Main violations identified by russian gmp-inspectorate

Journal "Remedium" №6, 2018

G.N. Gildeeva¹, PhD Pharmacology, Yu.V. Podbruzhnikov², PhD Pharmacology, V.N. Shestakov³

¹ GBOU VPO "First Moscow State Medical University. THEM. Sechenov »Ministry of Health of Russia
² National Pharmaceutical University of the Ministry of Health of Ukraine, Kharkiv
³ FBU "State Institute of Medicines and Good Practices"

Since April 2016, the Ministry of Industry and Trade of the Russian Federation conducts inspections of foreign pharmaceutical manufactures: foreign enterprises are checked for compliance with Russian standards of good manufacturing practice (GMP), which is essential for drug registration and drug circulation in Russia. Inspection is a key element in assessing the compliance of pharmaceutical companies with GMP requirements. Almost any inspection reveals inconsistencies or irregularities that are recorded in the inspection report and serve as the basis for regulatory actions, such as deciding whether or not to issue a GMP certificate, decree on resolving inconsistencies / violations, suspending or revoking the license, drug registration certificate, prohibition of production, etc.

The European GMP inspectorates, as well as the authorized bodies of the PIC / S, divide the inconsistencies into three levels according to their degree of importance, i.e. severity of the violation:

• critical;
• significant;
• other.

A similar classification recommended by WHO [1--3], the same approach is supposed to be used within the framework of the Eurasian Economic Union (EAEU) [4]. In Russia, the principles of classification coincide with the approach recognized all over the world - violations are divided into critical, essential and non-essential (approved by the order of the Ministry of Industry and Trade) [5].

Critical is a violation or inconsistency that leads or may lead to the production of a medicinal product that can cause harm to health, create a threat to human life.

A violation is considered to be significant, if:

• allows you to produce low-quality drug that does not pose a threat to human health and life,
• is a failure to comply with the requirements of the registration dossier for the drug,
• It is a collection of several minor violations, but together they are a significant violation and should be treated as such.

The least dangerous is other nonconformity which is a nonconformity, which is neither critical nor significant deviations, but indicates violation of certain GMP requirements.

Analysis of major errors during inspections

Inspection of foreign manufacturers by the Russian inspectorate began in April 2016 [6].

The first pant which successfully passed the Russian inspection and received the Russian GMP certificate was CJSC Pharmaceutical Plant EGIS, Hungary [7].

In just two years, from May 2016 to May 2018, the Russian inspectorate issued 746 positive conclusions on the compliance of foreign manufacturers with the requirements of Good Manufacturing Practice. But despite 25 years of experience in applying GMP standards in Europe, Russian inspectors found about 9,000 inconsistencies (2,500 critical, 3,000 significant and 3,500 insignificant). At present, Russian legislation does not have a clear definition of critical, serious and frivolous remarks, just as the permissible number of comments of each category has not been established. Another difficulty faced by foreign manufacturers in evaluating comments is the discrepancy between the criticality criteria adopted in different countries. After analyzing the legislation of different countries in the field of GMP, it is possible to form the following criticality criteria (see table).

Table. Criteria for the criticality of nonconformities identified during GMP inspections

However, the practical experience of the Russian inspectors of GILS and NP already allows you to identify general trends.

Examples of critical and significant inconsistencies identified during inspections [8]:

• release of the drug in violation of the requirements of the registration dossier (for example, the release of the drug to the market based on the results of the analysis of bulk products);
• inconsistency of the methods used by the manufacturer to control the quality of the finished product, the methods specified in the normative documentation (ND) and the registration dossier for the drug. Most often, the manufacturer uses analytical methods of the European and American Pharmacopoeia instead of those specified in the ND techniques Russian Pharmacopeia 13;
• lack of designated isolated areas for storing rejected / withdrawn products, as well as rejected raw materials and auxiliary materials (including for fully computerized storage systems);
• lack of traceability of the amount of printed packaging materials destroyed in the production process with variable information printed on them;
• lack of control of the microbiological purity of primary packaging materials (production of non-sterile solid dosage forms) in the absence of serial control of finished products for this indicator;
• failure to comply with the requirements of the regulatory documentation for a registered medicinal product to the conditions of storage in the finished product warehouse (for example, the requirement of a “dry” place in the Russian Pharmacopeia 13);
• lack of confirmation (validation) of time intervals between the end of the process and cleaning of production equipment, as well as between the cleaning and the start of the next process (clean hold time / dirty hold time).

In order to minimize the risks of refusing to receive a Russian GMP certificate, before inspection, many manufacturers conduct a pre-audit with an invitation from an independent GMP specialist and align the analytical documentation for the preparations produced for the Russian market to the requirements of the Russian regulatory documentation. This procedure allows manufacturers to save time and money, because in the case of a negative conclusion, the duties paid are not returned and it is necessary to collect the entire package of documents to submit a new application.

What to do if critical comments are received?

If a foreign manufacturer treats the inspection seriously and responsibly, when identifying comments during the inspection and in the process of preparing the report, he has the opportunity to present a plan of preventive and corrective actions (so-called CAPA), and in the event that comments can be eliminated by these actions they are removed. At the same time, if the comments related to the documents, a re-departure of the inspector will not be required (for example, at the time of the inspection, the manufacturer could not submit any documents or required changes to the registration dossier). And in the case of technical comments (for example, regarding the water treatment system or air purification), a second departure of the inspector may be required after the elimination of the observed violations.

All of the above applies not only to manufacturers of finished medicines, but also to manufacturers of pharmaceutical substances. If a substance is submitted for examination in order to be included in the State Register of Medicinal Products of the Russian Federation, its manufacturer must also undergo a GMP inspection. If the substance is part of the drug, its quality is the responsibility of the manufacturer of the drug.

Conclusion

The pharmaceutical industry today is one of the most successful in the Russian economy. The results of its work in 2017 were discussed at the main business meeting of the year - the XIII International Conference "Pharmaceutical business in Russia: a promising scenario for the development of the pharmaceutical market for 2018", which took place on February 20, 2018 in Moscow. Deputy Minister of Industry and Trade of the Russian Federation S.A. Tsyb became a guest of the conference and shared with its participants the results of the implementation of the Pharma-2020 course. “Big changes are needed, we are constantly opening up new horizons,” said Sergey Anatolyevich. - Today there is a formation of working groups to discuss priorities in the development of the industry until 2030. The ministry is open to dialogue and strongly supports the process of import substitution, because the main priority is to support our own developments and create additional measures to stimulate Russian products. ” Under these conditions, the earliest receipt of a Russian GMP certificate becomes for pharmaceutical companies a prerequisite for successful work in Russia and the EAEU countries. The sooner the producer receives a positive conclusion from the Russian inspectorate, the more chances he has for not only preserving, but also increasing the share of his presence in this market.

Reference
1. EMA/572454/2014 Rev.17. GMP Inspection Report – Union Format. P.175-178. http://www.ema.europa.eu/.
2. PI 013-3. Standard operating procedure PIC/S Inspection Report format. Annex. 1. PIC/S 25 September 2007. http://picscheme.org/.
3. Guidance on Good Manufacturing Practices: inspection report. WHO Technical Report Series, No 996, 2016 Annex 4. http://who.int.