Published: 22 February 2021

Consultations

Review of Code for Consultation

February 2021

 

Medsafe GMP auditors have reviewed the changes in the Code and summarised the main changes below. The changes noted are in relation to our current code which was instituted by PIC/S in 2009.

We encourage manufacturers to review the PIC/S Guide to Good Manufacturing Practice PE009-14 (https://picscheme.org/en/publications?tri=gmp#zone) and ensure they are familiar with all parts of the Code applicable to their operation.

Part 1 Chapter 1: Pharmaceutical Quality System

Minor changes that provide additional detail and clarification to pre-existing requirements.

• Clause 1.6: New clause, regular periodic review of the effectiveness of the quality system by senior management is expected and should be documented.
• Clause 1.7: Additional requirement to develop a quality manual (or similar document) that describes the quality management system and management responsibilities.
• Clause 1.9: Those manufacturers who do not currently retain retention samples of their finished pack due to pack size will have to ensure actual packs are retained.
• Clause 1.10 Manufacturers will be required to understand the supply chain for APIs and include this information in the PQR.

Part 1 Chapter 2: Personnel

Minor changes that provide additional detail and clarification to pre-existing requirements.

• Clause 2.4: Additional requirement to develop and maintain quality.
• Clauses 2.5 and 2.9: Additional responsibility for senior management regarding defining roles and responsibilities.
• Clause 2.23: Formal requirement to document consultants’ details, qualification, training, and scope of works.

Part 1 Chapter 3: Premises and Equipment

• Clause 3.6: A risk-based approach to using dedicated facilities is required. A Quality Risk Management approach can be used to assess the risks and requirement for dedicated facilities.
• Clarification of three factors to consider when dedicated facilities are required for manufacturing.

Part 1 Chapter 4: Documentation

No major changes, only minor changes with further details and guidance.

• Principle: Requirement to have a site master file.
• Clauses 4.10 – 4.12: Allow for a risk-based approach (QRM principles) to document retention of various documents other than batch records.
• Addition to the contents of certain instructions and records.
• Clause 4.29: Inclusion of a number of documents required.
• Clause 4.32: Inclusion of inventory of documents within QMS.

Part 1 Chapter 5: Production

Significant changes to most of the clauses related to section on cross-contamination and to starting materials. The additional requirements in this Chapter relate to the assessment and control of contamination and cross-contamination risks. It includes clarification of the operational and administrative controls that should be considered to prevent cross-contamination.

Part 1 Chapter 6: Quality Control

Minor changes that provide additional detail and clarification to pre-existing requirements.

• Clause 6.8: Risk-based approach to document retention as per requirements described in chapter 4.
• Clause 6.9: OOT procedures should be developed, implemented, and verified.
• Clause 6.16: Additional requirement mandating the trending of critical parameters.
• Clause 6.20: Where compendial reference standards are available – these should be used as primary reference standards (unless justified).
• Clauses 6.37- 6.41: Additional guidance for method transfer.

Part 1 Chapter 7: Outsourced Activities

• Principle and 7.1: All outsourced activities need to be covered by a contract.
• Clause 7.4.3: Monitor and review performance. Need processes for monitoring of outsourced providers.

Part 1 Chapter 8: Complaints and product recall

The Principle has been substantially expanded. Additional clarification in various clauses in relation to the management and investigation of product complaints and recalls.

Part II Section 2 on Quality Risk Management

No major changes, only minor changes with further details and guidance regarding application of Quality Risk Management to the manufacture of Active Pharmaceutical Ingredients.

Annex 2 on Manufacture of biological medicinal substances and products for human use

Major re-write of the annex to provide clarification on existing GMPs and new technologies used in the manufacture of biological medicines. The annex is now divided into two main parts: Part A (general guidance) contains supplementary guidance on the manufacture of biological medicinal substances and products. Part B (specific guidance for selected product types) contains further guidance on selected types of biological medicinal substances (API) and products.

The main changes include:

• Application of GMP principles to all critical stages in the production of biological medicine by following a risk-based approach and in alignment with international regulations.
• Greater emphasis been placed on the control of initial components used e.g. management of animals, materials sourced from animal or plant sources, establishment and maintenance of master cell banks and/or seed lots. Specific guidance has been included that emphasised the importance of managing risks associated with the starting materials used.
• Re-write of the annex to provide clarity on the GMP requirements for novel technologies used in biotechnology, including transgenic animal and plant products.
• Section B1 to B10: Clarification and additional requirements for different types of biological medicinal substances and products. Some of the medicinal substances and products are not currently manufactured in New Zealand.

