LAB-020 Management of Reference Substances

1. Primary and Impurity Reference Substance

1.1. Certified and reputable Primary and Impurity reference substances sources

1.1.1. Primary and Impurity Reference Substances as indicated under definitions, are substances manufactured and tested to compliance by a certified source.  The certified sources from which these quality Reference Substances can be obtained from are, British Pharmacopeia (BP), United States Pharmacopeia.

1.1.2. Analytical reagents can be used as Primary Reference Substances under special circumstances, particularly if the substances are not obtainable through the above Certified sources.  Where this is the case a Reputable Supplier should be used and a Certificate of Analysis for the substance should be obtained.

1.2. Ordering of Primary and Impurity Reference Substances

To arrange for an order of a Primary and Impurity Reference Substance to be ordered by the assigned Laboratory Staff doing Reference Substance maintenance, simply contact them with the complete details of:

a. Reference Substance needed

b. The Pharmacopoeia to buy from

c. The Pharmacopoeia catalogue number

d. The number of bottles needed (include weight per bottle, e.g. 2 x 25mg bottles)

e. The urgency requirement

It is appropriate for the assigned Laboratory staff doing Reference Substances maintenance to advise Laboratory staff that an order has been placed and indicate an estimated time of receipt.

The following should than be sent to the Pharmacopoeia (Note: Send by registered mail.):

a. Letter addressed to the department indicating enclosed items and indicating an order is being placed,

b. Copy of Purchase Order Number,

c. Copy of Licence to Import,

d. Payment details where applicable,

If the pharmacopoeias requested a statement of use for the Reference Substance being ordered, so it is appropriate to include in letter a statement for appropriate use.

Note: Follow local regulatory guidelines for importing reference substances.

1.3. Registration of the Primary and Impurity Reference Substances

1.3.1. When the reference substance is received, sign it off as received on the Laboratory “Order book”.

1.3.2. Assign a reference substance reference code and enter information as appropriate onto the “Reference Substances log” (see section 6).

1.3.3. Compile the data in the “Primary and Impurity Substance Summary Sheet” form Form-330 with the relevant information to reflect Reference Substances log Book entries.  File the manufacturer’s “Certificate of Analysis” in the appropriate Laboratory office cabinet.

1.3.4. Write on the actual label of the bottle of Reference Substance itself the information below.  Use a permanent ink pen and ensure information is clear.

a. Assigned Reference Number

b. Date received

c. Storage location

d. Expiry/ Retest dates are not straightforward for some products, but for Primary reference reagent solutions these can also be written on the bottles.

Place a protective layer of sticky tape on the information especially when written on the larger bottles.

1.3.5. Place some “masking tape” around the lid of the bottle for bottles that do not have a seal to break when first opened.  This tape will serve as a reminder for the analyst to write down a “Date bottle opened” date for the bottle and advise Authorised lab. person to update information on the Summary Sheet (Form-330) and on Reference Substances Log.

1.3.6. Place the bottle in the appropriate locations as instructed by the manufacturer:

a. The Laboratory Desiccator.

b. The Laboratory Freezer

c. The Laboratory Fridge

d. The Laboratory Safe

1.4. Coding of Primary and Impurity Reference Substances

The reference number is issued to each bottle of Reference Substance received to individually identify each bottle to its Certificate of Analysis and to correlate them to a controlled standards referencing system.  The reference number is generated using the following format:

a. e.g. P\ ISO\ XXX\ 2, Standard (ISO)here being Isosorbide-5-mononitrate

b. The first section indicates whether the Reference Substance is either Primary (P), or Impurity (I).  Note Impurities are also referred to as break down product (BDP) to avoid confusion in naming.

c. The second section indicates the first three letters of the Active family of the Reference Substance.

d. The third section is the manufacturer’s batch number of the Reference Substance collected from the C of A.

e. The fourth section is the bottle number of the batch received.

2. Primary Reagent Reference Solutions (PRRS)

Analytical standards supplied as a solution for direct use or accurate dilution, for example commercially prepared volumetric reagents are also be considered for use as PRS.  A reputable supplier should be used and a Certificate of Analysis for the substances should be attained.  These are referred to as Primary Reagent Reference Solutions (PRRS).

Note: Purchased volumetric solution for titrimetric use are not subject to the procedures described in this SOP.  Laboratory analyst using these must refer to SOP LAB-035.

