DECTOMAX 10 mg/ml Solution for Injection (doramectin)

Quality documentation Page 1

Part 2B - Method of Preparation

PART 2B -DESCRIPTION OF THE MANUFACTURING METHOD

B.1 MANUFACTURING FORMULA

Following batch sizes are used: 2000 to 8000 litres at Inovat and 5000 litres at Zoetis Spain.
Formulae for the manufacture of the typical commercial batches are presented below.

Table B. 1: Manufacturing Formula

Ingredient Kg / 2000 l Kg/ 5000 l Kg / 8000 l

Active
Doramectin1 20,0 50,0 80,0
Excipients
Ethyl oleate2 436,0 1090,0 1744,0
Sesame oil2 q.s. to 2,000 l q.s. to 5,000 l q.s. to 8,000 l
Nitrogen3 -- -- --
Total

The actual amount of doramectin added is adjusted for potency based on the assay result as
per the calculation given below.

Actual amount of doramectin to be added (kg) = Theoretical amount (kg) x 100 / % purity of
input material

Sample calculation

Actual amount of doramectin to be added to a 2,000 kg batch (kg) = 20 (kg) x 100 / 97

Where 20 kg is the theoretical amount of doramectin to be added to a 2000 l batch and %97 is
the assay result of the doramectin input material.
1
Contains no overage and assumes a potency of %100. The quantity of doramectin added is adjusted for potency based on
the assay result of the ingoing drug substance.
2
Contains 100 ppm nominal butylhydroxyanisole as an antioxidant (i.e. 0,5 kg BHA for a 5000 l batch)
3
Nitrogen is used as a processing aid and as an inert atmosphere during the manufacturing process.
B.2 MANUFACTURING PROCESS

B.2.1 Manufacturing sites

The following table lists the sites that have responsibilities in the production of Dectomax 10
mg/ml Solution for Injection and their specified functions.

Site Manufacturing steps

Zoetis Manufacturing & Research Spain, S.L. Ctra. Manufacture, primary packaging, secondary
De Camprodon s/n°, Finca La Riba Vall de Bianya, packaging, testing and release of the drug product
Gerona,
17813, Spain
Inovat Indu stria Farmaceutica Ltda Manufacture, primary packaging, secondary
Av. Presidente Tancredo de Almeida Neves, 1555 packaging, testing and release of drug product
CEP 07112-070, Guarulhos,
Sao Paulo, Brazil
B.2.2 Description of manufacturing process

B.2.2.1 Flow diagram of manufacturing process

Inovat Industria

Add the sesame oil to the

compounding tank
↓
Add the ethyl oleate to the sesame
oil and stir
↓
Heat the solution to 45 - 60°C. Add
the doramectin to the solution
↓
Maintain the temperature at 50°C ±
5°C and dehydrate the solution by
applying a nitrogen flow until a
satisfactory water content is
obtained
↓
Cool the solution to ambient
temperature
Sample the solution for in-
process control testing → ↓
(doramectin content)
Sterile filter the solution through a
0,2 micron membrane filter into a
sterilised receiving tank in the
aseptic processing area. If
necessary, a pre-filter may be used
before sterilising filtration.
↓
Fill the solution into vials and seal
with stopper and aluminium cap
↓
Submit a representative sample of
the vials to the Quality Control
Department for testing.
Zoetis Spain

Process tank
↓
Add Sesame Oil
↓
Add Ethyl Oleate
↓
Heat the solution to 45-60 °C and add the Doramectin → Temperature control
↓
Maintain the temperature at 50±5°C and dehydrate
the solution by applying N2
↓
→ Water control

Cool down to ambient temperature 25±5°C

→ Temperature control
↓
→ Bioburden control

Redundant sterile filtration

B.2.2.2 Description of manufacturing process

1. Add the sesame oil to the compounding tank.

2. Add the ethyl oleate to the sesame oil and stir.
3. Heat the solution to 45 - 60°C. Add the doramectin and stir to dissolve.
4. Maintain the solution at 50 ± 5°C. Dehydrate by applying nitrogen to the solution.
5. Cool the solution to ambient temperature (25 ± 5°C).4

Filter-to-hold process5

Filter the bulk solution from step 5 through a sterilizing 0,2 µm filter into a sterilised
receiving tank in the aseptic processing area. If necessary, a pre-filter may be used before
sterilising filtration6.

Under aseptic conditions, fill the solution into vials and seal with stopper and aluminium cap7.

The maximum hold time at Inovat is 7 days prior to filling.

