The Gxp Dictionary 1St Edition

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The GxP Dictionary 1st edition

Definitions relating to GxP and Quality Assurance Note: Some of the information contained in this GxP Dictionary does not apply equally to all countries. Depending on the respective local legislation, other definitions may apply to certain terms and topics. The sections affected are not separately identified.

2 Foreword

Efficacy, identity and purity are qual- The complex requirements of the ity attributes, which are required of “GMP-compliance” generate a variety products from the GMP-regulated of specific concepts and abbreviations. environment. The term “Good Manu- facturing Practice” sums up the quality This GxP-Dictionary explains the assurance requirements from nation- majority of terms relating to GxP, al and international regulations and qualification, validation and quality laws. Other GxP forms have now been assurance. It is intended as a compact developed, whose scope also expands reference guide and aid for all those to adjacent sectors such as medical involved in GxP, and does not purport devices and life sciences. to be complete.

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3 GxP Dictionary Contents

Contents

10 Terms and Definitions C 16 CAPA 0-9 16 Calibration 10 21 CFR 210/211 16 Capacity Test 10 483 16 CEP (certificate of suitability of monographs of the European A pharmacopoeia) 11 Active Pharmaceutical 17 CFR Ingredient (API) 17 CFU 11 Accompanying Validation 17 cGMP 11 Action Limits 17 Challenge Test 11 ADI (Acceptable Daily Intake) 18 Change Control 11 Airlock Concept 18 Clean Corridor Principle 12 Annex 19 Cleanroom Principle 12 Annual Product Review (APR) 19 Cleaning Validation 12 API 19 Cleanroom 12 APR 20 Cleanroom Classes 13 Audit 21 Compliance 13 Audit Trail 21 Computer System/ 13 Authorization Software Validation (CSV) 21 Computer Validation B 21 Conformity 14 Batch Record Review 21 Concurrent Validation 14 Batch 21 Containment 15 Batch Documentation 21 Contamination 15 Bulk Ware 22 Continued Process Verification (CPV) 15 Biological Safety Cabinet (BSC) 22 Continuos Validation 22 Corrective Action/Preventive Action (CAPA) 22 Culture Media Filling 22 CSV

4 D F 23 Data Review 28 Factory Acceptance Test (FAT) 23 Disaster Recovery 28 Fault Tree Analysis 23 Design Qualification (DQ) 29 FDA 24 Deviation 29 FDA Guidance for Industry – 24 Deviation Management Process Validation 24 DMS 29 FFDCA 24 Document Management System 30 Fishbone Diagram/Method (DMS) 31 FMEA (Failure Mode and 24 DQ Effects Analysis) 31 FMECA (Failure Mode, Effects E and Criticality Analysis) 25 EDMF 32 Formulation 25 eDMS 32 FTA 25 EC Directive 32 Functional Specification 25 EC Regulation 26 EMA/EMEA G 26 EMA Guideline 33 GAMP 26 EP 33 GCP 26 ETA 33 GDP 27 EU GMP Guidelines 33 GEP 27 European Pharmacopoeia 33 GLP 27 Event Tree Analysis 34 GMP 34 GMP-Compliant Plant Design 34 GSP 34 GxP

5 GxP Dictionary Contents

H M 35 Head of Production 42 Major Change 35 Head of Quality Control 42 Material Flow 42 Matrixing 42 Method Validation (analytical) I 43 Metrological Traceability 36 ICH 43 Minor Change 36 Information Officer 43 Monitoring 37 In-Process Control 37 Installation Qualification (IQ) 38 IPC N 38 IQ 44 NOAEL 38 Ishikawa Diagram/Method 44 NOEL 38 ISO 13485 39 ISO 14644 40 ISPE O 45 Official Calibration 45 OOS L 45 OOT 41 Life-Cycle Model 45 Operational Qualification (OQ) 41 Life-Cycle Approach 45 Out-of-Specification (OOS) 41 Logbook 45 Out-of-Trend (OOT)

6 P Q 46 Parenterals 51 QA 46 Particle Monitoring 51 QbD 46 Personnel Flow 51 Qualification 47 Performance Qualification (PQ) 51 Qualification Report 47 Pharmacology 52 Qualification Master Plan 47 Pharmaceutical Excipient 52 Qualification Plan 47 PIC/S 53 Qualified Person (QP) 48 Postal Audit 53 Quality Management Manual 48 PPQ 54 Quality Risk Management (QRM) 48 PQ 54 Quality Assurance (QA) 48 PQR 54 Quality by Design (QbD) 48 Primary Packaging 55 Qualified Person for 49 Process Performance Pharmacovigilance Qualification (PPQ) 49 Product Quality Review (PQR) 49 Product Specification 49 Prospective Qualification 49 Prospective Validation 49 Process 50 Process Capability 50 Process Capability Study 50 Process Validation (PV) 50 PV (Process Validation)

7 GxP Dictionary Contents

R S 56 RABS 61 Secondary Contamination 56 Reproducibility 61 Secondary Packaging 56 Restricted Access Barrier 61 Self-Inspection System (RABS) 61 Site Acceptance Test (SAT) 57 Reserve Sample 61 Site Master File (SMF) 57 Returns 62 SOP 57 Retrospective Qualification (Standard Operating Procedure) 57 Retrosibility Delimitation 62 Specification Agreement 62 Sterility 57 Requalification 62 Sterilization 58 Requirement Specification 62 Stress Test 58 Revalidation 62 Supplier Audit 58 Risk Analysis (RA) 59 Risk-Based Qualification Systems T 59 Risk Assessment 63 TAMC 59 Risk Communication (Total Aerobic Microbial Count) 59 Risk Management 63 Test Plan 59 Risk Priority Number (RPN) 63 Third-Party Audits 60 Risk Reduction 64 Traceability Matrix 60 Risk Control 64 Track & Trace 60 Risk Monitoring 64 Traceability 60 Robustness

8 U 76 URS (User Requirement 72 GxP Regulations and Guidelines Specification) 73 Notes 76 More Information/Contact

V 66 Validation 66 Validation Report 66 Validation Master Plan (VMP) 67 Validation Matrix 67 Validation Plan 68 V Model

W 69 Warning Limit 69 Warning Letter 70 WHO 70 Worst-Case Scenario 70 Work Directive

Z 71 ZLG

9 GxP Dictionary Terms and Definitions

Terms and Definitions

0-9 21 CFR 210/211 483 CFR: Code of Federal Regulations – The problem report is referred to as Federal Regulations of the USA Title 483, and it is issued by FDA inspectors 21: Food and Drugs – contains the (FDA) and documents the complaints regulatory provisions for the food and that arise during an inspection. The drugs sector. name is derived from Form No. 483, Part 210: current Good Manufacturing which is used to prepare the summary Practice (cGMP) in manufacturing, pro- report. A 483 is normally published, cessing, packing, or holding of drugs; but without naming the company or general product names concerned. Depending Part 211: current Good Manufacturing on the relevance of the documented Practice (cGMP) for finished pharma- defects, a warning letter is created on ceuticals the basis of the 483. The 21 CFR 210/211 contains very detailed GMP guidelines for the USA. Part 210 refers to the manufacturing and packaging process of drugs and food, while Part 211 primarily includes the rules for finished pharmaceuticals.

