GMP Compliance Adviser Update No 4/2022

The new or updated chapters provide a wealth of knowledge on: GMP for Cannabis products, IT systems for the optimisation of QM processes, validation of analytical methods and fight against counterfeit medicines.

The following overview lists the topics covered with this Update:


GMP in Practice

Chapter 0 Current Topics

  • 0.B.2 Medical Cannabis and GMP: 6 Keys to Focus on

Chapter 1 Quality Management Systems

  • 1.H IT Systems for the Optimisation of Quality Management Processes

Chapter 14 Laboratory Controls

  • 14.D Validation of analytical methods

Chapter 21 Inspections and drug safety

  • 21.H Fight against counterfeit medicines

GMP Regulations

Chapter C EU Directives and Guidelines    

  • C.8 Directive 2001/83/EC – medicinal products for human use
  • C.19 Q&A for MAHs on the CHMP Opinion for the Article 5(3) of Regulation (EC) No 726/2004 – nitrosamine impurities in human medicinal products, Rev. 11

GMP in Practice

Chapter 0 Current Topics

0.B.2 Medical Cannabis and GMP: 6 Keys to Focus on

Regulation of the medicinal use of the Cannabis sativa plant and its derivatives is evolving globally, with very different approaches pending on the authorities involved in the different countries. However, when dealing with medicines, the baseline to start from is the pharmaceutical regulation, stated with the main focus of protecting patients’ health, on the one hand by ensuring quality, safety and efficacy of medicines, and, on the other hand, by granting their access to authorized treatments.
When it comes to production activities, cultivation, post-harvest processing and extraction/purification of the active ingredient, need to be performed in compliance with GACP (Good Agricultural and Cultivation Practices) standards for the agricultural stages and GMP (Good Manufacturing Practices) standards for the further processing and handling stages.
However, the point from where GMP standards should be applied is a common point of discussion. Different guidances are available in existing regulations, such as GMP Part II or GMP Annex 7. The use of a risk-based approach is the key for identifying the first critical step of the production process, from which GMP standard should be applied.
As in any other GMP facility, having clear priorities for compliance with applicable standards is essential to focus efforts and ensure the achievement of the expected result. Let's review the key points to keep in mind:

  • Key 1: The Quality Management System
  • Key 2: The Life Cycle of Facilities, Equipment and Services
  • Key 3: Documents and Records
  • Key 4: Personnel
  • Key 5: Operations
  • Key 6: Materials and Products

(Marta Rodríguez)

Chapter 1 Quality Management System

1.H IT Systems for the Optimisation of Quality Management Processes

Typical QM processes such as deviation and change management, CAPA or complaints processing are generally faster, safer and more transparent when IT systems are used than corresponding paper-based systems. Thanks to multidimensional access to the stored information, such systems also offer better information capability and traceability, which is a major advantage, especially in view of regulatory requirements.
An electronic document management system (eDMS) stores not only the documents themselves, but also their attributes (metadata) and the relationships between users and documents.
While an eDMS focuses on the document, an electronic quality management system (eQMS) is mainly focused on the management of processes such as change and deviation management or CAPA. An eDMS is in effect a part and prerequisite of the eQMS. When working with an eQMS, key functions such as documentation, routing, substitute rules, deadline monitoring etc. play a central role.
The application of an eQMS is demonstrated based on the CAPA process.
By combining eDMS and eQMS, many advantages can be gained for the execution of quality management, e.g. the targeted querying of data for reviews (APR, PQR, Management Review), the statistical evaluation and trend analysis of deviations, complaints and recalls, etc. However, this requires that all necessary data is available in the system in a retrievable form.
Important prerequisites for the successful implementation of IT systems to optimise quality management are, in addition to the competence and experience of the supplier, a clear requirement specification by the user (URS), realistic resource planning, support by management and, last but not least, acceptance by the future users.
(Thilo Gukelberger)

Chapter 14 Laboratory Controls

14.D Validation of analytical methods

Test methods used in the GMP environment must be suitable for the intended application, i.e. validated. This suitability must be proven before the first routine use, but must also be ensured for each application, i.e. over the entire analytical life cycle.
The regulatory requirements for the analytical validation of test methods for active substances and medicinal products are described in ICH Guideline Q2(R1). Characteristics of method validation are: Precision, accuracy, specificity, linearity, detection and quantitation limit, depending on the relevance to the test. For other applications, for example during development or in the context of drug synthesis or drug manufacture, gradations adapted to the respective risk can be applied.
Regulatory requirements aside, well-planned and executed validation is in the user's own best interest, as inappropriate methods can pose significant safety and business risks. A prerequisite for effective and efficient validation is the identification of the performance parameters relevant to the intended application. Here, the requirements for measuring the respective quality attribute must be taken into account. Reliable knowledge of the performance parameters can be used to establish an effective and meaningful analytical control strategy, including meaningful minimisation of effort (e.g. a performance-based determination of the number of preparations or injections of samples or reference standards).
The assurance of the validated state throughout the analytical life cycle should be controlled by monitoring appropriate performance parameters of the test method, for example, system test parameters or by means of control charts.
(Joachim Ermer, PhD)

