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REVIEW Dr. Sthal 18 April 2023
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PartReview 18.04.23Feedback & Diskusi 25.05.23Hasil Diskusi FinalModulPart Document DossierStatusPICDue Date
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IntroductionReference number will be the WHO code when the application is accepted for assessment, i.e. CV-xxx. CV008 should be deleted.-Done (QOS rev1)
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2.3 S- Include the version number(s) including amendments (and/or date(s)) of the applicant’s/open and restricted/closed parts of APIMF449 in the provided spaces.-QOS QOS DoneTQMS
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2.3.S.1.3(d)-The hygroscopicity of Molnupiravir should be established from literature or be determined as per a pharmacopeial standard e.g., BP/EP.Penambahan info higroskopisitas: not hygroscopicQOS & Quality- 3.2.S.1.3 General Properties
- P2 		Done- Plant
- TQMS (P2)		31/05/23
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2.3.S.3.2(a)(i):Include the PhInt draft impurity codes (where applicable) for the listed impurities e.g. Impurity X = PhInt draft impurity A.--QOS & Quality- 3.2.S.4.1 Specifications
- 3.2.S.4.2 Analytical Procedures
- 3.2.S.4.4 Batch Analysis		DonePlant31/05/23
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2.3.S.3.2(b)(ii)--QOS- Done
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2.3.S.4.1(a)-The tests for description and colour of API should be merged and limit should indicate that the powder is crystalline (in line with what is stated in 2.3.S.1.3). Note that the final accepted limits will depend on the accepted APIMF449 specifications.QOS & Quality- 3.2.S.4.1 Specifications
- 3.2.S.4.2 Analytical Procedures
- 3.2.S.4.4 Batch Analysis
- 3.2.P2 Pharmaceutical Developmentt		Done- P. Bahan Baku
- TL
- Plant		31/05/23
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2.3.S.4.2-State if any API supplier’s or pharmacopoeial methods have been adopted."In house method (Adopted from API manufacturer Shanghai Desano)"QOS & Quality- 3.2.S.4.1 Specifications
- 3.2.S.4.2 Analytical Procedures
- 3.2.S.4.4 Batch Analysis		DonePlant31/05/23
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2.3.S.4.4-Provide batch data for a second API batch if available.-
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2.3.P.1(a): The type of capsule shell should be stated i.e. HPMC capsule shell. The description of the powder should be revised to ‘granular powder’.-"White granular powder in transparent HPMC Capsule Shell size 0"QOS & Quality- 3.2.P.1 (done)
- 3.2.P.2 (done)
- 3.2.P.5.2 (done)
- 3.2.P.5.4 (done)
- 3.2.P.8.3 Rekap Data Stab (07/06/23)		QOS : Done
Quality : Not Yet (stability)		- TL
- Plant
- TQMS (QOS)		31/05/23
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2.3.P.1(b): The quality standards of molnupiravir and capsule shell should be stated.
The average weight of empty capsule shell should be stated in the table.		The quality standard of molnupiravir and HPMC capsule should be stated as in-house.
Purified water should be added to the table (used during granulation).		BMR (hanya ditable formula)QOS & Quality- 3.2.P.1
- 3.2.P.2
- 3.2.P.3.2
- 3.2.R.1 BMR 		Done- TL
- Plant
31/05/23
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2.3.P.1(b)(ii): The composition of the capsule shell and any imprinting ink should be tabulated in this section. The quality standards of components/ingredients should be stated.Komposisi dibagian spesifikasi material (tidak masuk kedalam parameter diuji)QOS & Quality- 3.2.P.2
- 3.2.S.4.1 Specifications		Done- TL (P2)
- Plant		31/05/23
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2.3.P.2.2.1(a)-Include more information in the summary of formulation development and optimization including studies leading to the determination of final excipient amounts.QOSTechnical package merk (MSD)DoneTL31/05/23
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2.3.P.2.2.1(b)(i):
The batch numbers of FPP batch(es) used in the bioequivalence, dissolution profile, stability and validation studies should be included in the table.

