API Developers Note Upgrades, Successful Inspections

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.

Facility inspections
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.

Equipment upgrades
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.

Acquisitions and partnerships
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.

Achievements
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.

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