The Sixth International Conference on Harmonisation (ICH 6) – A Promising Future in Global Pharmaceutical Industry

 

Amitava Roy1*, Amitava Ghosh1, Supriya Datta1, Arindam Das2and Subarna Ganguli1

 

1Himalayan Pharmacy Institute, Majhitar, Rangpo, East Sikkim, 737136.

2Regional Institute of Pharmaceutical sciences and Technology, Agartala, Tripura.

 

* Corresponding Author E-mail: jamitamitava@yahoo.co.in / amitoli@rediffmail.com

 

ABSTRACT

With a view to determine future challenges for the ICH process in the ever-growing Pharmaceutical environment, the

Sixth International Conference on Harmonisation (ICH) motivated its focus on areas such as new technologies in the discovery of innovative drugs, opportunities and new challenges for regulatory harmonisation, Pharmacovigilance and global cooperation with regulatory harmonisation initiatives outside the ICH regions. The practical implementation of the Common Technical Document (CTD)-the common format for license application in the three ICH regions - was also an important focus of the ICH6 Conference. Three satellite sessions took place before the plenary Conference: "Partnerships in Harmonisation", "Gene Therapy" and "MedDRA Users' Group". The session on Partnerships in Harmonisation reflected the ICH commitment in establishing collaborative efforts through expanded Global Cooperation Group (GCG) activities with non-ICH Harmonisation initiatives.

 

 KEY WORDS              Harmonisation, Future in Global.                                                                                                                

 

INTRODUCTION:

The   term   ICH   is   International   Conference   for Harmonisation  of  technical  requirements  for registration of Pharmaceuticals for human use. In the beginning, ICH was just an abbreviation for a conference, but gradually it materialized more into a Harmonisation process. Going back into the history, the birth of ICH was initiated, in 1990, when the European community (now European Union) moved forward for the development of a single market for Pharmaceuticals between European Community, USA and Japan. Bilateral discussion and specific plans for action were initiated  and  materialized  at  the  International conference of Drug Regulatory Authorities (ICDRA) held in Paris in1989. A discussion of joint regulatory was undertaken along with International Federation for Pharmaceutical Manufacturers Association (IFPMA). An International Conference on Harmonisation was conceived at this meeting, later. The representatives of the regulatory agencies and industrial associations of Europe, Japan and USA met in April in 1990 at a meet, hosted by the European federation of Pharmaceutical industry associations (EFPIA) in Brussels.

 

The primary target of this conference was focused on planning the future conferences and to discuss the wider implications  of  the  topics  reviewed  in  the  conferences. Thus, a steering committee (SC) was established for the ICH  to  setup  the  working  patterns  and  identification of topics necessary for Harmonisation. The SC also played a vital role to establish expert working groups (EWGs) and to discuss scientific and technical aspects of various harmonisation topics. The issue of ICH, its purpose and objectives  was  stated  on  October 1990  in  Tokyo  at  the meeting of the SC1.

 

ORGANIZATION AND STRUCTURE:

Actually ICH is a joint initiative involving drug regulators

from the regulatory authorities and industry personnel as equal partners. There are altogether six parties directly involved  in  these  activities  representing  the  regulatory bodies and the research based industry associations in each region.  The  parties  involved  from  the  European  Union, Japan and USA are:

1. European Commission (EC)

2.European federation of Pharmaceutical Industries Association (EFPIA)

3. Ministry of Health and Welfare (MHW)

4. Japan Pharmaceutical Manufacturers Association (JPMA)

5. United States Food and Drug Administration (US FDA)

6. Pharmaceutical Research and Manufacturers of America (PhRMA)

 

 

All these six co-sponsors have two seats on the ICH steering committee (SC) and are responsible for overseeing the harmonisation activities.

There are three observers:

1. World Health Organization (WHO)

2. European Free Trade Area (EFTA)

3.International      Federation      for      Pharmaceutical

Manufacturers Association (IFPMA).

