The fight against counterfeit and gray-market drugs is worldwide. Under the 

, signed by President Obama in July 2012, the Attorney General shall give increased priority to efforts to investigate and prosecute counterfeiting. In addition, the US Sentencing Commission is to consider increased penalties for drug counterfeiting (1). In the European Union, the Falsified Medicines Directive 2011/62/EU takes effect on Jan. 2, 2013 (2). The Directive requires authentication features on individual prescription-drug packs to enable verification throughout the supply chain. It also strengthens requirements for control and inspection of manufacturers of active substances. Manufacturers also must report any suspicion of falsified medicines. Other provisions give penalties for the manufacturing, distribution, import, and export of falsified medicinal products and point out the dangers associated with sale of medicines via the Internet.

With a significant percentage of medicines purchased from Internet sites found to be counterfeit, FDA has embarked on a public education campaign, BeSafeRx: Know Your Online Pharmacy (3). Another tool used by FDA is its October 2011 

Guidance for Industry: Incorporation of Physical-Chemical Identifiers into Solid Oral Dosage Form Drug Products for Anticounterfeiting

 (4). FDA is also training field agents in the use of a handheld device to check for counterfeit products and packaging arriving at ports of entry. The CD3 (Counterfeit Detection Device #3) emits light in 10 wavelengths to check API and drug samples against stored scans. It also detects package tampering.

The World Health Organization’s (WHO) Working Group of Member States on Substandard/Spurious/Falsely-Labelled/Falsified/Counterfeit Medical Products takes a three-pronged approach: education, norms and standards, and technical support to countries (5). WHO also supports the International Medical Products Anti-Counterfeiting Taskforce, a group it launched in 2006 with a wide range of partners including, international organizations, nongovernmental organizations, enforcement agencies, pharmaceutical manufacturers’ associations, and drug and regulatory authorities.

The US Agency for International Development (USAID) provides technical assistance worldwide to identify fake and substandard products and help legitimate manufacturers meet internationally recognized good manufacturing practices. In some cases, its efforts are implemented by the United States Pharmacopeial Convention (USP).

USP also is finalizing General Chapter <1083> "Good Distribution Practices—Supply Chain Integrity". It will outline best packaging practices to combat counterfeit drugs and medical devices. Likely topics include tamper-evident designs, authentication technologies, serialization, pedigrees, machine-readable data carriers, repackaging, and information retention and security.

The European Federation of Pharmaceutical Industries and Associations (EFPIA) is collaborating in efforts to combat counterfeit drugs. One project, the European Stakeholder Model, advocates the use of two-dimensional barcoding technology to authenticate products and comply with the Falsified Medicines Directive. This serialization system will be run by stakeholder organizations on a nonprofit basis.

“Potential advantages include the possibility of allowing for the automated checking of expiry dates, better pharmacovigilance, a reduction in the number of fraudulent reimbursement claims, higher effectiveness in preventing recalled products from being supplied to the patient, more efficient handling of product returns, and improved stock management processes for pharmacies,” said Camilla Kent Hansen, market access manager for EFPIA, in a recent article (6).

For brand owners and makers of generic-drug products and dietary supplements, a constantly evolving array of anticounterfeiting technologies help discourage counterfeiting and authenticate products. Read the 

 online at PharmTech.com for details on packaging technologies, such as taggant- and ink-based approaches, holograms, security materials, and labels containing both covert and overt features.

S. 3187, US Senate, 112th Congress, 2nd Session (Washington, DC), June 27, 2012.

Buying Medicines Online? Be Wary, FDA Says

,” Consumer Updates, accessed Oct. 3, 2012. 

Medicines: Spurious/Falsely-Labelled/Falsified/Counterfeit (SFFC) Medicines, Fact Sheet N°275, May 2012

Tackling the Rise of Counterfeit Medicines

Articles

Production Lines

Overt and covert packaging technologies have evolved to authenticate drugs and fight counterfeits.

Protecting the Public: Anticounterfeiting

Clean-in-place (CIP) technologies improve cleaning processes and increase critical equipment uptime. An efficient cleaning cycle begins with equipment and automation systems designed to ensure successful cleaning.