10 0-9 A A Active Pharmaceutical Ingredient ADI (Acceptable Daily Intake) (API) The ADI specifies the amount of a The medically (pharmacologically) certain substance, e.g. of an active active ingredient in a drug. pharmaceutical ingredient, that does not present any health risk, on the Accompanying Validation assumption that a person is exposed The validation takes place while the to it on a daily basis over a lifetime. products intended for subsequent sale are being manufactured. Commence- Airlock Concept ment of routine production prior to the Airlock Concepts consist of several completion of the validation process rooms, arranged one behind the other, must be justified, documented and ap- which allow the transition of persons proved by authorized personnel. The and material from a cleanroom area validation batch is only released for to a cleanroom area with a higher or trading following successful validation. lower level of purity, without contami- nating one of the areas. Action Limits A limit value stipulated by laws, directives or internal company provisions. If this value is exceeded, then corrective actions must be initiated without delay, accompanied by analysis of the failure and removal of the cause.

11 GxP Dictionary Terms and Definitions

Annex API Annexes are various appendices to See Active Pharmaceutical Ingredient the EU GMP Guidelines. Currently there’s Annex 1 to Annex 19, there is APR no longer an Annex 18. Annex 18 was See Annual Product Review published in 2005 as EU GMP Guide- lines Part II.

Annual Product Review (APR) A retrospective review of the history of a drug, required by the FDA for products manufactured in or imported into the USA, undertaken on an annual basis.

12 A

Audit Audit Trail Inspection or survey of a site (e.g. a This is used to ensure the complete company, a production site) for the traceability of all activities, actions and purpose of verifying compliance with system states by recording “traces”, the requirements it is supposed to which indicate when, by whom and/ fulfil (here: compliance with the GMP or what, a process was influenced. It regulations and their specifications). usually consists of records of com- An audit can be carried out by various puter and software systems and is bodies (e.g. representatives of con- required by 21 CFR Part 11 as well as tracting authorities or representatives Annex 11 (EU GMP). of authorities other than the competent supervisory authority such as the Authorization FDA) and, in terms of how it is defined, Authorization refers to the marketing is separate from an inspection, which authorization for a medicinal product. may be carried out exclusively by the In this regard, the product must always competent supervisory authority, i.e. conform to the GMP. inspectors of the state authorities.

13 GxP Dictionary Terms and Definitions

B Batch Record Review Batch Batch Record Review is a system that A homogeneous and defined quantity collates all the information about the of starting material, medicinal prod- batch certification. For example, these ucts or packaging material produced include batch production and test in a single operation or in a series of reports, as well as all records of devi- operations ations and OOS reports. This information is used by the QP (Qualified Per- son) as the basis for making decisions regarding the release of a batch (batch release).

14 Batch Documentation Bulk Ware B The Batch Documentation includes = Any product which has passed instructions and protocols on manu- through all processing stages except facturing and packaging procedures, for final packaging. as well as the test report. This enables the entire history of a batch to be Biological Safety Cabinet (BSC) traced without any gaps. The Batch This is often used in microbiological or Documentation serves as a basis for analytical laboratories and is a “room the batch release and is particularly within a room” concept to protect important when, at a later stage, qual- employees and the environment, ity defects are identified which were along with the product, when carrying not detectable at the time of release. out critical processes. Class I: BSC with work access opening; prevents airborne suspended contamination via inward flow of air and filtration of the exhaust air. Class II: BSC with work access opening; reduces the risk of cross-/product contamination via fil- tered circulating air and filtration of the exhaust air. Class III: BSC (e.g. isolator) with completely closed-off working area (physical barrier). Intervention in the working area is possible, e.g. using gloves.

15 GxP Dictionary Terms and Definitions

C CAPA Capacity Test See Corrective Action/Preventive The Capacity Test is a long-term Action stress test to show whether an (IT) system remains functional even under Calibration full load over the long term. Possible Calibration is the comparison of a capacity limits are therefore visible. reading or a material measure with the For instance, a document man- correct value under stipulated condi- agement system should launch the tions, documentation of the deviation, correct workflow following a document calculation of the measurement uncer- becoming valid, even if, for example, tainty and creation of the certificate hundreds of documents become valid or calibration certificate. One of the at the same time. most important criteria for professional calibration is complete metrological CEP (certificate of suitability of traceability to national and internation- monographs of the European al standards. pharmacopoeia) The certificate confirming that a drug has been produced in line with the monographs of the European Pharma- copoeia.

16 CFR cGMP = Code of Federal Regulations: = current Good Manufacturing Practice: C Federal regulations of the USA. Exam- Since the US GMP guidelines are contin- ple: 21 CFR 210 and 211 uously being revised, the correct name is cGMP. Whereas in Europe the guide- CFU (Colony-Forming Unit) lines are only updated as required, so Used for the qualification of micro-or- the c (current) is not necessary. So its ganisms/germs in microbiology. In title here is just GMP. a wipe test, for example, nutrient medium is applied to a surface for a Challenge Test certain time (e.g. 10 seconds). Follow- Challenge Test refers to a qualification ing incubation of the nutrient medium, or validation test under worst-case the micro-organism multiplies and conditions. This method is often sup- becomes visible as a colony (= CFU). plemented by the deliberate induce- ment of faults in order to prove that these can be detected and remedied or prevented by the actions taken.

CFU on agar plate

17 GxP Dictionary Terms and Definitions

Change Control Clean Corridor Principle Formal system for maintaining the de- The Clean Corridor is a protection fined status, e.g. the validation status. concept for preventing cross-contam- A systematic, risk-based assessment ination. Here, a spatial arrangement is is carried out, to find out what meas- provided, in which the corridor, which ures are required due to an intended leads to various processing areas, is or actual change, in order to maintain the space with the highest pressure. GMP conformity and, for example, Thus, the overflow is directed towards the specification. These measures are the production rooms, which prevents assessed by qualified representatives a product from being discharged into of the relevant department. another area.

18 Cleanroom Principle Cleanroom The Cleanroom Principle is a protec- A cleanroom is a room designed so C tion concept that works via a shell as not to exceed a defined particulate and microbiological contamination. In Cleaning Validation accordance with the purity specifica- The Cleaning Validation is documented tions that this type of room fulfils on proof that a cleaning procedure can be a permanent basis, a purity classifi- used to achieve a plant status that is cation is attributed to it. Moreover, a suitable for the production of medic- cleanroom is equipped with airlocks inal products. The effectiveness and and access protection. reproducibility of the entire cleaning procedure is verified to this end. The four decisive parameters that influence the success of the cleaning are portrayed in the Sinner’s circle: Chemistry, mechanics, temperature and time (see Sinner’s circle). Another prerequisite for successful cleaning is GMP-compliant plant design.

