GMP Compliance Adviser: Updates Forecast & History

  • GMP MANUAL Update No. 22 (online version only)

    With this GMP MANUAL UPDATE you have direct access to all prime regulatory changes and to our GMP expert interpretations. Here are the new features at a glance:

    GMP in Practice

    3.B Material flow, personnel flow and layout
    3.I Qualification of premises and air-conditioning (HVAC) systems
    3.K Particle Monitoring (NEW)
    5.A Water qualities
    5.B Generation of pharmaceutical water
    14.B Substances used in laboratories (NEW, replaces former 14.B and 14.C)
    17.A Contract manufacture


    GMP Regulations

    C.5 EU GMP Guidelines, Part II – combined with APIC How to do-Guide on ICH Q7
    C.6.15 Annex 15: Qualification and Validation
    C.8.5.1 Importation of Active Substances for Medicinal Products for Human Use – Questions and Answers, Version 5.1
    C.8.6 NUMBERING MODIFICATION from C.19 to C.8.6
    C.8.7 Guidelines on the formalised risk assessment for ascertaining the appropriate good manufacturing practice for excipients of medicinal products for human use
    C.19 Reflection paper on the requirements for selection and justification of starting materials for the manufacture of chemical active substances
     

    GMP in Practice

    3.B Material flow, personnel flow and layout

    The design of the rooms with regard to size, layout and equipment does not only affect the quality of the pharmaceutical products, but also the cost-effectiveness of the production process. This includes the cost of investment, and the subsequent costs that depend on a well-designed material and personnel flow. The trick is to build quality rooms that meet the high standards required for both product and production processes while keeping the costs as low as possible. Different types of material flow design are presented and their pros and cons discussed. When the personnel flow is determined, the clean zone concept and lock design are extremely important. Material flow, personnel flow and layout are closely connected and can only be optimized in an iterating process. (Andreas Nuhn)

    3.I Qualification of premises and air-conditioning (HVAC) systems

    This chapter has been updated to reflect the current requirements of Annex 15 to the EU GMP Guidelines. When qualification of premises and utilities has to be planned, a distinction should be made between aspects necessary for the correct operation, where technical acceptance tests are sufficient, and aspects relevant for product and/or personnel safety, which require qualification. Point of departure for complex qualification tasks is a Qualification Master Plan. Subsequent to the preparation of the User Requirement Specification (URS), four qualification stages (DQ, IQ, OQ, PQ) are distinguished. Where complex technologies are involved, the qualification may be complemented by Factory (FAT) and frequently also Site Acceptance Tests (SAT). Successful completion of each qualification stage is documented by means of a qualification report. Detailed checklists are a powerful tool for establishing the exact extent of qualification activities. Examples are provided for each qualification step. HVAC systems require periodical requalification in appropriate intervals, where physical parameters and, where necessary, also microbiological parameters are to be verified. It is recommended to include a trend analysis into the requalification activities. Change control procedures covering all modifications to systems and their mode of operation continue to be in place throughout the entire life cycle of the facility and its utility systems. (Dr. Hans H. Schicht)

    3.K Particle Monitoring (NEW)

    Particle monitoring is an important part of cleanroom technology. Continuous and non-continuous (manual) monitoring of air cleanliness contribute significantly to QA in a cleanroom. Different types of particle counters are available for carrying out the measurements. The measuring principle based on the measurement of scattered light is the same in all of the devices, regardless of whether they are used in manual or continuous monitoring systems. Calibration with latex particles is carried out in the same way worldwide. This means that the measurement results for all cleanrooms are comparable. Automatic monitoring systems with different numbers of particle counters are available for different platforms. There are solutions that use computers as control and data recording systems. There are also systems that are integrated in the building control system and solutions that use built-in recorders. All of these systems have been developed and designed in such a way that they facilitate GMP-compliant monitoring. Particle counters with reduced functionality are available for use in monitoring systems. The selection of representative sampling locations can be a challenge. A risk evaluation and flow visualisation including the respective test measurements must be carried out to find suitable locations. (Thomas von Kahlden)

