INVOLVEMENT OF HEALTHCARE REGULATORY AFFAIR PROFESSIONAL IN OVERSEAS REGISTRATION PROCESS

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Examples include:
Replicate injections of a standard preparation for HPLC and GC methods.
Standardization of a volumetric solution followed by assays using the same burette for titrimetric methods.
Replicate scanning of the same standard preparation during UV-VIS assays, etc.
When the method in question utilizes an automated system such as a chromatograph or an atomic absorption spectrophotometer, a suitable standard preparation should be intermittently measured during the sample analysis run. The responses generated by the standard should exhibit a reasonable relative standard deviation. This is done primarily to demonstrate the stability of the system during sample measurements. System suitability for dissolution studies should be performed using both USP Non- disintegrating and disintegrating tablets prior to the validation of dissolution method.

OBSERVATION SUMMARY SHEET

S. No.

CONTENT

OBSERVATIONS

LIMITS

1.0

Specificity

For Permethrin sample was added in placebo the % recovery observed. Thus this has not any impact on the proposed method.

99.57% to 100.13%

98%  to 102%

2.0

Linearity & Range

Linearity was studied by preparing standard solutions at different volume & the linearity range was found 6.9427mcg to 12.8936mcg 

Correlation Coefficient is 0.99939

Correlation Coefficient is NLT 0.997

3.0

Accuracy

It was done by recovery studying using standard addition method known amount of Permethrin were added into the placebo and subjected them to the proposed HPLC method.

The % recovery observed is

99.57% to 100.13%

98% to 102 %

4.0

Precision

Six replicate samples were tested and the % RSD observed.

1.279%%

Less Than 2.0%

5.0

Intermediate Precision

Intermediate precision at inter day analysis as well as different HPLC system by another analyst and calculate the relative standard deviation of both analyst.

The maximum deviation against first analyst is 0.986%

Less Than 2.0%

Conclusion:

On the basis of the above observation it is concluded that the analytical method (UV) taken for validation is validated for different strength of same formulation.

Multicountry Regulatory Filling Strategy:
Taking advantage of the Common Technical Document (CTD) defined by the International Conference on Harmonisation (ICH), biopharmaceutical companies can significantly improve the speed and efficiency of preparing multi-country regulatory submissions while reducing the risk of costly delays. A strategic, multinational regulatory approach greatly increases the chances of marketplace success for both new and existing pharmaceutical products during these difficult times—assuming sponsor have the right resources and local expertise to effectively develop and implement the strategy. Leveraging the CTD The CTD is the key to leveraging the benefits of multi-country filings. Based upon the ICH M4 guide­lines set forth in “Common Technical Document for the Registration of Pharmaceutical for Human Use—Quality, Safety and Efficacy,”1 the CTD provides a standardized structure for regulatory submissions that is acceptable to all ICH members—the European Union, Japan and the US. Other countries, including Australia, New Zealand, Canada, India, China, Turkey, Serbia, Croatia, Bosnia-Herzegovina, Ukraine and Kazakhstan also have elected to accept the CTD for regulatory submissions. A similar submissions format—the ASEAN CTD (ACTD)—is being developed by ASEAN member countries including Brunei, Cambodia, Indonesia, Laos, Malaysia, Myanmar, Philippines, Singapore, Thailand and Vietnam.2 This format is closely aligned with the CTD guidelines and will further expand the utility of CTD-based dossiers. The implementation of the ACTD should also facilitate approval and marketing of pharmaceuti­cal products in these countries.

The ongoing switch to electronic submis­sions also facilitates the multi-country submis­sions process. By July 2009, the European Medicines Agency (EMEA) will strongly rec­ommend eCTD submissions;3 other electronic formats and paper will be the exception. For submissions via the Decentralized or Mutual Recognition Procedures, applicants are also encouraged to use the eCTD. The move to elec­tronic submissions minimizes the logistics of fil­ing paper submissions that add significant time and expense to multi-country filings.

Understanding Regional Differences in CTD Submissions
Although the CTD makes multinational filings easier, it is important to remember that regulatory submissions in the EU, the US and elsewhere in the world continue to have significant differences. For example, an EU CTD typically contains more summary data in the CTD modules, as opposed to the cross references to full reports typically seen in submissions to the US Food and Drug Administration. The fact that a product has been approved in one country or region does not guarantee its approval in others. A success­ful multi-country filing strategy requires close attention to local requirements, familiarity with previous regulatory decisions and knowledge of the country’s medical practices. At the same time, regulatory approval of a pharmaceutical product in a major market will often improve its chances for acceptance in other countries. In some coun­tries, for example Australia and New Zealand (see below), a CTD-based product dossier that has been approved for marketing in the EU or the US may be eligible for accelerated review and faster market approval.

