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Regulatory Focus Article Series, Volume 3, Number 4, 2020regulatoryfocus.org 1

Introduction: The Shifting Global Regulatory Landscape

IntroductionBy Renée Matthews

Advanced therapies: Navigation and application of EU and US guidelines during product developmentBy Kirsten Messmer, PhD, RAC, Richard Dennett, PhD

FDA warning letters in 2020 reveal concerns around purity, investigations, and data integrityBy Sarah B. Tanksley, MS, Audrey Francis

Regulation of cell and gene therapy products in ChinaBy Yingying Liu, MSc

Current Chinese NMPA clinical pathways for medical device registrationBy Grace Fu Palma, MBA, Jason Zhang, MD, Xiaolian Zou, and Beibei Xing, PhD

Regulatory tools for generic drug companies: Formal FDA meetings and con-trolled correspondenceBy Sonal Jagani, MS, RAC

EU regulatory tools for RA professionalBy Maria E. Donawa, MD

US-focused regulatory toolbox: The basicsBy Thomas Padula

Starting out: A beginner’s toolkit of regulatory resourcesBy Holly Korzendorfer, PhD

Adopting regulatory intelligence strategies to foster the evolving landscapeBy Darin S. Oppenheimer, DRSc, FRAPS, RAC, PMP, George A. Cusatis MS, RAC, Jessica L.

Hale, PharmD, Jessica Schlegel, MS, and Suraj Ramachandran, MS, RAC

Contents

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https://www.raps.org/news-and-articles


Introduction: Regulatory Intelligence

Renée Matthews


Welcome to the RAPS Q4 Regulatory Focus Article Series on Regulatory Intelligence. RI is a cornerstone of the regulatory landscape, and evidence-based information and the tools for monitor-ing and gathering it, are its prized com-ponents. RI professionals are regulatory sleuths, key players in pulling together that evidence to shape the policies, legislation, regulations, and guidances regulators use in strategizing for drug development, approval, and product maintenance. In this series, a number of articles by global regulatory affairs specialists write on aspects of regulatory intelligence that would help product developers stay current with the latest requirements and achieve their devel-opment goals in a timely, cost-effective manner. I thank the authors for their expertise and generosity in sharing their valuable contributions with the regulatory community.

Information sourcesAdvanced therapies require additional regulatory and strategic consider-ations because of their specific novelty and greater complexity of parts. In Advanced therapies: Navigation and application of EU and US guidelines during product development, RI experts Kirsten Messmer and Richard

Dennett, provide an overview and navigation guide through the many US and EU guidances for these therapies. In comparing the two sets of guidances, they highlight main points of consider-ation and outline general strategic map-ping and signposting of how best to orchestrate their respective uses during the course of product development for the EU and the US. Their takeaway is that one should “live and breathe the guidelines” when developing advanced therapies, because the documents are the product of expert regulatory staff and industry stakeholders with deep knowledge and experience of the devel-opment pathway.

Warning letters issued by the US Food and Drug Administration (FDA) provide important context for RI professionals in pharmaceutical manufacturing. In FDA warning letters in 2020 reveal concerns around purity and data integrity, regulatory experts Sarah Tanksley and Audrey Francis review 2020 warning letters related to good manufacturing practices and provide examples of common citations that point to larger trends in FDA enforcement. They found that citations often centered on inadequate qualifica-tion of supplier certificates of analysis and inadequate discrepancy investiga-tions, reflecting concerns around drug purity. Data integrity issues were also

https://www.raps.org/news-and-articleshttps://www.raps.org/news-and-articles/news-articles/2020/11/advanced-therapies-navigation-and-application-of-ehttps://www.raps.org/news-and-articles/news-articles/2020/11/advanced-therapies-navigation-and-application-of-ehttps://www.raps.org/news-and-articles/news-articles/2020/11/advanced-therapies-navigation-and-application-of-ehttps://www.raps.org/news-and-articles/news-articles/2020/11/fda-warning-letters-in-2020-reveal-concerns-aroundhttps://www.raps.org/news-and-articles/news-articles/2020/11/fda-warning-letters-in-2020-reveal-concerns-aroundhttps://www.raps.org/news-and-articles/news-articles/2020/11/fda-warning-letters-in-2020-reveal-concerns-around



of concern in many common citations. The authors use these findings and the discussions around then to highlight trends for consideration when manag-ing an internal surveillance program.

There have been significant chang-es in China’s regulatory bodies, espe-cially as the country opens its market to foreign drug development companies. In Regulation of cell and gene therapy products in China, Yingying Liu pro-vides an overview of the Chinese regu-lations and guidance documents for cell and gene therapy products (CGTPs), starting with a useful historical context for the development of the documents. She notes, however, that, unlike other countries or regions, such as the US or EU, China does not have ethically relevant laws and regulations, separate regulatory authorities for clinical trial applications and marketing authori-zations for CGTPs, and experienced technical reviewers in its regulatory authorities.

China’s National Medical Prod-ucts Administration (NMPA) is the agency responsible for regulating drugs and medical devices. In recent years, the agency has been focused on inter-national harmonization in its efforts to improve quality, safety, and efficacy of approved devices. In Current China NMPA clinical pathways for medical device registration, Grace Fu Palma, Jason Zhang, Xiaolian Zou, and Beibei Xing present a snapshot of current clinical pathways and their key highlights and discuss when the various clinical pathways should be used, based on NMPA regulations and guidance. The authors advise that pro-spective developers determine NMPA clinical pathways before applying for device registration, and, as with many regulatory processes, ensure they are working with the most recent require-ments.

The RI toolboxIt is important to know where to find the RI sleuthing tools, how to use them. In general, they are free, publicly available, and almost entirely web based. In Regulatory tools for generic

drug companies: Formal FDA meetings and controlled correspondence, Sonal Jagani, an expert in complex product submissions, discusses formal meetings and controlled correspondence for the generic drug industry and the use of these regulatory tools in the abbreviat-ed new drug application process. She notes the tools are useful in avoiding unexpected delays for product approval and therefore expediting generic drug approvals.

In EU regulatory tools for RA pro-fessionals, regulatory expert Maria E. Donawa takes regulatory professionals who need to understand the Europe-an regulation of healthcare products on a journey through the sources of information on basic EU legislation and guidance for medical devices and in vitro medical devices, pharmaceuti-cals/medicinal products, and substances of human. For each of those sectors, Donawa maps the primary sources of regulatory information, then explains how the information is organized and how best to navigate regional and local websites to access it.

Two articles examine the tools available for RA professionals interested in drug products and medical devices marketed in the US. In US-focused regulatory toolbox: The basics, regula-tory specialist Thomas Padula gives a detailed roundup of tools, mostly on the FDA website, but also the National Library of Medicine and ClinicalTri-als.gov. Regulatory specialist Holly Korzendorfer shares a starter toolkit for RA newcomers that includes 28 publicly available resources. In Start-ing out: A beginner’s toolkit of US regulatory resources, Korzendorfer drills deeper into the FDA resources and provides detailed information and guideline resources from a number of the agency’s centers.

The final article in the series ad-dresses the integration of RI and strat-egies into the product lifecycle for both new and existing products. In Adopting regulatory intelligence strategies to foster the evolving landscape, regula-tory experts Darin S. Oppenheimer, George A. Cusatis, Jessica L. Hale, Jessica Schlegel, and Suraj Ramach-

https://www.raps.org/news-and-articleshttp://Regulation of cell and gene therapy products in Chinahttp://Regulation of cell and gene therapy products in Chinahttp://Current China NMPA clinical pathways for medical device registrationhttp://Current China NMPA clinical pathways for medical device registrationhttp://Current China NMPA clinical pathways for medical device registrationhttps://www.raps.org/news-and-articles/news-articles/2020/9/regulatory-tools-for-generic-drug-companies-formalhttps://www.raps.org/news-and-articles/news-articles/2020/9/regulatory-tools-for-generic-drug-companies-formalhttps://www.raps.org/news-and-articles/news-articles/2020/9/regulatory-tools-for-generic-drug-companies-formalhttps://www.raps.org/news-and-articles/news-articles/2020/10/regulatory-tools-for-eu-based-ra-professionalshttps://www.raps.org/news-and-articles/news-articles/2020/10/regulatory-tools-for-eu-based-ra-professionalsUS-focused regulatory toolbox: The basicsUS-focused regulatory toolbox: The basicshttps://www.raps.org/news-and-articles/news-articles/2020/10/starting-out-a-beginners-toolkit-of-us-regulatoryhttps://www.raps.org/news-and-articles/news-articles/2020/10/starting-out-a-beginners-toolkit-of-us-regulatoryhttps://www.raps.org/news-and-articles/news-articles/2020/10/starting-out-a-beginners-toolkit-of-us-regulatoryhttps://www.raps.org/news-and-articles/news-articles/2020/3/adopting-regulatory-intelligence-strategies-to-1https://www.raps.org/news-and-articles/news-articles/2020/3/adopting-regulatory-intelligence-strategies-to-1https://www.raps.org/news-and-articles/news-articles/2020/3/adopting-regulatory-intelligence-strategies-to-1



andran discuss the opportunities and challenges of setting up and maintain-ing an RI. The authors conclude there is a strong business to support the addition of an RI program to enhance regulatory strategy, mitigate risk, and develop a competitive advantage. They provide a framework for developing a program, but caution that each program must be adapted according to organizations’ unique requirements and needs.

