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The U.S. Food and Drug Administration (FDA) has issued draft guidance to clarify how benefit-risk assessment (BRA) considerations are integrated into the agency’s premarket and postmarket decisions for new drugs and biologics marketing applications.

According to the FDA, BRA considers in addition to the extensive safety and effectiveness evidence presented, other factors such as the nature and severity of the condition that the product is intended to treat or prevent, the benefits and risks of other available therapies for the disease, and risk management tools that may be needed to ensure that the benefits outweigh the risks.

Examples of regulatory options to reduce and manage risks include the following:

• Clinical studies (pre- or postmarket) to further characterize safety, effectiveness, or dose response;
• Additional product quality information;
• Postmarket observational studies
• Enhanced pharmacovigilance;
• Labeling content (e.g., limitations of use);
• Risk evaluation and mitigation strategies (REMS).

BRA Lifecycle Approach / Periodic Benefit-Risk Evaluation Reports

The U.S. Authority views BRA as a life-cycle approach. In fact, it recognizes that knowledge of the risks and benefits of a product changes over time as new information about the safety and efficacy of that product becomes available.

According to FDA, sponsors find it useful to have a structured approach to producing the evaluations of new information, as well as the decisions made based on that new information.

In addition, the ICH E2C(R2) guideline recommends, although optionally, developing a Periodic Benefit-Risk Evaluation Report (PBRER).

In any case, sponsors should not wait for a periodic safety update to report a potentially serious safety concern. Any New information about a potential serious safety concern that could have an impact on a drug’s benefit-risk profile should be communicated promptly to FDA.

FDA Guidance Document “Benefit-Risk Assessment for New Drug and Biological Products“

USP recently added a new chapter “1469” on nitrosamine impurities to the U.S. Pharmacopeia. With this addition, USP intends to help both the Authority and pharmaceutical manufacturers assess the presence of nitrosamine impurities and implement appropriate control strategies and analytical procedures.

This chapter is aligned with current scientific and regulatory approaches developed to ensure appropriate control of nitrosamine impurities by eliminating or reducing their presence in drug substances and drug products. Thus, the approach described ensures product quality with respect to safety.

BRIEF OVERVIEW OF THE NEW CHAPTER: <1469> nITROSAMINE IMPURITIES

The new chapter has a more substantial structure articulated in nine paragraphs:

1. INTRODUCTION: clarifies the reasons why the presence of nitrosamines represents a significant concern and lists the main possible sources of nitrosamines
2. NITROSAMINE IMPURITIES: provides a detailed list of nitrosamines relevant to the pharmaceutical industry, including additional chemical information for each entry. It also positions nitrosamines from the ICH M7 perspective.
3. SOURCES OF NITROSAMINES: provides a general overview on how nitrosamines are formed and could end up in pharmaceutical products. It also indicates the risk factor associated (by observation or evaluation) with each of these sources
4. NITROSAMINES RISK ASSESSMENT – DEVELOPMENT OF A CONTROL STRATEGY: provides recommendations on how to perform the nitrosamines risk assessment and the development of a control strategy to ensure that the nitrosamine presence is avoided or at least reduce to levels below acceptable intake.
5. LIMITS OF NITROSAMINES: details the approach used to determine daily acceptable intake levels of nitrosamines and the criterion used to calculate concentrations limits and the maximum daily dose of the drug substance.
6. TESTING FOR THE PRESENCE OF NITROSAMINES: upon completion of the risk assessment, specify the possibility of performing exploratory testing to confirm the conclusions of the risk assessment and proposed control strategy.
7. TEST METHOD PERFORMANCE CHARACTERISTICS OF NITROSAMINE METHODS: provides guidance on the verification process, the procedures being implemented in the laboratory, and the validation of alternative procedures.

8. ANALYTICAL PROCEDURES: describes the four procedures validated or verified in USP laboratories
9. ADDITIONAL SOURCES OF INFORMATION: contains references to analytical procedures that are currently on the websites of regulatory agencies in the United States (FDA) and Europe (EDQM).

