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 3rd and 4th November 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, Ms A Thomson, Dr H Bowden (for item MC2(21)19 only), Ms K Busuttil

and Mr C Thompson.

Apologies: Dr K Foster (for 4th November session only).

511 Introductory Remarks

Welcome The Chairman welcomed members to the meeting and also welcomed Ms
K Busuttil and Mr C Thompson 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.

512 BP Update MC2(21)17

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

513 MINUTES
The minutes and summary minutes from the meeting held on the 5th and 7th May
2021 were confirmed without amendment.

514 MATTERS ARISING FROM THE MINUTES MC2(21)18

Matters arising and correspondence items from the meeting held on the 5th and 7th
May 2021 were noted. Members had no additional comments.

MONOGRAPHS

Dr G Cook, Mr J Cowie and Mr N Wynne declared interests in one or more agenda

items and appropriate action was taken.

515 Trimethoprim preparations: MC2(21)19

Trimethoprim Oral Suspension (Revised)
Trimethoprim Tablets (Revised)

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Content (Oral Suspension) Licensing colleagues indicated that all products should
be able to meet a tighter content limit therefore it was agreed that 95.0-105.0%
would be included in the draft monograph subject to public consultation.

Identification (Oral Suspension) Members agreed to replace TLC with UV-DAD

subject to laboratory investigation of characteristic UV absorbance. Concordance of
retention time in the HPLC assay would be retained as a secondary requirement.

Identification (Tablets) Members advised that the laboratory investigate an

alternative extraction solvent to replace chloroform in the infrared procedure.

Dissolution (Oral Suspension) The current monograph did not contain a

dissolution test. It was recommended by licensing colleagues that the monograph
should be revised to include one, on account of Trimethoprim’s BCS class 2 nature.
It was agreed that a dissolution test should be investigated as part of the laboratory
evaluation and that HPLC would be the preferred quantification method, over UV
absorbance due to potential excipient interference.

Dissolution (Tablets) As per BP policy it was proposed that the Trimethoprim

Tablets monograph be updated to include a dissolution test. It was agreed that the
dissolution test from the USP monograph would be included within the draft
monograph and tested in the laboratory.
The draft monograph proposed harmonising the dissolution quantification with the
HPLC assay, however the group agreed that given the UV was the original
quantification method, that this should be utilised in the laboratory investigation.
The limits were agreed at 75%Q at 45 minutes and would be subject to lab work and
public consultation.

Related substances (Oral Suspension) The related substances method from the
collaborating manufacturer’s data package had been included in the draft revised
monograph. The manufacturer’s method for related substances was harmonised with
the current BP assay method. It was agreed that this would be tested in the
laboratory for all products on the market.
It was noted that the current monograph did not specify a disregard limit. It is
proposed to align with ICH and the product specifications at 0.1% disregard, 0.2%
unspecified impurities and 0.4% total impurities. Comments from licensing
colleagues suggested there was low risk to degradation products and that these
limits should be sufficient control for the oral suspension monograph.
These limits would be subject to lab work and public consultation.
The manufacturers method included only a standard verification as a system
suitability. It was proposed that a resolution requirement be investigated as part of
the laboratory investigation. Alternatives to the resolution requirement agreed by the
group included peak tailing or symmetry.

Related substances and Assay (Tablets) The related substances method in the
current monograph was written in the old style and it was proposed to editorially
restyle the test. The current Assay method in the monograph was a UV absorbance
quantification method. It was proposed to harmonise the assay method with the
related substances, subject to laboratory investigation.
The limits were agreed by the group to be aligned with ICH with a disregard limit at
0.1%. unspecified impurity at 0.2% and total impurities at 0.4%. This would widen the
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 limits for the impurities from the current monograph however it was agreed, with
support from licensing colleagues that there is low risk of degradation products.
Based on the licensed product specifications the products on the market should be
able to meet these limits but they would be subject to the lab testing and the public
consultation.
The current system suitability method utilised the number of theoretical plates. It is
proposed that a resolution requirement be investigated as part of the laboratory
investigation. Alternatives to the resolution requirement agreed by the group included
peak tailing or symmetry.

Method evaluation assessment The group agreed to the following lab work
outlined in the method evaluation assessment. For the Oral suspension monograph
the Identification, dissolution, related substances methods would be tested. For the
Tablets monograph the Identification, dissolution and assay method would be tested.

516 Fenofibrate preparations: MC2(21)20

Fenofibrate Tablets (New)
Fenofibrate Capsules (New)

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

amendments and comments from manufacturers.

517 Atorvastatin Tablets (New) MC2(21)21

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

amendments and comments from manufacturers.

518 Latanoprost Eye Drops (New) MC2(21)22

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

amendments and comments from manufacturers.

519 Ciprofibrate Tablets (Revised) MC2(21)23

Identification Laboratory assessment of the IR test had found chloroform to be the

only suitable extraction solvent of the four solvents tested. As it was BP policy to
avoid the use of chloroform in monographs, where possible, members agreed that a
HPLC/UV-DAD identification test should be included in the monograph. Members
agreed that the UV spectrum of ciprofibrate was sufficiently characteristic for the
alternative test to be accepted.

Related substances Members were reminded an unspecified impurity limit of 0.1%,

aligned with product specifications rather than ICH guidelines (0.2%), had previously
been agreed. Licensing representatives noted that this may have been due to an
older approach of tightening in-line with batch data and that no patient safety
concerns had been identified that required limits tighter than ICH.. Members agreed
that the unspecified impurity limit should be harmonised with ICH guideline in the
absence of safety concerns. The other related substances limits were retained as
agreed at the previous review of the draft monograph.

