Susan Haigney is lead editor of Pharmaceutical Technology and Pharmaceutical Technology Europe.

Susan Haigney

	The quality-by-design (QbD) initiative, which focuses on building quality into a product from early on in the development process, has created a shift in the way pharmaceutical companies develop and produce drug products. With a focus on patient safety, QbD helps drug manufacturers incorporate a risk-based approach to development and production. “Many firms leverage the understanding gained from adoption of QbD principles to implement innovative manufacturing approaches, such as continuous manufacturing and real-time release testing. Furthermore, QbD is a continuum approach that supports demonstration that a manufacturing process is always in a state of control and capable of consistently manufacturing desired quality product throughout its lifecycle. Consequently, manufacturers implementing the QbD paradigm are implementing a science-  and risk-based lifecycle approach that allows for continuous improvement,” states an FDA spokesperson.

	The industry has become accepting of QbD, and companies have worked to implement it into their processes.  “The introduction of QbD has triggered a paradigm shift in drug development and manufacturing and provided a new toolbox of quality principles with several opportunities for the pharmaceutical industry. QbD is applied widely in drug development today and represents the leading and most favored principles where applicable and appropriate,” says Sven Stegemann, director for pharmaceutical business development at Capsugel. And Brian A. C. Carlin, director Open Innovation, FMC Health & Nutrition and Chair of the International Pharmaceutical Excipients Council of the Americas (IPEC-Americas) QbD Committee, believes that “the FDA Quality Metrics Initiative will further drive QbD manufacturing and quality approaches.”

	According to Siegfried Schmitt, principal consultant, PAREXEL, “QbD … requires intensive studies prior to the validation batches, resulting not only in higher success rates for validation, but an overall better controlled process during commercial manufacture. QbD therefore enhances control, understanding, and continuous performance.”


	Although many have adopted QbD, others are limited by what they see as barriers. 

 annual manufacturing and equipment survey found that while 28% of respondents stated they fully use QbD in process development/optimization for solid-dosage manufacturing and 56% apply QbD to some extent, 16% said they do not use QbD. Respondents indicated that a lack of knowledge, training, and clarification from regulators contributed to their reluctance to use QbD. Cost and time also factored into the decision to not incorporate QbD into their processes (1).

	But are these real or imagined barriers? “The barriers are in the peoples’ minds. They can no longer simply rely on a set of tight rules, but must use their powers of deductive reasoning rather than their memories (to paraphrase Leonardo Da Vinci),” says Chris Moreton, partner at FinnBrit Consulting and active member of the IPEC-Americas QbD Committee.

	According to an FDA spokesperson, several International Conference on Harmonization (ICH) guidelines were developed to help the industry implement QbD (2–5) as well as several Q&A documents drafted by the Implementation Working Group to answer industry questions and clarify guidance documents. “It has been the agency’s observation that there is some confusion amongst the manufacturers. There is currently an ongoing QbD pilot program with the European Medicines Agency (EMA), which has identified enhancements to the regulatory assessment process. The first and third Q&A documents from the FDA-EMA pilot clarify the agencies’ expectation regarding criticality and level of detail in submissions. Additionally, this topic is addressed in the just published FDA draft guidance on 

Established Conditions: Reportable CMC Changes for approved Drugs and Biologic Products 

(6). Additionally, the agency published the Manual of Policy and Procedures (MAPP), ‘Chemistry Review of Questions-based Review (QbR) Submissions,’ which provides transparency regarding the agency’s expectation for the submission of abbreviated new drug applications (ANDAs),” says the FDA spokesperson.

Applying QbD to solid-dosage manufacturing

 spoke with Carlin, Moreton, Schmitt, Stegemann, and FDA about the benefits and challenges of incorporating QbD into solid-dosage manufacturing.

 What specific aspects of the solid-dosage product lifecycle are most affected by implementation of QbD? Can you provide examples?

 is a patient-centric approach that encourages manufacturers to design a product and a process that always meets the needs of the patient. This starts with first identifying the product’s quality target profile such that it meets the need of the patient and then identifying critical quality attributes (CQAs) (i.e., measurable attributes) of the finished product that would ensure that the product always meets the desired quality target profile. Thereafter, a science- and risk-based approach is used to design a manufacturing process and control strategy that ensures that the product consistently meets the desired CQAs. For example, one of the aspects of solid oral-dosage manufacturing that has evolved since adoption of the QbD approach is delineating risks of each manufacturing step and then designing a control strategy that ensures that the risks are appropriately mitigated. Additionally, QbD has spurred implementation of novel approaches. For example, we have come across use of near infrared (NIR)-based procedures that include: identification testing of raw materials, blend uniformity monitoring, detection of blending end point, measuring moisture content in tablets/granules, detection of drying end point, detection of polymorphic forms, and measuring active content of tablets. Also, many solid oral-dosage manufacturing firms are looking to implement continuous manufacturing. In a recent interview, Dr. [Janet] Woodcock [director, Center for Drug Evaluation and Research (CDER), at FDA] commented that though making the switch from batch to continuous manufacturing may be difficult, costly, and time consuming, pharma manufacturers and CMOs should begin to consider the switch, because in the long-run it will end up saving companies time, money, and space (7).

 A fundamental understanding of the solid-dosage product and processes can be achieved by applying QbD principles early in development. This understanding can be augmented as development progresses and QbD is utilized to simplify the formulation and process development. During scale up, QbD can be applied to enhance product quality by determining and managing the critical product and process parameters. The knowledge gained through a QbD development program enables the shift from a batch-based process to a continuous process, increasing manufacturing efficiency and flexibility. QbD can also support technology transfer into regional manufacturing sites. Finally, monitoring the critical quality attributes and parameters can be used to ensure continuous commercial supply.

Design and development (and regulatory filing) have so far been the aspects of the solid-dosage product lifecycle most affected by QbD due to the increasing requirements to scientifically justify the product and process design. An interesting raw material example is the request for applicants to justify their reliance on pharmacopeial or supplier specifications.
	New manufacturing and analytical technologies are evolving in response to QbD. A good example is the rise of continuous manufacturing. The Center for Structured Organic Particulate Systems (C-SOPS) at Rutgers University has recently agreed to help FDA draft guidance on continuous manufacturing.

 All aspects of the solid-dosage form lifecycle are potentially affected by QbD, from pre-formulation through to commercial manufacture. The objective of QbD is to ensure we make the correct decisions based on good science, and that this translates into robust medicinal products where performance may be any combination of consistency in process output, stability, and/or in vivo performance.

 What challenges have pharmaceutical companies overcome in incorporating QbD into the manufacturing process for solid-dosage products? What challenges do they still face?

 The agency often observes that the main barrier to change is often internal to the company. For more than a decade now, FDA has been encouraging modernization of manufacturing. We have had countless public discussions on the topics and individual meetings with industry. The agency encourages continued dialogue with applicants to help lower their anxiety toward change.

 In production, it is essential to maintain a high level of automation with integrated feedback loops to exercise process controls in real time. It is also critical that expertise at the personnel level reaches across the R&D/commercial production divide to assist with technology transfer and troubleshooting. Another ongoing challenge includes the difficulty in finding regulatory professionals with appropriate expertise to put the QbD approach into expert dossier filings.

 The promised reduction in ‘extensive regulatory oversight’ in return for QbD has yet to be realized and may have to await quality culture/risk stratification. Reviewer interest and learning in QbD is to be welcomed but not on an applicant’s critical path. It may be difficult to justify investment for QbD in older legacy products.

	Incorporating QbD into the manufacturing process for solid-dosage products not only requires internal alignment, but should involve all stakeholders, including suppliers.

 The biggest challenge is the corporate mindset, particularly in my experience in regulatory affairs groups, but also in development and manufacturing. This type of resistance can only gradually be broken down. It may take another 5-10 years before the benefits of QbD are broadly seen.

 Are there specific challenges for companies working in international markets? Are the guidelines for QbD different in different markets? If yes, how are manufacturers addressing these differences?

 Basic principles of implementation of the QbD approach are based on ICH guidelines, which have been adopted in Japan, Europe, and the United States and are widely followed by other health authorities. For the countries in the ICH, there is an ongoing effort to harmonize regulatory expectations regarding implementation of the QbD approach.  The FDA-EMA QbD pilot program that was started in March 2011 is an example of one such initiative. This pilot program provides a platform for the regulators to engage in dialog with their global counterparts regarding new QbD-based concepts. One such example is implementation of continuous manufacturing for manufacture of solid oral-dosage forms. Additionally, the pilot has led to the publishing of  three Q&A documents. For example, the Q&A on design space verification explains  the similarities and differences between FDA and EU on this topic (8).