 

Table-1 Chronological Events of ICH Meeting

 

Steering Committee. Its purpose is to make information on ICH, its activities and guidelines widely available and to respond to regulatory authorities or Pharmaceutical companies worldwide those requests for information. The GCG is made up of one representative from each of the six parties on the ICH Steering Committee and the ICH Secretariat at  IFPMA. Two  Observers (WHO and  Health Canada) are also part of the GCG. ICH meetings are being held more or less every alternate year. These have taken place accordingly:

 

THE SIXTH ICH AND ITS ACTIVITIES:

Sixth International Conference on Harmonisation took place Nov. 2003 at the Osaka International Convention

 

Each of the three observer parties has a seat on the ICH steering committee along with IFPMA as two seats in the ICH steering committee as non-voting members. Each of the co-sponsors designates an ICH coordinator, acting   as   the   main   contact   point   with   the   ICH secretariat and ensures that ICH documents are distributed to the appropriate persons within the area of their responsibility. Also a contact network of experts within  the  own  organization  or  region  among  each party was established. This was done in order to ensure that, in the discussions, they reflect the views and policies of the cosponsors they represent.

 

Table-2: Limits of Organic Volatile Impurities before and after Harmonisation

 

ICH secretariat operates from the  IFPMA offices in Geneva and is particularly responsible for preparations and documentation of meetings of SC, EWGs and six party drafting groups. Liaison with the speakers is done by the ICH secretariat at the time of ICH conferences. The ICH Global Cooperation Group (GCG) was formed on March 11,  1999, as  a  subcommittee of  the  ICH Centre. The conference completed the second round of ICH activities among the three ICH regions. The Osaka conference attracted over 1800 participants representing regulatory in other govt. agencies and industry from ICH as well  as  non-ICH  region.  On  12th   Nov.  the  Convention Centre held three satellite sessions as a prelude to the main conference.

 

Opening plenary session, 13th Nov 2003: Discussions were held on the 1st  phase of activities, the target for ICH had been to remove redundancy and duplications in new drug development. The  2nd   phase  focused  more on  regulatory issues such as medDRA, CTD2, and a new emerging issue in   pharmacovigilance,   new   technologies   and   quality systems. Partnerships with non-ICH region and the establishment of global cooperation group (GCG) were also given priority. It was emphasized that a key factor in the success of ICH had been the commitment of the partners to the implementation of its policies and principles. The 21st century would be the century of biomedical innovations. The full potential of genomics, proteomics, nanotechnology and bioinformatics had yet to be explored promising a more effective, safer, more targeted, individual therapy and the modern drug discovery is experiencing a shift of paradigm from research into new medicines. It was also discussed about  the  innovations and  regulatory harmonisation in  a global environment, especially by the help of appropriate technical areas such as E6 (good clinical practice) and the acceptance of foreign data (E5)10. International approaches to the challenges of new technologies in the area of Pharmaceuticals were also discussed. The ICH initiative did not rely upon enforcement to be successful, it relied upon commitment and the benefits were visible in terms of the increased mutual understanding and confidence.

 

The 2nd  part of the opening plenary session focused on the implementation of  the  ICH  CTD  which  was  adopted  at ICH5, San Diego, 2000. The ultimate value of the CTD would be reflected in the effective implementation across the three ICH regions. Continued maintenance of the CTD and monitoring its implementation will allow maximum benefit  to  both  industry  and  regulatory  authorities.  At present the electronicCTD (eCTD) is used only for one way communication from industry to regulator but a two way message  system  may  be  introduced2. The  results  of  the internet based survey conducted by ICH during 2003 among Pharmaceutical companies and regulatory authorities showed a positive overall view of ICH with 100% regulators and 96% industry rating the initiative as a success and 8 out of 10 companies supporting the development of additional ICH guidelines.

 

Topic breakout session, 14th  Nov 2003: The Session was introduced with an overview of the topics that had been addressed by ICH Quality Expert Working Groups since it started in 1990. Only seven guidelines were listed   in   the   session   among   the   16   harmonised guidelines that had reached consensus before ICH5, in the  year  2000,  identified  and  were  agreed  between ICH5 and the current ICH6 Conference, highlighting the current quality issues that would be discussed in the Quality Breakout Session.

 

Stability Testing Guidelines Q1D, Q1E, Q1F:

Topic  Q1D   was  initiated   with  the   objectives  of identifying situations in which bracketing and matrixing can be applied and provides sample designs for illustrative purposes3.

Topic Q1E “Evaluation of Stability Data” which provides recommendations on how to use stability data generated  in  accordance  with  the  principles  of  the parent guideline Q1A and describes when and how extrapolation can be considered when proposing a retest period for a drug substance or a shelf life for a drug product that extends beyond the period covered by the long-term stability data. The guideline provides examples of statistical approaches to stability data analysis.

