VALIDATION

New Website ECA Validation Group: Version 02 of ECA´s Good Practice Guide on Validation online available

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The ECA Validation Group was founded in autumn 2011 by representatives of the pharmaceutical industry after ECA´s 4th European GMP Conference. The mission of the group is to assemble knowledge on Validation, for example by continuously developing ECA´s Process Validation Good Practice Guide. Now the Validation Group launched a new website.

Since the ECA Foundation was established back in 1999 its mission has been to provide support to the Pharmaceutical Industry and Regulators to promote the move towards a harmonised set of GMP and regulatory guidelines by providing information and interpretation of new or updated guidances. For that purpose the ECA has initiated and established various working and interest groups concentrating on different topics.

The ECA Validation Group was founded in autumn 2011 by representatives of the pharmaceutical industry after ECA´s 4th European GMP Conference. This group’s mission is to assemble knowledge on Validation, for example by continuously developing ECA´s Process Validation Good Practice Guide.

Now the group launched its new website to provide members and those interested with information and practical tools. Here’s what you can find on the new website:

  • Current News
  • A news archive
  • Training Courses and Validation Conferences
  • ECA´s Process Validation Good Practice Guide
  • Discussion Forum
  • Presentations
  • Useful links
  • Q&A section
  • Membership information

Members of the group have now the opportunity to download the version 2 of  ECA´s Good Practice Guide on Validation free of charge. On 174 pages the revised Good Practice Guide comprises the main elements of the new validation approach (“what to do”). On the other hand, it also serves as a supporting guide for the implementation (“how to do”).

To find out more we invite you to visit the ECA´s Validation Group new website.

 

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Questions and Answers on the Topic “Pharmaceutical Water”

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In the following News, you will find questions on pharmaceutical water preparation and distribution frequently asked during our courses, as well as their respective answers. Read more here.

http://www.gmp-compliance.org/enews_4422_Questions-and-Answers-on-the-Topic-%22Pharmaceutical-Water%22_8398,8427,8428,8526,Z-PEM_n.html

During our courses and conferences participants quite frequently raise questions on pharmaceutical water preparation and distribution. Therefore following you will find some of these questions and their respective answers.  

Question 1:  Which concentrations of ozone are required in water systems?

The technical literature delivers different information about the ozone concentrations in water systems: e.g. ISPE Baseline Water and Steam: 0.02 ppm – 0.2 ppm; Collentro, Pharmaceutical Water: 0.2 ppm – 0.5 ppm and W.Setz, Ciba-Geigy 1990: max 0.04 ppm, for sanitisation 0.05 ppm.
The indications provided by the ISPE Baseline refer to the concentration required to prevent microbial growth. One can thus assume that a concentration of 20 ppb ozone can prevent any growth.

If systemic protection is desired i.e. the constant presence of ozone in the water, lower ozone values are sufficient.
In practice, approx. 0.02 to 0.05 ppm should be sufficient for Aqua Purificata. For sanitisation, it naturally depends on the sanitation time intervals – daily or weekly. Finally, the required ozone concentration for the system should be determined within the framework of the validation for the whole system.

Question 2: How many ozone measurement points should be available in the water system?

If ozone is used for the sanitisation of the distribution system, the effect should also be proven by means of – indirectly – the determination of the KBE values on the one hand, and on the second hand through the proof that the ozone concentration is measured at the appropriate points in the water system. For this purpose, the ISPE Baseline mentions at least 3 measurement points:

  • In the storage tank
  • After the UV system
  • In the return flow

The measurement in the storage tank shows that the concentration is sufficient during the permanent ozonisation. After the UV system, a measurement is done to assure destruction of the ozone. The post-use point in the return flow of the pipeline system is measured to prove that the ozone concentration is sufficient during sanitisation.

Question 3: Is there – from a GMP point of view – a preferred sanitisation method?

Basically, the following three sanitisation procedures are used today:

  • Hot water sanitisation
  • Sanitisation with steam
  • Chemical sanitisation

The FDA, as well as the ISPE in its Baseline – are in favour of thermal sanitisation with steam. The Guidance for Industry: Sterile drug products produced by aseptic processing Prepared by Task Force (Japan) contains the following note:
Since water for injection needs to be microbiologically pure, the equipment used for its production should be capable of withstanding periodic sterilization with pure steam at temperatures over 121°C for a given length of time. If steam sterilization is not possible because of low heat tolerance, an alternative sterilization or sanitization procedure (e.g., hot water or chemical agents) should be used for the equipment.”
GMP doesn’t specify any method. According to the state of the art, one should prefer sanitisation with steam.

Question 4: Is cold storage allowed in WFI systems?

For WFI and purified water, different temperatures are used. WFI is usually stored under heat.
In FDA’s Guide to Inspections of High purity Water Systems you can find two indications of temperatures which are actually contradictory. The first temperature interval is described under “System Design”. “The fist chapter basically states under “System Design” that it is recognized that hot water systems (here to understand as 65 to 80°C systems) are self sanitizing. Another temperature interval is indicated in the chapter “Piping”. This concretely means here that the Guide applies to hot 75 – 80°C circulating systems. These indications are in connection with the 6D rule:
FDA – GUIDE TO INSPECTIONS OF HIGH PURITY WATER SYSTEMS
One common problem with piping is that of “dead-legs”. The proposed LVP Regulations defined dead-legs as not having an unused portion greater in length than six diameters of the unused pipe measured from the axis of the pipe in use. It should be pointed out that this was developed for hot 75 – 80°C circulating systems.”
It follows from the above that cold systems for WFI actually don’t comply with the requirements. Under these circumstances, it is likely that at least the FDA doesn’t accept cold WFI systems.

