International Pesticide Product Registration Requirements

Chapter 28

GLP Considerations on the Road to Mutual Acceptability: A Swiss Perspective

Downloaded by UNIV MASSACHUSETTS AMHERST on September 23, 2012 | http://pubs.acs.org Publication Date: June 16, 1999 | doi: 10.1021/bk-1999-0724.ch028

Iris R. Wüthrich Quality Assurance Unit, RCC Umweltchemie AG, Zelgliweg i, CH-4452 Itingen, Switzerland

Thanks to several agreements for the mutual acceptance of GLP between Switzerland and the OECD, U.S. EPA and FDA, as well as with different Japanese ministries, the Swiss GLP is accepted worldwide. Responsibility for the GLP compliance procedures in Switzerland lies with three authorities, the Federal Office of Public Health (BAG); the Federal Office of Environment, Forests and Landscape (BUWAL); and the International Office for the Control of Medicaments (IKS). The Swiss Guidelines, "Good Laboratory Practice in Switzerland, Procedures and Principles", March 1986, are based on the "Decision of the OECD Principles of Good Laboratory Practice," Paris, France, 1981. Besides GLP compliance, special reporting formats are required by different registration authorities, e.g., U.S. EPA PR Notice 86-5 or the German BBA. This can lead to complications since GLP allows only one final report.

The GLP Regulations in Switzerland were promoted to accommodate the large number of chemical and pharmaceutical companies and contract research organizations whose studies are being used for registration purposes worldwide. Compliant laboratories are inspected by the authorities every two years. Swiss GLP studies are accepted by the submission authorities all over the world; for instance, in the different EU countries, the USA, Japan and other Far Eastern countries. Regulatory Basis for GLP In Switzeriand The Swiss GLP Monitoring System operates in the following manner: Firstly, the testing facility intending to perform GLP studies has to apply for an authority inspection;

232

© 1999 A m e r i c a n C h e m i c a l Society

In International Pesticide Product Registration Requirements; Garner, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1999.

233 Secondly, the facility will be inspected by representatives of the concerned authorities; and Finally, after having successfully passed an inspection, the facility receives:


• An inspection report describing the observations, findings and deficiencies. • An official decision from the monitoring authority concerning the GLP compliance status. For purposes of information, the official decision also is included in two further documents, namely. • As a Statement of GLP Compliance, issued by the Department of the Interior. This certificate-like document is given to the testing facility for use as a submission document in countries like Germany. • As an entry in the annual report of the GLP authorities, which contains an inventory of all testing facilities inspected. This document is exchanged for information between GLP monitoring authorities of the OECD member countries. Usually after two years, but not later than three years, the inspection is repeated and the procedure described above begins anew. The Swiss GLP Guidelines. The present Swiss guidelines, "Good Laboratory Practice in Switzerland, Procedures and Principles" (7), March 1986, are based on the OECD Principles of Good Laboratory Practice of May 12, 1981 (2). This also includes the recommendation of the OECD Council concerning the Mutual Recognition of Compliance with GLP of 1983. Since the early eighties, however, times have changed a great deal in the Swiss GLP world: The requirements of the authorities have increased and GLP has expanded into new areas. Multi-site studies, Principal Investigators, electronic data processing, etc., are some examples. Therefore, several OECD Consensus Documents have been issued in the last few years describing how GLP should be applied. Some excerpts from several Consensus Documents have been included in the newly revised (1997) and published (January 1998) OECD GLP guidelines. As Switzerland is also an OECD Member State, the GLP changes described in the different Consensus Documents are normally included in daily GLP work as soon as the respective papers have been issued. In addition, once the 1997 OECD GLP guidelines (3) are officially translated into German, the Swiss GLP guidelines (1986) will bç revised accordingly. In Switzerland four official languages are recognized. The GLP guidelines are available in three of these languages: German, French and Italian, as well as in the internationally acceptable language, English. The Swiss GLP Authorities. The responsibility for monitoring GLP compliance in Switzerland is assigned to the Federal Office of Public Health (BAG), the Federal


234 Office of Environment, Forests and Landscape (BUWAL), and the Intercantonal Office for the Control of Medicaments (IKS), (Figure 1 and Table I).

