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The production of pharmaceuticals depends on water. Quality Monitoring the of both raw and portable water is crucial at every stage to guarantee patient safety. Scientists utilize sophisticated equipment to screen for chemical and microbiological pollutants, just like detectives follow hints. They are aware that even minute contaminants can change a medication’s purity and efficacy. The appropriateness of the raw water entering the facility for production uses is evaluated. To ensure that the purity of the purified water passing through pipes is maintained, samples must be taken often. In order to ensure that there is no cross-contamination, even portable water used for washing and rinsing is examined. Pharmaceutical professionals take water quality personally since patients’ health is at stake. They relentlessly search for any indication of risk until every last drop satisfies their exacting requirements.

Procedure for Quality Monitoring of Water in Pharmaceuticals

1.0   Purpose :

• • To describe the procedure for quality monitoring of water.

2.0   Scope :

• • This SOP is applicable to Purified water, Potable/Process water and Raw water storage tank & their user points of drug substance and drug product manufacturing locations.

3.0   Responsibility :

• • Quality Control Analyst / Microbiologist.

4.0   Reference(s) :

• • Schedule M
  • USP NF
  • Plims corporate specifications for water

5.0  Procedure for Quality Monitoring of Water

• Preparation of monthly sampling schedule

• • Prepare monthly sampling schedule as per attachment 3 referring below sampling frequency & attachments 1 to 2.

• Frequency for sampling & analysis of water

• • Quality Monitoring of Purified water user points including tank:

• • Each point shall be analysed for chemical and microbiological tests once in a month.

• • Wherever close circulation loop is not there, the tank sample shall be analysed daily.

• • Wherever close circulation loop is there no need to take tank sample daily.

• • Tank sample/return loops sample can be considered as one of the user points but shall be analysed once in a week.

• • Tank sample shall be analysed for microbiological tests (For all four pathogens) at least once in a month by Microbial Limit Test procedure.

• • Wherever close circulation loops are more than one, daily sampling points shall cover at least one point from each loop and loop-wise release shall be given.

• • Tank of each loop shall be analysed at least once in week.

• • Quality Monitoring of Purified water collected after after mix bed :

• • It shall be analysed for critical chemical tests  (e.g. Conductivity, TOC etc) and released for the further use after each regeneration of DM plant or as per location frequency whichever is stringent.

• • After mix bed sample shall be analysed for all 04 pathogens once in a month.

• • Quality Monitoring of Potable/process water:

  • At least one point shall be analysed in a month. All points including tank should be analysed once in six months.

• • Samples shall be analysed for chemical & microbiological tests by MLT method for all four pathogens and total viable count.

• • At least one tank sample shall be analysed once in a year as per Indian standard for drinking water specification as per attachment-11.

  • Quality Monitoring of Raw water :

  • At least one point shall be analysed in a month. All points including tank shall be analysed once in a year.

• • Raw water shall be analysed for chemical & microbiological tests by MLT method for all four pathogens.

• • Note : Above is the minimum frequency. Sampling at higher frequency can be conducted as per requirement.

•  Issuance of water analysis template for Quality Monitoring

  • Before analysis,  sample shall be registered and template shall be generated from plims which shall have test, specification and acceptance criteria.

• • A designated person shall issue the template & make necessary entries for the same as per attachment 4.

• • Template  issuance number shall be given using serial number & current year. For example the first template to be issued in the year 2024 shall be numbered as: 0001/24.

• Sampling of Water sample for Quality Monitoring

  • Monthly sampling schedule shall be referred  to decide daily sampling points.

• • Analyst shall sample the water as per procedure defined in plims template & make necessary entries in the same.

• • Sample container shall be having details as per attachment- 5.

• • After sampling, analyst shall make entries in water sampling and analysis register as per attachment-6.

• • 1 ml of 0.1M sodium thiosulphate per 100 ml sample quantity shall be added in the sampling container of potable water before it’s sterilization. This is to neutralize antimicrobial /chlorination agents added to make it potable water.
  • In case if the raw water source is other than bore water (e.g. municipal supply), the water shall be termed as potable water (if it meets potable water specification) and 1 ml of 0.1M sodium thiosulphate per 100 ml sample quantity shall be added in the sampling container before it’s sterilization.

