Steering Pharmaceutical Manufacturing into the 21st Century

Jan. 26, 2006
CMC (Chemistry Manufacturing and Control) policy makers at FDA are dedicated to the goals spelled out in the 21st Century Initiative, and are stepping up their efforts to move pharmaceutical regulation and compliance closer to the Desired State.

By Jon E. Clark, M.S., Associate Director for Policy Development and GMPs, Office of Pharmaceutical Science, CDER, FDA


The final report from the 21st Century Initiative [1] has been posted for over a year now and Ajaz Hussain has left the Center for Drug Evaluation and Research (CDER) for the private sector. Dr. Hussain was an evangelist, whose efforts were instrumental in pushing the Agency toward a more scientific and risk based approach to the regulation of pharmaceutical manufacturing. We sincerely thank him for all that he has done.

Evangelistic leadership is essential to alert people of the need to change the direction of their efforts. Once they’ve reached agreement on a new direction for those efforts, their work, of necessity, becomes more detailed and less apparent to the outside world.

We at CDER remain steadfastly committed to achieving the goals that Dr. Hussain articulated so well, and to improving the policies and practices that govern the way that Chemistry Manufacturing and Control (CMC) information is reviewed. In fact, we are intensifying our commitment and our efforts in this area, to ensure that the CMC review process incorporates the concepts of the 21st Century Initiative.

Separating the wheat from the chaff

Right now, we at CDER face the difficult task of identifying recommendations that are truly important and useful, and discontinuing those recommendations and other activities that are less useful, casting them off as “anchors” that impede progress.

We are also continuing to learn how best to allow pharmaceutical manufacturers to assume more ownership and accountability for the manufacturing controls that will improve drug quality.

We face a large and daunting task, but remain dedicated to advancing the principles that were spelled out in the FDA final report for the 21st Century Initiative. I’d like to review some of the efforts now underway at CDER.

Eliminating discrepancies

CDER has played an integral role in FDA’s efforts to produce CMC guidance documents that will explain, clearly, exactly what information is expected to be contained in drug applications. However, there is a need to update some of these documents, and to eliminate others that are no longer useful.

A look at the CDER web site shows that, after a surge of CMC guidance documents that were finalized in the late 1980s and early 1990s, quite a few have lingered on as “drafts not for implementation.” The recommendations in these guidances don’t always fit well with the recommendations from the 21st Century Initiative.

This may not seem like much of a problem. After all, the drafts are clearly labeled as “not meant for implementation.” Nevertheless, in the absence of better advice, many pharmaceutical companies may still use these documents as guides when they prepare applications.

Gap analysis

CDER’s CMC leaders now plan to address this problem. They will identify documents that might be problematic, assess each document’s strengths and weaknesses, and group them into topical areas. They then rewrite these documents so that they incorporate more of the spirit of the 21st Century initiative [2].

The new, revised documents will allow for the fact that some pharmaceutical companies do not wish not to change the way they handle CMC. However, for those manufacturers who desire greater regulatory freedom, the revised documents will also emphasize a more scientific and risk-based approach.

FDA has been concerned that, if older documents are taken down but aren’t replaced immediately with revised versions, some manufacturers will be confused about how to proceed with documents that are already in progress, in which they’ve used the older guidelines. Therefore, we’re identifying documents that are at least adequate, then performing a “gap analysis” upon which a new FDA guidance can be based.

Casting off anchors

Other “anchors” are also being addressed, including:

  • Reducing the lag time between creating and implementing adequate training for reviewers;

  • intensifying the interaction between review and field activities;

  • reacting to the industry’s understandable reluctance to include solid examples [of technologies or methodologies being applied] in applications.
I don’t have enough space here to elaborate on all the efforts that will be associated with addressing each of these points, but at CDER we are pursuing them all energetically.

New directions

Using process controls and monitoring to control process variability is a far more effective way to ensure product quality than employing methods that rely completely on sampling and laboratory testing after the manufacturing process is complete. The best process controls are designed so that measurement occurs with feedback to the process. Thus, the process itself becomes a lens, allowing manufacturers to focus materials to the desired characteristics.

