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Reagents

 

Here you will find answers to the following questions:

  • In what way do reagents differ from standards and reference substances?
  • How should reagents be labelled?
  • How are usage and stability regulated?
  • What are the requirements for the documentation?

Reagents or laboratory reagents are an integral part of quality control for assessing the quality of APIs and finished products. For this reason, they are generally subject to the same requirements as standards and reference substances, in terms of preparation and documentation. (see chapter 14.C Standards and reference substances)

The EU GMP Guideline (6.19) explicitly requests that particular attention be paid to quality and that preparation must be carried out in accordance with written procedures. In principle, it is irrelevant if the reagents concerned are intended for qualitative or quantitative analyses.

Depending on the field of use, the list of a selection of different reagents may be as shown in figure 14.B-1. The list makes no claim to completeness, and the corresponding reagents are to be used accordingly for further tests.

Figure 14.B-1 List of reagents

List of reagents

Qualitative investigations

  • Solvents and solvent mixtures (chromatography)
  • Spray reagents
  • Reagents for precipitation and colour reactions (identity tests)

Semi-qualitative investigations

  • Colorimetric solutions
  • Colour tables (e.g. Pantone)
  • Opalescence measurements

Quantitative investigations

  • Titration solutions
  • Buffer solutions
  • Calibration substances

11 Labelling

Laboratory reagents must be labelled with the date of receipt and date of opening (if purchased) or the date of manufacture (if manufactured in-house). Unlike for standards and reference substances, for reagents the EU GMP Guideline (6.21) recommends an identity test (in certain cases) or a different test after receipt or before use. Experience has shown that a corresponding test is usually indispensable during the examination on receipt of the reagents (factor assignment).

Reagents can be labelled with a code instead of a name. This must be unique and must not lead to confusion, either with other batches of the same reagents or with other reagents.

The EU GMP Guideline (6.20) can be consulted as a minimum requirement for the labelling of reagents (on the label). It stipulates that the information listed in figure 14.B-2 must be present.

Figure 14.B-2 Labelling of reagents

Labelling of reagents

  • Date of manufacture or date of opening
  • Signature of the person who prepared the reagents
  • Expiration date
  • Storage conditions
  • Date of the last factor assignment and the current value (volumetric solutions)

12 Usage and stability

In principle, reagents are for the intended use only. If they cannot be purchased, their preparation must be described in as much detail as the instructions for test procedures.

For all reagents used, a reasonable expiration dating period (stability) must be established. This should be based on historical operating data and written in an SOP. The expiration dating periods must be adapted to newly acquired findings, and the maximum permissible period is 5 years. Here, companies have a lot of freedom in stipulating (the deadlines), but not in selecting the reagents. The principle of documenting the stipulation in such a way that it can be understood by a competent professional applies here too. This means that the stipulation must not only be documented, but also scientifically substantiated.

For some reagents and groups of reagents, possible expiration dating periods are listed in figure 14.B-3. If reagents are purchased, the manufacturer's specifications should be used. However, caution is required if, for example, bottled buffer solutions for setting the pH meter are provided with an expiration dating period, but there are no specifications on how long the buffer solution can be used for after the bottle is opened. As experience shows, the user himself is required to set deadlines here. An elegant solution to this problem is the use of pH portion sachets which are all individually provided with a use-by date and are ideal for one-time usage. These are available in the optimal quality for pH meters by different manufacturers. This variant is also cost-effective, as open, half-empty bottles of usual pH solutions do not have to be discarded once the expiration dating period has been exceeded.

Figure 14.B-3 Examples of expiration dating periods for reagents

Examples of expiration dating periods for reagents

  • Organic solvent (manufacturer's specification)
    Note: THF is particularly critical 2 m - 2 y
  • Buffer solutions 2 w
  • Mobile phases without salt 6 m
  • Mobile phases with salts (buffer) 2 w
  • Water 2 d
  • Water with org. solvents (e.g. with MeOH
    for rinsing HPLC pump heads) 2 y
  • Solutions for SST (system suitability test) 6 -12 m
  • Colorimetric solutions (e.g. by Pharm.Eur. or USP) 2 y
  • Spray reagents 1 d - 6 m
  • Microbiological reagents/culture media according to application
  • Titration solutions 1 w - 3 m

d = day; w = week; m = month; y = year

It is important to specify the storage conditions (protection from light, refrigerator). It is well known that reagents often have a different expiration dating period to their solutions. If, for example, the resolution check as part of the SST in HPLC determinations is done with a mixture of substances (API and degradation products), then a suitable quantity of this substance mixture can be prepared once as an "SST solution" and used again at a later time. This requires the availability of the stability and storage condition tests/data (e.g. 6 months in a refrigerator protected from light).

13 Documentation

On the one hand, the documentation contains the receipt or preparation of the reagents, and on the other hand, it also contains their usage in quality control testing.

The preparation must be described accurately, preferably in the same format as the company uses for test instructions. The quality of chemicals to be used should also be stipulated. Each preparation process must be documented in such a way that at any time during use of the reagents it is possible to tell the date, manufacturer and chemicals used. In practice, the use of reagent log books has proven very useful. (See figure 14.B-4). In these log books, the preparation of reagents can be documented on templates.

When using reagents, the code, manufacturer's name and date of manufacture are used in the documentation during quality control testing. This ensures traceability. This data is completed with the expiration dating period. (see figure 14.B-5)

The stipulation of the expiration dating period must be documented. If any form of stability testing was carried out to this end, the results must be recorded. If there are new findings from the use of the reagents, the expiration dating period must be corrected accordingly.

Figure 14.B-4 Example of the management of a reagent log book

Reagent log book (manufacture)

  • The reagent log book is managed as a collection of loose sheets for each organisational unit (lab, group, department) in a specially labelled folder. For each reagent the documents are stored in a folder together with the preparation instruction.
  • For each preparation, a form in which the variables are entered (chemicals, initial weight, dilutions) is used.
  • The reagent can also be assigned a number (R number).

Company logo

Reagents log book 1999/3

QC- lab

Manufacture of 0.1 M NaOH (for pH adjustment) R-1999/3/02

in accordance with reagent preparation instruction RHV 14.2 (14-Oct-1999)

Reagents:

Name
NaOH p.a.
Water

Quality
E.g. Merck xxxx
E.g. MilliQ

Quantity
4 g
1000 mL

Number
E-15708
G-543

Initial weight
40.05 g
10.0 L

Note:
The E number is the incoming control number
The G number is the number of the water treatment system (equipment).
The numbers are the variables to be entered manually.

Date and signature of the manufacturer.

Figure 14.B-5 Example of logging when using reagents

Quality control test (referencing)

  • In the test documentation, only the entry in the reagent log book is referred to in relation to the manufacture of the reagent used.

Company logo Test protocol QC lab

Precipitation reaction for detection of substance C

in accordance with test regulation TV A 14.03 (13-Aug-1998)

Reagents:

Name Number Date/Manufacturer Expiration dating period

.... E-__________ ..

.... E-__________ .

NaOH 0.1 M R-1999/3/02 30-Nov-1999/JKU 31-Jan-2000

Note:
The E number is the incoming control number
The R number is the number of the reagent manufacture.

Execution:

..........

..........

Date and signature of the analyst.

Summary

Reagents differ from standards and reference substances in terms of their usage, but are also subject to careful control.

Reagents are to be labelled clearly. This includes the date of preparation, who prepared the reagent and when, the expiration date, the storage conditions, and the date of the last factor setting with the currently valid value.

Reagent preparation must also be documented (reagents log book), as well as the expiration dating period and the stability.



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