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GMP MANUAL

GMP in Practice: 24 chapters written by internationally renowned industry experts.

 

GMP Regulations: 8 chapters with the most important GMP guidelines and regulations.

 

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Updates Forecast & History

2015-01-07

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
 

GMP in Practice

Chapter 3 Premises

3.J Pharma monitoring of HVAC systems

The purpose of pharma monitoring of the HVAC system is collection, evaluation, recording and long-time storage of data relevant for the quality of medicinal products. Such data frequently will have to be incorporated into their batch documentation. Physical data requiring continuous or frequent recording are, at least in the case of premises for sophisticated production tasks, collected, processed and stored electronically - and this for an extended period of time well beyond the expiry dates of the products. Complementary physical and, above all, microbiological data, on the other hand, are collected and recorded manually. Both sets of data, i.e. those from computerized monitoring and those obtained through manual data compilationshould periodically be submitted to a trend analysis. In order to discover excursions from the specified data range and upcoming problems at an early stage, alert and action limits should be set for the physical monitoring parameters. Exceeding these limits should trigger alarms. The automatic and inextinguishable registration of such alarms is an important additional task of computerized pharma monitoring systems. Computerized systems for pharma monitoring must be validated. The V-model described in GAMP 5 offers an approach to perform validation in a GMP-compliant and efficient way. (Rainer Röcker, Dr. Hans H. Schicht)

Chapter 13 Packaging

13.D Blow-fill-seal technology (BFS technology)

BFS technology is a filling technology used for liquid products during which the plastic containers are manufactured, filled and sealed in a single cycle. This technology was developed about 50 years ago and is now a widely used aseptic filling method for pharmaceutical products. As a consequence, it has been included in the most important pharmaceutical guidelines. BFS technology is not only used in the pharmaceutical industry, but also for a diversity of applications in adjacent areas, e.g. in the cosmetics industry. Because of its large application spectrum and flexibility, its range of application is continuously growing. Various types of plastic can be used. High demands on barrier properties (e.g. against oxygen) can be met, for example, by combining different plastic layers. A major advantage of BFS technology is the extremely compact high-purity space which provides an appropriate level of safety during aseptic filling. BFS systems must be qualified in accordance with the general GMP regulations. The surrounding cleanroom and the media used in the process must also be taken into consideration. The filling process must be validated in a system-specific way with the cleaning and sterilisation processes included. When a BFS system is being operated, the rules generally accepted for aseptic working techniques apply. Particular attention should be given to the necessary process media and cleanroom environment. Personnel training should focus on interventions in the critical zone of the system, but the cleaning and sterilisation processes for the system must also be mastered. During ongoing system operation, critical parameters must be regularly monitored. These include, for example, the monitoring of air purity, filter integrity and the required overpressure. (Dr.-Ing. Manfred Grüneberg)

Chapter 14 Laboratory controls

14.H Test results outside defined criteria (OOX)

The concept for dealing with results outside defined criteria, also referred to as the OOX concept, dates back to the action taken by the FDA against the Barr Laboratories in the early 90s. A responsible approach to OOX results is often used during inspections to measure the error culture of a company. The main aim when dealing with OOX results is to guarantee the quality ofthe product and ensure the safety of the patient. It is generally accepted that the cause of the error must be determined using a structured predefined procedure so that appropriate corrective and preventive actions can be defined. Although the procedure was initially used for out-of-specification (OOS) results only, it was subsequently expanded as part of a growing awareness of quality to include results that deviate from expectations (OOE), trends (OOT), calibration values (OOC) and process parameters (OOL). All of these considerations are used to identify specification non-compliance as early as possible and prevent an OOS case. The OOX process also plays an important role during method transfers, validations and outsourcing. If the predefined responsibilities and documentation requirements are observed, the OOX process can also be carried out properly in an unproblematic way when third parties are involved. All persons involved should undergo thorough training. (Dr. Markus Limberger)

Chapter 21 Active Pharmaceutical Ingredients

21.G Biotechnological active substances

This chapter on biotechnological active substances encompasses a large number of additional regulatory requirements on GMP-compliant manufacturing of these products, which must be taken into account. Due to regulations to be observed elsewhere, these requirements are not always specifically related to GMP. Especially when living, sometimes pathogenic organisms, cells, tissues or infectious materials are involved, the regulations in effect serve not only to safeguard the product, but also to ensure the safety of employees and to protect the environment. The variety of different products and associated manufacturing processes is clearly greater than in the classic manufacture of active substances. Particularly the origin and makeup of the starting and raw materials used here are often specifically related to the product. It follows that the controls and tests to be applied to these materials differ accordingly, as do the resultant control strategies of the relevant manufacturing process. For these reasons it is considerably more difficult to create an unequivocal structure and clear outline of the applicable regulations on GMP-compliant manufacturing of biotechnological products. Instead, especially in this area the important thing is to define individual, specifically product-related requirements for starting and raw materials, the manufacturing process, the machines used and the control strategies to be applied. Quality risk management is crucial to this. This chapter is intended to filter out the specific GMP requirements that have to be taken into consideration for a certain product or group of products and to combine them with general GMP regulations. (Dr. Rainer Gnibl)

GMP Regulations

Chapter A Information

A.2 and A.3 GMP Abbreviations and GMP Glossary

The GMP Glossary and the GMP Abbreviations have been completely revised and updated. The Glossary now includes about 800 definitions of GMP terms which are relevant for the pharmaceutical industry.