    5.A Water qualities

    This chapter provides information on the various water qualities that are used in pharmaceutical production: Purified Water, Highly Purified Water and Water for Injection. The author gives an overview on the fields of application and methods of generation for each type of water. The requirements of the European Pharmacopoeia and the US Pharmacopoeia are presented in detail. The physical and chemical tests include the determination of conductivity, tests for certain ions and the determination of TOC. All water qualities must undergo microbiological monitoring. (Dr. Herbert Bendlin)

    5.B Generation of Pharmaceutical Water

    Drinking water is generally used as source material for the generation of pharmaceutical water. It has to undergo pretreatment to remove substances that are not desired during further processing. This is often standard softening. For the generation of Purified Water, various processes are combined in treatment systems. Purified Water is used as the starting product for generating Highly Purified Water and Water for Injection. The functionality and potential application of different technologies such as ion exchange, reverse osmosis, electro-deionisation, ultrafiltration and the various technologies used during distillation are described in detail. (Dr. Herbert Bendlin)

    14.B Substances used in laboratories

    GMP-compliant handling of substances which are used in analytical quality control and the quality of these substances have a major impact on the accuracy and comparability of the analytical results. In other words, an accurate statement about the quality of a sample is only possible if the relevant process steps are carried out in a GMP-compliant manner and the quality of the substances used is adequate, traceable and documented. The proper handling of standard substances and reagents places high demands on the quality system and personnel. This also includes manufacture, procurement, quality control and documentation. The current GMP regulations and ISO guidelines provide comprehensive and detailed information. Special emphasis is placed on testing the suitability of standards and reagents for their intended purpose. This also has an impact on the required qualification strategies which have to be clearly defined and documented. Most of the required standards can be procured from official sources (preferred) and commercial sources. Alternatively, suitable substances can be qualified as standard substances within the company. Clear specifications on documentation, identification, expiry dates and storage conditions ensure seamless traceability of the impact of standard substances and reagents on the final result.The regular audits also focus on these aspects. (Dr. Markus Limberger)

    17.A Contract manufacture

    The outsourcing of manufacturing steps or even of the entire manufacturing process to a third party is a widespread practice in the pharmaceutical industry which is expressly provided for in the pharmaceutical regulations. Chapter 7 of the EU GMP Guidelines contains a detailed description of the requirements that apply to contract manufacturers. Even the selection of the contract manufacturer should be anchored in the quality risk management system. The most important selection criteria include the technological options of the contract manufacturer, previous experience with comparable products, but also financial and logistical aspects as well as the inspection history. The scope of outsourced activities can vary and is defined at the very start of the contractual relationship. Both the contract giver and contract manufacturer have responsibilities that must be specified in the contract. The responsibilities of the contract giver include the qualification of the contract manufacturer before they start carrying out their tasks and the introduction of a risk-based monitoring system after the start of contract manufacturing. The contract acceptor has to provide the required resources and must exercise due care when changes and deviations occur. During the product transfer, the product knowledge and knowledge of the manufacturing process have to be transferred in a systematic and sustainable way in order to minimise the risks for commercial manufacturing. Integrating the transfer into the risk management system helps ensure a successful transfer process and achieve the transfer targets. (Dr. Christian Gausepohl)

    GMP Regulations

    C.5 EU GMP Guide Part II: Basic Requirements for Active Substances used as Starting Materials combined with GMP for APIs: “How to do” Document by APIC/CEFIC Interpretation of the ICH Q7 Guide

    We have editorially combined the text of the latest APIC/CEFIC “How to do” document with Part II of the EU GMP Guide. This provides you with a valuable interpretation tool directly related to the regulatory text. In November 2000 the first GMP rules for the manufacturing of active pharmaceutical ingredients (APIs) were published by the ICH with the Guideline Q7A Good Manufacturing Practice for Active Pharmaceutical Ingredients. These standards were taken over in the EU GMP Guide Part II: Basic requirements for Active Substances used as Starting Materials in 2006. As an interpretation aid the APIC/CEFIC published a “How to do“ document – Interpretation of the ICH Q7 Guide shortly afterwards. The document was developed by experts of the European industry. It provides examples of commonly applied solutions and practical assistance on how requirements and recommendations can be met and/or interpreted.

