the course

of the quality risk management, risk assessments are

always only a snapshot and therefore they must be

checked at regular intervals. Thereby, the actuality and

suitability of the risk assessment are ensured throughout

the entire life cycle and changes or new error sources

are considered and integrated into the risk management.

Risk communicationThe gained knowledge from the risk analysis process should be

communicated throughout the entire quality risk management

process; however at the latest at the conclusions, all decision-

makers and concerned parties should be informed, as the

recognition of a risk/danger only contributes to the quality

assurance purpose, if all involved process participants are

informed about these and the risks can be avoided specifically

though this.

Risk controllingAim of the risk control is to reduce risks to an acceptable level.

Appropriate measures to reduce a risk are determined (risk

reduction) or an acceptable risk is classified as uncritical (Risk

acceptance) ( Risk reduction).


73R

Risk management Quality risk management (QRM)

Risk priority number (RPZ)The formula for the determination of the risk priority number

(RPZ) is: RPZ = A x B (or S) x E

The individual parameters are defined as follows: A =

Probability of occurrence

B/S = Importance/Significance of error E = Probability of detec-

tion

Risk reductionThe risk reduction is part of the risk controlling and includes

measures to reduce the extent, the probability of an error or the

improvement, respectively the increase of the recognizability

of an error. The risk assessment should be re-estimated after

the implementation of the respective measures and possible

changes should be evaluated.

RLT-facility/air conditioning system= Ventilation and air-conditioning system; facility with

mechanical air transport

to fulfillment an air conditioning task.

RLT (HVAC)-systems are furthermore divided in systems with

or without air conditioning function. RLT (HVAC) systems with

air conditioning work with fresh air, whilst RLT (HVAC) systems

without air conditioning function work without outside air.

74R

RobustnessRobustness describes the ability of a system/ process that

does not react on external changes.

Risk monitoring Risk assessment


75S

SanitizationThe sanitization is applied for water systems. During the hot

sanitization, the number of bacterial counts is reduced to the

greatest possible extent or completely as a result of hot water

or steam (80–85 °C). For the cold sanitization, the sanitization

is carried out with ozone or for example sodium hydroxide

solution.

Safety workbench (SWB)Is often utilized in microbiological or analytical laboratories and

is a „room in room“ concept for the protection of employees

and environment as well as of the product during the

implementation of critical processes.

Class I: SWB with work access opening; avoidance of airborne

suspended matter contamination by the inward directed air

stream and filtration of the exhaust air

Class II: SWB with work access opening; Reduction of the

cross-/ product contamination risk through filtered circulating

air and filtration of the exhaust air

Class III: SWB (e.g. insulator) with a fully closed work area

(physical barrier). An intervention in the working area is only

possible with e.g. gloves.

Secondary contaminationSecondary contamination is considered as a contamination of

the product after the production e.g. through improper samp-

ling, packaging or storing.

Secondary packaging materialsThe secondary packaging material includes the primary

packaging and has, in contrast to this no direct contact with

SWB class III: Isolator (picture: Franz Ziel GmbH)

76S

the product.

Self-inspectionThe self-inspection is a critical consideration and inspection

of own processes. The head of production and quality have

a fundamental role for the successful implementation. This

internal quality audit is mandatory in the AMWHV and in the

EU-GMP-guideline.

Shell modelThe shell model means that in a clean room an over pressure

of 10-15 Pa should be maintained towards adjoining areas

with lower air purity. Furthermore, the personnel flow should be

designed in such a way that a passage through different zones

is delayed. Doors and locks should not be directly behind each

other in a row, but should rather be spatially shifted in order to

avoid a rapid passage through the different clean room zones.

Sinner circleThe Sinner circle describes the four parameters, which function

as influencing factors of a cleaning process. The presentation

in a circle diagram points out the combinability of the different

influencing factors. The success of a cleaning is just as

dependent on the appropriate chemical and mechanical effect

as on the duration of the effect and the existing temperature.

An ideal combination of these factors is prerequisite

for a GMP-appropriate and economical cleaning process.

SIP= Sterilization in Place = Sterilization in a closed system:

TIME

MECH

ANICS TEMPERATUR

E

Sinner circle


CH

EM

IESTRY

77S

SIP is a fully automated sterilization process using superheated

steam or a chemical process; this means all product-contacting

surfaces of a plant can be sterilized without major disassembly.

