SID & GP MINPROMTORG OF RUSSIA Corporate Communication Center IV ALL-RUSSIA GMP CONFERENCE STERILIZATION OF MEDICINES, PHARMACEUTICAL SUBSTANCES AND CONTAINERS FOR PRIMARY PACKAGING N.Yu. Popova Regional Quality Director, Abbott / Veropharm Abbott Laboratories, Established Pharmaceuticals Division

GUIDELINES OF EUROPEAN MEDICINES AGENCY (EMA) New edition of European legislation Guidelines for the sterilization of medicines, active pharmaceutical substances, excipients and containers for primary packaging. EMA/CHMP/CVMP/QWP/850374/2015 Approved: 06 March, 2019 Carrying into effect: October 01, 2019 General partner: Strategic partners: Official partners: Regional partners:

Introduction Sterility is a critical indicator for all sterile substances, products and containers for primary packaging. Thermal steam sterilization is the preferred method in comparison to sterilization by filtration and / or aseptic filling, because for thermal sterilization the mortality rate of microorganisms and the sterility assurance level (SAL) can be calculated, validated and controlled, thus ensuring the necessary security level. For highly sensitive products, for example, for most biological products for which thermal sterilization is not possible, sterilizing filtration and / or aseptic operations under validated and controlled conditions may also be acceptable.

Purpose and scope of application This guidelines applies to synthetic and biological medical products for human use and for veterinary products, but does not apply to veterinary immunobiological products. The guidelines must be applied together with the directive (Directive 2001/83 / EC) for medical products for human use and the directive (Directive 2001/82 / EC) for medical products for veterinary products and the European Pharmacopoeia. The guidelines must also be applied in conjunction with other relevant guidelines and directives published on the EMA website (www.ema.europa.eu).

REQUIREMENTS FOR THE PRODUCTION OF STERILE PRODUCTS AND STERILE COMPONENTS Sterilization methods STEAM STERILIZATION DRY HEAT STERILIZATION RADIATION STERILIZATION GAS STERILIZATION STERILIZING FILTRATION ASEPTIC PRODUCTION

Bioburden requirements for steam sterilization Cycle Process type Bioburden level before sterilization Bioburden feature Sterilization parameters Ph.Eur. 5.1.1. Standard cycle Sterilization 100 CFU / 100 ml (not routine testing) No Т ≥ 121 °С for ≥ 15 minutes F0 ≥ 12 minutes Т ≥ 121 °С F0 ≥ 8 minutes (routine testing) Т ≥ 115 °С Yes** Yes Т ≥ 110 °С F0 ≤ 8 minutes Aseptic filling, heat treatment 0 CFU / 100 ml, aseptic filtration before heat treatment Yes*** Т ≥ 110°С****  (routine testing) ** Control during the production process, demonstrating bioburden and its resistance to heat *** Bioburden prior to the sterilizing stage (e.g. filtration) should be characterized by thermal resistance **** A temperature below 110 ° C can be used if there is a documented justification.

Bioburden requirement With dry heat sterilization The time, temperature of the sterilization cycle and the level of bioburden before sterilization must be set. 100 CFU / 100 g or 100 CFU / 100 ml for parenteral finished products. 10 CFU / g or 10 CFU / ml - for the active pharmaceutical substance and finished products, not for parenteral administration. With radiation sterilization ISO 11137, Ph Eur, article 5.1.1 With gas sterilization ISO 11135, Ph Eur, articles 5.1.1 and 5.1.2

Bioburden requirements with sterilization filtration In commercial production, the bioburden in the bulk solution is monitored immediately prior to sterilizing filtration. Bioburden limits ≤ 10 CFU / 100 ml If a pre-filter is used, as a preventative measure, bioburden limits ≤ 10 CFU / 100 ml of the solution before pre-filtration. Bioburden limits > 10 CFU / 100 ml for the solution before pre-filtration are acceptable if it is known that the initial components are initially contaminated. In this case, it is necessary to demonstrate that pre-filtration allows achieving bioburden in the bulk solution before sterilizing filtration of ≤ 10 CFU / 100 ml

Choosing a sterilization method for water-based products Use steam sterilization F0 ≥ 8 minutes Carry out all production operations under aseptic conditions, use only components previously sterilized separately and as part of the mixture Use sterilization filtration, pre-sterilized primary packaging containers and aseptic filling Can the product be sterilized at F0 ≥ 8 minutes with SAL ≤ 10⁻⁶? T ≥ 121 ° C for ≥ 15 minutes Can the product be passed through a filter holding microorganisms? NO YES Can the product be steam sterilized at T ≥ 121 ° C for ≥ 15 minutes?

Can a product be passed through a filter holding microorganisms? Choosing a sterilization method for dry powders, non-aqueous liquids, semi-solid products Use dry heat sterilization with an alternative combination of temperature and time to achieve SAL ≤ 10⁻⁶ Use radiation sterilization with a minimum absorption dose of ≥ 25 kGy or a lower radiation dose confirmed by validation The product can be sterilized by dry heat with an alternative combination of temperature and time to achieve SAL ≤ 10⁻⁶ Use dry heat sterilization at T ≥ 160 ° C for ≥ 120 minutes Can the product be sterilized by radiation with a minimum absorption dose of ≥ 25 kGy or using a lower radiation dose confirmed by validation (ISO 11137) Can a product be passed through a filter holding microorganisms? NO YES Can the product be sterilized with dry heat at T 160 ° C for 120 minutes? Carry out all production operations under aseptic conditions, use only components previously sterilized separately and as part of the mixture Use sterilization filtration, pre-sterilized primary packaging containers and aseptic filling

Choosing a sterilization method for primary packaging containers Use radiation sterilization Choose another container Use gas sterilization Can the container be sterilized with radiation? Use steam or dry heat sterilization Can the container be sterilized with gas? NO YES Can the container be thermally sterilized?

Conclusion THE GUIDELINES GIVES CLEAR DEFINITIONS AND CONDITIONS FOR CHOOSING THE METHOD OF STERILIZATION. THIS DOCUMENT MAY BE CONSIDERED AS A BASIC DOCUMENT FOR CHOOSING A METHOD OF STERILIZATION FOR FINISHED MEDICINES, ACTIVE PHARMACEUTICAL SUBSTANCE AND CONTAINERS FOR PRIMARY PACKAGING. THE SELECTED METHOD OF STERILIZATION SHOULD BE DOCUMENTALLY SUBSTANTIATED AND DISPATCHED. BASIC REQUIREMENTS FOR EACH METHOD OF STERILIZATION ARE PROVIDED, THEIR BASIC INDICATORS, INCLUDING THE FACE FACTOR AND STERILITY ASSURANCE LEVEL (SAL). THIS DOCUMENT MUST BE CONSIDERED WITH OTHER DOCUMENTS: GMP RULES, STATE PHARMACOPOEIA AND OTHER LEGISLATION REQUIREMENTS.