Topic Q1F which dealt with stability data package for registration applications in climatic zones ΙΙΙ and ΙV and it was noted that parallel amendments had been made  to  the  parent  guideline  relating  to  testing  for zones Ι / ΙΙ performing worldwide harmonised stability studies3,15.

 

Impurity Testing Guidelines:

Q3A(R) provides an overview of guideline Q3A which relates to impurities in new drug substances produced by chemical synthesis and addresses safety aspects and the listing of impurities in specifications and defines the thresholds  for  reporting,  identification  and qualification. Among the reasons for revising the guideline were the need to clarify the decision-making criteria when impurities are close to the limit of 0.1% for identification and quantization.

Q3B(R)-  describes  the  revisions  to  guideline  Q3B which relates to impurities in new drug products (formulations) to achieve consistency with the revised drug substance guideline Q3A4.

Q3C (M) dealt with the residual solvent impurities was revised for the maintenance and reclassifications of the solvent according to potential toxicity with permitted daily exposure (PDE). The residual solvents are classified into four categories:

 

Ι) Class 1 solvent, which are, known to cause unacceptable toxicities and should not be used.

ΙΙ)  Class 2  solvents, which should be  limited to  protect patients from potential adverse effects.

ΙΙΙ) Class 3 solvents, which can be used.

ΙV)  Additional  solvents  for  which  no  toxicological data have been found.

 

Pharmacopoeial harmonisation: Q4/Q6A

This  session  dealt  with  the  relationship  between  ICH harmonisation and the ongoing process of revision and harmonisation for  the  Pharmacopoeias in  the  US  (USP), Japan (JP) and Europe (EP). These include the general chapters that have an impact on ICH guideline Q6A on specifications for new drug substances and products such as bacterial endotoxins, dissolution, disintegration and uniformity of  dosage  units.  Also  the  steps  taken by the industry since ICH5 was described in which expedition of the  Pharmacopoeial  harmonisation  process  identified  the ICH Q6A (specifications)5. Views about the interchangeability of harmonised sign of text of the PDG (Pharmacopoeial  discussion  group)  were  a  major contribution  to  the  harmonisation  programme. Harmonisation is essentially required among Pharmacopoeias for product registration exercises. That is product development can proceed as is, without the need for repeating of studies or testing to support registration in other than the original region5.

 

Q5E: comparability of  biotechnological and biological products: Establishing the need for the document of Q5E was discussed, the concept of comparability has emerged over the past two decades involves molecular biology, manufacturing technology, analytical technology and impact analysis of manufacturing changes6. The scope of new guidelines in the context of the types of products by other Q5  guidelines  were  reviewed  and  examination  of  the problems of  evaluating the  comparability of  biosynthetic proteins were also discussed. The planning, strategy and impact analysis for comparability studies, the vision of quality systems for the 21st  century includes vision for a single harmonised drug quality system based on quality by design and risk management was also nurtured.

 

Pharmacovigilance guidelines E2CAdd, E2D, E2E:

E2C periodic safety update reports for marketed drugs were

finalized in Nov 1996. E2CAdd was an addendum commenced in early 2002 and was finalized by 2003. E2D differed from E2A on post approval safety data management which had become apparent that the absence of harmonised guidance on Pharmacovigilance in the post marketing phase was  a  source  of  inconsistency that  could  be  potentially damaging to public health7. E2E deals with Pharmacovigilance planning and Pharmacovigilance specification and discuss the design and conduct of post approval safety studies. The inclusion of the specification and  plan  within  the  CTD  application  format  is  also covered2.

 

Regulatory communication: E2B (M), medDRA:

E2B   (M)   deals   with   the   maintenance   of   the harmonised     implementation    of     the     electronic transmission    of    individual    case    safety    reports (ICSRs)8.    Medical     Dictionary    for     Regulatory Activities (medDRA) was discussed in detail at the 6th ICH along with current activities in its upgradation, activities  of  the  maintenance  and  support  service organization(MSSO).   The   breakout   session   also provided an update on three key areas related to ICH safety  and  efficacy  guidelines.  Reporting  on  recent progress     and     development     on     QT     interval prolongation-    safety    pharmacology    studies    for assessing         potential    for     delayed    ventricular repolarisation by human Pharmaceuticals (S7B) 8,9.

 

Ethnic factors in the acceptability of foreign clinical data  (E5):  

E5  had  been  recognized  however,  the misunderstanding and confusion still exist regarding the intent of the advice in E510 and its implementation and it had been agreed that this should be addressed through the publications of question and answers (Q and As) Closing Plenary Session, 15th Nov 2003:

 

The first session of the closing plenary discussed the work of the ICH Global cooperation group (GCG)11 and outreach beyond the three ICH regions. The conference was informed of the new agreement by the ICH steering committee to extend membership of the GCG to representatives of the non-ICH harmonisation initiative that meet specified criteria for scientific objectives and ongoing activities. The final plenary session dealt with the “Future challenges new approaches for the development-assessment of the innovative therapies”14. This highlighted a number of new areas, which might be   considered   for   future   International   scientific dialogue, including novel types of medicines derived from biotechnological processes and the use of pharmacogenetics/ pharmacogenomics techniques to produce better-targeted medicines. It was stressed that ICH  should  also  pursue  its  efforts  to  maintain  and update existing guidelines and to monitor their implementation, in order to prevent inconsistencies arising across the ICH regions. The ICH partners reiterated their on-going commitment to pursuing harmonisation goals in a spirit of collaboration and it was also reaffirmed that public health promotion and protection  were  the  foundation  of  the  ICH harmonisation activities.

 

Satellite session-Ι:

The session dealt with “Partnerships in Harmonisation” organized by the ICH Global Cooperation Group. The main topics of discussion were firstly on non-ICH regional Harmonisation initiatives and  secondly experience of  Non-ICH Harmonisation initiatives with ICH guidelines11.

 

Satellite session-ΙΙ:

This session dealt with “MedDRA

users group” jointly organized by the maintenance and support services organization (MSSO) and the Japanese maintenance and organization (JMO).

 

Satellite   session-ΙΙΙ:   

This   session   dealt   with   “Gene therapy” organized by the ICH-Gene therapy discussion group, which was established in Brussels, July 2000.

The role of ICH steering committee: The ICH-Steering committee  and  its  EWGs  (expert  working  group)  made some decisions being announced during the conference as well as being published in a press briefing, released immediately after proceedings. The steering committee agreed at its meeting to the adoption of three new topics for harmonisation:

 

Q9: GMP risk management:

This was adopted as a new topic as a part of the ICH initiative on a risk-based approach to drug product quality and GMP. This will complement the work on topic Q8-“Pharmaceutical development-quality by design” that was agreed as a new topic July 2003.

S8: Immunotoxicology studies were agreed as a new topic for the development of an ICH harmonised guideline12.

M5:  Data  elements and  standards for  Drug  Dictionaries were agreed as a new harmonisation initiative8.

Other topics that achieved one of the ICH milestones in the stepwise ICH process were

Q5E: Comparability of biotechnological and biological products subject to changes in their manufacturing process (reached  step-2  process  released  for  regulatory consultation)6.

E2D: Post approval safety data management: Definitions and  standards for  expedited reporting (complement guideline E2A reached step-4 process adopted for implementation)7.

E2E: Pharmacovigilance planning intended to aid industry and  regulators  in  planning  Pharmacovigilance  activities these drafts guidance reached step-2 of the ICH process (released for regulatory consultation). Also additionally the steering committee endorsed the latest in a series of “questions and answers” (Q and As) on the implementation of the Common Technical Document (CTD)2, for the publication on the ICH website7.

 

OVERVEIW AND SUMMARY:

The ICH sixth conference provided an opportunity for the non-ICH regions for better understanding of the ICH activities via the Global cooperation group11,13. The symposium included a  thorough presentation on regional harmonisation initiatives outside the ICH region including the  Southern  African  Development Community (SADC), the Pan American Network for Drug Regulatory Harmonisation (PANDRH), and Asia Pacific Economic Cooperation (APEC) as well as work of the Association of South East Asian Nations (ASEAN). The issue of the ICH Stability Guidelines and their extension to cover all climatic zones (Q1F)3   was discussed in  detail and  the  impact of implementing the ICH Guidelines on Good Clinical Practice (E6) and on the Ethnic Factors in the Acceptability of Clinical  Data  (E5)10   were  also  reviewed  in  detail.  The User’s Group meeting provided an opportunity for an overview  and  update  on  progress  in  the implementation   of   MedDRA   by   the   regulatory agencies and industry in the EU, Japan and the USA. The session on gene therapy was another prime discussible where it was noted that the development of the guideline is not part of the objective of the ICH Group   but   the   possible   future   development   of‘consensus principles; regarding Gene Therapy safety issues’ is being considered.

