GMP Compliance Adviser Update No. 3/2020

With this GMP Compliance Adviser 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

Chapter 19

Quality Risk Management

19.A Agency expectations of quality risk management

19.B Application and benefits of QRM in the pharmaceutical industry

19.C The quality risk management process

19.D Methods and tools of quality risk management

19.E Application examples for QRM in the pharmaceutical industry

19.F Examples for QRM in the GMP Compliance Adviser

19.G Definitions

GMP Regulations

Chapter C 

EU Directives and Guidelines

C.4.1.1 Annex 1 – Second Draft, February 2020: Manufacture of Sterile Products

C.4.21  Draft Annex 21: Importation of medicinal products

C.8.2.1 Safety features for medicinal products for human use Questions and Answers – Version 17


GMP in Practice

Chapter 19 Quality Risk Management

Chapter 19.A Agency expectations of quality risk management

Whether in the professional or private environment – risks accompany us in all situations in life. Dealing with these risks is generally based on knowledge and experience. A methodical approach transforms the individualised handling of risks into structured risk management. On the other hand, disadvantages for the individual, the company and patient protection outweigh the risks in situations where risks are dismissed as a trivial matter or ignored.
For the pharmaceutical world, QRM is an instrument that is being demanded as an obligatory tool in more and more GMP-regulated areas. The areas of application for QRM in a company are complex and cover the entire life cycle of a medicinal product. The implementation of such a system is closely linked to the quality management system. At first it requires effort, but in the further course of time it is accompanied by many advantages. Therefore, management's commitment to risk policy and to operating a QRM system should be a real intention followed by honest implementation using life cycle thinking, not just lip service documented for the authority
With the aim of achieving the greatest possible drug safety, the QRM process starts with the assessment of the risks, i.e. their identification, analysis and evaluation. Based on the results of the first phase, the risk management phase follows. The aim here is to minimise the risks up to an acceptable residual risk. The regular review of previous results and assessments completes the life cycle of the QRM process.
QRM can be used both prospectively for risk avoidance and prevention and retrospectively for fault finding and harm limitation.
Dealing with risks in a planned manner is associated with a variety of opportunities and advantages for a company. This includes not only technical, but also entrepreneurial and business management aspects. (Petra Rempe, PhD)

Chapter 19.B Application and benefits of QRM in the pharmaceutical industry

Medicinal products must be manufactured in such a way that they do not pose any risk to the patient through lack of safety, purity, quality or efficacy. However, every step in the manufacturing process of medicinal products involves potential risks. Effective management, control and thus minimization of potential patient risks is only possible with the help of effective risk management.
The responsibility for efficient quality risk management lies with the top management level. QRM is a management concept that must be passed on to employees by the company management and decision-makers in the sense of a role model function. Regular training plays an important role in this respect.
The successful introduction and implementation of QRM requires regulatory knowledge, scientific and technical expertise, product and process understanding and risk understanding.
When applying QRM, the relationship between effort, stringency and formality on the one hand and criticality, risk level and complexity of the respective problem on the other hand should be appropriate.
QRM is applied in all phases of the product lifecycle, although the orientation, objectives and methods are different.
The systematic application of QRM should be guaranteed by an effective quality management system (QMS). To achieve this, the mechanisms for triggering QRM activities must be carefully defined and embedded in the core processes and supporting processes of the QMS.
The effort required for the introduction and implementation of QRM is compensated in the long run by many advantages. These include, above all, scientifically based decision-making, which is of decisive importance for numerous processes. This is linked to the focusing of resources on critical aspects, the avoidance of errors and thus ultimately a reduction in costs. At the same time, transparency and communication are improved. (Martin Mayer)

Chapter 19.C The quality risk management process

Quality risk management is understood as a systematic and continuous process that allows the assessment, management and control of product quality risks throughout the entire product life cycle.
The process model presented in ICH Q9 comprises 5 stages:

  • Introduction
  • Risk assessment
  • Risk management
  • Risk communication
  • Risk monitoring

The systematic application of QRM requires a link to an effective quality management system. To initiate QRM processes, appropriate starting mechanisms must be built into the core processes of the QMS and other processes relevant to product quality. Important for an efficient implementation are, among others, interdisciplinary teams and the integration of the Q departments.
Risk assessment is divided into 3 steps: the identification, analysis and evaluation of risks. This requires a systematic approach. Care should also be taken not to quantify risks if there is insufficient experience to do so. This leads to a feigned precision in which the actual risk is under- or overestimated.
Risk management is carried out in 2 stages: first, it is examined whether and how the identified risks can be reduced or eliminated. Then it must be decided whether the remaining residual risks are acceptable. At this stage of the QRM process, it is important on the one hand to keep a sense of proportion between effort and benefit. On the other hand, QRM must not be misused to "discuss
away" existing risks.
If risks are to be managed effectively, the knowledge gained in the QRM process must be communicated by the decision-makers and other parties involved both inside and outside the company. Risk communication is therefore a very important step within the QRM process.
The results obtained from a QRM process should be verified periodically. This is especially true if QRM has been applied prospectively. Risk review can be built into the QRM process as a recurring element, but it can also be triggered by single events. (Martin Mayer)

