Good Distribution Practice Update 2022/2023
Good Distribution Practice (GDP) is the sum of measures taken within the pharmaceutical supply chain to ensure that the quality and integrity of medicinal products and active pharmaceutical ingredients (APIs) are maintained. The requirements for the distribution of medicinal products have increased continuously. This affects not only all service providers involved in the supply chain, such as storage, transport and distribution companies and wholesalers, but drug manufacturers, as well.
A lot has happened in the last few months. For example, in the course of revamping veterinary drug legislation, the European Commission issued measures on good distribution practice for veterinary medicinal products or for active substances used as starting materials in veterinary medicinal products. The U.S. Food and Drug Administration (FDA) is seeking to standardize requirements for pharmaceutical wholesalers across U.S. states, and other agencies have also clarified their requirements and expectations for good distribution practice. In addition, there have been interesting non-compliance reports, FDA warning letters, and court rulings related to GDP issues, from which generally applicable requirements and expectations can also be derived.
This article summarizes some highlights from the GDP area in Europe and the USA. Developments from 2022 and the first quarter of 2023 are considered.
Extension of GDP Certificates Due to pandemic-related restrictions and the associated difficulties in conducting GDP inspections, back in early 2020, the European Commission, Heads of Medicines Agencies (HMA) and the European Medicines Agency (EMA) developed a Q&A document on regulatory expectations during the COVID-19 pandemic. Initially, the plan was to extend the validity of GDP certificates until the end of 2021, with no further action required on the part of the certificate holder. An analogous approach was to be taken with time-limited wholesale authorisations. This time frame has subsequently been adjusted several times. The current fifth revision of the document provides for automatic extension until the end of 2023.1
GDP for Veterinary Medicinal Products
With Regulation (EU) 2019/6 on veterinary medicinal products, which has been in force since January 28, 2022, the European Union has restructured the veterinary medicinal products legislation.2
Already in August 2021, the new Implementing Regulation 2021/1248 on measures of good distribution practice for veterinary medicinal products entered into force.3 According to Art. 1(2), it applies "to holders of a manufacturing authorisation performing wholesale distribution of the veterinary medicinal products covered by that manufacturing authorisation, and to holders of a wholesale distribution authorisation, including those established or operating under specific customs regimes, such as free zones or customs warehouses." The requirements are strongly based on the GDP guidelines for medicinal products for human use.4 This is already evident from the titles of the individual chapters. Many parts have been adopted verbatim or at least in spirit.
Berlin, Germany13/14 December 2023
Root Cause Analysis
The implementing regulation 2021/1280 regarding measures on good distribution practice for active substances used as starting materials in veterinary medicinal products also came into force in August 2021.5
It has many parallels in content to the GDP guidelines for active ingredients of medicinal products for human use.6 According to Art. 1 (2), the Implementing Regulation (EU) 2021/1280 applies to "importers and distributors of active substances used as starting materials in veterinary medicinal products, and to manufacturers who distribute active substances, which they manufactured, used as starting materials in veterinary medicinal products." Intermediates of active substances are explicitly excluded from the regulations according to Art. 1(3).
Questions and Answers Section of the EMA
The European Medicines Agency (EMA) publishes answers to frequently asked questions on Good Manufacturing Practice (GMP) and Good Distribution Practice (GDP) on its website.7 These have been compiled and agreed upon by the GMP/GDP Inspectors Working Group. Several additions have been made to this list in recent months.
In February 2022, a new chapter with six questions was added to address the requirements for active substances used as starting materials in veterinary medicinal products. It clarifies that manufacturers and importers of veterinary medicinal products are required to conduct audits "based on a risk-assessment on the manufacturers, distributors and importers from whom they source the active substances".
