The Gxp Dictionary 1St Edition

Testo Expert Knowledge

The GxP Dictionary 1st edition

Definitions relating to GxP and Quality Assurance

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

3 GxP Dictionary Contents

Contents

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

4 E 19 Continuous Validation 23 EC Directive 19 Continuous Validation/ 23 EC Regulation Verification 23 EDMF 20 Corrective Action/ 24 eDMS Preventive Action (CAPA) 24 EMA Guideline 20 Corrective and Preventive 24 EMA/EMEA Actions 24 EP 20 CPV 24 ETA 20 CSV 24 EU GMP Guidelines 25 European Pharmacopoeia D 25 Event Tree Analysis 21 Data Review 21 Design Qualification (DQ) F 22 Deviation 26 Factory Acceptance Test (FAT) 22 Deviation Management 26 Fault Tree Analysis 22 Disaster Recovery 26 FDA 22 DMS 27 FDA Guidance for Industry – 22 Document Management System Process Validation (DMS) 27 Fishbone Diagram/Method 22 DQ 28 FMEA (Failure Mode and Effects Analysis) 29 FMECA (Failure Mode, Effects and Criticality Analysis) 29 Formulation 29 FTA 29 Functional Specification

5 GxP Dictionary Contents

G L 30 GAMP 36 Life-Cycle Approach 30 GCP 36 Life-Cycle Model 30 GDP 36 Logbook 30 GEP 30 GLP M 30 GMP 37 Major Change 30 GMP-Compliant Plant Design 37 Material Flow 30 GSP 37 Matrixing 30 GxP 37 Method Validation (analytical) 38 Metrological Traceability H 38 Minor Change 31 Head of Production 38 Monitoring 31 Head of Quality Control N I 39 NOAEL 32 ICH 39 NOEL 32 Information Officer 33 In-Process Controls O 33 Installation Qualification (IQ) 39 Official Calibration 33 IPC 39 OOS 33 IQ 39 OOT 33 Ishikawa Diagram/Method 40 Operational Qualification (OQ) 33 ISO 13485 40 OQ 34 ISO 14644 40 Out-of-Specification (OOS) 35 ISPE 40 Out-of-Trend (OOT)

6 P Q 41 Parenterals 46 QA 41 Particle Monitoring 46 QbD 41 Performance Qualification (PQ) 46 QP 42 Personnel Flow 46 Qualification 42 Pharmaceutical Excipient 46 Qualification Master Plan 42 Pharmacology 47 Qualification Plan 42 PIC/S 47 Qualification Report 43 Postal Audit 48 Qualified Person (QP) 43 PPQ 48 Qualified Person for 43 PQ Pharmacovigilance 43 PQR 49 Quality Assurance (QA) 43 Primary Packaging 49 Quality by Design (QbD) 43 Process 49 Quality Management Manual 44 Process Capability 50 Quality Risk Management (QRM) 44 Process Capability Study 44 Process Performance Qualification (PPQ) 44 Process Validation (PV) 45 Product Quality Review (PQR) 45 Product Specification 45 Prospective Qualification 45 Prospective Validation 45 PV (Process Validation)

7 GxP Dictionary Contents

R S 51 RABS 55 Secondary Packaging 51 Reproducibility 55 Secondary Contamination 51 Requalification 55 Self-Inspection 51 Requirement Specification 56 Site Acceptance Test (SAT) 52 Reserve Sample 56 Site Master File (SMF) 52 Responsibility Delimitation 56 SOP (Standard Operating Agreement Procedure) 52 Restricted Access Barrier 56 Specification System (RABS) 57 Sterility 52 Retrospective Qualification 57 Sterilization 53 Returns 57 Stress Test 53 Revalidation 57 Supplier Audit 53 Risk Analysis (RA) 53 Risk Assessment T 53 Risk-Based Qualification 57 Test Plan Systems 57 Third-Party Audits 54 Risk Communication 58 Traceability 54 Risk Control 58 Traceability Matrix 54 Risk Management 58 Track & Trace 54 Risk Monitoring 54 Risk Priority Number (RPN) U 55 Risk Reduction 59 URS (User Requirement 55 Robustness Specification)

8 V 59 Validation Master Plan (VMP) 60 Validation 60 Validation Matrix 60 Validation Plan 60 Validation Report 61 V Model W 62 Warning Letter 62 Warning Limit 63 WHO 63 Work Directive 63 Worst-Case Scenario Z 64 ZLG

66 GxP Regulations and Guidelines

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 (see FDA, p. 26) and documents the regulatory provisions for the food and complaints that arise during an inspec- drugs sector. tion. The name is derived from Form Part 210: current Good Manufacturing No. 483, which is used to prepare the Practice (see cGMP, p. 16) in Man- summary report. ufacturing, Processing, Packing, or A 483 is normally published, but with- Holding of Drugs; General out naming the company or product Part 211: current Good Manufacturing names concerned. Practice (see cGMP, p. 16) for Fin- Depending on the relevance of the ished Pharmaceuticals documented defects, a Warning Letter 21 CFR 210/211: contains very de- is created on the basis of the 483. See tailed GMP guidelines for the USA. Warning Letter, p. 62. 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 Action Limits Airlock Concept A limit value stipulated by laws, direc- Airlock Concepts consist of several tives or internal company provisions. If rooms, arranged one behind the other, this value is exceeded, then corrective which allow the transition of persons actions must be initiated without de- and material from a cleanroom area lay, accompanied by analysis of the to a cleanroom area with a higher or failure and removal of the cause. lower level of purity, without contami- nating one of the areas. Active Pharmaceutical Ingredient (API) Annex The medically (pharmacologically) Annexes are various appendices to active ingredient in a drug. the EU GMP Guidelines. Currently there’s Annex 1 to Annex 19, there is ADI (Acceptable Daily Intake) no longer an Annex 18. Annex 18 was The ADI specifies the amount of a published in 2005 as EU GMP Guide- certain substance, e.g. of an active lines Part II. pharmaceutical ingredient, that does not present any health risk, on the assumption that a person is exposed to it on a daily basis over a lifetime.

