Combination products are considered combinations of a device, drug, biologic, or human cells, tissues, or cellular or tissue-based products (HCT/P) and are regulated by FDA under 

) 21 Part 4, Regulation of Combination Products (1). The guidance states that drugs, biologics, HCT/Ps, and devices—as constituent parts of a combination product—are required to conform to the current good manufacturing practice (CGMP) regulations pertaining to each constituent part. The guidance also identifies the specific 

Due to the complexity inherent in combination products, it is probable that drug sponsors will receive several deficiencies and compliance observations (known as 483 observations in the United States). That is why awareness of how regulatory authorities view method validation and what the common observations are will help sponsors minimize their regulatory risks.

This is part two in a series. Read part one: 

A Method Validation Framework for Combination Products

Adam Lambert, PhD, is the VP, product and process development, for Pharmatech Associates, a USP company.

When referring to this article, please cite it as A. Lambert, "Common FDA 483 Observations for Combination Products," 

Articles

Quality

Any improper validation of methods is likely to result in regulatory agency deficiencies that range in degree of severity.

Common FDA 483 Observations for Combination Products

Manufacturers, regulators, and other industry organizations are aiming to advance biopharmaceutical continuous manufacturing and to connect upstream and downstream into fully continuous processes. The United States Pharmacopeial Convention (USP), a nonprofit organization known for developing standards for quality, is actively involved in facilitating implementation of continuous manufacturing in the bio/pharmaceutical industry. 

spoke with John Kokai-Kun, director, External Scientific Collaboration at USP about these efforts.

Read “Facilitating Biopharma Continuous Manufacturing” in 

Pharmaceutical Technology’s Quality and Regulatory Sourcebook Ebook.

When referring to this article, please cite it as J. Markarian, “Facilitating Biopharma Continuous Manufacturing,” 

Pharmaceutical Technology’s Quality and Regulatory Sourcebook

Quality/Regulations

 USP is advancing understanding and developing guidance and standards to assist industry in implementing continuous manufacturing.

Facilitating Biopharma Continuous Manufacturing

Contamination is a serious issue in cleanroom operations, and controlling contamination generated by human operators and their clothing is a major concern. People disperse large numbers of particles that vary in number from person to person and over time. Thus, cleanroom garments must be designed to protect the environment and the process by containing the particles generated by the person while not becoming a source of contamination. An important decision that faces the manager of any cleanroom is the selection of a cleanroom garment or garment system, according to Anne Marie Dixon-Heathman, principal, Cleanroom Management Associates. Following up on a presentation given by Dixon-Heathman at INTERPHEX 2021 on in-use testing of garments, 

 spoke to Dixon-Heathman for further insight.

Pharmaceutical Technology’s March 2022 Quality and Regulatory Sourcebook eBook.

Feliza Mirasol is the science editor for 

, March 2022
March 2022
Pages: 24–26, 39

When referring to this article, please cite it as F. Mirasol, “In-Use Testing of Cleanroom Garments," 

Testing cleanroom garments while in use and during daily cleanroom operations is vital for contamination control.

In-Use Testing of Cleanroom Garments

Throughout a single project, contract development and manufacturing organizations (CDMOs) generate an abundance of essential data that require an array of computerized systems to manage. These systems provide many benefits, including reducing human error, making processes more efficient, and enhancing security. More importantly, these systems can be used to help implement technical controls for data integrity (DI).

The importance of ensuring DI, particularly when data are used in decision-making for the regulated good practice (GxP) processes, is highlighted by the consistent updating of regulations first mandated by FDA in the early 1960s. Since that time, FDA and other regulatory agencies have continued to publish guidance emphasizing the need to maintain DI controls.

Before any new technology implementation, CDMOs need to fully understand the system as well as establish its intended use and perform risk mitigation to ensure robust DI controls. However, understanding and implementing the requirements of regulations surrounding computerized systems continues to be a challenge to many CDMOs today. Technology is not the predominant challenge to achieving regulatory compliance, but the lack of critical thinking skills when designing a quality system.

Pharmaceutical Technology's March 2022 Quality and Regulatory Sourcebook eBook.

Calvin Kim is the senior director, head of IT quality systems and validation, for Samsung Biologics.

When referring to this article, please cite it as C. Kim, "How a Lack of Critical Thinking is Hindering Regulatory Compliance," 

Outsourcing

Why critical thinking must be applied before technology to ensure regulatory compliance.

How a Lack of Critical Thinking is Hindering Regulatory Compliance

The words ‘method’ and ‘validation’ do not appear together in medical device regulations. Yet, proper validation of methods is expected by regulatory agencies for combination product submissions, even without specific regulatory guidelines indicating precisely how medical device methods are to be validated. Regulatory authorities commonly investigate methods and validation during the review of marketing applications, and FDA regularly issues 483 observations for improper validation of methods during inspections.