Chapter C EU Directives and Guidelines

As a counterpart to chapter 21.G Biotechnological active substances in the “GMP in Practice”-Part, we provide two European Directives on this topic which are referenced in chapter 21.G:

C.16 Directive 2009/41/EC on the contained use of genetically modified micro-organisms

This Directive lays down the minimal standards applicable to the contained use of genetically modified micro-organisms (GMMs) and details the criteria for assessing the risks of GMMs to health and the environment.

C.17 Directive 2000/54/EC on the protection of workers from risks related to exposure to biological agents at work

Directive 2000/54/EC lays down minimum requirements for the health and safety of workers exposed to biological agents at work. The nature, degree and duration of worker's exposure must be determined, in order to make it possible to assess any risk to the workers' health or safety and to lay down the measures to be taken.

Chapter F PIC/S Guidelines

F.25 PIC/S PE 011-1 Guide to GDP for Medicinal Products

This Guide is based on the EU Guidelines on Good Distribution Practice (GDP) of Medicinal Products for Human Use (2013/C 343/01). Due to the fact that the GDP-related content of this PIC/S Guide is identical with the EU GDP Guidelines, we relinquish to reproduce the PIC/S text and refer to chapter C.14 Guidelines on Good Distribution Practice of Medicinal Products for Human Use of the GMP MANUAL. A link to the PIC/S GDP Guide is provided.

Chapter H WHO Guidelines

This new chapter has been created to compile the most important WHO guidelines on key issues of GMP. It will be supplemented continuously.

H.1 WHO GMPs for pharmaceutical products: main principles (TRS 986, Annex 2, 2014)

The WHO Guide on the main principles of GMP has been revised in 2014. The following sections were updated:

  • 1. Pharmaceutical quality system
  • 2. Good manufacturing practices for pharmaceutical practice
  • 7. Contract production, analysis and other activities
  • 17. Good practices in quality control

It is applicable to operations for the manufacture of medicines in their finished dosage forms. The good practices are to be considered general. For your information: Although EU and WHO GMP guidance documents differ in some details, the main principles remain the same. EU requirements fulfil all WHO recommendations.

H.2 WHO GMPs for active pharmaceutical ingredients (TRS 957, Annex 2, 2010)

This guide is intended to provide guidance regarding GMP for the manufacturing of active pharmaceutical ingredients (APIs) under an appropriate system for managing quality. It covers APIs that are manufactured by chemical synthesis, extraction, cell culture or fermentation, by recovery from natural sources or any combination of these processes. For your information: The revised Annex 2 is identical to the ICH Q7 Guideline. However, the WHO added two more appendices to this document:

  • A list with references to a number of corresponding WHO guidelines or Technical Report Series
  • A list of explanations and clarifications on various paragraphs of Annex 2

It should be pointed out that the 2010 revision of the EU GMP Guide Part II (which was identical with ICH Q7) concerning quality risk management has not yet been included in ICH Q7 and in the WHO GMPs for APIs up to now.

H.3 Guidelines on Quality Risk Management (TRS 981, Annex 2, 2013)

QRM is the overall and continuing process of appropriately managing risks to product quality throughout the product's life-cycle in order to optimize its benefit–risk balance. It is a systematic process for the assessment, control, communication and review of risks to the quality of the medicinal product. It can be applied both proactively and retrospectively. The aim of these guidelines is to assist the development and implementation of effective QRM, covering activities such as research and development, sourcing of materials, manufacturing, packaging, testing, storage and distribution. To protect patients in terms of quality, safety and efficacy of medicines, international medicines regulatory authorities (MRAs) are recommending pharmaceutical manufacturers to adopt a risk-based approach to the life-cycle of a pharmaceutical product. This guideline is addressed to both manufacturers and regulatory authorities.

H.4 Water for pharmaceutical use (TRS 970, Annex 2, 2012)

Water is the most widely used substance, raw- or starting material in the production, processing and formulation of pharmaceutical products. The guidance contained in this document is intended to provide information about the available specifications for water for pharmaceutical use. It gives guidance about which quality of water to use for specific applications, such as the manufacture of active pharmaceutical ingredients and dosage forms, and also provides guidance on good manufacturing practices regarding the design,installation and operation of pharmaceutical water systems.

H.5 GMPS for sterile pharmaceutical products (TRS 961, Annex 6, 2011)

The manufacture of sterile products is subject to special requirements in order to minimize risks of contamination. Much depends on the skill, training and attitudes of the personnel involved. Quality assurance is particularly important. This type of manufacture must strictly follow carefully established and validated methods of preparation and procedure. For your information: With this guideline published in 2011, WHO adapted its regulation regarding sterile production to the EU GMP Guide Part I, Annex 1. There are minor differences. All in all, the EU GMP Guide has a higher level of requirements.

H.6 Guide on transfer of technology in pharmaceutical manufacturing (TRS 961, Annex 7, 2011)

Transfer of technology is defined as a logical procedure that controls the transfer of any process together with its documentation and professional expertise between development and manufacture or between manufacturing sites. It requires a documented, planned approach using trained and knowledgeable personnel working within a quality system, with documentation of data covering all aspects of development, production and quality control. This document gives guidance in principle and provides general recommendations on the activities necessary to conduct a successful intra- or inter-site transfer of technology. The guide is intended to serve as a framework which can be applied in a flexible manner rather than a strict rigid guidance.

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