35th Anniversary Special: The Transformation of Regulation and Global Standards

Published on: 
Pharmaceutical Technology, Pharmaceutical Technology-07-02-2012, Volume 36, Issue 7

How FDA, USP, and ICH have redirected industry practice.

Since the initial introduction of Pharmaceutical Technology in 1977, many regulatory and compendial initiatives have transformed the way the industry does business not only in terms of global partnerships and supply chain management, but also in the laboratory and on the manufacturing floor. PharmTech's reports and special-themed issues have offered invaluable guidance and interpretation to the industry over the years when new standards and guidances are released. Some of the events and issues discussed in this publication have had long-term impact with respect to how the industry operates today. This roundup article highlights some of the organizations and key influential events that have shaped the pages of PharmTech and the way our industry works.

US Food and Drug Administration (FDA)

Tamper-resistant packaging regulations (1983). In September 1982, several deaths resulted from cyanide poisoning in Chicago, IL, and its suburban area. The investigation determined that the common denominator between the victims was taking Tylenol. Johnson & Johnson, the manufacturer of Tylenol, was ruled out as the source of contamination but on Oct. 5, 1982, the company issued a nationwide recall of an estimated 31 million bottles. This incident prompted the passing of tamper-resistant packaging regulations, which made it a felony to tamper with packaged consumer products. The industry developed standards for tamper-resistant packaging that are still used today.

Orphan Drug Act (1983). The Orphan Drug Act was passed in 1983 to encourage pharmaceutical companies to develop medicines for patients with rare diseases. Companies were given 7 years of exclusivity and tax incentives for pharmaceuticals that qualified for orphan-drug status. This act has lead to the successful treatment of or medical management of diseases such as multiple myeloma and cystic fibrosis. Before this law was passed, there were approximately 38 drugs approved to treat rare diseases. From 1983 to 2010, FDA approved 353 orphan drugs and granted orphan designations to 2116 active compounds.

Generic-drug scandal (1989). The generic-drug scandal began when a generic-drug manufacturer submitted a complaint to regulators after experiencing repeated delays in approval of its ANDAs. The complainant charged that FDA was discriminating against the generic-drug firm in favor of other companies. Three FDA officials plead guilty to accepting bribes from companies and two companies plead guilty to offering bribes to FDA officials. Ultimately, 13 generic-drug manufacturers were investigated for fraudulent practices and several products were recalled. This incident resulted in an increase in requirements for ANDA submissions. Today, about 65% of the prescriptions written are for generic-drug products, but it has taken this segment of the industry about two decades to recover from the 1989 scandal.


The Barr decision (1991). The Barr decision was the direct result of FDA investigations into questionable quality control practices for the handling of out-of-specification (OOS) results. FDA took Barr Pharmaceuticals to court for the perceived practice of testing products into compliance. Judge Wolin of the US District Court for the District of New Jersey presided over the proceedings. The result of the Barr decision changed the practice of how manufacturers' investigate laboratory results that do not meet specifications, and on how the industry determines whether a product meets it quality attributes.

Heparin adulteration (2006–2008). In late 2006, a leading pharmaceutical company recalled several lots of life-saving heparin after receiving numerous reports of adverse events, namely allergic reactions. The company ceased production of the product and began investigating the cause of the incidents. Approximately one month later, FDA issued a Public Health Advisory to the medical community, warning the public and healthcare providers not to use heparin. The company recalled all lots of the product, which was ultimately linked to more than 350 serious adverse reactions and several patient deaths. Contaminated API supplied by a manufacturer in China caused the reactions. This incident impacted the industry because it expanded the definition of supply chain and made companies responsible for the quality of all the ingredients going back to their root source, which in some cases turned out to be several layers deep. New focus was given to the importance of supplier audits, and several trade organizations began focusing on developing third-party audit capabilities to assist the industry in dealing with the vast amount of suppliers sourcing material to the pharmaceutical industry. The incident, for example, spawned a new trade organization, Rx–360, an international supply chain consortium, and redefined the concept of supply chain integrity.

Biosimilars guidances (2012). In February 2012, FDA issued three draft guidance documents regarding biosimilars. The agency announced that "the draft documents are designed to help industry develop biosimilar versions of currently approved biological products, which can enhance competition and may lead to better patient access and lower cost to consumers." These documents opened the door to generic-drug products in an area where there has been little competition to innovator products.

The United States Pharmacopeia (USP)

The US Pharmacopiea (USP) was established in 1820 and is the oldest continuously revised compendia in the world. The standards and information published by USP are recognized as the legal standards by FDA and by regulatory authorities in other countries that have voluntarily adopted them. This compendium contains monographs for excipients, APIs, drug products, biologics, biotechnology products, general test procedures, and general information all of which govern the strength, quality, purity, and potency of medicinal products marketed in the US.

