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

Adam Lambert

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.

Common FDA 483 Observations for Combination Products

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

A Method Validation Framework for Combination Products

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

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

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. 