USP: Protecting patients from harmful nitrosamine impurities

USP: <1469> Nitrosamine Impurities

EMA supports recommendations developed by the International Coalition of Medicines Regulatory Authorities (ICMRA) to facilitate the use of global track & trace systems. The agency states that the ICMRA paper identifies “common technical denominators that allow different systems to exchange and use the available information on medicines and their supply chains in order to protect public health“.

Given the globalized production and distribution of medicines, the rapid exchange of information between regulatory authorities is essential to protect the integrity of the supply chain and patient safety. Track and trace systems are therefore considered a useful tool to mitigate the risk of drug shortages and to fight against falsified medicines.

In this paper, international regulators emphasise that the interoperability of track and trace systems helps to protect public health by improving information sharing in case of quality defects and supporting pharmacovigilance activities.

ICMRA developed the recommendations in consultation with the World Health Organization (WHO), representatives from international medicines regulatory authorities and experts from the private sector.

Interoperability of track and trace systems: key to public health protection published

On July 27, 2021, ICH published the long-awaited draft of the Q13 Guideline on Continuous Manufacturing of Drug Substances and Drug Products.

The purpose of the guideline is to provide legal and scientific considerations for the design, implementation and operation of continuous manufacturing. In addition to batch definitions, the document describes the different approaches to continuous manufacturing and provides guidance on control strategy and approval issues.

The new guideline ICH Q13 Continuous Manufacturing of Drug Substances and Products covers active ingredient and drug production manufacturing as well as the production of therapeutic proteins and combined or integrated active ingredient and drug production.

ICH Q13 aims to:

• harmonize the principles of continuous manufacturing, focusing on the specific elements of GMPs
• present flexible approaches for the development and implementation of continuous manufacturing
• provide guidance to industry and regulatory authorities for process evaluation.

The current status of the document corresponds to Step 2 of the ICH process and is open for comment. At this stage, the draft guideline, based on comments received from the ICH Expert Working Group (EWG), is distributed to regulatory authorities in the ICH regions for review in accordance with national or regional procedures. An EWG meeting is scheduled in November 2021 to discuss the comments received. The final guideline is expected to be signed in November 2022 (Step 3).

draft of the Guideline ICH Q13 Continuous Manufacturing of Drug Substances and Products

In July 2021, the EDQM (European Directorate for the Quality of Medicines & HealthCare) renewed the document “Guidance for electronic submissions for Certificates of Suitability (CEP) applications“. The guidance provides explanatory guidance on the electronic submission of CEPs (Certificates of Suitability of Monographs of the European Pharmacopoeia).

The new version of the updated guideline will be implemented on October 01, 2021. The information and requirements described in this document are intended to facilitate the management and evaluation of CEP submissions and to maintain their lifecycle even if the submission is not an eCTD.

This guidance should be applied to all electronic submissions submitted to EDQM as part of CEP applications.

EDQM no longer accepts paper submissions; in fact, the eCTD format is mandatory for all submissions, with the exception of applications for TSE risk (PDF format) and for veterinary substances use only (eCTD format)

EDQM no longer accepts paper submissions; in fact, the eCTD format is mandatory for all submissions, with the exception of applications for TSE risk (PDF format) and for substances for veterinary use only (eCTD format).

Guidance for electronic submissions for Certificates of Suitability (CEP) applications

Adoption and Entry into Force of PIC/S Guidance on Good Practices for Data Management and Integrity in Regulated GMP/GDP Environments (PI 041-1)

On July 1, 2021, the PIC/S Guidance on Good Practices for Data Management and Integrity in Regulated GMP/GDP Environments (PI 041-1) became into force. The guidance has been developed primarily for inspectors, but also serves as a valuable resource for industry to provide clarity on areas of greatest risk and regulatory expectations.

The draft document was first published by PIC/S in 2016, and re-issued as a draft in 2018.