    C.6.15 Annex 15: Qualification and Validation

    Since Annex 15 was published in 2001 the manufacturing and regulatory environment has changed significantly and an update is required to this Annex to reflect these changes. The revision to Annex 15 takes into account changes to other sections of the EudraLex, Volume 4, Part I, relationship to Part II, Annex 1, ICH Q8, Q9, Q10 and Q11, EMA guidance on process validation, and changes in manufacturing technology. The revised document now reflects the changed regulatory requirements and the latest state of technology in the pharmaceutical industry.

    C.8.5.1 Importation of Active Substances for Medicinal Products for Human Use Questions and Answers Version 5.1

    This documents sets out frequently asked 'questions and answers' regarding the new rules for the importation of active substances for medicinal products for human use. In this revised version Q&A 34 has been updated to refer to the EudraGMDP database for statements of GMP non-compliance.

    C.8.6 Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities

    Change of number: Previously numbered C.19, this document has recently been listed under Part III – GMP related documents of EudraLex-Volume 4. We have therefore modified our numbering accordingly.

    C.8.7 Guidelines on the formalised risk assessment for ascertaining the appropriate good manufacturing practice for excipients of medicinal products for human use

    This important document regarding GMP for excipients was published in March 2015. The requirements for ascertaining and ensuring appropriate GMP are set high: The manufacturing authorisation holder is required to ensure that the excipients are suitable for use in medicinal products by ascertaining what the appropriate Good Manufacturing Practice is. The appropriate GMP for excipients of medicinal products for human use has to be ascertained on the basis of a formalised risk assessment in accordance with these guidelines. It is emphasized that the excipient risk assessment/risk management procedure should be incorporated in the Quality Management System of the Manufacturing Authorisation Holder and that importers of medicinal products must have the risk assessment/management documentation for appropriate GMP for excipients available on site. A risk assessment according to these Guidelines should be performed from 21 March 2016 onwards.

    C.19 Reflection paper on the requirements for selection and justification of starting materials for the manufacture of chemical active substances

    This reflection paper aims to clarify some of the expectations of EU competent authorities arising from the guidance found in ICH Q11 regarding the information to be submitted in marketing authorization dossiers to justify the selection of starting materials. Whilst ICH Q11 is not generally applicable to veterinary products, the principles outlined in this document should apply equally for active substances destined to treat both humans and animals.

    Interested in using the GMP MANUAL?

    >>> More information & order: GMP MANUAL

    Read more
  • GMP MANUAL Update No. 21

    With this GMP MANUAL UPDATE you have direct access to all prime regulatory changes and to our GMP expert interpretations. Here are the new features at a glance:

    GMP in Practice

    3.C Air cleanliness classes and grades
    3.E Barrier systems, isolators and safety cabinets
    4.C Hygienic Design in solids handling
    4.I Containment in solids handling
    13.A Packaging materials (new author)
    19.J Coding and serialisation of folding cartons
    19.K Outsourced activities


    GMP Regulations

    C.4.3 Chapter 3 Premises and equipment
    C.4.5 Chapter 5 Production
    C.6.1.1 Concept paper on the revision of annex 1 - manufacture of sterile medicinal products
    C.12.1 Commission delegated regulation (EU) No 1252/2014 supplementing Directive 2001/83/EC for active substances for medicinal products for human use
    C.19 EMA: Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities
    D.1.5.1 FDA: Current good manufacturing practice requirements for combination products – Draft guidance
    E.3.D ICH Q3D: Guideline for elemental impurities
    E.12 ICH Q12: Technical and regulatory considerations for pharmaceutical product lifecycle management – Final concept paper
    Read more
  • GMP MANUAL Update No. 20 (online version only)

    What is new?

