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PIC/S (Pharmaceutical Inspection Cooperation Scheme) has published the new version of guidance document PI 006-4 – Recommendations on Qualification and Validation, which comes into force on 1 October 2026. The document replaces the previous PI 006-3 dated 25 September 2007 and updates its content, drawing on the 2015 revision of Annex 15 and significantly expanding the level of detail in the specific recommendations on topics relating to qualification and validation in pharmaceutical manufacturing facilities.

The scope of the principles set out in the individual sections of this document equally applies to the manufacture of active pharmaceutical ingredients (APIs), intermediates and finished dosage forms.

One of the key topics throughout the document is the strengthening of the lifecycle approach to qualification and validation. Although this concept is already present in Annex 15, guideline PI 006-4 applies it in a more pragmatic way, linking together planning, change control, deviation management, continuous monitoring.

One of the most significant features of the new guidance is the evolution of the approach to process validation. PI 006-4 emphasises that the number of batches used for initial validation must be scientifically justified on the basis of process knowledge, process variability and the outcomes of the risk assessment.

The section on cleaning validation is one of the most extensive and detailed parts of the document and, compared with Annex 15, explains certain basic concepts more explicitly. Cleaning programs should be scaled according to toxicological risk assessments (e.g. based on HBEL values), which dictate the operational and technical controls required to deliver a validated cleaning process.

PI 006-4 addresses other topics relating to qualifications and validation, providing instructions on:

• Verification of Transportation
• Validation of Packaging
• Qualification of Supporting Utilities
• Validation of Test Methods

SOURCE:

PI 006-4 – Reccomendations on Qualification and Validation

Version 3 of the document was published on the Active Pharmaceutical Ingredients Committee (APIC) website in June 2026.

Compared with version 2, published in March 2019, version 3 has been expanded to include the requirements of Regulation (EU) 2021/1280 on good distribution practices for active substances used as starting materials in veterinary medicinal products.

The section Requirements for veterinary APIs states that:

“In general the guideline for veterinary APIs (Implementing Regulation (EU) 2021/1280) does not

change the underlying GDP principles established in guideline for human APIs (EU Guidelines on

GDP 19 March 2015); rather, it transforms them into binding, harmonised and enforceable legal

requirements for the veterinary sector […]”.

“Most significant difference is the legal status: The 2015 Guideline provides interpretative guidance under Directive 2001/83/EC and allows for flexibility in implementation. By contrast, Regulation (EU) 2021/1280 is adopted under Regulation (EU) 2019/6 and is directly applicable and legally binding in all EEA Member States (including Switzerland) […]”.

Chapter 4, which forms the core of the document, has been streamlined whilst retaining its structure as a comparison table.

The scope of both guidelines remains unchanged, excluding intermediate products. The EU guideline does not apply to intermediates or starting materials; it applies only to active substances.

In drafting this document, the following guidelines were taken into account and compared, adding explanatory notes that reflect APIC’s vision: WHO “Good trade and distribution practices for pharmaceutical starting materials – TRS 996, Annex 6”; ICH Q7 / APIC “How to do” Document on ICH Q7; “PIC/S Guide to Good Distribution Practice for Medicinal Products”; and Regulation (EU) 2021/1280 on good distribution practice for active substances used as starting materials in veterinary medicinal products.

SOURCE:

https://www.gmp-compliance.org/files/guidemgr/GDP_How-to-do_09June2026_clean.pdf

On 13 July, the EMA published a new brief Q&A paper entitled “What technical and organisational measures should be considered to prevent microbial contamination of non-sterile medicinal products?”

The document addresses issues concerning the control of contamination in non-sterile medicinal products in order to minimise the risk of product quality defects.

Compared with the requirements for the manufacture of sterile medicinal products, EU GMP requires that products and starting materials be protected from microbial contamination throughout the entire manufacturing process, without providing equally detailed guidance on contamination control measures for production areas of non-sterile medicinal products, although Annex 1 sets out principles that may be appropriately applied to the non-sterile medicinal products sector.

The EMA highlights that microbial contamination may also pose a risk to product quality and patient safety in the case of non-sterile medicinal products. It is therefore necessary to define appropriate control measures based on the principles of quality risk management, with particular attention to cleaning procedures, which must be validated and fully documented.

In summary

Answer A1 focuses on the selection of technical measures to be implemented, which are essentially based on the principles of the Contamination Control Strategy (CCS) set out in Annex 1, which also applies to non-sterile products.

Answer A2 covers the organisational measures that require special attention.

These organisational requirements arise from the results of the risk assessment process and are set out in EU GMP Chapter 5 and Annex 1; they are implemented as part of an integrated quality and risk management approach.

SOURCES:

EMA Q&A on prevent microbial contamination of non-sterile medicinal products.

The European Medicines Agency (EMA) has published an update concerns the section on “Reduced testing of incoming Starting Materials”.