A new sub-item added in October 2022 deals with the requirements relating the nature of check at the reception of veterinary medicinal products before being transferred to saleable stock. The question refers to the requirements under Article 23(3) of Regulation 2021/1248, according to which, batches intended for the Union market shall not be transferred to saleable stock before assurance has been obtained that they are authorised for sale. The response states that wholesalers must ensure that batches of veterinary medicinal products from another member state are accompanied by proof that the manufacturer's Qualified Person has certified that batch. This control could be done in different ways: Paper-based (copy of the control reports), electronically or by another equivalent system agreed with the supplier (manufacturer or wholesaler).
Another update was made in January 2023, adding three new questions to the GDP requirements. The first aspect relates to the monitoring of storage conditions for medicinal products for which no limits are specified on the outer packaging. The question whether it is acceptable that storage conditions are not monitored in such cases is answered with a clear "No". The Marketing Authorization Holder (MAH) must provide stability data to justify not making storage indications on the outer packaging. Such stability data are generated under climate zone I and II conditions. EMA writes that in such a case, it must be ensured that the conditions for climate zones I and II are met during storage and transport. The other two questions relate to the activities of brokers with contracting parties outside the European Economic Area (EEA): "May a broker have broker activities between parties outside the EEA?" and "May a broker have broker activities for medicinal products without a marketing authorisation in the EEA (but with a marketing authorisation in a county outside the EEA)?" With reference to the requirements of the EU GDP Guidelines, these two questions are also answered with "No".
The Pharmaceutical Inspection Co-operation Scheme (PIC/S) has published two new English language documents for GDP inspectors, which came into force on 01 February 2023. The documents were prepared by the PIC/S Expert Circle on GDP and are available for free download as PDF files from the PIC/S website.8
The first document is titled "Aide-Memoire on the Inspection of Good Distribution Practice (GDP) for Medicinal Products in the Supply Chain" The main body of the 22-page publication consists of a total of 10 tables that contain general aspects and specific issues to be considered during a GDP inspection. The tables also include references to supporting documents.
The second new document is entitled "Questions & Answers document regarding the PIC/S GDP Guide (PE 011-1)". Here, the questions and answers refer to the "PIC/S Guide to Good Distribution Practice (GDP) for Medicinal Products" of June 2014. On a total of 11 pages, various questions regarding the individual chapters of the PIC/S GDP Guide are answered.
With regard to developments in the UK, reference can first be made to the new 5th edition of the "Rules and Guidance for Pharmaceutical Distributors" (the "Green Guide"), compiled by the Medicines and Healthcare products Regulatory Agency (MHRA). The publication became available in March 2022 and supersedes the 2017 edition. The Green Guide includes current EU guidelines on good distribution practice, as well as key UK regulations, directives and guidelines. The collection has been updated to reflect changes following the United Kingdom's withdrawal from the European Union. It also includes new guidance on pharmacovigilance for wholesalers, naming sites on a license, self-inspection and the responsible person for import (RPi). The Green Guide is published by Pharmaceutical Press.9
One innovation concerns the pilot program for monitoring GMP and GDP activities, launched in mid-2022, under which approved consultants, known as Compliance Monitors (CMs), oversee the implementation of an agreed Compliance Protocol (CP). Individuals applying for this program must meet certain requirements. These include at least five years of experience in conducting independent audits of GMP/GDP companies. In order to be a CM specifically in the GDP field, sufficient experience is also required in relation to the distribution activity carried out by the company in question.10
Drug Supply Chain Security Act (DSCSA)
There is also quite a bit happening in the U.S. right now in the area of wholesale and good distribution practices. For example, the FDA has published several new documents related to the Drug Supply Chain Security Act (DSCSA). The DSCSA was enacted in 2013. It outlines steps to achieve electronic tracing of products at the package level to identify and trace certain prescription drugs. The DSCSA also directs the FDA to establish national licensure standards for wholesale distributors and third-party logistics providers (3PLs).11
In this context, the following laws or documents have been published, for example:
- "National Standards for the Licensure of Wholesale Drug Distributors Third-Party Logistics Providers": this draft legislation was first published in February 2022. The proposed regulation establishes national approval standards for the federal and state authorization of wholesale drug distributors and 3PL service providers. According to the agency, once enacted, the new law will provide greater assurance that supply chain participants are sufficiently vetted and qualified to distribute prescription drugs. This would further strengthen supply chain security. Originally, the comment period was scheduled to end on June 6, 2022. However, this deadline was extended to allow all stakeholders sufficient time to submit comments.12
- "Verification Systems Under the Drug Supply Chain Security Act for Certain Prescription Drugs": This March 2022 guidance revises the first version of the document, which was published in October 2018. The document addresses the verification systems that manufacturers, repackagers, wholesalers, and dispensers must establish to comply with the Federal Food, Drug, and Cosmetic Act (FD&C Act) as amended with DSCSA. The document does not contain any new requirements, but is simply intended to provide clarity on the existing requirements of the Act.13
- "Definitions of Suspect Product and Illegitimate Product for Verification Obligations Under the Drug Supply Chain Security Act": The 7-page document, dated March 2023, is intended to help the industry identify suspect and illegal products in the pharmaceutical supply chain in the U.S., according to FDA. It clarifies the agency's interpretation of certain terms used in the legal definitions of "Suspect Product" and "Illegitimate Product." Specifically, the new document further clarifies the following terms: counterfeit, diverted, stolen, fraudulent transaction, and unfit for distribution.14
New USP Chapters
The United States Pharmacopeia (USP) is continuing its efforts to expand its <1079> series of chapters on good storage and distribution practices.15
The current plan for the chapter series 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 Devices-Time, 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 that are numbered below 1000 are considered mandatory in the U.S. if they are referenced in a monograph, another applicable general chapter, or general notices. In contrast, USP general chapters numbered above 1000 are not mandatory. They are considered explanatory texts and contain information, definitions and descriptions.
6/7 February 2024
Combination Products - Live Online Training
The content of the chapters to date (some of which are still in draft form) can be summarized as follows:
- Chapter <1079> applies to organizations and individuals involved in the storage and transportation of medicinal products. It describes a risk-based approach to the storage and transportation of finished drug products and strategies to minimize risk.
- Chapter <1079.2> addresses the utility and application of mean kinetic temperature (MKT) for evaluating temperature variations in controlled room temperature (CRT) or controlled cold temperature (CCT) products.
- Chapter <1079.3> provides background information on the science and technology of temperature and humidity monitoring over time. It describes available technologies and features and provides recommendations for performance qualification.
- Chapter <1079.4> focuses on the qualification of storage areas to maintain temperature and provides procedures related to temperature mapping.
The introduction of the new USP chapters in the <1079> series was accompanied by several so-called stimuli articles. In recent months, the following two papers have been published:
"The Use of Mean Kinetic Temperature and the Need of Allowable Excursion Limits for Climatic Zone IVb": The author team writes that the purpose of the article is to present the arguments in favor of adapting Chapter <1079.2> and considering Climatic Zone IVb. The stimuli article provides an overview of the pharmaceutical supply chain and the risks associated with temperature deviations, followed by a suggestion for allowable excursion limits for climatic zone IVb.16
"The Use of Temperature Mapping for the Qualification of Storage Areas for the Proper Temperature Storage of Drug Products": In the article, the authors point out that maintaining temperature during storage is an important aspect to make sure that the safety, efficacy, and expiry of drugs are kept. This includes avoiding temperature excursions during storage. Temperature distribution studies are necessary to assess whether storage facilities can maintain the specified temperature. It lists what should be considered or documented when determining the number of temperature measurement devices needed and their placement. The main body of the article provides recommendations on the minimum number of probes/temperature monitoring devices and their placement. This is illustrated by several figures.17
GDP Non-Compliance Reports
The wholesale distribution of medicinal products requires a Wholesale Distribution Authorisation (WDA). Within the European Union, these authorisations are issued by the national competent authority of the member state in which the wholesale distributor operates. The member states shall enter the certificates of good distribution practices which they issue in the EudraGMDP. This database is maintained and operated by the European Medicines Agency (EMA).18 If an inspection reveals that the wholesaler's GDP compliance cannot be confirmed, a so-called GDP non-compliance report is issued.
