Registration Applications and Procedures

Before a new pharmaceutical product can be tested in clinical trials, the test product, its labelling and the intended trials must be approved. This is usually done by the same authority that is responsible for the market approval of the final product. The formal procedures to obtain permission for clinical trials vary. Some countries require only a notification to the authority, which may then object within a certified period, other countries require a formal application in order to obtain approval, e.g. by issuing a Clinical Trial Certificate (CTC), before the trials can commence. 

Notifications or applications for clinical trials are supported by summaries or full reports on the preclinical pharmacology and safety assessment. The kind of safety data (e.g. the type and duration of toxicity tests), which are expected at this time, should correspond to the intended route and duration of application. Data on process details and on the quality of the product are not always required. But it must be kept in mind that clinical trials can only render useful results for the later product registration, if the quality characteristics of the tested product and its method of production are the essentially same as for the final product. If available, clinical data from trials in other countries must also be provided. Protocols for the intended clinical trials are an essential part of the application. 

Abbreviated approval procedures may be applicable for products which are essentially identical to existing products, e.g. for clinical 

In the EEC, applications or notifications for clinical trials have to be lodged with the individual national authorities. A common procedure or even mutual recognition of clinical trial certificates does not exist. A list of the different national requirements is provided in The Rules Governing Medicinal Products in the European Communities Volume III, Annex 1. A discussion paper (III/ 3044/91) released in 1991 by the EEC Division for Pharmaceuticals (DG III) addresses various issues on the harmonization of approval of clinical trials and may eventually lead to common, non-binding recommendations. 

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As shown in Table 8.1, all the countries have written registration application forms, as well as written criteria for dmg assessment and registration. It is unclear, however, whether written documents detailing the registration procedures are available for the applicants, in addition to the application forms. 

Ultimately the technical objective of an analytical procedure, which is included as part of a registration application for pharmaceuticals, is the responsibility of the analytical department. This objective is directly related to the regulatory objective as defined by the regulatory professionals. For example, the regulatory professionals require a means to quantitate an API in a finished pharmaceutical for release between 95-105% of label claim. This translates into a technical objective for the analytical chemist that involves the selection of an analytical technique and the development of a method that has the required accuracy and precision to meet the requirements for release. 

A central EEC registration authority (European Agency for the Evaluation of Medicinal Products) will be established and "shall take up its responsibilities on 1 January 1995 (Council Directive 2309/93 of 22 July 1993). The Committee on Proprietary Medicinal Products, CPMP, which consists of members of the Commission and from the states authorities, plays a central role in the existing and future system. It is assisted by different working parties for specific areas. The CPMP coordinates the procedures, assesses applications and provides "opinion reports" and acts as arbitrator in the case of national discrepancies. However, the opinion reports and decisions of the CPMP are not (yet) binding to the member states. For veterinary products identical rules apply here a CVMP acts as the central body. 

Procedures that are put in place would provide for guidcmce for interested parties on the content and format of registration applications, as well as the circumstances under which an application for renewal, variation or extension will be required. It also has to detail from the onset the criteria on which licence applications will be evaluated. In effect, there should be issuance of guidelines on the procedure to be followed in order to help retain public confidence and respect. 

The multicenter trial approved procedure is described herein. First, the pharmaceutical sponsor submits to the SIPCDE all relevant documentation in accordance with the Instruction. .. (See Appendix 6), which requires a different set of documentation in comparison to product registration dossiers. The documentation is reviewed by the SIPCDE s specialized department and the Cliniced Trials Department, as well as by specialized SPLC commissions, after which they are forwarded for the SPLC s scientific and ethics review. The SPLC then issues a resolution which is issued to the applicant and the SCA. The procedure takes 3 months maximum (in case extra information is needed for approval) and normally lasts 1 month. 

After a theoretical review of the registration application, the MOH requests physical samples of the product for analysis. This cinalysis is performed in an institute called Refik Saydam Hifzisihha Mudurliigii according to the methods and procedure stated in the application file. If the product is to be produced in Turkey, it has to be produced and analysed in Turkey if the product is to be imported it has to be imported from the source declared in the application. The Refik Saydcim Institute analyses the products and compares the results stated in the file by the quality control laboratory. 

