Pharmaceutical Engineering Interviews

C hi-Wan Chen serves as Executive Director in Global CMC, Pfizer, responsible for regulatory policies and strategies with a focus on the Asia Pacific region. She is a member of ISPE’s Regulatory and Compliance Committee currently chairing the Asia Pacific Focus Group and serves as an ad-hoc CMC advisor to the multinational companies’ trade organization in China and in the South East Asia region. Prior to her joining Pfizer in March 2008, Chen spent 22 years with the US FDA. She represented the FDA at the ICH on several Quality Guidelines, including Q1AR, Q3AR/Q3BR, and Q8R. During 2005 to 2008, she provided technical leadership and management oversight for the FDA Quality by Design (QbD) Pilot Program.

In your opinion, is 2014 an especially active year for regulatory changes in China?

Maybe, because we don’t know for certain. There is no published list of proposed guidelines so we don’t know what is coming. At the end of last year, around November/December, the Center for Drug Evaluation (CDE) did indicate to both local and multi-nationals that they are planning to update a series of technical guides, most of which were published around 2005. They requested assistance from the R&D-Based Pharmaceutical Association Committee (RDPAC) to provide a gap analysis of 13 technical guides compared to US, EMA and ICH guidelines and to provide suggestions on how to update the technical guides. They want the guidelines to be updated in accordance with ICH CTD guidelines. These are all CMC guides, not GMP. This is an indicator that 2014 can be a very active year for regulatory changes in China. The CFDA has developed their own CTD based largely on the ICH CTD. The CTD published in 2012 was to encourage local generic companies to use it. Many large multinationals have started to submit in the CTD format and that is acceptable. There is no CTD format for new drugs, only for generics.

Are any recently published guidelines particularly burdensome?

Two guidelines are very burdensome.  These relate to compatibility of injectable drugs. One for compatibility with glass was published a year ago, and the other in plastic was published in November. These are drafts. There is another draft, not necessarily burdensome, but is the first attempt to incorporate ICH guidelines. This is the stability guideline. It was first published in 1995. It was published in February 2013 in draft and has not been finalized.

When a guideline is published in draft, do they ask for comments on the draft?

Yes – most draft guidance has a 30 day comment period, which includes translation of the document and translation of the comments. If the guidance is published in Chinese, companies need to translate the document and then translate the comments for submission.

What are the guides that are used to perform submissions?

  • Requirements for Preparing Application Dossiers in CTD Format for Chemical Drugs (July 2011)
  • Format and Content of the Overall Summary of Chemical Drugs – Summary of Pharmaceutical Development (March 2005)
  • Chemical Drug Quality Control Analytical Method Validation (March 2005)
  • Studies on Impurities in Chemical Drugs (March 2005)
  • Studies on Residual Solvents in Chemical Drugs (March 2005)
  • Standardization Process of Chemical Drug Specification Establishment (March 2005)
  • Basic Technical Guidance for Chemical Drug Product (March 2005)
  • Studies on Manufacture and Characterization of Chemical Drug Substances (March 2005)
  • Chiral Drug Pharmaceutical Research Techniques Guidelines (September 2007)
  • Pharmaceutical Studies on Synthetic Polypeptide Drugs (September 2007)
  • Pharmaceutical Study of Oral Sustained Release Preparations for Chemical Drugs (September 2007)
  • Research on Quality Control of Inhalant (September 2007)
  • Dissolution Test of Common Oral Solid Dosage Technical Guidelines (draft revision October 2012)
  • Stability Study of Chemical Drugs (Drug Substances and Drug Products) (draft revision February 2013)

These are in the process of being updated or finalized this year.

 There are also three technical guides published in draft or in final form in the last year:

  • Draft Technical Guideline for the Stability Study of Chemical Drugs (Drug Substances and Drug Products)

This draft stability guideline is a revision of the 2005 technical guide on the same subject by incorporating ICH Q1A(R2), Stability Testing of New Drug Substances and Products, and part of Q1B, Photostability Testing of New Drug Substances and Products. Certain information is not consistent with the source Q1A guidelines: (a) some added recommendations, e.g., stress testing, intended to serve as a guide to local companies during drug development, are very proscriptive; and (b) certain concepts, e.g., those underlying statistical analysis, from the Q1A guidelines have been revised or omitted. These discrepancies can lead to divergent requirements and practices.

  •  Draft Guideline on Compatibility of Injectable Chemical Drugs with Glass Containers (being updated to incorporate ICH Q1A)
  • Final guideline on Technical Requirement for Quality Comparability Studies for the Change of Vaccine Production Site

 We understand that there is a comment period after the draft is published, but is there any pre-consultation with industry or does CFDA decide how they want to proceed and then send out for comments?

It varies. In some cases, the CFDA or CDE would have informal meetings with trade representatives – local or multinational and inform the trade reps of their intent and open the door for them to provide suggestions. However, in most cases, the CDE or CFDA would issue the draft without consultation. In the case of the revised draft stability guidelines, because there was already a guideline, CDE who was responsible for the update, had informal meetings with local and multi-nationals, without showing a preview of the draft; however, they did highlight some major changes. After it is published as draft, the draft is officially published.

 The industry has 30 days to comment – is there a set period of time that CFDA has to address the comments and publish the final guidance?

There is no set timetable for CDE or CFDA to respond to the comments and to issue the final guidance.

There are a couple of other technical guides related to national level, top priority. There is five year plan. Currently, it is in the 12th five year plan, driven by economics. Under this umbrella, there is a Generic Drug Quality Consistency Evaluation (GDQCE). This started end of 2012. Last year, there were two technical guides: one policy and one technical guide – related to this initiative to enable companies to participate. This initiative is to reassure the quality and performance of generic drugs approved prior to 2007, which was the year that the regulations in China was revised to require BE studies for generic applications. Prior to that, there was no requirement to perform a BE study for generic drugs. In China, there is a general negative impression that generic drugs are not as safe and effective as innovator drugs. This is a sentiment shared by medical professionals and the general public. There are 1000s of applications before 2007 and many manufacturers that make products. The economic impact would be too great. There is no infrastructure to perform BE studies for all these products. The Chinese government came up with a compromise and that is to rely on dissolution testing to determine if the generic is the same quality. There are many problems to start – there is no list of reference drugs, and so they have to start establishing the RLD. They are identifying companies that they think can be the reference drug. Companies are invited to prove themselves as the RLD. Reference manufacturers have to submit samples, dissolution testing and profiles. Other than the procedural problems, which are large, the approach is non-scientific. They are worried about quality, safety and efficacy. The compromise approach will not assure this.