19 GxP Dictionary Terms and Definitions

Cleanroom Classes In DIN EN ISO 14644-1, the differ- cleanroom classes, and a distinction ent cleanroom classes (ISO 1-9) are is also made between production and classified according to the maximum idle state.model with overpressure to permissible particle concentration (in adjacent areas of low air purity. The particles per cubic metre of air). ISO overflow therefore moves away from class 1 is the cleanroom class with the the cleanroom, preventing any impure lowest permissible particle concen- air from getting into the cleanroom tration. In the EU GMP guidelines, (pressure cascades). the letters A to D are assigned to the

Classification limits in Annex 1 EC Guidelines to Good Manufacturing Practice, Revision to Annex 1, as of 2014

Maximum permissible number of particles per m3, equal to or greater than the tabulated size Room class Idle state Production 0.5 μm 5.0 μm 0.5 μm 5.0 μm

3,520 20 3,520 20 A ISO 5 ISO 4.8 ISO 5 ISO 4.8

3,520 29 352,000 2,900 B ISO 5 ISO 7

352,000 2,900 3,520,000 29,000 C ISO 7 ISO 8

3,520,000 29,000 Not defined D ISO 8

20 Compliance Conformity Conformity of conditions with stand- See Compliance C ards and specifications. GMP compliance is therefore com- Concurrent Validation pliance with the GMP Regulations, See Accompanying Validation i.e. the relevant laws, directives and guidelines (e.g. EU GMP Guidelines). Containment Containment of a biological agent Computer System/Software or other substance within a defined Validation (CSV) space. Primary containment: Prevents See Computer Validation leakage into the immediate work environment (e.g. via closed containers). Computer Validation Secondary containment: Prevents = Validation of computerized systems: leakage to the outside or into other According to the EU GMP Guidelines, work environments (e.g. via rooms with a computer consists of “a combination special ventilation systems/airlocks). of hardware components and associated software, designed and put Contamination together in order to carry out a specific The unwanted introduction of foreign function or group of functions”. substances or impurities, chemical or During computer validation, the microbiological, into or onto a starting suitability of this hardware/software material or intermediate or finished concept for achieving the required product during manufacture, sampling, functions is checked and the results packaging, storage or transport. documented.

21 GxP Dictionary Terms and Definitions

Continued Process Verification (CPV) Corrective Action/Preventive Action See Continuous Validation (CAPA) Systematic approach that includes Continuous Validation both corrective and preventive actions. Validation is no longer seen as a Corrective Action: Action taken to temporary, one-off activity, but as a eliminate the cause of a fault in an permanent verification that accompa- identified, undesirable situation and nies the process over the entire peri- to have a strong chance of preventing od, from the design phase through to recurrence in other areas too or in the market withdrawal of the product. another procedure. Preventive Action: The new process validation approach Action taken to actively prevent the therefore consistently follows the cause of a potential failure. This is of- life-cycle model. In a broader sense, ten done with the aid of risk analyses. therefore, each batch produced is a validation batch. Corrective and Preventive Actions See Corrective Action/Preventive Continuous Validation/Verification Action See Continuous Validation CPV = Continued Process Verification. See Continuous Validation

Culture Media Filling See Media Fill Test

CSV = Computer System Validation/Com- puter and Software Validation (See Computer Validation)

22 D Data Review Design Qualification (DQ) A Data Review can replace a practical Documented proof that the design C revalidation, assuming that no critical of facilities, plants and equipment D changes have been made to the process is suitable for its intended purpose. since the validation. In that case, evalu- The DQ, which is carried out prior to ating the process and product data for purchasing the equipment, covers the last period is sufficient; there is no documentation of the planning phase need to check the validated status for and incorporates the decision-making specific batches. with regard to purchasing a plant. The requirements for the planned Disaster Recovery installation should be defined and = Recovery following an IT blackout; specified. This includes the recovery of important The elements of the DQ are usually: data as well as the repair or replace- • The design qualification plan ment of destroyed hardware compo- • The user requirement specification nents. • The requirement specification (= the client’s requirements with regard to the scope of supply and services) • The functional specification (the contractor’s design for implementing the plant or the project) and • The design qualification report.

The DQ is the documentation of the comparison between the requirement specification and the functional specification, as well as the underlying laws, regulations and standards.

23 GxP Dictionary Terms and Definitions

Deviation DMS In general, a deviation may be de- See Document Management System scribed as a result or a situation within a process which does not comply with Document Management System the plan or expectations or even a (DMS) specific related provision. Examples of Electronic document management these are deviations involved in quality system (therefore also often called control, monitoring or product specifi- eDMS) in the form of an IT solution. cations. DQ Deviation Management See Design Qualification Deviation Management is the stand- ardized, controlled handling of a deviation. This includes the detection, analysis or monitoring and also remedying of a deviation. Both the causes of a deviation and the related implications must be recorded and classified. This procedure ensures that failures and their consequences are corrected efficiently, and enables early detection of critical situations as well as the implementation of appropriate countermeasures in future.

24 E EDMF eDMS = European Drug Master File: A Drug See Document Management System Master File documents the pharma- D ceutical production & quality assur- EC Directive E ance of drugs. This document is used = Legislation of the European Com- for submission to the competent munity: Member States have a certain authority for medicinal products for the amount of flexibility when it comes to authorization of a drug. An EDMF is their transposition into national law usually used when the manufacturer of (transposition into law or regulation). the drug and the manufacturer of the finished dosage form are not identical. EC Regulation The pharmaceutical manufacturer can = Legislative act of the European therefore safeguard its product secret Community: this has general appli- by describing the synthetic routes and cation, is binding in its entirety and process development of the prepara- is valid in all Member States – i.e. it tion only in the confidential section of does not have to be transposed into the Drug Master File. This section is national law, which also means that no accessible to the competent authority, modifications are possible. but not to the pharmaceutical manufacturer.

25 GxP Dictionary Terms and Definitions

EMA/EMEA EP = European Medicines Agency: The = European Pharmacopoeia: Pub- EMA is a decentralized EU agency lished by the European Directorate based in London. Since 1995, it has for the Quality of Medicines & Health been responsible for the scientific Care (EDQM); this contains the official evaluation of medicinal products de- standards and methods applicable to veloped by pharmaceutical companies medical devices and pharmaceutical for use within the European Union. substances within the EU. The EMA plays a central role in drug registration within the EU and the EEA ETA States, since the European Commis- See Event Tree Analysis sion issues authorizations on the basis of its assessments.

EMA Guideline Guideline issued by the European Medicines Agency, e.g. on human and veterinary drugs, health protection and GDP (Good Distribution Practice).