It is noted that the columns for Commercial batches have been deleted. The QOS template table should not be changed. You are requested to re-instate all the deleted columns and to fill as appropriate.		QOSDone (QOS rev2)
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2.3.P.2.2.1(c)-Indicate the batch size of the test product batch 12105NX.QOSDone (QOS rev2)
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2.3.P.2.2.1(d): Please include results from multimedia, multipoint dissolution profile studies on the BE batch I2105NX (and if being profiled on the comparator product batches). The dissolution profiles should be generated in three BCS media (pharmacopoeial buffered media are recommended) across the physiological pH range (pH 1.2, 4.5 and 6.8, paddle rotation speed 50 rpm, 500ml, 37oC, using 12 units). The BCS media used should be described including for example the pharmacopoeial reference (e.g. dissolution buffer pH 1.2 TS Ph. Int). The sinker brand and dimensions should be stated if one is used.Dissolution data should always be rounded, for the individual units and averages. The same applies for dissolution % RSD.

WHO COMMENTS: It is strongly recommended that the dissolution behaviour of the granules of the biobatch (without the capsule shells) in the routine QC dissolution conditions is studied whilst the BE batch is only a few months old. This may provide useful information to support certain future changes associated with the manufacture of the granules. Sampling could be stopped as soon as 85% or more of the Molnupiravir is released.

KF FEEDBACK: We already did dissolution testing of the granules as your recommendation. This is the data, showed that molnupiravir released more than 85% at 10 minute. should we testing granules dissolution in our QC release routine or just in development stage?		Dissolution testing of the granules only for the biobatch. QOS & Quality3.2.P.2 Product DevelopmentDoneTL
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The dissolution profile results summary should include the individual dissolution results for 12 units, mean dissolution results, % RSD for each time point, along with graphical presentation of the data.QOS & Quality3.2.P.2DoneTL
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Any observed high variability (e.g. at earlier time points) should be investigated and discussed. The importance of observations during dissolution testing is discussed in USP <1092>, “2.4.2. Observations” in particular with respect to variability.WHO COMMENT: Any observed high variability (e.g. at earlier time points) should be investigated and discussed. The importance of observations during dissolution testing is discussed in USP <1092>, “2.4.2. Observations” in particular with respect to variability.

KF FEEDBACK: To reduce the high variability dissolution data, Kimia Farma did an observation of the dissolution method of Molnupiravir with changes in the agitation speed 50 rpm to 100 rpm. The data showed 100 rpm, % RSD is meet the requirement NMT 20% at earlier time points and NMT 10% at next time point.
It’s okay about Kimia Farma justification, because in medium dissolution of molnupiravir (HCl 0,1 N) pH 1,2 the drug release is more than 85% at 20 minutes and %RSD is lower than 10%.QOS & Quality3.2.P.2DoneTL
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2.3.P.2.3(a)-WHO COMMENT : Include more details on the development and optimization of the process parameters at the critical steps of the manufacturing process.

KF FEEDBACK : Kimia Farma didn’t do any study on process development parameters, because Kimia Farma developed Molnupiravr Capsules refer to MSD Technical Package. And Kimia Farma will send the MSD Technical Package to WHO. 		For the development stage Kimia Farma allow to send the MSD Technical Package as supporting data of detail development and optimization of the process parameters at the critical steps of the manufacturing process. Done
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2.3.P.2.4(a)Include one –time moisture permeability results for the proposed HDPE bottle, generated as per USP <671> or other equivalent standard.- To be discuss R&D dan Plant
- Menunggu feedback dari supplier terkait pengujian tambahan		QOS & QualityP.7 Container Closure SystemAfter review from PQ WHOTL
Plant		July 2023
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2.3.P.3.2(a):-WHO COMMENTS: The potency adjustment formula for the API based on assay and water content results and corresponding adjustment diluent should be included in the BMRs and added as a footnote to the table.

