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

Susan Haigney

	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," 

Articles

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.

Moving Toward a Safer Supply Chain

Regulators and industry leaders take on the task of securing the drug supply chain.

Securing the Supply Chain

 spoke with Jamie Chasteen, manager of new product development at Cold Chain Technologies, and Rebecca E. Gentile, senior specialist, quality vaccine and biological stability at Merck & Co. about the challenges manufacturers experience when managing the cold chain for biopharmaceuticals and what advances in cold-chain technologies are helping to combat these challenges. 
  
  

 What top challenges do biopharmaceutical companies face when managing the cold chain for biopharmaceuticals? 
  
  

 A top challenge to managing the cold chain for biopharmaceuticals during distribution is temperature excursions, which can affect the safety and efficacy of the product. Reducing or eliminating temperature excursions during shipping is an important task. Clinical-trial material is shipped to multiple locations, typically in smaller packages, so ensuring that the appropriate packaging solution is being used to maintain the necessary temperature ranges is crucial. For commercial supply, it is crucial to understand the typical shipping lanes and what temperature exposures the product might encounter, work with partners to design and qualify appropriate shipping packages, and work with shipping partners to minimize delays and other potential points of temperature excursions. 

Particularly for commercial product, designing the Phase III stability studies and establishing a stability budget, so that the data can be used to support shipping at a temperature range broader than the label storage condition, can be beneficial. For biological products, consideration of shock and vibration effects during shipping should be considered along with stressed stability conditions. This approach allows for a broader and more economical choice of shipping solutions and reduces the chance for temperature excursions, while still ensuring the safety and efficacy of the product through shelf life. When the stability data are included in the regulatory filing, many agencies are supportive of this approach. 
  
  

 A recent Georgia Institute of Technology study highlighted that 90% of failures in the cold chain are attributed to human error. These errors can occur while the product is in transit, but data show the vast majority of errors are occurring during pack-out at the site of shipment origination. It is not uncommon for companies, whether in the commercial or clinical-trial space, to have multiple styles of insulated container for their various shipping needs. These containers can use several different refrigerant types and sizes. In many cases, these refrigerants require multiple stage conditioning or ‘sweating’ prior to use. These sweat and conditioning times can vary based on which refrigerant and system is being used for that particular shipment. Each package can also be packedout in very different ways, requiring employees to learn a myriad of different designs and methodologies. This confusion and complexity directly correlates to human error and costly excursions during shipment. The creation of high-performance modular shipping solutions is greatly reducing these failures. The newest shipping system families employ modular components, simple single-step refrigerant pre-conditioning, system-to-system design synergy, and only two refrigerant sizes across the entire line of payloads and durations. The emergence of simple-to-use high performance shipping systems is reducing the most prevalent cause of error in the industry today.

What are some recent advances in cold-chain technologies? 
  

 Two of the advancements in technologies to better control temperature within the supply chain are analytical thermal modeling tools and advanced phase-change materials (PCMs). The combination has resulted in the industry’s most innovative thermal shipping systems. Historically, empirical testing was the only successful tool for system development. With thermal modeling, we now have the ability to truly understand the internal thermal dynamics at play. System tweaks can be made in minutes and iterative models can be run in hours. Extremely efficient designs are the result. This efficiency is particularly important when working with advanced PCMs. Advanced PCM, at the component level, is more expensive than traditional water-based refrigerant. It is crucial that PCM be used in a very precise and judicious manner. Thermal modeling is the tool to develop PCM-based systems that are less costly than the water-based variants they replace.  

There is a huge shift taking place in the market. PCMs used to be solely considered for use in expensive solutions that combined the refrigerants with exotic insulation materials such as vacuum insulated panels (VIPs). The latest systems on the market combine advanced PCMs with less costly insulation materials such as polyurethane (PUR) and expanded polystyrene (EPS). These solutions are capable of being reused yet are more cost effective for single use than traditional EPS and PUR systems available. Because of the advanced designs and latest PCMs, they are better than previous water-based designs in every measurable category. Advanced PCM allows for smaller and lighter systems. This reduction in size and mass means a significant savings in both incoming and outgoing freight. Warehousing costs and carbon footprint are reduced. Most intriguing is that these new PCM systems are actually less expensive to purchase than traditional systems all while better handling the variability in real-world shipping environments. 

 Can you specify recent industry guidance with respect to supply-chain management?
  

 There are several new guidance documents that have recently been released or are in review for publication. One of the major changes foreseen in the US revolves around distribution in the ‘last mile.’ The last mile is the final leg of distribution to a provider, pharmacy, or directly to a patient. This portion of the industry has to operate under the tightest financial restrictions. There are four factors that are changing the landscape in the last mile: manufacturer’s transitioning from indirect to direct business models, increased pressure in the last mile from bodies such as state boards of pharmacy and accreditors, an increase in manufacturer emphasis in downstream brand protection even when title passes, and end-user awareness of temperature importance and demand for temperature indication. The Parenteral Drug Association recently published 

Technical Report No. 46 Last Mile: Guidance for Good Distribution Practices for Pharmaceutical Products to the End User. 

The adoption of this guidance poses challenges and opportunities for companies in the last mile to differentiate their service to an increasingly informed patient and provider population desiring temperature assurance. 

Industry experts discuss challenges in managing the cold chain.

Challenges in Managing the Cold Chain

To gain perspective on the implementation of quality by design (QbD) in sterile manufacturing, 

 spoke with key industry experts: Wolfgang Weikmann, vice-president quality assurance at Vetter Pharma-Fertigung GmbH & Co.KG; Hal Baseman COO and principal at ValSource LLC and chair elect of Parenteral Drug Association (PDA)Board of Directors and vice chair of PDA Science Advisory; and James E. Akers, president of Akers Kennedy and Associates.
  
  

In implementing a QbD approach, what would you identify as the critical quality attributes (CQAs) in sterile manufacturing and aseptic processing? 
  
  

: The critical quality attributes are related to the control and prevention of contamination, principally, microbiological, total particulate matter, and endotoxin although clearly the chemical purity and material uniformity issues that are a constant in pharmaceutical manufacturing apply to sterile and aseptic products as well.
  
  

: The potential critical quality attributes of a customer’s drug product in terms of aseptic processing are determined by the nature of the product and by the definition of its target product profile. Most common identified critical attributes refer to physical, chemical, and microbiological properties. We recognize sterility, bacterial endotoxin, and dose accuracy as three of the essential CQAs.
  
  

 Identification and understanding of CQAs are essential to designing a process that establishes and maintains those CQAs. They can be broadly defined as purity, safety, strength, and identity of the product. Therefore, the CQAs associated with aseptic processing and those that need to be established and maintained by the process are:

Those CQAs that assure that nothing is present in the product which should not be there (i.e., foreign material or cross contamination of product or chemical residuals).

Those CQAs whose absence will likely cause harm to the patient, then they would include sterility, sterility assurance, lack of endoxin, lack of particulate contamination.

Those CQAs that must be present to assure the effectiveness of the product, then they would include potency, active ingredient, and functionality

Those CQAs that assure that the product is what it purports to be, then they would include correct and complete indication of product identity, lot number, content, and potency.

 What measurement tools are typically used to measure critical process parameters and the resultant process inputs and outputs, including process analytical technology (PAT) tools, in sterile manufacturing? 

 Many of the key parameters in aseptic and sterile manufacturing can be measured directly and in real time. Sterilization of components, depyrogenation of some materials, fill volumes, and in some cases, package sealing, can be measured in real time. Also, key environmental factors, such as total particulate air quality, pressure differentials, and air-handler operational characteristics can be measured in real time. In modern isolator/aseptic chamber aseptic manufacturing and in terminal sterilization, those parameters listed are the most critical.

 Defining a quantifiable correlation between what can be measured and the intended outcome is particularly challenging for aseptic processing. Some tools and systems that can help better understand and design the process include:

Air profile/smoke studies and material/personnel flow studies to establish first-air principles and their relationship to potentially microbial contamination. These tools are essential for the design and assurance of the process control strategies.  

Environmental monitoring, including continuous nonviable and viable monitoring, to monitor performance of the process.

Risk assessments to better understand the relationship and impact of process control strategies on CQAs and critical process parameters.

Human factors and ergonomics to help create processes that minimize the effect of human performance and fatigue.

Differential pressure and airflow and velocity to maintain cleanliness of the cleanroom environment.

Temperature and humidity monitoring to reduce the potential for microbiological growth in the cleanroom.

Gown and personnel monitoring to assure control of environmental conditions.

  There is, however, a direct and measurable correlation between sterilization parameters, including:

Time, temperature, and pressure monitoring of steam-sterilization cycles to assure control of microbiological contamination of product contact parts and surfaces.

Some of the aseptic processes, such as lyophilization, may use PAT in their recipe management for process consistency and control outcome CQAs.

Filtration integrity testing to assure integrity and effectiveness of product sterilization methods. 
  

 How is equipment design and operation modified when implementing QbD in sterile and aseptic manufacturing? 
  
  

 Air profile/smoke studies can be used to determine the most optimal shape and configuration for aseptic processing equipment. Human factors can be used to determine and improve interventions. Risk-based evaluation of interventions and use of automation can be used to reduce the impact and risk of interventions on process variation and product quality.
  
  

 Looking first at equipment design, we feel strongly that the design review process has to be mentioned as an essential tool. Design review is a decisive milestone within the development process for a single piece of equipment. It is performed through the adjustment of an initially created design with its particular requirements. This is important to control the results of the former activities, as well as to identify and solve any existing problems prior to the start of the drug-manufacturing process. We primarily execute a design review within the construction phase for each cGMP relevant piece of major process equipment. An example element of this design review is conducting mock-up studies.
  Looking at the operations side, serving multiple customers with different product and process specific requirements, our equipment has to be set-up highly flexible. Such an arrangement offers the benefit that, based on the product specific requirements as well as based on the performed pump studies within the QbD approach, the specific equipment components, such as the most adequate product and process-fitting filling pumps, can be used right away for subsequent production.
  
  

 In the projects I’ve worked on over the past 20 years, I don’t think current emphasis on QbD has altered what we do because we’ve always been focused on arriving at the most effective, efficient, and safe design for a process. I think because of the current regulatory emphasis, we use the description QbD or as we say sterility by design more than in the past. So, there is some additional focus in thinking and speaking in QbD terms, particularly among some clients.
  
  

Challenges in implementing QbD
  PharmTech:

 What are the challenges in applying QbD in sterile manufacturing? 
  
  

 [The challenges are] the lack of quantifiable correlation between what we can measure and monitor, and the desired outcome or the undesired outcome. Also, one must be aware of residual risk and unintended consequences as a result of changes made to address risk and improve process. Each action taken to resolve or address a process risk represents a change that may have the potential to add a new risk or unintended consequence.  These new risks must be evaluated and addressed where possible.
  


  Akers (Akers Kennedy and Associates): 

QbD is not really a new requirement in my experience. I believe in sterile manufacturing; we’ve done QbD before it was formally termed QbD.  I believe much of what we now do as QbD was once part of our design qualification activities.  The design parameters for sterile production facilities in terms of cleanrooms and sanitary designs have been well defined for years.  
  
  

In our experience, the main challenges in applying a QbD approach are due to the intensity of time, cost, and resources in the early-development stage. Another significant challenge is the high degree of expertise that must be in place to run a proper QbD approach.

Regarding timing, a much longer timetable has to be included. As for costs, the higher costs are due to the variety of additionally performed studies. And higher resource management is due to equipment, different materials as well as staff. 

In summation, it is always a product-dependent balancing act between the risks and consequences on one hand, and the cost during the development stage on the other. Even if challenges as previously described appear in the early stages, the gained knowledge will likely result in an economic benefit in the long-term commercial lifecycle.
  
  

What additional understanding is gained through a QbD approach compared to a traditional approach? 
  
  

 The most important understanding gained by running an operation through a QbD approach versus the more traditional approach is to realize the necessary requirements of a customer´s product already in an early-development stage to accommodate the product target profile. These requirements are not limited to product quality only. They include the process performance as well as the applied systems and the environment, for example, optimized and reduced lyophilization process cycles.
  Based on various studies, differing possible cases are evaluated in detail. This examination ultimately leads to a better understanding of the process variations, thus resulting in an acceptable design space. Consequently, using a QbD approach offers the possibility of gaining better process knowledge, resulting in an improved robustness of the entire process.
  

 A better understanding of process variables and impact on risk to product quality [is gained], which will aid to design of the process and process control strategies.
  

Actually, Joseph M. Juran coined the phrase ‘quality by design’ in the early 1990s, and these ideas were widely adopted in aseptic processing before QbD re-entered the industry lexicon a few years ago.  I would estimate that 95% of aseptic product safety in 2013 emanates directly from the proper design of the equipment and the environment.   
  
  

How does QbD improve quality assurance and how can it mitigate problems in  manufacturing? 
  

 Through a greater importance given to process development activities and the resulting large number of development studies performed within a QbD approach, a better process understanding is gained. Within the risk-management approach, risks are already identified in an early stage. Consequently, risk mitigation activities can be developed, and a risk-based control strategy implemented from the very beginning of the commercial stage, forming the basis for improvement of quality assurance and quality oversight.
  

 I can’t point to a single specific area where I believe QbD has had an impact on sterile product quality assurance. Sterile product manufacturing has always been and will continue to be a detail-oriented endeavor. QbD may have increased awareness of the criticality of getting the facility and process designs right. Maybe we have a better appreciation for the primacy of good engineering and scientific process development in sterile products manufacturing operations. 
  

It can improve process understanding, including the identification and control of process variables. This can lead to improved process and less risk.
  

 How do QbD practices build on or complement approaches taken with respect to parametric release and related terminal sterilization parameters needed for release? 
  

Perhaps QbD, as previously noted, will strengthen the focus on process design and control. However, arriving at a process suitable for consideration for parametric release has always required very thorough science and engineering.  I personally believe that terminally sterilized products, given their robustness and reliability, should be parametrically released more often than not. The alternative to parametric release is the sterility test, which has limitations in terms of microbiological detection and sensitivity as well as in the area of sampling statistics. 
  
  

 Understanding the relationship between those parameters we can control, monitor, and measure, and the desired outcome or CQA is essential to designing effective processes. It may not be enough to know which parameters effect product quality and process performance; we must also know to what extent they do this and how well they are controlled. 
  
  

How is technology transfer improved under a QbD approach? 
  
  

Technology transfer indeed is one area that is especially improved through a QbD approach. It leads to improved possibilities to monitor and evaluate the process. Becoming familiar with a drug product´s frame and its limits through conducting numerous tech runs of varying versions allows one to define the product´s specification in which the process is running robustly. 
  
  A day-to-day business example to showcase the improvement of tech transfer through QbD for customers is by demonstrating the lyophilization cycle development of a customer’s product. For example, by using a QbD approach with gaining the corresponding data based on numerous performed lyophilization tests, we realized a significant reduction of the lyophilization cycle for a particular customer product. This reduction resulted in saving the customer a high amount of capital, primarily within the large-scale commercial production.
  
  

 I honestly don’t see much change. I’ve been fortunate enough to work with firms who always took the development of user-requirement specifications through detailed proof of principal testing very seriously.  
  
  

 It can result in a better understanding of the process and process variables, including which process steps require control--control measures that need to be included in tech transfer. 

Industry experts discuss the application, challenges, and benefits of a quality-by-design approach to sterile manufacturing.