11 GxP Dictionary Terms and Definitions

Annual Product Review (APR) of authorities other than the compe- A retrospective review of the history tent supervisory authority such as the of a drug, required by the FDA for FDA) and, in terms of how it is defined, products manufactured in or imported is separate from an inspection, which into the USA, undertaken on an annual may be carried out exclusively by the basis. competent supervisory authority, i.e. inspectors of the state authorities. API See Active Pharmaceutical Ingredient Audit Trail (API), p. 11. This is used to ensure the complete traceability of all activities, actions and APR system states by recording “traces”, See Annual Product Review (APR), which indicate when, by whom and/ p. 12. or what, a process was influenced. It usually consists of records of com- Audit puter and software systems and is Inspection or survey of a site (e.g. a required by 21 CFR Part 11 as well as company, a production site) for the Annex 11 (EU GMP). purpose of verifying compliance with the requirements it is supposed to Authorization fulfil (here: compliance with the GMP Authorization refers to the marketing regulations and their specifications). authorization for a medicinal product. An audit can be carried out by various In this regard, the product must always bodies (e.g. representatives of con- conform to the GMP. tracting authorities or representatives

12 B A Batch Batch Record Review B A homogeneous and defined quantity Batch Record Review is a system of starting material, medicinal prod- that collates all the information about ucts or packaging material produced the batch certification. For example, in a single operation or in a series of these include batch production and operations. test reports, as well as all records of deviations and OOS reports (see Batch Documentation Out-of-Specification (OOS), p. 40). The Batch Documentation includes This information is used by the QP instructions and protocols on manu- (Qualified Person) as the basis for facturing and packaging procedures, making decisions regarding the release as well as the test report. This enables of a batch (batch release). the entire history of a batch to be traced without any gaps. The Batch Documentation serves as a basis for the batch release and is particularly important when, at a later stage, quality defects are identified which were not detectable at the time of release.

13 GxP Dictionary Terms and Definitions

Biological Safety Cabinet (BSC) Bulk Ware This is often used in microbiological or = Any product which has passed analytical laboratories and is a “room through all processing stages except within a room” concept to protect for final packaging. employees and the environment, along with the product, when carrying out critical processes. Class I: BSC with work access open- ing; prevents airborne suspended contamination via inward flow of air and filtration of the exhaust air. Class II: BSC with work access open- ing; reduces the risk of cross-/product contamination via filtered circulating air and filtration of the exhaust air. Class III: BSC (e.g. isolator) with completely closed-off working area (physi- cal barrier). Intervention in the working area is possible, e.g. using gloves.

BSC Class III: Isolator (image: Franz Ziel GmbH)

14 C Calibration CEP (Certificate of Suitability B Calibration is the comparison of a of Monographs of the European C reading or a material measure with the Pharmacopoeia) correct value under stipulated condi- The certificate confirming that a drug tions, documentation of the deviation, has been produced in line with the calculation of the measurement uncer- monographs of the European Pharma- tainty and creation of the certificate copoeia. or calibration certificate. One of the most important criteria for professional CFR calibration is complete metrological = Code of Federal Regulations: traceability to national and internation- Federal regulations of the USA. al standards. Example: 21 CFR 210 and 211.

CAPA CFU (Colony-Forming Unit) See Corrective Action/ Used for the qualification of micro-or- Preventive Action (CAPA), p. 20. ganisms/germs in microbiology. In a wipe test, for example, nutrient medi- Capacity Test um is applied to a surface for a cer- The Capacity Test is a long-term tain time (e.g. 10 seconds). Following stress test to show whether an (IT) incubation of the nutrient medium, the system remains functional even under micro-organism multiplies and be- full load over the long term. Possible comes visible as a colony (= CFU). capacity limits are therefore visible. For instance, a document management system should launch the correct workflow following a document becoming valid, even if, for example, hundreds of documents become valid at the same time.

CFU on agar plate 15 GxP Dictionary Terms and Definitions

cGMP Clean Corridor Principle = current Good Manufacturing Prac- Protection concept for preventing tice: Since the US GMP guidelines are cross-contamination. Here, a spatial continuously being revised, the correct arrangement is provided, in which the name is cGMP. Whereas in Europe corridor, which leads to various pro- the guidelines are only updated as cessing areas, is the space with the required, so the c (current) is not nec- highest pressure. Thus, the overflow essary. So its title here is just GMP. is directed towards the production rooms, which prevents a product from Challenge Test being discharged into another area. Challenge Test refers to a qualification or validation test under worst-case Cleaning Validation conditions. This method is often sup- The Cleaning Validation is documented plemented by the deliberate induce- proof that a cleaning procedure can be ment of faults in order to prove that used to achieve a plant status that is these can be detected and remedied suitable for the production of medic- or prevented by the actions taken. inal products. The effectiveness and reproducibility of the entire cleaning Change Control procedure is verified to this end. Formal system for maintaining the de- The four decisive parameters that fined status, e.g. the validation status. influence the success of the cleaning A systematic, risk-based assessment are portrayed in the Sinner’s circle: is carried out, to find out what meas- Chemistry, mechanics, temperature ures are required due to an intended and time. Another prerequisite for or actual change, in order to maintain successful cleaning is GMP-compliant GMP conformity and, for example, plant design. the specification. These measures are assessed by qualified representatives of the relevant department.

16 Cleanroom Cleanroom Classes A cleanroom is a room designed so In DIN EN ISO 14644-1, the different C as not to exceed a defined particulate cleanroom classes (ISO 1 – 9) are and microbiological contamination. In classified according to the maximum accordance with the purity specifica- permissible particle concentration (in tions that this type of room fulfils on particles per cubic metre of air). ISO a permanent basis, a purity classifi- class 1 is the cleanroom class with cation is attributed to it. Moreover, a the lowest permissible particle con- cleanroom is equipped with airlocks centration. In the EU GMP guidelines, and access protection. the letters A to D are assigned to the cleanroom classes, and a distinction is also made between production and idle state.

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

17 GxP Dictionary Terms and Definitions

Cleanroom Principle Computer Validation The Cleanroom Principle is a protec- = Validation of computerized systems: tion concept that works via a shell According to the EU GMP Guidelines, model with overpressure to adjacent a computer consists of “a combination areas of low air purity. The overflow of hardware components and associ- therefore moves away from the clean- ated software, designed and put to- room, preventing any impure air from gether in order to carry out a specific getting into the cleanroom. function or group of functions”. During computer validation, the suitability of Compliance this hardware/software conception Conformity of conditions with stand- for achieving the required functions is ards and specifications. GMP com- checked and the results documented. pliance is therefore compliance with the GMP Regulations, i.e. the relevant Concurrent Validation laws, directives and guidelines (e.g. The validation takes place while the EU GMP Guidelines). products intended for subsequent sale are being manufactured. Commence- Computer System/ ment of routine production prior to the Software Validation (CSV) completion of the validation process See Computer Validation, p. 18. must be justified, documented and ap- proved by authorized personnel. The validation batch is only released for trading following successful validation.

