GMP Compliance Adviser: Updates Forecast & History
Posted: July 27, 2015|
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)
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.
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