ConclusionI hope you enjoy reading the full-length articles in this series, and per-haps share them with your regulatory colleagues. I would also like to invite you to join our Ask Me Anything dis-cussion session in mid-January between our expert panelists and members on the RAPS online community, Regula-tory Exchange. And, as always, I would welcome your feedback on the series.

About the authorRenée Matthews, Senior Editor, is re-sponsible for Feature articles for Regulatory Focus. She can be contacted at [email protected] for information on submitting articles to Regulatory Focus or the Ask Me Anything discussion.

Citation Matthews R. Regulatory Intelligence. Regulatory Focus [Q4 Article Series]. December 2020. Regulatory Affairs Professionals Society.

https://www.raps.org/news-and-articlesmailto:[email protected]:[email protected]


Advanced therapies: Navigation and application of EU and US guidelines during product development

Continued progression and un-derstanding in the development of advanced therapies has led to a significant increase in the number of products and types of indication under investigation, particularly for treating serious and life-threaten-ing conditions. Although the prin-ciple regulatory requirements and guidance, as issued for traditional biologic products, can be generally applied, advanced therapies require additional regulatory and strategic considerations because of their spe-cific novelty and greater complexity of parts. This article provides a high-level overview and navigation guide through the multitude of available advanced therapy guid-ance in the European Union and the United States.

Kirsten Messmer, PhD, RAC


Richard Dennett, PhD

IntroductionAdvanced therapies have gained in-creasing attention over recent years by offering a new and inventive angle of attack to treating an array of medical conditions. Although all drug products share a common development back-bone, the specific nature and design of cell and gene therapy (CGT) products have a greater degree of complexity compared with traditional pharma-ceutical and biological drug products, therefore requiring additional strategic considerations. Those more complex elements have been addressed in a com-panion article titled, “Advanced thera-pies: ‘Trip hazards’ on the development pathway.”1

The evolution of CGT products has necessitated a parallel maturation of regulatory frameworks and guide-lines. This has led to the growth of a strong library of comprehensive, clear, and accessible development informa-tion provided by regulatory authorities. However, there are some regional dif-




ferences in guidances, leading advanced therapy developers to carefully examine the starting point and how to best fit their strategic development plans. The volume of available guidelines may also create a sense of information overload among biotech developers in the field, leading them to wonder exactly where they should begin the process.

This summary article takes a high-level, comparative look at EU and US guidances for advanced therapy, highlighting main points of consideration and providing general strategic mapping and signposting of how best to orchestrate their respec-tive use during the course of product development for the EU and the US. The article is geared toward early stage biotech companies, but also should act as a quick memory aide for more expe-rienced and larger companies. Only a snapshot of some of the key guidance is provided. The reader is directed to the European Medicines Agency (EMA) and US Food and Drug Administration (FDA) websites for further guidance and related information.2-5

Some general points of comprehension:• Nomenclature

º Gene therapy, somatic cell therapy, and tissue-engineered medicines in the EU are referred to as advanced therapy medici-nal products (ATMPs).

º In the US, the comparative tags are cell and gene therapy prod-ucts and regenerative medicine advanced therapies.

º In effect, these terms broadly correspond with one another. However, there are slight differ-ences in the pathways of tissue regulation in the US. The termi-nology of advanced therapy and cell and gene therapy products is becoming more interchangeable.

º The term “advanced therapies” will be used in the remainder of this article to include all previ-ously mentioned product types.

• Regulatory bodies º In the EU, advanced therapies

are regulated by the EMA, with a scientific assessment by the Committee of Advanced Ther-apies (CAT) within the EMA, linking to the quality, safety and efficacy of the advanced therapy medicine. The CAT provides assessment feedback to the Committee for Medicinal Prod-ucts for Human Use (CHMP). The CHMP makes the approval or denial recommendations to the European Commission. Advanced therapy medicines are authorized centrally through a single evaluation and authoriza-tion procedure.

º In the US, the regulation of advanced therapies is overseen by the Center for Biologics Eval-uation and Research’s (CBER’s)Office of Tissues and Advanced Therapies, with the review of policies and product application data relating to the safety, effec-tiveness, and appropriate use by the Cellular, Tissue and Gene Therapies Advisory Committee, as needed by the agency.

• Strategy tip Most advanced therapy developers may initially target only one mar-ket, which will require conforming to either EU or US guidance. However, depending on the initial territory – marketing authorization application (MAA) for the EU, or investigational new drug (IND) and biologics license application (BLA) for the US – it is highly useful to explore the content and context of both sets of guidance to acquire a more complete understanding of regulatory requirements. Con-forming with requirements in both jurisdictions from the beginning will later save time and money for expansion of the target markets.

This summary article takes a high-level, comparative look at EU and US guidances for advanced therapy, highlighting main points of consideration and providing general strategic mapping and signposting of how best to orchestrate their respective use during the course of product development for the EU and the US.




• Main portals and guidelines º European Union

- Advanced therapy medicinal products: Overview2

- Guidelines relevant for advanced therapy medicinal products3

º United States - Cellular and gene therapy

products4 - Cellular and gene therapy

guidances5• How to use this article

The article is divided into develop-ment stages (Stage 0/Pre-IND, phases I-III, and end of phase II/phase III to marketing authorization) and provides key guidances and consid-erations at each of these stages. The reader should consider these to be highlights and further seek out the respective and applicable guidances. It is of utmost importance to read the guidances in full and follow their recommendation to ensure a regu-latory-compliant advanced therapy development program.

Stage 0/pre-INDAt the start of any development pro-gram, it is pertinent to determine ex-actly what the product is and what the target product profile might be: Is the advanced therapy a cell or gene therapy, both, combined with a medical device, or possibly so innovative that it might not yet be classified as either?

For some products, the developer might clearly determine that it is a cell or gene product, but sometimes the boundary might be less clear, for example, in terms of ex vivo gene-transduced cell product or cellular products with minimal manipulation. To support the understanding and determination of the advanced therapy product type, the EMA offers formal evaluation or classification, including a helpful classification listing of CGT products that provides clear examples the help in determining where a product might best fit.6

The EMA and FDA also maintain listings of approved products that can be used to determine the product type.

As a first step or starting point for understanding the regulatory require-ments and available guidance docu-ments for advanced therapies, the EU has a set of “overarching” guidelines, which are highlighted in green in (Table 1). These are essentially broad “parent guidelines” that spell out the main framework of the regulatory and development requirements for advanced therapies to take a product through to prospective license approv-al. These overarching guidances are supported by an in-depth set of more focused and product-specific guidelines.

The FDA has a similar set of baseline guidance documents covering the framework and factors necessary for nonclinical chemistry, manufacture, and controls (CMC) plus clinical con-siderations and requirements.

Table 1 provides a selected cross-section of principle guidance, including the overarching guidances noted. The reader should consult the respective regulatory agency websites for a more extensive guideline listing.

Front-end synopsis and building of understandingOverall, the full development con-tent of the EU and US guidances is very similar and provides logical title content for the various requirements. It should be reiterated here that the two guidelines highlighted below and taken from Table 1 are of particular value for early stage companies developing investigational products:• EU – The Guideline on quality,

nonclinical, and clinical require-ments for investigational advanced therapy medicinal products in clinical trials.9

• US – Chemistry, manufacturing, and control information for human gene therapy investigational new drug applications.10

The FDA has a similar set of baseline guidance documents covering the framework and factors necessary for nonclinical chemistry, manufacture, and controls (CMC) plus clinical considerations and requirements.




