Rita Peters is the former editorial director of 

Pharmaceutical Technology, Pharmaceutical Technology Europe

Rita C. Peters

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

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

API Developers Note Upgrades, Successful Inspections

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.

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

For a bio/pharma industry in flux, contract services are playing a greater—and more diverse—role in drug development. Representatives of contract research (CRO), contract development and manufacturing (CDMO), and contract manufacturing organizations (CMOs) discuss business, technical, and regulatory changes influencing outsourcing practices for drug development.

An influx of investment in the biotech sector, drug company mergers and consolidation, development partnerships, globalization, and new drug development strategies are shaping the way drugs are brought to market. The role that contract service organizations play in the process is evolving.

 Outsourcing Survey indicate a generally positive outlook for outsourcing firms, as drug sponsors reported steady or increased spending for contracted services (1). To provide a closer look at key issues, representatives of contract research (CRO), contract development and manufacturing (CDMO), and contract manufacturing organizations (CMOs) shared their perspectives on business, technical, and regulatory changes influencing practices in drug development with 


When bio/pharma companies consolidate due to mergers and acquisitions, the supplier base often changes. In the PharmSource-

 survey, however, less than 7% of the respondents from contract service organizations identified acquisition of products and companies by Big Pharma as the single greatest risk to their business in the next two to three years. Rather, many who responded to the editors’ questions saw opportunity.

 “A lot of consolidation is happening in the industry in the form of mergers and acquisitions. This will have beneficial effects on drug-development processes that are limited by funding and resources as mergers often provide an opportunity to increase spending for selected programs,” said Praveen Raheja, associate director, formulations, Dr. Reddy’s CPS. 

“Large Biotech and Big Pharma have made a shift in strategy to outsource. This is a significant change to the mind-set from just a few years ago,” said Andrew Strong, president and CEO, VP business development, Kalon Biotherapeutics. “As a result, the work process and communication flow between biopharma and CMOs has improved. It’s more collaborative and more conducive to long-term relationships and successful outcomes. The not-invented-here mentality has softened, the interaction [is] more collaborative than protective and allows for a more successful outcome.”

“The reductions of in-house capabilities of certain major pharmaceutical companies have resulted in an increase in business with outsourcing vendors,” said Richard J. Holl, director, pharmaceutical science, Catalent Pharma Solutions. “Accompanying this reduction, numerous venture-funded and small start-ups have been established that frequently do not have the infrastructure to support the development of their drug products, and rely more on outsourced vendors to provide these capabilities.”

Mayur Valanju, head of sales and marketing, Baxter BioPharma Solutions, expressed similar sentiments. “Several years ago, the majority of development work was being done by large pharmaceutical companies. Today, we are seeing more biotech firms and virtual companies doing the initial phases of drug development and, in some cases, full commercialization. Because biotech firms generally have less in-house expertise in manufacturing than large pharmaceutical companies, they rely more on the CMO to provide a broader range of services and expertise,” he said.

“There has been a trend, particularly in the small/mid-size drug sponsors or those new to the biopharmaceutical market, towards a more consultation-type relationship with the service provider,” said Mark Rogers, senior vice-president, SGS Life Science Services. “Rather than simply asking for a pre-determined list of tests, service providers are now becoming much more involved in experimental design and assistance with regulatory issues.”

“The number of virtual pharma companies is growing,” said John S. Ross, executive vice-president, Metrics Contract Services. “Thanks to their business models, these companies are committed to working with outsourcing partners, especially when it involves potent and cytotoxic products. In addition to observing more virtual operations among drug sponsors, we see them involving more consultants who are charged with providing regulatory and CMC guidance. Drug sponsors also are relying more upon domestic CDMOs for quality outsourcing.”


  Other shifts have been observed in big pharma business practices. “With major pharmaceutical companies, we are observing an increase in strategic partnering and outsourcing of development activities that were previously kept more in-house,” said Todd Stutzman, director, pharmaceutics, Catalent Pharma Solutions. “In addition, we have seen the establishment of operating units within major pharmaceutical companies that have more of an entrepreneurial approach to drug development than we have seen in the past.”

