Inspection activities aimed at confirming the compliance of a manufacturer of veterinary medicinal products with the requirements of Good Manufacturing Practice (GMP) are carried out by the Federal Service for Veterinary and Phytosanitary Surveillance (Rosselkhoznadzor).
Based on the Decree of the Government of the Russian Federation of December 3, 2015 No. 1314 and the Order of the Head of the Rosselkhoznadzor of February 29, 2016 No. 97, the Federal State Budgetary Institution “The All-Russian State Center for Quality and Standardization of Veterinary Drugs and Feed” (FSFI “VGNKI”) is an institution authorized to conduct inspections of manufacturers of veterinary medicinal products manufactured outside the Russian Federation (foreign manufacturers).
Inspection of foreign manufacturers of veterinary products began in 2017.
According to the register of issued conclusions published on the official website of the Rosselkhoznadzor 08.10.2019 , in the period from June 2017 to August 2019, inspectors of the FSFI “VGNKI” conducted 70 inspections (including follow-up inspections) in 22 countries of the world: Australia, Austria, Belgium, Bulgaria, Brazil, the UK, Hungary, Germany, Israel, Spain, Italy, China, Mexico, the Netherlands, New Zealand, Romania, Slovenia, the USA, France, Croatia, the Czech Republic and Estonia.
During this period, the largest number of inspections was carried out in Spain (11), France (10), the USA (7), the UK (6), Belgium (5) and Germany (5) (Figure 1).
REASONS FOR REFUSAL TO ISSUE A CONCLUSION
According to the register of issued conclusions, the reasons for refusing to issue a conclusion to foreign manufacturers were:
- non-compliance of the manufacturer with the GMP Rules requirements (37 refusals);
- decision of the authorized body to refuse to conduct inspections (14 refusals);
- failure to eliminate violations when submitting an application and / or lack of confirmation of the fact of payment for issuing a conclusion (7 refusals) (Figure 2).
RESULTS OF INITIAL INSPECTIONS
In the period from June 2017 to August 2019, employees of FSFI “VGNKI” conducted 62 initial inspections of manufacturing sites of foreign manufacturers:
- in 2017 – 18 inspections (11 refusals to issue a conclusion, which is 61% of the total number of inspections performed);
- in 2018 – 27 inspections (13 refusals to issue a conclusion, which is 48% of the total number of inspections performed);
- in the period from January to August 2019 – 17 inspections (11 refusals to issue a conclusion, which is 65% of the total number of inspections performed) (Figure 3).
An analysis of the results of initial inspections shows that manufacturing sites located in the USA and France received the refusals more often. Therefore, the participation of representatives of the regulatory authorities of these countries in the recent All-Russia GMP conference was especially important.
All 7 sites inspected in the USA were refused to issue a conclusion, and only one of the 9 sites inspected in France received a positive conclusion (Figure 4).
Among the largest foreign manufacturers of veterinary medicinal products, there are such companies as Zoetis, Boehringer Ingelheim Animal Health, MSD Animal Health, Elanco, Bayer Animal Health, Ceva Sante Animale. Historically, the market for veterinary products is quite closely associated with the market for medicinal products for human use. Key veterinary market players have or have had links with major pharmaceutical giants such as Pfizer, Novartis, MSD, Sanofi, Eli Lilly, Bayer, Boehringer Ingelheim.
The average percentage of refusals as a result of inspections of the manufacturing sites of the largest foreign manufacturers of veterinary products and the sites of their contract manufacturers (CMO) amounts to more than 60% of the total number of inspections carried out at these sites.
In 2018, employees of the FSFI “VGNKI” performed 5 follow-up inspections of manufacturing sites of foreign manufacturers who were refused in 2017. Based on the results of these inspection, all sites were issued conclusions on compliance with the GMP Rules requirements.
In the period from January to August 2019, 3 follow-up inspections were performed. Based on the results of these inspection, a conclusion was issued to one site, and two sites received a refusal.
WORK WITH APPLICANTS
This year, Russia has organized and carried out several different events, one way or another related to the inspection of manufacturers of veterinary products.
In January 2019, Moscow hosted one of the most famous agricultural events in Russia – the XXIV International Industrial Trade Fare “MVC: Cereals-Mixed Feed-Veterinary-2019”. Within the framework of the exhibition, the FSFI “VGNKI” organized a round table on the topic “Russian quality control system for medicinal products for veterinary use: 2018 results and development prospects” . At this round table, Danil Rudniaev, the head of the department of inspection of production for compliance with the requirements of Good Manufacturing Practice of the FSFI “VGNKI” presented the topic “The most frequently identified nonconformities with the requirements of the Rules of Good Manufacturing Practice (GMP) when inspecting the sites manufacturers of medicinal products for veterinary use. The recommendations on preparation for an inspection (verification of compliance with licensing requirements)”. The list of the most frequently encountered nonconformities was published on the FSFI “VGNKI” website .