 The application of QbD will support a global product launch and secure product quality in the case of technology transfers or production changes. Nevertheless, there are still different regulatory opinions that might restrict filings solely based on QbD principles in product -development.

 Not all regulatory authorities have adopted QbD, so companies working in international markets have to employ a mix of QbD and traditional filings.

 Though QbD is part of the international regulatory harmonization effort, many regulators are not equipped to professionally review QbD applications. Unlike FDA, few other regulators have put such emphasis on the benefits of QbD, and staffed their offices accordingly.

 How has QbD improved the solid-dosage product supply chain? Are excipient manufacturers, API producers, and other material suppliers applying QbD to their processes?

 QbD has put more emphasis on quality and variability of excipients in pharmaceutical manufacturing, leading to some QbD projects at supplier levels and the recognition that QbD principles can be applied to the same extent to excipient manufacturing. Some suppliers have taken responsibility and provided QbD data on their excipients for use in drug product development. For example, the variability of critical product parameters of hard capsules across a two-year manufacturing period was recently published to help companies make a science-based risk assessment in their capsule development program. Moreover, any regulatory quality initiative should trigger a reflection on suppliers’ own quality systems, leading to advancements. A good example is the development of enhanced and tighter process capabilities, which reduce the product variability, build better quality into the product and the process in order to reduce reject rates at the finished product manufacturing level. These enhancements in capsule manufacturing provide the means to move from AQL quality assurance scale to a Six Sigma scale and level. Producing capsules at Six Sigma quality levels for pharmaceutical product manufacturing will become the new quality standard due to the value it offers to pharmaceutical manufactures. Further, as industry leaders, Capsugel works to stay ahead of regulatory requirements to provide the highest quality products to its customers.

  Where a raw material, such as an API, is sold to clients who may not be willing to take on the additional expense, suppliers are very reluctant to invest without guaranteed payback. Excipient manufacturers are often reluctant to even apply GMP as their customer base may not require such controlled standards. Therefore, QbD is most successfully applied in vertically integrated enterprises where at least R&D, API, and drug product manufacture are all managed in-house. Achieving the same result with outsourced services is still a significant challenge.

 QbD has increased awareness that greater understanding of excipients is required beyond the specification or certificate of analysis. QbD as a pharma concept has been applied to both APIs and drug products, but one could criticize the disjointed approach where the quality of APIs (generally very pure crystals) is not related to their fitness for purpose in pharmaceutical manufacturing (insoluble, poorly compactible, and non-flowing). Regulatory uncertainty has hindered incorporation of excipients into composite APIs with optimized manufacturability. Is a co-crystal an API or drug product intermediate?

	Most high-volume pharmaceutical excipients have been manufactured continuously, decades before pharmaceutical industry awareness of QbD or continuous manufacturing. The level of material and process understanding required for excipient continuous manufacturing is essentially QbD, but may not be congruent with the QbD for a specific pharmaceutical product, especially if the major markets for that excipient are non-pharmaceutical.

 QbD encourages manufacturers adopting this approach for product design to establish specifications for the incoming raw materials (API and excipients) that would ensure consistent manufacture of desired quality finished product throughout its lifecycle. This, in turn, would encourage API and excipient manufacturers to design their processes such that the manufactured API and excipients consistently meet the quality desired by the finished product manufacturer. QbD also encourages the manufacturers to identify the risks in the supply chain and to come up with appropriate risk mitigation techniques.

 How can QbD be applied specifically to excipient manufacture, API manufacture, and ultimately final product manufacture?

 Quality needs to be built into the product. This means that QbD must start at API and excipient manufacturing, as these are the components that go into the pharmaceutical product formulation and development process. The application principles do not differ if it is the API, excipient, or finished product being manufactured. The principles aim to provide product and process understanding targeted to ensure that the final targeted product profile is constantly met over the lifecycle.

	Moreover, where the design space is limited by the excipient base properties, QbD can facilitate innovation through research initiatives. While gelatin capsules were the main polymers for capsules 10 years ago, additional capsule types are available today with gelatin-like properties, including hydroxypropl methyl cellulose (HPMC) capsules manufactured by thermal gelation and HPMC capsules with delayed-release properties.