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520 Dorzolamide preparations: MC2(21)24
Dorzolamide Eye Drops (Revised)
Dorzolamide and Timolol Eye Drops (Revised)

Related substances The Secretariat received correspondence from a manufacturer

requesting widening of the limit for Dorzolamide Impurity B in two drug product
monographs, qualified by (Q)SAR data and in line with the USP. Members did not
feel there was sufficient justification to widen the limit for Dorzolamide Impurity B
from 1.3% in Dorzolamide Eye Drops and 1.1% in Dorzolamide and Timolol Eye
Drops, to 2% in both. Licensing colleagues revealed that all of the UK licensed
specifications were in line with the current BP requirements as published, with none
limiting Dorzolamide Impurity B at 2.0% as per the request. Members wished to
remind the manufacturer that, should they be unable to meet specification, they
would need to file a variation request with Licensing.
Minor technical and editorial comments were made by members via the DRT and
would be taken into account.

521 Tranylcypromine Sulfate (Revised) MC2(21)25

Identification B A member recalled that Tranylcypromine Sulfate might not be able

to comply with Identification test B (characteristics of sulfates). The Secretariat was
not aware of reported issues and agreed to investigate further.

POST-MEETING NOTE: The Secretariat identified that this issue was reported on
the Phenelzine Sulfate monograph.

Hydrazine A manufacturer had provided a method for hydrazine which had been
included in the draft revised monograph. Members questioned whether the test was
capable of the level of precision needed for a 195 ppm limit and agreed that
introducing greater precision within the test solutions, an approach that EDQM take
in similar situations, was appropriate. Greater precision was preferred over rounding
to 200 ppm as 195 ppm was the calculated specification based on the maximum
daily dose and threshold of toxicological concern.

Related substances Members noted that solution (3) in the draft was 12.5 times
more concentrated than the limit for impurities C and D and recommended that a 10
times more dilute solution with a signal to noise ratio requirement of 10 was added to
the test. The Secretariat agreed to amend the monograph accordingly.

522 Sertraline Tablets (Revised) MC2(21)26

Dissolution A BP user query led to the discovery that the dissolution medium
described in the Sertraline Tablets monograph did not match that of the donor
method. As the user did not report problems with using the medium as linked in the
BP monograph, and given the similarity (both sodium acetate buffer solutions of pH
4.5), members agreed to retain the existing wording until the monograph was next
revised.

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523 Bupivacaine Injection preparations: MC2(21)27
Bupivacaine Heavy Injection (Revised)
Bupivacaine Injection (Revised)

Content (Heavy Injection only) Expression of the heavy injection strength content
in terms bupivacaine hydrochloride monohydrate had been questioned, compared to
the other bupivacaine containing BP monographs expressed the strength as
anhydrous bupivacaine hydrochloride. Licensing colleagues confirmed that the
strength of all current licensed Bupivacaine Heavy Injection was expressed in terms
of anhydrous bupivacaine hydrochloride and members agreed the monograph
should be amended to align with licensed products.

Content (Injection only) A proposal to tighten the content limits from 92.5% -
107.5% to 95.0% - 105.0% was accepted, subject to stakeholder comments.

Identification The identification tests had been rationalised in the draft revised
monographs with IR retained as a standalone identification test for bupivacaine. For
the Heavy Injection, the 2 identification tests for glucose were retained as neither test
was sufficiently discriminatory to be used individually.

Related substances Members endorsed the inclusion of an isocratic LC method

with UV detection which had been found to be suitable for controlling a number of Ph
Eur impurities, including impurity F (2,6-dimethylaniline) which the subject of a
separate test in both monographs. Limits of 0.5% for impurity B, 0.2% for
unspecified impurities and 1% for total impurities with a disregard limit of 0.1% were
agreed by members.

The limit for impurity F in the Heavy Injection was 800 ppm compared to 400 ppm in
the standard Injection monograph. Licensing representatives reported that recent
applicants had been asked to reduce their proposed specification to 10 ppm, as data
had not supported a higher limit, and agreed to investigate further and provide advice
on an appropriate limit for the revised monographs.

Assay Members endorsed harmonisation of the assay procedure with the revised
related substances test, subject to stakeholder comments.

Impurities Members accepted the transparency statement informing monograph

users that impurities B, E and F could be determined using the related substances
test.

524 Solifenacin Tablets (New) MC2(21)28

Comments were received from one manufacturer during the public consultation
window and presented to the group for consideration. The draft new monograph
would be included in a future BP publication subject to amendments.

FOR INFORMATION

525 Out of Stock BPCRS MC2(21)29

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 The Secretariat reviewed the out-of-stock BPCRS for monographs relevant to EAG
MC2 and presented these to the group. Members approved proposals for in situ
generation of Captopril Disulfide given its longstanding unavailability.

526 MC2 Work status and updates MC2(21)30

The MC2 work programme was presented to members for information.

527 Ph. Eur. Updates MC2(21)31

The Secretariat thanked members for their contributions to the ongoing
Pharmeuropa review, with the 33.4 public deadline end of December.

528 ANY OTHER BUSINESS

Nitroxinil Injection (Vet) The sole UK MAH had informed the Secretariat that they
were withdrawing the product from the market and were unable support the revision
of the monograph. Members agreed that the monograph should be put forward for
omission from the BP, subject to confirmation of the recommendation from Panel
Vet.

529 NEXT MEETING

Tuesday 10th May 2022 (and Thursday 12th May if held virtually).

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