After Heparin
Protecting Consumers from the Risks of Substandard and Counterfeit Drugs

Many of the active ingredients in the drugs that U.S. consumers take are made abroad, but there is insufficient oversight by the FDA and foreign authorities of materials made overseas for use in U.S. drugs. With extensive outsourcing and increased reliance on foreign suppliers, manufacturers may have less knowledge and control over production supply chains. These weaknesses are especially alarming in light of the risk of deliberate ingredient adulteration for profit.

To ensure the safety of the globalized pharmaceutical industry, companies must ensure greater control of manufacturing quality, both internally and with their suppliers. Companies sourcing pharmaceutical active ingredients and intermediates from emerging economies such as India and China have a responsibility to ensure that these drug components are safe and are made under appropriate conditions. These companies also must address proactively, to the greatest extent possible, the risk of economically motivated adulteration during stages of manufacturing.

Modern quality systems, including supplier management and risk assessment, must be required to ensure drug safety and address gaps in the FDA's cGMP requirements. Testing methods and standards must be continually reevaluated and updated to help protect against contamination and intentional adulteration.

On March 14 and 15, 2011, the Pew Health Group convened a roundtable meeting of key stakeholders to discuss concerns over safety of the U.S. drug supply and consider potential policy responses. Participants included representatives of the FDA, USP, state regulators, major pharmaceutical manufacturing and distribution trade associations, pharmacy organizations and medical professional groups, and academic and consumer organizations (see Appendix B for a complete list of participants).

Roundtable participants fully agreed that safety risks exist in our globalized pharmaceutical supply chain, and that the system can and must be improved. Participants called for improvements in quality systems, subcontractor agreements, supplier audits, supply chain documentation and transparency, as well as testing. Many present underscored the fact that you cannot inspect quality into a product; it must be built in to every process. One participant suggested the pharmaceutical industry still relies on "quality by inspection," and made a comparison to other regulated industries that have embraced a "quality by design" concept. These industries have very rigid control over raw materials and low product defect rates.

Stakeholders supported strong supplier assessment and management. FDA representatives called for industry implementation of quality systems to identify and mitigate hazards, and ensure sufficient scrutiny of suppliers and contractors. There was strong agreement that manufacturers must be held accountable for their full supply chain and that they need to have concrete knowledge of suppliers when they are selected, rather than after they have become part of the supply chain. Before doing business with a supplier, drug license holders should be sure that a supplier has good quality systems in place. One industry representative recommended that every supplier and sub-supplier within a manufacturing supply chain should be audited by someone. Another important action for manufacturers to take, according to the FDA and other participants, is to insist that their pharmaceutical ingredient suppliers in China are licensed pharmaceutical manufacturers rather than chemical companies, which receive no Chinese government oversight.

Several commenters focused on the importance of information sharing between companies and through groups such as Rx-360, as well as clear communication between companies and suppliers. A representative of Rx-360 suggested that quality agreements should define GMP expectations, list approved raw materials and provide clarification on which companies are authorized subcontractors. A representative of European fine chemical manufacturers noted that companies should be on alert for clues that indicate increased risk of tampering (such as the doubling of the heparin price discussed above). Additional recommendations included expanding enforcement of cGMP regulations to include excipients.

Several participants called for greater transparency throughout the supply chain. Consumer representatives called for public engagement so that the public understands where medications come from, with the caveat that those messages be balanced so that consumers do not stop taking their medications. Active-ingredient manufacturers and others supported companies listing publicly the country of origin of their drugs and active ingredients. Regarding testing, USP leadership encouraged greater collaboration with the FDA to update USP public monographs to include the most relevant, up-to-date testing standards.

The policy recommendations that follow have been informed by the roundtable discussions and presen-tations, but are not intended to constitute a consensus position and may not reflect the views of every participating organization.

A. Require 21st-century quality systems to protect drug safety through statute and regulation. 

1. Companies selling drugs in the United States should have in place a quality system to ensure the safety and integrity of their products, including drug ingredients manufactured by a contractor or supplier. A quality systems model is a holistic, preventive strategy to ensure that the drugs we take are safe. A quality systems provision in legislation would specify basic key components, but would not conflict with detailed technical requirements, such as those found in cGMPs (which are established through the FDA's regulation and permit recognition of evolving industry technologies). The FDA has shown clearly in guidance how a quality systems approach is harmonized with and can support adherence to cGMPs.
2. Quality systems should have the following key components (see recommendations B and D for additional discussion):
      a. Management responsibility: Management should be responsible for establishing the quality systems and ensuring that they are adequately resourced and function appropriately.
      b.Supplier management: Manufacturers should assess suppliers and contractors prior to engagement with them, and should perform periodic on-site audits to ensure adherence to quality and safety standards. Pre-assessment and periodic on-site audits are not currently required under U.S. cGMPs.
      c. Risk assessment: Companies should establish procedures to identify, monitor and evaluate risk factors that could impact product quality, safety, strength, purity and identity.
      d. Assessment and revision of analytical methods: Manufacturers should review and, where necessary, update tests to ensure that they are robust and are able to screen for substances that could affect product quality, safety, strength, purity and identity.

B. Industry should also independently improve its control of contract manufacturers and suppliers.

1. Strengthen supplier contracts to facilitate and improve oversight. Contracts should establish the authority of the purchaser to conduct on-site audits of suppliers. When necessary, contracts should specify that the drug company has the right to audit subcontractors involved in manufacturing the suppliers' products. Contracts should also specifically require drug company approval of any changes in ingredients sourcing or manufacturing processes.
2. Require clear, strong, quality agreements for suppliers. Quality expectations should be clearly established for, and contractually agreed to, by suppliers. Agreements should acknowledge U.S. quality requirements and establish that, if necessary, FDA officials will have access to a supplier's plant. Agreements should also require suppliers and contractors to report manufacturing changes to the purchasing company. If possible, quality agreements should be included as a part of main supplier contracts to clearly set expectations.
3. Increase information sharing among industry to ensure supply chain safety. Industry should share information on suppliers, risk signals, and other global market data that might help to ensure product quality and safety. Legal barriers to information sharing should be actively addressed through antitrust waivers, if necessary, or safe-harbor provisions in contracts.

C. Enhance documentation and transparency of the upstream manufacturing supply chain through legal requirements.

1. Companies should know and be able to document the companies involved in their upstream manufacturing supply chain. Drug companies must know the entities involved in the manufacture, processing, and transportation of their drugs and active ingredients. This documentation should be available to regulators on demand.
2. Require all drug companies to state country of origin for their drugs and active pharmaceutical ingredients on their websites. Pharmaceuticals should not be subject to less transparency than other consumer products. Country of origin should be listed for both the finished drug and the drug's active ingredients. While pharmacy dispensing may make country-of-origin labeling on drug bottles less useful for consumers, this information could be made available to the public through other means, such as package inserts or on a company's website.

D. Improve testing standards

1. Industry and regulators must continually seek to develop better testing methods to ensure the identity, purity and safety of drugs. Manufacturers must be responsible for ensuring the purity of their drugs and drug components through robust testing methods, and should review and update analytic methods in an ongoing manner. Regulators and industry stakeholders agree that better methods for detecting and measuring drug contamination are needed. In addition to improving their methods, drug companies could use multiple assays as a check against bad actors who might try to design fake ingredients that are able to fool specific tests.
2. Require continual assessment and updating of public testing standards. Compendial testing standards should be regularly reviewed to ensure adequacy. The FDA and USP should work to¬gether to ensure that public standards are robust and up to date, and identify and prioritize those assays that need to be updated and/or revised.