Bringing a Science-Based Approach to Regulation: The Story of the Product Quality Research Institute

The Product Quality Research Institute (PQRI) was established in 1999 as a vehicle to bring members of the pharmaceutical industry, academia and the US Food and Drug Administration (FDA) together to develop science-based approaches to regulation. Since its inception, PQRI has coordinated the volunteer work of industry and agency scientists and academics as they conducted in-depth studies of various technical issues important to the pharmaceutical industry.

History of PQRI

The concept of establishing a safe haven in which scientists from the pharmaceutical industry and the FDA could meet to conduct research to support the development of science-based regulatory policy was the brainchild of Roger Williams, who was at the time director of the FDA Office of Pharmaceutical Sciences. The concept was based on the then novel idea that regulation should be based on science.

Initial discussions of the concept transpired at an ad-hoc meeting in 1995 between Williams and representatives of a number of key drug industry trade associations. Follow-up meetings took place in which representatives from academia were included, and in October 1996, the Product Quality Research Initiative was publicly proposed for the first time. A steering committee was established to formalize the initiative. Bylaws were established and approved on June 10, 1999, and on Aug. 2, 1999, the State Corporation Commission of Virginia officially recognized the Product Quality Research Institute, Inc. (PQRI) as a nonprofit, tax-exempt corporation.

The significance of the PQRI concept was quickly recognized and the idea of PQRI was strongly endorsed by senior FDA leadership from the beginning. This was demonstrated by the statement issued by Jane Henney, MD, then FDA commissioner:

"PQRI is a tangible expression of a unique collaboration between academia, industry, and a governmental agency that brings us together for both the innovator and generic pharmaceutical companies. This collaboration will identify the best practices for manufacturing of high quality pharmaceutical products. It's an excellent means for leveraging FDA's intellectual and laboratory resources; to promote regulatory research programs designed to enhance the science base that we need to provide, and I am convinced it will be a win, win, win solution for the public, the industry, and the agency" (1).

As one of the founding members of PQRI, the American Association of Pharmaceutical Scientists (AAPS) played a significant role in providing substantive 'bricks and mortar' and managerial support to the fledgling institute. AAPS helped PQRI get off the ground and their support continues to this day. PQRI shares office space with AAPS in Arlington, Virginia, where PQRI has its only paid employee, an executive secretary.

The original member organizations of PQRI were:

• American Association of Pharmaceutical Scientists (AAPS)

• Consumer Healthcare Products Association (CHPA)

• Generic Pharmaceutical Industry Association (GPhA)

• National Association of Pharmaceutical Manufacturers (NAPM)

• National Pharmaceutical Alliance (NPA)

• Parenteral Drug Association (PDA)

• Pharmaceutical Research and Manufacturers of America (PhRMA)

• U.S. Food and Drug Administration, Center for Drug Evaluation and Research (FDA, CDER)

The membership quickly grew to include:

• United States Pharmacopoeia (USP)

• International Society of Pharmaceutical Engineers (ISPE)

• International Pharmaceutical Excipients Council -Americas (IPEC-Americas)

• International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS)

• Biotechnology Industry Organization (BIO) The current membership of PQRI consists of:

• American Association of Pharmaceutical Scientists (AAPS)

• Consumer Healthcare Products Association (CHPA)

• United States Pharmacopoeia (USP)

• International Pharmaceutical Excipients Council -Americas (IPEC-Americas)

• International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS)

• US Food and Drug Administration, Center for Drug Evaluation and Research (FDA, CDER)

• Health Canada

As of November 2009, the Parenteral Drug Association has withdrawn its membership in PQRI.

In 2007, PQRI expanded its scope internationally by including Health Canada as a second member regulatory agency.

Organizational structure

It was recognized by the early PQRI organizers that a formal structure would be required in order to manage the various projects planned for the institute. After extensive discussions a plan was established to have the institute managed by two governing bodies: a board of directors vested with administrative management and fiduciary duties and a steering committee responsible for all activities related to management and direction of scientific activities.

The PQRI board of directors comprises five individuals, three of whom are appointed by the AAPS executive council and two representing the steering committee. Current practice is that the chairman and vice-chair of the steering committee sit on the board of directors and provide the link between the two groups. The steering committee itself was set up to provide each of the member organizations with input into the scientific decision making and project goal setting for the organization. A system of technical committees and working groups was established by the steering committee to carry out and manage the projects (See Table 1).

Table I: Committee and working group structure of the PQRI.

A chart of the current organizational structure of PQRI is provided in Figure 1. Overall, it has changed only slightly from the arrangement established when the group was incorporated.

Figure 1: PQRI current organizational structure and committee membership. (Figure courtesy of PQRI)

Each PQRI project has a working group comprised of subject-matter experts recruited from the member organizations. These working groups generate, evaluate, and discuss information or data, and develop PQRI recommendations, technical reports, and scientific papers. They also coordinate conferences, workshops, seminars, and forums to collect input from the larger scientific community and to share the information they have gathered on the specific subject evaluated.

Each working group operates under the guidance of a technical committee. Currently there are three technical committees within PQRI that provide technical and scientific guidance, direction and review for PQRI working groups. The technical committees consist of scientists and regulatory experts from industry and the FDA, and make technical/scientific recommendations to the steering committee.

The current PQRI technical committees are:

• Development Technical Committee (DTC). The mission of the DTC is to conduct research projects which help to more clearly define through technical examples and applications the quality by design (QbD) concepts, science or related activities associated with QbD in the context of drug development. The DTC incorporates projects formerly managed by the Drug Product and Drug Substance Technical Committees.

• Manufacturing Technical Committee (MTC). The MTC leverages manufacturing expertise to define science-based approaches that appropriately integrate risk assessment and encourage innovation and continuous quality improvement in pharmaceutical manufacturing as well as flexibility in the associated regulatory processes.

• Biopharmaceutics Technical Committee (BTC). The mission of the BTC is to promote research in the area of biopharmaceutics. Areas of interest include: linkage of in-vitro drug dissolution/release methods to in-vivo drug bioavailability and bioequivalence, methods for the determination of bioavailability and bioequivalence, pharmacokinetic-pharmacodynamic relationships, and comparative clinical trials.

The activities of past and present technical committees and working groups are presented in Table II. Most teams meet regularly by conference call and periodically face-to-face. The length of time required for a group to complete a project varies considerably but often requires many months to complete.

Table II: Summary of technical committee and working group activities.

An expanded summary of PQRI activities and publications can be found on the institute's website (24).

Funding and support

PQRI was incorporated as a nonprofit corporation and the initial thought was that very little funding would be necessary. As mentioned above, AAPS provided office space and technical support to PQRI. After a few years, it became clear that a source of stable income was necessary in order to secure ongoing support for maintaining administrative activities, including a full-time administrative assistant. As a result, annual membership dues were implemented. These dues were set at the minimum level required to support administrative activities. The various members of the board of directors, steering committee, technical committees, and working groups all provided their efforts on a volunteer basis free of charge.

Initially, PQRI research consisted of collecting and compiling existing scientific information, which was then used as a basis for sound scientific decisions. AAPS provided office space and administrative support and committee meetings were held in member organization offices.

However, it was soon recognized that some of the questions brought up did not have answers readily available either in the literature or through data provided by member organizations (data mining). As a result, the working groups reported to their technical committee chairs the need for PQRI to conduct independent research in addition to literature searches and data mining.

Of course, projects requiring research resulted in the need for additional funds. Appeals were made to the pharmaceutical and allied industries for financial support, and several companies, recognizing the importance of the PQRI initiative, made significant contributions to the research fund. The appeals were answered very clearly and decisively, with approximately $500,000 collected to support independent research projects being conducted or planned (25).

Another source of research funding for the organization came through the various seminars and workshops conducted. All extra funds generated through these activities have been channeled back into the organization's research.

This robust, multisource funding mechanism has provided PQRI the ability to fund multiple research projects that benefit the industry, the public, and the regulatory agencies.

Some notable PQRI achievements

It is beyond the scope of this article to review all of the significant activities and accomplishments of PQRI since its inception. Instead, a selection of some of the arguably most successful projects will be reviewed, along with a discussion of the impact the outcomes of these projects have had on the pharmaceutical industry.

Blend uniformity. It was a common industry observation, and a significant problem, that samples of powder taken from a blended mixture did not show the same degree of active-dose uniformity as was seen in samples of compressed tablets taken from the press. One possible reason for this discrepancy was that the small sample of tablets tested was not really representative of the content uniformity of the batch. Another possibility was that sampling the powder blend introduced sampling biases that were not evident when sampling compressed tablets. Due to this uncertainty, the regulatory proposal was to test all blends for content uniformity of the active ingredient(s) and reject any batches that did not meet established criteria.