Table 1. Cross-section of key guidelines for advanced therapies in the EU and US8

Guideline

European Union

Gene therapy medicinal products7aThe overarching guideline for human gene therapy medicinal products is the guideline on the quality, nonclinical, and clinical aspects of gene therapy medicinal products (EMA/CAT/80183/2014)aGuideline on quality, nonclinical, and clinical requirements for investigational advanced therapy medicinal products in clinical trials

Guideline on safety and efficacy follow-up and risk management of advanced therapy medicinal products

Quality, preclinical, and clinical aspects of gene therapy medicinal products

Quality, nonclinical, and clinical aspects of medicinal products containing genetically modified cells

Development and manufacture of lentiviral vectors

Nonclinical studies required before first clinical use of gene therapy medicinal products

Nonclinical testing for inadvertent germline transmission of gene transfer vectors

Risk-based approach according to Annex I, part IV of Directive 2001/83/EC applied to advanced therapy medicinal products

Follow-up of patients administered with gene therapy medicinal products

Scientific requirements for the environmental risk assessment of gene therapy medicinal products

Cell therapy and tissue engineering8

aThe overarching guideline for human cell-based medicinal products is the guideline on human cell-based medicinal products (EMEA/CHMP/410869/2006)

aGuideline on quality, nonclinical, and clinical requirements for investigational advanced therapy medicinal products in clinical trials

Guideline on safety and efficacy follow-up and risk management of advanced therapy medicinal products

Potency testing of cell-based immunotherapy medicinal products for the treatment of cancer

Risk-based approach according to Annex I, part IV of Directive 2001/83/EC applied to advanced therapy medicinal products

Xenogeneic cell-based medicinal products

Continued on next page




Since most advanced therapies treat rare and/or life-threatening diseases, programs to expedite the development and/or assessment should be consid-ered. There are several programs – such as orphan drug designation, fast track, or accelerated assessment/approvals – available for all products, including small molecules and biologics. How-ever, applications also can be made for programs geared more specifically to advanced therapies – such as the EU’s PRIority MEdicine (PRIME)/accelerated assessment route or the US’s regenerative medicine advanced therapy (RMAT) designation – based on the clinical potential of the product and whether it addresses an unmet medical need:• EU – PRIME/other routes include

accelerated assessment and autho-rization under exceptional circum-stances.11

• FDA – RMAT (Expedited Pro-grams for Regenerative Medicine Therapies for Serious Conditions)/other routes to consider include fast track, breakthrough therapy, priori-ty review and accelerated approval.12

The transition from nonclinical to phase I/first-in-human is an important stage. The nonclinical study program and product CMC have to support the safety of initial human clinical studies. The manufacture of the investigational product needs to be representative of the product to be used at later clini-cal stages and the product, including product-critical quality attributes, has to be demonstrated to be comparable. In addition, the biological activity also needs to interrelate. It is important to make sure this fundamental stage is properly covered and to not let any time pressures place undue force on this.

Table 1. (continued)

Guideline

United States5

NonclinicalPreclinical assessment of investigational cellular and gene therapy products

CMCaChemistry, manufacturing, and control information for human gene therapy investigational new drug applications

Guidance for human somatic cell therapy and gene therapy

Regulatory considerations for human cells, tissues, and cellular and tissue-based products: Minimal manipulation and homologous use

Determining the need for and content of environmental assessments for gene therapies, vectored vaccines, and related recombinant viral or microbial products

Eligibility determination for donors of human cells, tissues, and cellular and tissue-based products

ClinicalaConsiderations for the design of early phase clinical trials of cellular and gene therapy products

Long-term follow-up after administration of human gene therapy products

Medical deviceEvaluation of devices used with regenerative medicine advanced therapies

aThe “overarching” guidelines spell out the main framework of the regulatory and development requirements for advanced therapies to take a product through to prospective license approval.




When addressing product-spe-cific complexity, the principle issue of advanced therapy products is that there is not only the diversity of types of products, such as cell, gene, and tissue products, but that each product type has a different array of considerations, such as the availability of animal mod-els, product characterization, autolo-gous/allogeneic manufacturing routes, stability, and logistics.

In addition, advanced therapies have a wider range of risk factors: genetic risk factors, immunogenicity, and interhuman genetic variability. These scenarios need to be derived, controlled, and addressed across CMC and clinical development programs and may need to be addressed differently with different diseases or disorders.

This has led to the generation of advanced therapy and/or disease-specif-ic guidelines discussing the regulatory agencies’ expectations (Table 2). Most of these guidances were generated reac-tively to the need to provide guidelines for products under development for

specific indications (e.g., knee cartilage repair, hemophilia).

Good practice requirements for advanced therapies

Bench scale development through to good manufacturing practice (GMP) in the manufacture of a clinical product is a special point of consideration for smaller and/or academic advanced ther-apy developers. Some universities and hospitals may have the benefit of early stage GMP-capable production units, but not necessarily for the full-fledged supporting facilities, layouts, and operations or for scaling up or scaling out production as the clinical develop-ment program matures. Some of these institutions may have implemented In-ternational Organization for Standard-ization (ISO) standards at best. These units are often found in product man-ufacture of ex vivo gene-manipulated autologous cell products where cells are taken from the patient, transduced, and then re-infused into the patient or cell/tissue-based products

Table 2. Regulatory guidance specific to products and/or advanced therapies for specific indications

Guideline

European Union

Reflection papers3

Clinical aspects related to tissue-engineered products

In vitro cultured chondrocyte containing products for cartilage repair of the knee

Stem cell-based medicinal products

Questions and answers on comparability considerations for advanced therapy medicinal products

United States5

Cellular therapy for cardiac disease

Considerations for allogeneic pancreatic islet cell products

Preparation of [investigational device exemptions] and [investigational new drugs] for products intended to repair or replace knee cartilage

Human gene therapy for rare disease

Human gene therapy for hemophilia

Human gene therapy for retinal disorders




The European Commission has recog-nized and bridged this GMP interme-diary situation by developing a GMP guideline specifically for early stage developers of advanced therapies in biotech and in university and hospital environments. This guidance adapts the EU GMP requirements to the specific characteristics of advanced therapies and addresses the novel and complex manufacturing scenarios used for these products, as well as imparting a risk-based approach to the manufacture and testing. The US has a GMP guideline for broader investigational products in phase I development:• EU – EudraLex Volume 4: The

Rules Governing Medicinal Products in the European Union – Good Manufacturing Practice: Guideline on Good Manufacturing Practice Specific to Advanced Therapy Me-dicinal Products.12

• US – Current Good Manufacturing Practice for Phase 1 Investigational Drugs.14

• Additional guidance – Current Q7 Good Manufacturing Practice for Active Pharmaceutical Ingredients.15 (Table 1 in this guidance titled, Application of this Guidance to API Manufacturing, shows where the GMP boundary between source and manipulated material should occur).

Similarly, there are additional guide-lines or updated documents for good laboratory practices (GLP) and good clinical practices (GCP) for advanced therapies:• EU – EudraLex me 10, chapter 5:

Guideline on Good Clinical Practice Specific to Advanced Therapy Me-dicinal Products.16

• CAT (with EC and Clinical Trial Facilitation Group) – Good lab-oratory practice (GLP) principles in relation to ATMPs. (A ques-tion-and-answer document on GLP principles to be taken into account in relation to advanced therapies).17

Ongoing phases I-III developmentIt is important to remember that advanced therapies are still biologics. Therefore, although the aforemen-tioned guidelines for advanced thera-pies should readily support develop-ment of these product classes through phases I-III, they should be read and applied in conjunction with guidelines for conventional biologics and those from pharmacopeia and the Inter-national Council for Harmonisation (ICH; Table 3).

In addition, advanced therapies are more complex than conventional therapies and may therefore need a higher number of validation batches as well as adequate supporting data. It is imperative to allow sufficient time for the generation of acceptable batch data. For any product, this needs to be backed by a watertight development package that frames a safe, quality-driv-en, and efficacious product. The data package also needs to confirm that the commercial process and product is robust and reproducible.

Emerging guidanceThe regulatory landscape is constantly changing and adapting to new expe-rience and knowledge gained for all pharmaceutical products. However, advanced therapies are a particularly rapidly evolving field. Global regulators have taken note and are committed to releasing timely guidance for an ever-increasing diversity of advanced therapies.