 QbD is patient-centric, so QbD must necessarily focus on the final product. API QbD will reliably deliver consistent API but not necessarily be congruent with performance or manufacturability in finished product.

	For excipients (and third-party APIs), the question is how can the suppliers support the final product QbD. This assumes they are made aware of the application, in which case they can advise:

		potential application-specific failure modes

		potential critical attributes (which may not be on specification)

		true variability of continuously produced material 

	This will improve robustness, strengthen the risk analysis, and inform control strategy.

 Relative to the cost of the finished product, API costs are typically in the range of 1-5%. Very rarely are API costs really high, maybe 20% or higher. Given the low cost contribution of excipients and APIs to a finished drug product, price is and remains the driving force. This is in direct competition to scientific progress. Thus, QbD for these product categories remains mostly out of bounds for QbD approaches, except for cases where these are part of the same company (i.e., all being part of the same company quality philosophy).

 QbD, as the concept introduced by Duran, can be applied to any product or service, and excipients are no exception. However, I would submit that excipient manufacturers have been applying their own form of QbD for many years in the form of process capability studies and process improvement projects. It is not recommended to build a plant capable of manufacturing thousands of tonnes of material per annum without having undertaken some serious development work. In addition, there is the lifecycle aspect, and the excipient manufacturers have been managing the lifecycle successfully for many years.

 39 (8) 24-28 (2015).
	2. ICH, Q8(R2) Pharmaceutical Development (ICH, November 2009).
	3. ICH, Q9 Quality Risk Management (ICH, June 2006).
	4. ICH, Q10 Pharmaceutical Quality System (ICH, 2009).
	5. ICH, Q11 Development and Manufacture of Drug Substances (Chemical Entities And Biotechnological/Biological Entities) (ICH, May 2012).
	6. FDA, Draft Guidance, Established Conditions: Reportable CMC Changes for Approved Drug and Biologic Products Guidance for Industry (CDER, CBER, May 2015).
	7. Z. Brennan, “FDA Calls on Manufacturers to Begin Switch from Batch to Continuous Production,” 

Guidance for Industry, Q8, Q9, and Q10 Questions and Answers(R4)

:
	When referring to this article, please cite it as S. Haigney, “Quality by Design in Solid-Dosage Manufacturing," 

Articles

QbD is improving the safety of solid-dosage drug products as well improving manufacturing processes, despite some industry reluctance.

Quality by Design in Solid-Dosage Manufacturing

 posted on FDA’s website, top FDA officials present an update on China’s pharmaceutical industry and FDA’s involvement in helping keep the country’s pharma exports safe. The trip to China was made by Howard Sklamberg, FDA’s deputy commissioner for Global Regulatory Operations and Policy; Richard Moscicki, MD, FDA’s deputy director of the Center for Drug Evaluation and Research; and Alonza Cruse, FDA’s acting director, Pharmaceutical Quality Program, Office of Regulatory Affairs.

	The FDA officials were in China to observe the Chinese drug industry and meet with representatives of the Chinese Food and Drug Administration (CFDA). They noted that the face-to-face meetings they had with CFDA were “the most important by-product of our trip.” The US FDA officials took a tour of a pharmaceutical manufacturing plant and addressed students at China’s Pharmaceutical University in Nanjing. The trip also included a meeting with 17 leaders of Chinese pharmaceutical companies to discuss quality, data integrity, and the drug approval process. 

	Talks with CFDA included the importance of securing the global supply chain. The FDA representatives stressed that the agency applies “the same quality and data integrity standards to all countries shipping drug ingredients into the United States.” Discussions also included revisions to China’s Drug Administration Law, implementation of the US Food and Drug Administration Safety and Innovation Act, regulatory science issues, and the importance of collaboration.

	The FDAVoice blog post also discusses FDA’s role in inspecting facilities in China and working with the local regulatory bodies. “Given the volume of US trade with China, we are working to expand our presence there to significantly increase the number of inspections we conduct. Staffing increases will allow FDA to enhance its training efforts and technical collaboration with Chinese regulators, industry, and others. In fact, in November 2014, we signed a Memorandum of Understanding with the Chinese government that expands our cooperation and will facilitate those staffing increases.”

