In the first seven months of 2014, eight API manufacturers were issued warning letters by FDA due to infractions ranging from failure to maintain records; labeling and branding issues; failure to perform laboratory tests and maintain accurate records; failure to investigate deviations and out-of-specification results; failure to follow equipment cleaning procedures; and failure to maintain equipment (1). During this same time, other API manufacturers generated positive news, through facility and equipment improvements, successful regulatory inspections, acquisitions, partnerships, and other achievements. This article summarizes business activities reported by the respective companies listed.


TAPI reported a number of successful audits at plants worldwide. FDA completed inspections at the Teva Czech (Galena) plant in Opava, Czech Republic; the Debrecen and Sajobaboy sites in Hungary; Teva Tech site in Ramat Hovav, Israel; the Malanpur, India facility; and two facilities in Italy, the Rho plant in Milano and the Bulciago facility.  Additional inspections were conducted by other national regulatory authorities.

In August, WuXiPharmaTech announced that a manufacturing facility of WuXi’s wholly owned subsidiary Shanghai SynTheAll Pharmaceutical Co. Ltd. (STA) passed an FDA inspection for the manufacture of an API for a branded commercial drug. The July FDA inspection was the first of STA’s facilities for the manufacture of an API. In 2013, STA’s manufacturing operations passed an inspection by  FDA for the manufacture of an advanced intermediate, the company reports.

Cambrex Corporation announced in July that FDA had completed an inspection of its API-manufacturing facility in Karlskoga, Sweden. The March 2014 inspection found the site to be compliant with the principles and guidelines of GMP, the company reports. One Form-483 observation was issued during the inspection, which has been satisfactorily resolved. 

Novasep reported in July that the company successfully completed FDA pre-approval inspections at two of its sites in France and is authorized to produce a new molecular entity approved in the United States. The inspection concerned a multi-site project Novasep manages for synthesizing and purifying a kinase inhibitor active ingredient. FDA inspections took place during June 2014 at Novasep’s Chasse-sur-Rhone and Pompey sites in France. The Chasse-sur-Rhone site is responsible for the synthesis of late-stage intermediates and the API; the Pompey site handles the last purification step.

In May, Novasep completed a $5.5 million investment to expand its highly potent API manufacturing capabilities at its Le Mans, France facility. The plant extension, which also produces registered advanced intermediates, recently passed FDA inspection. The facility combines chemical and purification capabilities to manufacture potent and extremely potent antibody drug conjugate payloads at commercial scale. 
Hovione announced in July that its API plant in Cork, Ireland has successfully passed a pre-approval inspection by FDA. The inspection confirmed the site to be compliant with GMP principles and guidelines and noForm-483 observations were issued. 

In January, Regis Technologies, Morton Grove, IL, reported that it successfully passed an FDA audit with no Form-483 observations. 


  Alphora Research, a small-molecule API development company in Mississauga, Ontario, Canada announced in July that the company has completed a $2-million capital investment, adding two flow chemistry platforms and additional process chemistry and analytical technologies to strengthen its process development focus to support GMP scale-up of small-molecule candidates. Also in July, AbbVie Ireland-Cork expanded its contract manufacturing capabilities to include bi-layer compression, which will provide the option to combine two or more APIs into one dosage form, enabling both flexible and dedicated different sequential release profiles. 

In June, Regis Technologies, announced plans to add potent compounds handling to its services including analytical and process development to GMP production at lab scale. The upgrade will enable the company to supply potent APIs for pre-clinical and Phase I/II clinical trials.


  In July, AMRI completed the acquisition of Oso Biopharmaceuticals Manufacturing, a contract manufacturer of highly complex injectable drug products. OSO Biopharmaceutical’s expertise in large-scale commercial production is complementary to AMRI’s early stage drug product manufacturing capabilities, the company reports. In April, AMRI acquired Cedarburg Pharmaceuticals, Inc., a contract developer and manufacturer of complex APIs for generic and branded customers. 

Hospira in July acquired an API manufacturing facility and an associated research and development facility from Orchid Chemicals & Pharmaceuticals, an Indian pharmaceuticals company, to help secure the supply continuity of beta-lactam antibiotic products. The API manufacturing facility, located in Aurangabad, India has capabilities for manufacturing sterile APIs. 

In June, BioVectra announced that it has agreed to purchase the previous Sepracor Canada Limited facility at Windsor, Nova Scotia, Canada. The 55,000-sq-ft facility was operated as an API manufacturing facility from 1997 to 2013; four APIs were produced for commercial use at the site. In addition to supporting the US market, the site is registered to supply APIs to Japan. The facility includes multiple process areas, cGMP warehousing and storage space, and analytical laboratories, which were used for clinical supply and process development activity, as well as production support. The company reported plans to use the existing facility infrastructure as well as evaluate plans to retrofit open process areas to serve additional volume demands for its manufacturing services. 

Also in June, BioVectra started expansion of its Aviation Avenue facility on Prince Edward Island. The new construction features laboratory, office, workstation, and amenity space. Current office and lab areas at the facility are being renovated to address new equipment and meeting configuration requirements. Completion of the $3.8-million project is expected by November 2014.

AAIPharma Services Corp. completed a multi-million dollar expansion of its cGMP parenteral manufacturing facility in Charleston, SC, which doubled the facility’s sterile product development and production capacity and added redundancies to its processing equipment. The expansion consisted of three suites designed and built by AES Clean Technology and equipped with a Chase-Logeman monoblock FSAS, Lytzen

ISO Class 5 depyrogenation oven, BMT Steripro cGMP steam sterilizer, and SP Hull pilot-scale lyophilizer. A production-scale lyophilizer will be added to triple the facility’s lyophilization capacity by late 2014.
  Chemic Laboratories and Euticals SpA announced the renewal of a joint cooperation agreement that will enable the companies to cooperate on a variety of client engagements, primarily in the areas of API research, development, and production. Under the cooperation model, Euticals will scale APIs to commercial scale following compound development by Chemic Laboratories. 


  CordenPharma Colorado, an API manufacturing facility in Boulder, CO, announced receipt of approval for the Potent Compound Safety Certification by SafeBridge Consultants. By meeting the criteria established under the SafeBridge program, CordenPharma Colorado is deemed competent and proficient in the safe handling of potent APIs and compounds of unknown toxicity and potency. The certification applies to specific laboratory and manufacturing areas involved in the manufacture of APIs and synthetic intermediates. 


  1.	FDA, Warning Letters 2014, www.fda.gov, accessed August 22, 2014. 

Articles

API Synthesis & Manufacturing

Added manufacturing capabilities, partnerships, and regulatory milestones mark recent achievements by API developers.

API Developers Note Upgrades, Successful Inspections

Biopharmaceutical manufacturing is following the general pharmaceutical market trend toward global expansion. Fewer clients are considering CMOs’ geographic proximity as a critical factor in their partner selection process, according to results from BioPlan Associates'

 11th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production

  (1). The study identifies the markets best poised to profit from the internationalization of the outsourcing, finding that emerging markets such as China and India are among top potential destinations for both US and Western European companies.

As part of the study, BioPlan asked respondents to consider their five-year time horizon (lead-up to 2019) and to evaluate their facility’s current plans for future international capacity expansion (not domestic). BioPlan identified more than 25 countries as potential outsourcing destinations. In cases where respondents did not have an immediate outsourcing need, BioPlan believes their answers reflect their hypothetical biases for destinations of choice (see

Among all respondents, the United States ranked highest again as a potential outsourcing destination, with 26.8% (up from 26.3% last year and 16.9% in 2012) of global respondents indicating that there was a “Likelihood” or “Strong likelihood” that they would outsource production to facilities there. Following the US was China (24%, up from 10.6% last year) in a rather dramatic jump to the second position after posting the ninth spot in 2013.