European UnionAt the time of writing, forthcoming adoption on quality, nonclinical, and clinical aspects of medicinal products containing genetically modified cells was expected in October 2020.21 The update will include further guidance on:• Reflection of experience gained

with products at MAA, scientific advice and PRIME,

• Consideration of new tools for the

The European Commission has recognized and bridged the GMP intermediary situation by developing a GMP guideline specifically for early stage developers of advanced therapies in biotech and in university and hospital environments.




genetic modification of cells (i.e., genome editing technologies),

• Reflection of the increase in clinical experience, especially with CAR-T cells and related products,

• Coverage of new categories of products (e.g., induced pluripotent stem cells), and

• Product comparability.

United StatesThe FDA’s CBER notes in its guidance agenda for 2020, which delineates the guidance documents the center plans to release in 2020, that guidance specific to CAR-T cell therapies and products involving genome editing will be released by the end of 2020.22 A guidance document addressing gene

therapies for neurodegenerative disease also is planned. These will be draft guidances so there is currently no indi-cation on the content. However, after draft guidances have been announced in the Federal Register, they will be open for public comment.

Take-home messagesThe navigation of advanced therapy guidelines is not always intuitive to developers in the very early stage of development. This article provides a general pathway that developers could follow across the development phases of cell and gene therapy products. Ad-vanced therapies are a fast-moving area and it is important to assess the latest

Table 3. Examples of additional guidance for biologics and advanced therapies, including monographs and chapters from the International Council for Harmonisation and pharmacopeiaa

Guideline

European Union3

Development and manufacture of lentiviral vectors

Gene therapy product quality aspects in the production of vectors and genetically modified somatic cells

Potency testing of cell-based immunotherapy medicinal products for the treatment of cancer

United States5

Process validation: General principles and practices

ICH18

Consideration all relevant biologics ICH guidelines

General principles to address the risk of inadvertent germline integration of gene therapy vectors (CHMP/ICH/469991/2006)

General principles to address virus and vector shedding (EMEA/CHMP/ICH/449035/2009)

ICH Topic Q5E Comparability of biotechnological/biological products

PharmacopeiaPhEur monograph 5.14 Gene transfer medicinal products for human use (01/2010:51400)19

PhEur General Chapter 5.2.12. Raw materials of biological origin for the production of cell-based and gene therapy medicinal products19

2.7.23 Numeration of CD34+/CD45+ cells in haematopoietic products

USP General Chapters: Cell and Gene Therapy2020

ICH, International Council for Harmonisation; PhEur, European Pharmacopoeia; USP, US Pharmacopeia.aThis list is not all inclusive.




guidance to capture any new advances.Advanced therapy guidelines

should be seen as enabling and helping with the overall development design and planning across nonclinical, CMC, and clinical development stages. They also provide an overview of what is re-quired to meet regulatory expectations and requirements.

If you are developing advanced therapies, the best advice is to “live and breathe the guidelines.” Guidance documents have been established and refined by combining expert input and insight from regulatory authority staff and industry stakeholders who are walking, or have walked, in the same development shoes.

AbbreviationsCAT, Committee of Advanced Therapies; CBER, Center for Biologics Evaluation and Research; CGT, cell and gene ther-apy; CHMP, Committee for Medicinal Products for Human Use; EMA, European Medicines Agency; EU, European Union; FDA, [US] Food and Drug Administra-tion; GMP, good manufacturing practice; ICH, International Council for Harmoni-sation; PhEur, European Pharmacopoeia; PRIME, PRIority Medicine; RMAT, regenerative medicine advanced therapy; US, United States.

References1. Messmer K, Dennett R. Advanced

therapies: ‘Trip hazards’ on the devel-opment pathway. https://www.raps.org/news-and-articles/news-articles/2020/8/trip-hazards-in-advanced-therapy-devel-opment. Regulatory Focus. July 2020. Accessed 30 October 2020

2. European Medicines Agency. Advanced therapy medicinal products: Overview. https://www.ema.europa.eu/en/hu-man-regulatory/overview/advanced-ther-apy-medicinal-products-overview. Accessed 30 October 2020.

3. European Medicines Agency. Guide-lines relevant for advanced therapy medicinal products. https://www.ema.europa.eu/en/human-regulatory/research-development/advanced-thera-

pies/guidelines-relevant-advanced-ther-apy-medicinal-products. Accessed 30 October 2020.

4. Food and Drug Administration. Cellu-lar & Gene Therapy Products. https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products. Current as of 20 June 2020. Accessed 30 Octo-ber 2020.

5. Food and Drug Administration. Cellu-lar & Gene Therapy Guidances. https://www.fda.gov/vaccines-blood-biologics/biologics-guidances/cellular-gene-ther-apy-guidances. Current as of 14 Febru-ary 2020. Accessed 30 October 2020.

6. European Medicines Agency. Sum-maries of scientific recommendations on classification of advanced therapy medicinal products. https://www.ema.europa.eu/en/human-regulatory/marketing-authorisation/advanced-ther-apies/advanced-therapy-classification/summaries-scientific-recommenda-tions-classification-advanced-thera-py-medicinal-products. Accessed 30 October 2020.

7. European Medicines Agency. Multidis-ciplinary: Gene therapy. https://www.ema.europa.eu/en/human-regulatory/research-development/scientific-guide-lines/multidisciplinary/multidisci-plinary-gene-therapy. Accessed 30 October 2020.

8. European Medicines Agency. Multi-disciplinary: Cell therapy and tissue engineering. https://www.ema.europa.eu/en/human-regulatory/research-de-velopment/scientific-guidelines/multi-disciplinary/multidisciplinary-cell-ther-apy-tissue-engineering. Accessed 30 October 2020.

9. European Medicines Agency. Guide-line on quality, nonclinical, and clin-ical requirements for investigational advanced therapy medicinal products in clinical trials. https://www.ema.eu-ropa.eu/en/guideline-quality-non-clin-ical-clinical-requirements-investiga-tional-advanced-therapy-medicinal. Published 21 February 2019. Accessed 30 October 2020.

10. Food and Drug Administration. Chemistry, manufacturing, and control (CMC) information for human gene therapy investigational new drug appli-cations (INDs). Guidance for industry. https://www.fda.gov/media/113760/

https://www.raps.org/news-and-articleshttps://www.raps.org/news-and-articles/news-articles/2020/8/trip-hazards-in-advanced-therapy-develophttps://www.raps.org/news-and-articles/news-articles/2020/8/trip-hazards-in-advanced-therapy-develophttps://www.raps.org/news-and-articles/news-articles/2020/8/trip-hazards-in-advanced-therapy-develophttps://www.raps.org/news-and-articles/news-articles/2020/8/trip-hazards-in-advanced-therapy-develophttps://www.ema.europa.eu/en/human-regulatory/overview/advanced-therapy-medicinal-products-overviewhttps://www.ema.europa.eu/en/human-regulatory/overview/advanced-therapy-medicinal-products-overviewhttps://www.ema.europa.eu/en/human-regulatory/overview/advanced-therapy-medicinal-products-overviewhttps://www.ema.europa.eu/en/human-regulatory/research-development/advanced-therapies/guidelines-relhttps://www.ema.europa.eu/en/human-regulatory/research-development/advanced-therapies/guidelines-relhttps://www.ema.europa.eu/en/human-regulatory/research-development/advanced-therapies/guidelines-relhttps://www.ema.europa.eu/en/human-regulatory/research-development/advanced-therapies/guidelines-relhttps://www.ema.europa.eu/en/human-regulatory/research-development/advanced-therapies/guidelines-relhttps://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-productshttps://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-productshttps://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-productshttps://www.fda.gov/vaccines-blood-biologics/biologics-guidances/cellular-gene-therapy-guidanceshttps://www.fda.gov/vaccines-blood-biologics/biologics-guidances/cellular-gene-therapy-guidanceshttps://www.fda.gov/vaccines-blood-biologics/biologics-guidances/cellular-gene-therapy-guidanceshttps://www.fda.gov/vaccines-blood-biologics/biologics-guidances/cellular-gene-therapy-guidanceshttps://www.ema.europa.eu/en/human-regulatory/marketing-authorisation/advanced-therapies/advanced-thhttps://www.ema.europa.eu/en/human-regulatory/marketing-authorisation/advanced-therapies/advanced-thhttps://www.ema.europa.eu/en/human-regulatory/marketing-authorisation/advanced-therapies/advanced-thhttps://www.ema.europa.eu/en/human-regulatory/marketing-authorisation/advanced-therapies/advanced-thhttps://www.ema.europa.eu/en/human-regulatory/marketing-authorisation/advanced-therapies/advanced-thhttps://www.ema.europa.eu/en/human-regulatory/marketing-authorisation/advanced-therapies/advanced-thhttps://www.ema.europa.eu/en/human-regulatory/marketing-authorisation/advanced-therapies/advanced-thhttps://www.ema.europa.eu/en/human-regulatory/research-development/scientific-guidelines/multidisciphttps://www.ema.europa.eu/en/human-regulatory/research-development/scientific-guidelines/multidisciphttps://www.ema.europa.eu/en/human-regulatory/research-development/scientific-guidelines/multidisciphttps://www.ema.europa.eu/en/human-regulatory/research-development/scientific-guidelines/multidisciphttps://www.ema.europa.eu/en/human-regulatory/research-development/scientific-guidelines/multidisciphttps://www.ema.europa.eu/en/human-regulatory/research-development/scientific-guidelines/multidisciphttps://www.ema.europa.eu/en/human-regulatory/research-development/scientific-guidelines/multidisciphttps://www.ema.europa.eu/en/human-regulatory/research-development/scientific-guidelines/multidisciphttps://www.ema.europa.eu/en/human-regulatory/research-development/scientific-guidelines/multidisciphttps://www.ema.europa.eu/en/human-regulatory/research-development/scientific-guidelines/multidisciphttps://www.ema.europa.eu/en/guideline-quality-non-clinical-clinical-requirements-investigational-adhttps://www.ema.europa.eu/en/guideline-quality-non-clinical-clinical-requirements-investigational-adhttps://www.ema.europa.eu/en/guideline-quality-non-clinical-clinical-requirements-investigational-adhttps://www.ema.europa.eu/en/guideline-quality-non-clinical-clinical-requirements-investigational-adhttps://www.fda.gov/media/113760/download