	The agency also reaffirms its commitment to keeping products safe when they are imported into the US. “The FDA’s office in China has also strengthened relationships with regulators and helped expand the country’s expertise in regulatory operations. And we have worked with industry and academia to explain our regulations and analyze trends and events that might affect the safety of FDA-regulated products exported from China to the US.”

Agency officials visit China to meet with Chinese regulators and industry representatives about keeping the pharma supply chain safe.

FDA Officials Comment on China Visit

	On June 1, 2015, the European Directorate for the Quality of Medicines & Healthcare (EDQM) announced the publication of its 

 for 2014, which was also the agency’s 50

 anniversary. Director Susanne Keitel detailed the directorate’s achievements during the past 50 years in the report’s forward. She also thanked the EDQM’s member states, saying “none of the EDQM’s achievements would have been possible without the unwavering support of its member states and all those who have helped build the EDQM and taken part in its activities.”

	An update on EDQM’s status with the International Organization on Standardization (ISO) shows that EDQM has maintained ISO 9001:2008 certification for the evaluation of applications for monograph suitability in the 

); management of site inspection programs; postmarketing surveillance studies for drug products and databases; coordination of Official Control Authority Batch Release procedures for biologicals; management and distribution of the writing and revision of 

 texts; and performing laboratory studies. The EDQM laboratory underwent an ISO 17025:2005 audit by BELAC, the Belgian accreditation body. The audit maintained the lab’s certification as technically competent and “able to generate technically valid results.”

	The report highlighted feedback from workshops performed during a three-day conference held in Strasbourg in October 2014 in honor of the 50

 anniversary. The following are some of the highlights:

 Monographs and Expectations for the Future” workshop was positive, according to the report, with recommendations including, “early availability of reference standards, provision of guidance on the cross validation of alternative methods, and the frequency of revisions to cover impurity profiles and new scientific and regulatory developments.”

		A workshop on quality by design (QbD) revealed that participants felt that more experience in the application of QbD was necessary and analytical methods and manufacturing processes should be examined.

		Participants of the “Finished Product Monographs” workshop identified the dissolution test as crucial. They also requested more harmonization of monographs among different pharmacopeias.

		New guidelines regarding impurities were discussed during the “Impurities” workshop. Collaboration between the Ph. Eur. and the industry was considered crucial for the workshop participants. Support for the International Conference on Harmonization (ICH) Q3D guideline on impurities was also expressed.

		Combatting counterfeit and illegal drugs was the topic of the “Combatting Illegal Medicines” workshop. Participants recommended the development of strategies to raise awareness regarding counterfeit drugs, providing new monographs, and developing new approaches to the problem, including a link to pharmacovigilance signals.

		The “Biologicals” workshop attendees expressed the need for flexibility and harmonization. “The application of the P4 procedure was considered to be a two-phase process; as a starting point, an evaluation of users’ needs and the elaboration of monographs on innovator products were considered necessary, followed, as more biosimilars emerged, by further evolution and standardization of thinking,” according to the report.

Monographs, general chapters, and reference standards added in 2014

	The EDQM Annual Report mentions the adoption of 26 new monographs including two on patent-protected active substances: imatinib mesilate (2736) and rosuvastatin calcium (2631). Two new general chapters cover the topics of methyl, ethyl, and isospropyl toluenesulfonate in active substances (2.5.40) and monographs on herbal drug extracts (5.23). Additionally, 191 texts were revised, including Reference Standards (5.12) and the monograph on herbal drug extracts (0765).

	The Ph. Eur. Commission adopted 76 batches of new reference standards and 172 replacement batches. Of the 55 assay reference standards established, 27 required collaborative study.

	Manufacturers applied for 347 new Certifications of Suitability in 2014, up from 338 in 2013, and 1632 applied for revisions, up 15% from 2013. EDQM issued 355 new certificates and 1374 revised certificates in 2014.

	Ph. Eur. Commission work programs initiated in 2014 included the following:

		a pilot phase for writing a product-specific monoclonal antibody monograph using a multisource approach in order to test such an approach

		approval of general principals for monographs on finished products containing chemically defined active substances

		addition of a general monograph on coprocessed excipients

		the appointment of members to the Live Biotherapeutic Products Working party

		collaboration on the “PaedForm” project to improve access to suitable and age-appropriate drugs for children.

	The Ph. Eur. Commission considered the following industry developments important in 2014:

		the approval of the Ph. Eur. bacterial endotoxins policy

		revision of guidance on second identification tests.