 Germany (15.5%) and India (12.7%) were next on the list after the US and China, while Singapore and Switzerland jointly rounded out the top five, each cited by approximately 1 in 10 respondents.

 Although China and India remain popular outsourcing destinations, certain factors limit their attractiveness to biomanufacturers. BioPlan’s 2014 study found that regulatory compliance expertise is an increasingly crucial CMO attribute. This expertise is likely a reflection of a growing interest in outsourcing core activities for which regulatory manufacturing-related requirements are more stringent compared with smaller-scale R&D, research reagents, and clinical supplies manufacture that have typified international outsourcing and off-shoring in the past.

A keener focus on regulatory issues might hinder the attractiveness of emerging destinations such as China and India, which may not fully have demonstrated, or at least perceived, expertise in this area to rival more established markets. As one respondent commented: “Off-shoring is too complex from a regulatory perspective outside EU/US.” This sentiment is probably more pronounced for developing markets, which also have to contend with companies’ intellectual property (IP)- and quality-related concerns when outsourcing to CMOs in developing countries, with these aspects also being important considerations when choosing a CMO.

China’s rebounddriven by Western Europe


Despite regulatory concerns, the data indicate that China and India are seen as potential destinations in the next five years. Interestingly, China’s prominence this year is the result of an increase in attractiveness in the eyes of Western European respondents. Indeed, this year, China tied the US as a potential destination for outsourcing over the next five years, each cited by approximately 47% of Western European respondents. That level was the highest of consideration on record for China, which in 2013 was cited in the single digits.

When asked about predictions of a “Strong likelihood” or “Likelihood” for international expansion of outsourcing during the next five years, Western European biomanufacturers actually indicated that China was top of their list, a likely destination for 33% of respondents, followed by the US at 27%.

The US and China are clearly the top potential destinations for Western European biomanufacturers, with Germany, UK, Switzerland, Brazil and Japan each cited by slightly more than 13% of respondents. Of those, the UK and Switzerland both grew as likely destinations from 2013; it should be noted that India did not make the list of top likely destinations for Western Europeans.

US biomanufacturerslook first to Singapore


While China certainly appears to have increased in its appeal to Western Europeans, the same can’t be said when it comes to US biomanufacturers. According to the study results, US respondents continue to see Singapore as a strong outsourcing destination, with a leading 39% citing the country as a ‘possible’ destination this year (up from 32% in 2013, 31% in 2012, and 28% in 2011). Germany is also growing in consideration, coming in a close second again this year, cited by 36% of US respondents as a possible destination (up from 29% in 2013, 25% in 2012, and 22% in 2011).

Trailing a little further behind are India (27%, up from 23%) and Ireland (also 27%, up from 19%) (multiple responses allowed). Rounding out the top five potential destinations was China, cited by one-quarter of US respondents, but the only country of the top five not to see an increase in appeal from 2013.

BioPlan also evaluated US responses indicating more positive consideration for country destinations as either a “Strong likelihood” or “Likelihood.” The top “Likely” destinations for US-based respondents are Singapore and Germany, each with 16% of respondents (19% last year) considering it either a “Likelihood” or a “Strong likelihood”. Next were China (14%) and India (11%), although Switzerland and Ireland each had more respondents indicating a “Strong likelihood” of outsourcing there. It is somewhat surprising that Canada did not make this list, despite Canadian CMOs likely used by more US clients currently than CMOs in countries such as Brazil and Spain, which did make the list of likely destinations.


There will be growing opportunities for CMOs around the world to forge new partnerships with clients, according to the study, as 47% of respondents indicated that they will offshore at least some of their biomanufacturing operations in the next five years, a significant increase from the 30% sharing that sentiment just three years ago. More respondents this year also expect to outsource some process development for biomanufacturing (43% vs. 35%) and clinical trials/operations (58% vs. 56%). Nevertheless, clients will tread lightly, estimating that they will only offshore somewhere around 10% of those activities in five-years’ time for biomanufacturing operations, clinical trials/operations, and process development for biomanufacturing.

While there will be growing pool of client prospects for CMOs to market their services, the market will be extremely competitive. Comments from respondents suggest that certain activities will be more likely to go off-shore, including:

Off-shoring administration and data management 

Outsourcing services that do not need to be performed in real-time 

Testing and other routine activities such as stability studies, analytical testing, and cleaning studies. 

For global CMOs opportunities will continue to grow. And as the BioPlan study shows, while certain regional considerations will come into play, clients are as ready as ever to work with partners around the world, if they have the right experience. 

11th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production


Eric Langer is president of BioPlan Associates, tel. 301.921.5979, elanger@bioplanassociates.com, and a periodic contributor to 

Outsourcing

Annual outsourcing study identifies the markets best poised to profit from the internationalization of the outsourcing.

Geographic Proximity Not a Factor in CMO Selection

The physical and chemical properties of an excipient can have an impact on the manufacture and performance of the pharmaceutical products. With regulators placing increasing emphasis on quality by design (QbD) in product development, the industry is now paying closer attention to the role of excipients in the formulation of drugs and the impact of excipient variability on the quality of the final drug product. Representatives of excipient development organizations addressed key aspects of excipient variability with 

Participants of this roundtable discussion include Bernhard Fussnegger, global development and technical marketing, BASF Pharma Ingredients; Dora Meissner, regulatory manager and Rick Mutchler, president, BioSpectra; Carl Mroz, director--global regulatory affairs, Colorcon; True Rogers, R&D pharma technology leader, Dow Pharma and Food Solutions; and Ann Gray, market segment manager oral excipients, Evonik Pharma Polymers & Services.

 What are common sources of excipient variability?

: Excipients come from two main sources: natural or naturally derived excipients, such as corn or potato starch, and synthetic or semi-synthetic excipients, derived through chemical processing of a feedstock source. Variability can be due to the feedstock source, which may be the growing conditions in the case of naturally derived excipients, or chemical processing for synthetic or ‘semi-synthetic’ excipients.
Batch-to-batch variability of the same material results from the combination of variances in the feedstock, process technology, process parameters, operator actions, and even environmental conditions. When different manufacturers produce the same excipient, this can lead to variability through the manufacturing processes, such as batch versus continuous processing and on the scale and/or location of manufacturing.

: Some common sources of excipient variability are inconsistent raw materials used during synthesis, inappropriate environmental conditions during manufacturing, packaging and storage, faulty or absent manufacturing controls, and skills/hygiene of operators handling and manufacturing the excipient. Additional sources of variability can be traced to manufacturing systems not designed for use to manufacture excipients and technology not designed for use to manufacture excipients. Multiple supply sources for raw materials with lack of equivalency can also lead to product variability. Further variability can be traced to lack of controls of in-process and finished goods during manufacturing stages.

 Product variability of excipients is mainly influenced by fluctuations in the specifications of starting materials. Critical are products derived from animal, vegetable, or mineral sources. Even seasonal and different regional provenance can have a remarkable impact. Also, variability of excipient properties is critically influenced by non-validated or manually performed production processes. The knowledge of critical product parameters and their link to the corresponding process parameters is key to help minimize fluctuations in excipient quality. Routinely maintained production equipment with well controlled and calibrated metering instruments will provide excipients with low variability.

: Raw materials and manufacturing processes are sources of excipient variability. Feedstock for naturally derived excipients can vary depending on species of crop, growing conditions, mining location, etc.  Higher natural feedstock variability can mean broader variation in functionalization, for example, the degree of substitution of natural polymers. The product specifications are often met by blending of batches.

In contrast, synthetic excipients are manufactured from synthetic substances and hence show limited risk of variability due to raw materials. Reliable functionality of synthetic polymers is integrated into the molecules by design and ensured through the use of predictable and tightly controlled conditions during manufacturing. 