 Tank and piping design should be reviewed for sanitary cleanability, as described in section SD-3.1 of the American Society of Mechancial Engineers Bioprocessing Equipment standard (1). This design may include: minimizing deadlegs; verifying pipes are sloped toward a drain; checking for low-point drains, sanitary connections, and valves; and verifying that all product-contact surfaces are accessible to cleaning solutions.

The next step in the cleanability review is to create a preliminary design of flow paths for CIP circuits. Segments of equipment and piping should be properly separated and/or combined into different cleaning circuits as part of a preliminary design. Important considerations include process and schedule requirements, potential residues, and piping design.

 Knowledge of the equipment’s use can provide insight on process hold or transfer times. Transfer lines and tanks may need to be chained together into a single CIP circuit for quick equipment turnaround to meet these demands. Clean and dirty hold times may also affect equipment scheduling and cleaning requirements.

 Characterizing residues through cleaning studies and identifying associated product-contact surfaces aid in parameter development. Certain residues may require different cleaning solutions, concentrations, and temperatures for suitable cleaning to occur. This analysis can help organize circuits by common cleaning parameters.

 Available transfer panel connections may limit the combination of certain transfer lines and tanks. The user should account for line sizes and lengths as major pressure drops may decrease flow and turbulence within the pipe. Additional pumps and other spool pieces may be required within the system. Caution should be exercised in these cases to minimize manual configuration steps and reduce the risk of setup errors. Finally, the user should consider the availability of low-point gravity drains throughout the CIP circuit. Gravity drains remain critical for efficient CIP cycles.


 The cleaning automation design should also be reviewed for efficient cleaning characteristics. Developing cycles and sequences that complement a particular automation-control system greatly reduces long-term operating costs. For instance, a fast response, direct-action, process-logic controller (PLC) may minimize rinse times and water consumption by toggling through every auxiliary path on a complex bioreactor quickly enough in parallel with the sprayballs while not extending sprayball coverage test durations. In contrast, the path-transition time within a distributed-control system (DCS) depends on its programming style and may require several layers of equipment module (EM) and sub-EM commands before finally reaching the target control modules (CMs). Only after waiting for valve and state confirmations can the next step begin. Here, creating a cycle that combines multiple transitions into a single grouping will result in the shortest and most cost-efficient cycle possible. Combining cleaning actions (e.g., rinse, drain, and air blow) within phases also reduces the cycle duration. In contrast, a strategy of using more modular, individual phases may elongate the cycle.

Various time and cost-reducing methods must be balanced with skid equipment capability. For example, one may be able to take advantage of integrated PLC capabilities of equipment (e.g., vendor-provided PLC-based centrifuges). These design considerations must be identified early in the project to ensure that quality and validation procedures can be developed to address the sampling, instrumentation, and verification requirements being built into the CIP and recipient systems.

For the CIP cycle itself, the automated step sequencing, step-transition criteria, and parameter values must be well defined and documented to optimize utility usage while providing sufficient process control.

 Typically, a cleaning cycle should start with water rinses followed by detergent cleaning and post-detergent rinses. In between any rinse or detergent wash, the system should be drained completely to prevent dilution or chemical reaction with the next cycle step. An air-blow step, placed before the drain, can greatly decrease the gravity drain time and thus decrease the overall cycle time.

 Defining step-transition criteria provides a way to control the critical cleaning-cycle parameters. For example, the chemical-wash duration, minimum temperature set point, and concentration target can all be set as requirements before the wash step transitions to the next step.

 Laboratory-scale process residue cleaning studies can provide an excellent starting point for CIP cycle parameters. Scalable attributes such as cleaning-agent concentration, process temperature, exposure time, and external energy can be explored within the cleaning design space to isolate the most critical parameter(s). Combined with an evaluation of the most effective cleaning agent and identification of worst-case residues in the process, these laboratory-scale efforts can dramatically reduce the number of cycle iterations that must be performed during commissioning and allow for a focus on improving efficiency.

The American Society of Mechanical Engineers, 

Andrew Wong and Cody Shrader are senior engineers at Hyde Engineering + Consulting, Boulder, CO, Andrew.Wong@Hyde-EC.com. 

