Alia Shahzad Head of QA / QC Bayer Pakistan, Lahore Plant.

Alia ShahzadHead of QA / QCBayer Pakistan, Lahore Plant.

Introduction of Presenter • Complete Name: Mrs. Alia Shahzad • Qualification: B. Pharm (PU) • M. Phil – Pharmacology (PU) • Position in Bayer: Head of QA / QC • Technical Experience: 17 years • Areas of Interest: - Validations & Qualifications • - Aseptic Processing • - GMP Inspections & Compliance • - Compendial Harmonization

WATER FOR INJECTION STORAGE, SAMPLING, TESTING REQUIRTEMENTS AND QUALIFICATION

Contents of the Presentation • PART 1 • Water Systems • PART 2 • Monitoring - Sampling and Testing Frequencies • PART 3 • Physical, Chemical and Microbiological Testing Parameters • PART 4 • Testing Methods and Requirements • Alert and Action Levels • Documentation and Trending of Data Monitored • PART 5 • Qualification and Requalification of Process Systems • PART 6 • Particular Considerations for Water Systems

Definitions Water systems Water systems (water used for product compounding or final rinsing of surfaces which will contact the product), are typically operated in the temperate ranges hot, ambient and cold: • ► Hot systems are operated above 70 °C • ► Cold systems are operated in the range between 2°C and 10°C • ► Ambient systems are operated in the range of the environment in which the system is located. • Purified water systems can be operated at any temperature. • WFI systems are preferably operated hot and with continuous recirculation to control microbial growth. When WFI is stored and distributed at cold or ambient temperatures, special precautions are taken to prevent the ingress and proliferation of microbial contaminants, as e.g. appropriate sanitization cycles which are defined as part of the system qualification

Water Systems (1) The water system distribution Configuration should allow for the continuous flow of water in the piping by means of recirculation. The use of non-recirculating, dead-end, or one-way systems or systems segments should be avoided whenever possible. points of use loop feed water storage tank

Water Systems (2) http://www.nayagara.net/ • Pharmaceutical water - used for product compounding or finalrinsing of surfaces - exists in different (compendial) qualities such as: • Preparation of the different types of water must be performed according to current USP and/or European Pharmacopoeia requirements and - if applicable - according to other pharmacopoeias (e.g. Japanese) and local requirements.

Monitoring – General Requirements • Water systems undergo periodic monitoring of the specified required characteristics. • The monitoring program is based on theresults of the qualification* work and/oraccording to the results of a risk assessment. • Monitoring is performed according to writtenprocedures, describing in sufficient detail theresponsibilities for sampling, the sampling sites,and the sampling frequencies. • Typical minimum sampling frequencies for process systems are described in slide 11-12. • Higher or lower sampling frequencies for specific processes or products are justified according to the results of a risk assessment.

Sampling • Sampling sites must be selected based on a riskevaluation and / or as result of the initialqualification. • Samples have to be taken from representativelocations within the distribution and processingsystem. • Selection of sampling sites must not compromise the quality (e.g.: microbiological status) of the system being monitored. • The sampling plan has to be dynamic allowing for adjustments to sampling frequency and locations based on system performance trends. • When routine monitoring points are reduced or increased, the reasonfor the change has to be documented. • Sampling practice must simulate the use of a process system during manufacturing, for example where water for manufacturing is delivered through a hose, sampling has to be performed through this hose.

Monitoring – Typical Minimum Sampling & Testing Frequencies 1

Monitoring – Typical Minimum Sampling & Testing Frequencies 2 Presentation Topic

Monitoring – Typical Minimum Sampling & Testing Frequencies 3 Sampling Point & Point of Use Sampling Point & Point of Use may or may not be the same (see the diagram below): sampling point sampling point point of use Preparation Vessel point of use = sampling point

Monitoring – Typical Minimum Sampling & Testing Frequencies 4 Points of Use Feed Water Particle Filter Ventilation Filter Inflow Return Mixed ion exchange bed UV disinfection unit UV Disinfection unit Storage Tank Pump Particle Filter

Monitoring – Typical Minimum Sampling & Testing Frequencies 5 ► depend on the construction and the technical conditions of the installation or system(e.g. begin and end [=return] of the distribution system). ► evenly distributed throughout the plant (e.g. one sampling point per floor). ► depend on the individual manufacturingprocess(e.g. from which water is taken… - for cleaning product contacting surfaces - during final crystallization of APIs - for final rinsing of product contacting - for aqueous granulation processes) ► not directly relevant for the production(e.g. in cleaning/washing areas) ► where purified water is ultra-filtered to meet the endotoxin specification) System-specific sampling points Relevant sampling points (API/Potable water) Critical points of use Selected sampling points Selected sampling points for Endotoxin testing

