A holistic view of international regulations and industry standards governing collection of plasma and manufacture of plasma-derived medicinal products

Introduction

Plasma-derived medicinal products (PDMPs) are essential therapies manufactured from human plasma. These include immunoglobulins, clotting factors, albumin and other proteins, which are indispensable for treating patients with rare immunological, hematological, neurological, and metabolic disorders. Since the inception of this industry in the early 20th century, many stakeholders have worked to drive industry-wide regulatory evolution and change, collaborate with regulators, and develop international best practices and voluntary industry standards (1,2).

Today, the plasma collection and PDMP manufacturing industries are among the safest (3,4) in the pharmaceutical sector and are governed by a complex network of national, regional, and international regulations, supplemented by industry-led Plasma Protein Therapeutics Association (PPTA) standards. In the United States (U.S.), the Food and Drug Administration (FDA) regulates plasma and PDMPs through the Code of Federal Regulations (CFR) and associated guidance. In Europe, the regulatory framework is driven by directives and regulations such as the Blood Directive, soon to be replaced by the new Substances of Human Origin (SoHO) Regulation, and the Medicinal Products Directive. Globally, organizations such as the Pharmaceutical Inspection Co-operation Scheme (PIC/S), the International Council for Harmonization (ICH), and the World Health Organization (WHO) provide standards and guidance. PPTA’s voluntary standards, the International Quality Plasma Program (IQPP) and Quality Standards of Excellence, Assurance, and Leadership (QSEAL), provide additional layers of assurance for plasma safety and donor protection.

As plasma collection and manufacturing is a global industry, an interconnected and increasingly harmonized regulatory environment continues to emerge. This paper explores international regulations and industry standards governing collection of plasma and manufacture of PDMPs, including the historical context that led to the existing regulatory and standards frameworks and the future evolution and direction of such frameworks.

Historical development of global regulatory frameworks and industry standards for plasma collection and PDMPs

Developed regulatory systems for plasma and PDMPs, notably the major producers—the U.S., European Union (EU) and China—all followed a similar arc: early ad hoc or fragmented national rules giving way to formal laws, technical standards, and adoption of international scientific guidance as plasma fractionation industries matured and viral-safety crises exposed vulnerabilities.

The human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) epidemic of the 1980s marked a critical turning point in these markets, exposing major safety gaps (5). Before reliable tests existed, plasma-derived clotting factors, and to a lesser extent other therapies, were implicated in the transmission of HIV and hepatitis viruses to patients, prompting sweeping reforms.

Industry—through individual efforts and the creation of PPTA’s voluntary standards—and regulators implemented stricter donor deferral policies, introduced serologic screening (first for HIV antibodies, later for hepatitis markers), strengthened donor selection, and instituted inventory hold procedures, transforming both collection practice and regulatory oversight. Techniques such as pasteurization, solvent/detergent treatment, and chromatographic purification were validated to eliminate enveloped and non-enveloped viruses. National frameworks, WHO recommendations and PPTA standards formalized expectations that manufacturers demonstrate viral safety through combined donor screening, testing, and validated pathogen inactivation or removal.

U.S.

The U.S.’ regulation of plasma collection and PDMPs evolved from local public health controls in the early 20th century to a comprehensive federal framework emphasizing donor safety, testing, manufacturing oversight, and validated viral reduction. The first major milestone was the 1902 Biologics Control Act (6), enacted after a fatal contamination incident, which established federal licensing for producers of serums and related biologicals and set the foundation for national oversight under the Federal Food, Drug, and Cosmetic Act (FD&C Act) (7), with regulatory authority consolidated under the FDA in the 1970s.

By the mid-20th century, increasingly specific standards for blood and plasma were codified in the CFR (8). These included licensing, Good Manufacturing Practice (GMP) requirements, and product-specific standards, creating the legal framework governing donor eligibility, plasma collection, processing, testing, recordkeeping, and facility controls for plasma intended for PDMP manufacture.

As in other countries, the HIV/AIDS epidemic of the 1980s catalyzed major change. In response, the FDA and industry established validated viral inactivation and removal steps as mandatory components of manufacturing. The FDA’s 1999 Guidance on Viral Safety (9) codified this three-pillar approach, which remains the cornerstone of PDMP safety and quality assurance (10).

Technological innovation continued to drive evolution. The introduction of nucleic acid amplification testing (NAT) in the late 1990s drastically reduced the diagnostic “window period” for HIV and hepatitis C virus (HCV) compared to serology. The FDA supported NAT adoption through licensure and guidance, requiring continuous adaptation of testing standards to evolving technology.

Today, U.S. regulation of plasma and PDMPs is an integrated system encompassing statutory law, CFR provisions, Biologics License Applications (BLAs), and a dynamic body of FDA guidance. This layered framework—prevention at the donor level, screening at collection, validated viral clearance during fractionation, and post-market surveillance—ensures safety throughout the plasma supply chain and continues to evolve alongside emerging technologies and pathogens.

