Manufacturing differences between biopharmaceuticals and low molecular weight drugs
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Manufacturing differences between biopharmaceuticals and low molecular weight drugs. Basant Sharma, PhD Vice President, Pharmaceutical Technology Centocor Raritan, New Jersey, USA. 1. September 2005. Manufacturing low molecular weight drugs.

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Manufacturing differences between biopharmaceuticals and low molecular weight drugs

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Manufacturing differences between biopharmaceuticals and low molecular weight drugs

Manufacturing differences between biopharmaceuticals and low molecular weight drugs

Basant Sharma, PhD

Vice President, Pharmaceutical Technology

Centocor

Raritan, New Jersey, USA

1

September 2005


Manufacturing low molecular weight drugs

Manufacturing low molecular weight drugs

Low molecular weight drugs are made by adding and mixing together known chemicals and reagents, in a series of controlled and predictable chemical reactions

This is organic chemistry

2


Manufacturing biopharmaceuticals

Manufacturing biopharmaceuticals

Biopharmaceuticals are made by harvesting the proteins that are produced and secreted by specially genetically engineered living cells

This is genetic engineering

3


Differences in manufacturing

Differences in manufacturing

  • The manufacturing process for a biopharmaceutical is far more complex than that for a low molecular weight drug

  • For biopharmaceuticals, much more than for low molecular weight drugs, the quality of the end product (including therapeutic efficacy and safety) is dependent on the manufacturing process

These differences clearly apply to biosimilars as well as to original biopharmaceuticals

4


How are biopharmaceuticals made

How are biopharmaceuticals made?

  • Develop host cell

  • Establish a cell bank

  • Protein production

  • Purification

  • Analysis

  • Formulation

  • Storage and handling

Each of these stages can have a major influence on the characteristics of the end product

5


1 develop host cell

1. Develop host cell

  • Identify the human DNA sequence for the desired protein

  • Isolate the DNA sequence

  • Select a vector to carry the gene

  • Insert the gene into the genome of a host(a suitable bacterial or eukaryotic cell)

The exact DNA sequence and the type of host cell used will significantly influence the characteristics of the product

6


2 establish a cell bank

2. Establish a cell bank

A cell bank is then established, using an iterative and elaborate cell screening and selection process, yielding a unique master cell bank

No two master cell banks are exactly alike

7


3 protein production

3. Protein production

The ‘engineered’ cells are then cultured on a large scale under strictly defined growth conditions that optimize cellular production and secretion of the desired protein

Cell bank frozen vial recovery

8


3 protein production cont

3. Protein production (cont.)

Spinners

Bioreactor

The conditions under which cells are cultured can affect the nature of the end product

9


4 purification

4. Purification

  • The cell culture medium is harvested

  • Undesired proteins and impurities are removed, in order to optimize the purity of the desired protein

10


4 purification cont

4. Purification (cont.)

  • Achieving maximum purity means that a considerable amount of product is lost

Large cost implications

Any change in the purification process can affect the clinical characteristics of the product

11


5 analysis

5. Analysis

  • Protein molecules are analysed for uniformity in terms of structure and potency

  • A wide variety of analytical tools is used to examine:

    • 3D structure

    • Aggregation

    • Isoform profile, including glycosylation patterns

    • Heterogeneity

    • Potency

These tests remain limited in their ability to detect all product characteristics that may affect clinical efficacy and safety

12


6 formulation

6. Formulation

  • After isolation, purification, and testing, the therapeutic protein is formulated:

    • e.g. adding antioxidants, osmotic agents, buffers

  • Formulation is a key step in stabilizing the protein

The components of the formulation, and the process used, can significantly affect the product’s behaviour in patients

13


6 formulation cont

Rotary

piston

pumps

Stoppers

Filling

needles

Product

Syringes

6. Formulation (cont.)

Syringe filling

14


7 storage and handling

7. Storage and handling

  • The formulated product is stored, handled, and administered to patients

  • Biopharmaceuticals are very sensitive to temperature changes and/or shaking

  • Strict storage and handling conditions are therefore essential for maintaining product integrity and stability

Poor adherence to (cold) storage requirements can affect clinical efficacy and safety

15

Crommelin DJA. EJHP 2003;1:73-94.


Additional issues

Additional issues

  • Each of the seven main steps consists of many smaller steps that must also be carefully controlled and validated

  • Experienced personnel familiar with the subtle nuances and proclivities of the process are essential for a consistent and productive operation

  • The average time from first cell culture to finished biological product is 8–9 months

Manufacturing biopharmaceuticals is a complex, high-tech, and time-consuming process

16


Conclusions

Conclusions

  • The manufacturing process for biopharmaceuticals (and biosimilars) is far more complex than for low molecular weight drugs (and generics)

  • Any (minor) change made at any stage may have a critical effect on the clinical efficacy and safety

  • Major manufacturing changes include:

    • producing a biosimilar

    • opening/starting a new production site

    • scaling-up to meet market demands

‘The process is the product’

17


Points to consider

Points to consider

  • Can a new manufacturer produce a biosimilar that is similar enough to the original biopharmaceutical to be considered the same?

  • How can the level of similarity be established without access to the bulk material?

  • Are there risks associated with currently undetectable differences?

How similar is similar enough?

18


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