• Tests, acceptance criteria & testing method of Water Sample

  • Each location shall prepare factory specification for raw water, potable water, after mix bed purified water and purified water referring Plims corporate specification and attachment-9 and 10.

• • Factory specification and template shall be generated from Plims which shall be approved by quality head and retained as master documents.

• • Microbiological testing method- For purified water :

• • PCA medium is mentioned in attachment -9 for total viable aerobic count test of the  purified water but R2A medium shall be used in case of analysis by filtration method.

• • If colony counts are high to uncountable using 50-100 ml sample volume, samples shall be diluted (1:10 i.e. 10 ml in 90 ml sample diluted to 100 ml with sterile purified water) and analyzed using filtration method.

• • Wherever analysis of PW is not possible by filtration method, it shall be analyzed using pour plate method using SCDA medium for bacterial count and sabouraud dextrose agar with antibiotic medium for fungal count.

• • Comparative study shall be done before changeover of the media and to derive incubation conditions.

  • Microbiological testing method- For potable/process  water :

  • 100 ml sample shall be analysed for 04  pathogens (E.coli, salmonella spp, S. aureus and P. aeruginosa.)

• • Double strength medium shall be used for sample enrichment for MLT (pathogen testing). i.e 100 ml sample plus 100 ml double strength medium like FLM for E.coli, salmonella and 100 ml double strength medium like SCDM for S. aureus and P. aeruginosa. Use of double strength medium is recommended to avoid dilution of medium due to 100 ml sample quantity.

• • 1:10 diluted sample (10 ml sample in 90 ml suitable media like diluting fluid) shall be used for total viable aerobic count. Alternative (filtration) method can also be used as mentioned in attachment-9.

• Microbiological testing method- For raw water :

  • Raw water shall be analysed as per microbiological limit test procedure as per IP/BP/USP.

• Hold time for water sample analysis for Quality Monitoring

  • Samples shall be analyzed  as soon as possible after being collected. If it is not possible to test the sample within about 2 hrs of collection, the sample should be held at refrigerated temperatures (2-8°C) for maximum of about 12 hrs to maintain the microbial attributes until analysis.

• • In the delayed testing scenario, the recovered microbial levels may not be the same as would have been recovered had the testing been performed shortly after sample collection. Therefore studies should be performed to determine the existence and acceptability of potential microbial enumeration aberrations caused by protracted testing delays.

•  Recording of Water results for Quality Monitoring

• • Raw data and results shall be recorded in the issued template.

• • Details required to generate analytical report shall be entered in plims.

• • The analyst shall get the template and analytical report checked & approved from the designated person.

• A.R. Numbering System

  • A.R. No. of purified water shall be given using sampling ID and date of sampling. For example, if purified water sample of point no. PW01 is analysed on date 01/01/24, then A.R. No. shall be PW01/010126.

• • In case of more than one close circulation loops, the water loops shall be released using suffixing for each loop. For example if the above sample represents loop-1 then A. R. No. shall be PW01/010124L1.

• Release procedure

  • Purified water

• • Initially purified water shall be released based on critical chemical tests for production or analysis purposes.

• • Necessary entries shall be made in template for chemical testing

• • Approved label shall be affixed on the tank with A. R. no. and A. R. no. shall be  informed to production.

• • Once microbial test results are available, necessary entries like A.R. No., Date of release, Remarks, if any shall be made in template and analytical report.

• • After mix bed water:

• •  Engineering shall be informed for release status of purified water sample collected after mix bed through the clearance report as per attachment – 7.

• • Raw/potable (process) water:

• • Raw/potable (process) water shall be released after ensuring proper documentation. Engineering and production shall be informed only if any failure is noticed.

• Handling of out of specification results during Quality Monitoring of Water

  • Chemical Analysis of Water

• • If the sample exceeds specified limit for chemical test, manufacturing and QC head shall be informed immediately for initial failure. Reanalysis of  the same sample shall be done. If fails in reanalysis, than resampling & testing shall be done. If resample passes, investigation shall be done for initial failure and documented the same.

