ASEPTIC PROCESSING: TWO - Risk Management Applications in Pharmaceutical and Biopharmaceutical Manufacturing - page 250

hazards are not an integral characteristic or predesigned constituent of the process
or therapeutic.

10.5.2 Extrinsic Hazards

Extrinsic hazards necessarily originate externally to the product, item, or opera-
tion and must gain access across or through a physical barrier or zone designed to
maintain sterility. Risks to product quality from extrinsic hazards during aseptic
manufacture may manifest in two related forms: the hazard of ingress, accessing,
and contaminating and secondly the risk of hazard retention. The hazard retention
risk is associated with the sustained physical presence or juxtaposition within,
or residing on, the product or aseptic process. On once accessing a product or
process there may be no mitigating process or conditions that physically remove
or destroy the contaminant. If the risk is constituted by microbial contamina-
tion, conditions may permit proliferation and even greater potential impact. An
example here might be the cleaning of container closures before sterilization; a
risk of extrinsic microorganisms (not associated with the closures) is foresee-
able during the cleaning cycle, accompanied by a risk that these microorganisms
may remain on or with the closures. The retention of these microorganisms or
their vestiges (potentially endotoxin) may continue to contaminate and jeopardize
product quality.
Invariably all aseptic manufacturing is vulnerable to varying degrees of risk
exacted by extrinsic hazards. For any hazard to exact harm, a hazardous situation
must first be encountered; initiating events, and a sequence of circumstances of
varying complexity are necessary [29]. Complexity of technology, processes, pro-
cedures, and the almost ubiquitous involvement of human-mediated tasks makes
aseptic processes particularly prone to risks from extrinsic hazard ingress [31].
Despite the diversity and complexity of aseptic processing, there exists only a
finite number of extrinsic hazards with the potential to exact a risk to prod-
uct quality. Invariably, the extrinsic hazards that contribute the greatest risks to
product quality are particulates [32] and microorganisms [5,33]. Pharmacopoeia
standards [34-37] for both large and small volume aseptically manufactured par-
enterals permit the presence of quantitative levels of particulates; in comparison,
the requirement for microorganisms is their complete absence. The levels of tol-
erance for these two critical quality attributes in finished products is mirrored
by the degree of control and requisite maximum quantities permissible within
the aseptic and clinical environments. The contrast between the required degree
of control for particulate and microbial hazard can be no more clearly exempli-
fied than the levels defined in the EU GMP's Annex 1 [38] for Grade A (ISO
4.8) cleanroom environments. Within these Grade A conditions, the CGMPs per-
mit no more than 20 particles ( 1 cfu/m 3 of air. An amount of

particulate is permissible in a product (and therefore the environment does not
necessarily need to be devoid of them), and no microorganisms must exist within
the product (and therefore the environment should be more stringently controlled
with respect to this extrinsic hazard). In any risk analysis of aseptic environments

≥ 5 μ m) and <