Advancements in medical device and ancillary technologies are leading to significant improvements in the new combination therapies available to patients. Coating technology advancements allow for devices—such as balloons and stents—that deliver various therapeutics enhancing the performance, safety, and efficacy of the treatment. These new developments lead to multifaceted design specifications and manufacturing processes, and they increase the complexity of the device tests and testing requirements.

When drugs and biologics are included as device components of a combination product, the criticality aspect of testing methods (upon which method validation is based) is heightened and becomes more complex.

This is part one in a series. Read part two: 

Adam Lambert, PhD, is the VP, product and process development, for Pharmatech Associates, a

When referring to this article, please cite it as A. Lambert, "A Method Validation Framework for Combination Products," 

The importance of getting buy-in from regulatory authorities early in the development process is critical in order to establish meaningful specifications. 

Computer system validation (CSV), also known as software validation, is required by regulatory agencies throughout the development timeline. Pharmaceutical Technology reached out to various experts associated with the FDA-Industry Computer Software Assurance (FISCA) team to discuss computer validation and add context to the ongoing discussion surrounding its use and importance in the greater regulatory landscape.

Grant Playter is the Assistant Editor for 

When referring to this article, please cite it as G. Playter, “Contextualizing Computer Validation," 

Experts weigh in on the current state of computer validation and its role in the greater regulatory landscape.

Contextualizing Computer Validation

Disruptions in the bio/pharmaceutical supply chain that impact capacity and capabilities result in longer lead times for drug products, according to Ari Ojinaka, production manager at Astrea Bioseparations. The past two years of the COVID-19 pandemic have highlighted the importance of a healthy supply chain. “Through the pandemic, we have witnessed a significant reduction in inter-country transportation of goods and services and in-country COVID-19 restriction impacting capacity and capabilities to manufacture,” says Ojinaka.

 spoke with Ojinaka as well as Steve Kirk, vice-president Global Procurement, Catalent; Vincent Colicchio, vice-president, Supply Chain and External Manufacturing, Dr. Reddy’s Laboratories; and Hamilton Lenox, senior vice president–Business Development & Operations at LGM Pharma about the impact of COVID-19 on the supply chain and what companies can do to ensure the quality of their products.

Susan Haigney is managing editor of Pharmaceutical Technology.

When referring to this article, please cite it as S. Haigney, “Supply Chain Considerations for Ensuring Quality," 

Disruptions in the bio/pharmaceutical supply chain can have serious impacts on the quality and availability of life-saving medicines.

Supply Chain Considerations for Ensuring Quality

The 2023 final deadline for full US FDA Drug Supply Chain Security Act (DSCSA) unit level interoperable traceability is looming. By now, most pharmaceutical manufacturers are properly barcoding products to meet current DSCSA-specified labeling requirements for unique product identification at the lot level. The barcodes contain digitized product data that will be used to improve patient safety by enabling major improvements in the track-and-traceability of drugs as they move through the supply chain.

Now it’s time for companies to begin exchanging the necessary data to ensure readiness for November 2023. Establishing interoperability between all stakeholders up and down the supply chain is a complex undertaking—it will take every bit of time that remains before the deadline.

Tracy Nasarenko is senior director Community Engagement, GS1 US.

When referring to this article, please cite it as T. Nasarenko, “DSCSA's Next Big Hurdle," 

Interoperability by 2023 depends on data standardization and systems compatibility between trading partners.

DSCSA’s Next Big Hurdle

In February 2020, travel ceased as the COVID-19 pandemic began to emerge. Since that time, we have come a long way with stay-at-home orders, social distancing, testing, tracing, and quarantine. Countries that implemented aggressive public health measures have had fewer cases and fewer deaths. The regulatory authorities also ceased to travel and were forced to utilize alternative mechanisms to assess industry compliance and review and approve new applications. This article discusses select industry experience with regulatory authorities utilizing alternative mechanisms for assessing compliance as part of their review and approval of existing marketing authorizations or new applications.

Until the time of the pandemic, the norm was that inspections would be performed as in-person on-site inspections. In the case of the European Union, Amended Directive 2001/83/EC, article 46(f) (1) explicitly states, “the holder of the manufacturing authorisation shall verify compliance by the manufacturer and distributors of active substances with good manufacturing practice and good distribution practices by conducting audits at the manufacturing and distribution sites…” [emphasis added by author].

James Stumpff, RPh, is principal consultant at Parexel International. Siegfried Schmitt, PhD, is vice president Technical at Parexel International.

When referring to this article, please cite it as J. Stumpff, S. Schmitt, “Remote Inspections - Lessons Learned," 

This article discusses select industry experience with regulatory authorities utilizing alternative mechanisms for assessing compliance as part of their review and approval of existing marketing authorizations or new applications.

Pharmaceutical Technology, Regulatory Sourcebook, March 2022