Chapter 19.D Methods and tools of quality risk management

The ICH Q9 guideline contains in its Annex 1 some of the most important methods that can be used in quality risk management by industry and regulatory authorities. The principles and possible applications of these methods are described in this chapter.
No method can be applied universally to every possible situation. In practice, the QRM user is faced with the challenge of selecting a method that is suitable for the specific problem. To do this, he must be familiar with the respective strengths and weaknesses of the methods and, if necessary, combine different methods and instruments with one another.
A fundamental step in QRM is the compilation and evaluation of data as a basis for decision-making. Graphical methods such as the creation of flow charts, process maps or tree charts (mind maps, Ishikawa diagrams) are suitable for organising and structuring data and information.
The use of formal and stringent methods is not always necessary and sometimes even obstructive because it ties up resources that are better used for more critical situations. Often informal methods can also be used, for example to set risk-based priorities for QRM activities. However, the term "informal" does not mean that no documentation is required; on the contrary - especially when informal methods are used, documentation is extremely important because the chosen procedure should be described, explained and justified and, of course, the results must be recorded.
The QRM methods can and should also be used in stages. This is explained using the example of planning, qualification and validation of facilities, processes and IT infrastructure.
The most important QRM methods are presented and their application is described by means of examples. Advantages and possible areas of application of the methods are shown, but also possible application errors and limitations are described.
When applying QRM, supporting statistical methods are often required to evaluate data. These include control charts, statistical design of experiments and process capability. The most important methods are presented in their main features. (Martin Mayer)

Chapter 19.E Application examples for QRM in the pharmaceutical industry

There are many possible applications for QRM in the pharmaceutical industry. A number of examples are presented in this section:
For the development of a control strategy, QRM is used to identify critical process parameters.
For the development, qualification or improvement of visual inspection methods, QRM provides a basis for action in the form of a defect catalogue.
For the handling of highly potent drug substances and medicinal products, QRM helps to identify appropriate containment measures and determine the personal protective equipment required.
The use of single-use technologies requires material qualification. Here, QRM can be used to determine the risk level in each case and derive the necessary qualification measures. (Martin Mayer)

Chapter 19.F Examples for QRM in the GMP Compliance Adviser

Quality risk management has been firmly anchored in the EU GMP guidelines for about a decade. It is therefore a regulatory requirement to apply QRM comprehensively in all areas that are relevant for drug quality.
Therefore, it is obvious that the application of QRM for various purposes has already been described in many places in the GMP Compliance Adviser.
In order to make it easier for you to find application examples as support for your own work, we have created an overview below. Here you will find a list of all examples of applied quality risk management contained in the GMP Compliance Adviser, arranged by topic. (Doris Borchert, PhD)

GMP Regulations

Chapter C EU Directives and Guidelines

C.4.1.1 Second Draft, Annex 1 Manufacture of Sterile Products

The European Commission published a revised second draft of Annex 1 Manufacture of sterile products on February 20, 2020. It is open for comments from selected organisations and stakeholders until 20 May 2020. In parallel, the document will also be submitted to the PIC/S and the WHO for specific comments. More than 6000 comments were received by the Commission on the first draft document, which have been incorporated into the second draft version.
The concept paper and the first draft document of December 2017 are available in the "Extras" column.

C.4.21 Draft Annex 21 Importation of Medicinal Products

The European Commission published a four-page draft version of the new Annex 21 Importation of medicinal products on 20 March 2020. In addition to the main chapters and annexes of the EU GMP guide, it has become necessary to establish specific guidelines for the activities of the import of medicinal products.
This annex contains the principles and guidelines of good practice requirements applicable to a holder of a manufacturing and import authorisation (MIA) who imports medicinal products (human and veterinary) across the EU/EEA borders and thus from third countries. Medicinal products imported with the sole intention of being exported to the EU/EEA and which are neither processed nor released for marketing in the EU/EEA are not covered by this annex. The draft document is of particular importance for importers (MIA holders) and companies involved in the supply chain.
The concept paper and the draft of the new Annex 21 are available in the "Extras" column.

C.8.2.1 Safety Features for Medicinal Products for Human Use – Version 17

On March 9, 2020, the European Commission published Version 17 of the Q&A on safety features for medicinal products. The document is updated on a regular basis.
Question 5.11 is new:

  • Q&A 5.11 clarifies whether wholesalers should be connected to the national repositoriesor to the European hub. Wholesalers physically holding products or performing activities according to the Articles 20–23 of the Commission Delegated Regulation (EU) 2016/161 should be connected to the national repository where the activities take place.

Question 1.22 received additions:

  • Q&A 1.22 deals with the handling of safety features by parallel traders. If a new, equivalent safety feature is placed by parallel traders, it should meet the requirements of the Member State in which the medicinal product is intended to be placed on the market. Centrally authorised products from which parallel traders remove or cover safety features are expected to display the original manufacturer's batch number. Traceability in the repository must be maintained in all cases.

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