download. Current as of 31 January 2020. Accessed 30 October 2020.

11. European Medicines Agency. PRIME: Priority medicines. https://www.ema.europa.eu/en/human-regulatory/research-development/prime-prior-ity-medicines. Accessed 30 October 2020.

12. Food and Drug Administration. Expedited programs for regenerative medicine therapies for serious condi-tions. Guidance for industry. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/expedited-programs-regenerative-med-icine-therapies-serious-conditions. Dated February 2019. Accessed 30 October 2020.

13. European Commission. Guideline on good manufacturing practice specific to advanced therapy medicinal products. https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-4/2017_11_22_guidelines_gmp_for_atmps.pdf. Dated 22 November 2017. Accessed 30 Octo-ber 2020.

14. Food and Drug Administration. Cur-rent good manufacturing practice for phase 1 investigational drugs. Guidance for industry. https://www.fda.gov/regulatory-information/search-fda-guid-ance-documents/current-good-manu-facturing-practice-phase-1-investiga-tional-drugs. Current as of 24 August 2018. Accessed 30 October 2020.

15. Food and Drug Administration. Q7 good manufacturing practice guidance for active pharmaceutical ingredients. Guidance for industry. https://www.fda.gov/media/71518/download. Dated September 2016. Accessed 30 October 2020.

16. European Commission. Guidelines on Good Clinical Practice specific to Advanced Therapy Medicinal Products. https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-10/atmp_guide-lines_en.pdf. Dated 10 October 2019. Accessed 2 November 2020.

17. Committee of Advanced Therapies, with the European Commission and Clinical Trial Facilitation Group . European Commission website. Good laboratory practice (GLP) principles in relation to ATMPs. https://www.ema.europa.eu/en/documents/other/good-laboratory-practice-glp-princi-

ples-relation-advanced-therapy-medic-inal-products-atmps_en.pdf. Dated 26 January 2017. Accessed 30 October 2020.

18. International Council for Harmonisa-tion. ICH guidelines. https://www.ich.org/page/ich-guidelines. Accessed 30 October 2020.

19. Council of Europe. European Pharma-copoeia. 10th ed. Strasbourg: Council of Europe; 2010.

20. US Pharmacopeia (USP). USP-NF29 – General Chapters: Chapter Cell and Gene Therapy. 2020. http://ftp.uspbpep.com/v29240/usp29nf24s0_c1046s1.html. Accessed 30 October 2020.

21. European Medicines Agency. Guideline on quality, nonclinical, and clinical aspects of medicinal products contain-ing genetically modified cells. https://www.ema.europa.eu/en/documents/scientific-guideline/draft-guide-line-quality-non-clinical-clinical-as-pects-medicinal-products-containing-ge-netically_en.pdf. Draft guidance as initially adopted in 2012 (update due October-November 2020). Accessed 30 October 2020.

22. Food and Drug Administration. Guid-ance agenda: Guidance documents CBER is planning to publish during calendar year 2020. https://www.fda.gov/media/120341/download. Updated October 2020. Accessed 30 October 2020.

https://www.raps.org/news-and-articleshttps://www.fda.gov/media/113760/downloadhttps://www.ema.europa.eu/en/human-regulatory/research-development/prime-priority-medicineshttps://www.ema.europa.eu/en/human-regulatory/research-development/prime-priority-medicineshttps://www.ema.europa.eu/en/human-regulatory/research-development/prime-priority-medicineshttps://www.ema.europa.eu/en/human-regulatory/research-development/prime-priority-medicineshttps://www.fda.gov/regulatory-information/search-fda-guidance-documents/expedited-programs-regenerahttps://www.fda.gov/regulatory-information/search-fda-guidance-documents/expedited-programs-regenerahttps://www.fda.gov/regulatory-information/search-fda-guidance-documents/expedited-programs-regenerahttps://www.fda.gov/regulatory-information/search-fda-guidance-documents/expedited-programs-regenerahttps://www.fda.gov/regulatory-information/search-fda-guidance-documents/expedited-programs-regenerahttps://ec.europa.eu/health/sites/health/files/files/eudralex/vol-4/2017_11_22_guidelines_gmp_for_athttps://ec.europa.eu/health/sites/health/files/files/eudralex/vol-4/2017_11_22_guidelines_gmp_for_athttps://ec.europa.eu/health/sites/health/files/files/eudralex/vol-4/2017_11_22_guidelines_gmp_for_athttps://www.fda.gov/regulatory-information/search-fda-guidance-documents/current-good-manufacturing-https://www.fda.gov/regulatory-information/search-fda-guidance-documents/current-good-manufacturing-https://www.fda.gov/regulatory-information/search-fda-guidance-documents/current-good-manufacturing-https://www.fda.gov/regulatory-information/search-fda-guidance-documents/current-good-manufacturing-https://www.fda.gov/regulatory-information/search-fda-guidance-documents/current-good-manufacturing-https://www.fda.gov/media/71518/downloadhttps://www.fda.gov/media/71518/downloadhttps://ec.europa.eu/health/sites/health/files/files/eudralex/vol-10/atmp_guidelines_en.pdfhttps://ec.europa.eu/health/sites/health/files/files/eudralex/vol-10/atmp_guidelines_en.pdfhttps://ec.europa.eu/health/sites/health/files/files/eudralex/vol-10/atmp_guidelines_en.pdfhttps://www.ema.europa.eu/en/documents/other/good-laboratory-practice-glp-principles-relation-advanchttps://www.ema.europa.eu/en/documents/other/good-laboratory-practice-glp-principles-relation-advanchttps://www.ema.europa.eu/en/documents/other/good-laboratory-practice-glp-principles-relation-advanchttps://www.ema.europa.eu/en/documents/other/good-laboratory-practice-glp-principles-relation-advanchttps://www.ema.europa.eu/en/documents/other/good-laboratory-practice-glp-principles-relation-advanchttps://www.ich.org/page/ich-guidelineshttps://www.ich.org/page/ich-guidelineshttp://ftp.uspbpep.com/v29240/usp29nf24s0_c1046s1http://ftp.uspbpep.com/v29240/usp29nf24s0_c1046s1http://ftp.uspbpep.com/v29240/usp29nf24s0_c1046s1https://www.ema.europa.eu/en/documents/scientific-guideline/draft-guideline-quality-non-clinical-clihttps://www.ema.europa.eu/en/documents/scientific-guideline/draft-guideline-quality-non-clinical-clihttps://www.ema.europa.eu/en/documents/scientific-guideline/draft-guideline-quality-non-clinical-clihttps://www.ema.europa.eu/en/documents/scientific-guideline/draft-guideline-quality-non-clinical-clihttps://www.ema.europa.eu/en/documents/scientific-guideline/draft-guideline-quality-non-clinical-clihttps://www.ema.europa.eu/en/documents/scientific-guideline/draft-guideline-quality-non-clinical-clihttps://www.fda.gov/media/120341/downloadhttps://www.fda.gov/media/120341/download



About the authorsKirsten Messmer, PhD, RAC, is a princi-pal regulatory affairs specialist in regulatory intelligence solutions at PPD. She received a doctorate in neuroscience from the Uni-versity of Sheffield, UK. She can be contact-ed at [email protected].