26 EU GMP Guidelines European Pharmacopoeia = Good Manufacturing Practice guide- See EP lines: The first version of these guidelines, in which the European direc- Event Tree Analysis E tives are implemented in detail, was The “Event Tree Analysis” is a method published in 1989. It now consists of 3 for determining the possible conse- parts in addition to Annexes 1-19. quences that are triggered by a failure. Part I: GMP principles for the manu- From an initial failure, a tree diagram facture of medicinal products. is developed via various paths, which Part II: Good Manufacturing Practice represent the possible reactions of for active substances Part III: GMP-re- the individual system components, lated documents (including quality risk culminating in all possible failure con- management) sequences and implications.

Adverse event

Consequence Consequence 1.0 2.0

Consequence Consequence Consequence Consequence 1.11 1.12 2.11 2.12

27 GxP Dictionary Terms and Definitions

F Factory Acceptance Test (FAT) Fault Tree Analysis Acceptance/control of ordered devices In Fault Tree Analysis, the tree diagram, and plants on site at the supplier's in contrast to the event analysis (see premises. The Site Acceptance Test Event Tree Analysis), progresses from (SAT) is usually carried out after deliv- the failure to the cause. In other words, ery and installation. this explores the most likely cause or combination of causes of a fault.

Adverse event

Basic event Basic event Basic event Basic event

28 FDA FDA Guidance for Industry – = U. S. Food and Drug Administration; Process Validation the FDA is the highest health authority Contains non-binding recommenda- in the USA and is responsible for drug tions for implementing the process licensing. In order to ensure com- validation, which are based on the F pliance with the standards also with current perspective of the US FDA regard to the many medicinal prod- agency. It is important to note that it is ucts imported into the USA, the FDA possible to also focus on other guide- operates internationally and carries lines, provided that compliance with all out audits among exporting producers GMP regulations is ensured. outside the USA. FFDCA See Federal Food, Drug and Cosmetic Act

29 GxP Dictionary Terms and Definitions

Fishbone Diagram/Method The Fishbone method (also Ishikawa often also named after the person who diagram) is a graphical method for developed it, Kaoru Ishikawa. Thanks displaying failures/causes and result- to the form of presentation, this ant effects (consequence of failures). method imparts a good understanding Its name is derived from the visual of the process, which leads to a clear similarity to a fishbone. The method is objective.

Cause Effect

Man Machine Environment

Measurement

Material Method Measurement

Main causes Sub-causes

30 FMEA (Failure Mode and Effects FMECA (Failure Mode, Effects and Analysis) Criticality Analysis) FMEA is a risk analysis method, which FMECA is an extension of the FMEA is used to analyze individual failures to include the “criticality” factor or the as well as failure effects and causes. “magnitude of the consequences of a F It is widely used in industries where failure”. See also FMEA. there are high standards with respect to product and process reliability. The FMEA is currently the most frequently used method for systematic risk analysis in the pharmaceutical industry and can also depict extremely complex considerations. Depending on the type of FMEA, the interaction of components in a complex system (system FMEA), the design of products or components (design FMEA) or the steps of a production or service process (process FMEA) are considered. In the FMEA, a Risk Priority Number is determined for each individual sub-step in a process. If this exceeds a pre-defined limit value, risk-reduction measures need to be taken.

31 GxP Dictionary Terms and Definitions

Formulation FTA The formulation of a medicinal prod- See Fault Tree Analysis uct includes its preparation with the appropriate ingredients as well as its Functional Specification form (dosage form). Once the formula- The Functional Specification contains tion process of a product is complet- the contractor’s comments on the ed, it is referred to as bulk ware. implementation and processing of a project (e.g. construction of a facility). It is the supplier’s detailed description for the implementation strategy of the Requirement Specification, and should therefore contain all the obligatory requirements referred to therein. Often no separate Functional Specification is created. Instead it is replaced by the contractor’s corresponding offer, provided that this has been adequately detailed.

32 G GAMP GEP = Good Automated Manufacturing = Good Engineering Practice; relevant Practice; Refers to the validation of to engineering: Good and effective computerized systems. planning of plants.

F GCP GLP = Good Clinical Practice; valid for = Good Laboratory Practice; relevant G clinical trials: Quality requirements for to laboratories: Validation of non-clini- planning and conducting clinical trials. cal safety tests and procedures.

GDP = Good Distribution Practice: Con- trolled, safe drug distribution channel, from leaving the manufacturer through to the end consumer.

33 GxP Dictionary Terms and Definitions

GMP GMP-Compliant Plant Design = Good Manufacturing Practice; Good Plant planning and construction, manufacturing practice for medicinal which is based on the GMP regula- products: Sum total of national and tions and aims to optimize subsequent international rules relating to medicinal GMP-compliant operation, for exam- product manufacture and quality as- ple easily accessible and cleanable surance, which are intended to protect machine components. (see Hygiene public health and to protect consum- Design) ers from dubious products. GSP = Good Storage Practice; relevant to storage: Storage under controlled, constant conditions (temperature, humidity, light).

GxP = Good x Practice; Umbrella term for specific GMP-regulated sub-areas, for example: GAMP, GCP, GEP, GLP, GDP, GSP.

34 H Head of Production Head of Quality Control The Head of Production is respon- The Head of Quality Control’s responsible for ensuring that production is sibilities include the testing of start- implemented properly, that the pro- ing materials, intermediate and final duction process is validated and that products, the approval of specifica- the production personnel are trained. tions, the validation of test procedures The Head of Production must have a and the training of personnel in his G sufficient professional qualification. division. Statutory requirements with H Appropriate proof of qualification and respect to the Head of Quality Con- reliability (certificate of good conduct) trol are the reliability required to carry must be submitted to the superviso- out his tasks and activities, as well ry authority. The Head of Production as familiarity with the products and must always be independent of the procedures. Head of Quality Control.

35 GxP Dictionary Terms and Definitions

I ICH Information Officer = International Conference on Harmo- The legal requirements with respect nization of Technical Requirements for to the Information Officer are compa- Registration of Pharmaceuticals for rable to those imposed on a Qualified Human Use; the ICH aims to harmo- Person. The Information Officer is nize the criteria for the authorization responsible for releasing scientific in- of a medicinal product in Europe, formation about the medicinal product the USA and Japan. The European and, in this respect, is responsible Commission, the FDA, and also the for compliance with the principle of Japanese Ministry of Health Labour not misleading. He must ensure that and Welfare (MHLW) are members. the labelling, package insert, technical information and advertising are consistent with the content of the authorization and registration. His work therefore forms part of the preventive consumer protection. The Information Officer may, at the same time, hold the position of Qualified Person and Quali- fied Person for Pharmacovigilance.

36 In-Process Control Installation Qualification (IQ) Tests carried out during ongoing pro- The installation qualification docu- duction are referred to as in-process ments the correct implementation of controls. The aim is to monitor and, previously defined requirements with where necessary, adapt the process to respect to the installation and modifi- the given specifications. In a broader cation of the plant. The IQ is primarily sense, inspection of the environment based on the specifications written and equipment may also be consid- in the DQ. The relevant documents ered part of the in-process controls. are checked to make sure they are I complete and correct, and updated and supplemented where necessary. Furthermore, the IQ documents prove that all equipment components were delivered, assembled and installed professionally and in accordance with the law. Classic IQ tests include monitoring the acceptance procedure, testing the electrical installation and measuring and control points, and testing the inputs and outputs (I/O test).

