Londa Ritchey

February 6, 2024

12 Min Read

Amid heightened concern over cross-contamination during biopharmaceutical manufacturing, regulators are turning their focus increasingly to risk management and mitigation. Health authorities around the world are taking steps to ensure that biomanufacturers follow the principles of quality risk management (QRM) to address cross-contamination risk and ensure patient safety. A number of significant programs, guidelines, and regulatory revisions have emerged in the past year that indicate a trend toward adoption of QRM and risk-based approaches in the manufacturing of medicinal products. One priority for regulators is to address the challenge of product shortages that result from process and product-quality problems, such as substandard practices at manufacturing plants and quality defects in finished products (1). In the year ahead, the focus on QRM will intensify. Regulators are likely to take further steps — through guidelines, inspections, warning letters, and so on — to safeguard patients.

EU Annex 1 and ICH Q9

Ensuring patient safety with regard to potential contamination is a primary concern for health authorities and was the key driver for the Annex 1 revision in the EudraLex good manufacturing practice (GMP) guidelines (2). In force as of August 2023 in the European Union, the Annex 1 revision applies QRM principles to contamination control. Although the QRM concept is not new, the revision introduces details that were not included in previous Annex 1 updates or the 2004 US Food and Drug Administration (FDA) guidance on sterile drug products produced through aseptic processing (3). With the implementation date now passed, health authorities in Europe are expected to carry out inspections for compliance with Annex 1. Biomanufacturers need to be prepared to demonstrate compliance.

No biopharmaceutical manufacturer should think of its contamination control strategy (CCS) as a fixed document; a CCS should be a living program. To determine whether their CCS programs are working or need updating, companies must perform continuous assessments of data from ongoing manufacturing processes. Annex 1 emphasizes that no single approach applies for all programs; strategies should be based on identifying risk points and monitoring processes to ensure patient safety.

Although the FDA will not inspect specifically for elements of Europe’s Annex 1, the US GMPs (21 CFR 211.113) require drug manufacturers to protect their products from microbiological contamination. A tripartite guideline revision adopted by the FDA in May 2023 includes as an example the application of QRM to facilities, equipment, and utilities, noting elements that are similar to those included in Annex 1 (4). Indicating the US expectations for taking a risk-management approach to contamination control, at least two recent FDA warning letters cite violation of 21 CFR 211.113 and require the responses to include “a comprehensive risk assessment of all contamination hazards with respect to your aseptic processes” (5, 6).

Stakeholders around the world are addressing the need to reduce drug shortages, which often are caused by poor product quality and/or contamination at manufacturing facilities (7). By association, manufacturers’ compliance with the Annex 1 QRM objectives should result in fewer drug shortages in Europe. The 2023 QRM guideline from the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH Q9) gives biomanufacturers deeper insight into regulatory expectations (8). Specifically, the FDA has noted that ICH Q9 provides guidance on “quality risk management principles and tools that can be applied to different aspects of pharmaceutical quality” (4).

The revised guidance offers examples illustrating how to use QRM to support decision-making, and it provides clarity on the rigor and formality of risk assessments depending on the level of uncertainty, importance, or complexity of a given issue. Whenever a more formal risk assessment is needed, manufacturers should consider assembling a cross-functional team for the risk-management activity and using a facilitator with expert knowledge of the QRM process.

ICH Q9 also emphasizes stringency based on the criticality of a given issue. That can be difficult to measure and implement, so it’s important for teams to define those criteria ahead of time. Recognized methods noted in the guidance can help companies assess and manage risk: e.g., basic decision trees and flow charts, as well as more complex failure mode effects analysis (FMEA) and failure mode, effects, and criticality analysis (FMECA) tools. Regardless of the means, it’s important for QRM teams to define which issues fall under which level of criticality — something that many companies tend to miss.

Although it isn’t stated in the guidance, a best practice is to have someone assigned to monitor and maintain the full list of risk assessments ongoing across each facility. Ideally that person should not be involved in day-to-day operations, but should have deep enough knowledge about them. Some large companies are introducing the role of contamination control manager/director, which includes oversight of complete programs in support of the risk-based approach to contamination control for production of sterile products. Doing so may not be viable financially for smaller companies, which can build specific contamination-control monitoring responsibilities into established roles relative to the type of processing involved. Including QRM in job descriptions can help to ensure ownership of the concept.

Quality Management Maturity

The FDA’s Center for Drug Evaluation and Research (CDER) has suggested a quality management maturity (QMM) program intended to encourage pharmaceutical companies to go beyond current good manufacturing practice (CGMP) requirements with their quality management practices (1). A key objective is to solve quality problems that have led to supply issues. According to a report from the multiagency US Federal Drug Shortage Task Force, a key contributor to such quality-related supply issues has been a lack of incentive for companies to implement mature quality management systems that help to detect problems early on (9).

In response to the report’s findings, CDER is proposing a program for companies to be rated on their QMM voluntarily. The pilot program is meant to measure quality culture, reliability, and processes for continuous improvement, supply-chain resiliency, and risk management at participating companies. Such assessment includes oversight of vendors/suppliers and ensuring that each drug manufacturer has a strong quality-management approach so that supplier shortages won’t initiate a domino effect.

That program raises some questions and concerns, however, related to incentivizing companies to be assessed and improve. Typically, facilities that experience contamination-control problems are those plants making low-cost generics rather than branded products. Driving them out of business through stringent, costly practices is more likely to increase product supply issues for some widely used drugs.

Rather than focus on cost-intensive initiatives, such facilities should emphasize a “quality culture” to move them toward strong QMM. Such an approach would not necessarily require more people but would ensure that everyone at a given facility puts quality and patient safety at the center of decision-making. The CDER initiative does emphasize the important role that management can play in setting a tone by communicating and modeling a quality culture within an organization.

In the year ahead, the FDA is likely to consider how to move its QMM program from theory into practice. Representatives already have reached out to industry and are seeking ways to understand its challenges and improve on related incentives.

Outsourcing and Advanced Therapies

With the growth of the cell and gene therapy (CGT) sector, both in terms of approvals and the number of products in the pipeline, comes increased demand for manufacturing capabilities in this space (10). That has created a need for contract development and manufacturing organizations (CDMOs) to take on advanced therapies. Many CDMOs are expanding existent facilities or building new ones specifically to take on CGT programs. According to Frost & Sullivan (F&S), interest in chimeric antigen receptor (CAR) T-cell therapies is “driving demand for the evolution of manufacturing technologies, models, and capacity expansion investment by CDMOs” (11). F&S predicts sevenfold growth for the CGT CDMO market — reaching US$10.11 billion in valuation by 2026 from $1.52 billion in 2020.

The challenge for such CDMOs, however, will be a lack of available expertise in CGTs. Most skilled and knowledgeable operators are accustomed to working with small-molecule drugs and protein-based biologics. If a problem occurs in a CGT process, manufacturers could lose a batch in minutes. It’s important that operators can recognize abnormalities so that they can respond quickly.

CDMO management teams must understand that operating costs will be greater for advanced therapies than for classical drugs and even protein biopharmaceuticals — and companies that wish to succeed will need to hire staff members who have specific technical skills. CGT makers will need experts in cell culture and harvest as well as micro-, molecular, and cell biology to support CGT development processes and be on hand to offer advice when problems arise.

In keeping with regulatory best practices, CDMOs must have stringent and robust processes to evaluate whether they have the expertise and capacity to support CGTs. Crucially, manufacturers must determine the impact that new products will have on other current programs and the associated risk to CGT products themselves — for example, related to cross-contamination. From industry experience, I haven’t seen many CMOs consider the contamination potential that a new product introduction will bring to existing facilities.

All responsibility for drug products ultimately remains with their sponsors. The FDA has made clear that it is up to the sponsor of an outsourced program to ensure that current GMPs are followed in the manufacturing facility where it resides (12). Meanwhile, FDA also has made clear that contractors must abide by GMP requirements (13).

Regulatory authorities are gaining confidence with CGT submissions and offering more specific guidance as time goes on. In July 2023, for example, the FDA issued a new guidance on manufacturing changes and comparability for CGTs (14). That guidance includes three main types of advice for makers of such products: management of manufacturing; reporting process changes; and design and assessment of comparability studies.

Compounding Pharmacies

The FDA also has been scrutinizing GMP compliance at human-drug compounding pharmacies. The agency lists such facilities as outsourcing facilities under section 503B of the Federal Food, Drug, and Cosmetic Act. Since early 2022, at least 15 warning letters have been issued against such companies (15). Their leaders tend to be pharmacists rather than experts in aseptic manufacturing. Thus, although they do understand pharmacy rules, they don’t necessarily understand GMP expectations embedded in the 503B requirements, which are relevant to formulating quantities of medicines for distribution.

To mitigate risk and meet health-authority requirements, compounding pharmacies will need to improve their focus on contamination control — which could mean adapting their organizational structures to bring in some industry support. Specifically, such companies need to conduct contamination-control risk assessments of their own. A best practice would be to review Annex 1 and follow its guidelines to shore up practices and prevent drug recalls. Although expertise helps in interpreting the legislation, Annex 1 provides great detail on which elements to prioritize for contamination control.

Staying Current

In the year ahead, all biopharmaceutical organizations should be focused on managing their risk assessments as living documents and working toward proactive mitigation of problems rather than using those assessments only to justify current practices. Companies should instill a continuous quality culture led by management, implement clear risk-management plans, and ensure that all personnel understand their responsibilities for patient safety.


1 CDER’s Quality Management Maturity (QMM) Program: Practice Areas and Prototype Assessment Protocol Development. US Food and Drug Administration: Silver Spring, MD, August 2023; https://www.fda.gov/media/171705/download?attachment.

2 Annex 1: Manufacture of Sterile Products. European Commission: Brussels, Belgium, 22 August 2022; https://health.ec.europa.eu/system/files/2022-08/20220825_gmp-an1_en_0.pdf.

3 CBER/CDER/ORA. Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing Practice. US Food and Drug Administration: Rockville, MD, 2004; https://www.fda.gov/media/71026/download.

4 ICH Q9(R1). Quality Risk Management. US Fed Reg. 88, May 2023: 28565–28566; https://www.fda.gov/regulatory-information/search-fda-guidance-documents/q9r1-quality-risk-management.

5 Godwin F. MARCS-CMS 660904 — Warning Letter: Cipla Limited. US FDA Center for Drug Evaluation and Research: Rockville, MD, 17 November 2023;


6 Godwin F. MARCS-CMS 662868 — Warning Letter: Intas Pharmaceuticals Limited. US FDA Center for Drug Evaluation and Research: Rockville, MD, 21 November 2023; https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/intas-pharmaceuticals-limited-662868-11212023

7 Shukar S, et al. Drug Shortage: Causes, Impact, and Mitigation Strategies. Front. Pharmacol. 12, 2021; https://doi.org/10.3389/fphar.2021.693426.

8 ICH Q9(R1). Quality Risk Management. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use: Geneva, Switzerland, January 2023. https://database.ich.org/sites/default/files/ICH_Q9%28R1%29_Guideline_Step4_2022_1219.pdf

9 Drug Shortages Task Force. Report — Drug Shortages: Root Causes and Potential Solutions. US Food and Drug Administration: Rockville, MD, 2020; https://www.fda.gov/drugs/drug-shortages/report-drug-shortages-root-causes-and-potential-solutions.

10 Cohen J. Cell and Gene Therapies Face Persistent Manufacturing Capacity Constraints. Forbes 6 July 2023; https://www.forbes.com/sites/joshuacohen/2023/07/06/cell-and-gene-therapies-face-persistent-manufacturing-capacity-constraints/?sh=44304115799e.

11 Fernandez M. Technological Advancements in Manufacturing Boost the Cell and Gene Therapy Market. Frost & Sullivan: Santa Clara, CA, November 2020; https://www.frost.com/news/press-releases/technological-advancements-in-manufacturing-boost-the-cell-and-gene-therapy-market-says-frost-sullivan.

12 Furma J. MARCS-CMS 665456 — Warning Letter: Dr. Berne’s Whole Health Products. US FDA Center for Drug Evaluation and Research: Rockville, MD, 22 November 2023; https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/dr-bernes-whole-health-products-665456-11222023.

13 Harlan L. MARCS-CMS 654226 — Warning Letter: Denison Pharmaceuticals, LLC. US FDA Division of Pharmaceutical Quality Operations: Rockville, MD, 26 July 2023; https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/denison-pharmaceuticals-llc-654226-07262023.

14 Lanucara F. New FDA Guidance Addresses Challenges with Cell and Gene Manufacturing Comparability and Complexity. DIA Global Forum November 2023; https://globalforum.diaglobal.org/issue/november-2023/new-fda-guidance-addresses-challenges-with-cell-and-gene-manufacturing-comparability-and-complexity.

15 Warning Letters. US Food and Drug Administration: Rockville, MD, 5 January 2024; https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/compliance-actions-and-activities/warning-letters. 

Londa Ritchey is quality director with the quality management and compliance group at Cencora PharmaLex in Philadelphia, PA;

[email protected]. She has spent more than 30 years
in the biopharmaceutical industry, focusing on quality assurance, including, quality risk management, aseptic quality operations, quality systems implementation, contamination risk management, and supplier quality management.

The contents of this article are solely the opinion of the author and do not represent the opinions of PharmaLex GmbH or its parent, Cencora. PharmaLex and Cencora strongly encourage readers to review all available information related to the topics mentioned herein and to rely on their own experience and expertise in making decisions related thereto.

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