Europe

The evolution of European regulations for plasma collection and PDMPs followed a similar path—a shift from disparate national rules to an integrated, science-based framework, intensified by the safety crises of the 1980s. Blood components first became subject to EU-level legislation in 1989 with Directive 89/381/EEC (11), which centralized scientific and regulatory oversight across Member States and stimulated harmonization of safety expectations (12).

Responsible for the ethical, safe, and scientific governance of blood and plasma collection, the Council of Europe (CoE) began addressing blood safety in the 1950s–1970s. The crises of the 1980s led to further codification of the early recommendations on donor selection, testing, and component preparation in the first edition of the “Guide to the Preparation, Use and Quality Assurance of Blood Components (Blood Guide)” in 1987.

The European Directorate for the Quality of Medicines & HealthCare (EDQM), founded in 1964, was charged with unifying quality standards for medicines and biologics, including blood and plasma, in conjunction with the European Pharmacopoeia (Ph.Eur.). The Ph.Eur. establishes standards governing the collection, testing, processing, storage and distribution of human blood and blood components.

The milestone EU Blood Directive (2002/98/EC) (13) established common standards of quality and safety for plasma destined for fractionation, with the “Blood Guide” adopted as technical reference. The Directive, operationalized by implementing measures that set technical requirements for donor selection, testing, storage and labelling, created a legal baseline requiring Member States to ensure equivalent protection.

Parallel to these blood component-sector rules, the European Medicines Agency (EMA) developed product-focused guidance for PDMPs. EMA developed guidance documents requiring manufacturers to submit a Plasma Master File (PMF) or equivalent scientific data describing plasma collection, testing, pool management and donor-screening policies that underpin the safety of a plasma pool used in a marketing authorization dossier.

EMA scientific guidance also specified expectations for manufacturing controls, validated viral inactivation/removal steps, GMP compliance, and pharmacovigilance for PDMPs. Guidelines on PDMPs set out detailed requirements for process validation, virus safety demonstration and donor-deferral policies, reinforcing the layered risk-reduction model encompassing donor selection, testing, validated removal/inactivation and pharmacovigilance used across jurisdictions.

Other developed and developing geographic areas

Other markets with well-developed regulatory structures for PDMPs, such as Australia, Canada, Korea (14) and Japan, have followed the same arc. They now employ similar frameworks, treating plasma and PDMPs within frameworks that combine product licensing, stringent GMP, and source-material expectations.

Regulatory evolution in many middle- and low-income countries has relied heavily on WHO technical assistance and regionally harmonized instruments to develop capacity for safe collection, cold chain, testing, and regulatory review. PIC/S guidance and WHO publications (including practical guides to increasing safe plasma supply and WHO infosheets on PDMP quality and safety) remain central references for regulators building or upgrading systems and emphasizing the same layered risk-reduction model.

China represents a prominent example of rapid regulatory modernization. Reforms in 1996 and 1998 (15) represented milestones in China’s move toward a structured, auditable system for plasma and PDMP safety—making great strides around donor selection and protection. This was followed by a cascade of technical regulations, standards and supervision measures directed at plasma collection, cold-chain logistics, donor eligibility, and collection-site quality systems. As China’s domestic fractionation industry expanded, regulators tightened requirements for plasma sourcing, testing, and manufacturing controls, and emphasized alignment with the international layered risk-reduction approach to viral safety.

Overall, the global pattern of regulatory development was one of progressive formalization, technical convergence toward internationally recognized viral safety principles, and increasing regulatory capacity-building, with jurisdictions adapting international standards to local legal frameworks, supply challenges, and health-system priorities.

Current global regulatory and industry standards for plasma collection and PDMPs

U.S. regulatory framework

The U.S. regulatory landscape for PDMPs is recognized as one of the most robust in the world and continues to evolve (Figure 1). The U.S. regulates plasma collection and PDMPs through the Public Health Service Act (PHS Act, 42 U.S.C. §262) (16) and the FD&C Act, 21 U.S.C. §§301 et seq) (17). Oversight rests with the FDA, which licenses all biological products, including source plasma and PDMPs, before interstate distribution. The FD&C Act also gives the FDA broad authority over product safety, labeling, donor eligibility, manufacturing controls, and post-market surveillance.

Figure 1 Existing U.S. regulatory network for plasma collection and PDMPs. CFR, Code of Federal Regulations; EDQM, European Directorate for the Quality of Medicines & HealthCare; EU, European Union; FDA, Food and Drug Administration; ICH, International Conference on Harmonization; PIC/S, Pharmaceutical Inspection Co-operation Scheme; PDMPs, plasma-derived medicinal products; PPTA, Plasma Protein Therapeutics Association; SoHO, Substances of Human Origin; U.S., United States.

Most operational requirements for plasma centers are set out in 21 CFR Parts 600–640, which is under the oversight of the Center for Biologics Evaluation and Research (CBER). Part 640 details standards for plasma collection, testing, processing, storage, and the reporting of serious donor reactions. Part 630 governs donor eligibility, and viral marker testing is required under Part 610. These rules ensure that donors are properly screened and each donation is tested for major blood-borne pathogens, including HIV, hepatitis B virus (HBV), and HCV, before it can be used.