37 GxP Dictionary Terms and Definitions

IPC ISO 13485 See In-Process Controls ISO 13485 defines the content and structure of the quality management IQ system for medical devices, which can See Installation Qualification be applied to the design and development, production, installation and also Ishikawa Diagram/Method maintenance of medical devices. It is See Fishbone Diagram/Method derived from ISO 9001, and adds to this the specific requirements for the field of medical devices.

38 ISO 14644 ISO 14644 deals with cleanrooms and • 14644-7: Separate devices (clean-air contamination control. The prod- hoods, glove boxes, isolators and ucts and processes that benefit from mini-environments) controlled airborne contamination • 14644-8: Classification of air clean- include those used in the aerospace, liness by chemical concentration microelectronics, pharmaceutical and (ACC) food industries as well as in medical • 14644-9: Classification of surface technology and healthcare. In addition cleanliness by particle concentration I to the particle purity of the air, lots of • 14644-10: Classification of surface additional aspects need to be taken cleanliness by chemical concentra- into consideration in the planning, tion specification, operation and monitoring • 14644-12*: Specifications for mon- of cleanrooms and other related areas. itoring air cleanliness by nanoscale The standard is therefore subdivided particle concentration into different parts (as of: 11/2014): • 14644-14*: Assessment of suitability for use of equipment by airborne • 14644-1*: Classification of air clean- particle concentration liness by particle concentration • 14644-2*: Monitoring to provide evidence of cleanroom performance related to air cleanliness by particle concentration • 14644-3: Test methods • 14644-4: Design, construction and start-up • 14644-5: Operations • 14644-6: Vocabulary

39 GxP Dictionary Terms and Definitions

ISPE = International Society for Pharmaceu- tical Engineering; ISPE is an international non-profit organization which currently has 20,000 members in more than 90 countries all over the world, and is engaged in training and sharing information among employees in the pharmaceutical industry. Members are involved in preparing the FDA and EMA guidelines and they publish their own ISPE Guides. These ISPE Guides are extremely detailed and are state-of-the-art for the pharmaceutical industry.

40 L Life-Cycle Model Logbook See Life-Cycle Approach A logbook is used for continuous documentation of critical items of Life-Cycle Approach equipment. These generally include Quality assurance approach, to ensure machinery, plants and devices, and in that all QA measures (risk manage- particular ventilation systems, water ment, qualification, validation, etc.) systems and rooms. The logbook depict the complete life cycle of a records all validations, calibrations, plant or process. The entire concept maintenance work and repairs, clean- I must be designed for the life-cycle of ing and sterilization as well as all 55 a process or the product. modifications, conversion work and, where necessary, further operations. L

41 GxP Dictionary Terms and Definitions

M Major Change Major Changes refer to changes to Matrixing the process/to a plant that require Matrixing is a cleaning validation monitoring, and which influence the method with the objective of reducing product quality and/or process safety. the scope of validation overall. The Examples of this are changes in approach is equipment-based imple- manufacturing/production, a move in mentation. the sense of a change of location or changes in the composition/process Method Validation (analytical) parameters. Proof that an analytical method, as specified in the test instructions, pro- Material Flow vides correct and reliable results. The Material Flow is the coordinated text and methodology are harmonized sequence of individual production and in the ICH Q2 for the EU, Japan and storage steps, from the raw materials the USA. through to the finished product. The purpose of the Material Flow is to eliminate the inadvertent omission of a quality-defining manufacturing or control step. Moreover, this prevents mix-ups and ensures compatibility with other manufacturing processes.

42 Metrological Traceability Minor Change The property of a measurement result Minor Change refers to a change that or the value of a standard whereby it requires monitoring, and which has can be related to stated references, an influence on a unit that requires usually international or national stand- monitoring. This includes, for example, ards, through an unbroken chain of replacing a component, changing a comparative measurements with stated detergent or changing the laundry for measurement uncertainties; metro- work clothes. logical traceability is thus ensured by referencing measurement results to Monitoring international or national standards via Monitoring compliance with specified an unbroken chain of calibrations. parameters, e.g. monitoring the air cleanliness or monitoring the room climate in cleanrooms. M

PTB National Normal

Accredited calibration laboratory Reference standard

In-house calibration laboratory Working standard/company standard

Operational test equipment

Calibration hierarchy Germany

43 GxP Dictionary Terms and Definitions

N NOAEL = no observed adverse effect level: Maximum dose of a substance with no negative observable effect.

NOEL = no observed effect level: Maximum dose of a substance with no observable effect or critical effect.

44 O Official Calibration OOT Official Calibration is the official check See Out-of-Trend for compliance with the calibration failure limits. An Official Calibration is Operational Qualification (OQ) carried out exclusively by the Lande- See Operational Qualification seichamt. Only those measuring instruments and material measures Out-of-Specification (OOS) with a type approval can be officially A result that does not meet the spec- calibrated. In contrast to Calibration, ification. during Official Calibration no deviation from the test specimen to a reference Out-of-Trend (OOT) is determined. Instruments used to A result which is still within the spec- protect consumers and to protect the ifications, but owing to the fact that it legal status (e.g. water meters, counter does not correspond to the observed scales, traffic radar gauges) are pri- trend over an extended period, exhib- N marily subject to Official Calibration. its a certain abnormality. O

OOS See Out-of-Specification

45 GxP Dictionary Terms and Definitions

P Parenterals Personnel Flow Parenteral means “bypassing the A well thought-out, coordinated flow digestive tract”. Accordingly, the of personnel is a prerequisite for European Pharmacopoeia defines GMP-compliant production. It forms Parenterals as “sterile preparations part of the implementation of the which are intended for injection, infu- hygienic zone concept and prevents sion or implantation into a human or cross-contamination. It is also used for animal body”. Enteral resorption and product and personal protection. The therefore the non-specific immune term “Personnel Flow” encompass- system (saliva, gastrointestinal tract) es requirements to allow access to are bypassed. Therefore, impurities in pharmaceutical areas only via airlocks parenterals are associated with high and changing areas, to only employ health risks. appropriately trained personnel, and to constantly determine the number of Particle Monitoring people required for operating, monitor- Particle Monitoring is used to monitor ing and maintaining the facilities. particulate air cleanliness. Excessive particle loading can result in excessive contamination of the relevant product with particles, but also with microbiological organisms.

