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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, qual- ity 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 com- pletely 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 manage- ment system should launch the cor- rect 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 A Data Review can replace a practical C revalidation, assuming that no critical D changes have been made to the pro- cess since the validation. In that case, evaluating the process and product data for the last period is sufficient; there is no need to check the validated status for specific batches.

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