02.08.2024

GDP Update for 2023/2024

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GDP stands for "Good Distribution Practice". It refers to the sum of measures taken within the distribution chain to ensure that medicinal products or active ingredients maintain the required quality, safety and efficacy during transportation and storage. Compliance with GDP is required by law in many countries and is monitored and inspected by the relevant authorities. Pharmaceutical and active ingredient manufacturers must therefore always ensure that their processes comply with GDP requirements. However, all service providers involved in the pharmaceutical supply chain, such as storage, transportation and distribution companies as well as wholesalers, must also comply with the GDP requirements relevant to them.

A lot has happened in the GDP environment in recent months. Following up on the article published here in GMP Journal last year, this article¹ summarizes some highlights from 2023 and the first quarter of 2024.

Regulatory developments in the EU

Further extension of GDP certificates

As already reported in the GDP Update 2022/2023, the pandemic-related restrictions and the associated difficulties in carrying out GDP inspections have made it necessary to extend existing certificates. At the beginning of 2020, the European Commission, the Heads of Medicines Agencies (HMA) and the European Medicines Agency (EMA) developed a question-and-answer document on regulatory expectations during the COVID-19 pandemic. The initial plan was to extend the validity of GDP certificates until the end of 2021 without the need for any further action on the part of the certificate holder. A similar procedure was to be followed for temporary wholesale permits. This timeframe was subsequently adjusted several times².

Although inspections can be carried out on site again without restrictions, a considerable number of postponed inspections are still pending. In December 2023, it was announced that the GMP/GDP inspectors' working group has decided to extend the validity of GDP and GMP certificates that expired at the end of 2023 until 2024 or until the completion of the next on-site inspection, which-ever comes first.³ The Medicines and Healthcare products Regulatory Agency (MHRA), the regulatory and supervisory authority for medicinal products in the UK, has decided on an analogous procedure in consultation with its international partners, as announced in the MHRA Inspectorate on December 11, 2023.⁴

In principle, the competent authorities reserve the right to carry out risk-based monitoring of sites through on-site or remote inspections and to continue to issue, withdraw or restrict GMP and GDP certificates depending on the outcome.

EMA: Work plan of the GMP/GDP Practice Inspectors Working Group

At the end of April 2023, the EMA presented the Annual report of the Good Manufacturing and Distribution Practice Inspectors Working Group 2022. An updated work plan 2021-2023 (Work plan for the Good Manufacturing Practice / Good Distribution Practice Inspectors Working Group 2021-2023) was also published.⁵

The following aspects relating to good distribution practice should be mentioned from the annual report:

Under the section "3. GMP and GDP inspections in 2022", it is pointed out that the COVID-19 pandemic and the associated travel restrictions and hygiene measures have had a significant impact on the work of GMP and GDP inspectors. Although on-site inspections have resumed as far as possible, there are still disruptions.
In section "6. GMP and GDP guidance", reference is made to the new Q&A documents, in particular those dealing with the requirements and changes in connection with the adaptation of veterinary medicinal products legislation.
Section "8. EudraGMDP database" lists the link between EudraGMDP and the EMA's Organization Management Service (OMS) as well as the extension of the Wholesale Distribution Authorization (WDA) and the Active Pharmaceutical Ingredients Registration (API-Reg) to the veterinary sector In this context, reference should also be made to the answers to frequently asked questions on Good Manufacturing Practice (GMP) and Good Distribution Practice (GDP), which are regularly updated.⁶

ZLG: Document on the inspection of the suitability of transport processes

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In late August 2023, the German Central Authority of the Federal States for Health Protection of Medicinal Products and Medical De vices (ZLG) published a newly created document entitled "Inspection of the suitability of transport processes" as part of its Quality Assurance Manual (QSH).^8,9 The document is applicable to GMP and GDP areas and is primarily aimed at employees of the responsible supervisory authorities. It is a so-called Aide mémoire (AiM), i.e. a catalog of specifications, questions and recommendations that serves to harmonize the preparation, implementation and follow-up of an inspection. It covers the transportation of medicinal products, veterinary medicinal products and active pharmaceutical ingredients.

As there is no legal definition of the term "transport verification", the EFG 10 expert group responsible for creating the document has introduced a description of the term:

Transport verification: "The purpose of transport verification is to confirm compliance with the predefined procedures, and limits for the quality-critical parameters of the transport."

The main part of the document deals with the following aspects:

Procedure for a transport verification: an example flowchart is used to describe the procedure for a transport verification, including the upstream steps. The definition of the transportation process and the controls as well as the topics of risk analysis, assessment and control are discussed.
Transport verification: This section lists the relevant points that must be verified using the documentation.
Transport verification vs. validation: The difference between the two terms is explained and it is pointed out that, due to the variability of transport processes, transport validation can often only be carried out for sub-processes.

MHRA: Summary of the GMDP Symposium

On 21 and 22 February 2023, the Good Manufacturing and Distribution Practice Symposia 2023, two symposia on good manufacturing and distribution practice organized by the MHRA, took place. The first day of the conference focused on regulatory developments in the area of GDP. The event was aimed at wholesalers and their responsible persons and quality assurance staff, as well as anyone involved in the procurement, supply, export and storage of medicinal products in general.

A summary of the GDP section was published on the MHRA's inspectorate blog.¹⁰ The post, dated May 02, 2023, mentions that the event covered a variety of topics, with a focus on updates on the regulatory position and the MHRA's role as a sovereign regulator. The blog post also provides a brief summary of the individual contributions. Topics presented included the impact of climate change on GDP activities and the role of the so-called Responsible Person (Import), RPi.

The MHRA has not yet set a date for the next GMDP symposium. It is expected to take place towards the end of the year or at the beginning of 2025.¹¹

Swissmedic: SwissGMDP database

Swissmedic, the Swiss regulatory and supervisory authority for medicinal products and medical devices, is planning to launch a SwissGMDP database, similar to the EudraGMDP database, in which the GMP and GDP certificates of every company in Switzer land that holds a valid Swissmedic establishment license will be publicly accessible.

A press release dated September 10, 2023 states:

"These SwissGMDP certificates contain all approved activities, i.e. in contrast to the EudraGMDP, the GDP activities and Switzerland-specific GMP activities of Swiss companies are also listed in the certificates. The GMP/GDP status of a company can be viewed very easily by all companies, authorities and persons on this SwissGMDP."¹²

Swissmedic: Shipment under quarantine
In February 2024, Swissmedic published a new English document on the subject of "Shipment under Quarantine".¹³ The document with the number I-SMI.TI.26e clarifies some situations in which a shipment under quarantine of active substances, intermediates or medicinal products would be acceptable for inspectors.

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The core of the new document is the fourth chapter (Interpretation). It outlines various situations that could, in principle, lead to a decision to consider quarantine shipping (e.g. limited storage capacity, long transportation times). At the same time, it is emphasized that quarantine shipping is generally not in line with GMP requirements and should therefore not be standard practice, and that appropriate safety measures must be implemented in all cases.

For five specific cases, a table indicates whether shipping under quarantine is acceptable or not. Within the five scenarios, a distinction is made between active substance, intermediate product and finished product. In the fourth example case (Transfer of manufactured goods to a central distribution hub under third party control), the transport is addressed to a main transshipment base. In such a case, shipment under quarantine is permitted if this central distribution hub is located in a country that applies the EU GDP regulations like an EU country or in a formalized manner through a bilateral agreement with the EU.

ICH: New version of ICH Q9 The ICH Q9 Guideline describes a systematic approach to the management of risks associated with the quality of medicinal products throughout their life cycle, from development to manufacture and use. Since the publication of the first final version in 2005, it can be regarded as state of the art. It was initially included in the EU GMP guidelines as Annex 20 and was then moved to Part III, where it is still located today.¹⁴

The new ICH Q9(R1) reached Step 4 of the ICH process on January 18, 2023 and was published on the ICH website.¹⁵ In addition, various materials have been made available. These include a presentation from 14.03.2023¹⁶as well as quite extensive training presentations¹⁷ with a total of over 300 slides, which are summarized in a zip file and were made available in October 2023.

Regulatory developments in the USA

FDA

The U.S. Food and Drug Administration (FDA) has driven forward its efforts in connection with the Drug Supply Chain Security Act (DSCSA). The DSCSA was passed in 2013. It outlines electronic drug traceability measures at the package level to enable the identification and tracking of certain prescription drugs. The DSCSA also instructs the FDA to define national approval standards for wholesalers and 3PL service providers (third-party logistics providers).¹⁸

The following publications are to be listed in this context:

