Author: Federica Carra

The United States Pharmacopeia (USP) is making important changes to series of chapters on Good Storage and Distribution Practices <1079> that will impact risk mitigation strategies for storage and transportation of finished pharmaceuticals.

This chapter focuses on packaging, storage, and transportation processes that maintain drug product quality and supply chain integrity. The proposed revision identifies common risks in the storage and transportation of drug products and recommends appropriate mitigation strategies.

The new USP <1079> changes are significant and highlight the need for companies who will store, handle or transport products with label temperature requirements to meet a thorough Quality Management System (QMS). USP <1079> defines good storage and distribution practices for temperature sensitive drugs during all stages of the cold chain.

The existing chapter is titled “Good Storage and Distribution for Drug Products.” The new proposed chapter title will be – “Risks and Mitigation Strategies for the Storage and Transportation of Finished Drug Products.

The <1079> Series

The current plan for the expanded series is as follows:

Chapters <1079> and <1079.2> are already effective. For <1079.3>, a draft is available for comments.

USP <1079.2>

The sub-chapter <1079.2> addresses the utility and application of mean kinetic temperature (MKT) for the evaluation of temperature excursion in controlled room temperature (CRT) and controlled cold temperature (CCT) products.

USP <1079.3>

Is a new sub-chapter. It provides background information about the science and technology of temperature and humidity monitoring over time. It also describes the available technologies and performance characteristics and provides recommendations for qualifying performance.

Sub-chapter <1118> “Monitoring Devices—Time, Temperature, and Humidity” will be omitted, as the information will be included in the new sub-chapter <1079.3>.

USP <1079.4>

<1079.4> is also a new chapter, which was first published for comments in the Pharmacopeial Forum, PF 48(5), in September 2022.

The draft versions of all proposed new chapters are available in PF Online.

Background

GAMP®5, now supplemented by several Good Practice Guides, is a globally accepted standard for the validation of computerised systems.

The progress of IT environments in recent years has made it necessary to revise and extend the guide, although the basic structure is still well suited to the current IT landscape and to the validation of computer systems.

The new edition “GAMP®5 2nd Edition” is not a new guideline but a revision of the existing guide. It was published at the end of July 2022 and can be ordered on the ISPE website. (https://ispe.org/publications/guidance-documents/gamp-5-guide-2nd-edition).

 

What are the news in the GAMP®5 2nd edition?

The structure, divided into 8 chapters, has remained unchanged:

  • 1-Introductio
  • 2-Key Concepts
  • 3-Life Cycle Approach
  • 4-Life Cycle Phases
  • 5-Quality Risk Management
  • 6-Regulated Company Activities
  • 7-Supplier Activities
  • 8-Efficiency Improvements

 

  • In the chapter 3-Life Cycle Approach, the subsection “Critical Thinking Through the Life Cycle” has been added,
  • in the chapter 8-Efficiency Improvements, the subsection “Using Tools and Automation” has been included in addition to some wording adjustments.
  • In the Management Appendices, the appendices M 11 “Infrastructure” and M 12 “Critical Thinking” have been added as well as some minor changes in the wording.
  • In the Development Appendices, in addition to some wording changes, Appendix D2 “Functional Specifications” has been removed and for new Appendices have been introduced:
    • D8 “Agile Software Development“,
    • D9 “Software Tools“,
    • D10 “Distributed Ledger Systems (Blockchain)“,
    • D11 “Artificial Intelligence and Machine Learning (AL/ML)“.
  • In the Operation Appendices, besides some wording adjustments, the Appendix O7 “Repair Activity” has been removed.
  • In the Special Topics Appendices, Appendix S5 “Managing Quality within an Outsourced IS/IT Environment” has been removed.
  • In the General Appendices, the previous Appendix G1 “GAMP Good Practice Guide Summary” has been removed.