The Blend Uniformity Working Group conducted extensive data mining and statistical analysis studies that confirmed the superiority of testing compressed tablet samples provided that a statistically valid sample was analyzed. An enhanced tablet-testing scheme was proposed and was adopted by FDA in 2003 as an alternate to the expensive and time-consuming blend-uniformity testing proposal (26). The resulting recommendation addressed both FDA and industry concerns by substantially enhancing product quality assurance without increasing the regulatory burden.

Aseptic processing. Another major problem tackled by a PQRI working group was related to aseptic processing. The goal of this project was to address key issues in the FDA's concept paper "Sterile Drug Products Produced by Aseptic Processing" (27). While not all areas of the concept paper were addressed, the 8 clarifications and 10 recommendations were developed by the working group based on the expert knowledge of the working group members, survey results, and publications where applicable and were presented in the final guidance document issued by FDA (28).

Leachables and extractables. The history of the PQRI Leachables and Extractables Working Group began with activities initiated by International Pharmaceutical Aerosol Consortium (IPAC) and its evolutionary organization IPAC-RS (Regulation and Science). IPAC formed in 1989 with a mission to address pharmaceutical regulatory consequences of the Montreal and Kyoto Protocols, and their impact on chlorofluorocarbon propellants used in metered dose inhaler (MDI) drug products. In 2001IPAC-RS was officially formed as a separate consortium with a mission to advance consensus-based and scientifically driven standards and regulations for all orally inhaled and nasal drug products (OINDP), with the overall goal of facilitating the availability of high-quality, safe, and efficacious drug products to patients. In collaboration with the Inhalation Technology Focus Group (ITFG) of AAPS, IPAC-RS formed "technical teams" to study various scientific and regulatory issues for OINDP, including a Leachables and Extractables Technical Team.

In March 2001, the IPAC-RS/ITFG Leachables and Extractables Technical Team submitted a technical paper entitled "Points to Consider" to FDA (29). Central to this paper were proposals for: 1) reporting and qualification thresholds for leachables, and 2) a leachables qualification process.

Based on the "Points to Consider" proposals and FDA's response to them, a formal proposal to develop safety thresholds and examine best practices for leachables and extractables in OINDP was drafted by IPAC-RS and submitted to PQRI. The proposal was accepted, and a working group was formed later in 2001, consisting of chemists and toxicologists from FDA, industry, and academia. Through the PQRI process of hypothesis definition, workplan and study protocol development, laboratory, and other scientific activities, the PQRI Leachables and Extractables Working Group developed the recommendations, "Safety Thresholds and Best Practices for Leachables and Extractables Testing in Orally Inhaled and Nasal Drug Products," which was submitted to PQRI and FDA in fall 2006 (30).

The working group also sponsored a public workshop that focused on its scientific process and proposals held prior to finalization of the recommendation document in December 2005. After formal submission of the recommendation document, the working group presented a series of "training courses" based on its work, three of which were held in the United States, one in Europe, and one in Canada (to Health Canada). Two peer-reviewed scientific publications based on the working group's results and conclusions have also appeared (31, 32). Currently, the working group is preparing a book on its safety threshold and qualification process for leachables, and contributing chapters to a second book on pharmaceutical development "best practices" for leachables and extractables in preparation by IPAC-RS.

Sulfonate esters. Since 2000 there has been an increased level of concern about the potential presence of genotoxic impurities within drug substances. This resulted, in 2007, with the European Medicines Agency (EMEA) Committee for Medicinal Products for Human Use (CHMP) releasing a final Guideline on the Limits of Genotoxic Impurities, which established the need to restrict levels of such impurities to a limit of 1.5 ug/day (threshold of toxicological concern (TTC)) (33). Building on this, PhRMA published a paper advocating the use of a staged TTC for studies of limited duration (34). FDA has also shown considerable interest in this area and released its own guideline which incorporated a modified staged TTC approach (35).

Within the context of this issue, of particular concern has been the presence of sulfonate esters. There is experimental data suggesting that a number of sulfonate esters (e.g. methyl methanesulfonate) are potential human carcinogens. This has lead to concerns over their levels and driven regulatory authorities to ask for these to be tightly controlled in line with the limit described above.

Sulfonic acids are widely used in synthetic processes to manufacture drug substances (in the form of catalyst, e.g. tosic acid, and are also formed as a by-product of their use as leaving groups) and in salt formation; sulfonic acids are widely used as they form very effective (highly crystalline) and safe salts. Elimination of the use of sulfonic acids is highly undesirable either from a synthetic process or salt formation perspective.