An example for the application of SIP is pharmaceutical

production plants (often in combination with CIP).

Site Acceptance Test (SAT)The acceptance of a device/a plant after delivery is called SAT.

All requirements, listed in the specification book and functional

specifications are being verified. The Site Acceptance Test

serves the determination of the actual state („as built“).

Subsequent changes must be taken into account in the

technical documentation of the manufacturer.

Site Master File (SMF)= Company description; Site Master File (SMF) is a self-deve-

loped company description for external administrative bodies

and customers. This should include general information about

the company, the quality management system, the products,

self-inspection and about the relevant systems. Requirements

on the SMF are explained in the GMP- guideline part III.

SOP (Standard Operating Procedure)= Standard-operating procedure; SOPs are documents, that

contain information and instructions in an organizational, admi-

nistrative and technical way to carry out regularly recurring

working procedures. Primarily, they are addressed towards the

employees of a company and should ensure that quality relevant

tasks are carried out correctly by every employee right away.

78S

Specialist responsible for technical matters In Switzerland, the regulations for the direct supervision of the

company responsible person who ensures that the guidelines

Good Manufacturing Practice (GMP) is observed and who

decides whether a batch is market released or not. The term

“Qualified Person” is used synonymously in the EU area. (Qua-

lified Person)

SpecificationThe specification is the total scope of testing inclusive the test

instruction, which is determined for the specific product and

which is basically based on the state of science and technology

(e.g. pharmacopoeia monography, pharmaceutical testing

guidelines). This includes the determination of acceptance

criteria as well as the specific requirements for storing.

Specification sheetThe specification sheet documents in the scope of the

qualification the requirements of the customer regarding the

scope of supply and delivery. These technical and regulatory

requirements are defined by the respective specialist

departments (Engineering and QS/QA) in cooperation with the

operator. Contents of the specifications are e.g.:

• Purpose of the device/facility

• Technical key data, like for example the dimensioning

• Construction details (Materials, product-contacting surfaces)

• The state of the control system

• Warranty services/service requirements for the supplier

• Requirements for material and surfaces

• Information to customer service (availability, reaction time

etc.)

• Requirements for GMP-compliance


79S

Step-by-step plan agentThe scope of tasks of the step-by-step plan agent comprises:

• The collection of reports regarding drug risks, its

evaluation and the coordination of necessary measures

• The monitoring of clinical tests in regard to drug risks

• The indication of serious side effects, interactions or abuse

• The notification of supervisory authorities in case of unusual

limits in the distribution (delivery stop, callback).

The step-by-step plan agent must have the appropriate

expertise like a university degree and at least two years of work

experience. In principle, he should be independent of sales and

distribution units; however, it is possible to work as an expert at

the same time (§ 63a AMG).

SterilitySterility is the complete absence of living microorganism,

including its resting stage (such as spores).

Steril filtrationDuring the germ removal with sterile filtration, the

microorganisms are isolated through filtration as only small

molecules can pass the membrane. It is the most important

procedure in the pharmaceutical, cosmetic and in the food

industry. The sterile filtration is often used for heat-sensitive

solutions, for example serum containing tissue culture solutions

application.

SterilizationDuring the sterilization, all microorganisms in the reproduction

and permanent stare are inactivated or killed respectively

viruses are inactivated. The sterilization in the GMP area

80S

is conducted in a physical way by a thermal process (heat

exposure) or by chemical procedure (e.g. through ethylene

oxide). Often the sterilization is utilized through high- energy

radiation (e.g. gamma radiation).

Stress testA stress test serves the inspection of the endurance of a

product respectively of a process to withstand extreme

conditions (high temperatures, humidity and others). This

includes in the case of pharmaceuticals for example the light

stability test.

SwissmedicSwissmedic is the Swiss licensing- and control authority for

remedies. Basis for the Swissmedic’s activity is the remedy

law. As a public-law institution of the Swiss Confederation

with its headquarters in Bern, the Swiss agency for remedy is

independent in its organization and management. The various

tasks are based on the legal order. The core competences of

Swissmedic include, among other things:

• Admission of pharmaceuticals

• Operating licenses for the production and wholesale trade as

well as inspections

• Market surveillance of pharmaceuticals and medical products

• Clinical studies and the laboratory analytical testing of the

drug quality

• National and international cooperation

Supplier audits=Auditing of a company/an organization (supplier) by a

customer.


81T

TAMC (Total Aerobic Microbial Count)= Total number of aerobic microorganisms

Target specification sheetThe target specification sheet consists of contractor statements

for the realization and processing of a project (e.g. plant con-

struction). It is the detailed description of the supplier for the

implementation strategy of the specification sheet and should

therefore include all listed obligatory requirements. Often no

separate specification sheet will be created. Instead it will be

replaced by a respective offer of the contractor, provided that it

is prepared in a detailed and appropriate way

Test planA test plan is a document that describes the objective(s),

design, methodology, statistical considerations as well as the

organization of a test prospectively.

Therapeutic Products Act/ Heilmittelgesetz (HMG)Federal law about pharmaceuticals and medicinal products

(Swiss)

Therapeutic Products Agency (Canto-nal in Switzerland)The current tasks of the Swiss supervisory authority are derived

from the following laws:

• Federal law about pharmaceuticals and medicinal products

• Federal law about narcotics and psychotropic substances

• Federal law about the university medical profession

82T

• Health law (Canton of Zürich)

In these decrees, the responsibilities of the involved federal and

cantonal supervisory authorities in the areas of market approval

and market monitoring of remedies are determined. The

cantons have transferred certain control tasks to their regional

specialist agencies. The cantonal therapeutic products agency

is one of these competence centers. The former intercantonal

control authority for remedies (IKS) was incorporated into the

Swiss agency for therapeutic products Swissmedic on 1st of

January 2002.

Third-Party Audits=Audit through a third party that is not directly involved in

the manufacturing of a product (neither manufacturer nor

subcontractor). For example, according to GMP-regulations a

pharmaceutical manufacturer is obliged to audit his suppliers of

active substances in order to ensure that the active substances

have been produced according to the specifications of good

manufacturing praxis.

These mandatory audits can be carried out by the

pharmaceutical manufacturer or also by an independent

qualified third party.

TOC-measurement= Total Organic Carbon-measurement; the TOC value is

the amount of the total organic carbon, which is, for

example, contained in a water sample. The measurement is

based on the determination of the amount of CO2, which is

set free through oxidation of the carbon compounds contained

in the water. A TOC-measurement is often carried out in

connection with a cleaning validation in order to determine the

water quality.


83T

TraceabilityTraceability refers to the ability to the possibility of tracing

all the steps and processes or a product, batch or also to

understand a measure retrospectively.

Tracematrix/Traceability MatrixThe tracematrix serves to display the connections between

user requirements, technical requirements, specifications

and test cases. It provides evidence of the complete

implementation of the transfer of user requirements about the

technical requirements in technical specifications to which

the project leader is obliged. Furthermore, the linkage of the

specification sheet and risk analysis requirements with the

qualification tests can take place.

Track & Trace=The individual marking of each product as well as the

registration of every movement and every transport step a

product goes through from the production to the end consumer

is understood as track and trace. In the pharmaceutical

industry this procedure can be used to combat counterfeit

products, as it possible to trace the origin of the product and

at the sale of each medicinal product whether it concerns an

original or a copy.

Turbulent currentsTemporally and spatially undirected flow profiles are

called undirected turbulent flows. They are used in most

pharmaceutical clean rooms

(Class B–D) as they are very suitable to remove particulate

contaminations and heat loads. Turbulent flows are generated,

84

for example, with the help of ceiling swirl diffuser.

TYMC (Total Yeasts/Moulds Count)= Total amount of yeasts and moulds


T

85

URS (User Requirement Specification)= User requirements; in the URS, the requirements for the

device/ system to be produced are described from operator’s

point of view. The URS forms, together with the technical and

regulative GMP requirements on the plant, the specification

sheet.

USP= United States Pharmacopeia; pharmacopoeia of the USA.

The USP is the collection of official standards which are valid

for medical products and pharmaceutical substances within

the USA. It is published by the United States Pharmacopeial

Convention (also called USP).