Chapter 21 Inspections and drug saftey

21.H Fight against counterfeit medicines

There is no uniform global definition of the term “counterfeit medicine”. Essentially, it is understood to refer to a medicinal product with false information about its identity, origin and distribution channel.
Counterfeit medicines are of inferior quality and, in the worst case, harmful to health or even life-threatening. In addition to the health risks they present, counterfeit medicines also pose both economic risks and liability and reputational risks for marketing authorisation holders and manufacturers, In the interest of patient safety in particular, defensive measures against counterfeit medicines are therefore essential. In the absence of a uniform definition, available statistics on the scale of the problem must be critically examined and a decision must be made as to which definition is appropriate for the area in question. At the same time, the absence of a uniform definition also hampers the exchange of information on counterfeit medicines.
In Europe, a first step in the fight against counterfeit medicines was taken in 2011 with the EU Falsified Medicines Directive. This directive provides for unique encoding and tamper protection. Specific provisions on the design of these safety features can be found in Delegated Regulation EU 2016/161.
Effective protection against counterfeit medicines can be achieved through counterfeit-proof features, tamper-evident closures and unique encoding with package-specific serial numbers. Coding and serialisation ensure a high level of transparency in the market. Finally, there are numerous possibilities for additional use of these codes. These include for example potential applications for the electronic provision of the package information leaflet or as part of the pharmacovigilance process.
The organisation of the fight against counterfeit medicines in the company comprises four essential aspects: monitoring, knowledge building, prevention and reaction. In terms of monitoring, a globally standardised database has proven to be a suitable tool for recording the global occurrence of counterfeit medicines and for establishing appropriate processes for case processing and notification of the authorities on this basis. A wide variety of sources, associations, committees etc. are available to build up and share knowledge on the phenomenon of counterfeit medicines. Preventive technical measures include the use of safety features and the effective communication of these features to the target groups for which they are intended.
Given that full protection against counterfeited medicinal products is unlikely to be achieved, an appropriate reaction following the discovery of a counterfeit is required on a regular basis. This includes not only the required notification of supervisory or investigative authorities, but also more extensive counteractive measures. The phenomenon of counterfeit medicines is not static, but rather highly dynamic and flexible. Continuous monitoring and evaluation are therefore just as necessary as the ongoing adaptation or further development of defense mechanisms and internal organisation.
(Stephan Schwarze, PhD)

GMP Regulations

Chapter C EU Directives and Guidelines

C.8 Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use

  • Directive 2001/83/EC was amended through Directive (EU) 2022/642 of the European Parliament and of the Council dated 12 April 2022 (M16):
    The aim of the amendment is to ensure the uninterrupted supply of medicinal products for human use to Northern Ireland after the withdrawal of the United Kingdom within the framework of the Protocol on Ireland/Northern Ireland. In addition, the Directive exceptionally allows, for a transitional period of three years, the marketing of medicinal products from the United Kingdom in Ireland, Malta and Cyprus, with derogations from the requirement that marketing authorisation holders be established in the European Union.
  • Corrigendum 6 transposes the repeal of Directives 90/385/EEC and 93/42/EEC on medical devices and corrections to Regulation (EU) 2017/745 (Medical Devices Regulation, MDR).

C.19 Q&A for marketing authorisation holders/applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) No 726/2004 referral on nitrosamine impurities in human medicinal products (Rev. 11)

For the fourth time in a row, the European Commission has updated its Q&A on nitrosamine impurities. Version 11 was published on 29 July 2022. Questions 3, 5, 10 and 14 have been revised.

Question 3:
For the ‘call for review’ for chemically synthesised and biological medicinal products, when and how should MAHs report steps 1 and 2 to competent authorities?

  • For product containing chemically synthesised APIs, confirmatory testing activities at Step 2 are expected to be finalized at the latest by 26th September 2022.
  • The deadline for the submission of any changes required to Marketing Authorisations (variation applications for chemical medicines) is by 1 October 2023.
  • For product containing biological APIs, confirmatory testing activities at Step 2 and submission of any changes required to Marketing Authorisations are expected to be finalized at the latest by 1 July 2023.

Question 5:
What should be done if new information (e.g., related to new potential risk factors or root causes) is identified after the submission of step 1 and/or step 2 responses?

  • In principle, it is expected that the risk assessment will be repeated routinely, even if information on step 1 and/or step 2 had already been submitted. Particular attention should hereby be given to questions 4 (on new risk factors) and 10 (on limit values for nitrosamines), which are regularly updated.
  • Marketing authorisation holders should pay particular attention to the risk of nitrosamine contamination from active substances containing a sensitive amine. During formulation of the final product and/or storage, this, together with traces of nitrite, leads to a high risk (see Q&A 4, 8).

Question 10:
Which limits apply for nitrosamines in medicinal products?

  • N-Nitrosodabigatran with 8 ng/day has been newly added to the table.

Question 14:
What is the approach for new and ongoing marketing authorisation applications (MAA)?

  • The link to a new risk assessment template to be used in authorisation applications has been added. You will find the template here.
  • Parallel to the Q&A, the CMDh has updated its practical guidance for MAHs on nitrosamine impurities. It gives detailed answers on
    • Step 1 – risk evaluation
    • Step 2 – confirmatory testing of the finished product for approved products
    • Step 3 – changes to the marketing authorisation