The Small Business and Industry Assistance (SBIA) Program at the Center for Drug Evaluation and Research (CDER) provided a recording of a webinar titled "Implementing DSCSA: Stabilization Period and Expectations" on November 3, 2023.¹⁹
On November 20, 2023, the FDA issued a Request for Information to better understand the status of implementing trading partner systems and processes for improved drug distribution safety under the Food, Drug and Cosmetic Act (FD&C Act).²⁰
On November 27, 2023, an overview article (FDA Voices) entitled "FDA Protects Patients from Harmful Drugs Through the Drug Supply Chain Security Act" was published.²¹
On November 29, 2023, the FDA held a conference call with stakeholders to discuss the implementation of the DSCSA.²²

The following publications should also be mentioned:

"Definitions of Suspect Product and Illegitimate Product for Verification Obligations Under the Drug Supply Chain Security Act": The March 2023 document clarifies the agency's interpretation of certain terms used in the legal definitions of "suspect product" and "illegitimate product". Specifically, the following terms are explained in more detail: "counterfeit", "diverted", "stolen", "fraudulent transaction", "unfit for distribution".²³
"Waivers, Exceptions, and Exemptions from the Requirements of Section 582 of the Federal Food, Drug, and Cosmetic Act": This guidance, published in early August 2023, is the final version of the draft guidance of the same name published in May 2018. According to the FDA, the changes to the draft guidance include recommendations for authorized trading partners and other parties on how to submit an application and the information required for waivers, exemptions, or exemptions from certain obligations.²⁴
"Enhanced Drug Distribution Security Requirements Under Section 582(g)(1) of the Federal Food, Drug, and Cosmetic Act - Compliance Policies": This document, published at the end of August 2023, describes the FDA's actions to enforce the requirements for electronic traceability of products at the package level under the FD&C Act.²⁵
"Enhanced Drug Distribution Security at the Package Level Under the Drug Supply Chain Security Act": This guidance, also published at the end of August 2023, is intended to help supply chain participants, particularly distributors, meet the requirements for enhanced drug distribution security at the package level under Section 582 of the Federal Food, Drug and Cosmetic Act (FD&C Act).²⁶
"DSCSA Standards for the Interoperable Exchange of Information for Tracing of Certain Human, Finished, Prescription Drugs": This document, dated September 2023, is the final guidance on the standards for the interoperable exchange of track and trace information for certain human prescription drugs.²⁷
"Wholesale Distributor Verification Requirement for Saleable Returned Drug Product and Dispenser Verification Requirements When Investigating a Suspect or Illegitimate Product Compliance Policies": In this September 2023 document, which is Revision 1 of the Guidance, FDA addresses how to minimize potential disruptions in the distribution of certain prescription drugs in the United States in light of the new requirements. The FDA does not intend to take action against distributors who fail to verify the product identifiers of suspect or illegal products until November 27, 2024.²⁸
"Verification Systems Under the Drug Supply Chain Security Act for Certain Prescription Drugs": This document from December 2023 deals with systems that trading partners must set up to detect and respond to suspicious drugs and inform the authority if necessary.²⁹

Since the DSCSA was passed in 2013, the FDA has published a whole series of other guidance documents and policies, as shown in the overview "Drug Supply Chain Security Act Law and Policies".³⁰

USP

The United States Pharmacopeia (USP) is still in the process of expanding or completing the series of <1079> chapters on good warehousing and distribution practices^.31

The planned structure is as follows:
<1079> Risks and Mitigation Strategies for the Storage and Transportation of Finished Drug Products
<1079.1> Storage and Transportation of Investigational Drug Products
<1079.2> Mean Kinetic Temperature in the Evaluation of Temperature Excursions During Storage and Transportation of Drug Products
<1079.3> Monitoring DevicesTime, Temperature, and Humidity
<1079.4> Temperature Mapping for the Qualification of Storage Areas
<1079.5> Qualification of Shipping Systems
<1079.6> Transport Route Profiling Qualification
<1079.7> Information Systems for Distribution Validation/Verification Studies

Chapters numbered below 1000 are considered mandatorily applicable in the U.S. if they are referenced in a monograph, another applicable general chapter, or in general notes. General chapters numbered above 1000 are not mandatory. They are considered explanatory texts and contain information, definitions and descriptions.

The General Chapter <1118> Monitoring DevicesTime, Temperature, and Humidity has been deleted as of December 01, 2023. In this context, the USP has identified other pharmacopoeia texts that refer to Chapter <1118> and are therefore affected by this deletion. According to a Notice of Intent to Revise dated April 28, 2023, this affects three chapters, namely <1079>, <1079.1> and <1079.2>.³²

During the period under review in this article, chapter <1079.1> was revised. With the revision, reference is made to the new USP Chapter <1079.3>, which officially came into force on December 1, 2023.