Specialty services offered by contract service providers are being used to fill gaps in knowledge, expertise, and resources. “Drug sponsors are now more inclined to outsource activities to CMOs with niche capabilities and CMOs that add value to the development process, either in terms of integrated operations, shorter time to market, or providing support throughout the lifecycle management of the product,” said Raheja. 

As in any purchasing arrangement, buyers are becoming more selective when weighing outsourcing options. “Drug sponsors have become more informed consumers of outsourcing services. We see a more savvy client, with better internal infrastructure to support outsourcing,” said Strong. “Even the smaller, more virtual companies understand what expertise they need from analytical, regulatory, and process development. The use of consultants to support their interactions with CMOs has increased the virtual company’s understanding of what it takes to get to the clinic.”

“There also is increased engagement and influence from procurement groups within client organizations, which makes pricing and costs a more critical factor in the selection of service providers,” said Magdalena Mejillano, vice-president, cGMP labs, PPD. Drug sponsors also are seeking ready access to data and technical documents through a centralized repository or portal that is interactive, flexible, and easy to navigate, she said. “Clients often request key performance indicators including quality metrics, project turnaround times versus targets, actual versus budgeted spend, project team utilization, etc.”


Growing interest in research and development of biologics-based drugs also is shaping the demands on contract service organizations. In the 

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

, BioPlan Associates estimates that the $190 billion worldwide market for biopharmaceuticals is growing at a healthy 15% annually (2). 

“The drug pipeline has continued to shift from small molecules and higher volume indications to biologics with lower volume indications. As the pipeline has shifted, so have the opportunities that are provided to CMOs,” said Valanju. “As such, it is increasingly important that CMOs have the technical expertise to manage biologics within their facility. Additionally, as volumes from individual molecules have dropped, CMOs have had to adapt and implement processes to manage more molecules at one time.”

A surge in investment in small biotech companies, especially in initial public offerings in the United States, has spurred activity. “The flow of investment, primarily from a very strong series of IPOs in the US market during 2013, has been welcome and has helped a number of our customers to progress lead drugs through the clinic,” explained John Sandles, business analyst, Fujifilm Diosynth Biotechnologies.

Outsourcing of biologics manufacturing has seen an increase over the past couple of years, said Mark Pearson, director business development, Dr. Reddy’s CPS. “This increase may be due to increased funding following the recession, and that drug companies have become more risk averse. Outsourcing mitigates risk of capital investment in manufacturing plants for the drug companies,” he said.

The increase in biologics drug development has spurred contract services activity for reasons other than cost cutting. Eric Langer, president of BioPlan Associates reports that new data from the his company’s annual study (2) indicates that cost control is becoming less of a driver of outsourcing activity. Instead, outsourcing is becoming more connected with higher-end, technical activities for which the right partner is more important than an extra dollar saved, he reports (3).

For example, analytical laboratories see increased demand for testing for biosimilars. Mejillano reports seeing “a definitive shift in outsourcing analytical services for biologics and biosimilars compared to small molecules. In addition, extractables/leachables for both small- and large-molecule products as well as generic product testing are on a growth trajectory in terms of outsourced work.”

Ron Connolly, senior vice-president, commercial operations, Frontage Labs, offered similar observations. “Many sponsors in the market segment of biosimilars are outsourcing most of the analytical work due to the need for trained chemists and equipment in order to perform testing to characterize molecules. As a specialized, high growth area, many sponsors do not have the capacity in house and look for organizations to guide them through the process,” he said.

However, the biologics market faces challenges. “The current biologics market is successful based on the criteria of revenue growth, and improvements made by biologics to people’s quality of life. This is balanced by project failures and reimbursement challenges,” said Aileen Ruff, strategic director, advanced delivery technologies, Catalent Pharma Solutions. “To be more successful, the basics need to be addressed. The industry needs to get better at discovery and at determining which products will succeed and applying technologies, clever development strategies, and quality by design to get product to market.”


With growth rates of biopharmaceutical consumption and production in emerging markets outpacing established economies, contract service providers see both opportunity and risk in these areas. 