The European Commission has decided to revise Annex 1 of the EU GMP “Manufacture Of Sterile Medicinal Products” to cover the current regulatory and technological developments in the manufacture of sterile medicinal products. In particular, the integration concerns some aspects addressed in ICH guidelines Q9 (Quality Risk Management) and Q10 (Pharmaceutical Quality System).

The Final Version of Annex 1 was published on 25 August 2022.

 

Deadlines

  • New Annex 1 will come into force on 25 August 2023
  • Chapter 8.123 “Lyophilizers and associated product transfer and loading/unloading areas” will come into force on 25 August 2024

 

Changes compared to the second draft version of 2020

The basic structure of Annex 1 has remained unchanged.

In this final version, are broadened topics such as:

  • “Barrier Technologies” – subchapter of the chapter “Premises”
    • The topics of background environment, gloves and decontamination methods have been dealt with separately for Isolators and RABS: “18 Isolators or RABS, which are different technologies, and the associated processes, should be designed to provide protection through separation of the grade A environment from the environment of the surrounding room. […]”
  • “Form-Fill-Seal (FFS)” (8.96) and “Blow-Fill-Seal” (8.105) – subchapter of the chapter “Production and Specific Technologies” go into much more detail.
  • In addition, there are new insertions in many chapters, as well as deletions and rewording.

The EDQM informs that the 11th Edition of the European Pharmacopoeia (Ph. Eur.) is now available.

The latest version comprises some updated monographs which will be implemented on 1 January 2023.

Holders of Certificates of suitability to the monographs of the Ph. Eur. (CEPs) are required to align their applications and thus the respective CEPs according to the revised monographs.

 

Responsibility

According to Directives 2001/83/EC and 2001/82/EC, as amended, it is the responsibility of the manufacturer to comply with the current version of a Ph. Eur. monograph, and therefore to update the specification when a revised monograph is issued.

In addition, the European Directorate for the Quality of Medicines & HealthCare (EDQM) ensures that CEPs always reference the latest version of the pharmacopoeia.

Besides the web notice, EDQM will contact CEP holders to provide more details on how to proceed. However, it remains the responsibility of the CEP holder to comply with the requirements of the monograph and, if necessary, to update their respective applications no later than the implementation date of the revised monograph, regardless of whether they have been contacted by EDQM.

The EDQM listed the substances covered by a CEP and for which a revised monograph will be implemented on January 1, 2023, classifying them into two categories, A and B, based on the required information

Case A:

The specification of the substance should be updated according to the revised monograph. The updated specification should be included in the next request for revision that is submitted to the EDQM.

Case B:

This case concerns amendments to the monograph which require the submission of data to the EDQM. An updated dossier demonstrating that the substance complies with the requirements of the revised monograph should be provided within three months of the EDQM contacting the CEP holder.

Where the required information has already been submitted in the approved dossier, a self-declaration is considered to be sufficient.

Source: EDQM Newsroom

The second revision of the “Guideline for Elemental Impurities Q3D(R2)” has achieved “step 4” (adoption by the Regulatory Members of the ICH Assembly) on April 26, 2022 and is available on the ICH website.

Compared with the draft dated September 2020, the final version of this second revision includes some revisions and adaptations:

§  Appendix 2: Established PDEs for Elemental Impurities PDEs (Permitted Daily Exposure) values for Gold, Silver and Nickel have been adjusted

§  Appendix 3: Individual Safety Assessments Gold and Silver monographs were revised

§  Appendix 5: Limits for Elemental Impurities by the Cutaneous and Transcutaneous Route was added in the second revision of the guideline and contains information on the limits for impurities for cutaneously or transcutaneously applied medicinal products.

The appendix focuses on the forms of impurities most likely to be detected following the application of pharmaceuticals to human skin. It also considers both local and systemic toxicities.

“[…] ICH decided to adopt a “generic approach” instead of an element-by-element one.

The reason for the choice is due to the results of the studies consulted. Indeed, these would tend to report a “disappearance” of impurities in the skin rather than transcutaneous absorption.”