In addition to FDA oversight, source plasma collection establishments must comply with the Clinical Laboratory Improvement Amendments (CLIA) of 1998, which is overseen by Centers for Medicare and Medicaid Services (CMS). Center personnel use digital refractometers to perform total protein measurements, which is considered a ‘Moderate’ complexity laboratory test under CLIA laboratory test categorization by the FDA based on their package insert review and criteria of complexity using defined criteria. These criteria cover knowledge needed to perform the test, training and experience, preparation of reagents and materials, automation of operational steps, calibration and quality control, test system troubleshooting and equipment maintenance, and finally interpretation and judgement. Therefore, plasma centers are required to obtain and keep a valid CLIA certificate, adhere to testing protocols, demonstrate staff competence, and meet standards for calibration, quality control, equipment checks, and thorough recordkeeping by meeting regulations in 42 CFR Part 493. The requirement to comply with CLIA is specific to the U.S.

The dual oversight created by these rules has resulted in both operational and regulatory challenges. Ongoing efforts, including those by the PPTA, aim to eliminate the CLIA requirement because in reality, performing this test is extremely simple and it is not easy to obtain an inaccurate test result due to this simplicity. Removing it would align regulatory provisions with actual risk, eliminate unnecessary overlap, and streamline plasma collection processes while maintaining the safety of donors and products.

Plasma centers must also meet Current Good Manufacturing Practice (cGMP) requirements, outlined in Part 606, which address staff training, facility standards, equipment, labeling, and meticulous recordkeeping. Registration and product listing under Part 607 support regulatory oversight and traceability. In practice, this means every step from donor screening to storage is closely monitored and documented.

Manufacturing of PDMPs takes place in licensed fractionation facilities that operate under BLAs as set out in Part 601. These facilities must comply with cGMP standards for both biologics and drugs (21 CFR Parts 210, 211, and 600–680). Manufacturers are required to validate all processes and implement layered viral safety steps, including solvent/detergent treatment, pasteurization, and nanofiltration.

State and local agencies add further oversight into the regulatory landscape. For instance, New York and California require supplementary licensing, conduct regular inspections, and enforce state-specific reporting obligations. Local authorities are responsible for biomedical waste disposal, zoning, and facility occupancy. While designed to ensure operational and community safety, this complex, multi-layered regulatory framework does present opportunities for state-level regulatory modernization.

Finally, because plasma, intermediates and finished products move around global manufacturing and markets, most U.S. plasma centers and PDMP manufacturing facilities are also approved by European regulators and therefore must follow some or all EU regulatory frameworks, laid out below.

EU regulatory framework

In the EU, the collection of blood components, including plasma for fractionation and PDMPs, are governed by separate but interdependent regulatory frameworks, which have undergone significant transformation over the past decades (Figure 2). Plasma collection is governed by the Blood Directive 2002/98/EC, as well as several implementing directives (Directive2004/33/EC) (18), Directive 2005/61/EC (19) Directive 2005/62/EC) (20), which established EU rules for donor selection, collection procedures, testing, storage, traceability, and donor protection. Once plasma enters industrial processing, it falls under the EU’s medicinal products regulations, which ensure compliance with the GMP rules, batch release, pharmacovigilance, and pharmacopoeia standards. Together, the frameworks provide continuous oversight from the collection of starting material to the manufacture of medicinal products, but create practical challenges due to differences in level of oversight, terminology, and compliance requirements between the plasma and pharmaceutical systems, which sometimes leads to ambiguities or gaps.

Figure 2 Existing European regulatory network for plasma collection and PDMPs. EDQM, European Directorate for the Quality of Medicines & HealthCare; EU, European Union; GMP, Good Manufacturing Practice; ICH, International Conference on Harmonization; PDMPs, plasma-derived medicinal products; Ph.Eur., European Pharmacopeia; PIC/S, Pharmaceutical Inspection Co-operation Scheme; PMF, Plasma Master File; PPTA, Plasma Protein Therapeutics Association; SoHO, Substances of Human Origin.

To ensure the consistent implementation of quality, safety and efficacy standards across the EU, the EMA has developed a comprehensive set of scientific guidelines for plasma and PDMPs. The cornerstone is the Guideline on Plasma-Derived Medicinal Products (EMA/CHMP/BWP/706271/2010) (21), which sets overarching principles for quality control, viral safety, and traceability of plasma and PDMPs. The EMA also established the Scientific Data Requirements for a Plasma Master File (EMEA/CHMP/BWP/3794/03) (22,23) regulatory rules for Epidemiological Data on Blood Transmissible Infections (EMEA/CPMP/BWP/125/04). In addition, EMA issued a number of clinical guidelines specific to plasma-derived coagulation factors and Summary of Product Characteristics (SmPCs) (24).

