Elemental impurity proposals affect excipients
PharmTech: USP has been actively involved with FDA and industry in discussing new general chapters and requirements for testing
metal impurities. ICH has formed a working group on the development of a Q3D Metal Impurities guideline to address a global
risk-based approach to controlling metal impurities. Excipients will be impacted significantly by the outcome of these efforts.
Do you foresee harmonization helping to minimize the testing required for products that are marketed around the world? Will
USP wait for the results from the ICH working group before moving forward with its proposed general chapters?
Sheehan: USP proposed three new General Chapters on Elemental Impurities Limits, Methods, and Dietary Supplements Metals Limits
in the January-February 2010 issue of the PF for public comment and review. Other related information appeared in PF 36(1), including a draft General Notices statement about the applicability of the standard to all monographs and two Stimuli
articles outlining the rationale for the limits chosen by USP and a summarizing the comments received from an original Stimuli
article and Heavy Metals Workshop and USP's response to the comments. The new elemental impurities proposed General Chapters
were available for public comment until Apr. 15, 2010.
The revisions focus on two areas of work: updating the methodology used to test for elemental impurities in drugs and dietary
supplements to include procedures that rely on modern analytical technology; and setting limits for acceptable levels of metal
impurities (including, but not limited to, lead, mercury, arsenic, and cadmium) in drugs and dietary supplements. The USP
Metal Impurities Advisory Panel, which reports to the USP General Chapters Expert Committee, worked with USP staff and stakeholders
to assess methodologies and limits that provide greater patient/consumer protection and can reasonably be deployed across
industry laboratories. The limits for exposure are toxicologically based and developed by an expert process to provide quality
standards that reflect consensus views about potential health/toxicity concerns. These new approaches are intended to replace
the existing methods in General Chapter <231> Heavy Metals. The proposal aligns well with the current European Medicines Agency
(EMA) guidelines on the specification limits for residues of metal catalysts. USP believes that the elements and limits proposed
in PF will align with what the ICH Q3D guideline will propose.
USP is currently evaluating the PF comments and will subsequently make a decision on how to move forward based on comments received. These comments should allow
USP to provide a better and more informed response on the ICH draft proposal once it is published. USP's perspective is that
given the public health issues involved, it is inappropriate to wait until ICH releases their first draft proposal before
moving forward with the proposed USP chapter revisions, although USP understands that a delayed implementation date will be
important to allow time for industry to comply with the new standard. USP agrees that the harmonization of elemental impurities
will lead to reduced testing required for products that are marketed around the world.
ICH's Q3D Expert Working Group is working to come to an agreement on an appropriate list of metals and their limits but will
not include testing. The working group is scheduled to meet during the June, 2010 ICH meeting in Tallinn, Estonia. The three
Pharmacopeia Discussion Group members (European Pharmacopoeia, Japanese Pharmacopoeia and the United States Pharmacopeia),
will attend the meeting. Three FDA representatives along with USP representative, Antonio DeStefano, vice-president of General
Chapters will also attend. According to the ICH process, the Q3D working group will commence work on the development of the
harmonized tripartite guideline and prepare an initial draft of the guideline, based on the objectives set out in the Concept
Paper, and in consultation with experts designated to the EWG. Upon reaching Step 4, the harmonized tripartite guideline moves
immediately to the final step of the process that is the regulatory implementation.
Pricing remains an eternal challenge
PharmTech: Many in industry are questioning whether all pharmaceutical companies fully and equally qualify every supplier
in their excipient supply chain and whether the prices or the quality evaluations dictate the decisions on whose material gets used. How can industry work through this?
Berg: Quality evaluations definitely dictate the decisions about whose material gets used. Quality of the material is key
and the quality systems and processes under which the materials are made are crucially important. On the price side, I want
to advocate that industry-purchasing individuals consider the total cost of ownership of the materials. Effective change control,
deviation management, and so forth, take resources and money to do well. In our business, we should expect prices to reflect
the total cost and we should be willing to pay. In my opinion, companies that treat these materials as commodities and squeeze
for the lowest cost should not be in the business of making medicines because they are promulgating insecure supply chains.
Busch: This is a somewhat difficult question for me to answer as an excipientsupplier, but the need for a good reputable supplier
is second to none. This goes well beyond the GMP requirement under which the excipient is produced and includes the entire
supply chain through which the material flows. While price is always a factor, the cost of any specific ingredient must be
weighed against how critical that excipient is in the final dosage form. If its use is critical, then the functionality of
the excipient and supply-chain integrity must trump any savings that may be incurred by using a questionable supplier. If
alternate suppliers are desired, it is, in my mind, better to try to do so early in the formulation development so that, if
needed, flexibility can be built into the formulation to account for the use of alternate materials with potentially different
functionality. At Dow Wolff Cellulosics, we have several manufacturing sites and we are constantly confirming the interchangeability
of the same grades of product produced between them. If the plants do not produce equivalent or interchangeable products,
we are sure not to claim such, and will sell those products under a different designation.
Velagaleti: We recognize that users of excipients are under regulatory scrutiny to make sure suppliers are qualified for GMP
compliance and that raw materials produced are of high quality. The qulaification of suppliers by users may include, but is
not limited to, testing incoming raw material, on-site inspections for GMP compliance of manufacturing facilities, and so
on. From a supplier's point of view, we encourage that kind of scrutiny, but there is one challenge. Take BASF, for example.
We manufacture several excipients in our facilities in the US and Germany, and if all of our customers were to visit us each
year or every other year for an audit, that would be an enormous drain on our resources in the plant, which are primarily
dedicated to manufacturing and GMP compliance. We have been innovative by conducting group audits at our excipient manufacturing
facilities in US. We provide specified dates that companies can come and audit our facility. We do a joint group presentation
of our quality systems, and arrange for plant and laboratory visits. Beyond this, customers can look individually at topics
of specific interest to them. This helps to fit, for example, audits from six different customers into one day. We are also
trying to be innovative by using qualified third-the party auditors, and USP Verification and Certification program.
Carter: IPEC's function is the safety of excipients and the organization is focused on standards that are based on objective
regulatory and scientific criteria. Price issues are not a focus of the organization. However, I hope that when looking at
the cost of an excipient, a pharmaceutical company will evaluate the total cost of using the excipient compared with the risk
and cost of the excipient. When you look at the total cost of manufacturing a drug, excluding the development and R&D cost,
the most expensive part may be the packaging, followed by the API, operational manufacturing cost, and lastly, the excipient
cost. When I am cooking for dinner guest, I would never risk spoiling an enjoyable evening by using a cheaper unfamiliar
spice or ingredient whose cost time quantity is less than the meat, a pharmaceutical company should not let the price of an
excipient risk the security of supply by using an excipient that can not be qualified throughout the entire supply chain.
The reality is that, in many companies, the procurement group that works with excipients is separate from the API procurement,
quality, and regulatory groups, and sits is a small section of operations with isolated goals for price savings in a silo
that prevents them from truly seeing how their choices fit into the overall cost and risk picture. In my opinion, all pharmaceutical
companies should change their organization so that the procurement organization reports to the quality unit organization.
*Janeen Skutnik, director of quality and regulatory policy at Pfizer and chair of IPEC–Americas, and Sherry Ku, former senior
director of pharmaceutical development at Wyeth Research, also participated in the live roundtable, which can be listened
to on the PharmTech Podcast Page.