In March 2019, on the Rosselkhoznadzor website, “A draft of fillable forms to eliminate nonconformities on the results of the inspection of manufacturers (foreign manufacturers) of medicinal products for veterinary use” was published . The draft includes the following fill-out forms:
- a plan of corrective and preventive actions based on the results of the inspection of the manufacturer (foreign manufacturer) of medicinal products for veterinary use;
- a report on the implementation of corrective and preventive actions based on the results of the inspection of the manufacturer (foreign manufacturer) of medicinal products for veterinary use.
In April 2019, on the Rosselkhoznadzor website, “Recommendations for application of the principle of bracketing when the validation of production processes” was published .
In April 2019, the IX International Veterinary Congress was held in Svetlogorsk . Within the framework of the congress, the conference “Current issues of circulation and production of veterinary medicines in the EAEU and foreign countries” was organized by the EEC, the Ministry of Agriculture of the Russian Federation, Rosselkhoznadzor and the FSFI “VGNKI”. The report of Danil Rudniaev on the topic “Dynamics and prospects of development of legislation in the field of organization of production of medicinal products for veterinary use. The interim report”, in particular, provided the following statistical data: in total, for 2017 and 2018, 70 applications for inspecting manufacturing sites of foreign manufacturers were received.
The Ministry of Agriculture of the Russian Federation has prepared a draft Federal Law “On amending certain legislative acts of the Russian Federation on the issue of putting medicinal products for veterinary use into civil circulation” . In the revised text of the draft, it was stipulated that before putting into the civil circulation each batch of a medicinal product for veterinary use imported (transferred) to the Russian Federation, the organization importing (transfer) the medicinal product into the Russian Federation represents to the federal executive body that exercises the functions on supervision in the field of circulation of medicinal products for veterinary use, among them a copy of the conclusion on the conformity of the manufacturer of medicinal products with the requirements of Good Manufacturing Practice issued for the manufacturing site of the veterinary medicinal product, introduced into circulation by the authorized federal executive body.
Rosselkhoznadzor has prepared a draft new methodology for calculating the maximum fee for the provision of services for inspecting manufacturers of veterinary medicinal products manufactured outside the Russian Federation for compliance with the requirements of Good Manufacturing Practice rules in order to issue certificates on compliance of manufacturers of veterinary medicinal products with the requirements of Good Manufacturing Practice. According to the text of the draft, the maximum fee for this service should be 4,781,183, 80 rubles .
ANSWERS TO CURRENT ISSUES
On September 24, in the framework of the IV All Russia GMP Conference with international participation, organized by the Ministry of Industry and Trade of Russia together with the FSI “SID & GP”, a panel discussion and a round table for manufacturers of veterinary medicines were held. Their organizer was FSFI “VGNKI”.
Representatives of the FSFI “VGNKI”, Rosselkhoznadzor and foreign regulators took part in the panel discussion “Issues of regulating production and circulation of veterinary medicines”.
First, Anna Babushkina, the deputy head of the section for internal veterinary supervision of Rosselkhoznadzor, spoke about the changes in the regulatory framework regarding the regulation of the circulation of medicinal products for veterinary use in the Russian Federation .
Then there were presentations of three foreign experts .
Steven Karli, the director of the Center for veterinary biologics, Animal and plant health inspection service, the United States Department of Agriculture (USDA), spoke about the particularities of organizing and conducting inspections of manufacturers of immunobiological medicinal products for veterinary use in the United States of America.
Vincent Neuviale, the inspector of manufacturers of veterinary medicines, provided information on the GMP inspection conducted by the French Agency for Veterinary Medicinal Products (ANMV).
Eric De Ridder, the Steering Committee member of the International Cooperation on Harmonization of Technical Requirements for Registration of Veterinary Medicinal Products (VICH), presented the work of his association.
Right after the panel discussion, a round table discussion “Actual issues of inspecting manufacturers of medicinal products for veterinary use for compliance with the requirements of Good Manufacturing Practice” was held. At this round table, Danil Rudniaev presented statistical data and commented on the most frequently encountered nonconformities when inspecting manufacturers of medicinal products for veterinary use a list of which was published on the FSFI “VGNKI” website. Below are just some of his comments.
Validation of aseptic processing does not include the process simulation test using a nutrient medium (filling with nutrient media, Media Fill Test). The requirements of the validation of aseptic processing (MFT) are not complied with: 1) Various interventions known to occur during normal production as well as “worst-case“ situations aren’t taken into account; 2) The frequency of the MFT and the participation of operators in it is not respected.
In February 2019, following our meetings with reference groups, we evaluated the approach to the validation of this process, took into account the experience of our foreign colleagues and developed recommendations for application of the principle of bracketing when the validation of aseptic filling. I think that ended up simplifying the organization of aseptic filling process validation after all, but I would like to draw the attention of manufacturers to the fact that we will only accept the bracketing process if the initial Media Fill Test was carried out in three consecutive tests, as specified in the GMP Rules: for each process, for each volume, for each type of packaging. Each operator who participates in this process should participate in the Media Fill Test once a year and carry out worst case situations, interventions that are imputed to functional responsibilities and which he subsequently performs the routine in the process.