The CoE’s activities in transfusion and plasma, as overseen by EDQM, derive mainly from its European Committee (Partial Agreement) on Blood Transfusion (CD-P-TS), which allows member states to coordinate on technical and scientific aspects related to medicines and biologicals. In addition to updating and publication of the “Blood Guide”, key functions include coordination of the CD-P-TS, which drafts and revises technical standards for blood and plasma; ensuring consistency between EDQM blood standards and the Ph.Eur.; and support of mutual recognition and harmonization initiatives among European blood establishments, including those supplying plasma for fractionation.

With an eye to the future, the European Commission evaluated both legal frameworks, along with the relevant guidelines and technical documents. While the Blood Directive represented an important first step in harmonizing EU rules governing the collection of blood and blood components, this evaluation (25) found that the legislation no longer fully reflects scientific, medical, and epidemiological developments; allows for inconsistency in legislation interpretation and implementation; and has gaps in oversight and concerns over supply resilience.

In response, the Blood Directive was repealed and the SoHO 2024/1938 Regulation (26) will be implemented in 2027, introducing a modernized approach to regulating all SoHO, including blood and plasma. The EU general pharmaceutical legislation revision is still ongoing. Such continued adaptation of the EU regulations is essential to address emerging challenges, including donor recruitment, plasma and PDMP supply security, and technological innovation in plasma product development.

The transition from Directive to Regulation also means a more harmonized and uniform legislative framework for all EU Member States, replacing the fragmented directives in these areas with a single risk-based, and future-proof legislative instrument. With the SoHO Regulation, the EU aims to strengthen traceability and surveillance, enhance cross-border plasma utilization and mandate national strategies for critical medicines. Together, these provisions establish an integrated system for donor and recipient protection, ensure continuity of supply across Member States, and reinforce EU health resilience.

Chinese regulatory framework

China’s plasma collection and manufacturing regulations are overseen through different structures, coming together in a broader framework covering every stage from plasma collection to product supervision. Plasma collection centers in China are subject to licensing, operational, and safety requirements monitored by the National Health Commission (NHC). The system emphasizes source plasma quality, donor eligibility, and infection control. The National Medical Products Administration (NMPA) serves as the primary authority for licensing, GMP compliance, lot release, and post-market surveillance of PDMPs. China’s regulatory structure for plasma collection and manufacturing differs somewhat from that of the U.S. and EU, particularly in areas such as requiring vertical integration of collection and manufacturing, national databases for unsuitable donors, and traceability technologies like radio frequency identification (RFID). One notable difference is China’s use of a “quarantine-retest” system of donor qualification, which requires plasma to be held for at least 60 days and a second set of negative test results to be obtained in order to use the plasma. The U.S. and other countries employ an inventory hold system which requires plasma to be held for 45 days and does not require retesting, as long as the donor had received an initial set of negative test results in the 6-month period preceding the donation.

In recent years, China has taken notable steps toward improving oversight and integrating digital systems into regulatory supervision. The NMPA’s 3-year action plan (27) aims to enhance the traceability and safety of plasma collection and processing. This initiative requires compliance with the Drug Administration Law (28,29) and GMP for Drugs while accelerating the adoption of information technology (IT) systems across the PDMP lifecycle—from source plasma collection to inspection. As regulation continues to evolve, there may be opportunities to further modernize specific guidelines for plasma center management and importation (30); IT system adoption, validation, and interoperability to improve data sharing, the volume of plasma collected, efficiency across institutions and ultimately, patient access.

Global regulatory frameworks

A note on regulatory harmonization

In today’s globally integrated industry, regulatory interconnectedness refers to the complex mesh of rules, institutions, and cross-border coordination. Plasma collection and PDMP manufacturing involve multinational supply chains, and plasma collected in one country may support patients in another (31). Navigating these overlapping systems requires continuous engagement, flexibility, and harmonization.

Harmonization streamlines regulatory approvals, reduces duplicative testing and documentation, which accelerates market access and reduces costs for manufacturers operating across regions. Reliance mechanisms, mutual recognition agreements (MRAs), and coordinated inspections reduce redundancy and build trust. As more countries develop their plasma sectors, international harmonization efforts through WHO, PIC/S, and ICH become increasingly vital.

In addition, harmonized regulations support operational efficiency and strengthen global supply chains by simplifying cross-border plasma sourcing, as well as transport and distribution of plasma, intermediate and finished products. They also foster international collaboration, enabling manufacturers, regulators, and organizations to adopt new technologies, improve donor safety, and develop innovative therapies within a shared framework. Aligned standards for collection, testing, and manufacturing encourage a uniform safety profile and maintain product reliability. Overall, regulatory harmonization is critical for scaling plasma operations safely and effectively while ensuring consistent access to essential therapies worldwide.

PIC/S

The Pharmaceutical Inspection Convention (PIC) and the PIC/S, established in 1970 under the European Free Trade Association and expanded in 1995, harmonizes GMP standards and inspection procedures across 50-plus regulatory authorities worldwide. Its purpose is to ensure mutual confidence among inspectors and consistent product quality across borders. With strong alignment to ICH and WHO guidance, PIC/S requires comprehensive quality system support through integrated quality management system platforms that manage Standard Operating Procedures (SOPs), deviations, corrective and preventive action (CAPA), and change controls. It also offers inspection-readiness checklists to help sites prepare for audits, along with certified training modules for regulatory and manufacturing personnel. Data-integrity tools ensure compliance with ALCOA+ principles, while document-control software helps maintain GMP documentation in line with PIC/S guidelines.