If appropriate measures (system design and sanitisation measures) can ensure that microbial growth is prevented, cold storage could basically be used. Different limits for cold storage can be found in guidelines and standards (Wallhäuser: 4°C;  ISPE: 4° to 10°C). A sanitisation concept for cold storage determined within validation is imperative and should also consider the increased high-risk of bio film formation.

Question 5: Are sterilizing filters permitted in water systems?

The answer to that question requires the examination of the legal provisions and the standards and guidelines on the topic “Water”. The EU GMP Guide describes in a few points the requirements for facilities and equipment. Relating to the sterilizing filters, the following indications may be authorised:

  • EU GMP 3.38: “Equipment should be installed in such a way as to prevent any risk of error or contamination.”
  • EU GMP 3.39: “Production equipment should not present any hazard to the products.”
  • EU GMP 3.36: “Manufacturing equipment should be designed so that it can be easily and thoroughly cleaned.”
  • EU GMP Annex 1: “Water treatment plants and distribution systems should be designed, constructed and maintained so as to ensure a reliable source of water of an appropriate quality.”

In almost all guidelines, references are made to sterilizing filters. As an example, see the following statement from a Japanese guideline: Sterile drug products produced by aseptic processing (Japan 2006)

“As a rule, sterilizing filters should not be placed at water use points since the filters could mask microbiological contamination in the water system. Endotoxins could also be released from dead microorganisms retained in the filters. If the use of filters is unavoidable, the interval of replacement should be based on validation results.”

In this Japanese document, the position to filters is obvious: no sterilizing filters should normally be used. Yet, there can definitely be exceptions. The filters shouldn’t serve for masking too high KBE values. Finally, one should justify the use of such a filter.

Analytical Method Validation

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GDP

1.0     Purpose     :   To lay down a procedure for Analytical Method Validation.
2.0     Objective   :  To provide documented procedure for Analytical Method Validation.
3.0     Scope        :   To define role/responsibility of various persons responsible for Analytical Method Validation.
4.0     Responsibility    :
·        Primary        :         Officer QA/ QC
·        Secondary    :         Manager QA/ QC
5.0      Procedure   :
·        General Concepts
Ø      Validation is the act of demonstrating and documenting a procedure that operates effectively.
Ø      The discussion of the validation of analytical procedures is directed to the four most common types of analytical procedure:
R           Identification tests
R           Quantitative tests for impurities content
R           Limit tests for the control of impurities
R           Quantitative tests of the active moiety in samples of drug substance or drug product or other selected components in the drug product.
Ø      Typical validation characteristics which should be considered are:
R           Accuracy
R           Precision
R           Specificity
R           Quantitation Limit
R           Linearity and Range
R           Robustness
·        Method Validation Parameter for the assay of —:
Ø      Linearity: —– to be analyzed as per proposed method. The results obtain is used to statistically evaluate for coefficient of determination (r2), standard error of estimate and y intercept.
Ø      Precision: Precision of the chemical method is ascertained by carrying out the analysis as per the procedure and as per normal weight taken for analysis. Repeat the analysis five times. Calculate the % assay, mean assay, % Deviation and % relative standard deviation and %RSD.
Ø      Accuracy: Accuracy of the method is ascertained by standard addition method at 3 levels. Standard quantity equivalent to 80%, 100% and 120% is to be added in sample.
·        Method Validation Parameter for residual solvent by GC for —:
Ø      Specificity: Resolution of the analyte peak from the nearest peak: Solution of each of the analyte was injected separately and their retention time is noted. The standard working solution containing a mixture of the component being analyze is also injected and each of analyte peaks is check for its resolution from the nearest.
Ø      Precision:
R     Repeatability: Six replicate injections of standard solution for system precision should analyze as per the proposed method and from the chromatograms obtained the percentage % RSD is calculated.
R     Intermediate precision: The purpose of this test is to demonstrate the intermediate precision of the method when method is executed by a different analyst and on different day. Results obtained will be compared.
Ø      Linearity and Range: Solution of analyte solvent, having different concentration should make separate from L.O.Q. concentration, which is 50% to 150%. The result obtained is statistically evaluated for coefficient of determination (r2), standard error of estimate and y intercept.
Ø      LOD & LOQ:
R     The limit of Detection (L.O.D.) was calculated as per below equation:
                      LOD          =              3.3     X       SD
                                                                  Slope 
R     The limit of Quantification (L.O.Q.) was calculated as per below equation:
                                                LOQ         =              10      X     SD
                                                                                         Slope
Ø      Accuracy / % Recovery (By Standard Addition Method): Accuracy of the method was ascertained by standard addition method at 3 levels.
R     Standard solution quantity equivalent to 50%, 100% and 150% are added in sample.
R     The solutions amount is analyzed by the proposed method and chromatogram obtained.
R     The amount recover by the method is compared to the amount added. Percent deviation is calculated at each levels and a grand average across all the levels are also calculated.
Methanol standard concentration ––  3000 ppm
Acetic acid standard concentration –– 5000 ppm
DMF standard concentration ––          880  ppm
Ø      Robustness:
R     The evaluation of robustness should be considered during the development phase and depends on the type of procedure under study. It should show the reliability of an analysis with respect to deliberate variations in method parameters.
R     If measurements are susceptible to variation in analytical conditions, the analytical condition should be suitably controlled or a precautionary statement should be included in the procedure.

R     One consequence of the robustness should be that a series of system suitability parameters (e.g. resolution test) is established to ensure that the validity of the analytical procedure is maintained whenever used.