18 Conformity Continued Process Verification See Compliance, p. 18. (CPV) C See Continuous Validation, p. 19. Containment Containment of a biological agent Continuous Validation or other substance within a defined Validation is no longer seen as a tem- space. Primary containment: Prevents porary, one-off activity, but as a per- leakage into the immediate work envi- manent verification that accompanies ronment (e.g. via closed containers). the process over the entire period, Secondary containment: Prevents from the design phase through to the leakage to the outside or into other market withdrawal of the product. work environments (e.g. via rooms with The new process validation approach special ventilation systems/airlocks). therefore consistently follows the life-cycle model. In a broader sense, Contamination therefore, each batch produced is a The unwanted introduction of foreign validation batch. substances or impurities, chemical or microbiological, into or onto a starting Continuous Validation/Verification material or intermediate or finished See Continuous Validation, p. 19. product during manufacture, sampling, packaging, storage or transport.

19 GxP Dictionary Terms and Definitions

Corrective Action/ Corrective and Preventive Actions Preventive Action (CAPA) See Corrective Action/ Systematic approach that includes Preventive Action (CAPA), p. 20. both corrective and preventive actions. Corrective Action: Action taken to CPV eliminate the cause of a fault in an Continued Process Verification (See identified, undesirable situation and Continuous Validation, p. 19) to have a strong chance of preventing recurrence in other areas too or in CSV another procedure. = Computer System Validation/Com- Preventive Action: Action taken to ac- puter and Software Validation (See tively prevent the cause of a potential Computer Validation, p. 18). failure. This is often done with the aid of risk analyses.

20 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 is D changes have been made to the pro- suitable for its intended purpose. The cess since the validation. In that case, DQ, which is carried out prior to pur- evaluating the process and product chasing the equipment, covers docu- data for the last period is sufficient; mentation of the planning phase and there is no need to check the validated incorporates the decision-making with status for specific batches. regard to purchasing a plant. The requirements for the planned installation should be defined and specified. The elements of the DQ are usually: • The design qualification plan • The user requirement specification • 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.

21 GxP Dictionary Terms and Definitions

Deviation Disaster Recovery In general, a deviation may be de- = Recovery following an IT blackout; scribed as a result or a situation within This includes the recovery of important a process which does not comply with data as well as the repair or replace- the plan or expectations or even a ment of destroyed hardware compo- specific related provision. Examples of nents. these are deviations involved in quality control, monitoring or product specifi- DMS cations. Document Management System (DMS) p. 22 Deviation Management Deviation Management is the stand- Document Management System ardized, controlled handling of a de- (DMS) viation. This includes the detection, Electronic document management analysis or monitoring and also reme- system (therefore also often called dying of a deviation. Both the causes eDMS) in the form of an IT solution. of a deviation and the related implications must be recorded and classified. DQ This procedure ensures that failures See Design Qualification (DQ), p. 21. and their consequences are corrected efficiently, and enables early detection of critical situations as well as the implementation of appropriate coun- termeasures in future.

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

23 GxP Dictionary Terms and Definitions

eDMS EP See Document Management System = European Pharmacopoeia: Pub- (DMS), p. 22. lished by the European Directorate for the Quality of Medicines & Health EMA Guideline Care (EDQM); this contains the official = Guideline issued by the European standards and methods applicable to Medicines Agency, e.g. on human and medical devices and pharmaceutical veterinary drugs, health protection and substances within the EU. GDP (see GDP, p. 30). ETA EMA/EMEA See Event Tree Analysis, p. 25. = European Medicines Agency: The EMA is a decentralized EU agency EU GMP Guidelines based in London. Since 1995, it has = Good Manufacturing Practice guide- been responsible for the scientific lines: The first version of these guide- evaluation of medicinal products de- lines, in which the European directives veloped by pharmaceutical companies are implemented in detail, was pub- for use within the European Union. lished in 1989. It now consists of 3 The EMA plays a central role in drug parts in addition to Annexes 1-19. registration within the EU and the EEA Part I: GMP principles for the manu- States, since the European Commis- facture of medicinal products. sion issues authorizations on the basis Part II: Good Manufacturing Practice of its assessments. for active substances. Part III: GMP-related documents (including Quality Risk Management).

24 European Pharmacopoeia See EP, p. 24.

Event Tree Analysis E The “Event Tree Analysis” is a method for determining the possible consequences that are triggered by a failure. From an initial failure, a tree diagram is developed via various paths, which represent the possible reactions of the individual system components, culminating in all possible failure consequences and implications.

Adverse event

Consequence 1.0 Consequence 2.0

Consequence 1.11 Consequence 1.12 Consequence 2.11 Consequence 2.12

25 GxP Dictionary Terms and Definitions

F Factory Acceptance Test (FAT) FDA Acceptance/control of ordered devic- = U. S. Food and Drug Administration; es and plants on site at the supplier’s the FDA is the highest health authority premises. The Site Acceptance Test in the USA and is responsible for drug (see Site Acceptance Test (SAT), licensing. In order to ensure com- p. 56) is usually carried out after pliance with the standards also with delivery and installation. regard to the many medicinal products imported into the USA, the FDA op- Fault Tree Analysis erates internationally and carries out In Fault Tree Analysis, the tree dia- audits among exporting producers gram, in contrast to the event analysis outside the USA. (see Event Tree Analysis, p. 25), pro- gresses from the failure to the cause. In other words, this explores the most likely cause or combination of causes of a fault.

Adverse event

Basic event Basic event Basic event Basic event

26 FDA Guidance for Industry – Fishbone Diagram/Method Process Validation The Fishbone method (also Ishikawa Contains non-binding recommendations diagram) is a graphical method for dis- for implementing the process validation, playing failures/causes and resultant which are based on the current perspec- effects (consequence of failures). Its tive of the US FDA agency. It is impor- name is derived from the visual simi- tant to note that it is possible to also larity to a fishbone. focus on other guidelines, provided that The method is often also named after compliance with all GMP regulations is the person who developed it, Kaoru ensured. Ishikawa. Thanks to the form of pres- entation, this method imparts a good understanding of the process, which leads to a clear objective.