 

There   was   always   a   need   to   explore   alternate approaches to the traditional ICH model of Expert Working Groups (EWGs), particularly in areas where constantly changing scientific information has been identified. The discussions of the sixth ICH had made it possible of  making better use of techniques such as videoconferencing and  electronic  communication, which can only serve to enhance the communication between the ICH parties, as well as with other involved parties.

 

REFERENCES:

1.     Singh  S.  International  Conference  on  Harmonisation- An update. The Eastern Pharmacist. 1998; 61:42-43.

1.     Giaquinto A, Juillet Y, Banfield G, Mahoney T, editors. CTD     implementation.     Proceedings     of     the     6^th International conference on Harmonisation. 2003, Nov 12-15; Osaka, Japan.

2.     Kojima S, Chen WC, Yoshioka S, Keitel S, Robert LJ, Schmuff N, editors. Quality Breakout Session. Proceedings of the 6th  International conference on Harmonisation; 2003, Nov 12-15; Osaka, Japan.

3.     S S Poddar, C Amit, P Paresh. Maintenance Process of Residual Solvent Guideline Indian J. Pharm. Educ. Res. 2006;40(2): 96-98.

4.     Artiges A, Sheinen E, Potter C, Tanimoto T, editors. Pharmacopoeial Harmonisation. Proceedings of the 6^th International conference on Harmonisation. 2003, Nov 12-15; Osaka, Japan.

5.     Gleixner R, Matsuki S, Ridgway A, Cherney B, Zorzi-Morrey P, Ramsbotham J, Yamada T, editors. Comparability of Biotechnological/Biological Products Subject to changes in their Manufacturing Process. Proceedings of the 6th International conference on Harmonisation. 2003, Nov 12-15; Osaka, Japan.

6.     Chen M, Iwaoka T, Tanigawara Y, editors. Pharmacovigilance Guidelines. Proceedings of the 6th International conference on Harmonisation. 2003, Nov 12-15; Osaka, Japan.

7.     Brosch S, Revelle P, editors. Regulatory Communication- Medical Dictionary for Regulatory Activity. Proceedings of the 6th International conference on Harmonisation. 2003, Nov

8.     12-15; Osaka, Japan.

9.     Strnad C, Bode G, Fujimori K, Siegl P, editors. Safety Pharmacology Studies for Assessing the potential for Delayed Ventricular Repolarisation by Human Pharmaceuticals. Proceedings of the 6th International conference on Harmonisation. 2003, Nov 12-15; Osaka, Japan.

10.  O Neill R, Naito C, Kato M, Mori K, editors. Ethnic Factors in the Acceptability of Foreign Clinical Data. Proceedings of the 6th International conference on Harmonisation; 2003, Nov 12-

11.  15; Osaka, Japan.

12.  Lonngren T, Ichikawa K, Bale H Jr., Rägo L, editors. ICH Global  Cooperation  Group.  Proceedings  of  the  6th International conference on Harmonisation. 2003, Nov 12-15; Osaka, Japan.

13.  12.  Vanderlaan     WJ,     Hastings     K,     Sawada     J,     editors. Immunotoxicological    Studies.    Proceedings    of    the    6^th International conference on Harmonisation. 2003, Nov 12-15; Osaka, Japan.

14.  Yetter R, editor. Partnership in Harmonisation. Proceedings of the 6th International conference on Harmonisation. 2003, Nov 12-15; Osaka, Japan.

15.  Juillet Y, Takenaka T, Hayakawa T, Hasimoto L, Peterson R, Lumpkin M, editors. Future Challenges: New Approaches for the Development – Assessment of Innovative Therapies. Proceedings of the 6th International conference on Harmonisation. 2003, Nov 12-15; Osaka, Japan.

16.  Carstensen JT. Drug Stability Principles and Practices. 2nd ed. New York : Marcel Dekker; 1995.

 

Accepted on 28.07.2008   © RJPT All right reserved