The question is: “What information should be included in marketing authorisation dossiers regarding the actual testing performed by the finished product manufacturer, on receipt of any incoming starting materials (e.g. active substances, excipients, packaging materials, etc) and before use in production of the medicinal product?”

The answer from the EMA clarifies that the analyses to be performed on receipt are governed by GMP; therefore, the specifications for incoming starting materials registered in the marketing authorization application should not include any reference to reduced testing.

References:

• For human medicinal products: EU GMP part I, chapter 5 (5.27 to 5.39)
• For veterinary medicinal products: Commission Implementing Regulation (EU) 2025/2091, Article 28

SOURCE:

https://www.ema.europa.eu/en/human-regulatory-overview/research-development/scientific-guidelines/quality-medicines-questions-answers-introduction/quality-medicines-questions-answers-part-2#reduced-testing-of-incoming-starting-materials-6973

On June 15, 2026, the Brazilian health authority ANVISA published Regulatory Instruction No. 451, which updates the criteria for the recognition of equivalent foreign regulatory authorities (AREEs) and reorganizes the administrative procedures for obtaining the certification of good manufacturing practices (CBPF). The changes introduced aim to ensure increased transparency and to facilitate and accelerate regulatory processes.

Among the main changes introduced, the most significant is the formal recognition of the decentralized regulatory authorities of countries with decentralized regulatory models, such as Germany, Spain, Switzerland, and Japan. The amendment introduced by IN 451/2026 allows ANVISA to make use of the inspection reports drawn up by the competent regional bodies, as they are recognized as having the same level of reliability as those issued by the corresponding central regulatory authority.

Another significant change concerns the reorganization of the AREEs classification system, which now provides for the standardization of procedures for the designation and exclusion of authorities recognized by ANVISA.

Overall, the optimization of the document analysis flow should be more streamlined and transparent, enhancing the traceability of information and making the procedure more in line with the operational reality of the certification processes.

SOURCE:

Anvisa atualiza Instrução Normativa e orienta sobre novo fluxo para CBPF

On June 9, 2026, the United Kingdom launched an initiative to test how artificial intelligence (AI) can help make medicines safer for patients through a regulatory “sandbox.” The program will explore how AI can improve the assessment of accuracy and safety, better predict risks, and detect effects that existing approaches might miss.

The sandbox will allow for the testing of AI tools to predict how medicines behave in the body, including absorption, metabolism, and potential toxicity. The program will also explore how to optimize the use of clinical data to better understand how medicines work in different populations, including those often underrepresented in studies, such as children, older people, and minorities.

This is part of a broader effort to modernize medicines development by addressing the known limitations of traditional development models to improve how medicines safety and efficacy are assessed.

In the first phase, up to five AI-driven approaches will be tested. The MHRA will begin collaborating with partners from industry and academia starting in the summer of 2026 to define how the sandbox will operate.

This initiative positions the United Kingdom at the forefront of regulatory innovation integrated with AI, enabling faster validation of emerging methodologies and defining future regulatory expectations regarding the use of AI.

SOURCE:

https://www.gov.uk/government/news

The European Directorate for the Quality of Medicines & HealthCare (EDQM) has published the updated version of the “Guideline on requirements for revision and renewal of certificates of suitability to the European Pharmacopoeia monographs” (PA/PH/CEP (04) 02).

Regulatory background

The guideline has been substantially revised with the aim of ensuring compliance with the requirements of current EU legislation specified in the following context by holders of a Certificate of Suitability (CEP):

• Regulation (EU) No. 1234/2008 of November 24, 2008, concerning the examination of variations to the terms of marketing authorizations for medicinal products for human use and veterinary medicinal products, and the documentation to be submitted pursuant to those procedures;
• Regulation (EU) No. 2024/1701 of March 11, 2024 amending Regulation (EC) No. 1234/2008 as regards the examination of variations to the terms of marketing authorizations for medicinal products for human use.
• Implementing Regulation (EU) 2021/17 of January 8, 2021 establishing a list of variations which, pursuant to Regulation (EU) 2019/6 (veterinary medicinal products), do not require an assessment.

In addition to formal legal alignment, the guideline addresses various points that are relevant from a pragmatic point of view:

• Distinction between “revision” and “new CEP application“: the guideline clarifies in which situations it is not possible to modify an existing CEP and a separate CEP application is instead required.
• Changes in the context of CEP 2.0: the guideline provides guidance on how to classify and manage changes in relation to the implementation of CEP 2.0.
• Risk assessment: the guideline describes when and how a risk assessment should be initiated, updated or adapted in the context of the changes to be implemented.

Transition period and date of full application

Following publication, a two-month transition period is planned. During this period, the application of the new requirements is expressly encouraged but not yet mandatory. The revised guideline will come into full force on July 1, 2026.

SOURCES:

The revised guideline can be found on the EDQM website under “Certification Policy Documents & Guidelines” in the section “Operational documents”.

