GMP Compliance Adviser Update No. 5/2023
GMP in Practice
Chapter 1 Quality Management Systems
1.F Management of corrective and preventive actions (CAPA management)
The term CAPA (Corrective Action and Preventive Action) refers to the process of dealing with errors and weaknesses with the aim of systematically avoiding them. This process is an important part of the pharmaceutical quality system (PQS).
Requirements for CAPA management can be found in all relevant GMP regulations. ICH Q10 "Pharmaceutical Quality System" refers in particular to the product life cycle.
The types of actions include corrections, corrective actions, and preventive actions. While corrections are intended to eliminate the actual defect, corrective actions are intended to eliminate the cause of the defect. Thus, both types of measures refer to existing defects. Preventive measures aim at avoiding potential defects.
CAPA management is directly related to the risk management system and interfaces with all systems where nonconformances occur. A high quality of root cause identification enables the determination of the appropriate corrective actions. Other essential elements are the effectiveness checks and periodic monitoring of CAPA management by company management with the aim of continuous improvement.
CAPA systems can be autonomous, integrated or established as part of an EQMS.
CAPA management is an essential part of the pharmaceutical quality system, for which the company management is responsible. In this central system, the heads of manufacturing and quality control as well as the Qualified Person have an important role. Quality Assurance usually acts as the system owner for CAPA management.
For regular monitoring of CAPA management, key performance indicators (KPIs) are used that provide information on the performance of CAPA management. These include, for example, CAPA on time rate or CAPA effectiveness rate.
(Christian Gausepohl, PhD)
Chapter 8 Cleaning Validation
8.B Cleaning procedures
The four most important technical factors influencing the success of equipment cleaning are the parameters mechanics, temperature, time and chemistry. The interaction of these parameters is also referred to as Sinner's circle.
Rising energy prices, the conscious use of resources and the demand for a reduction in CO2 emissions are also leading to a rethink in the cleaning of pharmaceutical plants. Optimizing cleaning processes with the aim of improving efficiency and environmental compatibility requires a sound understanding of the process.
This also includes knowledge of the composition and mode of action of the cleaning agents used. In the context of cleaning validation, it is also necessary to define limits for cleaning agent residues and to test compliance with them using suitable analytical methods. Thus, in-depth knowledge of the cleaning agents used is required both for the definition of residue limits and for their analysis.
In addition to the general hygienic requirements for visible cleanliness, the cleaning of equipment that comes into contact with the product is also subject to validation and documentation thereof. In order to create a validated and efficient cleaning process, standardized and reproducible process steps are necessary. This requirement is not always easy to meet, especially in manual cleaning processes. A higher degree of automation with modern technologies increases the reliability of the cleaning process.
Cleaning consumes resources as part of the process and also ties up additional capacities for analytics and documentation. To develop an efficient process, data on APIs, auxiliary materials and equipment should be analysed. Through a combination of laboratory experiments studying cleaning parameters (chemistry, temperature and mechanics), robust cleaning procedures can be developed. The implementation, i.e. the transition from laboratory to practice, often takes place under time pressure, also with regard to the required validation. Nevertheless, optimization should not be neglected, especially considering the energy intensive and high-priced resources as well as the time required for cleaning. Although optimization BEFORE validation initially means a time delay, it pays off in the long run through time and energy savings. Furthermore, additional effort for change control and revalidation is avoided.
The implementation of cleaning procedures must be described in the cleaning SOPs in a way that is easy to understand. Practical relevance is absolutely essential in training. The importance of cleaning as a quality assurance element should be clearly emphasized.
(Thomas Altmann, Torsten Knöpke)
GMP Regulations
Chapter C EU Directives and Guidelines
C.6.3 Commission Implementing Regulation (EU) 2021/1248 as regards measures on good distribution practice for veterinary medicinal products in accordance with Regulation (EU) 2019/6 of the European Parliament and of the Council
The Regulation lays down the measures on good distribution practice for veterinary medicinal products. It applies to
- holders of a manufacturing authorisation performing wholesale distribution of the veterinary medicinal products covered by that manufacturing authorisation, and
- to holders of a wholesale distribution authorisation, including those established or operating under specific customs regimes, such as free zones or customs warehouses.
Implementing Regulation (EU) 2021/1248 is aligned with GDP guidelines for medicinal products for human use (Guidelines of 5 November 2013 on good distribution practice for medicinal products for human use - 2013/C 343/01) structurally and in terms of content.
C.6.4 Commission Implementing Regulation (EU)2021/1280 as regards measures on good distribution practice for active substances used as starting materials in veterinary medicinal products in accordance with Regulation (EU) 2019/6 of the European Parliament and of the Council
This implementing regulation is again strongly based on the GDP guidelines for active substances of medicinal products for human use (Guidelines of 19 March 2015 on the principles of good distribution practice for active substances of medicinal products for human use - 2015/C 95/01). Some paragraphs have been taken over verbatim, as there are a considerable number of active substances used as starting materials for both human and veterinary medicines. The Regulation applies to
- Importers and distributors of active substances used as starting materials for veterinary medicinal products;
- Manufacturers distributing active substances used as starting materials for veterinary medicinal products from their own production.