: One source of variability is the manufacturing process to produce the excipient. Another is the inherent measuring variability of analytical methods used to characterize properties, such as those listed on a certificate of analysis (CofA). Yet another is the variability in the raw materials needed to produce the excipient. For example, one of the key components of cellulose ethers is the cellulose raw material itself. No two trees look identically alike, so it is naturally expected that there is some inherent variability from lot to lot of cellulose raw material.

: How significant is the impact of excipient variability on drug product performance? 

: The excipient is often one of the key enablers of drug product performance. For example, the excipient may enable the dosage form to release the API over an extended time period (i.e., 12- or 24-h release). Chemical properties of the excipient, such as molecular weight and structure, can dictate modified-release performance. Physical properties, such as particle size and shape, can impact the formulation processes during drug product manufacture. Lot-to-lot variations in excipient properties might impact processability and performance of the resulting dosage form. 

: The impact of excipient variability on drug product performance depends strongly on the function of the excipient in the drug product. Variability in a processing aid used in an immediate-release tablet, for example, may not affect drug product performance significantly. However, variability in a controlled-release polymer can, of course, strongly affect drug product performance. Examples of excipient properties that might affect manufacturability include viscosity, particle size, and flow properties; whereas parameters such as moisture content or impurities could possibly influence drug product stability, depending on the use and the API characteristics. 

: Excipient variability significantly impacts the performance of the drug product as 70-80% of the drug product can be composed of excipients. Excipients with unrecognized variability used in pre-final dose manufacturing can lead to mistakenly spending significant resources on investigating pre-cursor variability when the real variability was introduced earlier in the process.
Examples of excipient properties that may affect drug product performance are often tied to specifications that do not fully recognize the true impurity risk from the site of manufacture. Lack of uniformity in product characteristics, such as particle size, bulk density, trace impurities, moisture, and likely contamination from unidentified solvents and undesired chemicals used at the manufacturing site, can adversely affect recognized or expected solubility, manufacturing, stability, and bioavailability.

 FDA has presented recalls due to variability of excipients, resulting in poor dissolution. Examples are: 
  Variation in coating--Zein NF (a natural polymer derived from corn) resulted in variability of immediate-release profile of a coated tablet
Softgel capsules as result of cross-linking short-chain aldehydes--the interaction with API-affected bioavailability.

: As medical products are precisely characterized in regulatory documents with validated production parameters and product characteristics, any variability of the excipient can have a detrimental influence on drug manufacture and drug efficacy. In this respect, particle size distribution, morphology, or the specific surface area of a given excipient--all non-compendial parameters--may influence the final dosage properties. Even a simple parameter such as the pH value of a dissolved or dispersed excipient can affect the release character of a formulated API.


PharmTech: What guidance do the United States Pharmacopeia and European Pharmacopeia provide on excipient performance and functionality-related characteristics (FRC)?

; Excipient Performance suggests appropriate tests and specifications that ensure consistent and reliable performance should be added in a manner and at a level consistent with the risk level derived from a qualified assessment of the excipient. Additional specifications, even to those of existing monographs, should be added to reflect the required performance of the excipient when used in a drug formulation.

, Functionality-Related Characteristics of Excipients, in conjunction with the FRC section of each monograph, provides insight as to how the functionality of the excipients can be controlled and may require additional specifications based on the excipient’s critical role in a drug product formulation.

 General Chapter <1059> on Excipient Performance provides guidance on physical and chemical properties along with general chapters that could be useful in characterizing excipient critical material attributes (CMA). Ph.Eur. has added to selected excipient monograph sections “Functionality-Related Characteristics of Excipients” which are non-mandatory sections linking material attributes with intended function.

: For the time being, pharmacopeial monographs, as one traditional way to control and define the quality of an excipient, provide no binding guidance for an excipient’s functionality or performance. However, there are several concepts in monograph development or modification to address these aspects. Existing examples include family monographs (

., e.g., Macrogols), functionality-related testing 

, e.g., magnesium stearate) and attributes of different articles by type differentiation (

; e.g., ammonio methacrylate copolymer, Type A/Type B-NF). Proposed ideas include flexible- and performance-based monographs (both Ph.Eur. and USP-NF). All of these concepts can contribute to express excipient functionalities from an accepted pharmacopeial perspective.

. provide guidance on excipient definition and excipient safety, but provide little guidance on performance and functionality. These regulatory guidelines give manufacturers a set of boundaries within which to operate, while also providing flexibility to tailor solutions that may be required for a particularly sensitive formulation. Evaluation of excipient characteristics that impact the function of a drug product should be determined experimentally for each formulation and not dictated by pharmacopeial documents.

 USP intends to edit the General Chapter <1079> on excipient functionality. 

 has already started to define FRCs in some excipient monographs. As these are non-mandatory parameters and very much dependent on the dosage form an excipient is formulated in, they need to be considered as guidance only. Information deducted from QbD experiments in the course of medical product development will provide the best feedback on tolerances of product parameters and their variability. Whether or not they are congruent with compendially defined FRCs has to been proven for each and every finished dosage form.

: Not all excipients and not all properties of an excipient affect product quality and safety. How do you identify which ones are critical? What are the challenges in assessing the risk of excipient variability?

: Pharma companies are typically hesitant to share details on the exact use of excipients, especially in the early phase of projects. Exchanging information on the actual excipient application at an early stage is essential for the excipient manufacturer to identify parameters that can potentially influence the functionality of the drug product being developed. Risk assessment on the user and manufacturer side thus demands a mutual exchange of information on critical product properties and their acceptable and maintainable ranges.

: Critical properties are those that impact the chemical and physical properties of excipients and their end-use applications. Knowing the end use application of the excipient and its reactivity with other compounds will aid in identifying the critical quality and safety attributes to help eliminate negative impacts from excipient use. As excipients come closer to the ingredients found in the end product, the greater the need to identify them as critical. Challenges in assessing the risk of excipient variability are greatest when there is incomplete or mistaken communication or translation between the manufacturer and the user.

: A key is to link material attributes and process parameters to the drug product. Assessing the risk of excipient variability involves identifying which attribute or property has an impact on the performance of the finished dosage form and the extent of variation, then studying whether these influence performance or not. The concept of QbD is to understand variability, including excipients, to ensure the formulation is sufficiently robust to be able to withstand potential variability.

Risk assessment is a valuable science-based process used in quality risk management that can aid in identifying which material attributes and process parameters potentially have an effect on product CMAs.

: I have found that it is of paramount importance to tie drug product performance attributes back to both manufacturing process parameters and raw material properties. Doing this systematically enables one to hone in on the most critical process parameters and raw material attributes impacting processability and performance. Oftentimes, it is difficult to find raw materials exhibiting attributes at the edges of the specification ranges. Sound experimental design is essential for success. To address the challenges associated with QbD, excipient suppliers and drug product manufacturers should collaborate closely and earlier during the drug-product development process. 

: Proper risk assessment requires detailed knowledge of the excipient functionality in the finished drug product. The significance of a parameter such as size distribution of controlled-release polymer particles is different depending on whether the polymer is dissolved in an organic solvent to prepare a coating or used as matrix former in direct compression. We use our extensive polymer and formulation know-how as a base for helping our customers understand the effects of excipient variability in standard applications. Furthermore, in cases where our products are used in non-standard, novel ways, we work together with our customers to tackle the challenge of risk assessment.

Featured Content

Industry experts examine reasons why the quality and composition of excipients can vary including environmental factors, processing methods, raw material quality, manufacturing location changes, and operator actions.