The type of control and monitoring technology used is up to each manufacturer, and depends on the specific conditions at each manufacturing facility. It doesn’t really matter whether the measurement is conducted in-line with a high degree of automation, or whether it’s accomplished through a sampling technique that allows the measurement to be used to adjust or end the process.

The best process monitors are designed to give the user a significant amount of confidence that the measurements are representative of the entire batch, and to ensure that the characteristic being measured is within specifications.

Control and monitor measurements can then be used to provide confidence that the process is reliably under control, from batch to batch. The FDA is in the midst of determining the best practices for applying these concepts to the regulation of drug product manufacturing [3, 4]. In cases where the structure of the organization needs to be adjusted, we’re doing that, too [5].

Adopting a standards-based approach to drug product regulation was not one of the working groups in the 21st Century Initiative. However, it is part of FDA’s overall strategy. The Agency is directed, through the National Technology Transfer and Advancement Act (NTTAA) [6] to seek out and use standards where they are applicable to the regulatory process. Specifically, CDER is currently engaged in creating a network of standards for implementation of Process Analytical Technology (PAT) within ASTM International [7].

Coordinating efforts will be crucial, as is the case with any project involving many people working on so many different tasks. Some people, no doubt, consider that FDA’s progress has been excruciatingly slow, while others may believe that progress has been recklessly fast.

In fact, FDA’s progress with 21st Century Initiative and PAT is an evolving process, occurring on many fronts, and progressing at different rates, but all efforts are moving in the same direction. Steering the process in a transparent manner will ensure that the Agency doesn’t lose sight of its goals by focusing too much on process minutia.


  1. “Pharmaceutical cGMPs for the 21st Century – A Risk-Based Approach, Final Report – Fall 2004” is the full title of this 32-page report that summarizes the results of two years worth of discussion on 16 topics ranging from administrative to inspectional to review topics. It includes references to larger, more detailed reports on many of the working groups. The report is available at:

  2. International Conference on Harmonization (ICH) guidelines can frequently serve this role. These are available in the quality “Q” section of the web site, and are accessible via:

  3. A pilot program is under way in the Office of New Drug Quality Assessment (ONDQA), formerly the Office of New Drug Chemistry (ONDC). Officially named “Submission of Chemistry, Manufacturing, and Controls Information in a New Drug Application Under the New Pharmaceutical Quality Assessment System; Notice of Pilot Program,” information on being part of this pilot is available in the Federal Register notice at:

  4. The Office of Generic drugs is exploring a new way to prioritize review resources and focus on the important elements of the CMC section of the application. Details of this method can be accessed via:

  5. The ONDQA (formerly ONDC) personnel have been reorganized so that they are a coherent group and not distributed among the clinical review divisions. Details are available in the White Paper on ONDC’s New Risk-Based Pharmaceutical Quality Assessment System at:

  6. The National Technology Transfer and Advancement Act (NTTAA) and its accompanying directive to government agencies, Circular A-119, can be accessed via:

  7. ASTM International Technical Committee E55: Pharmaceutical Applications of Process Analytical Technology
    E55.01: PAT Systems Management
    E55.02: PAT System Implementation & Practice
    E55.03: General Pharmaceutical Standards
    E55:90: Executive Subcommittee
    E55:91: Terminology
    More detail is available at:

About the Author

Jon E. Clark is the Associate Director for Policy Development and GMP in the CDER Office of Pharmaceutical Science. He has been heavily engaged in the Pharmaceutical Quality CGMPs for the 21st Century initiative, the Product Quality Research Institute (PQRI), International Conference on Harmonization (ICH) and a member of ASTM E55. He frequently represents CDER's drug quality and CMC policy in public speaking engagements, working groups and publications.

Previously, Clark spent one year in the CDER Office of Information Management developing electronic submission policy with the ICH; three years developing and presenting CMC chemistry policy in the Office of New Drug Chemistry; and seven years in the Office of Generic Drugs reviewing Abbreviated New Drug Applications while managing the Computer Assisted Review Database System with the University of Maryland. He joined the Agency in 1992, after 12 years as an organic synthesis research chemist in the private sector, first at Beecham Laboratories then at Schering Plough Research.

He received his Bachelor in Chemistry at the University of Michigan in 1980 and his Master in Chemistry at Rutgers University in 1987.