2.1. Ordering of Primary Reagent Reference Solution.

2.1.1. Ordering of these PRRS is assigned to Laboratory staff doing Reference Substance maintenance.  The PRRS should be ordered through a reputable supplier, and a Certificate of Analysis should be attained.

2.2. Registration of the Primary Reagent Reference Solutions

2.2.1. When the PRRS is received, sign it off as received on the Laboratory “Order book”.

2.2.2. Assign a reference substance reference code and enter information as appropriate onto the “Reference Substances log Book” (see section 6).

2.2.3. Compile the data to the form Form-345 with the relevant information to reflect ‘Reference Substance Log Book” entries.  File the manufacturer’s “Certificate of Analysis” in the appropriate Laboratory office cabinet

2.2.4. Note: It is not important to place “masking tape” around the lid of the bottle.  These bottles are supplied with an unbroken seal, and the analyst should remember to write down “Date bottle opened” and advise the assigned laboratory person to update information on Summary Sheet and on Reference Substances Log.

2.2.5. These Reagent bottles are generally very big, so leave on them their own label, which is appropriate for toxicity information, and place a “Primary Reagent Reference Solutions” label (Form-360) on the bottle, which has been filled in with the appropriate known information.

2.2.6. When all information on the label has been filled in, normally by the time the “Date bottle opened” is known, place a layer of sticky tape over the label to protect the label.

2.2.7. Place bottle in “Main Lab Desiccator” storage location together with other PRRS.

2.3. Coding the Primary Reagent Reference Solutions

The PRRS are coded to be included in the Reference Substances Log Book.  The reference code for PRRS is generated using the following format:

a. PRRS\Sod\XXXX\1

b. The first section indicates that the substance is a Primary Reference Reagent Solution.

c. The second section indicates the first three letters of the reagent solution name.  The example above, “Sod” is for Sodium.

d. The third section indicates the manufacturer’s Batch number for the reagent solution collected from the C of A.

e. The fourth section indicates the container/unit number.

3. Secondary Raw Material Reference Substance (SRMRS)

3.1. Secondary Raw Material Reference Substance Source

The Secondary Raw Material Reference Substance (SRMRS) can be prepared by sampling the purchased Raw Materials active substance, test these against a Primary Reference Substance (PRS) to establish its purity and then use these in routine analysis.  These “Raw material” active substances are originally used for manufacturing products, received with manufacturer’s Certificate of Analysis and tested to conform to specifications by Laboratory on arrival.

3.2. Ordering Raw Materials for Secondary Raw Material Reference Substance

Raw materials to be used as Secondary Raw Material Reference Substance are sampled by sampling personnel in warehouse Sampling Booth at the time of arrival according to section 4 of SOP WAR-045.

a. Where a further sample of the raw material is needed from the bulk raw material, it can be ordered through the Warehouse system.  The assigned Laboratory staff should do this by compiling a Sample Request form (Form-010) (see SOP WAR-045) and sending to warehouse sampling personnel.

b. Collect the manufacturer’s Certificate of Analysis of the sampled raw material from the Raw Material Specification and Test Report prepared, when the raw material was tested first in the laboratory. See SOP LAB-060.  Check re-test/ expiry date of the raw material.  This will enable a sample of  longer shelf life.

c. The standard used to test a batch, should not be the same batch number as the material used in the batch.  Hence, when requesting a sample for SRMRS, ensure that the batch requested would not be used to manufacture future batches of finished Product.

d. In some exceptional circumstances, there may be no other material in the warehouse other than the one being used by production to make batches.  In such case, If the material is available as an Analytical Grade pure substance in chemical catalogues, purchase some and qualify it against a          PRS to convert it into a SRMRS.  When the material is not available as an analytical grade pure substance, then the standard SRMRS used to test a finished batch is allowed to be the same batch number as the material in the batch (as long as the SRMT2 has been qualified against a primary      standard before use).

e. The Secondary Raw Material Reference Substance arrives from the Warehouse to the Laboratory labeled as a “Secondary Sample”, with Product Name, Product Code, and the Laboratory Batch number. See SOP WAR-045.

3.3. Registration of the Secondary Raw Material Reference (SRMRS)

3.3.1. Assign a reference substance reference code and enter information as appropriate onto the “Reference Substances log Book” (see section 6).