Cause Effect F Man Machine Environment

Problem

Material Method Measurement

Main causes Sub-causes

27 GxP Dictionary Terms and Definitions

FMEA (Failure Mode and Effects Analysis) FMEA is a risk analysis method, which of components in a complex system is used to analyze individual failures (system FMEA), the design of prod- as well as failure consequences and ucts or components (design FMEA) or causes. It is widely used in industries the steps of a production or service where there are high standards with process (process FMEA) are con- respect to product and process relia- sidered. In the FMEA, a Risk Priority bility. The FMEA is currently the most Number (see Risk Priority Number frequently used method for systematic (RPN), p. 54) is determined for each risk analysis in the pharmaceutical individual sub-step in a process. If industry and can also depict extremely this exceeds a pre-defined limit value, complex considerations. Depending risk-reduction measures need to be on the type of FMEA, the interaction taken.

28 FMECA (Failure Mode, Effects and FTA Criticality Analysis) See Fault Tree Analysis, p. 26. FMECA is an extension of the FMEA (see FMEA (Failure Mode and Effects Functional Specification Analysis), p. 28) to include the “crit- The Functional Specification contains F icality” factor or the “magnitude of the the contractor’s comments on the consequences of a failure”. implementation and processing of a project (e.g. construction of a facility). Formulation It is the supplier’s detailed description The formulation of a medicinal prod- for the implementation strategy of the uct includes its preparation with the Requirement Specification, and should appropriate ingredients as well as its therefore contain all the obligatory form (dosage form). Once the formula- requirements referred to therein. Often tion process of a product is complet- no separate Functional Specification ed, it is referred to as bulk ware. is created. Instead it is replaced by the contractor’s corresponding offer, provided that this has been adequately detailed.

29 GxP Dictionary Terms and Definitions

G GAMP = Good Automated Manufacturing GMP Practice; refers to the validation of = Good Manufacturing Practice; good computerized systems. manufacturing practice for medicinal products: Sum total of national and GCP international rules relating to medicinal = Good Clinical Practice; valid for product manufacture and quality as- clinical trials: Quality requirements for surance, which are intended to protect planning and conducting clinical trials. public health and to protect consumers from dubious products. GDP = Good Distribution Practice: Con- GMP-Compliant Plant Design trolled, safe drug distribution channel, Plant planning and construction, from leaving the manufacturer through which is based on the GMP regula- to the end consumer. tions and aims to optimize subsequent GMP-compliant operation, for example GEP easily accessible and cleanable ma- = Good Engineering Practice; relevant chine components. to engineering: Good and effective planning of plants. GSP = Good Storage Practice; relevant to GLP storage: Storage under controlled, = Good Laboratory Practice; relevant constant conditions (temperature, to laboratories: Validation of non-clini- humidity, light). cal safety tests and procedures. GxP = Good x Practice; umbrella term for specific GMP-regulated sub-areas, e.g.: GAMP, GCP, GEP, GLP, GDP, GSP.

30 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 starting implemented properly, that the pro- materials, intermediate and final prod- duction process is validated and that ucts, the approval of specifications, the production personnel are trained. the validation of test procedures and The Head of Production must have a the training of personnel in his di- G sufficient professional qualification. vision. Statutory requirements with H Appropriate proof of qualification and respect to the Head of Quality Control reliability (certificate of good conduct) are the reliability required to carry out must be submitted to the supervisory his tasks and activities, as well as authority. familiarity with the products and pro- The Head of Production must always cedures. be independent of the Head of Quality Control.

31 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 (see Qualified Person (QP), nize the criteria for the authorization p. 48). The Information Officer is of a medicinal product in Europe, the responsible for releasing scientific USA and Japan. The European Com- information about the medicinal prod- mission, the FDA, and also the Jap- uct and, in this respect, is responsible anese Ministry of Health Labour and for compliance with the principle of Welfare (MHLW) are members. not misleading. He must ensure that 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.

32 In-Process Controls IPC = Tests carried out during ongoing See In-Process Controls, p. 33. production. The aim is to monitor and, where necessary, adapt the process to IQ the given specifications. In a broader See Installation Qualification (IQ), sense, inspection of the environment p. 33. and equipment may also be consid- ered part of the in-process controls. Ishikawa Diagram/Method See FDA Guidance for Industry – Pro- I Installation Qualification (IQ) cess Validation, p. 27. The installation qualification documents the correct implementation of ISO 13485 previously defined requirements with ISO 13485 defines the content and respect to the installation and modifi- structure of the quality management cation of the plant. The IQ is primarily system for medical devices, which can based on the specifications written in be applied to the design and develop- the DQ (see Design Qualification (DQ), ment, production, installation and also p. 21). The relevant documents are maintenance of medical devices. It is checked to make sure they are com- derived from ISO 9001, and adds to this plete and correct, and updated and the specific requirements for the field of supplemented where necessary. Fur- medical devices. thermore, the IQ documents prove that all equipment components were de- livered, assembled and installed pro- fessionally 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).

33 GxP Dictionary Terms and Definitions

ISO 14644 ISO 14644 deals with cleanrooms and • 14644-7: Separative devices (clean- contamination control. The products air hoods, glove boxes, isolators and and processes that benefit from con- mini-environments) trolled airborne contamination include • 14644-8: Classification of air clean- those used in the aerospace, micro- liness by chemical concentration electronics, pharmaceutical and food (ACC) industries as well as in medical tech- • 14644-9: Classification of surface nology and healthcare. In addition to cleanliness by particle concentration the particle purity of the air, lots of ad- • 14644-10: Classification of surface ditional aspects need to be taken into cleanliness by chemical concentra- consideration in the planning, speci- tion fication, operation and monitoring of • 14644-12*: Specifications for mon- 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 • 14644-1*: Classification of air clean- for use of equipment by airborne liness by particle concentration particle concentration • 14644-2*: Monitoring to provide * currently under revision, new release expected in evidence of cleanroom performance 2015 related to air cleanliness by particle concentration • 14644-3: Test methods • 14644-4: Design, construction and start-up • 14644-5: Operations • 14644-6: Vocabulary

34 ISPE = International Society for Pharma- ceutical 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 I are involved in preparing the FDA (see FDA, p. 26) and EMA (see EMA/ EMEA, p. 24) guidelines and publish their own ISPE Guides. These ISPE Guides are extremely detailed and are state-of-the-art for the pharmaceutical industry.