46 Performance Qualification (PQ) PIC/S Proof of the long-term specification = Pharmaceutical Inspection Cooper- conformity of a plant during operation. ation Scheme; merger consisting of Here, the interplay or compilation of lots of member states from all over all plant components is checked and the world, which has set itself the the performance limits are tested. goal of working together to further As a result, differentiation between develop GMP and harmonizing the Performance Qualification and Process resulting regulations. In addition, in Validation is not always clear. The order to prevent multiple inspections, Performance Qualification can be the mutual recognition of inspections differentiated to the extent that prod- is to be improved and the movement uct-specific proof of the effectiveness of medicines simplified by dismantling and reproducibility of the device/plant trade barriers. The PIC/S issues PIC/S is to be provided. Guides and PIC/S Recommendations.

Pharmacology Pharmacology is the study of the P interactions between drugs and living organisms.

Pharmaceutical Excipient Pharmaceutical Excipients are substances which form part of a medicinal product, but are not active ingredients themselves. They are added in order to influence the form of the medicinal product or its release in the organism.

47 GxP Dictionary Terms and Definitions

Postal Audit Primary Packaging A Postal Audit is carried out without The Primary Packaging is the part of an actual visit to the company being a package that immediately surrounds audited. Instead, a comprehensive the product, i.e. is in direct contact questionnaire is sent by the auditor to with it. Thus, primary packages are the supplier, who independently fills this often made of aluminium, glass or in with the appropriate information and plastic, since these materials are inert relevant references. This information or hardly cause any abrasion. may be verified at a later date during an on-site appointment.

PPQ See Process Performance Qualification

PQ See Performance Qualification

PQR See Product Quality Review Primary packaging of medicinal products

48 Process Performance Qualification Product Specification (PPQ) A Product Specification should include The PPQ is part of the new Life-Cycle all the information necessary for pre- Approach, and replaces or includes DQ, paring the precise written instructions IQ, OQ and PQ for the existing validation for processing, packaging, quality approach. The stability of the process control, batch release and shipment of must be demonstrated in the PPQ. (See a product. Life-Cycle Approach) Prospective Qualification Product Quality Review (PQR) Qualification of a new plant before the Periodic Product Quality Review; start of production. regular quality reviews of medicinal products, with the aim of confirming Prospective Validation the consistency of the current process Validation before the start of production/ and the adequacy of the current speci- marketing of a pharmaceutical product. fications for both the starting materials and for the finished product, in order Process P to highlight trends and identify product Any defined organizational sequence and process improvements. The PQR or step in a process chain related to should be carried out annually, taking the procurement, handling, manu- into account previous review results. facture and distribution of medicinal products. Processes are clearly defined and clearly differentiated with regard to responsibilities.

49 GxP Dictionary Terms and Definitions

Process Capability Process Validation (PV) Process Capability means that a Process Validation is documented evi- process is manageable, stable and dence that the process, within certain conforms to the specifications. This is parameters, produces a medicinal the case if the critical parameters are product that fulfils predefined spec- only subject to purely random variation ifications and quality attributes, in a (normal distribution) and the corre- manner that is effective and reproduc- sponding values are within the upper ible. Here, it must be demonstrated and lower control limits/tolerance that even difficult-to-control critical limits. process steps follow a predefined sequence and the overall process is Process Capability Study completely reproducible - with consist- Statistical method for comparing the ent quality and in compliance with the process information with the permis- specifications. The scope of the PV is sible tolerances, to draw conclusions determined by risk management. about the process capability. PV (Process Validation) See Process Validation

50 Q QA Qualification Report See Quality Assurance The Qualification Report always rep- resents the conclusion of a qualifica- QbD tion. All results are summarized here. See Quality by Design Changes to the test plans and any deviations must be documented accord- Qualification ingly. It should be noted that at this Qualification is documented proof that point, all critical deviations must be a device/plant is suitable for the in- remedied, only non-critical deviations tended purpose, to fulfil the specified can be accepted with appropriate jus- functions or to produce products, and tification. The report must also include that these meet the regulations and the maintenance programs, recalibra- standards on a permanent basis (= are tion data, operating instructions, SOPs GMP-compliant). and the qualification status of the installation. The Qualification Report is a prerequisite for clearance to use the plant or for validation. P Q

51 GxP Dictionary Terms and Definitions

Qualification Master Plan Qualification Plan The Qualification Master Plan is a The Qualification Plan contains the superior document which depicts the goal, subject and scope of the qualifi- qualification strategy and organization- cation, the designation of persons and al structure in general. The individual responsibilities within the qualification qualification objects are defined and team and the description of the quali- the necessary qualification steps are fication strategy. Key components are described, with the type and scope the detailed designation of individual of qualification activities. It therefore tests, the descriptions relating to their serves as an overview of equipment implementation, and the correspond- and plants with regard to scheduling, ing acceptance criteria (also referred and defines the appropriate responsi- to as test plans, which may also be bilities for completing the qualification separate from the qualification plan). activities. Furthermore, the plan should describe the qualification object and, if necessary, the process, should indicate the critical plant parameters and contain a list of documents. The document must finally be released.

52 Qualified Person (QP) Quality Management Manual The Qualified Person must have proof The Quality Management Manual is of the necessary expertise (authorized a superior, binding document which pharmacist or medical/scientific de- depicts a company's quality policy and gree with additional qualification). Ad- guidelines. As an essential element for ditional requirements are the reliability long-term implementation of the qual- required to carry out the tasks and ity management system, it includes activities as well as sufficient familiar- a description of the operational and ity with the products and procedures. organizational structure and refers to The Qualified Person is responsible for the relevant procedures, standards compliance with the relevant regula- and regulations. tions governing the manufacture, testing and release of medicinal products prior to placing a drug on the market. His tasks therefore include: • placing the batch release on the market • securing Reserve Samples • checking whether a company’s QM Q system is being maintained • being responsible for complete documentation, to demonstrate compliance with all regulations.

53 GxP Dictionary Terms and Definitions

Quality Risk Management (QRM) Quality Assurance (QA) (Quality) Risk Management is a sys- Quality Assurance is a far-reaching tematic process for the assessment, concept which covers all the areas that control, communication and monitor- individually or collectively control the ing of risks to the quality of medicinal quality of a product. It constitutes all the products over the entire life-cycle of planned measures, undertaken to ensure the product. According to ICH Q9, the that medicinal products are of the quality assessment of quality risks should be that is required for their intended use. based on scientific knowledge and should always be viewed in the con- Quality by Design (QbD) text of patient protection. This requires Quality by Design is a holistic, risk- extensive knowledge of the process based approach to the development as well as clearly defined framework and manufacture of medicinal prod- conditions. Quality Risk Management ucts, which aims to develop a process includes risk assessment, risk control, that identifies critical, quality-relevant risk monitoring and risk communi- steps, measures their impact, and cation. (See Risk Assessment, Risk determines this within a specified Monitoring, Risk Communication, “design space”. Risk Control)

54 Qualified Person for Pharmacovigilance The tasks of the Qualified Person for Pharmacovigilance include: • collecting reports on drug risks, assessing them and coordinating necessary actions • monitoring clinical trials with regard to drug risks • identifying serious side effects, interactions or misuse • notifying supervisory authorities in the event of an abnormal restric- tion on supply (stopping deliveries, recall).