Other regulatory developments

TITCK: Guideline on Inspections

The Turkish Medicines and Medical Devices Agency (TITCK) has published a new revision of its guideline on inspections related to the storage and distribution of medicinal products for human use. The first version of the guideline with document number IDD-KLVZ-01 came into force in February 2022. The document was revised for the first time in November 2022. The second revision came into force on June 20, 2023.

The purpose of the document, which was only published in Turkish, is to provide guidance for inspections related to the storage and distribution of medicinal products for human use. It also aims to ensure that inspections are carried out in accordance with the applicable national legislation and that the manner in which they are carried out is standardized.³³

GDP inspections and deficiencies

GDP non-compliance reports in EudraGMDP

Wholesale of medicinal products requires a wholesale authorization/license, which is issued within the European Union by the national competent authority of the Member State in which the wholesaler is based and carries out trade. If an inspection reveals that the wholesaler's GDP compliance cannot be confirmed, a noncompliance report is entered into EudraGMDP.

At the end of March, a total of 41 reports from the years 2014 to 2023 were available via the free and publicly accessible read-only access. However, this figure does not reflect the total number of all GDP non-compliance reports, as some reports have since been withdrawn and are therefore no longer displayed.

No reports have yet been entered in 2024 (as of 27.03.2024). If we look at the 11 GDP non-compliance reports in 2023, it can be seen that the deficiencies listed therein essentially relate to the requirements from chapters 1 to 5 of the EU GDP guidelines³⁴.

As in 2022, many of the deficiencies documented in the reports relate to the responsible person (Chapter 2). Either the availability of a responsible person was not guaranteed or the person did not perform their duties to the required extent. Another focus is on the operating rooms (Chapter 3) and storage (Chapter 5). In this con text, there were repeated complaints that activities were carried out in premises that were not covered by the permit. Several reports criticized the quality assurance system (Chapter 1), which was not applied and maintained or did not ensure that the products remained within the legal supply chain. It was also mentioned several times that the storage procedures (Chapter 5) did not ensure adequate security of stocks. Finally, the documentation (Chapter 4) was mentioned, in particular that purchases and sales were not adequately documented.

Counterfeit medicines

Counterfeit medicines do not meet the required safety, efficacy and quality standards and can pose a major risk to human and animal health. This is one of the reasons why the topic is explicitly addressed in the EU GDP guidelines. Despite all precautionary measures, several cases have recently come to light in which counterfeit medicines have entered the legal supply chain.

The example of Ozempic^® should be mentioned in this context. Ozempic^® is a drug that is approved for the treatment of type 2 diabetes, but has also become an increasingly popular weight loss drug in off-label use.

Following several confirmed counterfeit batches of Ozempic^® in the EU drug supply chain³⁵, the FDA³⁶ has also warned consumers about the use of counterfeit Ozempic^® found in the US drug supply chain.

Product recall

The required storage conditions for medicinal products must always be observed. If deviations are only discovered after the goods have left the warehouse, this may result in the need for a recall. This is illustrated by an example from the USA involving a possible pest infestation and temperature deviations. On August 23, a company announcement was published on the FDA website.³⁷ The company concerned has launched a voluntary recall of a whole range of so-called FDA-regulated products, i.e. products that fall under the supervision of the FDA. These include medicines, but also various food products, pet food and medical devices. The company announcement states that a pest infestation may have occurred during this time in the warehouse where the recalled products were located. In addition, it is possible that the products were exposed to temperatures above the storage conditions indicated on the product label due to recent hot weather conditions.

Associations

European GDP Association

The European GDP Association (GDPA)³⁸, which represents experts from all over the world, continued to expand its member base in 2023^.39 The group now has over 4,000 members.

2023, a change in the Board of Directors was announced. Dr. Martin Egger, CEO of Infrareal Holding and Pharmaserv, has decided to step down as a member of the Advisory Board.⁴⁰

The European GDP Association offers its members a range of publications (working aids, Q&A documents) and an increasingly popular discussion forum. The forum gives the opportunity to address GDP-related questions to a large audience. Membership is free of charge and can be applied for via an application form⁴¹.

About the Author
Dr Markus Funk joined CONCEPT HEIDELBERG in October 2019 as operational director and is in charge of the topics GDP and analytics.