GMP in Practice

Chapter 6 Qualification

6.A Official requirements and agency expectations for qualification

Qualification is intended to prove the suitability of facilities and equipment for its intended purpose. In this context, the plant design plays an important role: it not only influences the functionality of the plant with regard to the manufacturing process and process validation, but also the cleanability and thus the cleaning validation.

Especially in extensive qualification projects, many activities have to be planned and coordinated. This requires solid project management. The full breadth of knowledge and information should be accessible to all participants. To achieve this, effective knowledge management is required. Risk management is of fundamental importance for designing the scope of the qualification.

The requirement to perform equipment qualification is found in all relevant GMP regulations, such as the EU GMP Guide.

The head of manufacturing is responsible for the qualification of equipment in his or her manufacturing area. The same applies to the qualification of devices and equipment in the quality control area, for which the head of quality control is responsible.

Qualification is part of the life cycle of a plant. Usually, four phases are distinguished: design qualification (DQ), installation qualification (IQ), operational qualification (OQ) and performance qualification (PQ). FAT and SAT tests may be incorporated in these activities. After initial qualification is completed, a process for maintaining the qualification status must be implemented. Important elements are continuous plant monitoring, change control and the annual product quality review (PQR).

Close cooperation between the equipment supplier and the operator allows synergies to be exploited and duplication of work to be avoided. The prerequisite is GMP compliant documentation and processing on the part of the equipment supplier. Third-party qualification service providers can also be involved. If the qualification or parts thereof are carried out by third parties, appropriate contractual arrangements must be made. This also applies to the handling of qualification data.

Whether internal or external, many requirements must be observed when handling qualification data. For example, the integrity of raw data must be ensured from its acquisition through processing to archiving. The ALCOA+ principles must be used as a basis. All data transfers must be subjected to critical evaluation. The modalities of data backup and archiving should be defined at an early stage.

The key elements of qualification and validation should be described in an overarching validation master plan (VMP). The qualification of individual plants is documented in the form of qualification protocols and reports. The relationship between the documents must be clearly recognisable, e.g. by the assignment of code numbers. The general requirements for GMP compliant documentation according to Chapter 4 of the EU GMP Guide apply. In the case of electronic documentation handling, the requirements of Annex 11 must also be observed. A binding retention period is not defined, but it is recommended to apply the same standards as for the batch documentation.
(Michael Hiob, PhD)

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Chapter 8 Cleaning Validation

8.F Sampling procedures

The officially accepted sampling methods for the detection of active substance and detergent residues are the direct sampling of the surface using the swab test and the indirect sampling of the equipment using the rinse test.

The swab test offers the advantage that sampling can be carried out directly at the critical points and even sparingly soluble residues can be collected. The disadvantages are the high demands on analytical method development and the problem of reproducibility.

The rinse test offers the advantage that even closed systems, difficult-to-reach areas and large surfaces can be sampled. A disadvantage is that the rinse test can only be used for substances that are easily soluble in the solvent used.

When developing a test method, the sampling material, solvent, test execution as well as sample preparation and analytics must be carefully coordinated to obtain high rates of recovery.

The design of the production equipment, type and solubility of the residue to be detected and the analytical method to be used must be considered when selecting the appropriate procedure.

For the microbiological testing of surfaces, direct contact bioburden tests are typically implemented in practice.
(Doris Borchert, PhD, Diana Westerbarkey)

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8.G Analytical procedures

When validating analytical methods for residue determination, all parameters that are used in quantitative purity methods must also be observed for this purpose. For cleaning validation, the parameters recovery, stability and robustness play a special role and should therefore be examined more closely during validation of analytical methods for cleaning validation.

When selecting a suitable analytical method for active substance residues, if possible, the same specific analytical method should be used that is also used for raw material or finished product release testing. The process conditions (range, sample preparation) are to be adapted to the requirements of the cleaning validation.

When selecting a suitable analytical method for cleaning agent residues, the requirement for specificity cannot always be met. Provided that the method is validated correctly, and the test conditions are selected appropriately, reliable limit value tests can also be carried out using non-specific methods. In practice, conductivity and TOC analysis are the most commonly used methods. Both methods are non-specific and can be used to determine sum parameters.

Ionic components are detected using conductivity tests. The method is therefore suitable for the detection of alkaline or acidic detergent residues and is performed as a limit value test.

TOC analysis enables the quantitative determination of organic residues of active substances, excipients, degradation and reaction products, cleaning agents and microbiological residues in aqueous samples down to trace levels.
(Doris Borchert, PhD, Diana Westerbarkey)

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GMP Regulations

Chapter C EU Directives and Guidelines

C.3.3.2 ICH Guideline Q9 (R1) on Quality Risk Management

Please note: The European Medicines Agency (EMA) adopted the revised ICH guideline Q9 (R1) on quality risk management under Step 5 on 3 February 2023. Both, the EMA and the ICH guideline are identical in content.

The guideline provides principles and examples of tools for quality risk management that can be applied to different aspects of pharmaceutical quality. These aspects include development, manufacturing, distribution, and the inspection and submission/review processes throughout the lifecycle of drug substances, drug (medicinal) products, biological and biotechnological products (including the use of raw materials, solvents, excipients, packaging, and labeling materials in drug (medicinal) products, biological and biotechnological products).