Table L Delineation of Responsibilities


Types of Studies

Types of Chemicals Pharmaceuticals

Agrochemicals Industrial Chemicals

Physical/Chemical

IKS

BAG or BUWAL

BAG or BUWAL

Toxicological

IKS

BAG

BAG

BUWAL

BUWAL

BUWAL

Ecotoxicological or Environmental

The GLP Inspection Procedure. The GLP authority inspection process begins when a testing facility requests an inspection by writing to the responsible authorities. With a view towards international acceptance, a frequency of routine inspections of approximately every two years is recommended. Small testing facilities are subsequently inspected by one of the three authorities (according to Table I). The duration of the inspection varies depending on the size of the testing facility and the findings of earlier inspections. Usually, the inspection team consists of two inspectors. Larger testing facilities with activities in several fields may be inspected by more than one authority. Upon request of the testing facility inspections are performed in a coordinated way by the three responsible authorities. Test facilities that perform tests for different types of chemicals within the same laboratories may apply for a joint inspection of all authorities involved. The inspections are conducted in accordance with the OECD Series on Principles of Good Laboratory Practice and Compliance Monitoring: Guidance and Consensus Documents (No. 2-10) (4). A routine inspection of our company, RCC, with approximately 400 staff, requires 30 man-days of inspection. In practice, this means that six inspectors spend one week at RCC. After the inspection, the testing facility receives the authority's inspection report containing, among other things, the result of the inspection, specific findings and conclusions concerning compliance or noncompliance. Inspection reports are presented to the test facility in draft form for comments of inconsistencies. The test facility responds in writing, thus confirming the findings of the inspectors and where required, explaining what corrective actions will be taken to avoid future deficiencies. If the deficiencies found were only of minor importance and did not interfere with the integrity of data, and if the authorities are satisfied with the corrective actions promised by the testing facility in writing, the authorities issue an official decision confirming GLP compliance. Should, however, major deviations



235

Figure 1. The Agencies Responsible for GLP in Switzerland THE SWISS GLP AUTHORITIES

INTERKANTONALE KONTROLLSTELLE FUR HEILMITTEL OFFICE INTERCANTONAL DE CONTRÔLE DES MÉDICAMENTS UFFICIO INTERCANTONALE DI CONTROLLO DEI MEDICAMENTI

BUWAL,Bundesamt fur Umwelt, Wald und Landschaft OFEFP, Office fédéral de l'environnement, des forêts et du paysage UFAFP, Ufficio fédérale dell'ambiente, délie foreste e del paesaggio FOEFL, Federal Office of Environment, Forests and Landscape Bundesamt fur Gesundheitswesen

Office fédéral de la santé publique Ufficio fédérale délia sanità pubblica Swiss Federal Office of Public Health


236


from GLP be detected or only insufficient corrective actions be proposed, a negative decision may be taken. The testing facility will be mentioned in the annual report as not confirmed, and no Statement of GLP Compliance will be issued by the Department of the Interior. At present, the Swiss GLP compliance-monitoring program encompasses 70 testing facilities. Swiss GLP Compliance Statement If the inspection confirms that the principles of GLP are respected and followed, the Federal Department of the Interior will issue a GLP Statement of Compliance (usually written in English) containing the inspection dates and the names of the certified testing facilities (Figure 2). The areas of expertise for which the facilities are GLP certified are mentioned in the authorities' inspection reports and on the GLP Compliance Statement. International Acceptance of Studies Performed in Switzerland As a Swiss contract laboratory, RCC often finds itself in the situation where, at the special request of our sponsors, we have to take into account not only the Swiss GLP guideline, to which we are bound, but also to consider other national regulations, such as, the German "Chemikaliengesetz" or the American EPA (5) or FDA GLP Regulations. Based on the OECD decision on Mutual Acceptance of Data and due to additional bilateral agreements with other OECD member countries, the Swiss GLP Guidelines are recognized widely around the world, and studies performed according to them are accepted. In Europe, a bilateral agreement exists today between Germany (6) and Switzerland. Negotiations for a Mutual Recognition Agreement are currently ongoing with the Commission of the European Union. Further agreements have been signed with several Japanese ministries, namely, the Ministry of Agriculture, Forestry and Fisheries (MAFF) (7) in 1993 and the Ministry of Health and Welfare (MHW) and the Ministry of International Trade and Industry (MITI) (8) in 1994. In addition, a memorandum of understanding was signed between the Swiss authority and the American FDA in 1985 (9), and with the EPA in 1988 (10). An extract of the memorandum of understanding (MOU) between the U.S. EPA and the Swiss authority reads: "Although not identical, the GLP principles of both parties are comparable and, therefore, mutually acceptable. They are adequate to foster the collection of quality data and satisfy the Principles of Good Laboratory Practice recommended by the OECD." The respective agencies of both countries assess adherence to the principles of good laboratory practice through the conduct of periodic inspections by a trained government inspectorate.