KF FEEDBACK: We don't have any reference about diluent adjusment is permitted correspond to API assay and water content result. Can you give us suggestion about this issue?		Adjusment formula is permitted according to water content result of API. But it’s okay not to adjust formula if not common by your Indonesia FDA regulator.---
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2.3.P.3.3(b): The narrative description should be improved to include more details of the manufacturing process from the batch production documents i.e. all process steps, process parameters, equipment used etc.QOS & Quality3.2.P.3.3 manufacturing processDone
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A tabulated list of the critical equipment used for each batch size with model/make and capacity should be included.Penambahan list detail alat (nama alat & kapasitas)QOS & Quality3.2.P.3.3 manufacturing processDone
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2.3.P.3.4:The process controls (and their acceptance criteria) at the critical manufacturing steps and the frequency with which they are performed should be stated in the table.Average fill weight of capsules should be tightened to +/-3% (i.e., 285.711mg+/-3%) and be monitored during encapsulation at least once every 30 minutes. The acceptance criteria of uniformity of dry mixing should be clarified: is 95.0-105,0% for mean or individual values? Note that uniformity of final blend is required for the BE batch and the validation batches. An acceptable limit would be: individual assays, each 90.0-110.0% of the label claim and RSD NMT 5.0%.

Filling capsules: Clarify the test of uniformity of mass of capsule (acceptance criteria 95.0-105.0%).

Note that test of individual capsule weight variation is also required to be monitored during capsule filling. See 5.2 Uniformity of mass for single-dose preparations chapter of the PhInt.

The maximum hold time for intermediate and bulk products (e.g., final lubricated blend, filled capsules) should be stated. Any hold time for any intermediate and bulk product greater than 30 days should be supported with stability data.
To be confirm PQ WHOQOS & Quality - 3.2.P.2
- 3.2.P.3.2
- 3.2.P.5.1
- 3.2.P.5.2
- 3.2.P.5.4
- 3.2.P.8.1
- 3.2.P.8.3
- BMR
- Valpro		After review from PQ WHO- TL
- Plant
- TQMS
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The intermediate specifications for final blend should be summarized.QOSDone (QOS rev1)
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The hold times for intermediate and bulk products should be stated.QOSDone (QOS rev1)
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2.3.P.3.5: State if the validation batches I2105NX, I2103NX and J2106NX (batch size 100,000 capsules) were manufactured consecutively or not. Include a summary of the process validation protocols and reports focused on the identified critical steps of the manufacturing process. Also, include a discussion regarding similarity of the dissolution profiles of the validation batches (generated in the QC medium) to that of the biobatch profile I2105NX.State if the validation batches I2105NX, I2103NX and J2106NX (batch size 100,000 capsules) were manufactured consecutively or not. Include a summary of the process validation protocols for batch size 140 kg/491,228 capsules and of report for batch size 28.5 kg/100,000 capsules (for batches I2105NX, I2103NX and J2106NX), focused on the identified critical steps of the manufacturing process.

Also, include a discussion regarding similarity of the dissolution profiles of the primary validation batches I2103NX and J2106NX (generated in the QC medium) to that of the biobatch profile I2105NX. 		Revisi: penambahan tanggal

Similarity of the dissouliton profiles: to be confirm PQ WHO (after review from WHO)		QOSP5.4 cover
P5.4 CoA Produk Jadi
P5.4 Laporan pengujian 		DoneTL
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2.3.P.4.1: Specifications for HPMC Capsule shell (body and cap) as well as ink specifications (if applicable) should be provided and summarized in the QOS. The shell excipients and their standards should be indicated.The shell supplier(s) should be identified. The composition of the shells should be provided from the supplier(s), i.e. on supplier letterhead.QOS & Quality- P2
- P4 spesifikasi HPMC		Done
P2: Not Yet
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2.3.P.4.5: Reference to lactose should be deleted (not used in the formulation).-QOSDone (QOS rev1)
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2.3.P.5.1: The capsule appearance should be described fully e.g., colour, any imprinting or markings etc. The description of the powder should be revised to ‘granular powder’.WHO COMMENT: A second identification test should be added as per ICH Q6A. The limit for unspecified degradation products should be revised to NMT 0.13% in line with ICH Q3B (based on a maximum daily dose of 1600mg). Test and acceptance criteria for moisture content should be included.

The dissolution limit should be revised to NLT 80%(Q) of the labelled amount of Molnupiravir should dissolve in 20 minutes, based on the dissolution profile/behaviour of the BE batch I2105NX (in QC dissolution conditions).

Acceptance criteria for microbial limit test should be revised to be in line with harmonized pharmacopoeial requirements (i.e., Aerobic Microbial Count: NMT 103 and Total Yeast & Mould Count: NMT 102).