U

86

ValidationA validation is providing a documented evidence, which shows

with high certainty, that a product is produced by a specific

process or by a standard operating procedure to meet the

predetermined specifications and quality features according

to AMWHV § 2–16. The validation thus verify that procedures,

processes, facilities, devices, materials and systems lead to

the expected results in accordance with the principles of good

manufacturing process. The validation ensures and docu-

ments the most important characteristics of a process: repro-

ducibility and robustness.

Validation reportThe validation report is used to document the validation. It

contains the production protocol including the in-process

controls results, the validation test results including identified

deviations as well as the evaluation and assessment of the

validation and the respective conclusions for the routine

production, change control and, if necessary, the revalidation.

Validation master plan (VMP)The validation master plan (VMP) defines the validation strate-

gy and philosophy of a company and summarizes terms,

intentions, responsibilities and procedures in regard to the

validation. According to the EU-GMP-guideline Annex 15 „all

validation activities should be planned. The key elements of

a validation program should be defined and documented

clearly in a validation master plan (VMP) or similar documents “.

The qualification master plan can be part of the VMP.V


87V

Validation matrixA validation matrix is used to present the relational connections

between the individual validation components (products,

processes, systems) and their associated actions (validation-/

qualification tasks). In order to keep the overview of complex

validations, the corresponding responsibilities and priorities

should be noted additionally.

Validation planThe validation plan is created before the implementation of

the validation and contains information about the product

(specifications, analytical methods) and about the process

(process description incl. flow chart, RA) as well as about the

rooms and facilities (assignment of rooms, hygiene status,

calibration status) and about the process validation (tests,

sampling, analytical methods, acceptance criteria, time plan,

responsibilities).

VDI 2083VDI 2083 is the guideline of the Association of Germany

Engineers (Verein Deutscher Ingenieure ) on the subject clean

room technology. In the sheets 1 to 16, the guidelines about

different sub-areas, such as particle purity classes of the air,

measurement technology in clean room air, cleanliness of

process media etc. are listed.

VAV: Agreement for the delimitation of responsibility The VAV regulates the interfaces, the tasks and responsibilities

completely and clearly between all involved parties in the

production, handling and distribution of a pharmaceutical.

88V

It is the basis of a legal secured cooperation, which, among

other things, guarantees that all requirements for the quality

assurance of a pharmaceutical are fulfilled.

V-ModellIn the so-called V-Modell, all activities and documents, which

have a qualification and validation, are displayed in a logical

order. Furthermore, it shows the direct references between the

requirements documents (URS, specification-, requirement

sheet) and the appropriate qualification documentation (PQ,

OQ, IQ).

Userrequirements(URS)

Riskanalysis

Realization/Installation

Specificationsheet

Designqualification(DQ)

Calibration

Operatingqualification(OQ)

Functionalspecification

FATSAT

Installationqualification(IQ)

Performancequalification(PQ)


89W

Warning limitThe warning limit is a defined limit value, which enables an

early warning of a possible deviation of regular operating pa-

rameters. This does not necessarily have to be a correction

measure, however requires a review of the cause.

Warning LetterA warning letter is sent by the FDA to a pharmaceutical

company, when critical deficiencies were found during a

previous inspection (or an audit) and these have not been

rectified. The team of inspectors lists the deficiencies in a

483-form. The company is granted a deadline in which time

the defects have to be rectified; otherwise the company is

threatened with a refusal of admission or an import ban. A

warning letter will be published by the FDA on its website, so

that all grievances of the respective company can be noticed

by the public.

WHO= World Health Organization; The WHO is the superordinate

instance of the United Nations in the matter of international

health care. It currently has 194 member states. The WHO

agenda has six central points:

• Two health goals: Promoting the development and the health

security;

• Two strategic needs: Strengthening the health systems and

utilization of research results, -data and -realization;

• Two operative approaches: Expansion of partnerships and

improvement of performances.

90

WIP= Washing In Place; automatized cleaning process within

a plant, which differentiates from CIP as WIP requires

additional manual cleaning steps, for example the cleaning

of individual plant components. (cf. CIP)

Worst-Case-SzenarioThe worst-case scenario describes the most critical state

that could possibly occur. This means that for example

the process parameter reaches their upper or lower limit

values and thereby an occurrence of a process- or product

failure is much more likely.

W


91Z

ZLG= Central Authority of Federal States for Health Protection with

regard to medicinal products and medical devices (Zentralstelle

der Länder für Gesundheitsschutz bei Arzneimitteln und

Medizinprodukten). As the coordination body of the federal

states in the human- and veterinary drug area, the ZLG is

responsible for the maintenance and improvement of the quality

and safety of pharmaceutical and medical devices. Through the

unification of the inspection standards within Germany, which is

initiated by the ZLG, Germany is, despite the federal structures

in the healthcare system, presented as a closed unit towards

Europe.

92

Germany:

• Law on the movement of medicinal products (Arzneimittelgesetz– AMG/

Medicines Law)

• Regulation about the use of good manufacturing praxis for the production

of pharmaceuticals and active substances and about the use of the good

professional practice when producing products with human origin Ordinance

on the Manufacture of Medicinal Products an Active Pharmaceutical

Ingredients – AMWHV( Arzneimittel- und Wirkstoffherstellungsverordnung)

• Aide mémoire 07121105 the central authority of the countries for health

protection for pharmaceuticals and medical products: Inspection of

qualification and validation in pharmaceutical production and quality control

Europe:

• EG-guideline of a good manufacturing Practice (EU-GMP-guideline part I, II,

III; annexes attachments 1-19), incl. additional guidelines

• Guidelines for the good distribution praxis of human medicine.

(GDP-guideline)

USA:

• 21 CFR 210 Current Good Manufacturing Practice in Manufacturing,

Processing, Packing, or Holding of Drugs; General

• 21 CFR 211 Current Good Manufacturing Practice for Finished

Pharmaceuticals

• 21 CFR 11 Electronic Records; Electronic Signatures

• FDA Guidance for Industry Process Validation: General Principles and

Practices, January 2011

• FDA Guidance for Industry Sterile Drug Products Produced by Aseptic

Processing – Current Good Manufacturing Practice

Others/Standards:

• DIN EN ISO 14644 clean room and related clean room areas

• DIN EN ISO/IEC 17025 Quality management and general requirements on

the competence of test- and calibration laboratories

GxP-Regulations and Guidelines

GxP-Regulations und Guidelines

93

GxP-Regulations and Guidelines

For further information, please visit our homepage:

www.testotis.com

We would be pleased to send you further information about our services,

seminars or other topics regarding qualification, validation and calibration.

Additional Information

http://www.testotis.com

94

contact

Our contact details:

Contact

TestoIndustrialServicesGmbHGewerbestraße379199Kirchzarten GERMANY

Phone: +49766190901-8000Fax: +49766190901-8010E-Mail: [email protected]

TestoIndustrialServicesGmbHGeblergasse941170Wien AUSTRIA

Phone: +43148626110Fax: +4314861142E-Mail: [email protected]

TestoIndustrialServicesGmbHPILaBailetaC/B,nº5ES-08348Cabrils(Barcelona) SPAIN


TestoIndustrialServicesGmbHZoned’activitésEurozone3rueJulesVerneF-57600Forbach FRANCE


TestoIndustrialServicesAGGewerbestrasse12a8132Egg SWITZERLAND

Phone: +41432771030Fax: +41432771031E-Mail: [email protected]

95

www.testotis.com

www.testotis.ch

Testo Industrial Services AGGewerbestrasse 12a8132 Egg SWITZERLAND

Fon +41 43 277 1030Fax +41 43 277 1031E-Mail [email protected]

www.testotis.at

Testo Industrial Services GmbHGeblergasse 941170 WienAUSTRIA

Fon +43 1 486 26 11 0Fax +43 1 486 11 42E-Mail [email protected]

www.testotis.com

Testo Industrial Services GmbHGewerbestraße 379199 KirchzartenGERMANY

Fon +49 7661 90901-8000Fax +49 7661 90901-8010E-Mail [email protected]

0980

.422

3/F/

11.2

018

Here you will find our fibula range online:

Documents

The GxP-Lexicon – Definitions around the topics GxP and ......16 Bioburden 16 BMG 16 BP (British Pharmacopoeia) 16 Bracketing 16 British pharmacopeia (BP) ... 38 FMEA (Failure Mode