The PQRI working group conducted research studies to first develop highly sensitive analytical test methods to detect sulfonic acid esters and then employ these methods to study the stability of these compounds under varying conditions, most notably pH and water content. The outcomes of these studies have contributed significantly to the scientific understanding of the chemistry of these molecules and provided the industry with a path forward in managing this critical issue.

Stability shelf-life. The PQRI Stability Shelf-Life Working Group was established in late 2006. The membership includes statistical and pharmaceutical scientists from industry, FDA, and academia.

The objectives of the group include:

• Extending scientific knowledge with respect to evaluating pharmaceutical product stability data

• Proposing best practices with respect to estimating stability quality attributes (i.e. shelf-life)

• Investigating statistical methods for estimating shelf life consistent with FDA's QbD initiative.

The current activities of this group are centered on two primary topics. Consideration has been given to formal definitions of "shelf-life." The primary intention of a shelf-life claim is to provide a storage time during which it is ensured that the drug product (stability-limiting characteristics) remains within specification. Existing definitions are at best ambiguous when applied to designing statistical approaches to the analysis of stability data. Based on discussions within the working group and in public forums, the group is preparing a publication dealing with the fundamental issue of defining in a more formal manner shelf-life and related terms.

The second primary activity concerns developing and evaluating alternate statistical techniques for estimating shelf-life. The working group's efforts are directed toward providing an alternative methodology for estimating shelf-life that is predictive of future batch performance, and based in QbD philosophy. Among the approaches under consideration is a coupling of quantile regression and calibration techniques.

The work to date has been presented in several public forums including a PQRI-hosted webinar and various professional meetings (36).

Find out more

Additional information about PQRI is available on the organization's website. There you can learn about upcoming conferences and workshops, review past publications and regulatory submissions, and keep current on active projects. The website can be found at http://pqri.org/

Of course, PQRI is always looking for science-based research projects that it may take on in the future to help reduce regulatory burden and improve drug development, production, and testing. If you would like to submit such a request for research, the forms are available on the website. Also, if you would like to volunteer to be a member of an expert working group, you can indicate your interest. You will need to provide your member organization (e.g. AAPS), along with your areas of expertise and areas of interest.

Summary

It has been 10 years since the founding of PQRI. Based on the many significant project contributions and impacts of the institutes work, it is clear that the vision of the founders has been realized—with clear wins for the industry, academia, and regulatory agencies. PQRI provides a platform where dedicated volunteers with expert knowledge can work together to develop regulations based on sound science.

Gordon Hansen*, is vice-president of Analytical Sciences at Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Rd., PO Box 368, Ridgefield, CT 06877-0368, tel. 203.798.5701, gordon.hansen@boehringeringelheim.com and Chris Allen recently retired from Bayer Healthcare, where he was vice-president of product supply for the Consumer Care Division.

*To whom all correspondence should be addressed.

References

(1) PQRI. "FDA's Commitment to PQRI." PQRI News, March 2002, page 2, http://www.pqri.org/newsletter/newsletter0302.pdf.

(2) PQRI Container Closure Working Group, "Basis for Using Moisture Vapor Transmission Rate Per Unit Product in The Evaluation of Moisture-Barrier Equivalence of Primary Packages for Solid Oral Dosage Forms" PQRI Whitepaper, September 2004 http://www.pqri.org/pdfs/whitepaper.pdf.

(3) PQRI Leachables and Extractables Working Group, "Safety Thresholds and Best Practices for Extractables and Leachables in Orally Inhaled and Nasal Drug Products", Submitted to FDA Sept. 8, 2006, http://www.pqri.org/pdfs/LE_Recommendations_to_FDA_09-29-06.pdf.

(4) D. Christopher et al., J. Aerosol Med. 16 (4), 235-247 (2003).

(5) J. Mitchell, J. Aerosol Med. 16 (4), 433 (2003).

(6) PQRI Mass Balance Working Group, "Mass Balance Proposal for FDA Guidance Document", submitted to FDA Oct. 26, 2006, http://pqri.org/pdfs/Mass_Balance_Submission_to_FDA_10_26_06.pdf.

(7) W.P. Adams et al., PharmSciTech. 8 (1), Article 4, 2007.

(8) D. Christopher et al., PharmSciTech. 8 (1), Article 5, 2007.

(9) D. Christopher et al., PharmSciTech. 8 (4). Article 90, 2007.