    GMP in Practice

    New Chapters:

    • Chapter 3 Premises
      • Chapter 3.J.6 Validation of a monitoring system in accordance with GAMP5
    • Chapter 13 Packaging
      • Chapter 13.D Blow-fill-seal technology (BFS technology)
    • Chapter 21 Active Pharmaceutical Ingredients
      • Chapter 21.G Biotechnological active substances

    Updated Chapters:

    • Chapter 3 Premises
      • Chapter 3.J Pharma monitoring of HVAC systems
    • Chapter 14 Laboratory controls
      • Chapter 14.H Test Results outside defined criteria (OOX)

    GMP Regulations

    New Chapters:

    • Chapter C EU Directives and Guidelines
      • C.16 Directive 2009/41/EC on the contained use of genetically modified micro-organisms
      • C.17 Directive 2000/54/EC on the protection of workers from risks related to exposure to biological agents at work
    • Chapter F PIC/S Guidelines
      • F.25 PIC/S PE 011-1 Guide to GDP for Medicinal Products
    • Chapter H WHO Guidelines
      • H.3 Guidelines on Quality Risk Management
      • H.6 Guide on transfer of technology in pharmaceutical manufacturing

    Updated Chapters:

    • Chapter A Information
      • A.2 GMP Abbreviations
      • A.3 GMP Glossary
    • Chapter H WHO Guidelines
      • H.1 GMPs for pharmaceutical products: main principles
      • H.2 GMPs for active pharmaceutical ingredients
      • H.4 Water for pharmaceutical use
      • H.5 GMPS for sterile pharmaceutical products
     
    Read more
  • GMP MANUAL Update No. 18

    What is new?

    GMP in Practice

    New Chapters:

    • Chapter 2 Personnel
      • Chapter 2.A Human Resource Management
      • Chapter 2.B Health Monitoring and Occupational Health and Safety
    • Chapter 19. Quality Unit
      • Chapter 19.A Quality Assurance Duties
    • Chapter 10 Quality Risk Management (formerly Considerations on Risk Management, completely new version)

    Updated Chapters:

    • Chapter 2 Personnel
      • Chapter 2.C Training

    GMP Regulations

    New Chapters:

    • Chapter C EU Directives and Guidelines
      • C.4.3.1 EU-GMP Guide Part I, Draft Chapter 3 Premises and Equipment
      • C.4.5.1 EU-GMP Guide Part I, Draft Chapter 5 Production
      • C.4.8.1 EU-GMP Guide Part I, Draft Chapter 8 Complaints, Quality Defects and Product Recalls
      • C.6.15.1 EU-GMP Guide Part I, Draft Annex 15 Qualification and Validation
      • C.6.16.1 EU-GMP Guide Part I, Draft Annex 16 Certification by a Qualified Person and Batch Release
      • C.14.1 Good Distribution Practice for Medicinal Products for Human Use Questions and Answers
      • C.17 Guideline on Process Validation for Finished Products – Information and Data to be Provided in Regulatory Submissions
    • Chapter D CFR and FDA Guidelines
      • D.6 Pharmaceutical CGMPs for the 21st Century – A Risk Based Approach
      • D.7 General Principles of Software Validation; Final Guidance for Industry and FDA Staff

    Updated Chapters:

    • Chapter C EU Directives and Guidelines
      • C.4.6 EU GMP Guide Part I, Chapter 6 Quality Control
     

    Read more
  • GMP MANUAL Update No. 19

    What is new?

    GMP in Practice

    New Chapters:

    • Chapter 4 Facilities and Equipment
      • 4.A: Facility Planning
      • 4.B: Materials
      • 4.H: Cleaning of Facilities

    Updated Chapters:

    • Chapter 4 Facilities and Equipment
      • 4.C Hygienic Design in Solids Handling (formerly 4.L, still under revision)
      • 4.D System Controllers and Process Control Systems (formerly 4.C and 4.K)
      • 4.E Technical Documentation (formerly 4.F)
      • 4.F Calibration (formerly 4.G)
      • 4.G Maintenance (formerly 4.H)
      • 4.I Containment (personnel protection) in Solids Handling
        (formerly 4.J, still under revision)

    GMP Regulations

    New Chapters:

    • Chapter C EU Directives and Guidelines
      • C.18 Guidance for the template for the qualified person’s declaration concerning GMP compliance of active substance manufacture “The QP declaration template”
      • C.18.1 Qualified Person’s declaration concerning GMP compliance of the active substance manufacture “The QP declaration template”

    Updated Chapters:

    • Chapter C EU Directives and Guidelines
      • C.4 Part I Basic Requirements for Medicinal Products
        C.4.3.1 Chapter 3 Premises and Equipment (entry into force 1 March 2015)
        C.4.5.1 Chapter 5 Production (entry into force 1 March 2015)
        C.4.8.1 Chapter 8 Complaints, Quality Defects and Products (entry into force 1 March 2015)
        C.5 Part II Basic Requirements for Active Substances used as Starting Materials
        C.8.5.1 Importation of Active Substances for Medicinal Products for Human Use – Questions and Answers Version 5.0
    • Chapter D.1 Code of Federal Regulations
      • D.1.1 21 CFR Part 210
      • D.1.2 21 CFR Part 211
      • D.1.3 21 CFR Part 11
      • D.1.4 21 CFR Part 820
      • D.1.5 21 CFR Part 4
      • D.1.6 21 CFR Part 606
      • D.1.7 21 CFR Part 606
    • Chapter F PIC/S Guidelines
      • F.9 PIC/S PE 009-11 GMP Guide Introduction
      • F.10 PIC/S PE 009-11 GMP Guide Part I
      • F.11 PIC/S PE 009-11 GMP Guide Part II
      • F.12 PIC/S PE 009-11 GMP Guide Annexes

     
    Read more
  • GMP MANUAL Update No. 17

    The content of Update No.17 is outlined below:

    GMP in Practice

    New Chapters:

    • 13.C Qualification of a servo-controlled blister packaging line
    • 21. Active Pharmaceutical Ingredients (completely new version)

    Updated Chapters:

    • 13.B Packaging Process
    • 13.D References
    • 15.B GMP-compliant Documentation

    GMP Regulations

    New Chapters:

    • Chapter D: CFR and FDA Guidelines
      • D.1.5: 21 CFR Part 4 – Regulation of Combination Products
      • D.1.6: 21 CFR Part 600 – Biological Products: General
      • D.1.7: 21 CFR Part 606 – cGMP for Blood and Blood Components
    • Chapter F: PIC/S Guidelines
      • F.22: PIC/S PE 010-4 – Guide to Good Practices for the Preparation of Medicinal Products in Healthcare Establishments
      • F.23: PIC/S PI 021-2 – GMP Particularities in the Manufacture of Medicinal Products to be Used in Clinical Trials on Human Subjects

    Updated Chapters:

    • Chapter C: EU Directives and Guidelines
      • C.4.2: EU GMP Guidelines, Chapter 2 Personnel
      • C.14: Guidelines on Good Distribution Practice of Medicinal Products for Human Use
    • Chapter G: GMP of other Regions
      • G.2.2.7: Canadian Regulations, Annex 14 to the Current Edition of the Good Manufacturing Practices Guidelines – Schedule D Drugs, Human Blood and Blood Components (GUI-0032)
    • Chapter H: Information
      • H.3: Addresses
     

    Read more
  • GMP MANUAL Update No. 16
     
    Read more
  • GMP MANUAL Online - Interim Development - September 2013

    Dr. Christoph Frick and Dr. Nicola Spiggelkötter have written the following new chapter to our GMP MANUAL:

    GMP in Practice

    • Chapter 24 Transport (completely new version, replaces chapter 11.N Transportation)
     
    Read more
  • GMP MANUAL Update No. 15

    The recent update of the GMP MANUAL (April 2013)c encompasses approx. 650 pages. The contents of Update No.15 are outlined below:

    “GMP in Practice”

    New Chapters:

    • 15: Documentation
      • 15.F: Electronic Batch Recording and Batch Release (replaces 15.C.3)
      • 15.G: Document Management Systems
    • 19: Quality Unit
      • 19.E: Deviations (replaces 11.K)
      • 19.H: Complaints and Recalls

    Updated Chapters:

    • 19: Quality Unit
      • 19.F: Batch Record Review (formerly 15.C.5)
      • 19.G: Product Quality Review and Annual Product Review (formerly 15.F)
    • Chapter 22: Excipients (formerly 21.C)

    “GMP Regulations”

    New Chapters:

    • B: National Bodies and Pharmaceutical Associations
    • C: EU Directives and Guidelines
      • C.8.5: Template for the “written confirmation” for active substances exported to the European Union for medicinal products for human use
      • C.8.5.1: Importation of Active Substances for Medicinal Products for Human Use; Questions and Answers
      • C.14: Guidelines on Good Distribution Practice of Medicinal Products for Human Use
    • E: ICH Guidelines
      • E.10.2: ICH Quality Implementation Working Group: Points to Consider (R2); ICH-Endorsed Guide for ICH Q8/Q9/Q10 Implementation
      • E.11: ICH Q11: Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/Biological Entities)
    • F: PIC/S Guidelines Chapter F.13: PIC/S PI 037-1 Recommendation: A Recommended Model for Risk-based Inspection Planning in the GMP Environment
      • F.14: PIC/S PI 038-1 Aide-mémoire: Assessment Of Quality Risk Management Implementation
      • F.15: Questions & Answers Document regarding Distribution Activities for Active Pharmaceutical Ingredients (APIs) Chapter F.16: PIC/S PI 030-1 Aide-mémoire: Inspection of Active Pharmaceutical Ingredients

    Updated Chapters:

    • E: ICH Guidelines
      • E.10.1: Quality Implementation Working Group on Q8, Q9 and Q10: Questions & Answers (R4)
     
    Read more
  • GMP MANUAL Update No. 14

    The recent update of the GMP MANUAL (October 2012) encompasses approx. 860 pages for the print version and 50 additional pages for the CD and online versions.

    The contents of Update 14 are outlined below:

    “GMP in Practice"

    New Chapters:

    • Chapter 12: Sterile Production
      • 12.H Testing for Endotoxins
    • Chapter 19: Quality Unit
      • 19.D Corrective and preventive actions (CAPA)

    Updated Chapters:

    • Chapter 12: Sterile Production
      • 12.F: Freeze drying / Lyophilization (formerly 12.J)
      • 12.G: Testing for sterility (formerly 12.H)
      • 12.I: Testing for tightness and particles
      • 12.J: Microbiological monitoring (formerly 12.G)
      • 12.K: References
    • Chapter 15: Documentation
      • 15.A: Official requirements
      • 15.G: References
    • Chapter 18: Inspections
      • 18.H: Questionnaire for preparing GMP-inspections
    • Chapter 19: Quality Unit
      • 19.C: Change Management (formerly Change Control)
      • 19.E: References (formerly 19.D)

    “GMP Regulations”

    New Chapters:

    • Chapter C: EU Directives and Guidelines
      • C.8.5: New Rules on Importing Active Pharmaceutical Ingredients
        into the European Union
      • C.8.5.1: Importation of Active Substances for Medicinal Products
        for Human Use Questions and Answers
      • C.13: Guideline on Real Time Release Testing
    • Chapter D: USA: CFR and FDA Guidelines
      • D.13: Incorporation of Physical-Chemical Identifiers into Solid Oral
        Dosage Form Drug Products for Anticounterfeiting
    • Chapter E: ICH Guidelines
      • E.7: ICH Q7 / APIC How-to-do Document
    • Chapter G: GMP of other Regions
      • G.1.4: WHO TRS 961 (2011), Annex 9: Model Guidance for the Storage
        and Transport of Time- and Temperature-sensitive Pharmaceutical
        Products (online only)

    Updated Chapters:

    • Chapter C: EU Directives and Guidelines
      • C.4.1: EU GMP Guide Part I, Chapter 1
      • C.4.7: EU GMP Guide Part I, Chapter 7
      • C.6.2: EU GMP Guide Annex 2
    • Chapter D: USA: CFR and FDA Guidelines
      • D.1.1: 21 CFR Part 210
      • D.1.2: 21 CFR Part 211
      • D.1.3: 21 CFR Part 11
      • D.1.4: 21 CFR Part 820 (formerly chapter D.13)
     
    Read more

Our Network

Our Network

More than 70 GMP advisers oder authors provide their expert knowledge and answer questions.
Safety

Safety

Use recognized GMP expertise to make safe decisions.
Relevance

Relevance

Our editors continuously observe the authorities and always keeps you well informed.