The Qualified Person for Pharmacovig- ilance must have appropriate expertise in the form of a completed universi- Q ty degree plus at least two years of professional experience. In principle, he should work independently of sales and distribution units; however, it is possible for him to act as a Qualified Person at the same time (§ 63a AMG).

55 GxP Dictionary Terms and Definitions

R RABS Restricted Access Barrier System See Restricted Access Barrier System (RABS) RABS is a concept for isolating a ma- Reproducibility chine, often used in aseptic produc- Reproducibility is understood to tion or as personal protection in the be consistent product quality and case of highly active substances. As invariable production processes. A a mixture of conventional cleanroom process is GMP-compliant only if its technology and isolator technology, result is reproducible. This is the only active intervention is only possible us- way to ensure that, for example, when ing gloves; the process itself remains testing a batch by random sampling, separated from the operator. the findings obtained from this can also be transferred to all the individual products in this batch.

RABS (Image: Franz Ziel GmbH)

56 Reserve Sample Responsibility Delimitation A Reserve Sample is a sample, for Agreement example, from a fully packaged unit This completely and unambiguously from a finished product batch, which is sets out the interfaces, tasks and stored for identification purposes. responsibilities between those involved in the manufacture, handling and Returns distribution of a medicinal product. It The return of a medicinal product to provides the basis for legally secure the manufacturer or distributor, regard- cooperation, which, for example, en- less of whether or not there is a quality sures that all requirements for ensuring defect. the quality of a medicinal product are fulfilled. Retrospective Qualification A Retrospective Qualification is a Requalification qualification for already established Qualification following changes or systems or a qualification based on periodic, cyclical inspection of critical historical data. Retrospective Qualifi- parameters to ensure that the plant/ cation can only be carried out if suffi- device is still in a qualified cient data is available for subsequent state. assessment and review of the critical R parameters. From a GMP perspective, a Retrospective Qualification is no longer accepted.

57 GxP Dictionary Terms and Definitions

Requirement Specification Revalidation Forming part of the qualification, the A periodic, cyclical inspection or requirement specification documents repetition of a validation to ensure that the requirements of the client regard- changes to the process or equipment ing the scope of delivery and services. made in accordance with certain These technical or regulatory require- change control procedures do not ments are defined by the relevant impair the process characteristics or departments (Engineering and QA) in the product quality. collaboration with the operator. Con- tents of the requirement specification Risk Analysis (RA) may be: The Risk Analysis forms part of the • Purpose of the device/plant Risk Assessment. In the Risk Analy- • Key technical data, such as sizing sis, the assessment or weighting of • Details of the design (materials, sur- the risk/possible failure previously faces in contact with the product) identified during the Risk Assessment • The nature of the control system is carried out. In GMP-regulated areas, • Warranty services/service require- the Risk Analysis is often carried out ments for the suppliers using the FMEA method (see FMEA). • Requirements with respect to materials and surfaces • Information on customer service (availability, response time, etc.) • Requirements for GMP compliance

58 Risk-Based Qualification Systems Risk Communication The goal of the Risk-Based Qualifica- The findings obtained from the Risk tion System is to ensure GMP compli- Analysis process should be commu- ance throughout the entire life-cycle nicated throughout the quality risk of a plant/device. To this end, the Risk management process; however, all Analysis, i.e. determining the influ- decision-makers and participants encing factors which have a negative really need to be informed about the impact on product quality, is used as conclusions, because identifying a the basis for the qualification meas- risk can only contribute to the quality ures and for determining their scope. assurance if all process participants The effort put into the qualification and are informed about it and it can be documentation of it are tailored to the purposefully avoided. seriousness and significance of the risks. Risk Management Risk Assessment See Quality Risk Management (QRM) The goal of the Risk Analysis is to identify hazards as well as to analyze Risk Priority Number (RPN) and assess the risks arising from these The formula for determining the Risk hazards. To this end, the problems Priority Number (RPN) is: and issues posed by the risk must first RPN = P x S x D. Where the individual R be clearly defined as part of the Risk parameters are defined as follows: Assessment. Firstly, potential hazards P = Probability of occurrence are identified (risk identification), as a S = Severity of the failure result of which the Risk Analysis takes D = Detection probability place (what is the probability of occurrence and of detecting the fault?). Finally, the Risk Assessment (what are the consequences?/what is the extent of this?) is carried out.

59 GxP Dictionary Terms and Definitions

Risk Reduction Risk Monitoring Risk Reduction forms an integral Since the Risk Assessments made as part of Risk Control, and includes part of the quality risk management measures to reduce the extent and only ever represent a snapshot, they probability of a failure, or to improve must be checked at regular intervals. or increase the detectability of a This ensures the timeliness and suita- failure. The Risk Assessment should bility of the Risk Assessment through- be re-evaluated once the appropriate out an entire life-cycle, and takes measures have been implemented and account of changes or new sources the potential change assessed. of failure and integrates these into the Risk Management. Risk Control The goal of Risk Control is to reduce Robustness risks to an acceptable level. Appro- Robustness describes the capacity of priate measures are established to a system/process not to respond to reduce a risk (Risk Reduction) or external changes. an acceptable risk is classified as non-critical (Risk Acceptance). (See Risk Reduction)

60 S Secondary Contamination Site Acceptance Test (SAT) Secondary Contamination refers to SAT refers to the acceptance of a contamination of the product after device/plant after delivery. All the manufacture, e.g. due to improper requirements specified in the Require- sampling, packaging or storage. ment Specification and the Functional Specification are checked as part of Secondary Packaging this process. The Site Acceptance Test The Secondary Packaging encloses is used to determine the as-built state. the Primary Packaging and, unlike Subsequent changes must therefore this, is not in direct contact with the be taken into consideration in the man- product. ufacturer's technical documentation.

Self-Inspection Site Master File (SMF) Self-Inspection is a critical evaluation = Company description; The Site Mas- and review of in-house processes. ter File (SMF) is an internally-generat- The Head of Production and the Head ed company description for external of Quality Control play a fundamental authorities and customers. This should role in carrying this out. This internal include general information about the quality audit is mandatory in the EU company, the QM system, products, GMP Guidelines. self-inspection and relevant plants. R Requirements for the SMF are ex- S plained in the GMP Guidelines Part III.

61 GxP Dictionary Terms and Definitions

SOP (Standard Operating Procedure) Sterilization SOPs are documents that provide or- During Sterilization, all micro-organ- ganizational, administrative, and tech- isms are killed or viruses inactivated nical information and instructions for during reproduction and dormancy. carrying out regularly recurring work Sterilization in GMP areas is carried processes. They are aimed primarily out physically by means of thermal at a company's employees and are in- processes (heat treatment) or chemical tended to ensure that quality-relevant processes (e.g. via ethylene oxide). work is carried out correctly by every Sterilization via high-energy radiation employee right from the start. is also frequently used (e.g. gamma radiation). Specification The Specification covers the entire Stress Test scope of testing, including the test A Stress Test is used to check the instructions, which are established stability of a product or process under for each specific product and which extreme conditions (high tempera- are, in principle, based on the latest tures, humidity, etc.). In the case of developments in science and tech- medicinal products, this includes the nology (e.g. pharmacopoeial mon- light stability test, for example. ograph, guideline on drug testing). This includes the establishment of Supplier Audit acceptance criteria as well as specific Auditing of a company/organization requirements for storage. (supplier) by a customer. See Audit

Sterility Sterility refers to the complete absence of living micro-organisms, including their resting stages (such as spores).

62 T TAMC Third-Party Audits Total Aerobic Microbial Count Audit by a third party not direct- ly involved in the manufacture of a Test Plan product (not manufacturer or suppli- A Test Plan is a document that er). For example, according to GMP describes the objective(s), design, regulations, a pharmaceutical manu- methodology, statistical considera- facturer is required to audit its active tions as well as the organization of a ingredient suppliers to ensure that the test prospectively. active ingredients were produced in accordance with Good Manufacturing Practice. However, the pharmaceutical manufacturer can also use an appropriately qualified, impartial third party to have these mandatory audits carried out at the supplier.

S T

63 GxP Dictionary Terms and Definitions

Traceability Matrix Track & Trace The Traceability Matrix is used to Track & Trace refers to the individual display the relationships between labelling of each product, as well as user requirements, technical require- the recording of every movement and ments, specifications and test cases. every transportation step that a prod- It provides proof that the user require- uct goes through, from manufacture to ments, via the technical requirements, end consumer. In the pharmaceutical have been fully converted into tech- industry, this method can be used to nical specifications, which the project combat product counterfeiting, be- manager is obligated to adhere to. It is cause the sale of each pharmaceutical also possible to link the Requirement product can be retraced in order to de- Specification and Risk Analysis re- termine where the product comes from quirements with the qualification tests. and whether it is an original or a copy.

Traceability Traceability refers to the ability to trace all the steps and processes of a product, a batch or even a measure itself at a later date.

64 U URS (User Requirement Specification) In the URS, the requirements for the device/plant being manufactured with respect to the product to be produced are described from the user's perspective. The URS, together with the technical and regulatory GMP requirements for the plant, forms the Requirement Specification.

65 GxP Dictionary Terms and Definitions

V Validation Validation Report Provision of documented proof which The Validation Report is used to docu- provides a high degree of assur- ment the validation. This contains the ance that a specific process or a production protocol, which includes Standard Operating Procedure will the results of the in-process controls, produce a product that conforms to the results of the validation tests the pre-defined specifications and including any deviations detected, and quality characteristics – in accordance also the evaluation and assessment of with AMWHV § 2-16. The Validation the validation and the related implica- therefore provides proof that meth- tions with regard to routine production, ods, processes, plants, equipment, change control and, where necessary, materials and systems bring about the revalidation. expected results in accordance with the principles of Good Manufacturing Validation Master Plan (VMP) Practice. Validation therefore ensures The Validation Master Plan (VMP) and documents the most important specifies a company's validation strat- attributes of a process: Reproducibility egy and philosophy and summarizes and Robustness. concepts, intentions, responsibilities and procedures with regard to validation. According to EU GMP Guidelines Annex 15, “all validation activities should be planned. The key elements of a validation program should be clearly defined and documented in a Validation Master Plan (VMP) or similar document”. The Qualification Master Plan may form part of the VMP.

66 Validation Matrix Validation Plan A Validation Matrix is used to de- The Validation Plan is written before pict the relational links between the the validation is carried out, and it individual validation components contains information about the product (products, processes, systems) and (specifications, analytical methods) the assigned actions (validation/quali- and about the process (process de- fication tasks). In order to simplify the scription including flow chart, RA) as overview of complex validations, the well as about rooms and facilities (allo- appropriate responsibilities and priori- cation of rooms, hygienic status, cali- ties should also be noted. bration status) and about the process validation (tests, sampling, analytical methods, acceptance criteria, timeta- ble, responsibilities).

67 GxP Dictionary Terms and Definitions

V Model In the so-called V Model, all activities documents (URS, Functional Speci- and documents containing a qualifica- fication, Requirement Specification) tion and validation are depicted in their and the corresponding qualification logical sequence. Moreover, the direct documentation (PQ, OQ, IQ) are links between the requirement demonstrated.

Performance Qualification User requirements (URS) (PQ)

Operational qualification Requirement Specification (OQ)

Installation Qualification Functional Specification (IQ)

Risk Analysis

Design Qualification Calibration (DQ)

FAT SAT

Implementation/installation

V Model

68 W Warning Limit Warning Letter The Warning Limit is a defined limit A Warning Letter is issued by the FDA value, which enables early warning to a pharmaceutical company if critical of possible deviation from regular deficiencies were identified and not operating parameters. This does not remedied during a previous inspection necessarily involve corrective meas- (or audit). The team of inspectors lists ures, but the cause does need to be the deficiencies on the 483 form. The investigated. company is granted a period within which the deficiencies must be dealt with, otherwise there is a risk that the authorization will be rejected or imports banned. A Warning Letter is published by the FDA on its website, in order to bring the shortcomings therein and the company concerned to the notice of the public.

V W

69 GxP Dictionary Terms and Definitions

WHO Worst-Case Scenario = World Health Organization; the World The Worst-Case Scenario describes Health Organization is the superior the most critical state that could pos- authority of the United Nations when sibly occur. This means, for example, it comes to international healthcare. It that process parameters reach their is currently made up of 194 member upper or lower limit values, making it states. The WHO agenda contains six significantly more likely that process or key points: product failures will occur. • two health objectives: promoting development and promot- Work Directive ing health and safety; See SOP • two strategic requirements: strengthening the health system and utilizing research results, data and findings; • two operational approaches: ex- panding partnerships and improving performance.

70 Z ZLG = Central Authority of the Länder for Health Protection with regard to Medicinal Products and Medical Devices; as a coordinating body for the German federal states in the field of human and veterinary medicine, ZLG is responsible for maintaining and improving the quality and safety of medicinal products and medical devices. Thanks to standardization of the inspection standards within Germany, which ZLG initiates, in comparison to Europe, Germany is portrayed as one cohesive unit despite federal structures in the healthcare system.

71 GxP Dictionary GxP Regulations and Guidelines/Notes

GxP Regulations and Guidelines

Europe: • EC Guidelines on Good Manufacturing Practice (EU GMP Guidelines Part I, II, III; Annexes 1-19), including supplementary guidelines • Guidelines on Good Distribution Practice for medicinal products for human use (GDP guideline)

Other/standards: • DIN EN ISO 14644 Cleanrooms and associated controlled environments • DIN EN ISO/IEC 17025 Quality management and general requirements for the competence of testing and calibration laboratories

72 Notes

73 GxP Dictionary Notes

74 75 www.testo.com

2980 XXXX/alf/I/06.2017 Subject to change, including technical modifications, without notice.