Australian public assessment for Albumin (human)

I. Introduction to product submission

Submission details

Type of submission:	New biological medicine
Decision:	Approved
Date of decision:	15 July 2015
Date of entry onto ARTG	30 July 2015
Active ingredient:		Albumin (human)
Product names:		Albunate 5: 250 mL; Albunate 5: 500 mL; Albunate 20: 50 mL; Albunate 20: 100 mL; Albunate 25: 50 mL and Albunate 25: 100 mL
Sponsor’s name and address:		CSL Limited^1 189-209 Camp Road Broadmeadows VIC 3047
Dose form:		Solution
Strengths:		50 g/L, 200 g/L and 250 g/L
Container:		Vial
Pack sizes:		1
Approved therapeutic use:		Restoration and maintenance of circulating blood volume where volume deficiency has been demonstrated und use of a colloid is appropriate The choice of albumin rather than artificial colloid will depend on the clinical situation of individual patient
Route of administration:		Intravenous infusion
Dosage:		The concentration of the albumin preparation, dosage and the infusion rate should be adjusted to the patient's individual requirements. For further details see the Product Information.
ARTG numbers:		223744, 223741, 223739, 223743, 223740, 223742

Product background

This AusPAR describes the application by CSL Limited (the sponsor) to register Albunate 5, Albunate 20 and Albunate 25 for the following indication:

Restoration and maintenance of circulating blood volume where volume deficiency has been demonstrated and use of a colloid is appropriate.

The choice of albumin rather than artificial colloid will depend on the clinical situation of the individual patient.

Albumin (human serum albumin (HAS)) is a biological medicine. However, the sponsor is not proposing this product is a biosimilar to Albumex (the only albumin product currently registered and marketed in Australia). Instead, the sponsor is proposing registration as a stand-alone product.

The sponsor is seeking to register a Swiss manufactured albumin product. Currently there is only one albumin product registered and marketed in Australia: Albumex, which is manufactured at the sponsor’s Broadmeadows site in Melbourne (from Australian starting plasma collected by the Australian Red Cross Blood Service (ARCBS)). This is a different situation from that in other similar high-income countries, where various different albumins are registered and marketed.

The Swiss manufactured albumin (Albunate) and the Australian manufactured albumin (Albumex) are produced using different methods. However, both products are manufactured from large pools of human plasma in compliance with the European Pharmacopoeia (Ph.Eur.) monograph for “Human Albumin Solution”.

There have been shortages of albumin in Australia. The sponsor has advised that this Swiss manufactured albumin is proposed to support continuous supply of albumin in Australia.

Regulatory status

Overseas regulatory history

Albunate is a plasma derived product in clinical use for nearly 40 years. It has been registered and used in multiple jurisdictions but with different trade names. In the US the trade name and concentrations registered are: AlbuRx, 5% and 25%; these have been registered since 1976.

In Switzerland the trade name is Albumin CSL, registered at 5%, 20% and 25% concentrations since 1978.

It has been registered in 25 other European markets and European Economic member states since 1997 with the trade name of Alburex, and others, 5%, 20% and 25%, and a number of other Asian/Middle Eastern States.

Overall the 20% strength is more commonly registered in Europe while the 25% strength is registered in the US and Canada. The 20% and 25% strengths (hyper-oncotic albumin) are used in similar settings.

No application has been rejected or withdrawn in the other markets.

Product Information

The product information (PI) documents approved with the submission which is described in this AusPAR can be found as Attachment 1. For the most recent PI, please refer to the TGA website at .

II. Quality findings

Drug substance (active ingredient)

Structure

Human serum albumin (HSA) is a single peptide chain of 585 amino acid residues and contains essentially no carbohydrate. It has a very low content of tryptophan and methionine and a moderately low content of isoleucine and glycine. HSA is relatively resistant to denaturation. The molecular weight of HSA is approximately 66,500 Daltons; the Stokes-Einstein radius is 3.53 nm, and the isoelectric point is around pH 5. The viscosity of HSA is low because its molecule is shaped as a symmetrical ellipsoid.

Manufacture

The proposed human albumin 5%, 20% and 25% solutions are manufactured according to the Kistler and Nitschmann procedure.

After skin thawing, the frozen plasma containers are cut, the plastic containers removed and the frozen plasma blocks continuously pooled into a double jacketed 300 litre thawing tank. The plasma is then thawed under constant stirring to a temperature of  2 to + 3°C. The cryoprecipitate (cold insoluble globulins) is removed by continuous centrifugation at a temperature of 0 to 6°C and subsequently used for the manufacture of factor VIII, if the plasma quality is suitable for the isolation of coagulation factors, or discarded. The cryo-poor plasma is collected either in a 45.00 L stainless steel tank or directly transferred into the fractionation tank. After the homogenisation in the fractionation tank, the plasma pool samples are drawn.

The pH of the plasma is lowered to pH 5.7 to 6.0 with acetate acetic acid buffer (pH 4). Ethanol 96% is added continuously to a concentration of 19% (V/V) while stirring and cooling to a temperature of  5.5°C ± 1.0°C. The pH is then adjusted to 5.70 to 5.90. The suspended precipitate A is removed by filtration after addition of perlite (volcanos earth filter aid) on polypropylene sheets. Precipitate A is used in the manufacture of immunoglobulin products.