The primary focus of the guidance is on data management as it relates to GMP/GDP considerations.

The scope of the guidance includes both on-site and remote inspections, while follow-up inspections, conducted for cause to probe vulnerabilities found in the first inspection, are excluded.

Data governance principles are addressed by introducing the concept of the data lifecycle, i.e., “how data are generated, processed, reported, checked, used for decision-making, stored, and finally discarded at the end of the retention period,” following a risk-based approach.

For the original document, please see link below.

PIC/S Adapting EU GMP Annex 16 on Authorised Person and Batch Release

PIC/S is considering adopting Annex 16 of EU GMP and harmonizing its requirements. The new document will be called Authorized Person and Batch Release.

Following the revision of Annex 16 in 2016, PIC/S has been discussing whether to transpose Annex 16 in order to harmonize international requirements related to batch release and has now started step 2 of the adoption process which involves consultation of PIC/S Member Authorities with stakeholders.

This consultation will be launched on 15 June 2021 for a period of 3 months.

For the original document, please see link below.

FDA has officially endorsed the ICH Q12 guideline for post-approval change management

The guideline ICH Q12 “Technical and regulatory considerations for pharmaceutical product lifecycle management”, provide a globally agreed framework to facilitate the management of post-approval chemistry, manufacturing, and controls (CMC) changes in a more predictable and efficient manner across the product lifecycle.

This guideline establishes a harmonized approach to defining which elements in an application are considered necessary to ensure product quality (Established Conditions for Manufacturing and Control” – ECs) and therefore would require regulatory submission if changed after approval.

ICH Q12 Core Guideline

defines the concepts of:

• Post-Approval CMC (chemistry, manufacturing, and controls) changes,
• Established Conditions(ECs),
• Post-Approval Change Management Protocols(PACMPs),
• Product Lifecycle Management (PLCM)

ICH Q12 Annexes

FDA also published the Annexes to ICH Q12 which contains illustrative examples describing how to use the principles in the guidance as a framework for managing postapproval changes.

Q12 Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management Guidance for Industry

Q12 Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management Annex

ICH Q12: Implementation Considerations for FDA-Regulated Products

Revision of PIC/S GMP Guide (PE 009-15)

The PIC/S GMP Guide to Good Manufacturing Practice (GMP) for Medicinal Products has been revised to include a new Annex 2A and 2B:

• Annex 2A: Manufacture of Advanced Therapy Medicinal Products for Human Use (ATMP); and
• Annex 2B: Manufacture of Biological Medicinal Substances and Products for Human Use

Annex 2A provides PIC/S GMP requirements for ATMP – it is not a standalone document but it enables reasonable harmonisation with the standalone ATMP Guidelines published by the European Commission.  Annex 2B had very minor revisions and continues to harmonise with the EU Annex 2 for human use biological medicinal substances and products.

The revised GMP Guide (PE 009-15), with the new Annex 2A and 2B, will enter into force on 1 May 2021. All non-EEA Participating Authorities of PIC/S and Applicants have been invited to transpose the revised Chapters of the PIC/S GMP Guide into their own GMP Guides.

For the original document, please see link below.

Q3C(R8) Adoption of Part VI of Q3C(R8) (PDEs for 2-MTHF, CPME, TBA) by the Regulatory Members of the ICH Assembly under Step 4

The ICH Q3C(R8) Residual Solvents guideline has been updated and Permitted Daily Exposure (PDE) values have been added for the following substances:

• 2-methyltetrahydrofuran (50 mg/day)
• Cyclopentyl methyl ether (15 mg/day)
• Tertiary butyl alcohol (35 mg/day)

These values has been developed by the appropriate ICH Expert Working Group (EWG) based on the toxicity details.

On March 25, 2020, ICH had already published the document open for public consultation (Step 2). The proposed values were then adopted as final and included in the final draft of the document (step 4). This will allow for adoption by the regulatory parties of ICH regions, in accordance with the ICH Process (step 5), concluding the review.

For the original document, please see link below.