Filter-to-fill process

Filter the bulk solution from step 5 through a sterilizing 0,2 µm filter into a sterilised
receiving tank into a sterilised closed circuit and filled into sterile vials.

Sterilizing filters

Inovat Industria

The sterilizing filter used by Inovat Industria is a 0,22 µm hydrophilic filter.

Integrity testing of the sterile filter will be performed before and after filtration by measuring
bubble point and diffusion value according to filter manufacturer specification.

Zoetis Spain

The sterilizing filter used by Zoetis Spain used is of polyethersulfone with a filtration area of
1.71 m2 and nominal pore size of 0,2 µm.
Two sets of two filters are used for sterilizing filtration. No pre-filters are used at this site.
Integrity testing of the sterilising filter is performed before and after filtration with the
forward flow test using Dectomax as a humectant fluid and a pressure of 1200 mbar of
nitrogen. An acceptance criteria of ≤57,7 ml/min is applied before and after filtration.
4
Prior to filtration, any previous step may be repeated to obtain a solution of proper product characteristics.
5
This process is not performed at Zoetis facility in Spain. Zoetis will only perform the filter-to-fill process.
6
If a low bioburden cannot be guaranteed prior to filtration, a pre-filtration step can be included
7
A terminal clarifying filter may be used during filling.
Notes

A nitrogen8 atmosphere over the product is set in some steps of the manufacture and filling
process. Nitrogen is sterilized by filtration through a sterilized 0,2 µm filter when used in
aseptic steps.
8
Nitrogen meets the Ph. Eur. requirements
B.2.2.3 Method of sterilization

Sterilization process of sterilizing filters

Inovat Industria

Filters are sterilized by steam in place for 45 minutes at 122-135°C.

Zoetis Spain

Filters can be sterilized by irradiation using a gamma-irradiation level of 25-40 kGy or

sterilization-in-place by steam for at least 30 minutes at 125°C or above.

Sterilization process of primary packaging materials

Inovat Industria

The injection vials are washed and rinsed with Water for Injections and subsequently
sterilized by dry heat in a sterilisation tunnel by a temperature equal to or above 285°C for 1
minute. The sterilization process was validated and the report is presented in annex-2b1.

The stoppers are depyrogenated and sterilised using a validated process. The validation of the
process can be found in annex-2b2.

Zoetis Spain

Empty glass vials are sterilized and depyrogenated by using dry heat sterilization. Dry heat
sterilization is frequently used for both sterilisation and depyrogenation of glassware and is a
process aimed at the reduction in the level of pyrogens with the use of hot air to temperatures
typically above 300°C.
Each vial will be exposed to a minimum heat and time period to ensure a 3 log reduction of
heat-resistant endotoxins potentially present in the vials. The heat and temperature
requirements for each vial size are summarized below.

Vial size Temperature required Heating time

Stoppers are sterilized by moist heat prior to use by autoclaving at 121°C or 122°C for a
minimum of 30 minutes. These conditions meet the recommendations of the Ph. Eur. which
states that sterilization should be achieved by submitting the product to 121°C for 15 minutes.
B.2.2.4 In-process controls

During compounding

Samples are taken after nitrogen purging and prior to sterile filtration.
The tests performed on the samples at the different manufacturing sites are described below.

Inovat Industria

After nitrogen purging

The water content of the solution after nitrogen purging should be %0,05 w/w maximum.

Before sterile filtration

The solution concentration should be within the range 9,5 to 10,5 mg doramectin per ml. The
doramectin concentration of the solution is determined using the HPLC assay procedure D
144,2, which is presented in Part 2E.

The bioburden of doramectin injectable solution is checked directly before final filtration to
ensure that counts are kept at not more than 10 CFU/100 ml.

Zoetis Spain

After nitrogen purging

The water content of the solution after nitrogen purging should be % 0,05 w/w maximum.

Before sterile filtration

The bioburden of the solution will be controlled to not more than 10 CFU per 100 ml.

During the filling operation

The tests performed at the different manufacturing sites are described below.

Inovat Industria

The first filled vials are inspected for particulate matter and clarity.
The filled vials are periodically checked for adequate sealing.

The filled vials are routinely checked throughout the filling run for fill volume, which should
not be less than the nominal volume.
Zoetis Spain

An automatic fill weight control is performed on % 100 of vials during filling to ensure that
minimum fill weights are maintained. Following limits apply:

not less than 46,71g

All vials are visually inspected for defects and visible particles.