Regulatory Babel: Another Case for Harmonization

May 26, 2009
Novo Nordisk’s Birgitte Holst makes the case for getting global regulators on the same page more often.

There are five main challenges to regulatory harmonization around the globe, says Birgitte Holst, Manager of Manufacturing Science & Quality at Novo Nordisk, Inc. In no particular order they are differences in:

  • Pharmacopeias
  • Regulatory terminology
  • Methods and degrees of risk assessment
  • Variation/comparability protocols
  • Anticounterfeiting efforts

Until these differences can be resolved, regulatory harmonization will be just a dream, she told an audience May 19 at the BIO 2009 conference in Atlanta. And without harmonization, the regulatory burden on individual companies will be unreasonable. “Regional differences cost money,” she says. Harmonization will lower those costs.

1. Different Pharmacopeias

For companies doing business in the U.S. and E.U., pharmacopeial tests have to be repeated by differing sets of analytical methods, and results are evaluated differently. As a result, something as straightforward as pharmaceutical-grade water must be tested for every pharmacopeia, Holst says.

To harmonize: First, we need the same pharmacopeial texts for use in all the ICH regions, she says. And then we need WHO standards. “We need to take it a bit further and have a world standard,” she says.

2. Different Terminology

Differences in regulatory terminology between countries results in confusion, double workload, and misinterpretations, Holst says. It adds to confusion when we talk to suppliers, distributors. Should we “verify the cold chain,” “qualify the distribution chain”? It is very confusing. (See chart below.)

Harmonization in this regard would simply mean getting international regulatory bodies to agree on standardized terms (and to use similar measuring systems such as the metric system).

Disharmony: Differences in Validation Terminology

FDA Draft
ISO 9000 ICH Q8
Validation  X    X  
Quality Characteristic      X  
Critical Quality Attribute      
Process Validation  X  X    
Process Design    X    
Design and Development      X  
Process Performance Qualification*        
Qualification Process      X  
Process Qualification    X    
Product Performance Qualification*        
Qualification  X      
Verification      X  
Continued Process Verification    X    X
In-process Control  X      
Design Qualification  X      
Review      X  
Installation Qualification  X      
Operational Qualification  X      
Performance Qualification  X  X    

     * Terminology from old FDA guidelines

Courtesy: Birgitte Holst, Novo Nordisk

3. Different Approaches to Risk Assessment

Though most regulators allow for initial risk assessments, this harmony can be disrupted by additional standards for different bodies. “In some areas we might have guidances that might set further rigid standards,” says Holst. “For example, we have the ICH guideline for the manufacture of an API. Water use is clear; but then we have an EU note for guidance on water used for pharmaceutical use.”

An overlapping problem is that some “standards” are open to interpretation. “We sometimes hear that the rigid requirements from the EU are written rigid, but can be interpreted. But sometimes they cannot. It’s very difficult for manufacturers.”

We need to create confidence in performing risk assessment, Holst says. Using the ICH guidelines to establish a common frame of assessment will be critical.

4. Variations/Comparability Protocols

At present, changes cannot be implemented at the same time in the EU, Japan and the U.S., she says. For instance, FDA allows for a faster launch of products with changes in than does the EMEA. “We must allow specified types of CMC changes by submission of comparability protocols,” she says.

5. Different Anticounterfeiting Approaches

In the future, we may see a very fragmented production scheme due to country-specific requirements. We must create global solutions, Holst says. ICH or even WHO guidelines for supply chain security may be needed.

Despite these five very real challenges, “harmonization can be done!” Holst says. The device industry has use the ISO umbrella to harmonize its technology standards, she says. And ICH Q7A, Good Manufacturing Practice for APIs, is an example of global cooperation within the drug industry.

About the Author

Paul Thomas | Senior Editor