35 GxP Dictionary Terms and Definitions

L Life-Cycle Approach Logbook Quality assurance approach, to ensure A logbook is used for continuous that all QA measures (risk manage- documentation of critical items of ment, qualification, validation, etc.) equipment. These generally include depict the complete life cycle of a machinery, plants and devices, and plant or process. The entire concept in particular ventilation systems, wa- must be designed for the life-cycle of ter systems and rooms. The logbook a process or the product. records all validations, calibrations, maintenance work and repairs, clean- Life-Cycle Model ing and sterilization as well as all mod- See Life-Cycle Approach, p. 36. ifications, conversion work and, where necessary, further operations.

36 M Major Change Matrixing Major Changes refer to changes to Matrixing is a cleaning validation the process/to a plant that require method with the objective of reducing monitoring, and which influence the the scope of validation overall. The product quality and/or process safe- approach is equipment-based imple- ty. Examples of this are changes in mentation. manufacturing/production, a move in the sense of a change of location or Method Validation (analytical) changes in the composition/process Proof that an analytical method, as parameters. specified in the test instructions, provides correct and reliable results. The Material Flow text and methodology are harmonized Material Flow is the coordinated se- in the ICH Q2 for the EU, Japan and L quence of individual production and the USA. M storage steps, from the raw materials 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.

37 GxP Dictionary Terms and Definitions

Metrological Traceability Minor Change The property of a measurement result Minor Change refers to a change that or of the value of a standard, whereby requires monitoring, and which has the result can be related to appropriate an influence on a unit that requires stated references, usually interna- monitoring. This includes, for example, tional or national standards, through replacing a component, changing a an unbroken chain of comparisons, detergent or changing the laundry for which all have stated measurement work clothes. uncertainties; metrological traceability is thus ensured by relating measure- Monitoring ment results to international or national Monitoring compliance with specified standards via an unbroken chain of parameters, e.g. monitoring the air calibrations. cleanliness or monitoring the room climate in cleanrooms.

38 N O NOAEL Official Calibration = No Observed Adverse Effect Level: Official Calibration is the official check Maximum dose of a substance with no for compliance with the calibration negative observable effect. failure limits. An Official Calibra- tion is carried out exclusively by the NOEL Landeseichamt. Only those measuring = No Observed Effect Level: Maximum instruments and material measures dose of a substance with no observa- with a type approval can be officially ble effect or critical effect. calibrated. In contrast to Calibration, during Official Calibration no deviation from the test specimen to a reference is determined. Instruments used to protect consumers and to protect the legal status (e.g. water meters, counter scales, traffic radar gauges) are pri- N marily subject to Official Calibration. O

OOS See Out-of-Specification (OOS), p. 40.

OOT See Out-of-Trend (OOT), p. 40.

39 GxP Dictionary Terms and Definitions

Operational Qualification (OQ) Out-of-Specification (OOS) Documented evidence that facilities, A result that does not meet the spec- plants and equipment, as installed or ification. modified, are functioning within the framework of all the intended operat- Out-of-Trend (OOT) ing areas as prescribed. A result which is still within the spec- The OQ documents that all plants, ifications, but owing to the fact that it including all related pieces of equip- does not correspond to the observed ment, can be operated in line with the trend over an extended period, exhib- specifications. Furthermore, the con- its a certain abnormality. trol of the operating parameters must conform to the previously determined definitions.

OQ See Operational Qualification (OQ), p. 40.

40 P Parenterals Performance Qualification (PQ) Parenteral means “bypassing the Proof of the long-term specification digestive tract”. Accordingly, the conformity of a plant during operation. European Pharmacopoeia defines Here, the interplay or compilation of Parenterals as “sterile preparations all plant components is checked and which are intended for injection, infu- the performance limits are tested. sion or implantation into a human or As a result, differentiation between animal body”. Enteral resorption and Performance Qualification and Pro- therefore the non-specific immune cess Validation is not always clear. system (saliva, gastrointestinal tract) The Performance Qualification can be are bypassed. Therefore, impurities in differentiated to the extent that prod- parenterals are associated with high uct-specific proof of the effectiveness health risks. and reproducibility of the device/plant is to be provided. Particle Monitoring Particle Monitoring is used to monitor O particulate air cleanliness. Excessive P particle loading can result in excessive contamination of the relevant product with particles, but also with microbiological organisms.

41 GxP Dictionary Terms and Definitions

Personnel Flow Pharmacology A well thought-out, coordinated flow Pharmacology is the study of the of personnel is a prerequisite for interactions between drugs and living GMP-compliant production. organisms. It forms part of the implementation of the hygienic zone concept and pre- PIC/S vents cross-contamination. = Pharmaceutical Inspection Cooper- It is also used for the product and per- ation Scheme; merger consisting of sonnel protection. The term “Personnel lots of member states from all over Flow” encompasses requirements to the world, which has set itself the allow access to pharmaceutical areas goal of working together to further only via airlocks and changing areas, develop GMP and harmonizing the to only employ appropriately trained resulting regulations. In addition, in personnel, and to constantly determine order to prevent multiple inspections, the number of people required for the mutual recognition of inspections operating, monitoring and maintaining is to be improved and the movement the facilities. of medicines simplified by dismantling trade barriers. The PIC/S issues PIC/S Pharmaceutical Excipient Guides and PIC/S Recommendations. 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.

42 Postal Audit Primary Packaging A Postal Audit is carried out without an The Primary Packaging is the part of actual visit to the company being au- a package that immediately surrounds dited. Instead, a comprehensive ques- the product, i.e. is in direct contact tionnaire is sent by the auditor to the with it. Thus, primary packages are supplier, who independently fills this in often made of aluminium, glass or 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 (PPQ), p. 44.

Primary packaging of medicinal products PQ See Performance Qualification (PQ), Process P p. 41. Any defined organizational sequence or step in a process chain related to PQR the procurement, handling, manu- See Product Quality Review (PQR), facture and distribution of medicinal p. 45. products. Processes are clearly defined and clearly differentiated with regard to responsibilities.