• • If the resample exceeds specified limit for any of the parameter, inform to head quality, engineering, production and QA shall be informed for necessary investigation and action.

• • If a result for TOC exceeds the alert limit, investigation shall be carried out.  Resampling and analysis of the same sampling point and one other point shall be done.

• • Necessary record for repeat analysis and/resample analysis shall be maintained.

• • Microbiological : Alert limit

  •  For any of the samples, if results exceeds the alert limit, head of the department, QA, production and engineering shall be informed as per attachment-10.

• • Cause for the out of limit results shall be investigated in consultation with QA.  For example,

• • • Evaluation of sanitization record of PW system,

• • • Evaluation of sampling record.

• • • Review of the results of other samples collected on the same day.

• • • Evaluation of usage of the particular sampling point.

• • Based on the the above investigation, corrective actions shall be planned.

• • Based on  the above investigation and corrective actions, decision shall be taken for additional quality monitoring of the particular sampling point.

• • Microbiological : Action limit

  • For any of the sample if the result exceeds action limit, head of the department, QA, production and engineering shall be informed as per attachment-10.

• • Cause for the out of limit results shall be investigated in consultation with QA as explained above.

• • Samples of the same user points shall be analyzed for 3 consecutive working days.

• • If any of the these samples exceeds the action limit, head quality, engineering,  production shall be informed for further investigation and action.

• • Decision for the further use of the water shall be taken by head quality.

• • Impact of the out of specification results of water on final quality of the product shall be evaluated.

• • Microbiological limit test shall be done for the batches in which water of the particular day was used and results within limit shall be ensured.

• • Isolation and identification of atypical colonies/out of limit count of microbiological growth up to species level shall be done.

•  Investigation report

  • Investigation report can be prepared as per incidence investigation procedure.

• Trending of Results for Quality Monitoring of Water

  • Purified water quality parameter trending shall be done on monthly basis, trend charts shall be reviewed & conclusion shall be made.

• • Potable (Process) and raw water trending shall be done quarterly (every three months), trend charts shall be reviewed & conclusion shall be made.

•  Identification of microorganisms (water isolate):

  • Water isolates shall be identified due to following reasons.

• • • Identifying the isolates recovered from water monitoring methods may be important in instances where specific water borne microorganisms may be detrimental to the products or processes in which the water is used.

• • • Microorganism information such as this may also be useful when identifying the source of microbial contamination in a product or process.

• • Often a limited group of microorganisms is routinely recovered from a water system.

• • After repeated recovery and characterization, an experienced microbiologist may become proficient at their identification based on only a few recognizable traits such as colonial morphology and staining characteristics.

• • This may allow for a reduction in the number of identifications to representative colony types, or, with proper analyst qualification, may even allow testing short cuts to be taken for these microbial identifications.

6.0   Attachments for Quality Monitoring of Water

Attachment – 1

Attach lay out of water system including user points of purified water, process water and raw water.

Attachment – 2

Format for the list of  water sampling points

Attachment –3

Format for monthly water sampling schedule

Attachment –4

Format for plims water template issuance register

Attachment –5 

Format for sampling container label

Attachment –6

Format for water sampling & analysis register

Attachment – 7

Format for purified water  (After Mix Bed) clearance report

(Only Chemical Test)

________________________________________________________________________

Date Of Sampling :

AR No.                 :

Remark                 :

1. Satisfactory/ Unsatisfactory
2. Atypical colony observed/not observed.

_________________________________________________________________________

Clearance given by   :

(Date & Signature)

Attachment – 8

Format for the intimation of out of limit results of microbial analysis of  water

                                                                            Attachment-9

Suggested methodology for Microbiological  testing (TVAC) of water

 Attachment-10

Recommended tests for Purified Water (USP/Ph Eur)

Recommended tests for Purified Water (IP)

Recommended tests for Potable (Process) Water (USP/IS)

Recommended tests for Raw Water (IH)

Attachment-11

Indian standard for drinking (potable) water.

Refer separate file attached with guideline.