29.02.2024

GMP Compliance Adviser Update No 1/2024

Focuses of this update are: Barrier systems (RABS and isolators) for sterile manufacturing and manufacture of terminally sterilised products

 

The following overview lists the topics covered with this Update:

GMP in Practice

Chapter 3 Premises

  • 3.F Barrier systems (RABS and isolators) for sterile manufacturing

Chapter 12 Sterile Production

  • 12.C Manufacture of terminally sterilised products

GMP Regulations

Chapter C EU Directives and Guidelines

  • C.7 Compilation of Union Procedures on Inspections and Exchange of Information
  • 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

Chapter E ICH Guidelines

  • E.2 ICH Q2(R2) Validation of Analytical Procedures
  • E.5.A ICH Q5A(R2) Viral Safety Evaluation of Biotechnology Products Derived From Cell Lines of Human or Animal Origin
  • E.14 ICH Q14 Analytical Procedure Development

The following overview lists the topics covered with this Update:

GMP in Practice

Chapter 3 Premises

3.F Barrier systems (RABS and isolators) for sterile manufacturing

The use of barrier systems to protect sterile medicinal products is required in Annex 1 to the EU GMP Guidelines.
As a result of this requirement, RABS and isolators have become established in the pharmaceuticals industry. There are different designs for both systems, which differ in terms of safety and cost. In terms of sustainability and product safety, isolators are the preferred barrier system.
Isolators are used for sterile production in combination with a filling line, for the production of cell and gene therapies and also for sterility testing.
Important requirements for isolators are given in Annex 1 concerning airflow as well as compliance with first air, surface decontamination, gloves, and safe transfer of the medicinal product and all necessary components into the isolator system.
Airflow over critical areas ("first air") should not be interrupted.
Surface decontamination can be carried out by means of vaporized or nebulized hydrogen peroxide. Biological indicators are used to verify the success of decontamination.
Gloves are a critical component on the isolator. The material must have sufficient mechanical and chemical resistance. Glove systems must be regularly checked for integrity and changed at a specified frequency.
Various technical systems are available for material transfer into and out of the isolator. These include material airlocks decontaminated with hydrogen peroxide, e-beam units for surface sterilization, as well as rapid transfer ports and sterile connectors.
(Richard Denk)

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Chapter 12 Sterile Production

12.C Manufacture of terminally sterilized products

All basic GMP requirements apply to the manufacture of sterile medicinal products, such as the qualification of premises and equipment, validation of processes and sufficient employee qualifications. In addition, there are specific requirements for manufacturing technologies and the minimization of particulate and microbial contamination.
The Pharmaceutical Quality System (PQS) of a sterile manufacturer should cover the specific requirements of sterile products and thus ensure that the risk of particulate and microbial contamination (including endotoxins) is minimized.
The new contamination control strategy introduced in the revised Annex 1 plays a special role here. It comprises a series of interlinked and interrelated individual measures to minimize and control particulate and microbial contamination, which are effective in their entirety and in combination.
To protect against microbial and particulate contamination, critical production steps must be carried out in clean areas and cleanrooms. A distinction is made between different air cleanliness classes. They are characterized by the permissible particle and microbial count in the air as well as the microbial status of surfaces. Pressure cascades ensure that areas of higher air purity classes are not affected by air from lower air purity classes. Today, liquid, sterile pharmaceuticals are usually manufactured on an industrial scale on highly automated and integrated production lines in which the individual machines are connected to each other via transport systems.
The manufacturing process is divided into bulk batch preparation, filtration, filling and sterilization. The primary containers and container closure systems must undergo a special washing process before use.
To create an efficient process management and control strategy, the func-tional relationships between the input variables and the product quality at tributes must be identified. A process flow chart should be created which indicates the control points.
To produce a bulk batch, the required starting materials are prepared, weighed and dissolved. Suitable measures must be taken to prevent the formation of dust and foam.
For the washing process, primary containers and seals must first be carefully unpacked, avoiding particulate contamination. The subsequent washing process must be validated. The success of the cleaning process is checked using the final rinse water.
Filling usually takes place in a grade C cleanroom, whereby laminar flow systems or barrier systems are used to protect the product. The filled containers are sealed and crimped. Alternatively, form-fill-seal technologies can also be used. After filling, the containers are inspected.
Sterility, endotoxins and particles are key quality aspects in the validation of manufacturing processes for sterile medicinal products. A risk analysis is carried out to identify the critical process steps and critical process parameters.
(Martin Mayer)

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GMP Regulations

Chapter C EU Directives and Guidelines

C.7 Compilation of Union Procedures on Inspections and Exchange of Information

The Compilation of Union Procedures has been revised twice in recent months.

Rev 19, June 2023: Modifications were introduced through the revision 19 as a result of the entry into application of Regulation (EU) 2019/6 on veterinary medicinal products and repealing Directive 2001/82/EC and Regulation (EU) 2019/5 amending Regulation (EC) No 726/2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency. A new procedure was added: EU/EEA Programme for Maintenance of Equivalence in Supervision of Good Manufacturing Practice (GMP) Compliance of Pharmaceutical Companies.

Rev. 19.1, September 2023: Minor modifications to remove mention of repealed Directive 2003/94/EC and further minor editorial changes were introduced.

Due to the large size of the document and the frequent updates, we now link to the EMA website.

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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 revision 20 of 15 January 2024 amends Q&A 3 and Q&A 10 to include guidance on non-mutagenic nitrosamine impurities (NMI) handling. In addition, Q&A 9 has been updated to clarify sensitivity requirements for analytical methods. Q&A 10 has been amended to include Ames test acceptability timelines.

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Chapter E ICH Guidelines

E.2 ICH Q2(R2) Validation of Analytical Procedures

The ICH Q2(R2) revised Guideline reached Step 4 of the ICH process on 1 November 2023.

The scope of the revision of ICH Q2(R1) includes validation principles that cover analytical use of spectroscopic or spectrometry data (e.g., NIR, Raman, NMR or MS) some of which often require multivariate statistical analyses. The guideline continues to provide a general framework for the principles of analytical procedure validation applicable to products mostly in the scope of Q6A and Q6B. These guidelines (Q2(R2) and Q14) are intended to complement ICH Q8 to Q12 Guidelines, as well as ICH Q13 for Continuous Manufacturing.

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E.5.A ICH Q5A(R2) Viral Safety Evaluation of Biotechnology Products Derived From Cell Lines of Human or Animal Origin

The ICH Q5A Guideline reached Step 4 of the ICH process on 1 November 2023.

The revision retains key principles of the original Guideline and provides additional recommendations on the established and complementary approaches to control the potential viral contamination of biotechnology products and describes the evaluation of the viral safety of biotechnology products including viral clearance and testing, and outlines what data should be submitted in marketing applications for those products.

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E.14 ICH Q14 Analytical Procedure Development

The new Q14 Guideline reached Step 4 of the ICH process on 1 November 2023.

The guideline harmonises the scientific approaches of Analytical Procedure Development and provides the principles relating to the description of Analytical Procedure Development process. This new guideline intends to improve regulatory communication between industry and regulators and facilitate more efficient, sound scientific and risk-based approval as well as post-approval change management of analytical procedures.

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