Biopharmaceutical Manufacturing: The Challenge of Global Regulatory Compliance - Pharmaceutical Technology

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Biopharmaceutical Manufacturing: The Challenge of Global Regulatory Compliance
This article provides an overview of regulatory issues facing companies that seek to market their biopharmaceutical agents globally, including a trend toward harmonization of requirements as well as the differences in rules concerning applications, GMP standards, and communication with reviewers.

Pharmaceutical Technology

Ensuring global GMP compliance

To ensure compliance with regulatory authorities, pharmaceutical manufacturers must meet CGMP standards for quality and sterility, but the nature of these standards can be open to differing interpretations depending on the regulatory authority involved. Companies will find that regulators don't always agree on what constitutes an acceptable process validation or even how to define aseptic conditions. EMEA, for example, requires clear separation parameters for aseptic and nonaseptic materials that are much more restrictive than those of the other two regulatory bodies.

As a consequence, a CMO or manufacturer looking to maintain global regulatory compliance for its manufacturing operations will incorporate the most stringent requirement of all the regulators into its manufacturing process. Therefore, designing a facility that meets FDA, EMEA, and MHLW requirements is a complicated, expensive process, but it is absolutely necessary in a global economy.

To this end, companies should be aware of differences among regulators in terms of GMP standards for validation of procedures and equipment, facility inspections, and evaluation of raw materials. Knowledge of current GMP trends within the industry and regulatory agencies is also a must.

Be prepared to complete validation before European clinical trials. To obtain regulatory clearance, a pharmaceutical company must validate every step in manufacturing, including formulation, fill, and finishing, to verify that every process and machine consistently does what it is supposed to do. For companies developing new biopharmaceutical agents, validation is a tedious process because it can be difficult to determine a robust, repetitive, and reliable process for manufacturing biologically based APIs.

FDA and EMEA differ concerning the point in a product's development at which the validation of processes and facilities must be finalized. The EU requires biopharmaceutical manufacturers to complete process development and have processes and facilities fully validated for GMP before agents are used in early-stage clinical trials (7). This rule means that European requirements for investigational products are closely aligned with those of commercial products.

Although US rules concerning GMPs are generally in accord with those of Europe, FDA gives academic researchers, manufacturers, and CMOs some latitude when producing small batches of experimental drugs by assuming that phase-appropriate CGMP compliance will be used and controls will develop with the process and product through clinical development. FDA rules for investigational new drug applications, therefore, are intended to encourage early-stage biopharmaceutical research (8). As a result, regulatory guidelines in the US protect the safety of clinical-trial subjects but also enable biopharmaceutical producers to test more products in early-stage clinical trials before investing in processes and facilities that are fully validated and compliant.


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