3.3.2. Compile a form Form-325 with the relevant information to reflect the Reference Substance Log Book entries. Collect a copy of Manufacturer’s Certificate of Analysis and a copy of the completed “Raw Material Specification and Test Report” for the material, attach all previous testing records for this bottle.  File the documents in the designated folder of the laboratory office.

3.3.3. Place some “masking tape” around the lid of the bottle.  This tape will serve as a reminder for the Technician to write down a “Date bottle opened” date for the bottle and advise authorised laboratory Staff to update information on the summary sheet (Form-325) and on Reference Substances Log.

3.3.4. Remove the Warehouse label off the bottle and replace it with an In-process SRMRS Label Form-355.This label serves to segregate the substance under quarantine and will remain in place until the substance has been tested to qualify for use as a Secondary Reference Substance in routine analysis.

3.3.5. Place the bottle for collection by the team members in either of the appropriate locations, for testing:

a. The Laboratory Fridge

b. The Laboratory Freezer

c. The Laboratory Desiccator.

d. The Laboratory Safe

Contact to the team to advise reference substance ready for collection.

3.4.  Coding the Secondary Raw Material Reference Substance (SRMRS)

The Secondary Raw Material Reference Substance is coded to be included in the controlled standards referencing system.  The reference code for Secondary Raw Material Reference Substance generated using the following format:

a. SRMRS\ Iso\ XXXX\ YY\Z

b. The first section indicates that the substance is a Secondary Raw Material Reference Substance.

c. The second section indicates the first three letters of the Active family of the Secondary Raw Material Reference Substance.

d. The third section indicates the Laboratory Batch number of the original “Raw material”.

e. The fourth section indicates the last 2 numbers of the year the sample was taken from the “Raw material” bulk to be used as a Secondary Raw Material Reference Substance.

f. The fifth section indicates the number bottle sampled.

3.5. Secondary Raw Material Reference Substance testing completion

3.5.1. Once testing on the Secondary Reference Substance is completed, enter results and information onto Form-325. Attach all calculation sheets including chromatographs to the sheet.

3.5.2. All tests are done according to control Testing Methods listed in the “Raw Material Specification and Test Report” for the corresponding material.

3.5.3. The sample bottle, test results and printed documents and the filled Summery sheet Form-325 will be handed over to authorised Laboratory staff to check thoroughly the testing results and approve the Secondary Raw Material Reference Substance
for use as such by signing the bottom section of the “Secondary Raw Material Reference Substance Summary Sheet” (Form-325) to confirm the “Checks required” as described below have been performed.

3.5.4. Checks required:

a. Check all calculations.

b. Check that the physical appearance is correct when compared against Raw Material Control Method or Pharmacopoeia.

c. HPLC testing has been performed under recommended guidelines i.e. number of samples prepared and injections performed conform, including % relative standard deviation, averages and all calculations results show to be within specified limits of accuracy.  Check also that the standard preparations have been made to fit the linear range validation for the control method used in the testing.  Also check chromatogram quality is acceptable.

d. The assay results must reflect the intended use concentration expression as well as the expression shown in the relevant pharmacopoeia for the substance and both should be shown.

e. Water Content or Loss on Drying results for the SRMRS have been done where appropriate and results also conform to specified limits of the pharmacopoeia.

f. Check that all fields of the “Secondary Raw Material Reference Substance Summary Sheet” have been completed by the Laboratory analyst who tested the SRMRS sample, including book references for results traceability.

Note: Where a sample is found to be outside any limits for either of the tests conducted an Out of Specification investigation should be conducted.  See SOP LAB-055.

3.5.5. Enter information onto the “Reference Substances Log Book”.

3.5.6. Remove the “In-process Secondary Raw Material Reference Substance” label off the bottle and replace it with a “Secondary Raw Material Reference Substance” label (Form-350).

3.5.7. File the completed “Secondary Raw Material Reference Substance Summary Sheet” with attachments in the designated Laboratory folders

3.5.8. Place the bottle for collection by the team members in either of the appropriate locations:

a. The Laboratory Fridge.

b. The Laboratory Freezer.

c. The Laboratory Desiccator.

d. The Laboratory Safe.

Contact to the Laboratory analysts to advise reference substance is ready for collection.

