BRITISH PHARMACOPOEIA COMMISSION

Expert Advisory Group MC2: Medicinal Chemicals

SUMMARY MINUTES

A meeting of this Expert Advisory Group (EAG): Medicinal Chemicals 2 (MC2) was held via
videoconference on the 5th and 7th May 2021.

Present: Dr G Cook (Chairman), Mr C Goddard (Vice-Chairman), Prof J Birchall, Ms K Boon, Mr J

Cowie, Dr K Foster, Mr E Hook, Dr J Lim, Prof J Miller, Dr A Ruggiero and Mr N Wynne.

In attendance: Ms H Corns, Dr H Bowden, Ms A Thomson, Ms K Busuttil and Ms M Nanasi.

Apologies: None

491 Introductory Remarks

Welcome The Chairman welcomed members to the meeting and also welcomed Ms
K Busuttil and Ms M Nanasi who attended from the BP Laboratory.

Confidentiality Members were reminded that all papers and minutes were
confidential and should not be disclosed outside the BP Commission.

Declaration of Interests Members were reminded that they are required to inform
the Secretariat of any changes to their interests throughout the year.

492 BP Update MC2(21)01

Members were provided with an update on recent BP activities and personnel
changes.

493 MINUTES
The minutes and summary minutes from the meeting held on the 6th & 9th October
2020 were confirmed without amendment.

494 MATTERS ARISING FROM THE MINUTES MC2(21)02

Matters arising and correspondence items from the meeting held on the 6th & 9th
October 2020 were noted. Members had no additional comments.

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 MONOGRAPHS

Dr G Cook, Mr E Hook, Mr J Cowie and Mr N Wynne declared interests in one or

more agenda items and appropriate action was taken.

495 Levothyroxine preparations: MC2(21)03

Levothyroxine Tablets (Revised)
Levothyroxine Oral Solution (Revised)

Identification Members agreed to introduce HPLC/UV-DAD identification tests into

the monographs.

Related substances (Oral Solution) It appeared from previous lab work that the
method was capable of detecting additional impurities to impurity A, which was the
only impurity listed in the transparency statement. The Secretariat agreed to further
investigate in order to add greater clarity to the Impurities section of the monograph.

Related substances (Tablets) One stakeholder had requested that that a total
impurity limit of 10% was included in the monograph, to clarify that the content limits
of 90.0 – 105.0% needed to be met whilst the impurity limits allowed up to 13% of
total impurities. The impurity limits had been written to accommodate a range of
product specifications. Members agreed that a total impurity limit would be beneficial
and the Secretariat agreed to confirm suitability of the limits with MHRA License
Assessors prior to publication of the revised monograph.

Uniformity of content/Assay (Tablets) One stakeholder reported poor

reproducibility when analysing 25 µg tablet samples. The methods had not been
changed in the draft revised monographs and the Secretariat would seek further
information from the stakeholder.

Another stakeholder requested that a separate assay procedure was retained within
the monograph. The BP practice was to use the average result of uniformity of
content testing for assay, to reduce the number of tests required to demonstrate
compliance. Discussion highlighted that for release testing the BP approach was
more convenient as both tests were required; however, this was not the case for
stability testing. Members concurred that there was insufficient justification to
recommend the proposed change to BP policy, as this would shift the inconvenience
to release testing rather than resolve an issue.

496 Liothyronine preparations: MC2(21)04

Liothyronine Tablets (Revised)
Liothyronine for Injection (New)

The draft new monograph for Liothyronine for Injection would be included in a future
BP publication, subject to amendments and comments from manufacturers.

Identification (Tablets) No comments were made on the proposals to introduce

HPLC/UV-DAD identification tests into the monographs. Members confirmed that
this test should be included.

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 Dissolution (Tablets) No comments received on the proposed dissolution medium
of water, agreed at the previous meeting. Members confirmed that this test should
be included.

The MHRA lab reported that poor recovery had been obtained, during pre-approval
testing, when using the PVDF filter specified in the draft revised monograph. GMF
filters, found suitable in other assessments gave approximately 80% recovery. The
lab opted for centrifugation which was found not to affect recovery. Members noted
that each test in the monograph contained a different filtration or centrifugation step
and recommended that, based on advice from the lab, a consistent approach was
taken across all tests.

Related substances (Tablets) Comments received from stakeholders indicated

that the drafted method was suitable for compendial use with corrections applied. It
was noted that the correction factor in the draft monograph was the reciprocal of the
true value, which had been amended and would be brought to the attention of MAH.
It was also noted that solution A had been incorrectly transcribed, which was the
likely cause of the peak splitting reported in one set of comments.

A reference solution closer in concentration to the limit for impurity 1 was advised, to
avoid a combination of multiplication factors.

497 Duloxetine Gastro-resistant Capsules (New) MC2(21)05

The draft monograph would be included in a future BP publication, subject to

laboratory evaluation and stakeholder comment.

498 Mebeverine preparations: MC2(21)06

Mebeverine Tablets (Revised)
Mebeverine Prolonged-release Capsules (New)

The draft new monograph for Mebeverine Prolonged-release Capsules would be

included in a future BP publication, subject to amendments and comments from
manufacturers.

Identification (Tablets) The laboratory investigated the use of dichloromethane as

a replacement for chloroform in the IR extraction and found this to be a suitable
alternative. The revised extraction had been drafted into the monograph and was
accepted by the group.

Dissolution (Tablets) Introduction of a dissolution test to the monograph proved to

be difficult as the test needed to provide suitable control of film-coated and sugar-
coated tablets. It was agreed that further investigation was needed before a test
could be included in the monograph.

Related substances (Tablets) A related substances test had been found to be

suitable the tablets. All samples tested were able to pass the drafted impurity limits.

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 It was agreed that the quantification of impurity C should utilise an external BPCRS
standard, as a correction factor greater than 5 was determined in the laboratory
assessment.

Assay (Tablets) The Assay method had been based upon manufacturer’s data and
was found to be suitable. All samples tested were able to pass the drafted limits of
95.0-105.0%.

499 Adrenaline Injection preparations: MC2(21)07

Adrenaline Injection/Epinephrine Injection (Revised)
Dilute Adrenaline Injection 1 in 10,000 /Dilute Epinephrine
Injection 1 in 10,000 (Omission)

Medication error data and BP Labelling requirements Data had been received
from NHS Improvement’s National Reporting and Learning System (NRLS) and
discussed with MHRA colleagues. There was general consensus that moving away
from the 1 in 1000 and 1 in 10,000 strength labelling would be beneficial for
healthcare providers and could reduce medication errors. Once new labelling had
been agreed, along with timelines for the change implementation, the BP labelling
requirements would be revised.

Adrenaline Injection/Epinephrine Injection MHRA colleagues had recommended

that a single, open strength BP monograph covering all Adrenaline
Injection/Epinephrine Injection products would be beneficial, as this would also cover
the 0.05% w/v licensed product. Members agreed the recommendation and noted
that correction of the draft was required which the Secretariat agreed to address prior
to the stakeholder consultation process.

Dilute Adrenaline Injection 1 in 10,000 /Dilute Epinephrine Injection 1 in 10,000

As a consequence of the revision to create an open strength Adrenaline
Injection/Epinephrine Injection monograph, a separate monograph for the dilute
injection was no longer required. Members agreed the monograph should be taken
to BPC for omission.

500 Solifenacin preparations: MC2(21)08

Solifenacin Oral Suspension (New)
Solifenacin Tablets (New)

The draft new monographs for Solifenacin Oral Suspension and Solifenacin Tablets
would be included in a future BP publication, subject to amendments and comments
from manufacturers.

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501 Tranylcypromine Sulfate (Revised) MC2(21)09

Nitrosamine formation risk assessment The outcome of a risk assessment

provided by a manufacturer showed that there was no requirement for a test or
production statement in the monograph.

Elemental impurities Justification provided by a manufacturer demonstrated that

tests for elemental impurities were not required in the monograph.

Hydrazine A manufacturer reported that hydrazine was monitored as a process-

related impurity and members agreed that a test should be included in the
monograph.

Related substances Members agreed that an improved method should be adopted

with limits more aligned to regulatory expectations.

Assay Members agreed that the titration method for assay should be retained in
the drug substance monograph as it offered greater precision than an HPLC method.

502 Mitoxantrone Sterile Concentrate (Revised) MC2(21)10

Title Members approved proposals to revise the monograph title from Mitoxantrone
Infusion to Mitoxantrone Sterile Concentrate. The infusion requirements under
Definition, Bacterial endotoxins and Labelling were deleted from the monograph.

Acidity Members approved a revised pH requirement of 2.5 – 4.5 requested by

manufacturer and supported by the data which demonstrated stability in the lower pH
range.

Related Substances The test would be revised to introduce means to identify the
peak due to impurity D.

503 Phenoxybenzamine Capsules (Revised) MC2(21)11

Content A request to retain the lower content limit of 92.5% was received during the
consultation window. Members required further information before the request could
be agreed.

Dissolution Members questioned whether a reduced dissolution medium volume of

500 mL was necessary and if the standard 900 mL volume could be applied.

Assay Members agreed that the assay sample preparation should be scaled up
from 5 capsules to 10 capsules, ensuring that 20 dosage units were used for the test.
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504 Diclofenac Diethylamine (Revised) MC2(21)12
Diclofenac Gel (Revised)

Monograph note (Gel) The Secretariat had revised the BP monograph to cover
both salt forms used to formulate diclofenac gels within the UK market. An additional
note had been added to the top of the monograph that stated: “Diclofenac Gel
prepared from Diclofenac Diethylamine is not necessarily interchangeable with
Diclofenac Gel prepared from Diclofenac Sodium.” A lack of data was available to
assess the bioequivalence of the different gel formulations.

Definition (Gel) The Secretariat had revised the definition to cover both
diethylamine and sodium salt forms, taking into account BNF and SPC data. The
approach received approval from members.

Content (Gel) The Secretariat had revised the content statement to incorporate the
different salt forms, retaining limits of 95.0% to 105.0% for both. Members confirmed
that the limits remained suitable.

Identification (Gel) A TLC method that used the same mobile phase composition
and spray derivatisation for spot visualisation, without the use of chloroformwas
approved for inclusion in the Diclofenac Gel monograph.

Related substances (Diethylamine, Gel) Confirmation of the requirement for

correction factors for impurities A and F (0.7 and 0.3 respectively) was received and
included in the monographs. The test had been revised to direct users to prepare the
sample solution based on an amount equivalent to the diclofenac base.

Assay (Gel) The test had been revised to account for the quantification of the
content via the diclofenac base. Salt corrections had been added to allow conversion
to the sodium and the diethylamine forms.

FOR INFORMATION

505 LC/UV-DAD for Identification MC2(21)13

Guidance for EAG members was provided to support adoption of LC/UV-DAD for
Identification tests, following approval by BPC in November 2020.

506 Out of Stock BPCRS MC2(21)14

A review of out of stock BPCRS for monographs relevant to EAG MC2 was
presented to the group.

507 MC2 Work status and updates MC2(21)15

The MC2 work programme was presented to members for information.

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508 Ph. Eur. Updates MC2(21)16

The Secretariat thanked members for their contributions to the ongoing

Pharmeuropa review.

509 ANY OTHER BUSINESS

510 NEXT MEETING

Wednesday 3rd November 2021

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