237

Figure 2. Swiss GLP Compliance Statement EIDGENOSSISCHES DÉPARTEMENT


DIPARTIMENTO

GLP

It

DEPARTEMENT FÉDÉRAL

DE

FEDERALE

D E S I N N E RΝ

L'INTÉRIEUR DELLINTERNO

Compliance Statement

i s hereby c e r t i f i e d

that

on

F e b r u a r y 12-16, 1996 F e b r u a r y 19-23, 1996 June 14, 1996

the

testing

facilities

of

RCC H o l d i n g Company L t d 4414 Fûllinsdorf Switzerland

were i n s p e c t e d by t h e F e d e r a l O f f i c e o f P u b l i c H e a l t h , the F e d e r a l O f f i c e o f Environment, F o r e s t s and Landscape and the I n t e r c a n t o n a l O f f i c e f o r t h e C o n t r o l o f Medicaments w i t h r e s p e c t t o the c o m p l i a n c e w i t h t h e Swiss GLP P r i n c i p l e s . The i n s p e c t i o n was p e r f o r m e d i n agreement w i t h t h e OECD G u i d e l i n e s f o r N a t i o n a l GLP I n s p e c t i o n s and A u d i t s and c o m p r i s e d t h e following testing f a c i l i t i e s : -

RCC R e s e a r c h and C o n s u l t i n g Company L t d , I t i n g e n RCC Umweltchemie AG, I t i n g e n RCC P h a r m a n a l y t i c s L t d , I t i n g e n BRL B i o l o g i c a l R e s e a r c h L a b o r a t o r i e s L t d / M i c r o b i o l o g y , Fûllinsdorf

I t was found t h a t t h e a f o r e m e n t i o n e d t e s t i n g f a c i l i t i e s were o p e r a t i n g i n c o m p l i a n c e w i t h t h e Swiss P r i n c i p l e s o f Good L a b o r a t o r y P r a c t i c e (Good L a b o r a t o r y P r a c t i c e [GLP] i n S w i t z e r l a n d , P r o c e d u r e s and P r i n c i p l e s , March 1986) a t t h e time they were i n s p e c t e d .

FEDERAL DEPARTMENT OF THE INTERIOR

^—A Bern, J u l y 9, 1996

Ruth D r e i f u s s Federal C o u n c i l l o r



238 The inspection programs, which are mutually acceptable, permit assessment of current laboratory and field operations, as well as the audit of final reports of selected studies. Switzerland, for example, was recently (1996) visited by the U.S. FDA. The last inspection performed at one of R C C s testing facilities by the FDA-equivalent Swiss authority was attended and observed by Mr. Stan Woollen, Director, Division of Compliance Policy, FDA. As a result of this inspection, RCC received a written confirmation from the Swiss authority. The EPA has announced that it plans to inspect the Swiss authorities some time in 1998. GLP Regulations Versus Different Reporting Requirements for Registration The reporting requirements from the different registration authorities, e.g., the German BBA, the EU and the American EPA PR Notice 86-5 (77), may have an impact on the GLP compliance of a finalized report. The first example relates to the general report format. The differences become apparent within the first few pages. A report written for submission for a German registration of an agrochemical requires, on the second page, a copy of the authority's GLP Compliance Statement of the testing facility where the study was performed. A report for EPA submission - on the other hand - doesn't need this GLP Compliance Statement, but it does require, the following (72): • • • •

the statement of data (no) confidentiality claims (page 2) the GLP compliance statement (page 3) certification by the applicant that the report is an unaltered copy as received from the testing facility (page 4) the QAU statement (page 5)

If a pharmaceutical/chemical company wishes to submit his EU report to the United States EPA, the administrative pages of this document must be modified according to the submission requirements of the EPA PR Notice 86-5 and the testing guidelines, as described above. Statements of Compliance: EU versus EPA. The second example concerns the GLP compliance statement. For EU submissions, the Statement of Compliance is only required to be signed by the Study Director. The GLP Statement of Compliance for EPA submissions, however, requires the sponsor to sign the Statement of Compliance in addition to the Study Director, as both bear joint responsibility for the performance of the study in conformity with GLP. A third signature has to be given by the person submitting the study to the authorities. Concerning the Statement of Compliance, RCC was once faced with the following problem: A European agrochemical company was taken over by an American company. Consequently, the American company became the owner of the studies previously performed and, naturally, wanted to use them in the U.S. for submission.