Monitoring – Typical Minimum Sampling & Testing Frequencies 6 Inflow Return

Monitoring – Typical Minimum Sampling & Testing Frequencies 7 ► depend on the constrction and the technical conditions of the installation or system(e.g. begin and end [=return] of the distribution system). ►evenly distributed throughout the plant(e.g. one sampling point per floor). ►depend on the individual manufacturingprocess(e.g. from which water is taken… - for cleaning product contacting surfaces - during final crystallization of APIs - for final rinsing of product contacting - for aqueous granulation processes) ► not directly relevant for the production(e.g. in cleaning/washing areas) ► where purified water is ultra-filtered to meet the endotoxin specification) System-specific sampling points Relevant sampling points (API/Potable water) Critical points of use Selected sampling points Selected sampling points for Endotoxine testing

Monitoring – Typical Minimum Sampling & Testing Frequencies 8 process-relevant but not critical: organic coating critical: aqueous coating

Monitoring – Typical Minimum Sampling & Testing Frequencies 9 ► depend on the constrction and the technical conditions of the installation or system(e.g. begin and end [=return] of the distribution system). ► evenly distributed throughout the plant(e.g. one sampling point per floor). ► depend on the individual manufacturingprocess(e.g. from which water is taken… - for cleaning product contacting surfaces - during final crystallization of APIs - for final rinsing of product contacting - for aqueous granulation processes) ►not directly relevant for the production(e.g. in cleaning/washing areas) ►where purified water is ultra-filtered to meet the endotoxin specification) System-specific sampling points Relevant sampling points (API/Potable water) Critical points of use Selected sampling points Selected sampling points for Endotoxine testing

Monitoring – Typical Minimum Sampling & Testing Frequencies 10 selected: washing/cleaning

Physical, Chemical and Microbiological Testing Parameters

Test Methods and Method Requirements • All methods must be performed according tocurrent USP and/or European Pharmacopoeiaand, if applicable other pharmacopoeia and/orlocal requirements (e.g. in case of potable water). • All methods or culture media have to be suitableto detect microorganisms that may be present.The cultivation conditions, are selected to beappropriate for the specific growth requirementsof microorganisms to be detected, for example: • Total aerobic count can be obtained by incubating at 30 to 35 °C for not less than three days • Suitable culture media (low nutrient medium) is used for monitoring of water systems (30 to 35°C, at least 5 days). • Testing of viable monitoring samples is performed under aerobic conditions unless there are indications that the process is at risk for contamination with anaerobic microorganisms. • It must be assured that cleaning or disinfection agents remaining on surfaces sampled does not interfere with microbial recovery when methods using culture media are applied.

Alert and Action Level in Microbiological Monitoring (1) • An Alert level in microbiological monitoring is that level of microorganisms that shows significant differences from normal operating conditions. • Alert levels are usually based upon historical information gained from the routine operation of the process in a specific controlled environment. • In a new facility, these levels are based on prior experience from similar facilities/ processes. • Alert levels are re-examined and – if necessary – re-set at an established frequency. Trends that show a deterioration of the environmental quality require respective CAPAs. • An Action level is that specification level of microorganisms or particles that when exceeded requires immediate follow-up and, if necessary, corrective action. Common procedure of setting alter level based on a set of at least 12 months data: 95% of all results < alert level AND 5 % of all results ≥ alert level Typically, the initial alert level is set to… 50 % of the action level (specification limit)

Alert and Action Level in Microbiological Monitoring (2) • Procedures when an Alert level is exceeded • Exceeding the Alert level does not necessarily requirea definitive corrective action, but it prompts at leastdocumented follow-up measures, as established ina local procedure. • These measures include but are not limited to the following: • Comparison with results obtained concurrently with other related sampling points. • Comparison with historical data from the same sampling point. • If possible re-sampling of the affected sampling point; routine sample(s) taken from the affected point(s) within this period can be considered as resample. consecutive Alert level exceeding => escalation of measures (e.g. following the procedures of exceeding an Action level) no further Alert level => no additional action again Alert level exceeding => repetition of re-sampling according to the procedure described above

Action and Alert Level in Microbiological Monitoring (3) • Procedures when an Action level is exceeded • As soon as an Action level excursion is reported,“immediate corrective actions” and an investigationhave to be performed as described in a local procedure. • An evaluation of the potential impact this exceedinghas on manufactured products has to be made. • When a definitive cause for the excursion can be determined immediately, specific corrective actions are performed before re-sampling starts. • Re-sampling of the affected points has to be performed immediately after the implementation of “immediate / specific corrective actions”. • Monitoring critical sampling points includes routine identification of microorganisms to the species (or, where appropriate, genus) level at least when Alert and Action Levels are exceeded.