A company’s ability to understand and accommodate local regulatory differences will have a substantial impact on the success of its multi-country submissions strategy. Many phar­maceutical companies contemplating multina­tional filings find that they benefit from outside regulatory resources with specific knowledge of local and regional regulations to help them refine their multi-country strategy and position their regulatory submissions for approval in the tar­geted markets.

Developing an Effective Multi-Country Submissions Strategy
While a multi-country filing strategy is important to maximize product potential, it does not mean that submissions should be filed simultaneously in each country. The appropriate submission strategy depends upon a variety of factors, such as:
product indication, location of potential • patients and clinical practice
pricing and reimbursement issues•
sponsor size and resources •

whether the product is a novel therapy • or an established treatment expanding into new market analysis of market penetration and mar­• ket share potential, as well as the current market leader manufacturing capacity and distribution • logistics.

Companies expanding into new countries or regions have additional issues to consider, such as unfamiliarity with regulatory differences and the common requirement that a sponsor have a local legal entity and designated responsible person in order to sell pharmaceutical products in a partic­ular country. When targeting the EU, companies must decide whether to follow the Centralized Procedure (which is mandatory for specified products and indications) or the Decentralized/Mutual Recognition route for their submissions.4 For eligible products, the Centralized Procedure via EMEA provides the advantage of receiving a single authorization covering all 27 EU Member States, plus Iceland, Norway and Liechtenstein. The Decentralized and Mutual Recognition Procedures afford the opportunity to select specific Member States based upon product acceptance, ease of market access or market value.

The order and timing of multi-country fil­ings can have a significant effect on whether a submission is reviewed and approved quickly or is subject to delays. Although every situation is unique, the following are examples of sound stra­tegic approaches for three common multi-country filing scenarios:

Mid-sized and Large Multinational Biopharmaceutical Companies

With New Products
It is often advantageous for major biopharmaceu­tical companies to submit their initial marketing authorization applications in the US and the EU in parallel to maximize their return on investment during the patent protection period. These appli­cations would typically be followed by a “second wave” of applications in other important markets such as Canada, Australia, New Zealand, China and India, which have implemented most or all of the applicable ICH/CTD guidelines.

The key to this strategy is to develop a robust core dossier that can be adapted to accom­modate the differing requirements of FDA and EMEA. This approach greatly reduces duplica­tion of effort. Consideration of exact require­ments and expectations in second wave countries is important early in the process, to ensure an awareness of local regulations so appropriate adjustments can be made to the file, as required. This advanced strategic planning can significantly reduce the risk of regulatory delays by anticipat­ing questions typically raised by the individual regulatory agencies, such as requests for ethnic data or the selection of a comparator.

Small Companies With Novel Therapies
Smaller biopharmaceutical companies usually seek initial regulatory approval for their products in their home countries, and then use the approved dos­sier as the basis for applications to other countries. Innovative therapies are of interest in every country, so small companies are encouraged to submit their products for approval elsewhere. Smaller companies also face greater financial risks if their applica­tions fail, so they must be aware of region-specific requirements, standard therapeutic-area practices and existing reference products when preparing applications for new areas. Medical and regulatory experts with local knowledge of the targeted country or region can be vital in formulating submissions that have the greatest chances for success.

Mid-sized and Larger Companies Already in the EU Seeking to Expand Market Reach
Pharmaceutical companies with a portfolio of approved products in the EU can leverage their existing approvals to expand into non-EU European countries such as Croatia, Serbia, Ukraine and Russia. Recent dossiers in CTD format can be used for submission to these countries, although some countries require local language translations and country-specific docu­ments. Products that have been on the market for a number of years may require an updated dossier—not only to facilitate assessments in new markets, but also to maintain support for the license in the existing markets. Experience has shown that a local presence and established relationships with regulatory authorities can be important for market success in these countries.

The Importance of Local Knowledge
In all of these scenarios, knowledge of regulatory differences and other country-specific require­ments is crucial to the success of any multi-coun­try submissions strategy. Familiarity with local differences in advance of preparing a submis­sion can mean the difference between a smooth review process and significant delays or failures. Following are a few examples that illustrate the importance of understanding and anticipating unique local situations.