Richard Dennett, PhD, is a senior director of regulatory affairs CMC, global devel-opment solutions at PPD. He obtained his doctorate and BSc (Hons) degrees in applied biochemistry at Liverpool John Moores University, UK. He can be contact-ed at [email protected].

Both authors are members of PPD’s Ad-vanced Therapy Forum, a group of dedicated professionals with global expertise and hands-on experience in nonclinical, clinical, CMC, and regulatory aspects of gene- and cell-based therapies, as well as tissue-engi-neered products.

Citation Messmer K, Dennett R. Advanced therapies: Navigation and application of EU and US guidelines during product devel-opment. Regulatory Focus. November 2020. Regulatory Affairs Professionals Society.

https://www.raps.org/news-and-articlesmailto:Kirsten.Messmer%40ppdi.com?subject=mailto:Richard.Dennett%40ppdi.com?subject=

Need a boost in your career? Enroll in a RAPS Online University Certificate program.Jump-start your regulatory career with a RAPS Online University Certificate. Offered in two tracks—pharmaceuticals and medical devices with the option to take both together—RAPS Online University certificates offer flexible and cost-effective regulatory education.

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FDA warning letters in 2020 reveal concerns around purity, investigations, and data integrity

Warning letters issued by the US Food and Drug Administration (FDA) provide important context for regulatory intelli-gence professionals in the pharmaceutical manufacturing space. In this article, the authors review 2020 warning letters related to good manufacturing practices (GMP) and provide examples of com-mon citations that point to larger trends in FDA enforcement. Among the warn-ing letters, citations frequently pointed to inadequate qualification of supplier certificates of analysis (CoAs) and inadequate discrepancy investigations, reflecting concerns over drug purity. In addition, data integrity issues underlay a wide range of common citations.

Introduction and backgroundPatterns of enforcement activity by the FDA often emerge in response to pressing public health concerns and can yield valuable regulatory insights. An ongoing and systematic review of warning letter content is a critical ele-ment of a strong regulatory intelligence

Sarah B. Tanksley, MS


and internal surveillance program. FDA warning letters are one mode of action through which the agency may notify companies and the public of significant violations of the Code of Federal Regulations Title 21 (CFR 21) discovered during FDA inspec-tions. A company’s failure to correct concerns cited in a warning letter can lead to the FDA taking more serious legal action. In recent years, concerns over nitrosamine contamination have surfaced following the discovery of N-Nitrosodimethylamine (NDMA) in widely used drugs, including valsartan, losartan, irbesartan, and ranitidine, prompting increased oversight of drug purity.1 This focus on drug purity is evident in the FDA’s scrutiny of control of incoming materials and the under-standing of the commercial manufac-turing process. Furthermore, against a backdrop of increasing digitization in the pharmaceutical industry, data in-tegrity problems underpin a wide array of warning letter citations.2

In this article, we discuss themes

Audrey Francis




from drug GMP warning letters issued in 2020, along with examples of nota-ble offenses, to illustrate trends for con-sideration when managing an internal surveillance program. We did not ex-amine nondrug-related warning letters, such as those from the Center for Food Safety and Applied Nutrition, Center for Devices and Radiological Health, or Center for Biologics Evaluation and Research – although the ongoing 351 versus 361 product story chronicled in CBER warning letters, which can be viewed on the FDA’s warning letter da-tabase, is interesting. We also excluded producers of homeopathic products, including those citing unauthorized/unapproved COVID-19 products. As of 10 August 2020, we had 33 warning letters from 33 companies on which to base the current discussion.

Of those warning letters, the majority of recipients were over-the-counter (OTC) drug producers and were heavily overrepresented among companies cited for identity and puri-ty-related issues. Until recently, OTC companies had not been routinely inspected in the way prescription drug companies are.3 A review of warning letters over the past 4 years makes it clear that OTC manufacturers lag far behind the rest of the industry in terms of implementation and management of current good manufacturing practice (cGMP) controls, and have egregious violations, such as having not having a quality system in place. The heavier focus on component origin and quality likely reflects heightened concerns around drug purity in response to recent discoveries of nitrosamine con-tamination in widely used drugs.

Among non-OTC companies, a large proportion of warning letter citations focus on failure to thoroughly investigate discrepancies and maintain appropriate controls for computerized systems.

For both OTC and non-OTC drug manufacturers, data integrity issues also surfaced in a variety of ways,

often buried in citations that did not explicitly mention data integrity. In to-tal, 13 warning letters included explicit calls for data integrity remediation, and many others showed less obvious signs of data integrity failings. For example, citations relating to quality unit (QU) inadequacies were often attributable to underlying data integrity problems and will be discussed later in this article.

Furthermore, non-OTC compa-nies demonstrated numerous examples of data integrity lapses relating to digital recordkeeping and computer controls, reflecting a need for increased vigilance and quality control in digital data management. The frequency of data integrity problems at the core of numerous and disparate citations underscores the importance of detailed regulatory surveillance by regulatory intelligence professionals.

Drug purity concerns predominate at OTC companiesIn an effort to crack down on drug quality and purity transgressions, par-ticularly among OTC manufacturers, during the period under review, the FDA cited a high number of offenses dealing with failure to test incoming components (21 CFR 211.84) and fail-ure to verify conformance of each batch of drug product to final specifications (21 CFR 211.165[a] and/or [b]).

In total, 12 firms were cited for 21 CFR 211.84(d)(1) and/or (2) for failing to appropriately qualify supplier certificates of analysis (CoAs) for in-coming components. Most recipients of this citation were non-US based manufacturers, with companies from China and India collectively compris-ing half of the citations for 21 CFR 211.84. All recipients of this citation manufacture predominantly OTC drug products, reflecting a crackdown on OTC drug manufacturers that has spanned several years.3

The details of citations for 21 CFR 211.84 were highly similar between firms. Many firms failed to conduct

Furthermore, non-OTC companies demonstrated numerous examples of data integrity lapses relating to digital recordkeeping and computer controls, reflecting a need for increased vigilance and quality control in digital data management.




identity testing for each component lot used in drug product manufactur-ing, as required by 21CFR211.84(d)(1). The firms also relied on supplier CoAs without appropriately validating the quality and reliability of suppliers’ components. Firms were reminded that CoAs may be relied upon only for component attributes – such as purity, strength, and quality – provided the supplier’s test results are validated at appropriate intervals.

A recent FDA guidance on controlling nitrosamine impurities in human drugs4 emphasized that compliance with 21 CFR 211.84 should factor in the supplier’s history of quality and consistency, which must be verified through an ongoing supplier qualification program. Firms’ responses to the warning letters were frequently deemed insufficient by the agency because they lacked detail regarding specific procedures needing to be implemented for qualifying supplier CoAs and for testing the attributes of incoming components. Response letters from two firms, Hangzhou Linkeweier Daily Chemicals and JHS Svendgaard Hygiene Products, were found to be insufficient because they did not com-mit to retrospectively assessing OTC drug products that had been manu-factured and released using unverified components. Simply correcting future practice and failing to extend correc-tive actions to material already on the market is a classic and common gap in warning letter responses. Concerns over component quality and origin were further exemplified by Cosmelab, which was cited for failure to establish an adequate QU (21 CFR 211.22[a] and/or [d]) after unknowingly releasing OTC drug products to the US market that had been produced by a contract manufacturing organization (CMO) on the FDA’s Import Alert 66-40.5

In addition to the FDA’s focus on component identity and purity, it also made a point to call out companies for inadequate testing of final drug

products. Collectively, 14 companies were cited for 21 CFR 211.165(a), failure to test final product for con-formance to specifications, and 21 CFR 211.165(b), failure to conduct appropriate laboratory testing required to be free of objectionable microorgan-isms. Non-US companies comprised the majority of recipients of 21 CFR 211.165 citations, with only one com-pany, Trilogy Laboratories, based in the US. Again, 100% of the recipients of this CFR citation were OTC manu-facturers. Three firms (Sunstar Guan-zhou, DermaPharm A/S, and Huaian Zongheng Bio-Tech) were specifically called out for inadequate testing of final drug products designated for use by children.