43 GxP Dictionary Terms and Definitions

Process Capability Process Performance Qualification Process Capability means that a (PPQ) process is manageable, stable and The PPQ is part of the new Life-Cy- conforms to the specifications. This is cle Approach, and replaces or in- the case if the critical parameters are cludes DQ (p. 22), IQ (p. 33), OQ only subject to purely random variation (p. 40) and PQ (p. 43) of the exist- (normal distribution) and the corre- ing validation approach. The stability sponding values are within the upper of the process must be demonstrated and lower control limits/tolerance in the PPQ (see Life-Cycle Approach, limits. p. 36).

Process Capability Study Process Validation (PV) Statistical method for comparing the Process Validation is documented process information with the permis- evidence that the process, within sible tolerances, to draw conclusions certain parameters, produces a me- about the process capability. dicinal product that fulfils predefined specifications and quality attributes, in a manner that is effective and reproducible. Here, it must be demonstrated that even difficult-to-control critical process steps follow a predefined sequence and the overall process is completely reproducible - with consistent quality and in compliance with the specifications. The scope of the PV is determined by risk management.

44 Product Quality Review (PQR) Prospective Qualification Periodic Product Quality Review; Qualification of a new plant before the regular quality reviews of medicinal start of production. products, with the aim of confirming the consistency of the current process Prospective Validation and the adequacy of the current speci- Validation before the start of produc- fications for both the starting materials tion/marketing of a pharmaceutical and for the finished product, in order product. to highlight trends and identify product and process improvements. The PQR PV (Process Validation) should be carried out annually, taking See Prospective Validation, p. 45. into account previous review results.

Product Specification A Product Specification should include all the information necessary for preparing the precise written instructions P for processing, packaging, quality control, batch release and shipment of a product.

45 GxP Dictionary Terms and Definitions

Q QA Qualification Master Plan See Quality Assurance (QA), p. 49. The Qualification Master Plan is a superior document which depicts the QbD qualification strategy and organization- See Quality by Design (QbD), p. 49. al structure in general. The individual qualification objects are defined and QP the necessary qualification steps are See Qualified Person (QP), p. 48. described, with the type and scope of qualification activities. It therefore Qualification serves as an overview of equipment Qualification is documented proof that and plants with regard to scheduling, a device/plant is suitable for the in- and defines the appropriate responsi- tended purpose, to fulfil the specified bilities for completing the qualification functions or to produce products, and activities. that these meet the regulations and standards on a permanent basis (= are GMP-compliant, see GMP, p. 30).

46 Qualification Plan Qualification Report The Qualification Plan contains the The Qualification Report always rep- goal, subject and scope of the qualifi- resents the conclusion of a qualifica- cation, the designation of persons and tion. All results are summarized here. responsibilities within the qualification Changes to the test plans and any de- team and the description of the quali- viations must be documented accord- fication strategy. Key components are ingly. It should be noted that at this the detailed designation of individual point, all critical deviations must be tests, the descriptions relating to their remedied, only non-critical deviations implementation, and the correspond- can be accepted with appropriate jus- ing acceptance criteria (also referred tification. The report must also include to as test plans, which may also be the maintenance programs, recalibra- separate from the qualification plan). tion data, operating instructions, SOPs Furthermore, the plan should describe and the qualification status of the the qualification object and, if neces- installation. The Qualification Report is sary, the process, should indicate the a prerequisite for clearance to use the critical plant parameters and include a plant or for validation. list of documents. The document must finally be released. Q

47 GxP Dictionary Terms and Definitions

Qualified Person (QP) Qualified Person for The Qualified Person must have proof Pharmacovigilance of the necessary expertise (authorized The tasks of the Qualified Person for pharmacist or medical/scientific de- Pharmacovigilance include: gree with additional qualification). Ad- • Collecting reports on drug risks, ditional requirements are the reliability assessing them and coordinating required to carry out the tasks and necessary actions activities as well as sufficient familiar- • Monitoring clinical trials with regard ity with the products and procedures. to drug risks The Qualified Person is responsible for • Identifying serious side effects, compliance with the relevant regula- interactions or misuse tions governing the manufacture, test- • Notifying supervisory authorities in ing and release of medicinal products the event of an abnormal restriction prior to placing a drug on the market. of supply (stopping deliveries, re- His tasks therefore include: call). • Placing the batch release on the The Qualified Person for Pharmacovig- market ilance must have appropriate expertise • Securing Reserve Samples in the form of a completed university • Checking whether a company’s QM degree plus at least two years of pro- system is being maintained fessional experience. In principle, he • Being responsible for complete doc- should work independently of sales umentation, to demonstrate compli- and distribution units; however, it is ance with all regulations. possible for him to act as the Qualified Person at the same time.

48 Quality Assurance (QA) Quality Management Manual Quality Assurance is a far-reaching The Quality Management Manual is concept which covers all the areas a superior, binding document which that individually or collectively control depicts a company’s quality policy and the quality of a product. It constitutes guidelines. As an essential element for all the planned measures, undertaken long-term implementation of the qual- to ensure that medicinal products are ity management system, it includes of the quality that is required for their a description of the operational and intended use. organizational structure and refers to the relevant procedures, standards Quality by Design (QbD) and regulations. Quality by Design is a holistic, risk- based approach to the development and manufacture of medicinal products, which aims to develop a process that identifies critical, quality-relevant steps, measures their impact, and determines this within a specified “design space”. Q

49 GxP Dictionary Terms and Definitions

Quality Risk Management (QRM) (Quality) Risk Management is a systematic process for the assessment, control, communication and monitoring of risks to the quality of medicinal products over the entire life-cycle of the product. According to ICH Q9, the assessment of quality risks should be based on scientific knowledge and should always be viewed in the con- text of patient protection. This requires extensive knowledge of the process as well as clearly defined framework conditions. Quality Risk Management includes risk assessment, risk control, risk monitoring and risk communication. (see Risk Assessment, p. 53, Risk Monitoring p. 54, Risk-Based Quali- fication Systems p. 53, Risk Control p. 54)