Intermediate products are explicitly excluded from the regulations.
C.10.1 Regulation (EU) 2017/745 of the European Parliament and of the Council (MDR) on medical devices, amending Directive 2001/83/EC, Regulation (EC) No 178/2002 and Regulation (EC) No 1223/2009 and repealing Council Directives 90/385/EEC and 93/42/EEC
For readability and usability, the version of the MDR provided in the GMP COMPLIANCE ADVISER is the consolidated version of the Regulation (EU) 2017/745 on medical devices (MDR) of 5 April 2017. Newly included are the
- Commission Delegated Regulation (EU) 2023/502 of 1 December 2022, and
- Regulation (EU) 2023/607 of the European Parliament and of the Council of 15 March 2023.
- Regulation (EU) 2023/502 covers the re-assessment procedure of notified bodies by the responsible authority of the Member State in Article 44, Paragraph 10.
- Regulation (EU) 2023/607 covers the new transitional periods in Article 120, Paragraph 2, 3, 4 and Article 122.
C.10.2 Regulation (EU) 2017/746 of the European Parliament and of the Council of 5 April 2017 on in vitro diagnostic medical devices and repealing Directive 98/79/EC and Commission Decision 2010/227/EU
For readability and usability, the version of the IVDR provided in the GMP COMPLIANCE ADVISER is the consolidated version of the Regulation (EU) 2017/746 on in vitro diagnostic medical devices (IVDR) of 5 April 2017. Newly included are the
- Commission Delegated Regulation (EU) 2023/502 of 1 December 2022, and
- Regulation (EU) 2023/607 of the European Parliament and of the Council of 15 March 2023.
- Regulation (EU) 2023/502 covers the re-assessment procedure of notified bodies by the responsible authority of the Member State in Article 44, Paragraph 10.
- Regulation (EU) 2023/607 covers the new transitional periods in Article 110, Paragraph 4 and Article 112, Paragraph 2.
C.19 Questions and answers 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
With this update the Q&A on nitrosamine impurities is available as Revision 18. The revision concerns Q&As 3, 20, 21 and 22 and a correction of the table including the potency score calculation in example 4 for N-nitroso-l-nebivolol. It had been omitted in the previously revised version 17 and has now been re-introduced. In short:
Q&A 3: Regarding the “call of review” and how to report steps 1 and 2 to the competent authorities, the update highlights the responsibilities of MAH(s) to control, report, and mitigate the detection of Nitrosamine impurities throughout the product life cycle, using the established procedure.
Q&A 20: What are the regulatory steps taken by authorities following the identification of an N-nitrosamine exceeding the AI (Acceptable Intake)?
Q&A 21: What is the approach to control the presence of nitrosamines until a substance-specific AI is established?
The Q&As 20 and 21 were amended regarding the approach to control the presence of nitrosamine while the AI is being established. It is clarified that as the AIs can be established with the new carcinogenic category approach (CPCA) the approach for a universal temporary AI (t-AI) while a formal AI is established is no longer considered necessary (we reported).
Q&A 22: What is the approach to control the presence of N-nitrosamine exceeding the AI during CAPA implementation?
The scope of authorised products for chronic use has been extended and the applicable limits and exemptions are clarified. Reference to chronic conditions which should not be treated for more than 10 years has been removed. The table including the potency score calculation in example 4 for N-nitroso-l-nebivolol on page 40 has been re-introduced. It had been omitted in a previous revision.
Chapter F PIC/S Guidelines
F.9, F.10, F.11, F.12 PE 009-17 Guide to Good Manufacturing Practice for Medicinal Products
The updated PIC/S GMP Guide PE 009-17 now includes the new EU Annex 1 on Sterile Manufacturing of Medicinal Products, which entered into force on 25 August 2023. The PIC/S actively participated in the development of this important document alongside the WHO. Having been adopted by both organisations, Annex 1 of the EU GMP Guide is applicable on a global basis.
F.17 PE 005-4 PIC/S Good Practice Guidelines for Blood Establishments and Hospital Blood Banks
PE 005-4 is aligned with the EU/EDQM Good Practice Guidelines (GPG) for global harmonisation for GMP requirements for collection, processing, testing, storage and distribution of blood and blood components. This includes plasma for fractionation and blood and blood components intended either for transfusion or as starting material for further processing or manufacture of plasma-derived medicinal products. It applies to blood establishments and to hospital blood banks. The GPG presented in this document are equivalent to GMP and the two terms can be used interchangeably, depending on national legislation.