One of PIC/S’s most important contributions has been the development of harmonized GMP guidance for medicinal products (32-34). PIC/S plays a central role (35) PDMPs. Through its guidance (Annex 14 on blood establishments and plasma warehouses) (36), PIC/S aims to ensure high standards of safety, quality, and efficacy. PIC/S has also published Good Practice Guidelines for Blood Establishments (37) the collection, processing, testing, storage, and distribution of blood and blood components used for PDMP manufacturing. In addition, there are several guidelines that cover plasma center inspections and Site Master File documentation for plasma centers (38) and plasma warehouses (39).

The PIC/S GMP Inspection Reliance pilot program (40) aims to provide a framework for evaluating GMP compliance at overseas facilities remotely, allowing regulators to determine when another authority’s oversight is sufficient to confirm an acceptable level of compliance without conducting an onsite inspection. This model complements existing and future MRAs and could be a key tool for advancing those.

ICH

The ICH of Technical Requirements for Pharmaceuticals for Human Use (41) develops international guidelines which establish the scientific and regulatory framework for maintaining the integrity, safety, and consistency of plasma-derived and recombinant biological medicines. These outline specifications, testing procedures, and acceptance criteria for biological products, as well as providing standards for viral safety evaluation in biotechnological manufacturing. Additional guidelines covering comparability after manufacturing changes and preclinical safety evaluation of biotechnology-derived pharmaceuticals, support consistent product quality and safety assessment for PDMPs.

Member agencies often reference ICH guidelines when formulating their own detailed technical requirements for plasma collection, manufacturing, and quality control. Furthermore, the accession process drives regulatory maturation in applicant markets and serves as a demonstration of commitment to international best practices. As a result, ICH’s work provides the foundational global standards for biological quality and safety that underpin PDMP regulation worldwide, ensuring harmonization across jurisdictions and supporting safe, effective, and consistent plasma-derived therapies.

WHO

The WHO actively supports the safe and sustainable manufacturing of PDMPs through global standards, policy frameworks, and technical guidance. Its “Guidance on Increasing Supplies of Plasma-Derived Medicinal Products in Low- and Middle-Income Countries through Fractionation of Domestic Plasma” (42) outlines pathways for nations to strengthen domestic PDMP production—from improving plasma quality to establishing contract fractionation agreements and, when appropriate, developing in-country manufacturing capacity.

To complement policy development, WHO provides hands-on technical assistance, facilitating regional training programs and workshops to strengthen professional competencies across blood services, regulatory agencies, and manufacturing facilities.

PDMPs are included in the WHO Model List of Essential Medicines, and their production is integrated into broader blood systems initiatives (43). WHO also works with national regulatory authorities (NRAs) and national control laboratories (NCLs) to build technical capacity in quality control, lot release, viral validation, and GMP specific to PDMPs.

Through these collaborative efforts, WHO promotes harmonized regulatory standards, improved product safety, and sustainable PDMP supply chains—ultimately helping countries reduce dependence on imports and expand access to life-saving plasma-based therapies.

PPTA industry standards

IQPP

PPTA’s IQPP (44) are a set of voluntary industry standards first developed in 1991 to provide additional layers of safety and quality during the plasma collection and handling processes. Administered by PPTA and audited by third-party auditors, IQPP has grown to a set of 9 standards covering donor health and suitability, and center operations. IQPP Standards are routinely evaluated for relevance and translate FDA and EU regulations into practice, adding industry specificity, ensuring consistency, and demonstrating proactive industry alignment.

The “Donor Safety Standard” (45) encompasses several key provisions. Cross-donation management requirements prevent donors from donating more frequently than legally allowed, done in the U.S. through the Cross Donation Check System (CDCS). Donor education requirements go further than regulatory minimums through comprehension checks and wellness education. Finally, donor fluid administration requirements ensure rehydration following plasmapheresis and reinforce the industry’s commitment to donor health and safety. Donor safety is reiterated through the “Donor Adverse Events Recording Standard” (46), which requires that centers have processes in place to monitor, manage and document donor adverse events (DAEs). This standard requires that plasma centers classify and record DAEs in accordance with defined parameters.

Other standards focus on the health of the donor in respect to the safety of the finished product. The “Qualified Donor Standard” (47) requires two negative viral marker test results within six months before plasma can be used for fractionation, adding an extra layer of safety and strengthening donor selection credibility. The “Viral Marker Standard” (48) sets viral marker alert limits for HIV, HBV, and HCV, which if exceeded by centers, initiates a CAPA process which if not resolved, can lead to loss of certification. It also introduces consistent epidemiological reporting across those viruses.