Monograph harmonization (1989). USP has a history of impactful events but none have been more significant than its efforts to harmonize monographs with its counterparts, the European and Japanese Pharmacopoeias (Ph. Eur. and JP, respectively). The harmonization process began in 1989, when representatives of the three pharmacopeias met with industry representatives in an open forum to discuss the need to harmonize like procedures to reduce the regulatory burden on pharmaceutical companies. Prior to harmonization efforts, companies were required to meet the specifications in the governing pharmacopeia for the region of the world where they wanted to market their product. To accomplish this goal, the three pharmacpeias established the Pharmacopeial Discussion Group (PDG) and developed a 7-step process for unifying monograph requirements. Under this model, more than 100 items have been harmonized. The efforts to harmonize monographs continue today.

Stakeholder forum (1999). USP introduced stakeholder forums in 1999, and the events became an officially recognized component of the USP family by vote at the 2005 USP Convention. Stakeholder forums allow for a free interchange of ideas between USP and industry trade organizations. The Prescription/NonPrescription Stakeholder Forum is the most active bi-annual meeting with USP. Among the participating organizations are IPEC, PDA, the Midwestern Compendial Discussion Group, and the Western Compendial Discussion Group. Through PDG, several USP initiatives have been implemented across the industry with little or no disruption to compliance. An example is the collaboration to implement the residual solvents standard, which took effect in 2008.

Flexible monographs (2004). The pharmaceutical industry has long recognized there is more than one way to synthesize an API and that the impurity profile for the ingredient is dictated by the specific route chosen. To accommodate impurity profiles based on the route of synthesis, USP started adopting multiple impurity methods to ensure all manufacturers of an API or the subsequent dosage form are able to reference the USP standard. These are identified and "Method 1," "Method 2," and so forth in the monograph. This practice has provided pharmaceutical manufacturers flexibility and sourcing alternatives for their products.

Globalization efforts (2011–2012). During the past decade, USP has changed its mission statement to indicate that it wishes to "improve the health of people around the world through public standards and related programs that help ensure the quality, safety, and benefit of medicines and foods." Its current vision is "...to be a leader in promoting the public health by creating a unique knowledge base—consisting of quality standards and information on proper use—for medicines and related products and practices. USP will ensure that people throughout the world have access to this knowledge base." USP has opened offices in Switzerland, India, China, and Brazil. In addition, at the USP 2010 Convention, the organization passed Resolution 4, which deals with supporting and advancing global public-health initiatives. USP is also expanding its role in India and China and exploring relationships with the Association of Southeast Nations and Middle East and North African nations.

The International Conference on Harmonization (ICH)

In this author's opinion, the establishment of ICH has had the most influence on the pharmaceutical industry. The first ICH meeting was held in 1990 and the body of work produced by this organization and its impact on the industry is staggering. ICH's work has changed our language and established global stability requirements, and GMPs for APIs, and laid the foundation for the modern quality system.

ICH Q2 Validation of Analytic Procedures (1994). This document established validation requirements for analytical tests, including identifications, quantitative impurities, controlled impurities, and active moiety. It standardized industry terminology for the various parameters needed for validation, including definitions for specificity, accuracy, precision, repeatability, linearity, robustness, and reproducibility. The EU, MHLW, and FDA adopted the document and it continues to define how the industry approaches analytical methods validation.

ICH Q7 GMP Guide for APIs (2000). This document provided the first comprehensive GMPs for APIs. It touched on everything from the necessary quality management to personnel qualifications to the design and construction of the buildings and facilities. Adopted by the EU, MHLW, and FDA, it serves today as the gold standard for API manufacturing requirements.

ICH Q10 Pharmaceutical Quality System (2008). Adopted by the EU, MHLW, and FDA, this harmonized guideline was the first to define the modern quality system and to discuss how it should be integrated into all aspects of the pharmaceutical business. The document recognized that Quality should not be a stagnant policing organization but a vibrant organization concerned with "continual improvement of process performance and product quality throughout the product lifecycle." It openly discussed management responsibility and challenged the industry to consider that management of outsourced activities was a crucial element of a quality system. The impact of this document on the industry is still being discussed at conferences, and companies are implementing many of its requirements.

ICH Q11 Development and Manufacture of Drug Substances (2012). Released in May 2012, this guideline has only been adopted by the EU to date. Q11 describes approaches to developing and understanding the manufacturing process of the drug substance, and offers guidance on what related information should be included in the Common Technical Document (CTD). The impact of Q11 is currently unknown but this author is sure it will follow the tradition of the other ICH documents.

As outlined herein, there have been rnage several changes in the pharmaceutical industry during the 35 years that Pharmaceutical Technology magazine has been in existence. A broader industry timeline is contained within these anniversary pages as well. Let's hope the next 35 years are as exciting and successful as the past 35.