The majority of firms cited for 21 CFR 211.165 failed to verify the strength and identity of the active pharmaceutical ingredient (API) in final drug products. Two companies, Guangzhou Tinci Materials Technol-ogy and Hangzhou Linkeweier Daily Chemicals, failed to adequately mon-itor final drug products for microbial contamination. Again, the companies’ responses to the warning letters were often found to be inadequate because they had insufficient detail regarding testing protocols and their failure to address previously released batches, including reserve samples designated for the US market.

To comply with GMPs, companies should critically evaluate procedures regarding CoA reliance and final drug product testing. Firms should be particularly cognizant of FDA scrutiny surrounding possible sources of nitro-samine impurities and should conduct risk assessments to determine the potential for nitrosamine contamina-tion at each stage of the manufacturing process. Companies should prepare for a predictable trend of an increased reg-ulatory scrutiny of all impurity issues as the focus on nitrosamine contam-ination unfolds. Adequate testing of both incoming components and final

In addition to the FDA’s focus on component identity and purity, it also made a point to call out companies for inadequate testing of final drug products.




drug products is vital to ensuring the high level of purity and safety the FDA demands from drug manufacturers.

Inadequate investigationsBoth OTC and non-OTC companies received numerous citations relating to inadequate investigations of discrep-ancies. Among warning letters issued to non-OTC companies, including pre-scription drug companies and certain CMOs, five firms received citations for failure to thoroughly investigate un-explained discrepancies or failure of a batch or any of its components to meet specifications, whether or not the batch had already been released (21 CFR 211.192). Often, companies made an apparent attempt to investigate discrep-ancies, but failed to provide sufficient evidence for their claimed root cause, or failed to extend the investigation to consider the impact on all potentially affected drug lots, including those already on the market. The breakdown between US and non-US manufactur-ers was roughly even for this citation, with four US companies and five inter-national companies receiving warning letters citing 21 CFR 211.192. This is not surprising, as failing to perform thorough investigations both in the laboratory and in manufacturing is a top citation every year, both within and outside of the US.

Eosera, a manufacturer of OTC ear medications, obtained an out-of-specification (OoS) result during microbial testing of one of its pediatric drug lots conducted by a con-tract testing lab. Rather than initiate an investigation into the OoS result, the firm instructed its contract lab to re-test the drug lot. After a second test yielded passing results, the firm released the batch without trying to determine the cause of the initial result failure or the potential for contamina-tion in other affected drug lots. Such an action puts consumers at risk from potentially contaminated drugs that are

released on the basis of cherry-picked test results. In addition, the firm’s response was incongruent with what it initially told FDA officials during the inspection. During the inspection, management conceded to FDA in-spectors that no investigation had been performed to determine the root cause and scope of microbial contamination observed during initial testing of lot P193084. However, in its response to the FDA later, the company claimed an investigation had been performed by the QU but not properly documented. In either case, there was no record of an investigation demonstrating the cause of the OoS microbial result had been identified and addressed with adequate corrective and preventive action (CAPA). The discrepancy in the information provided to the FDA was further evidence that the company may not be operating in a state of control.

Inadequate investigations and fail-ure to implement adequate CAPA also contributed to warning letters issued to non-OTC companies. For example, Takeda discovered black particles in multiple batches of drug products. After conducting a rudimentary inves-tigation, the firm determined that the particles consisted of metal fragments. They rejected the vials containing visi-ble black particles and stated that there was no product impact because all remaining products passed final testing. However, they failed to provide evi-dence that visual inspection of the vials was sufficient to detect the presence of metals above an acceptable limit. Instead, the firm continued operating under the assumption that its testing and visual inspection methods were sufficient to ensure consumer safety, even though its existing operations had permitted entry of metal contaminants into drug products. In such cases of unexplained discrepancies, apparent one-time incidents cannot simply be swept under the rug, even if remaining test results continue to yield expected

Eosera, a manufacturer of OTC ear medications, obtained an out-of-specification (OoS) result during microbial testing of one of its pediatric drug lots conducted by a contract testing lab.




integrity issues, as discussed in the following section.

Data integrityAcross both OTC and non-OTC com-panies, a close examination of warning letter citations often revealed data integrity violations as a major contrib-utor to noncompliance issues. Often when data integrity failures were noted in warning letters, the warning letter contained a citation against the quality unit for failing to detect or prevent the data integrity issue from occurring (21 CFR 211.22[a] and/or [d]). Most of the companies cited for QU deficien-cies were OTC manufacturers, but numerous prescription drug manufac-turers and CMOs also demonstrated data integrity violations that were ulti-mately attributed to the QU. With the exception of Eosera, all manufacturing facilities cited for 21 CFR 211.22 were based outside of the US.

A warning letter issued to Wind-las Healthcare provides an example of intentional data withholding and manipulation for which the QU bore responsibility. The warning letter, issued in March 2020, describes an incident in which an investigator “observed numerous employees in the process of moving off-site cartloads of trash bags containing shredded and torn documents and binders” found to contain “reconciliation forms, cleaning and dispensing logs, training assess-ments, and scale balance printouts.” The incident was ultimately classified as a QU failure in the warning letter and resulted in a citation for noncompli-ance with 21 CFR 211.22(a). The pat-tern of a warning letter citing specific grievances, and then also citing the QU for failing to detect the objectionable issues, is not new, and this pattern is an increasing trend in the number of warning letters with data integrity findings. This emphasis on the failure of the QU is not surprising, given that the FDA’s guidance on data integrity and compliance with continuous GMP

results. GMP compliance requires that any unexplained discrepancy be fully investigated, which includes determin-ing a root cause and corrective action that are substantiated by scientific evidence.6 Furthermore, the company failed to extend its investigation and risk assessment to include products that had already reached the US market, placing consumers at risk from product contamination that was poorly under-stood.

In another case of inadequate investigations, Stason Pharmaceuti-cals, a manufacturer of prescription generics, obtained OoS results during dissolution testing of its temozolo-mide capsules. After investigating these OoS results, the firm proposed a relaxed specification for dissolution tests, which was approved by the FDA. However, at least one lot failed dissolu-tion testing under the new specification and was voluntarily recalled. The firm tested alternative desiccants to deter-mine whether a less absorptive desic-cant would improve the dissolution profile of the capsules, but the data did not support this solution. Furthermore, the firm failed to implement adequate CAPA, because it had not established a root cause for the dissolution variabil-ity. Again, this example demonstrates the importance of root cause identi-fication backed by sound evidence. Adjusting the specifications would have been a convenient solution to the problem of dissolution variability, but without understanding the root cause of the issue, the company could not respond appropriately when the issue arose again.

Non-OTC companies also re-ceived a number of citations for failure to exercise appropriate controls over computer systems (21 CFR 211.68[a] and/or [b]) and failure to establish and follow procedures designed to prevent microbiological contamina-tion of sterile drug products (21 CFR 211.113[b]). Both of these citations frequently pointed to underlying data

In another case of inadequate investigations, Stason Pharmaceuticals, a manufacturer of prescription generics, obtained OoS results during dissolution testing of its temozolomide capsules.




suggests personnel be trained to detect and prevent data integrity issues.7

Windlas Healthcare was further admonished for failure to ensure that laboratory records included complete data derived from all tests (21 CFR 211.194(a)). Investigators cited the company for disabling the peak detec-tion function multiple times during gas chromatography testing of its incoming API, which was used to manufacture drugs released to the US market, and for failing to report instances of un-known peaks. Tender Corporation, an OTC drug manufacturer, received the same CFR citation for injecting “unof-ficial” samples on its high-performance liquid chromatography system without noting these tests in official records used for batch-release decisions. Such recordkeeping practices prevent regula-tors from accessing a clear and trace-able chain of data to verify the state of a product throughout its lifecycle. The practice of using samples during unofficial “test runs” also raises red flags that the company may be attempting to manipulate its sample into achiev-ing a passing result and is therefore prohibited by the FDA.2 Test runs of product samples are discussed in the FDA guidance on data integrity7 and have been the reason for many warning letters over the past 5 years. However, many companies still perform test injections of blanks or standards. In 2020, the FDA has also objected to this practice in warning letters, such as the one sent to Cosmaceutical Research Lab, in which the laboratory is cited for injecting what they claimed was a standard, rather than product, as a test injection.