This is complemented by the “Use of the National Donor Deferral Registry (NDDR) Standard” (49), which requires that donors with reactive tests to those relevant transfusion-transmitted infections (RTTIs) be entered into the NDDR in the U.S., permanently deferring them from donating, or a similar system in other jurisdictions. Finally, the “Community-based Donor Standard” (50) allows centers to define donor recruitment areas, and exclude transient and likely one-time donors while ensuring mobility of qualified donors between centers.

Other standards focus on center operations, including the “Personnel Education and Training Standard” (51), which defines minimum requirements across donor center roles, and the “Plasma Collection Facility Standard” (52) which ensures facility professionalism through requirements for appearance, donor flow, security, and sanitation.

Finally, the “Quality Assurance (QA) Standard” (53) requires documented independence of QA functions and comprehensive oversight, reflecting EU and FDA expectations. Altogether, the IQPP standards not only demonstrate a commitment to donor safety and plasma quality but also serve as vital advocacy tools and reputational safeguards for the industry.

QSEAL

The PPTA QSEAL Program (54) is a set of voluntary, industry-developed standards for manufacturing facilities, designed to exceed regulatory requirements, demonstrate commitment to product integrity and strengthen trust in the plasma supply chain. It relies on independent, third-party verification, requiring certified facilities to undergo regular audits by qualified external auditors who evaluate compliance, review operational data, and verify robust quality systems. Through this rigorous, transparent oversight, QSEAL assures regulators, patients, and other stakeholders that participating facilities consistently meet the highest standards of quality and safety.

The QSEAL program is comprised of specialized standards that target key quality drivers. For example, the “NAT Testing Standard” (55) requires the use of NAT for viral markers, supporting early detection and reduces the risk of transmitting viral infections through PDMPs. Other standards, such as the “Controls on Incoming Plasma” (56), “Recovered Plasma Specification” (57) and “Intermediates Purchased from an External Supplier” (58) further promote the consistency, quality and traceability of plasma and intermediate products being incorporated into final therapy. Notably, the “Inventory Hold Standard” (59) established as an added protection to allow for retrieval of single units of Source Plasma prior to preparation of the manufacturing pool. The standard plasma to be held for at least 45 days before being released for further manufacturing, which was subsequently adopted by the FDA (60).

In summary, the PPTA QSEAL Program is a key component of the plasma industry’s quality framework. Through rigorous standards, independent verification, continuous improvement, and collaborative engagement, it elevates quality and safety across plasma collection operations and reinforces confidence in the production of lifesaving PDMPs.

Regulatory evolution: concepts, priorities and regulatory direction that impact collection of plasma and manufacture of PDMPs

The regulatory landscape governing plasma collection and the manufacture of PDMPs is undergoing a period of significant transformation. As scientific understanding, manufacturing technologies, and global health priorities evolve, too must the frameworks that ensure the safety, quality, and sustainability of these life-saving therapies. Concepts and developments, such as harmonization, risk-based oversight, reliance and convergence, donor and patient centricity, AI, emergency preparedness and sustainability are reshaping traditional regulatory paradigms. These shifts require a new era of regulatory thinking—one that seeks to balance innovation with vigilance, harmonization with flexibility, and global collaboration with regional needs.

Risk-based regulatory decision making

Regulatory oversight of plasma collection and PDMPs has shifted from rigid, prescriptive rules toward flexible, science-driven, risk-based approaches. Early systems aimed for “zero risk” through strict donor selection criteria, testing requirements, and manufacturing controls. As screening technologies, pathogen inactivation, and scientific understanding improved, regulators adopted proportionate models that target interventions to areas of highest risk. Modern risk-based decision making now balances empirical evidence with evolving social norms, prioritizing transparency, adaptability, and ethical considerations. Regulatory bodies and industry continue to refine these approaches to maintain safety while enabling operational efficiency. Today, risk-based principles underpin global standards such as ICH Q9 (61), WHO guidance (62,63) EMA guidelines, the EU SoHO Regulation, U.S. FDA guidance, and China’s informatization reforms.

The 1990s introduction of nucleic acid testing (NAT) and validated inactivation methods marked a turning point, allowing regulators and manufacturers to focus on residual risk rather than absolute hazard elimination. By the early 2000s, authorities such as the FDA and EMA incorporated formal risk-based frameworks, emphasizing critical control points in plasma collection and manufacturing. From the 2010s onward, guidance increasingly promoted systematic risk assessment, probabilistic modeling, quality management, and continuous improvement to prioritize interventions effectively.

There are several case studies showing the evolution of risk-based decision making and its incorporation into regulation. In the decades following the HIV and hepatitis crises of the ‘80’s, epidemiological data, advances in NAT, and behavioral research prompted gradual policy evolution: deferrals were shortened to 12 months in 2015, then to three months in 2020, culminating in the FDA’s 2023 adoption of an individualized risk assessment (IRA) approach in its “Recommendations for Evaluating Donor Eligibility Using Individual Risk-Based Questions”, which advises blood establishments to assess donor eligibility based on individual risk factors rather than broad categorical deferrals, aiming to reduce HIV transmission risk while enhancing inclusivity in the donor population.

