the establishment of threshold values for the
products manufactured and provides examples
of potential “operational” and “technical” measures.
The toxicological evaluation is important for companies in designing and renovating facilities as it provides
the basis to calculate projected product carryover in a forward-looking cleaning validation program. It pulls the cleaning validation program from an afterthought to the design
phase where it can used to make scientific based decisions.
This “right sizing” decision making process can save companies money by preventing the overdesigning and overbuilding of facilities unnecessarily out of perceived risk rather
than scientific rationale. Formalized Risk Assessments,
employed as part of a company’s Quality Risk Management
program must be based on the toxicological data of the
products manufactured. The outcome of the Quality Risk
Management process should be the basis for determining the
necessity for, and the extent of, operational and technical
measures. The appropriate measures may range from sharing the equipment and facility, to dedicating specific product
contact parts or areas within a facility, and to the complete
dedication of the entire manufacturing facility. The Risk
Assessment data must demonstrate and justify that cross
contamination is appropriately controlled in multi-product
and multi-purpose facilities.
For companies that have been slow to react and implement
Formal Risk Assessment processes as part of their Quality Risk
Management program, the time to act is now. Documented Risk
Assessments will be required to demonstrate to regulators that
facilities and equipment are fit for their intended use” In the future the use of qualification documentation/protocols (IQ, OQ,
and PQ) alone will not suffice without the support of formalized
risk assessment documentation.
There are already many tools and guidelines that are
available for developing and implementing formal risk assessment programs. ICH Q9 Quality Risk Management should
be the foundation for a company to build and establish their
policies and procedures. Other industry guidelines such
as the ISPE Baseline Guide for Risk Based Manufacture of
Pharmaceutical Product (Risk – MAPP, Sep 2010), provides
specific guidance as related to the identification of means of
cross contamination and potential operational and technical
measures to mitigate the potential risks.
Occupational Safety: Unlike most chemicals, a majority of
pharmaceutical APIs Occupational Exposure Limits (OELs)
have not been established by occupational safety regulatory
or standard setting agencies, or organizations such as the
US Occupational Safety and Health Administration (OSHA)
and the American Conference of Governmental Industrial
Hygienist (ACGIH). Since adhering to OELs is considered an
effective and proven way to protect workers from developing
deleterious health effects caused by chemicals, many pharmaceutical companies have opted to determine OELs for
their drug substances for internal use. A brief description of
the OEL setting process is summarized below.
A RISK BASED APPROACH FOR MANUFAC-
TURING PHARMACEUTICAL PRODUCTS
I. Hazard Characterization
A risk-based approach for manufacturing pharmaceutical products comprises the following components:
1. Identification of hazards
2. Assessment of dose-response relationships
3. Establishment of health-based limit, both Occupational
Exposure Limits (OELs) and Acceptable Daily Exposures
The (1) identification of hazards and ( 2) assessment of
dose-response relationships are collectively referred to as
hazard characterization. Performing a hazard characterization of the pharmaceutical products is critical to evaluating
risks and deciding on appropriate exposure controls.
For hazard identification, a formal review of all available
animal and human data should be performed for each pharmaceutical product. For the innovator companies that developed
the APIs, the data used in the analysis should include the data
submitted in the regulatory filing. Contract Manufacturing
Organizations (CMOs) should request this information and the
rationale for the setting of the OEL and ADE or PDE (permissible
daily exposure) in the EU from the innovator company asking
them to manufacture the pharmaceutical product. Generic manufacturers should evaluate each of the pharmaceutical products
by searching public data bases for OELs and ADEs, as well as
the database developed within their organizations. For the hazard characterization of the pharmaceutical product, the reviewer
should have access to the full range of preclinical and clinical
data required for approval of the drug. For non-proprietary
compounds, all relevant information on the potential hazards of
the material should be obtained through referenced databases.
Standard toxicology and pharmacology reference texts should
be consulted and a literature search (e.g., on PubMed) should be
performed. Once all of the information and data has been compiled, the hazard characterization process should commence.
II. OEL Setting
An Occupational Exposure Limit is the time-weighted
average concentration of a substance in air to which it is
believed that workers may be exposed, without personal
protective equipment, for eight hours per day, 40 hours per
week without adverse effect. An OEL may also have an associated Short Term Exposure Limit (STEL), to which personnel may be exposed for only 15-minute intervals, and/or a
Ceiling or Maximum Acceptable Concentration, which should
never be exceeded. Most innovator pharmaceutical companies establish OELs for their pharmaceutical products.
An example OEL calculation (expressed in milligrams or mi-
crograms per cubic meter of air) is shown as:
OEL (µg/m3) = Dose (mg/unit time)
UFC × MF × α × AF × V(m3/day)
Dose = The lowest dose associated with the critical effect(s),
human or non-human.
PHARMACEUTICAL PROCESSING | SEPTEMBER 2014 13 ■