The number of GDP Non-Compliance Reports entered into the EudraGMDP database in 2022 is quite moderate, as is the total number of reports entered there. In 2022, a total of 11 reports were newly entered. The deficiencies described therein mainly concern the requirements from chapters 1 to 5 of the EU GDP Guidelines.19
One key focus is on the responsible person. Either the availability of a responsible person was not ensured, or the person did not perform his or her duties to the required extent. Another focus is on the premises (Chapter 3). In this regard, for example, it was repeatedly criticized that activities were carried out in premises not covered by the authorisation. Inadequate access controls and the lack of temperature monitoring were also repeatedly cited. The principles set out in Chapter 5 (Operation) were also not complied with on several occasions by the companies concerned, for example because the authorities had fundamental doubts as to whether proper operation was possible at all. The lack of qualification of suppliers or customers was also mentioned several times. Finally, several reports criticized the quality management system (Chapter 1) and the lack of documentation (Chapter 4).
FDA Warning Letters
In recent months, the FDA has sent out several warning letters addressing GDP-relevant issues.
In this context, for example, a Warning Letter to Amazon.com, Inc. is worth mentioning. The letter, dated 04 August 2022, went directly to Amazon CEO Andy Jassy. In the letter, the FDA states that it has purchased mole and skin tag remover products on amazon.com. These products, it says, were introduced or delivered for introduction into interstate commerce by Amazon through its so-called "Fulfillment by Amazon Service." However, the products had not been evaluated by the FDA for safety, efficacy or quality, nor did they have FDA approval. The FDA makes clear in the letter that it is Amazon's responsibility to ensure that all requirements of federal law, including FDA regulations, are met. The FDA expects that Amazon will no longer introduce, deliver, or cause the introduction or delivery into interstate commerce of such products.20
A warning letter dated 03 October 2022 documents product mix- Ups and insanitary conditions at a U.S. repackager. The FDA accused the company of failing to adequately investigate the presence of foreign tablets in the drug products. During an FDA inspection, one operator was observed to pick individual tablets up off of the floor and place them directly into the feed hopper. Even this apparent GMP violation was not seriously addressed by the company.21
Another warning letter, dated 28 October 2022, again concerns the company Amazon. The agency writes that it purchased three products via the amazon.com website and subsequently conducted a laboratory analysis of these products. It turned out that all of them contained the active ingredient diclofenac. However, this ingredient was not listed on the product labels. The FDA considers this a potential health risk for consumers. Diclofenac belongs to the group of analgesics known as non-steroidal anti-inflammatory drugs (NSAIDs). From a legal perspective, the FDA classifies the products as so-called "new drugs", which cannot be legally imported or supplied in interstate commerce without prior FDA approval. In addition, the products are misbranded because the labeling is false or misleading.22
A warning letter sent to Walmart on 28 October 2022 concerns the same products. FDA ordered this product through the walmart. com website. The items were introduced or delivered for introduction into interstate commerce by Walmart through Walmart Fulfillment Services. In this case, laboratory analyses also revealed that diclofenac was present in the product.23
Another warning letter, dated 22 November 2022, stems from an inspection conducted from 25 April to 09 May 2022 at a Pennsylvania Company that repackages and relabels Active Pharmaceutical Ingredients (APIs). According to the FDA, the company was not properly monitoring storage conditions for the APIs. The temperature probes monitoring the storage area and the refrigerator were not operating at the time of the FDA inspection. The company could not provide temperature and humidity monitoring records to demonstrate that the active ingredients were stored under appropriate conditions at the facility. There was also no documentation to show that the locations of the temperature and humidity probes reflected worst-case conditions or that a temperature distribution study had been conducted. Among other things, FDA required the company to submit a comprehensive evaluation of temperature and environmental monitoring controls.24
Finally, there is an interesting case documented in a Warning Letter published on 14 March 2023. The letter, which was already sent on 20 January 2023, is addressed to a company in Massachusetts, USA, which manufactures homeopathic finished medicinal products. It stems from an inspection at the company's manufacturing facility in July and August 2022. One of the deficiencies addressed in the warning letter concerns the adequate storage and warehousing of drug products. Of particular note: the FDA criticized not only the lack of temperature monitoring, but also humidity monitoring. FDA believes that not only temperature but also humidity should have been monitored in the warehouse because a supplier's certificate of analysis for a bulk drug indicated that it was sensitive to heat, sun light, and moisture.25
Letter The FDA issued a so-called Untitled Letter to Valisure, LLC, a U.S. contract laboratory that performs drug contract testing and other services, on 05 December 2022. In it, the FDA writes that the company violated the FD&C Act and the DSCSA. Specifically, the case involves a former subsidiary of the company, which has since been sold, that had been operating a pharmacy and wholesale drug distribution business. During an inspection, FDA staff reviewed various records. Among the findings were complaints that products suspected of being counterfeit were not investigated further and that manufacturers were not notified of suspected counterfeit products. The FDA concludes that the company did not have a system in place to ensure compliance with the DSCSA.26
The I. Civil Senate of the German Federal Court of Justice (BGH), which is responsible for competition law, referred questions regarding the sale of pharmaceuticals via Amazon to the Court of Justice of the European Union (CJEU) in decisions dated 12 January 2023 (case numbers: ZR 222/19 and I ZR 223/19). Specifically, the issue is whether a pharmacist who sells medicines on an internet sales platform is in breach of the data protection provisions applicable to health data, and whether such a breach can be pursued by another pharmacist with an action under competition law before the civil courts. The two underlying legal disputes essentially concern the same facts. In each case, a pharmacist had sued another pharmacist who had sold over-the-counter medicines via Amazon, although they may only be obtained from pharmacies. In the first case (I ZR 222/19), the plaintiff took the view that the sale of pharmacy- only medicines via Amazon violated the provisions of the German Medicines Act (AMG), the German Drug Advertising Act (HWG), the Pharmacy Operations Regulation (ApBetrO) and the Professional Code of Conduct for Pharmacists on the one hand, and data protection regulations (DSGVO) on the other. In the second case (I ZR 223/19), the plaintiff pharmacist complained that no consent had been obtained for the collection and processing of personal data as part of the ordering process. The defendant already had doubts about the plaintiff's standing to sue and, moreover, took the view that there was no processing of health data and that the data processing was also lawful. The BGH suspended both proceedings pending the ECJ's decision.27
Also in January 2023, a federal court in the USA issued a consent decree of permanent injunction against a Florida-based pharmaceutical importer and distributor. Accordingly, the company is prohibited from distributing active pharmaceutical ingredients (APIs) that are not manufactured, processed or stored in compliance with the FD&C Act. This was preceded by a legal dispute with the FDA, which was officially settled after the court decision.28, 29
Association The European GDP Association (GDPA), which represents more than 4,000 professionals from around the world, announced a change in its board of directors in mid-June 2022. Dr. Afshin Hosseiny has served as the European GDP Association's Advisory Board Chair since its foundation. He has been in charge of developing its various activities. Under his leadership, the association has developed considerably in recent years. As Dr. Hosseiny had announced some time ago that he would retire from the Board of the European GDP Association in the medium term, Alfred Hunt joined the Board as Vice Chairman in 2021. After one year of close cooperation, Alfred Hunt has taken over the role of Chairman.30
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.