	The report goes on to detail EDQM event activities, results from a variety of working groups, training courses, and collaborative efforts by the Commission on a number of topics and initiatives from 2014. The full report can be downloaded from EDQM’s website.

The directorate highlights achievements accomplished during the year of its 50th anniversary.

EDQM Releases 2014 Annual Report

	Worldwide standards organizations implemented changes to pharmacopeial standards, published new guidelines, and continued to work toward harmonization as 2014 drew to a close. The following are a few of the latest developments.
	
	


	The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Steering Committee has moved Q3D 

 (Q3D) to Step 4 of the ICH process, recommending it for adoption by regulatory agencies. The guideline now enters the implementation period (Step 5), which is carried out according to national or regional procedures that apply to other regional regulatory guidelines and requirements in the European Union, Japan, United States, Canada, Switzerland, and other areas.
	
	Q3D, which is available for download on the ICH website, applies to new finished drug products (as defined in ICH Q6A and Q6B) and new drug products containing existing drug substances, provides a global policy for limiting metal impurities qualitatively and quantitatively in drug products and ingredients. According to the Q3D document, it “presents a process to assess and control elemental impurities in the drug product using the principles of risk management as described in ICH Q9. This process provides a platform for developing a risk-based control strategy to limit elemental impurities in the drug product.”

	Impurities are classified in an existing ICH Q3A guideline as “organic, inorganic, and residual solvents,” and Q3A and Q3B discuss requirements for organic impurities. ICH Q3C provides clarification of the requirements for residual solvents. The new Q3D guideline would provide similar clarification of the requirements for metals, which are included in the ICH inorganic impurities classification.
	
	


	In November 2014, the United States Pharmacopeial Convention (USP) published the 

 to provide access to quality-related standards for compounded medicines. The compendium gives compounding practitioners access to all compounding-related general chapters from the 

United States Pharmacopeia-National Formulary

) and features more than 40 supporting general chapters and more than 170 compounding preparation monographs. It also includes the 

 General Notices and Requirements, “which provide definitions and important information necessary to correctly interpret and apply compounding standards.”
	
	The 

 will be updated with the release of each new 

 edition and supplement. Subscribers can access and download all updates during their 12-month subscription period. USP has partnered with the International Academy of Compounding Pharmacists (IACP) and the National Community Pharmacy Association (NCPA) to enable their members to purchase the 

 directly through the IACP and NCPA websites.
	
	In their continuous efforts to harmonize standards, USP and the Chinese Pharmacopoeia Commission (ChP) jointly hosted the ChP & USP Science Symposium and 2014 ChP Science Annual Meeting on Nov. 13-14 in Chengdu, China. The theme of the meeting was “Strengthening cooperation, Harmonizing standards, Promoting mutual recognition” and focused on international coordination and mutual recognition of pharmaceutical standards in chemical medicine, biologics, traditional Chinese medicine, pharmaceutical excipients, packaging materials, and other related fields.  
	
	The two-day forum featured leaders and experts from pharmacopoeias and regulatory authorities in the United States, China, Europe, the United Kingdom, Japan, Brazil, and other countries. The symposium also included more than 400 representatives from China Food and Drug Administration (CFDA) and China’s National Food and Drug Inspection System, along with scientific research institutes and drug manufacturers.
	
	An industry roundtable session included representatives from industry associations and multinational pharmaceutical companies. As part of the open discussion, according to a press release, “ChP and USP encouraged participants to engage with pharmacopoeias to explore ways of promoting international cooperation and harmonization, and mutual and multilateral recognition. USP and ChP also engaged in bilateral discussion about future opportunities to work together.”
	
	


	The European Pharmacopoeia Commission held its 150th session in Strasbourg in November 2014, in which it adopted 13 new texts for inclusion in the 

). Six revised general chapters and 28 revised monographs were also adopted during the session.
	
	Revised monographs included the suppression of reference to calomel electrodes, because of EU regulation 847/2012, which restricts the use of mercury in measuring devices. Revised general chapters included “Water: micro-determination (2.5.32)” and “Potentiometric titration (2.2.20).”
	
	At the session, the Commission endorsed the inclusion of tests for pro-coagulant activity in monographs on immunoglobulins (intravenous and subcutaneous), which will require collaboration with worldwide regulators.
	