The European Pharmacopoeia has published significant revisions to its standards for pharmaceutical water in Ph. Eur. Issue  12.3, affecting WATER FOR INJECTIONS (0169), WATER, PURIFIED (0008), and TOTAL ORGANIC CARBON IN WATER FOR PHARMACEUTICAL USE (2.2.44). These changes represent a major step toward international harmonization, particularly with the USP, by adopting state-of-the-art testing methodologies.

Transition to TOC Testing for Sterilised Water (SWFI)

The most notable regulatory shift is the complete replacement of the traditional test for oxidisable substances with the Total Organic Carbon (TOC) test for Sterilised Water for Injections (SWFI). This is facilitated by the addition of Method B to General Chapter 2.2.44, which is specifically designed for SWFI. Notably, Method B introduces container-dependent TOC limits, defining three different acceptance criteria based on the size of the container.

Refinements for Bulk Water (WFI and Purified)

For both Water for Injections and Purified Water in bulk, the revisions focus on clarification and alignment without introducing entirely new content requirements:

• Methodological Consistency: for the TOC test in bulk water, the monographs now explicitly refer to Method A of Chapter 2.2.44.
• Numerical Precision: the TOC limit value has been updated from 0.5 mg/L to 50 mg/L to align with the concentration of the standards used in the general chapter.
• Conductivity Calibration: a metrological clarification has been added to the conductivity test. The accuracy of the measurement and the permissible deviation during system calibration must now be based on the expected conductivity value of the reference solution rather than the measured value.

Reagents and Implementation

To simplify laboratory processes and enable the use of USP reference standards, the reagents sucrose R and 1,4-benzoquinone R are being replaced by Chemical Reference Substances (CRSs).

These revised monographs are scheduled to officially come into force on 1 July 2026

SOURCES:

European Pharmacopoeia (Ph. Eur.) Issue 12.3

The European Medicines Agency (EMA) and the Pharmaceutical Inspection Co-operation Scheme (PIC/S) have proposed a targeted revision of Annex 15 of the Good Manufacturing Practice guidelines. The concept paper proposes the transition of Annex 15 from its current status as optional supplementary guidance for active substance (AS) manufacturers to a mandatory requirement. This new scope will encompass manufacturers of both chemical and biological active substances.

The proposal stems from lessons learnt from the presence of N-nitrosamine impurities in sartan medicines, which was made public in June 2020. Investigations into these cases revealed that the contamination was often due to gaps in knowledge of processes and products, as well as GMP deficiencies among active pharmaceutical ingredient manufacturers. By making Annex 15 mandatory, regulatory authorities aim to ensure better contamination control and a more robust investigation of quality issues.

The revision intends to align validation practices with quality standards and includes several critical updates:

• Quality Risk Management (QRM): validation and qualification activities will be updated to align with the revised ICH Q9 (R1) guideline, emphasizing the use of QRM throughout the product lifecycle, including the design of monitoring systems.
• Enhanced Documentation: AS manufacturers will be expected to adopt the concepts of the “Validation Master File” and “Qualification and Validation policy” to improve how activities are defined and documented.
• Process Oversight: the new guidelines will focus on sound process development, stricter change control as part of knowledge management, and more rigorous supplier qualification.
• Qualification Stages: concepts such as User Requirements Specifications (URS) and Factory/Site Acceptance Testing (FAT/SAT) will be formally extended to AS manufacturing.
• Transport and Distribution: in line with Good Distribution Practices (GDP), the revision will provide guidance on verifying transportation to ensure that the quality of active substances is not compromised during transit.

Implementation Timeline

The revision process is already underway. A public consultation period is scheduled from February 9 to April 9, 2026. Following the review of comments and final endorsements, the European Commission is expected to publish the finalized guideline by December 2026.

SOURCES:

concept-paper-revision-guidelines-good-manufacturing-practice-medicinal-products-annex-15-qualification-validation_en.pdf

The Committee of Experts on the Classification of Medicines as Regards their Supply (CD-P-PH/PHO), co-ordinated by the European Directorate for the Quality of Medicines & HealthCare (EDQM), has just published five new evidence-based classification reviews (EBRs) on herbal medicines.

The five new ERBs, drafted in 2025, concern the following herbal substances:

• castor oil (Ricinus oleum);
• St John’s wort (Hypericum herba);
• capsicum (Capsicum);
• ivy leaf (Hedera helix folium);
• agnus castus fruit (Agni casti fructus).

The CD-P-PH/PHO adopted a new format for EBRs following the roll-out of the recently developed assessment approach described in the new guidelines on the classification of active pharmaceutical substances as regards their supply.

The CD-P-PH/PHO issues a recommendation for a non-prescription status or exemptions to a prescription-only status if the benefits clearly outweigh the risks, as demonstrated by in-depth Evidence-Based Classification Reviews (EBR).

The EBRs are published on the CD-P-PH/PHO Programme results web page, maintained by the EDQM. More information is available in the EDQM Newsroom.

SOURCES:

https://www.edqm.eu/en/-/cd-p-ph/pho-publishes-5-new-evidence-based-classification-reviews