(10) PQRI Excipient Working Group, Pharm. Technol. 30 (9), 90-98 (2006).

(11) R. H. Seevers, "Report to FDA of PQRI RFID Working Group", submitted to FDA Dec 1, 2005, http://www.pqri.org/pdfs/RFID_Report_to_FDA_23Mar2006.pdf.

(12) PQRI Blend Uniformity Working Group, "The Use of Stratified Sampling of Blend and Dosage Units to Demonstrate Adequacy of Mix for Powder Blends", submitted to FDA Dec. 30, 2002. http://pqri.org/blenduniformity/imagespdfs/011003rec.pdf.

(13) G. Boehmet al., PDA J. of Pharm. Sci. and Technol., 57 (2), March/ April 2003, 64.

(14) "HPLC Column Classification" USP Pharmacopeial Forum 31 (2), Mar.-Apr. 2005, 637-645.

(15) L. Snyder et al., J. Chrom. A. 1057, 49-57 (2004).

(16) PQRI Specification and BACPAC Working Group, "Final Recommendation" submitted to the FDA June 2004.

(17) A. Teasdale et al., Org. Process Pre. Dev. 13 (3), 409 (2009).

(18) PQRI Stability Shelf Life Working Group: You can find a glossary,presentation slides and copies of posters at http://www.pqri.org/structure/wg.asp#sslwg.

(19) PQRI Aseptic Processing Working Group "Final Report" submitted to FDA Mar. 19, 2003, http://www.pqri.org/aseptic/imagespdfs/f inalreport.pdf.

(20) PQRI Post Approval Changes For Sterile Products Working Group Recommendations, submitted to FDA Apr. 19, 2007, http://www.pqri.org/pdfs/PAC_Final_Report_041907.pdf.

(21) PQRI Process Robustness Working Group, "Process Robustness" a PQRI Whitepaper, http://www.pqri.org/publications/index.asp.

(22) PQRI Risk Management Working Group, "Quality Risk Management Principles and Industry Case Studies", http://pqri.org/publications/index.asp

(23) S. Buchholz et al., PDA J. of Pharm. Sci. and Technol. 61 (3), 147-153 (2007).

(24) PQRI, "PQRI Achievements," Aug. 2007, http://www.pqri.org/pdfs/PQRI_ AccompBroPages.pdf.

(25) PQRI, "PQRI Contributors," PQRI News, Sept. 2002, page 14, http://www.pqri.org/newsletter/newsletter0902.pdf.

(26) FDA, Guidance for Industry, Powder Blends and Finished Dosage Units - Stratified In-Process Dosage Unit Sampling and Assessment (Rockville, MD, Oct. 2003).

(27) FDA "Concept Paper Regarding Aseptic Processing" to solicit early input prior to formal issuance of a draft guidance for public comment, Rockville, MD, Sept. 27, 2002.

(28) FDA, Guidance for Industry Sterile Drug Products Produced by Aseptic Processing (Rockville, MD, Sept. 2004).

(29) PQRI Leachables and Extractables Technical Team, "Leachables and Extractables Testing: Points to Consider." A response to the FDA draft Guidance for Industry: Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug Products Chemistry, Manufacturing, and Controls Documentation; and Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Products Chemistry, Manufacturing, and Controls. Documentation ITFG/ IPAC-RS Collaboration, Mar. 27, 2001.

(30) Leachables and Extractables Working Group, "Safety Thresholds and Best Practices for Extractables and Leachables in Orally Inhaled and Nasal Drug Products," submitted to FDA Sept. 8, 2006.

(31) D. Ball et al., Toxicol. Sci., 97 (2), 226-236 (2007).

(32) D. L. Norwood et al., Pharm. Res., 25 (4), 727-739 (2008).

(33) European Medicines Agency, Committee for Medicinal Products for Human Use, Guideline on the Limits ofGenotoxic Impurities, effective Jan. 2007.

(34) Mueller et al., Reg. Toxicol. and Pharmacol. 44 (3), 198-211 (2006).

(35) FDA, Guidance for Industry "Genotoxic and Carcinogenic Impurities in Drug Substances and Products: Recommended Approaches, (Rockville, MD, Dec. 2008).

(36) AAPS Annual Meeting 2008, IPAC-RS 2008, ENAR 2008, Midwest Biopharmaceutical Statistics Workshop 2008, Non-Clinical Statistics Conference 2008 and AAPS Stability Workshop 2007.