The emergence of variant Creutzfeldt-Jakob Disease (vCJD) in the UK led to bans on the use of UK plasma for PDMP manufacturing. Over time, surveillance data, prion research, and manufacturing risk assessments demonstrated low infectivity risk, leading to the gradual reintroduction of UK plasma for immunoglobulin and albumin manufacture between 2021 and 2023. This evolution illustrates how risk-based decision-making and evidence accumulation can guide regulatory relaxation (64-66).

Turning from epidemiology to donor safety, plasma volume limits for donors were historically based on rigid weight categories, with maximum volumes capped at 880 mL (including anticoagulant). Beginning in 2020, the FDA approved an individualized nomogram based on donor height, weight, and hematocrit, allowing more precise plasma collection up to 1,000 mL (67,68). This approach represents a risk-based shift towards personalized donor safety and efficiency.

Artificial intelligence (AI)

AI is starting to change how PDMPs are developed and manufactured. Global plasma companies are increasingly deploying and exploring opportunities to use AI in the PDMP ecosystem to include source plasma collection, research, development, and manufacturing (69). In some cases, companies are using AI to analyze donations and other indicators to predict donors’ behavior with the aim of helping to stabilize center throughput and safeguard the continuity of the source plasma supply needed to make lifesaving PDMPs (70). Additionally, companies have started using AI in their donor-facing apps to tailor reminders and visit schedules with the goal of improving the donor’s experience and retention.

In other areas of the PDMP manufacturing and R&D ecosystem, companies are using AI in their production processes, improving operational efficiency and patient access (71,72). Finally, some companies are exploring the use of AI to mine real-world data for new indications (73,74). To date, widespread use of these tools in PDMP manufacturing remains limited as a result of regulatory uncertainty, data reliability, and cybersecurity challenges (75,76).

The U.S. lacks a federal statute that specifically regulates the use of AI in the manufacture of therapeutic products or plasma collection (77). By 2025, the FDA had released several guidance documents on the use of AI in regulatory decision-making (78), all rely on the FD&C Act and 21 CFR Parts 210–211, for compliance (79).

Federal policymakers have adopted a cautious approach to AI regulation to retain U.S. competitiveness (80). Executive Order 14179 and the 2025 AI Action Plan both advocate for limited federal oversight (81). In the absence of federal standards, states have passed (82) creating a patchwork of compliance obligations for manufacturer. For example, Utah established an Office of Artificial Intelligence Policy in 2024 to assess risks associated with AI high-risk systems in 2026 (83). These different approaches reflect attempts to balance innovation with public safety (84).

While, the U.S. has taken a patchwork approach to the AI regulation, the EU established a comprehensive legal framework with the passage of the AI Act in 2024 (85). The AI Act applies to both developers and users holding both parties to the same standard across Member States. The Act divides AI applications into unacceptable, high, limited, and minimal risk categories (86). For example, AI used in clinical trial management would be considered high risk and be subjected to strict criteria for quality management, data governance, and human involvement in decision-making points (87). Whereas AI used in minimal risk environments faces no mandatory rules and is simply encouraged to follow voluntary guidelines. By categorizing AI in this way, the EU aims to protect public safety and foster trust without stifling innovation (88).

To make the AI Act practical, EMA has published guidelines tailored to the medicinal product sector. The reflection paper provides additional considerations for developers to support a human centered, risk-based approach that keeps patient safety, autonomy, and individual rights at the forefront by ensuring developers employ strong cybersecurity protocols, regularly validate models, and maintain ongoing oversight (89). The combined efforts ensure the creation of a consistent regulatory environment across the Member States (90).

While AI offers significant opportunities to advance PDMP manufacturing, the above strategies illustrate two distinct philosophies. The U.S.’s decentralized approach may encourage experimentation, but risks fragmented implementation. The EU’s harmonized framework offers clarity and consistency while trying to balance innovation. Ultimately, the way each of these regions respond to their unique set of challenges and opportunities will further shape the use of AI in PDMP manufacturing (91).

Emergency preparedness

As a critical component of regulatory oversight, the U.S. and EU and other stakeholders have developed comprehensive emergency preparedness frameworks to ensure continuity of supply, rapid response to public health threats, and protection of public health during crises. Recent health (92) and geopolitical outbreaks have emphasized the importance of a robust supply chain (93).

In the U.S., the Pandemic and All Hazards Preparedness Reauthorization Act allows the use of unapproved therapies to treat serious diseases or conditions through the issuances of Emergency Use Authorization (EUA). This facilitates rapid availability of critical medical countermeasures without the previous need for the Secretary to make a formal declaration of a public health emergency (94). In some cases, the FDA may waive or modify current cGMP requirements. To ensure continuity of operations, the FDA recommends that manufacturers develop written emergency plans in advance of crises, such as pandemics or natural disasters (95).

The FDA also monitors supply chain vulnerabilities (96). FDA’s role, collaborating with industry, other U.S. government agencies, and foreign regulators to identify risks, facilitate access to alternative sources, and expedite lot release of critical products. Advanced manufacturing technologies, such as continuous manufacturing are employed to enhance resilience and capacity for medical countermeasures.

In the EU, the EMA has strengthened its crisis-preparedness role under Regulation 2022/123 (97), providing oversight of critical medicine shortages, scientific advice on emerging therapies, and fast-tracked evaluation through its Emergency Task Force (ETF). EMA also monitors biological, chemical, and radiological threat agents as part of the EU-wide preparedness architecture.

In 2024, EMA issued guidance on Shortage Mitigation Plans (SMPs) for marketing-authorization holders (MAHs), requiring them to identify potential or actual medicine shortages and propose mitigation strategies. During the coronavirus disease 2019 (COVID-19) pandemic, EMA, together with the European Commission and national authorities, issued Q&A guidance to allow regulatory flexibility in manufacturing, importation, labeling, packaging, and quality changes while maintaining safety and efficacy. EMA also applies exceptional transparency measures during emergencies, including accelerated publication of regulatory decisions, scientific advice, and safety monitoring.

The 22nd edition of the EDQM “Guide to the Preparation, Use and Quality Assurance of Blood Components” (98) introduces dedicated guidance on Blood Supply Contingency and Emergency Planning (BSCEP). This framework provides harmonized technical and organizational standards for blood establishments, hospital blood banks, and national blood systems to ensure continuity of supply during emergencies.

Finally, industry efforts, such as the PPTA Global Pathogen Safety Working Group, strengthen industry preparedness for emerging infectious diseases, working collaboratively with regulators and conducting continuous monitoring and research on emerging pathogens, evaluates pathogen inactivation and reduction (PI/PR) technologies, and provides scientific guidance to regulators, patient organizations, academia, and industry.

Data integrity and privacy

Data integrity is a fundamental element of pharmaceutical quality, encompassing the completeness, consistency, and accuracy of data across its lifecycle. Regulatory authorities in the U.S. and Europe, as well as PIC/S guidance, increasingly emphasize data integrity as a core component of GMP, reflecting its critical role in ensuring the safety, efficacy, and quality of medicines.

In the U.S., the FDA provides detailed guidance on data integrity, notably through “Data Integrity and Compliance With CGMP: Questions & Answers”, stressing the application of risk-based strategies, and ALCOA principles. Additional FDA guidance addresses data integrity in bioavailability and bioequivalence studies, highlighting its relevance in clinical and bioanalytical contexts.

In Europe, the EMA emphasizes data integrity as essential to public health. Its GMP/GDP Q&A guidance covers system design, lifecycle management, risk assessment, and controls for both paper-based and computerized systems while additional guidance addresses outsourcing, requiring that vendors adhere to the same integrity standards. In addition to strong EU data privacy regulation (99,100) the EMA Data Quality Framework standardizes assessment of data reliability, including real-world data, reinforcing the agency’s commitment to trustworthy information for regulatory decisions.

Across these frameworks, ALCOA principles, senior management accountability, and a robust quality culture are central. Together, these regulations underline that data integrity is essential for pharmaceutical quality, compliance, and patient safety.

Sustainability

Sustainability, from reducing energy use to packaging waste and reducing the use of harmful chemicals—are likely to inform future regulations, such as with regulation of plasticizers (101,102). Companies are proactively implementing sustainability measures including water usage reduction, improvement in solid waste disposal, reduction of greenhouse gas emissions in transportation, and other improvements in anticipation of likely changes to regulation of environmental, health, and safety requirements and regulations.

Conclusions

The global system governing plasma collection and the manufacture of PDMPs has evolved into one of the most comprehensive and safety-focused regulatory landscapes in the pharmaceutical sector. Driven by scientific progress, lessons from past public-health crises, and decades of coordinated work by regulators, industry, and international organizations, today’s frameworks employ layered viral-safety strategies, risk-based oversight, and continually improving quality systems. While countries differ in structure and maturity, convergence toward shared principles—donor protection, validated pathogen-reduction, GMP compliance, and robust surveillance—is unmistakable.

As demand for PDMPs grows worldwide, regulatory modernization remains essential. Emerging themes such as harmonization, reliance, risk-based approaches, digitalization, AI, and sustainability are reshaping expectations for both regulators and manufacturers. At the same time, ensuring supply resilience, strengthening global preparedness, and maintaining transparency will be critical to safeguarding the plasma ecosystem.

Ultimately, the continued alignment of national regulations, international guidance, and voluntary PPTA standards will be central to advancing safety, supporting innovation, and ensuring equitable access to life-saving plasma-derived therapies for patients around the world.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editor (Jan Hartmann) for the series “Source Plasma” published in Annals of Blood. The article has undergone external peer review.

Peer Review File: Available at https://aob.amegroups.com/article/view/10.21037/aob-2025-1-52/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://aob.amegroups.com/article/view/10.21037/aob-2025-1-52/coif). The series “Source Plasma” was commissioned by the editorial office without any funding or sponsorship. J.R.K., C.P., E.K., J.P. and J.F. are employees of the Plasma Protein Therapeutics Association (PPTA). The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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