The frequency of particles monitoring in clean areas in the production of sterile medicinal products for veterinary use is not respected. When performing aseptic processes, microbiological monitoring is not performed by all the methods provided.
The requirements of Appendix 1 to the GMP Rules indicate that particle monitoring should be carried out continuously in Grade A areas. But the Rules also give some concessions in this: if there is a risk of contamination by biological agents or contamination of the counter itself, in such cases monitoring during routine equipment set up operations should be undertaken prior to exposure to the risk. Such monitoring should be carried out without fail, and information on this monitoring should be taken into account when compiling the batch dossier. Annex 1 to the GMP Rules clearly defines what types of microbiological monitoring should be used in aseptic processes. All results of this monitoring should be reflected in each batch dossier.
Process validation did not include three successive consecutive batches (cycles), at which the parameters were within the established limits.
For whatever reason, in many enterprises, inconsistent batches are included in the validation. An enterprise, for example, selects two consecutive batches, then some batches are manufactured routinely, and after some time the next batch is included in the validation report. The GMP rules state that validation is carried out in three consecutive batches, and only in this case validation can be accepted as a completed process.
Absence of cleaning validation for technological equipment that are in contact with the product as well as laboratory glassware.
Although the GMP rules clearly stipulate that cleaning should be validated, we still face the fact that it either does not take place at all, or factors that should be taken into account during validation are not taken into account. The main factors that must be taken into account during cleaning validation are the residual amount of the product, which may affect the quality of the subsequent product, and the residual amount of detergents. Accordingly, here it is necessary to conduct a risk assessment to select the worst case or to validate each product separately and determine the residual amount.
The time and temperature of storage or thermolabile medicinal products for veterinary use outside the established conditions are not determined.
Here we are talking about the cold chain. This applies to those products for which special storage conditions are required.
The requirements of storage conditions established by the manufacturer for starting materials, packaging materials and finished products are not complied with, or their monitoring is not performed (temperature, humidity).
For the starting materials, the manufacturer of these starting materials has established storage conditions: temperature criteria, relative humidity criteria. At enterprises, either these limits are often exceeded, or, for example, one of the parameters (most often this is relative humidity) is not controlled in principle. Or, if controlled, it is not taken into account during qualification.
The storage of reference samples of every batch of starting materials, primary packaging materials and finished products is not carried out. The size of the reference samples is not sufficient to permit the carrying out of two full analytical controls on the product batch.
It should be said that, as a rule, enterprises for some reason miss reference samples of packaging materials, primary packaging materials. GMP rules clearly stipulate that the reference sample should be of sufficient size to permit the carrying out on two occasions of the full analytical controls on the batch. That is, we are talking about the fact that for storage it is necessary to store the number of products that will be enough to carry out control on all quality indicators that were provided in the registration dossier.
Retention samples are not representing the batch of finished products in the form in which they are distributed in the Russian Federation.
At some enterprises, we were faced with the fact that they do not always see the difference between retention and reference samples. In many cases, the reference and retention samples of the finished product are identical, but only if the reference samples are stored in the form in which they are sold to the consumer.
The control methods used in the quality control laboratory don’t meet the requirements of the Registration dossier for the submitted medicinal products for veterinary use.
Here we can talk about the use of equipment, and the time required for the control, and about the reference samples that are used, and about the age and sex of the animal which is used for quality control. If the control method is described in the registration dossier, then this control method should be used by the enterprise to production.
The program on the on-going stability studies is not included annually one batch of medicinal products in each dosage and in each type of primary packaging. The program on the on-going stability studies does not include the bulk products stored for a long period before being packaged.
This requirement is clearly described, both in the Russian GMP Rules and in the EU GMP Rules, but we are still faced with the fact that only one type of product, once a year in only one volume is often included in the stability programme; whereas each volume must be included. The stability of bulk products that are stored for a long period before being packaged should be studied.
Absence of Outsourced activities control.
Outsourced activities should be monitored and audited by the enterprise, reporting documents should be available. But sometimes this is not even provided for in technical agreements, contracts with a service provider.
Then Danil Rudniaev, Anna Babushkina and the head of service of monitoring of efficiency and safety, standardization and examination of medicinal products for veterinary use and of feed additives of the FSFI “VGNKI” Vasilina Gritsyuk, answered questions from foreign and Russian manufacturers of medicinal products.
The round table lasted more than two hours, and experts were able to answer more than 30 questions from manufacturers. Also, as part of the Conference, representatives of Rosselkhoznadzor and the FSFI “VGNKI” held separate negotiations with Steven Karli, the USDA representative. The parties expressed interest in cooperating and informing each other about upcoming inspections and discussed the systems of inspection of manufacturers of medicinal products for veterinary use in Russia and the USA .
The material presented was prepared using data relevant to 14.10.2019. In the case of new or additional data, the article can be updated.
Konstantin Morozov, GMP Specialist of Ceva Sante Animale LLC
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