GMP Compliance Adviser Update No 1/2023
GMP in Practice
Chapter 6 Qualification
6.J Example SOP for the qualification of equipment and machinery
What information does this SOP example provide?
This example for a qualification SOP is applicable for all kinds of equipment up to standard off-the-shelf equipment. With the aid of an assessment matrix these are classified into different risk categories. Depending on the risk category, the qualification requirements differ in type and scope.
(Silke Ohlendorf, Cornelia Wawretschek)
Chapter 9 Computer System Validation
9.E Qualification and validation of computerised systems
Verification, qualification and validation are terms used in many GxP-relevant contexts. Interestingly, definitions of these terms for the use case "computerised systems" are not always to be found in the GxP regulations. Here, own context-related definitions have to be derived:
- Verification is a documented proof that the development of a computerised system complies with the prior-specified requirements.
- Qualification is the documented proof that the computerised system to be qualified is suitable for the specified tasks in the company's infrastructure.
- Validation is the documented evidence that the computerised system to be validated meets the requirements for the specified purpose in the operational business with the specified reliability and under the specified conditions (environment, processes, people).
The structure of a qualification and validation master plan is based on the content and formal requirements of Annex 11 Computerised Systems and Annex 15 Qualification and Validation. This includes information on validation policies, responsibilities, risk management, inventory, development of acceptance criteria, change management and life cycle approach. The master plan should also include documentation templates.
A prerequisite for validation is an inventory of the hardware and software. It is useful to create a validation matrix for this purpose.
The system life cycle includes the conception, project, operation and de-commissioning phases. The validation activities cover the first two phases of the life cycle and are described in detail in this chapter. Traceability of all validation activities must be ensured throughout the system life cycle. This can be ensured by a traceability matrix.
The validation process is concluded with the validation report, followed by the formal release and transfer of the computerised system to the operational phase.
Not only the validation itself, but also the handover must be carefully planned and documented. This includes the preparation of a transition plan, important operating procedures for the operator and user training.
(Dennis Sandkühler, PhD)
Chapter 17 Outsourced Activities
17.A + 17.B Extras:
- Quality Agreement
- Technical Agreement and Delimitation of Pharmaceutical Responsibilities
- GMP-Questionnaire: Contract manufacturing/Contract analysis
GMP Regulations
Chapter C EU Directives and Guidelines
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
The document was revised twice in December (Versions 13 and 14).
The additions and amendments made in early December relate mainly to
Q&A 10: Which limits apply for nitrosamines in medicinal products?
With version 13 newly included limits are:
- N-nitrosofluoxetine, with 100 ng/day
- N-nitrosoparoxetine, with 1300 ng/day
- N-nitroso-diphenylamine NDPh14 (86-30-6), with 78000 ng/day
- N-nitroso-mefenamic acid, with 78000 ng/day
- N-nitroso-pyrrolidine NPYR3,7 (930-55-2), with 1700 ng/day
- N-nitroso-diethanolamine NDELA 3,7(1116-54-7), with 1900 ng/day
With mid-December version 14 came
- the introduction of Q&A 22 on the approach to control the presence of an N-nitrosamine exceeding the AI while CAPAs are being implemented
- an update of Q&A 20 to consider the possibility of an interim limit based on the LTL approach during CAPA implementation
- an update of Q&A 21 for increased clarity on the application of the temporary universal limit.
Chapter E ICH Guidelines
E.3.C ICH Q3C(R8): Impurities: Guideline for Residual Solvents
The editorial corrections approved by the Q3C(R8) Working Group have been implemented and finally published. They concern the main text on the general principles on page 8 of the document and the deletion of Methyltetrahydrofuran from Table 4 (Solvents for which no adequate toxicological data was found). It is now listed in Table 3 as a Class 3 solvent with low toxicological potential (Class 3 solvents which should be limited by GMP or other quality-based requirements).
E.13 ICH Q13: Continuous Manufacturing of Drug Substances and Drug Products
With the final adoption of ICH Q13 Guideline on „Continuous Manufacturing of Drug Substances and Drug Products (Step 4)“ within the ICH organisation, the guideline is considered harmonized and thus represent the current state of science and technology.
The 46-pages guideline
- builds on existing ICH Quality Guidelines
- provides clarification on continuous manufacturing (CM) concepts
- describes scientific approaches, and presents regulatory considerations specific to CM of drug substances and drug products
- puts its focus on the integrated aspects of a CM system in which two or more unit operations are directly connected
- includes scientific and regulatory considerations for the development, implementation, operation, and lifecycle management of CM.
The introductory Part I of the guideline addresses CM concepts, the scientific approach, and regulatory considerations.
Part II includes five annexes that offer concise explanations and practical examples.
Chapter F: PIC/S Guidelines
F.9–F.12 PIC/S GMP Guide PE 009-16
The Pharmaceutical Inspection Co-operation Scheme (PIC/S) has revised its PIC/S GMP Guide to Good Manufacturing Practice (GMP) for Medicinal Products to include
- the revised Annex 13 on the Manufacture of Investigational Medicinal Products and
- the new Annex 16 on the Certification by the Authorised Person and Batch Release.
PIC/S Annex 13 has been revised based on EC Regulation No. 536/2014 on Clinical Trials, which finally entered into force on 31 January 2022. Article 63(1) of the regulation necessitated a revision of Annex 13.
PIC/S Annex 16 is a new annex to the PIC/S GMP Guide. Historically, PIC/S did not adapt EU Annex 16, when it was adopted as part of the EU GMP Guide. PIC/S considered this annex to be EU-specific and difficult to transpose for PIC/S purposes, in particular since the PIC/S GMP Guide is limited to the manufacture of medicinal products and not to import and distribution. Following a consultation of PIC/S Participating Authorities in 2017, it was agreed to make an attempt to transpose EU Annex 16, considering that a PIC/S adaptation could offer added benefit to better convey expectations associated with product release and further international harmonisation efforts in line with PIC/S’ mission to lead the international development, implementation and maintenance of harmonised GMP standards and quality systems of inspectorates in the field of medicinal products. PIC/S also agreed that elements in Annex 16 related to imported medicinal products would be voluntary, dependent on national law.
The Annexes entered into force on 1 February 2022.