Annex 6 on Medicinal gases

No major changes, only minor changes with further details and guidance that includes the application of QRM in various areas.

• Clauses 5 and 6: Requirements for staff to be trained on hazards to patients and for subcontractor staff to be trained by the manufacturer.
• Clauses 17 and 18: Addition of some parameters to be recorded during batch manufacture and specifically repeats part of this overview for bulk deliveries to hospitals.

Annex 7 on Herbal medicinal products

No major changes, only minor changes with further details and guidance.

• Introduction of QRM principles in various clauses and reference to international Good Agricultural and Collection Practices as a standard for herb growers to comply with.
• New Clause 7 includes requirements for comprehensive documentation on audits of the herbal starting material suppliers.

Annex 11 on Computerised systems

• The changes involve a re-write of the Annex to align with the current industry guidance GAMP.
• Clause 11: Introduction of a new periodic review of computerised systems for their validated state. The periodic reviews will ensure validity of the system and address any issues.
• Introduction of Quality Risk Management principles to various clauses.

Annex 13 on Investigational medicinal products

Principle and various clauses: Providing additional detail and clarification.

• Principle: include description of manufacturing steps of investigational medicinal product (IMP) that would be subject to a manufacturing authorisation and clarification of the meaning of reconstitution and exclusion of the reconstitution step from a manufacturing authorisation.
• Clauses 28 to 30: Terminology change.
• Clauses 36 and 37: Additional information on retention and reference samples, relating to quantities, storage, and control. These requirements aligned with existing Annex 19.
• Clause 43: Additional responsibility of the Sponsor to align the release responsibility of the Authorised Person with the accepted clinical trial application by the Competent authorities.

Annex 14 on Manufacture of medicinal products derived from human blood or plasma

Major re-write of the annex to provide clarification on existing GMPs and plasma fractionation facilities. New Zealand does not have any plasma fractionation facilities, hence much of the new Annex 14 specific to plasma fractionation does not apply. Adverse Event reporting (Pharmacovigilance systems) is defined in the new Code.

Annex 15 on Qualification and validation

Changes with further details and guidance and clarification of existing requirements.

• Removal of the provision to perform retrospective process.
• Clause 1.5: Updates on additional data required for VMP.
• Clause 3: Introduction of the validation life-cycle concept.
• Clause 3.2: Additional requirement to develop and verify URS documentation to support validation activities.
• Clause 5.8: Allow the use of other batch sizes (smallest and largest batch sizes) for process validation as long as appropriate justification and QRM principles are in place. Process validation may not be required for intermediate batch sizes based on risk assessment.
• Clause 5.10: Requires the relevant information relating to the development of the process or products, to be available to the manufacturing site, unless scientifically justified.
• Clause 5.12: Introduction of QRM principles to suppliers of critical starting materials that have not been qualified.
• Clauses 5.19 - 5.20: Introduction of QRM principles in determining batch and sample numbers for process validation. The three batches approach is acceptable, justification required for less than three batches.
• Clauses 5.21 and 5.22: Introduction of Critical Quality Attributes and Critical Process Parameters (CQA and CPP). The CQA and CPP should be used in the design, validation and control of manufacturing processes.
• Clauses 5.23 - 5.27: Applied to products developed by Quality by Design (QbD) approach.
• Clauses 5.28 – 5.32: New requirements for ongoing process verification (OPV) during lifecycle. Frequency of verification should be based on risk management principles.
• Clauses 6.1-6.4: New requirements for the verification of transportation.
• Clause 10.5: Additional documentation for assessment of cleaning practices.
• Clause 10.6: Additional documentation for toxicological assessments.
• Clause 10.13: The minimum number of times cleaning validation should be repeated (three times) is replaced with QRM principles to risk assess and/or to verify the effectiveness of the cleaning validation.

Annex 17: Real Time Release Testing (RTRT) and Parametric Release

Updated Annex provides additional guidance and requirements for the application of RTRT, which may replace the conduct of finished product testing in some circumstances.