PHARMACEUTICAL PRODUCT MANUFACTURING - Risk Management Applications in Pharmaceutical and Biopharmaceutical Manufacturing - page 275

11.2.1.2 Active Pharmaceutical Ingredients and Excipients Raw materials
used to formulate the product need to be potent, safe, of a defined purity, and
be of the correct composition, identity, and quality. If any of these aspects
are compromised, product safety and efficacy are at risk. The risk assessment
should address any of the chemical, physical, and microbial attributes of the
material that are critical to product safety and be in relation to the specific use
of the material. For example, water is used in the manufacture of both a liquid
and a solid product. Poor microbial water quality would be a relatively greater
risk for a liquid product where water is the main ingredient as compared to the
manufacturing of a solid product where typically water plays a much smaller
role and is eliminated by drying during the process.
In particular with raw materials, lot-to-lot variability of incoming lots poses
a major risk to the quality of the finished product. Those characteristics of the
material critical to consistently delivering the intended product quality need to
be determined and controlled for incoming lots. For example, if low moisture
content of a powdered material is critical to its use for a solid product, then
moisture would be a characteristic required to be at a certain level in every lot
received. Lots with high moisture content could adversely affect the granulation
or drying processes. The bulk product may be too moist to properly compress to
the proper hardness, affecting the final unit potency.
Particle size may be a characteristic identified to be critical to product quality.
In a liquid formulation, a larger particle than expected could require more mixing
time to allow for longer particle-to-water contact or greater agitation for full
dissolution of the material. Likewise, in solid dose manufacturing, larger particles
may not blend properly during the granulation process. Inadequate mixing or
blending could produce a nonhomogeneous batch where pockets of the batch are
superpotent, containing undissolved, concentrated amounts of active material,
and other portions of the batch are subpotent, containing substandard amounts of
active material. Depending on how and where the batch is sampled for testing,
the discrepancy may not be uncovered during in-process or final product testing.
The obvious safety risk is that the patient may either be overdosed (superpotent)
or inadequately treated (subpotent).
Control of lot-to-lot variation in the microbial quality of incoming active and
excipient ingredients is important for finished products that have an established
microbiological limit. The control strategy would need to include monitoring
of incoming lots for microbial content as well as controls to protect the mate-
rial from microbial contamination during the sampling process from personnel,
instruments, and the sampling environment.
11.2.1.3 Supplier Management In-house testing of the critical attributes in raw
materials allows a manufacturer to know their incoming quality levels. Monitor-
ing the incoming quality mitigates the risk of using materials that will not meet
finished product specifications. It does not, however, mitigate the risk of receiving
materials that do not meet incoming specifications. A drug manufacturer should
have confidence that the quality of material received from the supplier will not