Documentation and Trending of Monitoring Data • All monitoring activities are documented properly (typically on form sheets which are laid down in SOPs). • The results from critical sampling locations must be assignable to the respective activity at the time of sampling (important in case of batch-related monitoring, i.e. the environmental monitoring data must have a formal linkage to product release as defined by procedures). • Monitoring data must be summarized on a periodic basis and issued to the responsible senior management on a periodic basis (e.g. via Product Quality Review). • Based on this summary, trends have to be evaluated and corrective action to be defined, if appropriate.

Q & A • Purified water systems have to be sampled (monitored) daily for microbiological testing. • For chemical/physical testing of water systems, it is highly recommended to define the last point of use (return) in the system as a routine sampling point. • Any Alert Level excursion initiates an immediate OoS-procedure. • Purified water with endotoxin limit is required for the final purification of a non-sterile API to be used in a sterile parenteral Drug Product.

Process Systems – General Qualification Provisions • Qualification is required for any process system (e.g. Water, Nitrogen, Clean Steam, Compressed Air) … • that is involved in the manufacture of APIs (beginning with theregulatory starting materials), Drug Products or intermediates • that may affect testing results of an API, Drug Product orintermediate, • that is involved in final cleaning processes, • where the utility supplied directly contacts an API, DrugProduct or intermediate, • where the utility supplied comes in contact with surfacesthat have direct contact with APIs, Drug Products or intermediates, • … and, therefore, could have an impact on the quality of the API, Drug Product or intermediate.

Prerequisites for Qualification of Process Systems Before beginning the qualification of a process system, the following documentation has to be available:

Test Items for Qualification of Process Systems (1) • Following table outlines parameters and aspects to be checked, evaluated and tested within the qualification study of a process system, provided that these are relevant for the particular qualification (see following slide).

Test Items for Qualification of Process Systems (2) • Based on this table, the qualification team determines by means of a risk-based • approach … • the sampling points, e.g. by answering the following questions… • Which points of use are critical ? • Which points of use are system-specific ? • Is it necessary to realize a particular sampling point (due to the unattainability of the point of use) ? Usually, selected sampling points include… significant points of use return loop points prior to and after each significant treatment step storage tank

Requalification of Process Systems • For-Cause Requalification • Generally, in case of changes or modifications, the same test items apply for requalification as for initial qualification. However, based on a risk evaluation, the extent of a requalification may be reduced in comparison to the initial qualification. • Periodic Requalification • The following periodic requalificationintervals apply: • However, the regular evaluation of the • existing documentation such as… • monitoring data, • quarterly reports, • change documentation, • logbooks, • maintenance/servicing documentation, • technical reports • … equates to periodic requalification, provided that relevant • requalification item are appropriately covered. “streamlined”requalificationapproach

Particular Considerations for Water Systems (1) • In case of water systems, the qualification process entails a three-phase approach in order to satisfy the objective of demonstrating the reliability and robustness of the system in service over an extended period.

ParticularConsiderationsforWater Systems(2) • Phase 1: • Initial phase, usually taking 2 to 4 weeks, serves to establish operating parameters and procedures, • Does not end until the system operates stable and within the required ranges, • Might be shortened in case of modifications to a water system already in use. • Phase 2: • Short-term control phase usually taking 2 to 4 weeks, serves to demonstrate consistent operation within the established ranges, • Before water is permitted to be used for pharmaceutical purposes, an interim qualification report is required, documenting the successful completion of Phase 2. • However, water can also be used for pharmaceutical purposes during this phase, provided that the respective batches are not released until the interim qualification report has been finalized.

ParticularConsiderationsforWater Systems(3) • Phase 3: • Long-term control phase usually taking 1 year, serves to demonstrate continuous and consistent operation irrespectively of external and seasonal variations. • Physico-chemical properties, microbial counts (as well as endotoxin where required) are monitored and evaluated at close intervals, • Where the season affects the quality of the feed water (e.g. potable water), sampling should be increased. • Phase 3 ends with the preparation of the final Qualification Report. End of Presentation

THANKS

Alia Shahzad Head of QA / QC Bayer Pakistan, Lahore Plant.