1 EMA, Notice to stakeholders: Questions and answers on regulatory expectations for medicinal products for human use during the COVID-19 pandemic, https://health.ec.europa.eu/system/files/2022-08/guidance_regulatory_covid19_en.pdf
2 Regulation (EU) 2019/6 of the European Parliament and of the Council of 11 December 2018 on veterinary medicinal products and repealing Directive 2001/82/EC, https://eur-lex.europa.eu/legal-content/EN/ALL/?uri=CELEX%3A32019R0006
3 Commission Implementing Regulation (EU) 2021/1248 of 29 July 2021 on measures of good distribution practice for veterinary medicinal products in accordance with Regulation (EU) 2019/6 of the European Parliament and of the Council, https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX:32021R1248
4 Guidelines of 5 November 2013 on Good Distribution Practice of medicinal products for human use, https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX%3A52013XC1123%2801%29
5 Commission Implementing Regulation (EU) 2021/1280 of 2 August 2021 as regards measures on good distribution practice for active substances used as starting materials in veterinary medicinal products in accordance with Regulation (EU) 2019/6 of the European Parliament and of the Council, https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX:32021R1280
6 Guidelines of 19 March 2015 on principles of Good Distribution Practice of active substances for medicinal products for human use - 2015/C 95/01, https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=celex%3A52015XC0321(01)
7 EMA, Guidance on good manufacturing practice and good distribution practice: Questions and answers, https://www.ema.europa.eu/en/human-regulatory/research-development/compliance/good-manufacturingpractice/guidance-good-manufacturing-practice-good-distribution-practice-questions-answers
8 PIC/S Publications, https://picscheme.org/en/publications
9 Rules and Guidance for Pharmaceutical Distributors 2022 (The MHRA Green Guide),
10 MHRA, Compliance Monitor (CM) Overview and Application Process,
11 Public Law 113-54, https://www.govinfo.gov/content/pkg/PLAW-113publ54/pdf/PLAW-113publ54.pdf
12 National Standards for the Licensure of Wholesale Drug Distributors and Third-Party Logistics Providers,
13 Verification Systems Under the Drug Supply Chain Security Act for Certain Prescription Drugs,
14 Definitions of Suspect Product and Illegitimate Product for Verification Obligations Under the Drug Supply Chain Security Act,
15 Desmond G. Hunt, USP Efforts on the Storage and Distribution of Drug Products: Historical Background, General Chapters and What Next?,
16 Glaucia K. Braga, Luciana S. Takara, Chris J. Anderson, Robert H. Seevers, Søren Kåre Nielsen, Desmond G. Hunt, The Use of Mean Kinetic Temperature and the Need of Allowable Excursion Limits for Climatic Zone IVb,
17 Chris Anderson, Desmond G. Hunt, Robert Seevers, The Use of Temperature Mapping for the Qualification of Storage Areas for the Proper Temperature Storage of Drug Products, https://online.uspnf.com/uspnf/document/2_GUID-D8691A77-2F19-48EE-9A00-71AEC3CAA546_10101_en-US
18 A free read only access to the EudraGMDP database is available via http://eudragmdp.ema.europa.eu/
19 Guidelines of 5 November 2013 on Good Distribution Practice of medicinal products for human use - 2013/C 343/01,
20 FDA Warning Letter, Amazon.com, Inc.,
21 FDA Warning Letter, Legacy Pharmaceutical Packaging LLC,
22 FDA Warning Letter Amazon.com,
23 FDA Warning Letter, Walmart Inc.,
24 FDA Warning Letter MD Pharmaceutical Supply, LLC,
25 FDA Warning Letter Atlantic Management Resources LTD dba. Claire Ellen Products,
26 FDA Untitled Letter Valisure, LLC, https://www.fda.gov/media/163682/download
27 Bundesgerichtshof, Press Release No. 006/2023, 12 January 2023, https://www.bundesgerichtshof.de/SharedDocs/Pressemitteilungen/DE/2023/2023006.html
28 FDA, Press Release of 30 January 2023 - Federal Court Enters Consent Decree Against Florida-based Drug Importer and Distributor,
29 Department of Justice, Press Release No. 23-114, 30 January 2023 - District Court Enters Permanent Injunction Against Florida-Based Drug Importer and Distributor, https://www.justice.gov/opa/pr/district-court-enters-permanent-injunction-against-florida-based-drug-importer-and
30 European GDP Association (GDPA), https://www.good-distribution-practice-group.org/