Excipient Variability: Causes, Identification, Control

As demand shifts from high-margin branded drugs in Western regions to low-margin generics in emerging markets, successful bio/pharmaceutical companies are adopting new business models that include significantly more outsourcing and require a deeper understanding of costs all along the value chain. Enterprise resource planning (ERP) systems that have been effective for the internal management of sourcing and production are insufficient for managing the extended relationships and multidirectional communications needed in this new environment. Bio/pharmaceutical companies are therefore turning to cloud-based services to achieve greater transparency and facilitate collaboration.


  The biggest trend driving changes in the market today is the shift from a focus on Western markets to growth areas in emerging regions, according to Diane Palmquist, vice president of product management for GT Nexus, a cloud supply-chain platform provider. “High-margin blockbuster drugs are coming off-patent and mature Western markets are experiencing limited growth. Consequently, the focus has shifted to emerging markets, where the growth rate is higher. However, the demand in these regions is greatest for low-cost, low-margin products, and buying habits are very different (buy the dose, not the bottle),” she observes. The result: bio/pharmaceutical companies need to completely transform their old business models.

The biggest impact can be seen in the higher level of outsourcing now taking place. “Pharmaceutical companies are outsourcing nearly every aspect of the business, including some research-related activities, API manufacturing, drug product formulation, packaging, and logistics,” says K.R. Karu, industry solution director for Sparta Systems, a provider of enterprise quality management solutions. Palmquist adds that currently approximately 40% of industry business is outsourced, and that number is expected to increase to 80% over the next several years.


  As outsourcing has increased, companies have lost control over many aspects of the supply chain. “Companies are still trying to manage interactions with suppliers and service providers through personal communications, which is not only inefficient, but ineffective given the number and complexity of relationships and issues that must be managed,” Karu says. The low margins of today also do not support this approach. ERP systems, which in the past have been used to connect purchasing with production operations, are also not capable of managing the complex interactions between service providers and pharmaceutical companies, according to Palmquist. Furthermore, to meet the demand of emerging markets, pharmaceutical companies must be very responsive and need solutions quickly. ERP systems generally take about 18 months to get up and running, and often by that time the opportunity has been lost.

One of the key issues for bio/pharmaceutical companies is the lack of visibility into contract manufacturers. Often pharma companies do not find out about issues that can impact the delivery of API or finished drug product until much later because the suppliers are trying to solve the problem. The common response, according to Palmquist, is to try and stay on top of potential problems by constantly contacting the suppliers via phone or e-mail, which is not a practical, sustainable, or effective approach.

“The challenge lies in the need to manage a whole host of different suppliers at the same time that the customer base is changing dramatically and bringing an entirely new set of customer expectations. The key to this puzzle is to obtain visibility on both the supply side and the value side, from inventory to quality excursions to government fees,” Palmquist asserts. 


Cloud-based services give bio/pharmaceutical companies the ability to extend their visibility into all parts of the value chain, while at the same time enabling vendors to access the information they need in order to provide optimum services. Raw materials suppliers, contract research organizations, contract manufacturers, brokers, and distributors can all interact simultaneously under very controlled conditions that ensure that important information gets to the only the right people when it needs to, according to Palmquist.


  There are several other practical advantages of using cloud-based systems, according to Karu. Because cloud-based software systems are developed by software experts, they are consistent for all users. Maintenance and upgrades are provided on a continual basis, as well as any necessary validation procedures to meet special compliance requirements for the pharmaceutical industry. There is also no need for investments in extensive information technology infrastructure; the servers are maintained by large companies (think Google and IBM). In addition, redundant systems located around the world ensure non-stop operation. 

Perhaps most importantly, though, is the controlled nature of the interactions through cloud-based systems. “Generally the information that is being shared using cloud-based systems is already being shared via phone calls and e-mails. There are, however, much stronger controls in place in cloud-based systems that ensure that information only goes to the people who should see it. There are no such controls around the use of e-mails with file attachments,” Karu explains


  Overall, according to Palmquist, cloud-based systems offer bio/pharmaceutical companies assistance with achieving assurance of supply. All business activities can be integrated in the cloud and important issues, exceptions, and problems flagged automatically, so that efforts are appropriately focused on resolving potential issues. Not only purchasing systems, but logistics and quality management systems can be linked through the cloud so that the bio/pharmaceutical company is always up to date on what is happening and can readily share information that impacts multiple vendors.

“Moving an established quality system to the cloud and sharing it with raw material suppliers and contract manufacturers makes it possible for these vendors to exchange information immediately. In addition, these vendors can be directly included in specific activities, such as investigations of excursions and remedial actions, leading to much more rapid resolution of problems,” Karu comments. Similarly, cloud computing can benefit other aspects of supply chain management and aid in the rapid response to any type of possible interruption in the supply, from natural disasters to manufacturing malfunctions to distribution issues.


  “The key to success for bio/pharmaceutical companies with such complex supply networks is collaboration across the value chain. Cloud computing is an effective way to enable such relationships,” Karu says. “There is definitely a growing realization in the pharmaceutical industry that suppliers must be thought of as extensions of the company. To be truly successful, we believe that the relationships between bio/pharmaceutical companies and their suppliers should be viewed more like joint ventures, with real transparency of information,” adds Palmquist.

The idea of allowing vendors to see into their business operations is the most challenging aspect of cloud computing for biopharmaceutical companies. “Most companies are at least initially very resistant to letting suppliers see their company information. It is not possible, however, for vendors to effectively participate in quality investigations, audits, and remediation efforts without two-way communication. He adds that the pharmaceutical industry tends to be very conservative about adopting new technology, in part due to concerns about acceptance by regulatory agencies, and cloud computing is no exception. “Both pharmaceutical companies and their suppliers are interested in cloud-based solutions, but neither is convinced that the other is willing to implement them. The greatest challenge at this point, therefore, is to convince the various members of the pharmaceutical industry supply chain to take the first step.


  Companies that have already moved forward with the use of cloud-based services are those that have been pushed fastest towards emerging markets and have realized that ERP systems are insufficient and leave them “flying blind,” according to Palmquist. Pfizer is one example. “Pfizer needed to figure out a way to not only maintain but grow its revenue stream despite having 9 of its blockbuster drugs lose patent protection¾a Herculean task,” she says. Not only did the company need to better manage the supply side, it also needed help tracking costs (taxes, fees, etc.) on the value side in detail, something that was not a concern in the past with high-margin products.

“We expect that more companies will be in this same position and looking for solutions that enable simultaneous, multidirectional communications with numerous members of the value chain. As that occurs, there will also be greater realization that any dollars spent in the supply chain ultimately comes from the pharmaceutical company,” says Palmquist. In the past, it was easy for manufacturers to separate supplier costs from their costs because margins were high. That will no longer be the case as the industry becomes a low-margin business. “As we see in the consumer electronics industry, where every penny is tracked throughout the supply chain, it will be necessary for bio/pharmaceutical companies to look at supplier costs as their costs in order to maximize profits. Connect with suppliers through cloud-based systems will help not only control costs, but also quality and all other aspects of their operations,” she concludes.

For those reasons, Karu anticipates an explosion in demand for cloud-based services in the pharmaceutical industry. “The many-to-many relationships that are possible with cloud-based systems provide a much more efficient mechanism for processing information and managing interactions, which will be critical to the success of pharmaceutical companies in the increasingly challenging business environment they are facing,” he says.

Multidirectional collaboration is critical for the new pharma business model; cloud-based information services can offer a communications alternative.

Pharma Outsourcing Driving Need for Cloud-Based Services

It is now more than a year since FDA brought out its 

 notice asking input from the industry on quality metrics. The goal is to stratify along increasing levels of quality all the manufacturing sites regulated by FDA. 

exemplifies the current view on the matter. This paper argues that while the direction is right, the approach is too complex and unnecessarily detailed. Moreover, two major ingredients are missing from the debate. First, quality culture is barely addressed. FDA, CEOs, and regulators in general have not devoted much attention to this primary driver of product quality. What is uppermost in their mind is the verification of compliance (i.e., the effect of quality), and the current debate seems limited to measuring quality system performance. Second, the willingness to learn from others is absent. There is no evidence that anyone wants to go beyond their comfort zone.

Over the years, FDA has been shown repeatedly to be a thought leader. For example, FDA demanded GMPs for APIs 40 years before such a requirement became law in Europe. FDA has also been behind process analytical technologies (PAT) and quality by design (QbD). Major medicine breakthroughs, such as Vertex’s Kalydeco (ivacaftor) for the treatment of cystic fibrosis patients, would not have been possible without FDA’s innovation of the breakthrough therapy designation. The stratification that FDA is seeking to implement must happen, but it needs a leap of faith and major innovative thinking in a direction that is different from current proposals.

FDA’s thermometer is one that only measures negative temperatures. FDA, as well as other regulators, tends to focus on the “floor” with medicine agencies explicitly defining a threshold level below which quality performance is deemed unacceptable. But what does FDA issue when it wants to say “Well done!”? Presently there is no FDA form for “Well Done.” Yet FDA is keen that we move in the direction of its 21st-century vision with concepts such as process understanding, risk management, and supply reliability. FDA has nothing in its arsenal to encourage the proactive pursuit of greater manufacturing quality.

At the same time, sanctions for non-compliance, especially when non-compliance is a business strategy, are insufficient to be an effective deterrent. Because the type of sanctions hurt primarily shareholders and not management, rogue behavior is encouraged by positive payback. Because non-compliance pays, rogue players often win. For example, has anyone been caught (let alone jailed) for causing hundreds of deaths in the heparin tragedy?

Safety and quality have much in common, with both being crucial aspects of industrial activity. Both depend directly on constant management attention and require the right tone at the top. Yet in terms of metrics, safety is easy (while quality is complex). The number of deaths, lost time due to accidents, the gravity and frequency indices are well-established metrics and are sufficiently comparable across all sectors. What we are trying to measure is simple. Research has also taught us to expect correlations between near-misses and accidents.


The Occupational Safety and Health Administration (OSHA) is the USA’s authority that enforces safety and health in the workplace. It performs regular compliance surveillance through surprise inspections. OSHA’s voluntary protection program (VPP) rewards workplaces that have consistently no lost time accidents by removing them from the inspection roster. VPP Star program recognition drives appropriate behaviors--a reduction in insurance premiums is a financial benefit, but paramount is the pride workers have in a safe workplace, and no effort is wasted in maintaining that status.

Just like FDA, OSHA has defined where the “floor” lies. Below such minimum acceptable safety level, sites get closed down and fines are levied. But OSHA’s thermometer also measures positive temperatures--the VPP Star program identifies the role models. OSHA thus has a three-level stratification of the safety performance of all the sites it regulates. The VPP Star program is an effective reward mechanism and a confirmation of a sound and vibrant safety culture.

The metrics used to assess the safety of workplaces exhibit the attributes that FDA is looking for, which include “not amenable to gaming, objective, cross all sectors, are non-intrusive and relevant” (1). It is simple, has virtually no cost, and enables the deployment of inspections of resources where they are really needed. The quality metrics currently under discussion involve setting up systems that are complex, require annual data input, need supervision and funding, and will necessarily introduce behaviors focused on improving “the site’s position in the league table” rather than just doing the right thing for the patient.

In accidents, harm to the worker is a simple common denominator. No comparable measure exists in quality. All the metrics that have been proposed may be objective and may ultimately correlate with recalls and adverse events, and elegant mathematics may make them comparable across sites and across all sectors of the pharmaceutical industry. Such metrics, however, are unable to measure whether the CEO is really committed to developing and nurturing a quality culture in his or her organization.

Sections 705 and 706 of the FDA Safety and Innovation Act (FDASIA) mandate that metrics be made available so that FDA can deploy its inspection resources appropriately. It does not say it needs to be complicated or costly, or that FDA cannot get inspiration from an OSHA-type VPP Star program. FDA could publish a simple list of manufacturing sites that are role models. When this list is published, FDA will have done enough to define the right behaviors and will have done so at a low cost.

The metrics being discussed tend to focus on the deciles from the bottom all the way to the top, which is both unnecessary detailed and costly. The only stratification the industry has today is a well mapped-out lower level, below which quality is unacceptable. What is needed now is a definition of an upper level, beyond which the quality performance is in the right direction and deserves recognition and applause (see


For FDA to establish a stratification of its sites in at least three classes, such as OSHA, it will need to define the border between “being in compliance” and “being ahead.” And those sites that make it beyond that threshold join what has been described as Commissioner Hamburg’s Dean’s List (2).

 It is unlikely that the shape of the distribution today approximates the normal distribution because there is nothing defining the right side of the bell shape. Once a driver of behaviors, such as a Dean’s List, exists, one could expect a normal distribution.

This paper argues that metrics pulled from a quality system alone will not help define where Commissioner Hamburg’s Dean’s List starts. The industry and regulators need to start acknowledging that what genuinely assures compliance and then takes an organization to levels of quality beyond the minimum is the organization’s quality culture. An organization’s quality culture is embedded in the values of the people that make any site function. A quality system will only assure quality if it is backed-up by a well-nurtured quality culture that permeates the entire manufacturing organization. Without a culture of quality, a quality system assures nothing. An article from

 magazine, “Dirty Medicine,” provides a good description of an organization where incidents of fabrication of compliance evidence were endemic (3). In other words, in an organization that has no culture of quality, it is not a system of controls and documents that will safeguard quality.

The large number of warning letters and import alerts issued to sites based in India in the past two years may not be statistically significant given the considerably large number of FDA sites in that country. What is both significant and of concern is that they are all related to data-integrity issues. The chief executive of an Indian drug maker was recently quoted as saying, “When a company is small, it can be managed by strong supervision. As companies get bigger, supervision can break down … You need systems and a culture to maintain proper supervision—and we are in that process of growing up, I think” (4). Indian generic companies’ grew at a rate so fast that the nurturing of such quality culture needed to be miraculous.

The agency should consider whether an organization that has a culture of fraud instead of a culture of quality can ever be reformed, or whether it should be given a second chance (5). The agency should also consider whether drug shortages are not inevitable when unscrupulous companies compete unfairly in the market through systematic non-compliance and destroy the competitiveness of compliant firms. A regulator’s job is not limited to the oversight of the quality of drugs. Regulators must take decisive action when non-compliance becomes an obvious competitive advantage that hurts the fabric of the industry. “A firm can have all the SOPs, systems, and controls required but, without a quality culture, product quality and business continuity are not assured” (6).


A quality culture is not the result of procedures, specifications, audits, a quality unit, or enforcement by regulators. Although some of these elements do help establish a quality organization, by themselves, they are insufficient.

It is surprising that of the 128 comments to FDA’s docket, only Pfizer’s refers explicitly to quality culture as preeminent: “The indicators mentioned above are only useful when coupled with a strong quality culture, which we believe is the foundation of consistent quality performance” (7).

The conditions where a quality culture  will develop are likely to include:

The right tone at the top, a focus on the right values

A constant display of concern for quality, for putting the patient ahead of everything else

An organization that consistently “walks the talk” 

An organization with great people skills and strong values 

Shareholders who expect more than just financial rewards.

 The indicators of a strong quality culture include: 

Quality-driven productivity brought about by sustained change through the introduction of improvements and innovation

Adoption of and investment in technology including IT to ensure a better state of control over systems and timeliness of event follow-up 

Prompt adoption of best practices, promotion of change, and continuous improvement in the quality system itself

Pro-active and transparent behavior with regulators leading to a rich relationship with regulators based on dialogue, sound science, and mutual respect 

Intense participation in the standard setting-process

Good performance in other areas such as safety, business conduct, and sustainability

  The degree of maturity of the quality culture will correlate with where the site is in terms of the following journeys: 

An evolving mind-set that accumulates as second nature habits such as deviation recording, change-control, trend analysis, risk management, process understanding that defines the space of process capability, and so on

Evolving from a rigid machine organization with inflexible quality systems towards a rationale-based approach that adjusts controls appropriately to each situation.

These aspects mirror the maturity of the quality culture in an organization. As the quality culture and system of an organization evolve and mature, the cost of quality diminishes and its capability becomes greater and more efficient. This approach can help map the progress of a quality culture and could be used to define the criteria and boundaries at the right of the bell shaped curve.

 An organization with a sound quality culture is easilyrecognized as it believes in the following two principles:

Product and process understanding (e.g., sufficient depth of science that provides an explanation of why a process deviation has or does not have impact on the quality of the product).

Sensible business management—Too fast growth and operating at the limit of capacity are often triggers of quality issues or of non-compliance. It is obvious that in many Indian generic-drug companies the product portfolio growth outstripped the company’s quality system. Senior management failed in its oversight. 


The following additional attributes of a manufacturing site could be used by FDA to set the bar for that site to be listed in Commissioner Hamburg’s Dean’s List:

A solid track record of consistent good performance at FDA inspections (frequency of successful inspection in the recent past)

Frequency of filings in the recent past that include a growing pattern of QbD approaches and the application of PAT controls

Providing FDA with IT access to perform at any time and in real-time remote inspection of all quality data related to commercial batch manufacturing and release (including seeing deviations, change control and analytical data, and trending thereof, and the measure of timeliness to close events)

Visible active participation in the standard-setting process 

Allowing FDA inspector training at the site.

Most importantly, FDA should add a further element to its compliance inspections. Inspectors should determine the existence and maturity of the quality culture in the inspected site. Simple cross-examination of operators and candid conversations with management at various levels will quickly tell what tone is set at the top, what costs of non-quality are accepted, and how much power the quality assurance department has over budgets, over purchasing, or finance departments decisions. An assessment of quality culture should be central to any quality metric assessment—this has to be done by FDA on-site during an inspection.

In lieu of the complex metrics that are being discussed, the industry and FDA could agree on what is the roadmap to reach the Dean’s List standard, what are the desired minimum attributes that would allow a site to apply to be invited into the program. It would be up to the site to check whether it meets the criteria, and application would be voluntary. To be accepted as an applicant would require a successful inspection that would assess the maturity of the quality system and the vibrancy of the quality culture. This accepted applicant status itself will be a great motivator to improve quality performance and inspection readiness, while also having a marketing value. It does not require much additional financial cost to the agency and allows any plant to set its sights on an ambitious goal.

Finally, for those that make it to the Dean’s List, FDA needs to go public and be able to say, “Well done!” and publish the names of those sites that made it onto the list. FDA has to decide how it will do this and also how it removes sites from the list (the same way as the Michelin or Zagat guides give and remove stars to restaurants and neither justifies it).

Being on this public list of role models does not need to trigger any special treatment as in the case of OSHA’s VPP Star program. Being listed will be in itself a worthwhile reward. Being listed will be a relevant element in FDA’s risk assessment and many new drug applications or abbreviated new drug applications are likely to be approved without pre-approval inspections if their product is produced in a listed site. FDA needs its best manufacturers to be profitable and to grow. A transparent and public three level stratification of quality performance will enable a better site to charge a price that rewards enhanced quality.

It is disappointing to hear that many in the pharmaceutical industry believe that a site’s quality metrics and ranking should remain confidential. When Deborah Autor of Mylan argued for a site’s ranking to be made public at a recent public meeting, other representatives of large multinational companies said that they were completely opposed. This is wrong. Transparency has become a motto of the 21st century. Our industry needs to change. Of course none of what is being proposed is in FDA’s comfort zone but as the breakthrough therapy designation and other examples illustrate, FDA’s greatest accomplishments happen when it innovates


1.	GPhA/FDA CMC Workshop Meeting (Bethesda, Maryland, June 2013).
  2.	Guy Villax, 

,” Fortune, accessed Aug. 19, 2014.
  4.	Reuters, “FDA bans imports from Sun Pharma plant in India crackdown,” Press Release, March 13, 2014. 
  5. 	IPQ, “

FDA Data Integrity Concerns Continue in India as Three More Firms Draw GMP Warning Letters

,” accessed Aug. 19, 2014.
  6. 	Mary Oates, Pfizer, “Risk-based approach to quality oversight in contract manufacturing - outsourced activities,” presentation at the APIC Annual Conference (Budapest, November 2011)
7.	Pfizer’s March 13, 2014 Response to Docket FDA-2013-N-2014. PT


Guy Villax is CEO of Hovione FarmaCiencia SA, Sete Casas, 2674-506 Loures, Portugal,

Regulation & Compliance

Quality is a matter of culture more than metrics. In this opinion article, the author presents arguments for an FDA Dean's List as a means to nurture a quality culture within the industry.

Guest Viewpoint: A Case for an FDA Dean's List

With a quality-by-design approach, robust processes consistently deliver quality product. Small drug manufacturers looking to adopt a quality-by-design (QbD) approach aim to scientifically determine product and process characteristics that will meet specific criteria set after careful analysis of the intended drug application. These critical quality attributes (CQAs) of the final drug product (and often of the API) include the physico chemical properties and performance behavior of the formulated drug (drug substance). The manufacture of small-molecule APIs often requires the production of multiple intermediates using different processes. To consistently achieve these CQAs, it is necessary to ensure that each of these processes is robust. Critical process parameters (CPPs) are, therefore, important components of an effective control strategy for ensuring that the API process consistently delivers product with the appropriate CQAs.


While true CQAs are found in the final specification for a drug product, there are several different aspects of a formulated drug, and particularly the API, that are affected by process parameters. These aspects, therefore, must be linked to the CPPs for each manufacturing process required for the preparation of an API, according to Chris Senanayake, vice-president of chemical development for Boehringer Ingelheim Pharmaceuticals. These characteristics include, but are not limited to, total purity, individual impurity levels, the polymorph(s), solvates, pH, water content, and particle size.

For the API, the most common CQAs are related to impurities from chemical processes and the solid-state properties (e.g., particle size, polymorphism) of the drug substance, according to Gert Thurau, group leader, Technical Regulatory at Roche. It is essential to control impurities for the safety of the drug product, while control of the solid-state properties of the drug substance is necessary to achieve consistent product properties, including bioavailability. “Once these attributes have been defined, it is possible to define what is important to the process and build a process that comes closer to quality by design and is, therefore, highly robust,” he says. The assay and impurity profile of an API are essentially inter-related and are important because low impurity levels translates to safety for patients, while a high assay indicates appropriate efficacy, according to Vishwanath Nadig, associate director of quality assurance for Dr. Reddy’s Custom Pharmaceutical Services (CPS). Nadig adds that moisture content is also important because, in some cases, the presence of moisture may accelerate degradation of the drug substance.

These CQAs should be selected such that if the final product has these attributes, then it will work for its intended purpose. CPPs should then be selected because they have a relationship to the final CQAs and, when controlled, will assure the manufacture or a product with the right CQAs, according to Senanayake. “CPPs are the process parameters that affect the critical quality attributes of the API, and it is important to determine the range for each critical process parameter expected to be used during routine manufacturing and process control,” adds Mark TePaske, director of regulatory affairs, quality, and compliance for Cambrex. Most importantly, it is essential to establish appropriate CPPs for each individual process step because they will ultimately affect the quality of the drug, which in turn can impact efficacy, according to Nadig. “Establishing and meeting CPPs and CQAs allows quality to be built into the process and affords robustness beyond release testing,” adds TePaske.  He also notes that well-defined CPPs ensure that a process operates in a state of control and in a validated state, which is crucial, because process validation is a cGMP requirement.

The definition of the CQAs for the final drug product and API is the first step in a comprehensive risk-based approach to product and process development, according to Thurau. “The starting point of the analysis is typically the quality target product profile, which leads to defining the critical quality attributes for the final product, and in turn, the critical quality attributes for the drug substance. Since the most important CQAs of the final API are the process-related impurities, which mostly result from the starting and raw materials, it is essential to understand the chemistry of the individual process steps,” he explains. In addition to risk assessment, Senanayake adds that prior knowledge, designed experiments, and regulatory expectations all play a role in determining CQAs and CPPs.


Once CQAs are defined, typically during the initial scale-up phase, it is necessary to identify the appropriate CPPs. “At Boehringer Ingelheim, we believe that using a design of experiment (DOE) approach is the best method for demonstrating the interdependency of CPPs and the CQAs for individual process steps,” Senanayake says. Along with general risk assessments, the use of design failure mode and effects analyses (FMEA) is also effective for defining critical parameters of drug products, drug substances, and production processes, according to Nadig. “When applied appropriately, these two approaches are sufficient for defining the important attributes,” he says.

While orthogonal experiments can also be used, Senanayake notes that with DOE, knowledge is gained about the design space for each process that cannot be obtained using screening experiments, although they are useful when determining certain aspects of processes, such as the most effective solvents or catalysts. TePaske adds that once defined, critical attributes should be affirmed experimentally and control limits established, with processes, procedures, equipment and/or facilities revised as needed.

It should be noted that the risk-assessment methods used today are much more rigorous than the processes used in the past. “Historically, process and CQA definition was driven by the process development chemist, and the depth and breadth of the investigations were chemist-dependent,” observes TePaske. As a result, process development was primarily viewed as a laboratory exercise.  He goes on to note that current approaches are more disciplined, and studies are defined by multidisciplinary project teams. “These teams review and reconcile findings and risk assessments, and the concerns of the production, materials, quality, engineering, and other departments involved in manufacturing are integrated into the development process.  In effect, CQA definition and process development have evolved from a laboratory exercise to a global preparation for process validation and commercial GMP manufacturing.” He concludes that this team-oriented approach is the best practice because it integrates the needs of all of the disciplines involved in commercial manufacturing and virtually eliminates the possibility that CQAs and CPPs that cannot be performed in the available facilities and equipment will be defined.


  Based on the results of the quality risk assessment, various reaction and work-up conditions can be investigated, and the products from each process step can be carefully analyzed with regard to their impurity profiles and other properties, according to Thurau. “For example, the structures of the impurities can be determined, and consequently the process conditions can be adjusted to minimize the impurities and/or their fate in downstream steps can be determined. The result is the elimination of the impurities or the determination of safe limits for them,” he explains. He stresses that it is important in this part of the process to be systematic, and to consistently maintain a link between the CPPs being evaluated and the drug product and drug substance CQAs.


  While there are many benefits to a QbD approach and the establishment of CPPs that are linked to final product and drug substance CQAs, there are challenges to implementing such an approach. For Senanayake, the time and resources required remain the biggest barrier to obtaining a useful understanding of a process. “These barriers must be overcome, though, because having thorough knowledge of a process once it has reached commercial manufacturing is critical for success, and therefore, it is necessary to take the time to fully understand the design space,” he asserts.  Thurau agrees that the major limitations are practical in nature and can typically be overcome. He does, however, note that there are some open questions on the definitions and differences in the applicability of the concept by various health authorities. “As registrations for products developed and manufactured using the QbD approach become more detailed and explicit about criticality, the hope is that the increased knowledge will lead to more flexible approaches to change management (do and tell) as opposed to the current set approach (tell and do).

Both Nadig and TePaske point to the need for participation of knowledgeable team members from across different functions of the organization as a challenging aspect of QbD and the establishment of effective CQAs and CPPs. “The multidisciplinary approach requires up-front involvement of disciplines whose primary job responsibility has historically been manufacturing and requires a new way of thinking,” says TePaske. He also adds that the risk-assessment approach often focuses on what can be done, which can stifle innovation.


Despites these barriers and limitations, many companies have recognized the value of a QbD approach and the importance of linking critical process parameters for individual process steps with the critical quality attributes of small-molecule APIs and the corresponding formulated drug products. Boehringer Ingelheim, for example, is monitoring process robustness at each development stage and focusing on understanding how this robustness translates to the commercial scale using batch histories, according to Senanayake. In addition, the company is trying to complete DOEs on the important steps in its manufacturing processes. “Our success to date is demonstrated by our validation efforts and the control charts we have established for individual steps,” he says.

At Dr. Reddy’s CPS, when defining CPPs for each process step, a cross-functional team meets to discuss the key sensitivities of the process parameters and material attributes, which are first weighted in importance, and then tolerances on the variables are established, according to Nadig. DOE screening is then performed to identify the critical parameters, followed by optimization and definition of the design space to understand what will happen to the CQAs under different parameter settings. “Importantly, we are trying to engage senior members from cross-functional teams during these pre-planning meetings so that an exhaustive risk assessment is conceptualized and a mitigation plan worked out,” he comments. The company also emphasizes the importance of clear communications, participation with the customer, and giving weight to all stakeholder concerns throughout the process.


The consequences of not establishing CPPs that are effectively linked to CQAs can be severe. “If the proper controls for an intermediate step in the manufacturing process are not in place, then it is possible for a material to be produced that does not meet specifications for unknown reasons. Such a situation can in turn result in a recall if the intermediate is carried through the entire commercial process. In addition, without proper controls, processes often deliver poor quality product or product of inconsistent quality,” asserts Senanayake. In addition, according to Thurau, if inappropriate process parameters or in-process material attributes are established, the quality of the final product may appear high, but it is the result of testing quality into it, and not of process design and process understanding. Finally, TePaske stresses that operation in a state of control is fundamental to process validation and continued process performance in a validated state. 

With a quality-by-design approach, robust processes can help deliver quality product consistently.

QbD Facilitates Robust API Development

Although significant attention has recently been directed towards biocatalysis as the way forward for commercial-scale asymmetric synthesis, chiral transformations mediated by traditional metal-based and organic catalysts remain important for the manufacture of pharmaceutical intermediates and APIs. In addition, much effort continues to be invested in the development of novel enantioselective methods for the synthesis of building blocks necessary for the manufacture of biologically active molecules. A brief survey of recent literature underscores the breadth of chiral chemocatalysis and interesting new techniques for the selective preparation of asymmetric compounds. Selected examples are highlighted in the following.


Many natural and non-natural amino acids and derivatives contain both nitrogen and sulfur substituents, thus the synthetic methods for the enantiomeric synthesis of building blocks containing these two elements are of significant interest. Scott Denmark and Hyung Min Chi reported an enantioselective route to chiral pyrrolidines, piperidines, and azepanes bearing thiol substituents (1). In their method, terminal and trans disubstituted alkenes with a pendant tosyl-protected amine group are converted to the desired products through the formation of a thiiranium intermediate via Lewis base-catalyzed intramolecular sulfenoamination using a chiral BINAM (1,1’-binaphthyl-2,2’-diamine)-based selenophosphoramide catalyst.