50 R RABS Requalification See See Restricted Access Barrier Qualification following changes or System (RABS), p. 52. periodic, cyclical inspection of critical parameters to ensure that the plant/ Reproducibility device is still in a qualified state. Reproducibility is understood to be consistent product quality and invari- Requirement Specification able production processes. A process Forming part of the qualification, the is GMP-compliant only if its result is requirement specification documents reproducible. This is the only way to the requirements of the client regard- ensure that, for example, when testing the scope of delivery and services. ing a batch by random sampling, the These technical or regulatory require- findings obtained from this can also be ments are defined by the relevant transferred to all the individual prod- departments (Engineering and QA) in ucts in this batch. collaboration with the operator. Con- tents of the requirement specification may be: • Purpose of the device/plant • Key technical data, such as sizing Q • Details of the design (materials, sur- R faces in contact with the product) • The nature of the control system • Warranty services/service requirements for the suppliers • Requirements with respect to materials and surfaces • Information about customer service (availability, response time, etc.) • Requirements for GMP compliance

51 GxP Dictionary Terms and Definitions

Reserve Sample active intervention is only possible us- A Reserve Sample is a sample, for ing gloves; the process itself remains example from a fully packaged unit separated from the operator. from a finished product batch, which is stored for identification purposes.

Responsibility Delimitation Agreement This completely and unambiguous- ly sets out the interfaces, tasks and responsibilities among those involved in the manufacture, handling and RABS (Image: Franz Ziel GmbH) distribution of a medicinal product. It provides the basis for legally secure Retrospective Qualification cooperation, which, for example, en- A Retrospective Qualification is a sures that all requirements for ensuring qualification for already established the quality of a medicinal product are systems or a qualification based on fulfilled. historical data. Retrospective Qualifi- cation can only be carried out if suffi- Restricted Access Barrier System cient data is available for subsequent (RABS) assessment and review of the critical RABS is a concept for isolating a ma- parameters. From a GMP perspective, chine, often used in aseptic produc- a Retrospective Qualification is no tion or as personal protection in the longer accepted. case of highly active substances. As a mixture of conventional cleanroom technology and isolator technology,

52 Returns Risk Assessment The return of a medicinal product to The goal of the Risk Assessment is to the manufacturer or distributor, re- identify hazards, as well as to analyze gardless of whether or not there is a and assess the risks arising from these quality defect. hazards. To this end, the problems and issues posed by the risk must first Revalidation be clearly defined as part of the Risk A periodic, cyclical inspection or rep- Assessment. Firstly, potential hazards etition of a validation to ensure that are identified (risk identification), as a changes to the process or equipment result of which the Risk Analysis takes made in accordance with certain place (what is the probability of occur- change control procedures do not rence and of detecting the fault?). impair the process characteristics or Finally, the Risk Assessment (what are the product quality. the consequences?/what is the extent of this?) is carried out. Risk Analysis (RA) The Risk Analysis forms part of the Risk-Based Qualification Systems Risk Assessment. In the Risk Analysis, The goal of the Risk-Based Qualifica- the assessment or weighting of the tion System is to ensure GMP compli- risk/possible failure previously iden- ance throughout the entire life-cycle R tified during the Risk Assessment is of a plant/device. To this end, the Risk carried out. In GMP-regulated areas, Analysis, i.e. determining the influ- the Risk Analysis is often carried out encing factors which have a negative using the FMEA method (see FMEA impact on product quality, is used as (Failure Mode and Effects Analysis), the basis for the qualification meas- p. 28). ures and for determining their scope. The effort put into the qualification and documentation of it are tailored to the seriousness and significance of the risks.

53 GxP Dictionary Terms and Definitions

Risk Communication Risk Management The findings obtained from the Risk See Quality Risk Management (QRM), Analysis process should be commu- p. 50. nicated throughout the quality risk management process; however, all Risk Monitoring decision-makers and participants Since the Risk Assessments made as really need to be informed about the part of the quality risk management conclusions, because identifying a only ever represent a snapshot, they risk can only contribute to the quality must be checked at regular intervals. assurance if all process participants This ensures the timeliness and suita- are informed about it and it can be bility of the Risk Assessment through- purposefully avoided. out an entire life-cycle, and takes account of changes or new sources Risk Control of failure and integrates these into the The goal of Risk Control is to reduce Risk Management. risks to an acceptable level. Appro- priate measures are established to Risk Priority Number (RPN) reduce a risk (Risk Reduction) or The formula for determining the Risk an acceptable risk is classified as Priority Number (RPN) is: non-critical (Risk Acceptance). RPN = P x S x D. Where the individual parameters are defined as follows: P = Probability of occurrence S = Severity of the failure D = Detection probability

54 S Risk Reduction Secondary Packaging Risk Reduction forms an integral The Secondary Packaging encloses part of Risk Control, and includes the Primary Packaging and, unlike measures to reduce the extent and this, is not in direct contact with the probability of a failure, or to improve product. or increase the detectability of a failure. The Risk Assessment should be Secondary Contamination re-evaluated once the appropriate Secondary Contamination refers to measures have been implemented and contamination of the product after the potential change assessed. manufacture, e.g. due to improper sampling, packaging or storage. Robustness Robustness describes the capacity of Self-Inspection a system/process not to respond to Self-Inspection is a critical evaluation external changes. and review of in-house processes. The Head of Production and the Head of Quality Control play a fundamental role in carrying this out. This internal quality audit is mandatory in the EU GMP Guidelines. R S

55 GxP Dictionary Terms and Definitions

Site Acceptance Test (SAT) SOP (Standard Operating SAT refers to the acceptance of a Procedure) device/plant after delivery. All the SOPs are documents that provide or- requirements specified in the Require- ganizational, administrative, and tech- ment Specification and the Functional nical information and instructions for Specification are checked as part of carrying out regularly recurring work this process. processes. They are aimed primarily at The Site Acceptance Test is used to a company’s employees and are in- determine the as-built state. Sub- tended to ensure that quality-relevant sequent changes must therefore be work is carried out correctly by every taken into consideration in the manu- employee right from the start. facturer’s technical documentation. Specification Site Master File (SMF) The Specification covers the entire = Company description; The Site Mas- scope of testing, including the test ter File (SMF) is an internally-generat- instructions, which are established ed company description for external for each specific product and which authorities and customers. This should are, in principle, based on the latest include general information about the developments in science and tech- company, the QM system, products, nology (e.g. pharmacopoeial mon- self-inspection and relevant plants. ograph, guideline on drug testing). Requirements for the SMF are ex- This includes the establishment of plained in the GMP Guidelines Part III. acceptance criteria as well as specific requirements for storage.