239 The studies performed almost a decade ago were intended for European submission only. The respective reports contained the European version of the Statement of Compliance, signed only by the Study Director and not, as required by 40 CFR 160, with the Study Sponsor's and Submitter's signatures in addition. Occasionally, reports which were finalized more than ten years ago, do not contain a Statement of Compliance. At that time, neither the OECD nor the Swiss or German GLP guidelines required one. A representative of the American company, mentioned above, wanted to submit the study reports to the U.S. EPA authority. Not being familiar with the MOU between the U.S. and Switzerland, he asked RCC to add or to revise a Statement of Compliance - revised in the sense of a rewritten and newly signed statement. How could the problem best be solved? If the Study Director was still employed by RCC, the only solution would be to modify the final report to comply with the EPA submission requirements. However, what would happen if the Study Director had left the testing facility? For the studies concerned, the Study Director must be changed by amendment to the report. That would mean, however, that a "new" Study Director would have to sign a statement for a study he does not know and was never involved in! Such an action would be a real GLP violation and, therefore, unacceptable. A further point which must be taken into account is the Study Sponsor's signature. The original Sponsor Representative may have another position within the company or even works for a different organization. Considering these facts, it would be impossible to revise the Statement of Compliance since this would violate the point of GLP. The situation was discussed with the Swiss GLP authority in order to find a solution. They referred to the existing MOU between EPA and Switzerland. In the scope of the mutual acceptability, the old European reports must be accepted as they are, without any revised Statement of Compliance. The American company was informed accordingly and they accepted our proposed procedure. Conclusion The objectives of the GLP regulations are similar in all countries, namely, the performance of scientifically sound and well documented studies. Thanks to mutual acceptance, duplication of studies can be avoided and, therefore, animals, materials and money can be saved! Hopefully, the authorities of all OECD member nations will, in future, accept studies in spite of some variations which may occur in the GLP regulations of these different countries. Finally, it should be emphasized that good communication between all involved is essential in order to create a solid basis of confidence between the testing facility, the sponsor and the different authorities. This is a vital prerequisite for the success of any study.


240 Acknowledgments Special thanks are due to Dr. H. A. Hosbach of the Federal Office of Environment, Forests and Landscape (BUWAL) and Dr. M. J. Mirbach of RCC Umweltchemie AG for their review and constructive comments, and to S. Pendley for preparing the text.


Literature Cited

1. Federal Department of the Interior. Good Laboratory Practice (GLP) in Switzerland, Procedures and Principles; March 1986. 2. OECD Principles of Good Laboratory Practice, May 12, 1981. Republished as document OECD/GD (92) 32 in 1992. 3. OECD Principles of Good Laboratory Practice. [C(97)186/Final]; as revised in 1997. 4. OECD Series on Principles of Good Laboratory Practice and Compliance Monitoring. GLP Consensus Document No. 2-10; 1995. 5. Environmental Protection Agency; 40 CFR Part 160. Federal Insecticide, Fungicide and Rodenticide Act, Final Rule; August 17, 1989. 6. Bundesministerium für Umwelt, Naturschutz und Reaktorsicherheit. Bekanntmachung über Vereinbarungen zwischen der Bundesrepubli Deutschland einerseits undÖsterreich,der Schweiz und den Vereinigten S von Amerika andererseitsüberdie Gute Laborpraxis bei Arzneimi Chemikalien und Pflanzenschutzmitteln; 8. Februar 1989. 7. The Ministry of Agriculture, Forestry and Fisheries of the Japanese Government and the Federal Department for Economic Affairs of the Swiss Confederation. Arrangement; January 18, 1993. 8. Ministry of Health and Welfare and the Ministry of International Trade and Industry of the Japanese Government and the Federal Department for Economic Affairs of the Swiss Confederation. Arrangement; March 28, 1994. 9. The Federal Office for Foreign Economic Affairs, Federal Department of Public Economy of the Swiss Confederation and the Food and Drug Administration U.S. Department of Health and Human Services. Memorandum of Understanding; April 29, 1985. 10. The Federal Office for Foreign Economic Affairs, Federal Department of Public Economy of the Swiss Confederation and the United States Environmental Protection Agency. Memorandum of Understanding; June 22, 1988. 11. Akerman, J. W. PR Notice 86-5, Notice to Producers, Formulators, Distrib and Registrants; U.S. Environmental Protection Agency: Washington D. C., July 29, 1986. 12. Garner, W. Y., Barge, M. S., Ussary, J. P. Good Laboratory Practice Standards; Applications for Field and Laboratory Studies; American Chemical Society: Washington D. C., 1992.


International Pesticide Product Registration Requirements

Recommend Documents