3.5.9. Place a layer of sticky tape over the label to protect it.

4. Using Reference Substance in routine analysis

4.1. Before using a RS, the analysts should confirm that the RS is within expiry/ re-test period by referring to the “Reference Substances Log Book”, the appropriate “summary sheet” for the RS or the pharmacopoeia catalogues.  The authorized laboratory staff responsible for RS and updating the information on the “Reference Substance Log Book” should do a regular monthly check of expiry details against the pharmacopoeia catalogues.

4.2. Laboratory analyst using the RS, must use the RS with consideration to use the ones received earliest first, and then follow in order of receipt.  Where there is more than one bottle of the same RS available, there should be only one bottle in use at any one time in numerical order unless specific circumstances are applicable.

4.3. When the RS is first opened, an “opened date” must be written on the label of the container.  This date must be reported to authorised staff responsible for RS maintenance who will update this information on the appropriate “Reference Substance Summary Sheets” and on the “Reference Substance Log book”.

4.4. RS must be equilibrated to room temperature before use, unless other considerations are applicable for the substance.

4.5. When a RS requires to be pre-treated before use, make sure only the portion to be used is pre-treated and not the whole contents of the bottle.

4.6. When opening a Pharmacopoeial PRS, store by covering lid with Para film wrap and place in a container that contains a little desiccant, then store as all other bottles.

4.7. RS bottles finished or expired must be returned to the authorised Laboratory staff assigned to RS maintenance. The date bottle discarded should be entered onto the “Reference Substance Summary Sheets” and on the “Reference Substance Log Book”.

5. Expiry date and Re-test date for Reference Substances

Over time, the terminology used in the description of the “Use by” date for Substances has become more defined.  The term “Expiry” date was around initially and now we are finding the term “Re-test” date is also being used.

“Expiry” date now signifying the absolute date beyond which the substance may no longer be used, whereas the Re-test date is the date beyond which the substance cannot be used unless it has been confirmed by re-testing to be suitable for continued use and at which point this re-test date can be extended further.

Both “Expiry” date and “Re-test” date are taken to mean the date beyond which the Reference Substance can no longer be used, unless, it has been confirmed by re-testing to be suitable for continued use.

The following rules are also applied:

5.1. PRS – Pharmacopoeia RS- Primary Reference Substances are given a maximum shelf life of 18 months after opening. When the expiry date published by the pharmacopoeias is within this period, the pharmacopoeial expiry date will take precedence.  Substances that are purchased for identity use, once opened, can be used until the PRS expiry date is published, unless special consideration requirements are applicable for the substance.

5.2. PRRS – the manufacturer’s expiry date is the final use by date of any bottle of solution.  When the bottle is opened and in use, a one-year expiry date from the date the bottle is opened is set for the solution, providing this date does not exceed the manufacturer’s expiry date in which case this date must be adhered to.

5.3. SRMRS – These RS should be re-tested in-house yearly against PRS.  The re-test date for these may be set at a maximum of 1 year from this testing date, but the substance may not be used beyond the Expiry/ Re-test date on their Certificate of Analysis or the documented stability profile time frame for the substance, where expiry or re-test details are not published by the manufacturer or would indicate substance can be used further.

5.4. NO EXPIRY – Where an Expiry/ Re-test date is not provided by the manufacturer of any RS, a maximum use by period of 3 years from the date of manufacture (or receipt when date of manufacture not available) of the RS can be applied for the RS, unless special expiry requirements must be adhered to.  Reagent Substances used as PRS with no expiry can be extended to a 5-year use by period from the date of manufacture or date bottle received as in general analytical use if used for identity purposes only.  It is appropriate to contact manufacturer’s to endeavour to obtain an Expiry/ re-test date for substances.

6. The Reference Substances Log Book

6.1. The log book is divided into several “sections” identifying the separate “types” of Reference Substance and relevant information.

6.1.1. Notes section – This section provides the space to point out relevant general information regarding the spreadsheet including notes on how to make changes and find your way around it.

6.1.2. Primary and Impurity RS section – This section is for information on Primary and Impurity Reference Substances.

6.1.3. Primary Reagent Reference Solutions (PRRS) section – This section is for information on Primary Reagent Reference Solutions.

6.1.4. Secondary Raw Material Reference Substance section – This section is for information on Secondary Raw Material Reference Substance..

6.1.5. Expiry Check PRS section – This section provides communication of expiry dating checked by the authorised Lab. staff responsible for Reference Substances maintenance checked against pharmacopoeial catalogue.

7. Summary of Changes