56 T Sterility Test Plan Sterility refers to the complete ab- A Test Plan is a document that de- sence of living micro-organisms, in- scribes the objective(s), design, meth- cluding their resting stages (such as odology, statistical considerations as spores). well as the organization of a test pro- spectively. Sterilization During Sterilization, all micro-organ- Third-Party Audits isms are killed or viruses inactivated Audit by a third party not direct- during reproduction and dormancy. ly involved in the manufacture of a Sterilization in GMP areas is carried product (not manufacturer or suppli- out physically by means of thermal er). For example, according to GMP processes (heat treatment) or chemical regulations, a pharmaceutical manu- processes (e.g. via ethylene oxide). facturer is required to audit its active Sterilization via high-energy radiation ingredient suppliers to ensure that the is also frequently used (e.g. gamma active ingredients were produced in radiation). accordance with Good Manufacturing Practice. Stress Test However, the pharmaceutical manu- A Stress Test is used to check the facturer can also use an appropriately stability of a product or process under qualified, impartial third party to have S extreme conditions (high temperatures, these mandatory audits carried out at T humidity, etc.). In the case of medic- the supplier. inal products, this includes the light stability test, for example.

Supplier Audit Auditing of a company/organization (supplier) by a customer. See Audit, p. 12.

57 GxP Dictionary Terms and Definitions

Traceability Track & Trace Traceability refers to the ability to trace Track & Trace refers to the individual all the steps and processes of a prod- labelling of each product, as well as uct, a batch or even a measure itself at the recording of every movement and a later date. every transportation step that a product goes through, from manufacture to Traceability Matrix end consumer. In the pharmaceutical The Traceability Matrix is used to industry, this method can be used to display the relationships between user combat product counterfeiting, be- requirements, technical requirements, cause the sale of each pharmaceutical specifications and test cases. It pro- product can be retraced in order to de- vides proof that the user requirements, termine where the product comes from via the technical requirements, have and whether it is an original or a copy. been fully converted into technical specifications, which the project man- ager is obligated to adhere to. It is also possible to link the Requirement Spec- ification and Risk Analysis requirements with the qualification tests.

58 U V URS (User Requirement Validation Master Plan (VMP) Specification) The Validation Master Plan (VMP) In the URS, the requirements for the specifies a company’s validation strat- device/plant being manufactured with egy and philosophy and summarizes respect to the product to be produced concepts, intentions, responsibilities are described from the user’s perspec- and procedures with regard to valida- tive. The URS, together with the tech- tion. According to EU GMP Guidelines nical and regulatory GMP requirements Annex 15, “all validation activities for the plant, forms the Requirement should be planned. The key elements Specification. 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.

T U V

59 GxP Dictionary Terms and Definitions

Validation Validation Plan Provision of documented proof, which The Validation Plan is written before provides a high degree of assurance the validation is carried out, and it that a specific process or a Standard contains information about the prod- Operating Procedure will produce a uct (specifications, analytical meth- product that conforms to the pre-de- ods) and about the process (process fined specifications and quality char- description including flow chart, RA) acteristics. The Validation therefore as well as about rooms and facilities provides proof that methods, process- (allocation of rooms, hygienic status, es, plants, equipment, materials and calibration status) and about the pro- systems bring about the expected re- cess validation (tests, sampling, ana- sults in accordance with the principles lytical methods, acceptance criteria, of Good Manufacturing Practice. timetable, responsibilities). Validation therefore ensures and documents the most important attributes Validation Report of a process: Reproducibility and The Validation Report is used to docu- Robustness. ment the validation. This contains the production protocol, which includes Validation Matrix the results of the in-process controls, A Validation Matrix is used to depict the results of the validation tests in- the relational links between the individ- cluding any deviations detected, and ual validation components (products, also the evaluation and assessment of processes, systems) and the assigned the validation and the related implica- actions (validation/qualification tasks). tions with regard to routine production, In order to simplify the overview when change control and, where necessary, it comes to complex validations, the revalidation. appropriate responsibilities and priori- ties should also be noted.

60 V Model In the so-called V Model, all activities Specification) p. 59, Functional and documents containing a qualifi- Specification p. 29, Corrective and cation and validation are depicted in Preventive Actions p. 20) and the their logical sequence. Moreover, the corresponding qualification documen- direct links between the requirement tation (PQ p. 43, OQ p. 40, IQ documents (URS (User Requirement p. 33) are demonstrated.

User requirements (URS) Performance Qualification (PQ)

Requirement Specification Operational Qualification (OQ)

Functional Specification Installation Qualification (IQ)

Risk Analysis

Design Qualification (DQ) Calibration

FAT SAT

Implementation/installation

V Model

61 GxP Dictionary Terms and Definitions

W Warning Letter Warning Limit A Warning Letter is issued by the FDA The Warning Limit is a defined limit (see FDA, p. 26) to a pharmaceu- value, which enables early warning tical company if critical deficiencies of possible deviation from regular were identified and not remedied operating parameters. This does not during a previous inspection (or au- necessarily involve corrective meas- dit). The team of inspectors lists the ures, but the cause does need to be deficiencies on the 483 form (see 483, investigated. p. 10). The 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 short- comings therein and the company concerned to the notice of the public.

62 WHO Work Directive = World Health Organization; See SOP (Standard Operating the World Health Organization is the Procedure), p. 56. superior authority of the United Na- tions when it comes to international Worst-Case Scenario healthcare. It is currently made up of The Worst-Case Scenario describes 194 member states. the most critical state that could pos- The WHO agenda contains six key sibly occur. This means, for example, points: that process parameters reach their • Two health objectives: upper or lower limit values, making it promoting development and pro- significantly more likely that process or moting health and safety; product failures will occur. • Two strategic requirements: strengthening the health system and utilizing research results, data and findings; • Two operational approaches: expanding partnerships and improving performance.

63 GxP Dictionary Terms and Definitions

Z ZLG = Central Authority of the Länder for Health Protection with regard to Me- dicinal 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.

64 Z

65 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

66 Notes

67 Subject to change, including technical modifications, without notice. modifications, without notice. change, including technical Subject to