Australia
A non-Australian company wishing to register a new medicinal product in Australia must have a sponsor, located in Australia, responsible for the drug’s manufacture, supply and marketing. The sponsor must be registered with the Therapeutic Goods Administration (TGA) before any sub­missions can be made. Pre-submission meetings with TGA are strongly encouraged. In addition to standard (Category 1) submissions, Australia offers an abridged (Category 2) submission pro­cess for products that have already been approved and marketed in other “acceptable” countries. The review timeframe is 20 weeks shorter than the standard (Category 1) process—about one-third faster. However, the product must be identical to the one registered in the acceptable countries in formulation, directions for use and indications.

New Zealand
A shortened review process also is offered by New Zealand for products that have been approved and marketed in the US, Canada, Australia, the EMEA (Centralized Procedure) or the United Kingdom (National procedure5). The product must be identical in all aspects to the approved product, including manufacturing site, specifica­tions, indications and warnings. The Extended Abbreviated Process is completed within 135 days, instead of an average of 450 days, and also offers the sponsor significant savings on fees.

Indonesia
In November 2008, Indonesia’s Ministry of Health issued a new regulation that requires for­eign companies marketing drugs in Indonesia to manufacture them there. The regulation states that foreign-owned companies will not be permit­ted to register imported drugs for sale unless they have an Indonesia-based drug production facility. The regulation, which has not yet been imple­mented, gives pharmaceutical manufacturers two years to comply.

Malaysia
Only local companies can submit an application for drug registration. Foreign companies with no local presence in Malaysia must designate a locally established legal entity to be the Market Authorization Holder (MAH). The MAH is responsible for submitting the product applica­tion and ensuring the product’s quality, safety and efficacy. In addition, the country’s National Pharmaceutical Control Bureau (BPFK) only accepts web-based submissions.

Succeeding With Multinational Filings
Today’s highly competitive marketplace requires biopharmaceutical companies to maximize the value of their products by shortening time to approval and launching the products in strategic markets as quickly as possible. A proactive, multi-country regulatory filing strategy helps biophar­maceutical companies of any size to accomplish both of those goals by increasing global sales, reducing regulatory submission costs and lower­ing the risk of regulatory delays or failures. To succeed with multinational registrations, a spon­sor must:
identify key target markets for • submissions
understand important regional • differences
find the right local resources to avoid • regulatory pitfalls

create a robust CTD• develop a submissions strategy that • leverages the CTD to secure regulatory approvals in the shortest possible time.
A strategic multi-country approach will maximize the return on product investments while bringing important therapies to patients who need them around the world—a desirable outcome in any economic environment.

POSSIBLE BENEFITS:-
*    Drug management functions are undergoing transformation in many countries as different ways of health sector reform are being implemented.
*    Introduce the concept of governmental “regulation” and provide a framework for discussions about regulation in developing countries.
*    Regulations and administrative guidelines are “enabled” by legislation enacted into constitutions or statutory law.
*    Regulation of pharmaceuticals as a commodity (i.e., an article of commerce) has inherent contradictions
*    Decentralization of drug regulatory authorities
*    Licensing/GMP/QC
*    Regulatory Changes regarding Drug Schedules
*    Regulatory Changes regarding Facility Inspections
*    Regulatory Changes regarding Advertising/Marketing
*    Regulatory Changes regarding Accreditation of Facilities and Personnel
*    Regulatory Changes regarding Pharmacovigilance

CONLUSION:-
Incorporating regulatory affairs into the pharmacycurriculum will make the pharmaceuticalprofessionals working in the area of regulatory affairs.
By their very nature, the existence of systems to regulate pharmaceuticals create costs and barriers to pharmaceutical availability. To protect the public health, however, access and quality of pharmaceuticals must be regulated.  The means to accomplish this must be based on evidence of the effect of such regulation on availability and quality. It cannot be based on faith or belief.

Our present evidence base in this regard is very weak. To accomplish the laudable goal of basing pharmaceutical regulations on evidence of their effect on drug availability and quality, we need to be creative in studying existing regulatory systems and, in particular, we must pay attention to pharmaceutical availability and quality prior to, during, and after transition periods when  the regulations undergo change(s).  The World Health Organization and should coordinate and promote such studies.

REFERENCES:-

  1. International Conference on the Harmonisation of Technical Requirements for the Registration of Human Drugs. ICH Harmonised Tripartite Guideline Organisation of the Common Technical Document for the Registration of Pharmaceuticals for Human Use M4 (R3). 13 January 2004. Accessible at ich.org/cache/compo/276-254-1.html.
  2. “The ASEAN Common Technical Dossier (ACTD) for the Registration of Pharmaceuticals for Human Use. Organisation of the Dossier.” Accessible at hsa.gov.sg/publish/etc/medialib/hsa_library/health_prod-ucts_regulation/western_medicines/files_guidelines.Par.22449.File.dat/ACTD_OrganizationofDossier.pdf.
  3. “EMEA Implementation of Electronic-only Submissions and eCTD Submissions in the Centralised Procedure: Statement of Intent,” 22 January 2008, EMEA/563366/2007. Accessible at: www.emea.europa.eu/pdfs/human/regaffair/56336607en.pdf.
  4. Volume 2—Pharmaceutical Legislation Notice to applicants and regulatory guidelines medicinal products for human use. EudraLex. Accessible at ec.europa.eu/ enterprise/pharmaceuticals/eudralex/vol2_en.htm.
  5. New Zealand Regulatory Guidelines for Medicines, March 2009. Accessible at medsafe.govt.nz/regulatory/Guideline/Full%20-%20NZ%20Regulatory% 20Guidelines%20for%20Medicines.pdf.
  6. Gupta, P. K. 1998, "Development of Bhutan Medicines Act, 1998 and Bhutan Medicines Regulations, 1998", WHO: Regional Office for South East Asia, vol. WHO Project: BHU DAP 001,
  7. Pharmaceutical Inspection Cooperation Scheme (PICS) 1995, "Pharmaceutical Inspection Cooperation Scheme (PICS)", Pharmaceutical Inspection Cooperation Scheme (PICS) no. PIC/S/1/95, Available at: picscheme.org/docs/pdf/picschem.pdf.
  8. World Health Organization 1991, "The Public/Private Mix in National Health Systems and the Role of Ministries of Health", World Health Organization.
  9. World Health Organization 1993, "WHO Expert Committee on Specifications for Pharmaceutical Preparations", World Health Organ Tech Rep.Ser.33rd Report, vol. 834, pp. 1-30.
  10. World Health Organization 1995, Use of the WHO Certification Scheme on the Quality of Pharmaceutical Products Moving in International Commerce, WHO/DAP/94.21
  11. World Health Organization 1996, "Good pharmacy practice (GPP) in community and hospital pharmacy practice”, World Health Organization, vol. (unpublished WHO document WHO/PHARM/DAP 96.1).,
  12. World Health Organization 1998, How to Implement Computer-Assisted Drug Registration, World Health Organization, Geneva, Switzerland, WHO/DMP/RGS98.2.
  13. World Health Organization 1999a, "Effective Drug Regulation: what can countries do?", World Health Organization Technical Report Series, vol. WHO/HTP/EDM/MAC(11)/99.6,
  14. World Health Organization 1999b, Marketing Authorization of Pharmaceutical Products with Special Reference to Multisource (Generic) Products, WHO/DMP/RGS98.5 edn.
  15. World Health Organization 2000, Quality assurance of pharmaceuticals: A compendium of guidelines and related materials-Good Manufacturing practices and inspection, Volume 2.
  16. World Health Organization 2001, " Improving the quality and usefulness of drug regulatory authority websites." WHO Drug Information, vol. 15, no. 3/4, p. 82.
  17. World Health Organization 2001a, Good laboratory practice: training manual (TRAINER) , TDR/PRD/GLP/01.
  18. World Health Organization 2001b, Handbook: Good laboratory practice
  19. Quality practices for regulated non-clinical research and development, TDR/PRD/GLP/01
  20. World Health Organization. 2002a. The Importance of Pharmacovigilance. World Health Organization/Uppsala Monitoring Center ,pp. 1-48.
  21. World Health Organization 2002b, WHO's Ethical and Scientific Criteria for Pharmaceutical Advertising" , World Health Organization, Annex 3, DGO/ETHCDP/87.3, WHA21 .41.
  22. Pharmacovigilance;en.wikipedia.org/wiki/Pharmacovigilance.
  23. pharmaceutical-drugmanufacturers.com/articles/pharmacovigilance.html
  24. Careers in regulatory affairs from practitioner to professional, nature jobs biotechnology, Vol 20(4), page no. 409-410,april 2001
  25. ijprd.com
  26. sgs.com
  27. cdsco.nic.in
  28. emea.org
  29. fda.org
  30. ec.europa.eu/health/files/eudralex/vol-9/pdf/vol9_10-2004_en.pdf

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