The “Harmonized Guideline for Elemental Impurities Q3D(R2)” can be found on the ICH website.

Last May, EMA opened a brief, one-month public consultation procedure (13 May 2022 – 13 June 2022), on a draft question and answer document on remote certification of batches by the Qualified Person (QP): “Public Consultation concerning the physical Attendance and the Location of Personal Residency of The Qualified Person“.

The COVID-19 pandemic has affected standard way of working, requiring the need to work remotely to ensure operations under business continuity mode.

To minimise risks of shortages while ensuring that the high standards of quality, safety and efficacy of medicines made available to patients in the EU were maintained, EMA has therefore developed, in cooperation between the European Commission and the Coordination Group for Mutual Recognition and Decentralised Procedures – Human Medicine (“CMDh”), guidance on adapting “regulatory expectations” as a result of the new context created.

This guidance contemplates the possibility that the work of QPs needs to be adapted to allow remote batch certification when on-site presence is not possible. The GMDP inspectors’ working group is currently evaluating the possible flexibility for the physical presence of the QP at the authorised manufacturing site when batch certification or confirmation is carried out routinely and not only on an emergency basis.

The draft Q&A document, published on May 11, discusses the appropriate requirements and conditions for allowing QP work remotely.

The text clarifies that since the ultimate responsibility for the interpretation of EU legislation lies with the European Court of Justice, the content of this document is therefore subject to any other interpretation by the European Court of Justice.

Proceeding from the requirements in Annex 16 regarding validation and certification activities carried out by the QP, the text outlines four clarifications, expressed in question-and-answer form:

1.    Is remote batch certification/ batch confirmation by the QP allowed on a routine basis?

2.    Where remote QP certification / confirmation is allowed on a routine basis, what conditions should apply?

3.    Is the QP required to be a resident in the Member State where the authorised site is located?

4.    What are the technical requirements for the remote access and the signature used for batch certification / confirmation?

Commissione Europea, EMA ed HMAs – Q&A on regulatory expectations for medicinal products for human use during the COVID-19 pandemic

The U.S. Food and Drug Administration (FDA) has updated (Revision 1) its Guidance for Industry on Out-of-Specification (OOS) Results. The first version of the document was dated October 2006.

The guide follows a step-by-step approach consisting of three main phases for investigating OOS test results

  • LABORATORY INVESTIGATION
  • FULL-SCALE OOS INVESTIGATION
  • CONCLUDING THE INVESTIGATION

The process outlined in the text follows quite closely the requirements laid out in 21 CFR part 211.

Definition

The definition of “OOS” has not changed.

«the term “OOS results” includes all test results that fall outside the specifications or acceptance criteria established in drug applications, drug master files (DMFs), official compendia, or by the manufacturer.  The term also applies to all in-process laboratory tests that are outside of established specifications

Comparison with the 2006 version

The revision of the guideline contains some formal adjustments from the previous version, and also focuses on updating references to other FDA relevant guidelines and regulatory requirements (USP chapters, CFR paragraphs, etc.)

In addition, the new text contains some clarifications or rewordings from the 2006 edition, the following changes are worth mentioning:

  • section IV.C.2.: the wording on “Outlier Tests” has been amended as follows:
  • Version October 2006“Occasionally, an outlier test may be of some value in estimating the probability that the OOS result is discordant from a data set, and this information can be used in an auxiliary fashion, along with all other data from the investigation, to evaluate the significance of the result.”
  • Version May 2022“Occasionally, an outlier test may be of some value in understanding how discordant from a data set a result is, but can be used solely in an informational capacity in the course of an investigation to determine the distance of a result from the mean.”
  • Section V.B. – Cautions: has been divided into three subsections:
  1. Averaging results from multiple sample preparations from the original sample
  2. Averaging results from same final sample preparation
  3. Borderline results that are within specification

Both versions of the guideline can be downloaded from the FDA homepage.

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.