Prescription drug manufacturer Takeda demonstrated that such issues are not isolated to OTC companies when it received a warning letter cita-tion for failure to “establish adequate written responsibilities and procedures applicable to the quality control unit and to follow such written procedures

(21 CFR 211.22[d]).” At first glance, the citation may seem to have been a procedural issue rooted in insufficient documentation. Indeed, the QU fell short in a number of areas, including failure to maintain cleanroom con-trol, failure to conduct aseptic process simulation per the required procedure, and failure to investigate OoS results appropriately. However, a closer look at the specifics of the case reveals significant data integrity issues as well. Investigators discovered documentation errors covered up by new paper, data recorded asynchronously with tests, sample IDs missing from records, and electronic data that was not reviewed before the final laboratory test results were released. A single instance of noncontemporaneous, missing, or otherwise questionable data calls into question the reliability of all other data in a manufacturing facility, and it is therefore paramount that the QU carry out its responsibilities with a keen focus toward data integrity.Takeda also received an additional citation for 21 CFR 211.113(b), failure to establish and follow appropriate written procedures designed to prevent microbiological contamination of drug products purporting to be sterile, which can be traced to data integrity failures. During a media fill, intact vials were removed and not incubated, and no justification was provided for their removal. Without a continuous record for these vials, including the reason for their removal, it is impossible to know whether they were tampered with, incurred a discrepancy, or were simply removed for routine testing, as the company claimed. Again, while 211.113(b) has not commonly been associated with data integrity issues, the practices described in this warning letter impede the traceability of data so that even properly recorded data must be called into question.

Citations for unexplained dis-crepancies also contained data integ-

TTender Corporation, an OTC drug manufacturer, received the same CFR citation for injecting ‘unofficial’ samples on its high-performance liquid chromatography system without noting these tests in official records used for batch-release decisions.




rity issues beneath the surface. Pfizer Healthcare India was cited for failure to adequately address unexplained discrepancies (21 CFR 211.192) for its response to a sterility failure for a batch of injectable drug product. The FDA reported that during a period of 3 months in 2018, there were procedural deviations in microbial testing owing to a number of environmental monitoring and testing plates that were incubat-ed beyond the acceptable incubation period. The firm blamed a “lack of qualified personnel” for the deviations, and results were repeatedly invalidated without scientific justification. The firm failed to address the possibility that positive microbial growth re-sults obtained during these tests were indicative of actual contamination and instead allowed production to continue by attributing the positive results to human error. Often, a root cause of “human error” indicates that the root cause analysis was incomplete (why did the human make the error? The answer is probably the real root cause). Even if human error is the suspected cause of an unexpected deviation, the source of the deviation must be investigated and thoroughly documented before determining whether to invalidate the result.6

In both OTC and non-OTC com-panies, digital data integrity issues and insufficient digital audit trail manage-ment were also common issues. Three companies received citations for 21 CFR 211.68(b) and/or (a), failure to exercise appropriate controls over com-puter or related systems, with two of three of these companies based in the US. For example, Stason Pharmaceuti-cals was cited for using a computer that was not properly secured to operate its spectrophotometer, making data files vulnerable to deletion without over-sight by the QU. Chemland was cited for 21 CFR 211.22(a), inadequate QU, for storing master batch records as unlocked Excel files, putting them at risk for access and manipulation by

unauthorized personnel. Indeed, several Excel files containing sample prepara-tion data and final calculations were found to be missing or deleted upon inspection. Vega Life Sciences, a CMO for API production, was cited for similar offenses, including for missing raw data files, having quality control analysts who shared the same username and password, failing to back up data, and failing to establish a procedure to ensure the existence and retention of an audit trail. These breaches compro-mise the metadata necessary for FDA inspectors to assess the full lifecycle of a product. Furthermore, they prevent accountability by failing to ensure that all changes can be traced to the individ-ual responsible for them. Companies should remember that digital records and computerized systems must meet the same requirements for retention and review as any other form of recordkeeping in order to comply with GMPs.2

The preponderance of data integrity issues underlying a variety of CFR 211 citations demonstrates the importance of rigorous documentation and data management across all areas of pharmaceutical manufacturing. It is a common misconception that com-pliance with CFR part 11, electronic records and electronic signatures, is enough to avoid data integrity viola-tions and demonstrate adequate control over digital documentation. However, from the examples provided, it is clear that compliance with the 211s requires vigilant data management, and data integrity problems frequently co-occur with other CFR noncompliance issues.

ConclusionWarning letters issued in 2020 reflected ongoing concerns regarding drug purity, challenges in adequately addressing unexplained discrepancies, and a variety of data integrity failures wrapped up in other instances of CFR noncompliance. Non-US manufactur-ing companies comprised the majority

In both OTC and non-OTC companies, digital data integrity issues and insufficient digital audit trail management were also common issues.




of warning letter recipients for most of the citations analyzed, particularly citations concerning purity and the QU. However, for issues concerning discrepancy investigations (21 CFR 211.192) and digital audit trails (21 CFR 211.68), the breakdown between US and international companies was more even.

Companies should be aware of the FDA’s focus on identifying and controlling sources of nitrosamine impurities is likely to result in a more holistic focus on all impurities, as well as verifying the quality of drug components via intermittent com-ponent attribute testing and CoA qualification. The increased scrutiny of process validation that began in 2017 is likely to continue, as the topic directly relates to control of impurities. These considerations, if not already included, should be incorporated into site quality management programs, and challenged during internal audits to avoid surprises during regulatory visits.

Although warning letters about purity were addressed largely to OTC drug producers, both prescription and OTC drug producers alike should evaluate their strategies for identifying and mitigating impurity risks through-out the drug manufacturing process. In cases of unexplained discrepancies and OoS results, companies should be pre-pared to conduct full investigations and identify root causes backed by scientific evidence.

Finally, companies must consider data integrity at every level of manu-facturing, including data collection, computer controls, recordkeeping, pro-cedural deviations, information access, and audit trails in order to maintain a chain of traceable information that supports the manufacture of safe and high quality drug products.

AbbreviationsAPI, active pharmaceutical ingredient; CAPA, corrective and preventive action; CFR, Code of Federal Regulations; cGMP, current good manufacturing practice; CMO, contract manufacturing organization; CoA, certificate of analysis; FDA, [US] Food and Drug Administration; NDMA, N-Nitro-sodimethylamine; OTC, over the counter; OoS, out of specification; QU, quality unit.

References1. White MC. Understanding and

preventing (N-Nitrosodimethylamine) NDMA contamination of medications. Ann Pharmacother. 2020;54(6):611-4.

2. Bartlow S, Takahashi K. Current expectations and guidance, including data integrity and compliance with CGMP. Presentation at Society of Quality Assurance Annual Meeting; 30 March 2017. https://elsmar.com/Cove_Members/CDER-OMQ_CGMP_Guidance_Plenary_3-20-2017_S508.pdf. Accessed 22 September 2020.

3. Unger B. US Sites play surprise starring role in FDA's drug GMP wa§§rning let-ter report. https://www.lifescienceleader.com/doc/u-s-sites-play-surprise-starring-role-in-fda-s-drug-gmp-warning-letter-re-port-0001. Published online 21 February 2020. Accessed 22 September 2020.

4. Food and Drug Administration, Center for Drug Evaluation and Research. Control of nitrosamine impurities in drugs: Guidance for Industry. https://www.fda.gov/media/141720/down-load. Last updated 2 September 2020. Accessed 20 September 2020.

5. Food and Drug Administration. Import Alert 66-40. https://www.accessdata.fda.gov/cms_ia/importalert_189.html. Published 6 November 2020. Accessed 22 September 2020.

6. Food and Drug Administration, Center for Drug Evaluation and Research. Guidance for Industry: Investigat-ing Out-of-Specification (OoS) Test Results for Pharmaceutical Production. https://www.fda.gov/media/71001/download. Last updated October 2006. Accessed 22 September 2020.

Companies should be aware of the FDA’s focus on identifying and controlling sources of nitrosamine impurities is likely to result in a more holistic focus on all impurities, as well as verifying the quality of drug components via intermittent component attribute testing and CoA qualification.

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7. Food and Drug Administration. Guid-ance for Industry: Data Integrity and Compliance with Drug GMP Ques-tions and Answers for Industry. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/da-ta-integrity-and-compliance-drug-cg-mp-questions-and-answers-guid-ance-industry. Last updated December 2018. Accessed 14 October 2020.

About the author

Sarah Tanksley, MS, has more than 20 years of experience in the pharmaceutical industry, both in the laboratory and in quality/compliance. She is an expert on a range of compliance issues. Tanksley has served as a reviewer and inspector with the Center for Biologic Evaluation and Research and FDA and has worked in the Laboratory of Imm

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