BIOPHARMACEUTICAL MANUFACTURING - Risk Management Applications in Pharmaceutical and Biopharmaceutical Manufacturing - page 351

TABLE 12.4 Summary Table of Manufacturing Process Stages and
Associated Risks
Process Stage

Risks Associated with Individual Process Stages

Raw materials Lot-to-Lot variability; vendor qualification; origins of

raw material; contamination; stability

Cell banking Viral/TSE/BSE clearance; bacterial endotoxins;

mycoplasma; facilities; equipment; personnel
training; documentation; improper storage
conditions

Fermentation/cell culture Contamination; suitable environment; selection of

stable strain; culture media; oxygen requirements;
sterilization; facilities and equipment; scale-up
considerations

Downstream processing Inefficient harvest/recovery conditions; inefficient

purification conditions; viral contamination;
endotoxins (pyrogens)

Scale-up of production
process

Inappropriate purification techniques/process design;
viral contamination; inadequate of process
controls; inappropriate facilities

Excipients Lot-to-lot variability; vendor qualification; origins of

raw material; contamination; stability

Primary packaging Excipient interactions; environmental and chemical

hazards; packaging operations

Extractable/leachables Suitability of use of materials; technical risks;

regulatory risks; contaminants in elastomers

Distribution and cold chain
supply

Insufficient primary/secondary/tertiary packaging;
inappropriate qualification of distribution and
supply chain warehouses and shippers; inadequate
testing; inappropriate storage and handling
conditions; transit times

TABLE 12.5 Example of Risk Acceptability Definitions
Risk Level Risk Acceptability

Broadly acceptable These are acceptable risks. No further risk control

measures needed. Minimal impact to product
safety and efficacy

As low as reasonably
practical

All practical risk mitigations have been undertaken.
Further risk reduction is not practical and the
benefits outweigh the residual risk

Intolerable Unacceptable if no further risk reduction measures

are feasible. Individual risks may be accepted on a
case-by- case basis by proving that the risk/benefit
ratio is favorable, once all reasonable risk
reduction measures have been taken