	The European Directorate for the Quality of Medicines & Healthcare (EDQM) published the list of revised monographs and adopted texts on the EDQM website. The revised texts will become effective on Jan. 1, 2016 in the 37 member states and will be published in supplement 8.6 of the 

: When referring to this article, please cite it as S. Haigney, "Standards Organizations Update," 

In late 2014, standards organizations continued to work towards harmonization and securing drug safety.

Standards Organizations Update

The Generic Pharmaceutical Association (GPhA) has issued a 

 in support of competition in the pharmaceutical drug market. The statement, issued by Ralph G. Neas, president and CEO of GPhA, requests that Congress take initiative by reviewing potential abuse of patient safety programs, such as risk evaluation and mitigation strategies (REMS); encouraging FDA to review generic-drug applications more quickly, and by asking FDA to enact regulations for biosimilar approvals and support a competitive biosimilar naming policy. 
  

“The most effective way to continue to keep prescription drugs affordable for patients is to increase competition. Millions of patients and the entire healthcare system would benefit from streamlining and expediting the approval process so that more generics can reach the market sooner. As the newly released report from Matrix Global Advisors shows, there are opportunities for FDA to facilitate pharmaceutical competition,” Neas says in the statement.  

Neas expresses the association’s disappointment in what it considers the Healthcare Supply Chain Association (HSCA)’s mischaracterization of generic-drug facts reported by the IMS Institute of Healthcare Informatics and Express Scripts.  

“Their data is missing one crucial element: perspective. The examples cited by the Healthcare Supply Chain Association on recent purchases by group purchasing organizations (GPOs) focuses on 10 drugs in a marketplace of more than 12,000 safe, affordable generic medicines. In fact, thousands of generics have seen significant price erosion over time due to the competitive nature of the marketplace. One such example is that of Lipitor—for which generics have saved all involved an estimated $7 billion per year. In addition, many generic prices are so low that thousands of stores across the country offer them to consumers for four dollars or even for free.” 
  
  According to Neas, IMS reported that generic drugs saved $239 billion in 2013 and more than $1.46 trillion during the recent decade. The Express Scripts 2013 

 states that, while the price of brand drugs has almost doubled, generic drug prices have been roughly cut in half since 2008, according to the GPhA statement. 
  
  “Generic manufacturers can proudly point to a legacy of savings and access that will continue to bring expensive treatments within reach for millions of people,” says Neas.

Ralph G. Neas, president and CEO of the Generic Pharmaceutical Association, requests that Congress get involved in the support of a more competitive drug market.

GPhA Issues Statement on Generic Drug Costs

The pharmaceutical supply chain has been an increasing focus for regulators and the industry in the past couple of years. Drug shortages and counterfeiting have spurred the creation of legislation and industry guidelines to combat the situation and prevent suspect drug products from entering the market. 

Regulators and Congress have stepped up in the fight against counterfeit and unsafe drugs by enacting legislation to ensure supply-chain safety. “The recent and upcoming changes to the FDA Safety and Innovation Act (FDASIA) have added a number of requirements intended to ensure a safe supply of medicines. Many of these enhancements are included in Title VII of the act, parts 701-718. The changes outlined in Title VII are important because they allow the agency to collect more comprehensive, accurate, and timely information about the pharmaceutical supply chain,” says Susan Schniepp, vice-president, Quality and Regulatory Affairs at Allergy Laboratories.

In addition, Schniepp explains that FDASIA helps establish the same requirements for foreign and domestic manufacturers, allowing the agency to work more effectively with their overseas counterparts. The Act gives FDA tools to protect the integrity of the global supply chain. FDA can collect and analyze product data to enable risk-informed decision making on incoming products and partner with foreign authorities to leverage resources through information sharing and recognition of foreign inspections of facilities. “These changes have already resulted in two draft guidance documents: 

Specification of the Unique Facility Identifier (UFI) System for Drug Establishment Registration and Circumstances that Constitute Delaying, Denying, Limiting, or Refusing a Drug Inspection

In June 2014, FDA issued draft guidance on how to identify suspect drug products in the supply chain (1). Developed under the Drug Supply Chain Security Act, the guidance describes potential signs that drug supply-chain stakeholders can look for to identify suspect drugs, including product labeling that may contain misspelled words or looks different than the standard labeling; packaging that has missing lot numbers or expiration dates or has been opened, damaged, or altered; or a change in shape or color from the standard product. 

