# Pharmaceutical cGMPs for the 21^st^ Century: A Risk-Based Approach *A science and risk-based approach to product quality regulation incorporating an integrated quality systems approach*

## Introduction

> FDA oversees the quality of drug products^\*^ using a two-pronged
> approach involving review of information submitted in applications as
> well as inspection of manufacturing facilities for conformance to
> requirements for current Good Manufacturing Practice (cGMP). These two
> programs have served the country well by helping to ensure the quality
> of drug products available in the US. Now, as we approach the 25^th^
> anniversary of the last major revision to the drug cGMP regulations,
> it is time to step back and evaluate the currency of these programs so
> that:

-   the most up-to-date concepts of risk management and quality systems
    approaches are incorporated while continuing to ensure product
    quality;

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-   the latest scientific advances in pharmaceutical manufacturing and
    technology are encouraged;

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-   the submission review program and the inspection program operate in
    a coordinated and synergistic manner;

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-   regulation and manufacturing standards are applied consistently;

-   management of the program encourages innovation in the
    pharmaceutical manufacturing sector; and

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-   FDA resources are used most effectively and efficiently to address
    the most significant health risks.

> To these ends, FDA is undertaking an initiative, "Pharmaceutical cGMPs
> for the 21^st^ Century: A Risk-Based Approach."

##### **Merging Science-Based Risk Management with an Integrated Quality Systems Approach**

> Over the last two decades, significant changes in the environment of
> pharmaceutical regulation have occurred and have resulted in
> incremental adjustments in FDA's regulatory approach to product
> quality. These changes include:

-   Increased number of pharmaceutical products and a greater role of
    medicines in health care

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-   Decreased frequency of FDA manufacturing inspections as a result of
    fewer resources available for pharmaceutical manufacturing
    inspections

-   FDA's accumulation of experience with, and lessons learned from,
    various approaches to the regulation of product quality

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-   Advances in the pharmaceutical sciences and manufacturing
    technologies

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-   Application of biotechnology in drug discovery and manufacturing

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-   Advances in the science and management of quality

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-   Globalization of the pharmaceutical industry

> The cumulative impact of these changes has been greater than the sum
> of the parts, and warrants a systematic reappraisal of FDA's
> approaches to product quality regulation. The following principles
> will guide implementation of the reappraisal:
>
> *Risk-based orientation* In order to provide the most effective public
> health protection, FDA must match its level of effort against the
> magnitude of risk. Resource limitations prevent uniformly intensive
> coverage of all pharmaceutical products and production. Although the
> agency has been implementing risk-based programs, a more systematic
> and rigorous risk-based approach will be developed.
>
> *Science-based policies and standards* Significant advances in the
> pharmaceutical sciences and in manufacturing technologies have
> occurred over the last two decades. While this knowledge has been
> incorporated in an ongoing manner into FDA's approach to product
> quality regulation, the fundamental nature of the changes dictates a
> thorough evaluation of the science base to ensure that product quality
> regulation not only incorporates up-to-date science, but also
> encourages further advances in technology. Recent science can also
> contribute significantly to assessment of risk.
>
> *Integrated quality systems orientation* Principles from various
> innovative approaches to manufacturing quality that have been
> developed in the past decade will be evaluated for applicability, and
> cGMP requirements and related pre-approval requirements will be
> evaluated according to applicable principles. In addition, interaction
> of the pre-market CMC review process and the application of cGMP
> requirements will be evaluated as an integrated system.

#### International cooperation The globalization of pharmaceutical manufacturing requires a global approach to regulation. FDA will collaborate with other regulatory authorities, via ICH and other venues.

####### Strong Public Health Protection The initiative will strengthen the public health protection achieved by FDA's regulation of drug product manufacturing and will not interfere with strong enforcement of the existing regulatory requirements, even as we are examining and revising our approach to these programs.

> To accomplish the reappraisal, FDA will carry out the following broad
> actions:

-   Perform an external review of the existing cGMP program and product
    review practices, including evaluation of potential inconsistencies
    in implementation

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-   Reassess and reevaluate our current scientific approach to both the
    product review process and the cGMP program to achieve a consistent,
    integrated systems approach to product quality regulation

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-   Enhance the scientific approach of cGMPs to emphasize risk-based
    control point analysis and to facilitate the latest innovations in
    pharmaceutical engineering

#### The following immediate steps are planned:

-   Holding scientific workshops with key stakeholders

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-   Enhancing expertise in pharmaceutical technologies (e.g.,
    pharmaceutical engineering and industrial pharmacy) by additional
    training and hiring, and by leveraging external expertise

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-   Encouraging innovation within the existing framework of statutory
    provisions and regulations by allowing certain changes in the
    manufacturing process without prior review/approval (e.g.,
    comparability protocols)

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-   Evaluating the optimal mechanisms to effectively and efficiently
    communicate deficiencies to industry, including content,
    consistency, disclosure, and education

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-   Shifting the agency lead on implementation of Part 11 to CDER, with
    continued involvement from the other Centers and ORA

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-   Including product specialists, as needed, as a part of inspection
    teams.

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-   Having Centers provide a scientific and technical review of all drug
    cGMPWarning letters

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-   Developing a technical dispute resolution process that integrates
    technical experts from the Centers and addresses perceived
    inconsistencies between Centers

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-   Emphasizing a risk-based approach in the work planning process

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-   Improving the operations of Team Biologics

#### Intermediate Steps

-   Use emerging science and data analysis to enhance compliance
    programs to target the highest risk areas

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-   Evaluating the feasibility of establishing dedicated cadres of
    pharmaceutical inspectors

> *Long term Steps*

-   Enhanced training of agency staff on new scientific approaches and
    innovative pharmaceutical manufacturing technology

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-   Develop and publish policies and procedures reflecting a
    science-based, risk management approach

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-   Educate industry on new regulatory approaches encouraging innovation

> Authority
>
> Current regulations (21 CFR Parts 210, 211, 600 and 610) appear to
> provide a degree of flexibility to allow the agency to shift the
> emphasis to a science-based, risk management approach. However, an
> evaluation of the comments from the May 1996 proposed drug cGMP
> amendments will continue and consideration will be given to revising
> these regulations and others (e.g., 21 CFR 11) in the future. In
> addition, efforts currently underway to revise existing regulations
> (e.g., 21 CFR 600-610) to allow for more flexibility will continue.