The filtrate of Precipitate A is collected in another stainless steel tank for further processing to albumin. The temperature is reduced to  7 ± 0.5°C, and simultaneously 96% ethanol is added to a final concentration of 40% (V/V). The pH of this solution is adjusted, if necessary, to 5.95 to 6.00. Fraction IV precipitates and is then, by the use of filter aids (perlite and diatomaceous earth), filtered through a filter matrix support in order to remove the precipitate.

The pH value of filtrate IV is adjusted by 1.1 M acetic acid to 4.8 ± 0.1 at a constant ethanol concentration of 40% and under cooling to a temperature of  7 ± 1°C. Precipitate C precipitates and is then separated from the ethanol solution by filtration with diatomaceous earth. Precipitate C contains almost exclusively albumin and filter aids. For further processing Precipitate C from one or more fractionation lots is first resuspended in water for injection (1 kg paste + 1.7 kg water for injection) and then filtered at pH 4.7 ± 0.1 through asbestos free depth filters. The pH of Filtrate d is adjusted to 7.2 ± 0.1 by means of 1 M NaOH.

The neutralised solution is concentrated to about 130 to 140 g/kg albumin by ultrafiltration, then diafiltered first with at least five times the actual volume of 0.1 to 0.3 M sodium chloride, then with 0 to 3 times the amount of water for injection. By this process aluminium, other low molecular salts and ethanol are removed. A sample of the solution is drawn to examine the protein content and the sodium concentration.

The final adjustment of the properties of the final product is achieved by calculated analysis. The sodium content is adjusted by sodium chloride to a concentration of 140 mmol/L. Then 0.08 mmol sodium caprylate and 0.08 mmol sodium N-acetyl-tryptophanate per gram of protein, corresponding to 20 mmol/L for 25% albumin, 16 mmol/L for 20% albumin and 4 mmol/L for 5% albumin, are added to the albumin solution as stabilisers. Water for injection is added to a protein concentration of 233.6 g/kg (for 25% albumin) 188 g/kg (for 20% albumin) and 49 g/kg (for 5% albumin). If necessary the pH is adjusted by hydrochloric acid or sodium hydroxide solution, respectively.

In the manufacture of Albumex additional steps including anion and cation exchange and gel exclusion chromatography are used. In terms of manufacturing process, this distinguishes the two products Albumex and Albunate from one another. Data has not been provided to demonstrate comparability or similarity between these 2 products.

All viral/prion safety issues have been addressed in a secondary specialist evaluation.

Drug product

The drug products contain appropriate amounts of albumin as the captive ingredient according to Ph. Eur. as well as the following excipients: sodium N-acetyltryptophanate: stabiliser; sodium caprylate: stabiliser; sodium chloride: tonicity agent; water for injections: solvent. Protein content is adjusted as required to manufacture 5%, 20% and 25% Human Albumin Solution (HAS). The drug product meets the European Pharmacopoeia (Ph.Eur.) standard.

Stability

Stability data have been generated under stressed and real time conditions to characterise the stability profile of the product. Photostability data: the product is photo-stable.

The proposed shelf life is 36 months when stored at 25C. This is supported by the data.

Quality summary and conclusions

The administrative, product usage, chemical, pharmaceutical, microbiological data submitted in support of this application have been evaluated in accordance with the Australian legislation, pharmacopoeial standards and relevant technical guidelines adopted by the TGA.

In their response to questions the sponsor confirmed that Albunate and Albumex are manufactured by very different processes. Although the processes for both Albunate and Albumex produce a final product which meets the Ph. Eur. monograph for ‘Human Albumin Solution’ (01/2013:0255) the evaluator commented that the use of consecutive cold ethanol precipitation method alone (Albunate)as opposed to a combined method of Cohn cold ethanol precipitation followed by multiple chromatographic steps (the currently registered Albumex) will possibly lead to products that while similar in albumin content are not similar in other impurities such as clotting factors. Quality data has not been provided to address the level of similarity between the proposed product and the currently registered Albumex product.

For this reason and because of the admitted differences in the manufacturing processes for the two albumin products the evaluator felt that the PI for Albunate should make it clear that Albunate was not identical to Albumex in its mode of manufacture. The sponsor has done this.

The above issues have been resolved following discussions between the quality evaluation area and the Delegate.

Conditions of registration

Batch Release Testing by the TGA Laboratories Branch. It is a condition of registration that, as a minimum, the first five independent batches of;

Albunate 5 (50 g/L (5% w/v) 250 mL)

Albunate 5 (50 g/L (5% w/v) 500 mL)

Albunate 20 (200 g/L (20% w/v) 50 mL)

Albunate 20 (200 g/L (20% w/v) 100 mL)

Albunate 25 (250 g/L (25% w/v) 50 mL)

Albunate 25 (250 g/L (25% w/v) 100 mL

imported into Australia are not released for sale until samples and/or the manufacturer’s release data have been assessed and endorsed for release by the TGA Laboratories Branch.