Supply-chain stakeholders are encouraged by FDA to be cautious when purchasing drugs from a new or unknown source, from the Internet, or purchasing drugs on the drug shortage list. Unsolicited offers for lower-priced drugs should also be avoided. The draft guidance provides supply-chain stakeholders with information on how to notify FDA of illegitimate products and details a process for stakeholders to follow when terminating previously made notifications. 


  FDA initiated the Secure Supply Chain Pilot Program, in February 2014, to enhance the security of imported drugs. FDA published a notice in the

 in August 2013 to solicit companies to voluntarily submit applications for participation in the program (2). Thirteen prequalified companies were designated to take part in the program. Participating companies received expedited entry for the importation of up to five selected drug products into the United States.

The companies met multiple participation conditions, including committing to comply with requirements of the Food, Drug, and Cosmetics Act; having a validated secure supply-chain protocol per the US Customs and Border Protection’s Customs-Trade Partnership Against Terrorism program; having a plan in place to quickly correct potential problems FDA identifies regarding importation of specific products; having effective recall and corrective action plans in place; and maintaining control over their drugs from the time of manufacture abroad through entry into the US.
  
  “By creating incentives for manufacturers to adopt best practices for supply chain integrity, we can enhance the quality and safety of imported drugs,” said Carol Bennett, acting director of the Office of Compliance in the FDA’s Center for Drug Evaluation and Research, in a press release. “The program also allows the FDA to focus resources on the areas with the greatest potential risk to consumers.”

“FDA’s Supply Chain Pilot Program is designed to help in addressing the increasing issues and problems associated with importations that have arisen from the globalization of the pharmaceutical supply chain. The goal of the program is to expedite the importation of legitimate materials, APIs, and product coming from abroad. The pilot program will collect data from 20142016. At the end of this period, the data will be evaluated to establish a system where there is an efficient use of time and resources to evaluate items of importation. The system would rely on specific code numbers that would require little human intervention. Instead, time can be spent on evaluating the questionable materials that require a more detailed human review,” says Schniepp.


  The pharmaceutical industry has also taken steps of its own to ensure the security of the drug supply chain. In 2009, the industry created Rx-360, a pharmaceutical industry supply-chain consortium that includes more than 80 companies and organizations. The consortium is committed to creating communication between pharmaceutical companies, suppliers, and contract manufacturers to better secure the pharmaceutical supply chain.

In an August 2013 interview with Pharmaceutical Technology, Rx-360 Chair Brian Johnson states, “Rx-360 believes that freely sharing information, such as alerts on potential supply-chain threats, is vital to the industry’s success. Industry collaboration on sharing audit information and jointly conducting audits is crucial to improving the transparency of our increasingly complex and global supply chains” (3).

Organizations unite
  The United States Pharmacopeial Convention (USP) is taking part in the “Fight the Fakes” campaign. The campaign is designed to spread awareness about the negative impact of fake medicines to create a global movement of organizations. 

“Combating counterfeit and substandard products is an essential part of USP’s mission to improving public health by promoting quality medicines around the world,” said USP CEO Ron Piervincenzi in a press release. “The challenges we face today, with raw materials and finished products circling the globe before they reach the hands of patients and consumers, require collaboration to stem the tide of fakes” (4).  

The campaign was established in 2013 and includes 25 healthcare groups, research institutes, foundations, non-profits, and private sector organizations including the Generic Pharmaceutical Association, the Global Pharma Health Fund, the International Federation of Pharmaceutical Manufacturers and Associations, and the Partnership for Safe Medicines. 

These continued efforts by regulators and the industry will hopefully prove to be a positive impact on the availability of medicines and the ensurance of patient safety.

Guidance for Industry, Drug Supply Chain Security Act Implementation: Identification of Suspect Product and Notification, Draft Guidance

 (Silver Spring, Md., June 2014).
  2.	FDA, 

, 78 FR 51192, Aug. 20., 2013.
  3.	A. Siew, Supplement to 

., s46 (August 2013). 
  4.	USP, “USP Welcomes New Partners to ‘Fight the Fakes’ Campaign,” Press Release, USP.org. 

FDA's Secure Supply Chain Pilot Program, RX-360, and other industry efforts advance actions to secure the drug supply chain.