Protionamide 250mg tablets(LEKHIM Joint Stock Company), TB353

WHOPAR Part 6

September 2021

This part outlines the scientific assessment and knowledge about this product at the time ofprequalification. Updates to this information are included in parts 1 to 5 and 8 of this WHOPAR.

SCIENTIFIC DISCUSSION
Name of the Finished Pharmaceutical [TB353 trade name]*
Product:
Technolog Private Joint Stock Company
Manufacturer of Prequalified Product:
8, Stara prorizna street, Uman City
Cherkassy Region, 20300
Ukraine
Active Pharmaceutical Ingredient (API):
Pharmaco-therapeutic group(ATC Code):
Therapeutic indication:

ProtionamideAntimycobacterials, combinations of drugs fortreatment of MDR tuberculosis or lepra (ATCcode: J04AD01)[TB353 trade name] is indicated in
combination with other anti-tuberculosis
agents for the treatment of multi-drug resistanttuberculosis caused by Mycobacterium
tuberculosis.
[TB353 trade name] is only indicated as asecond-line antimycobacterial drug when
resistance to or toxicity from first-line drugs
has developed.

1. Introduction[TB353 trade name] is indicated in combination with other anti-tuberculosis agents for the treatmentof multi-drug resistant tuberculosis caused by Mycobacterium tuberculosis.
[See Part 4 Summary of Products Characteristics (SmPC), for full indications].
[TB353 trade name] should be initiated by a health care provider experienced in the management oftuberculosis.
2.

Assessment of quality

The assessment was done in accordance with the requirements of WHO’s Guidelines on submission ofdocumentation for a multisource (generic) finished pharmaceutical product for the WHO
Prequalification of Medicines Programme: quality part.
Active pharmaceutical Ingredient (API)Protionamide has been prequalified by WHO according to WHO’s Procedure for assessing theacceptability, in principle, of active pharmaceutical ingredients for use in in pharmaceutical products(WHO Technical Report Series No. 953, 2009, Annex 4). This procedure provides an assurance thatthe API, used in the manufacture of [TB353 trade name] is of good quality and manufactured inaccordance with WHO Good Manufacturing Practices (GMP). API prequalification consists of acomprehensive evaluation procedure that has two components: Assessment of the API master file(APIMF) to verify compliance with WHO norms and standards, and inspection of the sites of API
manufacture to verify compliance with WHO GMP requirements.
Trade names are not prequalified by WHO. This is the national medicines regulatory authority’s responsibility.

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Protionamide 250mg tablets(LEKHIM Joint Stock Company), TB353

WHOPAR Part 6

September 2021

Additional user requirements in the FPP manufacturer’s specifications for the BCS low soluble
protionamide include tests for particle size distribution, with limits based on the data obtained for theAPI batch used in the manufacture of the FPP biobatch.
Other ingredients
Other ingredients used in the core tablet formulation include croscarmellose sodium, crospovidone,copovidone, colloidal anhydrous silica, hypromellose, lactose monohydrate, microcrystalline cellulose
and magnesium stearate, all being pharmacopoeial controlled. The film-coating mixture contains
hypromellose, lactose monohydrate, titanium dioxide, macrogol and FD&C yellow #6 / sunset yellow
FCF (E110). TSE/BSE free certificates have been provided for lactose monohydrate and magnesiumstearate.
Finished pharmaceutical product (FPP)
Pharmaceutical development and manufacture
The multisource product is an orange coloured, round, biconvex film coated tablet. The tablets arepackaged in a clear PVC-aluminium blister card.
The objective of the formulation development strategy was to develop a product with a quality profile
similar to that of the WHO recommended comparator product, Peteha 250 mg film-coated tablets. The
quality target product profile and critical quality attributes were established. The excipients were sameas the composition of the WHO recommended comparator product. An aqueous wet granulation
process was selected for the manufacture of the tablets. Appropriate in-process controls were set toensure batch-to-batch reproducibility.
Specifications
The finished product specifications include tests for description, identification of API (HPLC, UV andvisible absorption spectrophotometry) and colorants (UV and colour reaction), average mass,
uniformity of mass, disintegration time, dissolution (HPLC detection), assay (HPLC), related
substances (HPLC), uniformity of dosage units (mass variation), assay (HPLC), loss on drying,
thickness of tablet and microbiological purity. The test procedures have been adequately validated.
Stability testingStability studies have been conducted at 30°C/75%RH as long-term storage conditions and for six
months at accelerated conditions in the packaging intended for marketing of the product. The data
showed that results for all parameters remained within acceptable limits, at both storage conditions.
The data support the proposed shelf life at the storage conditions as stated in the SmPC.
Conclusion
The quality part of the dossier is accepted.
3. Assessment of Bio-Equivalence
The following bioequivalence study has been performed in 2019 according to internationally accepted
guidelines.
A randomized, open label, balanced, two-treatment, two-period, two-sequence, single dose, crossover
bioequivalence study of protionamide (Protech) coated tablets 250 mg of Private Joint Stock Company
Technolog (Group of Pharmaceutical Companies Lekhim) Ukraine, with Peteha® (protionamide) film
coated tablets 250 mg of Riemser Arzneimittel AG (Fatol Arzneimittel GmbH), Germany, in normal,
healthy, adult, human subjects under fasting conditions (study no. ARL/18/366).
The objective of the study was to compare the bioavailability of the stated protionamide 250 mg tablet
manufactured by/for Private Joint Stock Company Technolog, Ukraine (test drug) with the reference
formulation Peteha® (Riemser Arzneimittel AG) and to assess bioequivalence. The comparison wasperformed as a single centre, open label, single dose, randomized, crossover study in healthy subjects
under fasting conditions. Each subject was assigned to receive each of the following two treatments ina randomized fashion:

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Protionamide 250mg tablets(LEKHIM Joint Stock Company), TB353

Treatment T:

Treatment R:

WHOPAR Part 6

September 2021

Test – 1 tablet Protionamide 250 mg(protionamide 250 mg)
Batch no. 20216.
Reference – 1 tablet Peteha® 250 mg(protionamide 250 mg)
Batch no. 047065.

A 12 day wash-out period was observed between administration of test and reference. Serial bloodsamples (1 pre-dose sample and 19 samples within 16 h post dose) were taken during each study period
to obtain bioavailability characteristics AUC, Cmax and tmax for bioequivalence evaluation. Drugconcentrations for protionamide were analyzed using a validated LC-MS/MS method. The limit ofquantification was stated to be about 50 ng/ml for protionamide.
The study was performed with 32 participants; data generated from a total of 31 subjects were utilized
for analysis to establish pharmacokinetic parameters and assess bioequivalence.
Arithmetic mean and geometric mean values of the pharmacokinetic variables for protionamide as well
as statistical results are summarised in the following table:
Protionamide
PharmacokineticParametertmax (h)Cmax (ng/mL)
AUC0-t (ng. h/mL)
AUC0-inf (ng h/mL)

Test formulation(T)arithmetic mean ± SD(*)
1.45 ± 0.86
1903 ± 889(1734)
6107 ± 2203
(5768)
6323 ± 2247--Reference(R)arithmetic mean ± SD(*)
1.57 ± 0.83
1648 ± 569(1561)
5713 ± 1650
(5494)
5921 ± 1668--

log-transformed parameters
Ratio
Conventional
T/R (%)
90% CI(ANOVAlog)
111.1
102.5 – 120.4
105.0

100.3 – 109.9--*geometric mean

The results of the study show that preset acceptance limits of 80 -125 % are met by both AUC and Cmax
values regarding protionamide. Accordingly, the test protionamide 250 mg tablet meets the criteria forbioequivalence with regard to the rate and extent of absorption and is therefore bioequivalent to thereference Peteha® (Riemser Arzneimittel AG).
4. Summary of Product Safety and Efficacy[TB353 trade name] has been shown to conform to the same relevant standards of quality, efficacy andsafety as those required of the innovator product. [TB353 trade name] has been established to bebioequivalent to the reference product Peteha® (Riemser Arzneimittel AG. The clinical safety of thisproduct is considered to be acceptable when guidance and restrictions as stated in the Summary of
Product Characteristics are taken into account. Reference is made to the SmPC (WHOPAR part 4) fordata on clinical safety.
5. Benefit risk assessment and overall conclusion
Quality
Physicochemical and biological aspects relevant to the uniform pharmaceutical characteristics havebeen investigated and are controlled in a satisfactory way. The quality of this product is considered tolead to an acceptable clinical performance [TB353 trade name] is used in accordance with the SmPC.
Bioequivalence[TB353 trade name] is bioequivalent to the reference product Peteha® Riemser Arzneimittel AG.

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Protionamide 250mg tablets(LEKHIM Joint Stock Company), TB353

WHOPAR Part 6

September 2021

Efficacy and Safety
Regarding clinical efficacy and safety, [TB353 trade name] is considered effective and safe to use
when the guidance and restrictions in the Summary of Product Characteristics are taken intoconsideration.
Benefit Risk Assessment
Based on WHO's assessment of data on quality, bioequivalence, safety and efficacy, the team ofassessors considered that the benefit–risk profile of [TB353 trade name] was acceptable for thefollowing indication: “for the treatment tuberculosis”, and has advised that the quality, efficacy andsafety of [TB353 trade name] allow inclusion of [TB353 trade name] , manufactured at Technolog
Private Joint Stock Company 8, Stara prorizna street, Uman City, Cherkassy Region, 20300, Ukraine
in the list of prequalified medicinal products.

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