Identifikasi: Spektro UV

Moisture Content: 1-2% 		Jika ada sampel stabilitas berlebih maka identifikasi spektro dan moisture content diuji untuk data stabilitas 6 bulan.

Dissolution:
NLT 80% (Q) + 5% 		QOS & Quality
- 3.2.P.2 (done)
- 3.2.P.5.1 (done)
- 3.2.P.5.2 Spesifikasi Produk jadi
- 3.2.P.5.4 CoA Produk Jadi
- 3.2.P.8.1 Summary (done)
- 3.2.P.8.2 Protokol
- 3.2.P.8.3 Data Stabilitas (07/06/23)		QOS : Done (rev 2)
Quality : Not Yet		- TL
- Plant
- TQMS		31/05/23
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The routine QC dissolution conditions (e.g. apparatus, agitation speed, medium, volume, the sinker brand and dimensions etc.) should be included in a footnote to the table.QOS & Quality
3.2.P.5.2 		Done
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2.3.P.5.4-Dissolution results should include the averages, maximum and minimum values (or individual results). -> QOS

For degradation products, results should be indicated as either below LOQ or LOD instead of 0.00% (as reported for NHC)		For degradation products, results should be indicated as either below LOQ or LOD instead of 0.00% (as reported for NHC)QOS & Quality- 3.2.P.2 (done)
- 3.2.P.5.4 analysis batch (07/06/23)
- 3.2.P.8.3 stability data (07/06/23)		QOS : Done (rev 2)
Quality : Not yet		- TL
- Plant		31/05/23
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2.3.P.5.5 (a)-Include a discussion on the potential and actual degradation products of the FPP, including Impurity F of Ph.Int. draft monographs. Note that while the Ph.Int. draft monographs are unfinalized and continue to be in a state of flux, they can however provide an indication of potential expectations.QOS & QualityKomitmen dengan timelineHOLD
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2.3.P.5.5 (b)(i):-The maximum daily dose of 1600mg should be indicated in the table and the ICH thresholds revised accordingly (ICH Q 3B)QOS QOS QOS : Done
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2.3.P.7.1(a): The container closure system should be fully described in column 1.QOS QOS : Done
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2.3.P.7.1(b)-WHO COMMENT :The specifications for the HDPE bottle, HDPE cap and silica gel should include a specific identification test.

KF FEEDBACK: The specifications for the HDPE bottle, HDPE cap and silica gel should include a specific identification test. We wiil do a specific identification test. but our question is the test should do in our 		Identification test and permeability moisture of bottle HDPE should be done by Kimia Farma.

- To be discuss R&D dan Plant
- Menunggu feedback dari supplier terkait pengujian tambahan		QOS & Quality- QOS
- P.7 Container Closure System 		After review from PQ WHO
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2.3.P.8.1(a)-Include a summary of photostability data generated as per ICH Q1B referred to in section 2.3.P.2.4 of the QOS.QOS- P2QOS : Done
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2.3.P.8.1(b): The complete and proposed test intervals should be corrected.QOSQOS : Done
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Long term and accelerated stability data should be summarized separately. The summary should include the range of actual results where applicable e.g., assay, degradation products, dissolution, disintegration time etc. For degradation products, results for specified impurity N-hydroxycytidine, any unspecified impurity and total degradation products should be summarized separately. For dissolution, report average and range of individual results at each test station.- The proposed and completed test intervals in the table appear to be switched. (QOS only)
- Results for moisture content and for dissolution after 20 minutes should be generated and reported going forward for accelerated and long-term stability batches.		QOS & Quality- 3.2.P.8.1 Stabilty Sumary (done)
- 3.2.P.8.3 Data Stability (07/06/23)		QOS : Done (rev2)
Quality : Not Yet		Plant31/05/23
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2.3.P.8.2(c)-Table should be completed with respect to stability commitment for the annual batch allocation i.e. At least one production batch per year (unless none is produced that year) in each container closure system.Hanya di Protokol Stabilitas (tidak dibuat komitmen)QOS & Quality3.2.P.8 Protocol Stability
DonePlant31/05/23
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2.3.R.1.2 (a)-The codes of blank BMRs should be stated.QOSQOS: Done TL
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