Outsourcing: Meeting Standards

It is probably safe to say that Asia’s role in global pharmaceutical outsourcing remains optimistic despite the on-going issues with quality. How that role is going to continue evolving however, depends on suppliers’ desire to become among those who will “rise to the occasion,” in a market where cost may no longer be the primary motivator.

Learning from Experience

Key quality events in the past few years have had far-reaching effects that were felt across multiple continents, according to G Harris, New York Times, Apr 22, 2008. Western countries have repeatedly experienced contamination in not only toys and food products (for both human and animal consumption), but also in pharmaceutical raw materials, as reported by the US Food and Drug Administration (FDA), “Melamine Contamination in China”, 2009; and “Pet Food Recall”, 2008. However, most major pharmaceutical organizations admit that as part of their global intention to expand and reduce cost, the use of external international partners is still a requirement, according to Pharm Tech 33(1), 2009.

Pharmaceutical companies have heard the complaints of consumers and those of angry regulatory agencies. These companies and are actively moving to put into place an infrastructure which will control the quality of the companies they work with on an international scale – particularly in Asia. In an effort to balance risk and outstanding market opportunity, many of the larger pharmaceutical companies are looking toward compiling a network of suppliers, manufacturers and external partners that they will work with over the coming years. These companies are more likely to outsource to those that have been approved within the quality network.

This initiative provides an opportunity for external partners that are looking to acquire a piece of the outsourcing puzzle from these pharmaceutical companies. One of the most recent and far reaching issues facing pharmaceutical products today, as well as over-thecounter (OTC) products, is the United States Pharmacopeia (USP) Monograph <467> Residual Solvents Testing requirements.

Despite being staged to become effective in 2007, the complexity of the monograph’s scope and debate among the scientific community, as well as the panel of experts at USP, delayed this chapter’s arrival until just this past year. Many companies are simply not prepared to be compliant despite the notice given by regulatory agencies.

Ensuring Compliance

The implications of USP <467> are global and widespread to say the least. As pharmaceutical companies are trying to get up to speed with the regulations (harmonized and similar to those listed in ICH guidelines Q3C and EP guidelines), they must recognize that these requirements also apply to suppliers, manufacturers and New Drug Applications (NDA) / Abridged New Drug Applications (ANDA) holders.

Raw material suppliers and manufacturers need to be able to provide a certain amount of residual solvent (RS) information to their customers so that the purchaser may determine if the components meet the permitted daily exposures (PDE) requirements listed in <467> and ascertain if/what further RS testing is necessary. Anyone involved in pharmaceuticals (NDA/ANDA) must be compliant. However, the responsibility to ensure compliance ultimately lands on the owner of the NDA or ANDA. In the case of OTC and veterinary products, <467> does not apply, although ICH Q3C often does and with respect to RS are fairly equal in requirements.

Many trade journals state that pharmaceutical companies must go above and beyond the government’s standards and ensure their own standards of quality, according to Contract Pharma 1(7), 2008. If raw material suppliers and manufacturers can anticipate the needs of their potential customers and provide this information in a forthcoming manner, it reduces the sting of these additional testing requirements and the burden placed on the NDA/ANDA holder.

Raising Productivity

This can improve release testing and overall turn-around times and ultimately lower the cost to the parent company. Once a vendor has been adequately qualified – it must still be re-qualified on a regular basis as deemed prudent. External partners adhering to a strict quality testing regime that regularly and reliably provides data to the purchasing company, demonstrates a desire to be a better supplier. It also shows a commitment to excellence that can be appreciated by potential customers while ensuring the return of existing ones. While these additional steps may be tedious at the beginning, they can be carried out fairly easily and routinely at minimal cost, after implementation. As potential and existing customers are presented with this valuable data, a few key deliverables can be expected:

1. A platform to demonstrate consistent quality in a product can be created and shared between the purchasing and external partner, ensuring an overall commitment to excellence and quality;

2. The purchasing relationship is fortified and hopefully continued over a long period of time;

3. Expenses can be saved on both sides during the partnership as the customer validates the vendor’s process/data, reducing unnecessary testing.

Providing USP monograph <467> data is one way of becoming a more valuable vendor. The monograph uses specific wording and requires that testing be performed only for solvents “likely to be present.” If the solvent is used or produced in the final manufacturing stages; or if it is used in previous stages and not removed by a validated method; or if it is contained in some of the starting material and not removed during the process, then RS testing must be performed, as reported by Pharmacopeial Education, Feb 12, 2009.

For additional guidance, the US Food and Drug Administration (FDA) has also published a Draft Guidance, as well a Question and Answer summary for RS and ANDAs. As the FDA is first concerned with patient safety, questions pertaining to RS testing should be directed to the administration.

Once it has been determined that testing is required; and the type of testing that needs to be performed, the monograph lists two options for establishing the amounts of RS in a product, assuming a 10g/day dosage according to USP/NF, 2009:

• Option 1: allows each component of a product to meet a concentration criteria (ie, less than the ppm specified);

• Option 2: allows for acceptance criteria based upon a Permitted Daily Exposure (PDE) limit (ie, daily exposure is calculated as the sum of the components in mg).

By performing this testing ahead of time, a supplier can determine RS information in ppm or in mg (daily exposure) and be ready to provide the data to the buyer upon its purchase of the material of interest. This quality initiative simplifies the process for all parties involved and provides the platform for building lasting quality relationships in global pharmaceutical outsourcing.