The revised version addresses additional guidance on:

• the levels of subjectivity in risk assessments and in QRM outputs,
• the product availability risks and the management of supplies,
• the lack of understanding as to what constitutes formality in QRM work, and
• the lack of clarity on risk-based decision-making.

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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 EMA Q&A on N-nitrosamines was updated as of 7 July 2023. Revision 16 comes with an amendment to Q&A 10 on the limits that apply for N-nitrosamines in medicinal products. Introduced are the Carcinogenic Potency Categorization Approach (CPCA) and the Enhanced Ames Test (EAT) for establishing acceptable intakes (AIs) for N-nitrosamines.

CPCA is considered as an approach for assigning an N-nitrosamine impurity (including nitrosamine drug substance-related impurities) based on an assessment of activating or deactivating structural features present in the molecule.

The Ames assay, a bacterial reverse mutation test, is based on standard recommendations provided by the Organisation for Economic Co-operation and Development (OECD)’s Test Guideline No. 471 “Bacterial Reverse Mutation Test”. For N-nitrosamines, enhanced testing conditions for the Ames assay are recommended due to the reported reduced sensitivity of the assay under standard conditions for some N-nitrosamines such as N-nitroso-dimethylamine.

Along with the new approaches comes the addition of

• Appendix 1, listing the N-nitrosamines for which AIs have been established by the Non-clinical Working Party (NcWP), including new AIs for N-nitrosamines determined using the CPCA,
• Annex 2, describing the Carcinogenic Potency Categorization Approach for N-nitrosamines,
• Annex 3, describing the Enhanced Ames Test Conditions for N-nitrosamines

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Chapter E ICH Guidelines

E.9 ICH Q9(R1): Quality Risk Management

Please note: The revised ICH guideline Q9(R1) on quality risk management was released under Step 4 on 18 January 2023. The European Medicines Agency (EMA) adopted the guideline in February 2023 as part of the EU GMP Guide Part III. Both, the EMA and the ICH guideline are identical in content.

The guideline provides principles and examples of tools for quality risk management that can be applied to different aspects of pharmaceutical quality. These aspects include development, manufacturing, distribution, and the inspection and submission/review processes throughout the lifecycle of drug substances, drug (medicinal) products, biological and biotechnological products (including the use of raw materials, solvents, excipients, packaging, and labeling materials in drug (medicinal) products, biological and biotechnological products).

The revised version addresses additional guidance on:

• the levels of subjectivity in risk assessments and in QRM outputs,
• the product availability risks and the management of supplies,
• the lack of understanding as to what constitutes formality in QRM work, and
• the lack of clarity on risk-based decision-making.

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Chapter H WHO Guidelines

H.5 WHO good manufacturing practices for sterile pharmaceutical products (Technical Report Series, No. 1044 (2022), Annex 2)

This document is a revision of the WHO good manufacturing practices for sterile pharmaceutical products, previously published in the WHO Technical Report Series, No. 961, 2011. The guideline incorporates the principles of CCS, design of premises, cleanroom classification, qualification, validation, monitoring, and personnel gowning, as well as the principles of QRM. These should be applied to ensure that microbial, particulate and endotoxin/pyrogen contamination is prevented in the final product.
The revised version was harmonized in close collaboration with the EU and the PIC/S, to benefit national regulatory authorities and manufacturers.

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H.6 WHO guidelines on technology transfer in pharmaceutical manufacturing (Technical Report Series, No. 1044 (2022), Annex 4)

The transfer of technology is considered an integral part of the product life cycle management and is subject to regulatory expectations, including in the areas of a risk-based and science-based process and method design (such as a quality by design approach), achieving a state of control, and data governance. These guidelines provide guiding principles on technology transfer, including transfer from research and development to production sites, and between two production sites. The document is applicable for transferring the technology of manufacturing processes and analytical procedures relating to active pharmaceutical ingredients (APIs), isolated API intermediates, bulk drug products and finished pharmaceutical products.

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H.9 WHO: Guidelines on good manufacturing practices for the manufacture of herbal medicines (Technical Report Series, No. 1010 (2018), Annex 2)

These guidelines are intended to complement the principles provided in Good manufacturing practices for pharmaceutical products and the additional standards addressed for herbal medicines should be considered supplementary to the general requirements. They relate specifically to the production and control of herbal medicines, in so far as they mainly focus on identifying the critical steps needed to ensure good quality. The application of GMPs in their manufacture is an essential tool to assure high quality. The guidelines should provide WHO Member States with general and minimum technical requirements for quality assurance and control in the manufacture of herbal medicines and deal exclusively with those products. The guidelines do not cover combination of herbal materials with animal materials, mineral materials, chemicals and other substances.

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H.10 WHO: International Atomic Energy Agency and World Health Organization guideline on good manufacturing practices for radiopharmaceutical products (Technical Report Series, No. 1025 (2020), Annex 2)

This guideline provides a general overview of the minimum GMP requirements for radiopharmaceutical products. It covers the topics of QMS, qualification and validation, product complaints and recalls, outsourced activities, personnel and training, premises, and equipment. Reference is made to the WHO Guidelines for Pharmaceutical Products and the Guidelines for Sterile Medicinal Products for the main principles of GMP in more detail.

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