“The emergence of BRIC [Brazil, Russia, India, and China] countries is highly significant and it has become increasingly important to serve these regions with development, delivery, and supply solutions, which is why it’s imperative to continually invest in new facilities and capabilities,” said Min Park, group product manager, advanced delivery technologies, Catalent Pharma Solutions.

A global supply chain for raw materials may provide some cost-effective options for drug manufacturers, but not without quality risks. The emergence of low-cost API and products primarily from India and China puts additional pressure on costs, reports Franco Negron, vice-president, N. America operations and integration, Patheon Inc.

“Drug sponsors are experiencing higher uncertainty with the ability of offshore markets to comply with GMP regulations, an uncertainty that’s been fueled in recent years due to high-profile lapses in drug product integrity,” said Ross. “As a result, they are relying more upon domestic CDMOs that offer proven high-quality standards and more transparent operations.”

“The supply chain within the pharmaceutical industry has become more complex due to high market dynamics and globalization. A growing number of customers and products and a fluctuating market demand make it more challenging for contract manufacturers to plan ahead,” said Peter Soelkner, general manager, Vetter Pharma International GmbH. 

Regulatory oversight offers positives and challenges


Foreign regulatory agencies have also increased their inspection of drug manufacturing facilities, said Stutzman. “These organizations sometime have unique interpretations of cGMP requirements and differing opinions as to how to achieve compliance,” he commented.

“Harmonization has had a positive impact on the analytical services,” said Paul Skultety, vice-president, pharmaceutical development services, Xcelience. “This makes it easier to meet the regulations as you have one set of criteria to test against.” 

Others see progress and room for improvement. “Regulatory bodies, in general, have increasingly strengthened their requirements,” said Soelkner. “While it’s challenging to keep abreast of changing regulatory standards, the relentless push to increase quality is vital to patient safety. More explicit requirements, like the cGMP rule for combination products from the FDA, gives us as a contract manufacturer a better insight into what authorities expect on a granular level. Ideally, we would like to see a move toward global harmonization of regulatory standards.”

“CDMOs continue to be challenged by the various standards for GMP processes at different developmental stages as established by different country’s regulatory authorities,” said Ross. “It would be helpful to have more global consistency.” 


Recent regulatory action has created additional opportunities that contract service organizations are addressing. A risk-based approach to drug development allows industry to institute product elements during the development phase based upon product knowledge of interactions with container/closure systems and the manufacturing process, said Kelly Davis, director, regulatory affairs, Baxter BioPharma Solutions. “The utilization of this approach requires industry to better understand the impact of container/closure and manufacturing process changes. Industry is now provided the ability to manage their products based upon scientific data vs. legalistic interpretation of regulatory guidances.”  

“The implementation of quality by design (QbD) and its acceptance in the industry is creating the need for an updated approach in the drug-development process,” said Connolly. “The increased work to understand the finished dosage form can be substantial depending on the product and manufacturing process. There has been a notable increase in the amount of sample analysis required to understand the process design space and critical quality attributes.”

“The most significant change is the focus on supply-chain security,” said Negron. “Better control of suppliers, more reliable processes, and greater flexibility to meet shifting demands is increasingly important. Also, CMOs and sponsor organizations are now jointly responsible for the integrity, safety and efficacy of their products,” he said.


  1.	J. Miller, “Positive Outlook for Outsourcing,” 

, 38 (8 supp.) 6-12.
  2.	BioPlan Associates, 

 (Rockville, Md, 2014).
  3.	E. Langer, “Outsourcing No Longer Just for Cost-Cutting,”  

Contract service providers are playing a more diverse role in drug development.

Contract Providers Assume Expanded Responsibilities

The quality and composition of excipients can vary due to environmental factors, processing methods, raw material quality, manufacturing location changes, and even operator actions.

Meeting the Challenges of Excipient Variability

API development and manufacturing companies expanded their capabilities, built partnerships, and achieved milestones in regulatory inspections.

API Developers Pass Inspections and Upgrade Capabilities

For a bio/pharma industry in flux, contract services are playing a greater-and more diverse-role in drug development.