Water System

Parenteral Drug Association - Technical Report No.: 4, Design Concepts for the validation of Water for Injection System.

Parenteral Drug Association - Technical Report No.:13 Rev 2, Fundamentals of an Environmental Monitoring Program.

Water for Pharmaceutical Purposes USP <1231>.

Alert level: are levels or ranges that when exceeded, indicate that the process may have drifted from its normal operating condition. Alert level constitutes a warning, necessary investigation has to be done, may not require a corrective action.

Action level: are levels or ranges that, when exceeded, indicate that the process has drifted from its normal operating range. Exceeding an action level, necessary investigation shall be performed and Corrective Action and Preventive Action (CAPA) shall be taken as appropriate.

PRETREATED/ POTABLE/DRINKING WATER GENERATION AND DISTRIBUTION SYSTEM (NEW SYSTEM) = Feed water for purified water system

Pre-treated water from the outlet of pre-treatment system shall be tested (microbial and chemical analysis) with respect to drinking water/ potable water specification for 7 days, before connecting to purified water system.

Analysis shall be done in In-house Laboratory as well as sample shall be sent for analysis to external Laboratory.

PERFORMANCE QUALIFICATION OF PURIFIED WATER GENERATION AND DISTRIBUTION SYSTEM (NEW SYSTEM)- Three phase approach shall be followed

§  Phase – I (Investigational Phase): 2 to 4 weeks

§  Phase – II (Verification of control): 2 to 4 weeks

§  Phase – III (Verification of long-term control):12 month (Including phase I & II)

Collection of samples for microbial analysis shall be done by using hose pipes at respective point of use (PoU), if the same is being used for routine production and sampling shall be carried out without flushing to simulate worst case. Points other than where hose pipes are not being used shall be sampled from the applicable sampling points.

During Phase I, sanitization (to control the proliferation of microorganisms during routine use) of Purified Water Generation and Distribution system shall be carried out based on the manufacturer recommendation/ Site specific requirements.

Adequacy of Sanitization frequency shall be assessed after reviewing the microbial trends and based on data the same shall be modified and recommended in subsequent phases, if required.

After successful completion of Phase I, chemical and microbial analysis data shall be reviewed and if found satisfactory, water can be released for commercial purpose through interim compiled report.

For other than commercial purpose, water shall be released after 3 days of chemical and microbial successful results.

Alert and Action limits for critical parameters shall be established based on statistical methods as mentioned below or any other statistical methods or in accordance with existing limits and utilized.

a)  Cut-off Value Approach:

b)  Normal Distribution Approach:

a) Cut-off Value Approach:

All the test data is to be arranged in a histogram and the alert and action levels are set at values whose monitoring results are respectively 5% and 1% higher than the level selected. Other percentiles may be used in establishing levels. A variation is to take the last 100 monitoring results and use the 95th and 99th percentile values as the alert and action levels.

b)  Normal Distribution Approach:

The mean and standard deviation of the data are calculated and the alert and action levels are set at the mean plus two (2) and three (3) times the standard deviation, respectively. This approach shall be used for high counts and when the data is normally distributed only. (Refer PDA TR No. 13, Rev 2).

After satisfactory completion of validation Phases, Phase I, II and III, final report with trend evaluation shall be compiled.

Review of online process parameters (Physical, Chemical) shall be carried out during all phases and trends shall be prepared for critical parameters. (e.g. Flow, Pressure, Temperature, Conductivity, TOC, as applicable).

WFI-

Sanitization / Flushing (to control the proliferation of microorganisms during routine use) of WFI distribution system shall be carried out with the help of steam, if available and or with WFI at higher temperature as per site specific requirement.

After successfully completion of Phase I, chemical and microbial analysis data shall be reviewed and if found satisfactory water can be released for intended purpose through interim compiled report.

TOTAL MICROBIAL TEST & PATHOGEN TEST

Sub culturing for species of bacteria shall be performed on any microbial colonies detected for all WFI samples.

If any colonies of bacteria observed during PQ for water for Injection system, it should be identified up to the species level.

CHANGE CONTROL AND REQUALIFICATION

If any modification / extension / change / replacement / incorporation of purification steps, etc planned to the existing / validated water system, then in such case the system shall be validated as per the recommendations of applicable change control, and shall be determined based on the impact of change.

EXAMPLES-

-       Loop modification

-       Replacement of RO

-       Addition of any critical purification step/s

-       Incorporation of additional generation system

-       Change in PLC (Programmable Logic Controller) Logic

-       Replacement of resins

Apart from above routine performance evaluation, re-qualification of Purified water / WFI generation and distribution system shall be carried out once in every three years through re-qualification protocol.

Due date for requalification will be calculated from the date of summary & conclusion of Phase I validation report for first RQ.

During requalification, review of following shall be carried out but not limited to:

Review of Quality Trend (Chemical and Microbiological)

Failure events & Investigations.

Out of Specifications (OOS) from monitoring.

Water System -

5 Steps validation system -
1. System description + Construction + Operating considerations
2. IQ
3. OQ
4. Initial Qualification
5. Documentation & monitoring program

Subsystem of water system -
1. In-plant pretreatment systems
2. Distillation unit
3. Water holding system
4. Distribution network

A. Pretreatment system for feedwater divided into two categories -
1. Filtration (Sand filter + Charcoal filter + Cartridge filter etc)
2. Primary water treatment (Water softener + Deionizer + Reverse osmosis unit etc)

Sand Filter- for removal of colloidal material and extraneous particles.

*Channeling- Poor packing of bed allowing unfiltered water to pass to the next stage.
*Sand breakthrough- May creates if retention screen in filter becomes defective.
* Colloidal build-up- May block water flow.

Charcoal Filter- to remove chlorine in order to prolonge the life of the anion bed in the deionizer.
*Loss of adsorptive capacity- High chemical content in downstream water (charcoal filter cannot be regenerated).
* High microbial counts- Bacterial growth in filter may increase the microbial counts in downstream water, leads to high release of endotoxins which could overchallenge the distillation system to remove endotoxins.

Softners and Deionizers-
*Resin depletion or contamination- When conductivity reading significantly increases or microbial counts approches action limits, regeneration is required.
*Resin exhaustion- Need for increased frequency of regeneration indicates the resin beds are exhausted and should be replaced.

The FDA has set the following maximum permissible endotoxin levels for drugs distributed in the United States:

• Drug (Injectable, Intrathecal) - 0.2 EU/kg body weight
• Drug (Injectable, non-intrathecal) - 5 EU/kg body weight
• Sterile water - 0.25-0.5 EU/ml (depends on intended use)