Many procedures, including technical guidelines and format and content of registration applications have been grouped and have successfully been harmonized. These are readily available to the scientific community. 

In 1996 and 1997 the International Conference on Harmonization (ICH) published guidelines for analytical method validation [8]. These documents present a discussion of the characteristics for consideration during the validation of the analytical procedures included as part of registration applications submitted within the European Union, Japan, and the United States. 

A registration application should include documented evidence that the analytical procedures are validated and suitable for the detection and quantification of impurities (see ICH Q2A and Q2B on Analytical Validation). Technical factors (e.g., manufacturing capability and control methodology) can be considered as part of the justification for selection of alternative thresholds based on manufacturing experience with the proposed commercial process. The use of two decimal places for thresholds does not necessarily reflect the precision of the analytical procedure used for routine quality control purposes. Thus, the use of lower precision techniques (e.g., thin-layer chromatography) can be appropriate where justified and appropriately validated. Differences in the analytical procedures used during development and those proposed for the commercial product should be discussed... 

Q3A (R2) Impurities in New Drug Substances Page 3 The registration application should include documented evidence that the analytical procedures are validated and suitable for the detection and quantification of impurities (see ICH Q2A and Q2B Guidelines for Analytical Validation)... 

In 1996 and 1997 the International Conference on Harmonization (ICH) published guidelines for analytical method validation [18]. These documents present a discussion of the characteristics for consideration during the validation of the analytical procedures included as part of registration applications submitted within the European Union, Japan, and the United States. Regulatory agencies have emitted documents, largely inspired by ICH documents. It is the case of the FDA [19, 20], the European Medicines Agency (EMA) [21,24], and the Australian Pesticides and Veterinary Medicines Authority [25], to name just a few. 

The scope of ICH QIE addresses the evaluation of stability data that should be submitted in registration applications for new molecular entities and their associated drug products. A systematic approach should be adopted in the presentation and evaluation of the stability information. The stability information should include, as appropriate, results from physical, chemical, biological, and microbiological tests. Mass balance should be assessed and the factors that can cause an apparent lack of mass balance the mechanism of degradation and the stability-indicating capability and inherent variability of the analytical procedures. 

The use of the surface ultrasonic waves seems to be convenient for these purposes. However, this method has not found wide practical application. Peculiarities of excitation, propagation and registration of surface waves created before these time great difficulties for their application in automatic systems of duality testing. It is connected with the fact that the surface waves are weakened by soil on the surface itself In addition, the methods of testing by the surface waves do not yield to automation due to the difficulties of creation of the acoustic contact. In particular, a flow of contact liquid out of the zone of an acoustic line, presence of immersion liquid, availability of chink interval leads to the adsorption and reflection of waves on tlie front meniscus of a contact layer. The liquid for the acoustic contact must be located only in the places of contact, otherwise the influence on the amplitude will be uncontrolled. This phenomenon distorts the results of testing procedure. 

The general assessment indicates that the pharmaceutical industry experiences problems with transparency of dmg registration in two out of the 10 countries— Cypms and Uganda. The main problems cited involve communication between the DRA and the industry regarding clarity of procedures and adequacy of official explanations for the rejection of an application. In Cypms, the Dmg Council also raised issues concerning the fairness of treatment of foreign versus domestic industry, and the arbitration of contradictory quality analysis results provided by different laboratories, both belonging to the Dmg Council. 

Information should be provided in the form of a detailed summary in the ADRAC Blue Card format. Even if initial information is scanty, these details should be forwarded to the TGA pending receipt and provision of further data. This procedure should be followed even when the medicine in question is the subject of an application for registration and imder evaluation by the TGA. 

The contents of the manual are divided into three major sections objectives, quality manuals, and standard operating procedures. The first section addresses the definition of quality, basic changes, correspondence between international standard ISO 9001 (1994) and ISO 9001 2000, and the process of documentation development and application for registration and certification. 

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