Author: Federica Carra

The Pharmaceutical Inspection Co-operation Scheme (PIC/S) has adapted EU GMP Annex 16 (“Certification by a Qualified Person and Batch Release”) and calls it “Certification by the Authorised Person and Batch Release“.

In Europe, each holder of a manufacturing authorisation for medicinal products needs to name at least one Qualified Person (QP). The legal basis for the appointment of a QP is defined in the DIRECTIVE 2001/83/ EC and in DIRECTIVE 2001/82/EC; these directives clearly determine the educational background and professional experience a professional requires to act as a QP as well as the duties and responsibilities associated with this function.

Annex 16 of the EU GMP Guide covers in depth the activities related to certification and batch release and all the responsibilities that fall to the QP.

Until now, PIC/S had not adapted EU Annex 16, as it considered it too EU-specific and difficult to implement for PIC/S purposes. The decision to address an implementation of the Annex shows the international harmonization effort.

The new PIC/S GMP Guide (PE 009-16), updated with the revised Annex 13 and the new Annex 16 entered into force on February 1, 2022. All Participating Regulatory Authorities of PIC/S Committee and non-EEA/EU applicants have been invited to transpose Annexes 13 and 16 into their own GMP Guides.

It will be interesting to see how these Authorities approach a possible implementation.

The European Medicines Agency (EMA) provides answers to frequently asked questions on Good Manufacturing Practice (GMP) and Good Distribution Practice (GDP) on its website. These have been discussed and agreed by the GMP/GDP Inspectors Working Group.

The guide, in the form of a question and answer (Q&A), provides further interpretation of the GMP and GDP guidelines published by the European Commission.

On January 28, 2022, Directive 2001/82/EC – EU Code for Veterinary Medicinal Products was repealed, as a result, the legal requirements for veterinary medicinal products have been updated and will be regulated according to Regulation (EU) 2019/6 of the European Parliament and of the Council on veterinary medicinal products. This regulation includes provisions on authorisation, post-authorisation measures, manufacture, import, export, supply and use of veterinary medicinal products, as well as restrictions and sanctions. Accordingly, the questions and answers have been supplemented and updated.

The new chapter deals with requirements for active substances that are used as starting materials for the manufacture of veterinary medicinal products.

The following are some questions that have been answered:


  1. Do active substances used as starting materials in veterinary medicinal products have to comply with Good Manufacturing Practices (“GMP”) for active substances for human medicinal products?
  2. Are there new obligations for active substances used as starting materials in veterinary medicinal products under the Veterinary Medicines Regulation?
  3. Is a GMP certificate mandatory for manufacturing sites?
  4. Can inspections conducted by third country competent authorities be considered when deciding whether a Union inspection should be triggered?


The complete list of questions and answers is available on the EMA website.

On 28 January 2022, the Veterinary Medicinal Products Regulation (Regulation (EU) 2019/6), updating the existing rules on the authorization and use of veterinary medicinal products in the European Union, entered into force.

Regulation (EU) 2019/6 repealed Directive 2001/82/EC; bringing new measures to increase the availability and safety of veterinary medicines, it should also strengthen EU action against antimicrobial resistance. In addition, it amended the provisions of Regulation (EU) 726/2004 on the authorization and supervision of veterinary medicinal products, which currently governs the centralized marketing authorization procedure for both human and veterinary medicinal products.

In accordance with Regulation (EU) 2019/6, the European Commission added two standalone GDP regulations, all documents can be found in Eudralex Volume 4:

The documents were developed analogously to the GDP guidelines for for medicinal products for human use and related active substances.

In the Pharmacopeial Forum, PF 48(1), a proposal for a new general chapter <1504> Quality Attributes of Starting Materials for the Chemical Synthesis of Therapeutic Peptides was published. The draft of the new chapter is available on PF Online.

Structure of the New Chapter

The new chapter is divided into the following sections:

  • Scope
  • Introduction
  • Supplier qualification and evaluation of synthetic route
  • Amino acid derivatives (AAD)-related impurities originating from amino acids
  • AAD-related impurities originating from the AAD manufacturing process
  • Non-AAD impurities
  • Conclusion and recommendations for AAD specifications


According to the Expert Panel, the purpose of the new chapter is to provide an overview of the minimum quality attributes required for Starting Materials used in the production of synthetic therapeutic peptides. Consideration in the new chapter focuses on the most commonly used protected amino acid derivatives (AAD). However, the general concepts and guidance described can be applied to all peptide starting materials.

As these starting materials (amino acids, protected amino acid derivatives, and fragments ) have the potential to directly impact the quality of the drug substance, special attention must be paid to the quality attributes.

The synthetic route for the amino acid derivative could potentially lead to several impurities, which depending on the classification could be related to a different degree of criticality.

According to the new chapter, the most common quality attributes to be used for protected amino acid derivative starting materials are:

  • Appearance
  • Identification
  • Related impurities
  • Other impurities (not related)
  • Assay by titration
  • Other components

Attending to 61° SIMPOSIO AFI as speaker at the workshop + Booth n. 58.
8-9-10 june 2022 Rimini (Italy)

In August 2020 the International Coalition of Medicines Regulatory Authorities (ICMRA) established a working group “Remote GCP and GMP Regulatory Oversight Inspections” that has published a report entitled “Reflections on the regulatory Experience of remote Approaches to GCP and GMP regulatory Oversight during the COVID-19 Pandemic

ICMRA is a voluntary association of internationally cooperating medicines regulatory authorities

The International Coalition of Medicines Regulatory Authorities (ICMRA) set up this working group to focus on the transition from GCP and GMP inspections to remote inspections during the pandemic. The working group was chaired by the UK MHRA and included representatives from the US FDA, EMA, Health Canada, Swiss-medic, HPRA Ireland, AEMPS Spain, ANSM France, PEI Germany, MHLW/PMDA Japan, TGA Australia, ANVISA Brazil, HSA Singapore, WHO, and Saudi FDA.

The purpose of this paper is to report reflections based on combined experience during conducting remote assessments, inspections, and determinations of GCP and GMP regulatory activities conducted globally shared through the workgroup during 2020-21.

Obviously, variable experience is reported across inspection types and areas, sites, and jurisdictions.

Experiences with different types of digital means, such as visual technology, are also discussed.

Essentially the ICMRA working group conveyed that remote inspections cannot replace regular and routine on-site GMP inspections, but they have allowed regulators to maintain a minimal oversight program. Some regulators expressed interest in continuing to supplement their inspections with remote inspections and/or hybrid approaches in the future, or even replacing an on-site inspection completely in some cases, such as to address an urgent concern, to support an application evaluation and approval decision, or to review certain corrective/preventive actions.

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.


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.
  1. ANALYTICAL PROCEDURES: describes the four procedures validated or verified in USP laboratories
  2. 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