Tsuyoshi Mita and Yoshhihiro Sato at Hokkaido University in Japan reported the asymmetric synthesis of α-amino acids via the stereopsecific carboxylation of optically active α-amino silanes, which were obtained through the enantioselective silylation of N-tert-butylsulfonylimines using a Cu-secondary diamine complex (2). The carboxylation proceeded under 1 atmosphere of CO

. Spirocyclic oxindolo-β-lactams were prepared in high yields with excellent diastereo- and enantioselectivities by Song Ye at the Chinese Academy of Sciences (3). In this case, ketenes were subjected to an N-heterocyclic carbene (NHC)-catalyzed Staudinger reaction with isatin-derived ketimines using NHCs with free hydroxyl groups as the catalyst.


  Chiral fluorinated compounds are also of interest, because incorporation of the highly electronegative fluorine atom can have an impact on the physico-chemical properties of APIs. Gregory Fu and colleagues at the California Institute of Technology tackled the challenge of preparing chiral tertiary alkyl fluorides, and particularly α-fluorocarbonyl compounds (4). They reported a method for the asymmetric synthesis of tertiary α-fluoroesters via the catalytic asymmetric coupling of aryl alkyl ketenes with commercially available N-fluorodibenzenesulfonimide and C

ONa as a nucleophile using a chiral ferrocenyl PPY (4-pyrrolidinopyridine) catalyst. The alkoxide was crucial for freeing the catalyst from an acylated intermediate. Meanwhile, Qing-Yun Chen and Yong Guo at the Chinese Academy of Sciences reported the asymmetric synthesis of tertiary α-fluoro ketones via the Tsuji-Trost reaction of racemic acyclic α-fluorinated ketones using a palladium/phosphinooxazoline catalyst (5). The desired products were obtained in up to 90% yield with up to 90% enantiomeric excess (ee). 
  
  The preparation of chiral compounds with trifluoralkyl groups is also important for drug development. Liang Hong and Rui Wang at Lanzhou University in China developed a practical method for the enantioselective introduction of a monofluoroalkyl group into the oxindole framework (6). The reaction of a wide range of 3-bromooxindoles and α-fluorinated β-keto gem-diols afforded the desired products with diastereoselectivities of >20:1 and enantioselectivities of 93-99%. Xufeng Lin and colleagues at Zhejiang University reported the first highly enantioselective iso-Pictet-Spengler reaction of C-2-linked 

-aminobenzylindoles with trifluoromethyl ketones (7). The reaction is mediated by chiral spirocyclic phosphoric acids as organocatalysts, and the benzazepinoindoles bearing trifluoromethylated quaternary stereocenters were obtained in up to 98% yield and up to >99.5% ee.


  Asymmetric hydrogenation is one of the most widely used enantioselective chemocatalytic reactions used at commercial scale. Even so, advances in this technology, including its application to a widening range of substrates, continue. A recent example was reported by Xumu Zhang at Wuhan University in China (8). His group developed a Rh-DuanPhos ((1

-(1,1′)biisophosphindolyl) complex for the synthesis of chiral cyclic allylic amines with up to 99% ee from cyclic dienamides. The products are ideal building blocks for the preparation of chiral, cyclohexane derivatives with multiple substituents. Meanwhile, Virginie Ratovelomanana-Vidal at PSL Research University and Zhaoguo Zhang at Shanghai Jiao Tong University reported the enantioselective synthesis of γ-hydroxy amides with up to 99% ee via the asymmetric hydrogenation of γ-ketoamides in the presence of a Ru-Xyl-SunPhos-Daipen catalyst (9).


  Functionalization of chiral intermediates can also be achieved via asymmetric C-H insertion reactions. In 2013, the H.M.L. Davies group at Emory University reported the enantioselective synthesis of highly functionalized 2,3-dihydrobenzofurans from derivatives of veratrol and anisole via two sequential enantioselective C-H insertions involving an intermolecular carbene insertion catalyzed by rhodium followed by an intramolecular C-H alkoxylation reaction catalyzed by palladium (10). The products could also be further functionalized via a palladium-catalyzed intermolecular Heck-type sp2 C-H functionalization reaction.


Carbon-carbon (C-C) coupling reactions have become key tools in the synthesis of pharmaceutical  and other fine chemical intermediates, and chiral C-C coupling reactions are highly valued. Several new methods have been reported recently, including the diastereo- and enantioselective coupling of alcohols and vinyl epoxides to form asymmetric quaternary carbon centers, which was developed by Michael J. Krische at the University of Texas at Austin (11). In this iridium-catalyzed reaction, primary alcohol oxidation leads to reductive C-O bond cleavage in isoprene oxide to generate aldehyde-allyliridium pairs that combine to form products of tert-(hydroxy)-prenylation, many of which are observed in terpenoid-type natural products. Notably, the reaction proceeds without the use of premetalated reagents or unwanted stoichiometric byproducts.

Meanwhile, Brian M. Stoltz at the California Institute of Technology prepared (trimethylsilyl)ethyl ester protected enolates via fluoride-induced “thermodynamic” enolate formation and used them in palladium-catalyzed asymmetric allylic alkylation reactions to obtain α-quaternary six- and seven-membered ketones and lactams (12). The reaction expands the scope of allyl substrates beyond traditional β-ketoesters and has a high tolerance for reactive functionality.

Two rhodium-catalyzed enantioselective C-C coupling reactions were also recently reported. Vy M. Dong at the University of California, Irvine reported the enantioselective cross-coupling of aldehydes and α-ketoamides via intermolecular hydroacylation to provide α-acyloxyamides using a new Josiphos ligand (13). Separately, Chen-Guo Feng and Guo-Qiang Lin developed the enantioselective rhodium-catalyzed 1,2-addition of arylboronates to cyclic N-sulfamidate alkylketimines, which provides chiral sulfamidates that can be readily reduced to chiral β-alkyl-β-aryl amino alcohols (14).

Finally, Amir Hovedya at Boston College reported the copper/NHC-catalyzed enantioselective allylic substitution of di- and trisubstituted alkenes with readily accessible (pinacolato)alkenylboron compounds to generate 1,4-dienes bearing an asymmetric tertiary carbon (15). The reaction tolerates a wide range of olefins and provides the desired products in up to >98% yield with >98:2 selectivity for the SN2′ vs. SN2 addition and a 99:1 enantiomeric ratio (er). The group also demonstrated the applicability of the reaction in the synthesis of several natural products.


  Multicomponent reactions are attractive because they often enable the synthesis of complex intermediates in an atom-economical manner from basic starting materials. These reactions are even of more interest when they proceed with high stereo- and regioselectivity. At the Universidad de Oviedo in Spain, Francisco J. Fañanás and Félix Rodríguez developed a one-pot, gold phosphate-catalyzed, three-component coupling reaction of alkynols, anilines, and glyoxylic acid that generates sprioacetals with incorporated α-amino acid functionality (16).


  Cascade reactions, like multicomponet reactions, are attractive because they provide direct access to complex structures in one pot with few or no undesirable byproducts. Adrien Quintard and Jean Rodriquez of Aix Marseille Université developed a cascade reaction involving the enantioselective reaction of allylic alcohols with diketones catalyzed by an iron catalyst with iminium activation followed by chemoselective acyl transfer (17). The γ-chiral alcohol products (3-alkylpentanols) are obtained in up to 96% yield with a 96:4 er and are useful for natural products synthesis.

 136 (25), 8915-8918 (2014).
  2.	T. Mita et al.,

 16 (11) 3028-3031 (2014).
  3.	H.-M. Zhang et al., 

 16 (11) 3079-3081 (2014).
  4.	M. Zhaou et al., 

 16 (13) 3484-3487 (2014).
  5.	W. Wang et al., J.

 79 (13) 6347-6353 (2014).
  6.	C. Wu et al., 

. 16 (7) 1960-1963 (2014).
  7.	X. Li et al., 

 50, 7538-7541 (2014).
  8.	M. Zhao et al., J. 

A literature survey underscores the breadth of chiral chemocatalysis and interesting new techniques for the selective preparation of asymmetric compounds.