In the Mixer

An efficient cleaning cycle begins with equipment and automation-system design.

Designing a Clean-in-Place System

Q. We are a GMP laboratory and are setting up a pipette calibration program. Do we need “as-found” data? If so, how do we collect it?

A. While not every laboratory needs “as-found” or “as-received” data, these data are crucial components of pipette calibration for those that must comply with GMP regulations or international standards, such as ISO 17025.  As-found data are gathered prior to any preventive maintenance or calibration. These data are used to document the performance of the instrument since its last recorded service event. Each pipette is first identified by serial number for record-keeping purposes and then tested for inaccuracy and imprecision against defined tolerances. The as-found test should be conducted using at least three samples per volume at two to three different volume settings (e.g., typically 10%, 50%, and 100% of nominal volume). A statistical analysis of these data produces the as-found pass/fail status of the instrument. Pipettes that pass their as-found analysis can be assumed to have been within tolerance since their last documented calibration event, especially when supported by a performance verification program; pipettes that fail their as-found test should be assumed to have been performing outside of tolerance since their last recorded service event.

GMP regulations require that equipment managers ensure adequate and continuous performance of measurement equipment with respect to accuracy and precision. ISO 17025 requires that out-of-tolerance equipment and the measurements produced with that equipment be investigated to determine what impact, if any, the use of the out-of-tolerance equipment had on customer data and internal processes. These standards, and others, require that organizations conduct studies to determine the consequences of having used out-of-tolerance equipment upon their products, process, data, and results. Any lab that requests and documents as-found, instrument performance data needs to have a plan in place to address as-found failures. As-found failures should generate a series of activities (i.e., impact investigation) to determine the degree to which the instrument was out of tolerance and what impact, if any, that degree of out-of-tolerance had upon the work performed since the pipette was last documented to be within tolerance. The goal of the impact investigation is to determine whether or not the out-of-tolerance pipette could have produced data significantly out of tolerance to the company’s process. All data produced with the out-of-tolerance pipette between calibration events may be suspect; the longer the interval between calibration events, the more data that must be reviewed and analyzed. Many labs also use as-found data statistics for performance trending and adjust their calibration program accordingly to eliminate as-found failures altogether.

 and Erin Lenhardt is the Director of Business Development at 

If you have a problem with your equipment or process, an industry expert may have the solution. Please send your question to 

, editor of Equipment and Processing Report, and we may be able to provide an answer in a future issue. All questions will remain anonymous.

Troubleshooting

As-found data is a crucial component of pipette calibration for laboratories that must comply with GMP regulations.

Using As-Found Data in a Pipette Calibration Program

Malvern Instruments
 Dynamic light scattering system measures microrheology and protein structure


 The Zetasizer Nano ZSP is an addition to the Malvern Instruments’ range of dynamic light scattering (DLS) systems. The Nano ZSP measures both size and zeta potential (i.e., electrophoretic mobility) of proteins. A new protein mobility measurement type in the software that controls data acquisition guides the user through the measurement and assesses and reports on data quality. The Nano ZSP uses a new version of Zetasizer software that enables microrheology measurements for the first time on Zetasizer instruments. This DLS-based optical technique allows rheological characterization of weakly-structured and highly strain-sensitive materials using only microliter sample volumes. Applications include measuring the viscosity of polymer and protein solutions and determining the onset of protein aggregation. 

GEA Pharma Systems
 Continuous high-shear granulation and drying system improves efficiency


 The ConsiGma continuous high-shear granulation and drying system from GEA Pharma Systems uses continuous production technology instead of traditional batch technology to produce granules. The system is about one-fourth the size of a traditional granulation line and can run from 500 g for research and development up through production-size batches. Because it is a continuous process, larger amounts do not require a larger machine, but only a longer time.  Eliminating scale-up helps reduce development time and cost. ConsiGma has been shown to improve intra-granular porosity and compressibility characteristics.

Products from Malvern Instruments and GEA Pharma Systems

Equipment and Processing Report-11-21-2012

Protecting the Public: Anticounterfeiting

Designing a Clean-in-Place System

Using As-Found Data in a Pipette Calibration Program

November 2012 Editor's Picks: Products from Malvern Instruments and GEA Pharma Systems