Regulatory trends and case studies SID & GP MINPROMTORG OF RUSSIA Corporate Communication Center IV ALL-RUSSIA GMP CONFERENCE A risk-based approach to the classification of detected non-conformities with GMP requirements. Regulatory trends and case studies

Classification of non-conformities ORDER N 261 dated February 4, 2016 MINISTRY OF INDUSTRY AND TRADE OF THE RUSSIAN FEDERATION  DECISION N 83 dated November 3, 2016 ON ADOPTION OF THE RULES FOR CARRYING OUT PHARMACEUTICAL INSPECTIONS COUNCIL OF THE EURASIAN ECONOMIC COMMISSION Critical - caused or may cause harm to human health or life Major - led or may lead to the production of poor-quality medicinal product for medical use that cannot cause harm to human health or life, or violation (non-conformity) of the requirements of the registration dossier or a combination of several minor violations Minor - which are not attributed to either critical or major violations Critical - cause or lead to a significant risk of the possibility of producing a medicine that is dangerous to human health and life Major - cannot be classified as critical, but: - led to the production or may lead to the production of a medicinal product that does not comply with the registration dossier; - indicate a significant deviation from the Rules of good manufacturing practice or other legislative acts in the field of circulation of medicines; - indicate the inability of the inspected subject to carry out batch production of drugs of uniform quality or the inability of the qualified person to perform their duties; - a combination of non-conformities. Others - non-conformities that cannot be classified as critical or major. General partner: Strategic partners: Official partners: Regional partners:

“CLASSIFICATION OF TYPICAL NON-CONFORMITIES IDENTIFIED IN THE PROCESS OF INSPECTION” (Federal State Institution “State Institute of Drugs and Good Practices”) Is used to classify non-conformities identified during the inspection process. The procedure allows for an unambiguous approach to assigning the degree of criticality of non-conformities identified as a result of inspections of drug manufacturers. The assessment of compliance with the principles of Good Manufacturing Practice shall be commensurate with the degree of risk, which takes into account the nature and degree of deviation regarding the category of products evaluated. When compiling an inspection report, identified deviations are reflected in non-conformities with a certain degree of criticality, while taking into account the degree of risk of possible harm to human health or life. The assigned degree of risk shall be related to the nature of the non-conformity, the frequency of its occurrence and the criticality of the product. The classification of the part of non-conformities, which are identified as major in the procedure, can be increased to critical in the manufacture of products with a high degree of risk. General partner: Strategic partners: Official partners: Regional partners:

“CLASSIFICATION OF TYPICAL NON-CONFORMITIES IDENTIFIED IN THE PROCESS OF INSPECTION” (Federal State Institution “State Institute of Drugs and Good Practices”) High-risk product - a product for which one of the following criteria may apply: narrow therapeutic range; sterile product; biological drug; complex production process: a process in respect of which minor deviations in the control of parameters can lead to a heterogeneous product or a product that does not meet its specification. Any product that may cause a health risk even in small concentrations (after cross-contamination). This group includes (but not limited to): beta-lactam antibiotics, certain cytotoxic and biological products. General partner: Strategic partners: Official partners: Regional partners:

“CLASSIFICATION OF TYPICAL NON-CONFORMITIES IDENTIFIED IN THE PROCESS OF INSPECTION” (Federal State Institution “State Institute of Drugs and Good Practices”) Examples of critical non-conformities: The fact of falsification or distortion of the results of analytical tests is established. Missing or improper validation of critical sterilization cycles (sterile products). Aseptic filling continues even after receiving unsatisfactory test results simulating the filling process with nutrient media. A qualified person at a company producing drugs with a critical or high level of risk does not meet the requirements established by law for relevant education and work experience. Examples of major non-conformities: Equipment and / or computerized systems that are used during critical stages of production, packaging, labeling, as well as when conducting quality control of starting raw materials or products, are not qualified. Cleaning procedures for production equipment are not validated (including related analytical methods). Inadequate capacity and / or limited production space, which can lead to mix-up. Stability studies associated with changes in production (in the recipe) or changes in packaging material are not conducted. General partner: Strategic partners: Official partners: Regional partners:

PIC / S Guide to Classification of Non-Conformities with GMP Requirements dated January 1, 2019 Purpose and intended use of the document - harmonization of classification GMP non-conformities to ensure uniformity of uniformity of reporting on GMP non-conformities according to inspection results from various inspectorates. When categorizing non-conformities, risk management principles depending on the type of product or process being implemented apply. The guide presents: classification of non-conformities; non-conformities classification process flow diagram examples of classification of non-conformities that can be used in determining classification; facts that increase / decrease risk. General partner: Strategic partners: Official partners: Regional partners:

Critical non-conformity: Major non-conformity: PIC / S Guide to Classification of Non-Conformities with GMP Requirements dated January 1, 2019 Critical non-conformity: Major non-conformity: Other non-conformity creates a high risk of manufacturing products harmful to human or animal health; manufacturer engages in fraud, misrepresentation or falsification of products or data; may consist of several related non- conformities, none of which in itself can be “Critical”. led or may lead to the production of products that do not comply with MA, CP of products, pharmacopeia or reg. dossier; does not guarantee the effective implementation of the required control measures according to GMP; indicates a major deviation from the conditions of the marketing authorization; indicates the impossibility of fulfilling satisfactory batch production procedures or the impossibility of fulfilling their duties by qualified persons; consists of several “Other” non-conformities, none of which is “Major” in itself, but together constitute a systemic violation. A non-conformity that is not classified as Critical or Major, but indicates a deviation from Good Manufacturing Practice (GMP) management. Non-conformity may be classified as “Other” due to the lack of sufficient information to classify it as “Critical” or “Major”. Single minor non-conformities, as a rule, are not officially registered as non-conformities, but are indicated and communicated to the manufacturer in the form of comments. General partner: Strategic partners: Official partners: Regional partners:

Non-conformity detected General diagram of non-conformity classification process (PIC / S Guide to Classification of Non-Conformities with GMP Requirements dated January 1, 2019) Does the action or process pose a significant risk of obtaining the products described for the patient, or contribute to the accumulation of hazardous components in the animal used to obtain food? Yes Critical non-conformity No Yes Is data falsification or intentional misrepresentation or falsification of products proven or observed? No Carry out a detailed assessment of the classification of non-conformity in accordance with Figure 2 Assess risk reduction or increase factors. Mitigating factors Increasing factors There are no factors that reduce or increase the level of risk. Decrease in initial classification Confirmation of the initial classification Increase in the initial classification Classification of non-conformities Other non-conformity Major non-conformity Critical non-conformity General partner: Strategic partners: Official partners: Regional partners:

PIC / S Guide to Classification of Non-Conformities with GMP Requirements dated January 1, 2019 Increasing Factors (increase in initial classification): Mitigating Factors (decrease in initial classification): Repeated or regular non-conformities; Group or combination of non-conformities; Product Risk. Failure by the manufacturer to take appropriate measures to mitigate the risk to the patient to an acceptable level (unreasonably long implementation of corrective measures, corrective measures have not been implemented). Minimization of the risk associated with the product; Minimization of the risk to patient safety; Actions taken by the manufacturer, such as the CAPA plan to reduce the risk of non-conformity; Other risk factors;   General partner: Strategic partners: Official partners: Regional partners:

PIC / S Guide to Classification of Non-Conformities with GMP Requirements dated January 1, 2019 Examples of critical non-conformity:  No sterilization validation (applies to all sterile products). Inadequate control measures leading to actual (or significant risk) of cross-contamination above the level of maximum permissible exposure in subsequent products. Falsification or distortion of analytical results or records (applies to all manufacturers). Failure to guarantee the quality and / or authenticity of raw materials (applies to all manufacturers). Invalid HVAC systems for sterile products (applies to manufacturers of sterile products) Examples of major non-conformity: Insufficient validation of critical processes (may be “Critical” for small dosage / highly toxic drugs; in particular, for sterilization processes for sterile products). Persons holding senior positions in quality control / production are not sufficiently qualified by education, competencies and experience. Invalid cleaning procedures for production equipment. Shortened raw material quality control tests without supplier certification data. Inappropriate deviation handling system. General partner: Strategic partners: Official partners: Regional partners: