IVT’s 5th Annual        Validation Week EU

) General Chapters <41> Balances and <1251> Weighing on an Analytical Balance became official on Dec. 1, 2013.  These revisions aim to ensure weighing accuracy and eliminate unnecessary over-testing for US pharmaceutical manufacturers and suppliers. The chapters attempt to simplify previous descriptions and reflect current state-of-the-art weighing practices. Revisions include modified balance test procedures, which focus on the determination of minimum weight, and the execution of routine testing. 

  The new requirements of General Chapter <41> are mandatory. The revised chapter now states that accurate weighing must be performed using a calibrated balance. It also details a relatively demanding balance assessment, describing accuracy and repeatability tests with new acceptance limits. These requirements apply for balances used to weigh analytes for quantitative measures. 

 For accuracy testing, using a test weight of 5–100% of the balance capacity is now applicable. Accuracy, defined by USP as the systematic error, must be determined at higher loads close to the balance capacity (i.e., largest systematic error), as it cannot be detected reliably below 5%. Hence, accuracy testing below 5% is no longer allowed. In the lower weighing range, repeatability is the dominant source of error. 

In contrast, repeatability testing and minimum-weight determination should be carried out using a small weight below 5% of the balance capacity. In this lower range, the repeatability is virtually independent of the test weight. With higher weights (i.e., above 5%), repeatability will increase, leading to higher minimum weight values.  For more information on balance testing, the USP video tutorial can be viewed at: 

  Advisory Chapter <1251> provides additional clarification and extends the scope to any balance used for an analytical procedure. These major revisions focus on balance qualification and operation. For example, performance verification should be carried out using a risk-based approach. Crucially, weighing net samples sufficiently above the minimum weight is recommended to take balance performance fluctuations into account. This requirement is clearly applied to the sample weight, not including the tare vessel. Every balance has an individual minimum weight, depending on the type and performance of the load cell, the location, and the environmental conditions. The minimum weight of every balance should be periodically assessed for conformance. 

  Applying a safety factor minimizes the risk of out-of-calibration, out-of-specification (OOS), or out-of-tolerance (OOT) results. The safety factor is the quotient between the smallest net weight and the experimentally determined minimum weight. It accounts for environmental influences and variations in operators, samples, and statistical factors. The safety factor applied should depend on the risk. It should be higher for more critical applications and unstable environments. 

 Another consequence of the USP revisions is that a daily balance check, typical in the pharmaceutical industry, is no longer a requirement.  Instead, the type and frequency of balance checks should be determined by the risk and process tolerance of the application. The more critical the impact of an incorrect result, the more testing should be carried out, to reduce the risk of OOS or OOT results. In any case, it should contain at least a regular calibration with determination of measurement uncertainty and periodic sensitivity and repeatability testing. Performing the right tests at the right intervals will ensure quality results.  During a webinar in December 2013, a majority of balance users (77% of those surveyed) admitted to still carrying out balance checks daily or before every use (1). This result indicates that many companies could potentially benefit from eliminating unnecessary testing, which brings significant time and cost savings. 

Commercially available programs, like Mettler Toledo’s Good Weighing Practice, can help pharmaceutical manufacturers and suppliers to comply with the new USP guidelines by putting the guidelines into practice in a structured and effective way. Services can, for example, perform risk assessments and provide test methods and frequencies based on specific risks.

Further educational resources relating to these USP revisions can be accessed at: 

To learn more about this topic, view the full recording of the webinar at: 


1. G. Martin, M. Huber, and J. Ratcliff, “Ensuring USP Compliance with Revised Chapters on Weighing,” 

Joanne Ratcliff, PhD, is communications project manager for Laboratory & Weighing Technologies at 

Articles

Troubleshooting

USP's revised Chapters 41 and 1251, which became official in December 2013, have new requirements for weighing, including balance calibration and testing.

Complying with Revised USP Chapters on Weighing

Omega Design Corporation’s Intelli-Code Carton Coding and Inspection System prints unit-level data on individual cartons using thermal ink-jet or laser printing and employs an integrated vision system to verify printed data. The system can be incorporated into new or existing carton lines or deployed as part of an independent serialization cell.  It supports a variety of customer choices regarding preferred printing technologies, camera and inspection vision systems, and connectivity to serialization software from a variety of providers. 

The Intelli-Code Carton Coding and Inspection System connects to serialization data-management systems.

Omega Design Corporation System Prints and Verifies Unit-Level Data on Cartons

Schreiner MediPharm’s SecuMed pharmaceutical labeling system offers authentication and protection against counterfeiting in a multi-step security concept. The SecuMed labeling system can be customized according to the specific requirements of pharmaceutical manufacturers. The labels can integrate a specific mix of overt, covert, and machine-readable security features. Options include complex holograms, ShiftSecure color-shifting ink, thermo-reactive print (in which colors change at various temperatures), and a covert feature known as LaserSecure, which involves invisible, machine-readable security pigments that can be integrated into all graphic elements and colors. The company will introduce the SecuMed labeling system to the North American market at INTERPHEX 2014. 

A combination of overt and covert features protects against counterfeiting.

Schreiner MediPharm Introduces SecuMed Labeling System

Microencapsulation is a promising drug delivery technology in which APIs are encapsulated with a natural or synthetic material that targets delivery by controlling the API’s release. Microsphere drug-delivery systems are used commercially and in many developmental products for both small molecules and biopharmaceuticals. 

Conventional technology for microencapsulation involves emulsification in a specially designed homogenizer. Although current technologies enable adequate dispersion, the ability to easily scale up to commercial production is a significant hurdle, says Frank de Jong, CEO of EmulTech, which has developed a new technology that solves the scale-up challenge and has advantages in reproducibility and process control. EmulTech's microfluidic platform was a finalist for best innovation in formulation in the 2013 CPhI Pharma awards. The Emulsion Technology for Microencapsulates (ET4ME) technology produces highly uniform microspheres, and the process can be controlled to make spheres of any size. 

The EmulTech system uses simple scaleup from a single-channel device that produces in the mg/h scale to a multi-channel device (MCD) with up to 400 channels that produces on the laboratory or preclinical scale of up to 100 g/h. A stack of MCDs can produce hundreds of grams up to the kg/h range, and the company is currently preparing to deliver its first clinical-scale equipment. Because the process parameters are strictly controlled, the process has reproducibility from batch to batch and from smaller to larger scale, adds de Jong. ET4ME operates at a much lower shear and temperature range than conventional technologies, making it useful for sensitive APIs such as biomolecules. ET4ME is a closed system with disposable parts, which simplifies operation under aseptic conditions and allows for easy sterile-suspension production. The ET4ME technology offers high control over droplet formation that produces a narrow particle size distribution. "Particle size control is crucial for microspheres," notes de Jong. "Particles that are too small can cause an immune response that leads to dose dumping. Particles that are too large can block the delivery device." Particles in the 30-90 micron range are used for subcutaneous applications. Particles in the 1-5 micron range are used in inhaled formulations, and particles in the 1-3 micron range are used in vaccines, says de Jong. Particles less than 1 micron are in the nanoparticle range, which puts them in a different category with different requirements.

Filtering, washing, and drying microsphere products


  No matter which encapsulation technology is used, the resulting microspheres must be washed, filtered, classified by size, and dried. Sieving is commonly used to classify microspheres, but, although this method is readily achieved on a non-sterile laboratory scale, it is difficult to scale up to larger production, says Camille Flores, business development manager at Powder Systems Limited (PSL). Scale-up difficulties include mesh blocking, lengthy dry times, poor product recovery, and difficulty incorporating steam-in-place (SIP) sterilization. PSL's Microsphere Refiner was designed to address these challenges and can be used from laboratory through production scale. The Microsphere Refiner combines classification, filtration, cake washing, drying, and sterile product recovery in one system. When necessary, a scalping unit first removes the oversized particles, and then the refiner removes the undersized particles. The desired particles are then washed, filtered, and dried. An agitator and filtration system keeps the microspheres in suspension, which avoids the problem of mesh blocking. The refiner is operated under vacuum using a heated jacket for efficient drying. In addition, the refiner is SIP-capable and is tiltable to accommodate sterile discharge, explains Flores.

Technologies such as these should allow easier scale-up to commercial, sterile production as more microsphere products move from development to commercialization. 

Production Trends

New methods of encapsulation and filtering address scale-up challenges.

Developments in Producing Microspheres

Counterfeit medicines are an enormous problem in many parts of the world. The World Health Organization (WHO) estimates the problem accounts for between seven and 15% of all medicines circulated in developed countries. It is far worse in developing countries, where up to 25% of all medicines are likely to be falsified (1). 

 In response, regulatory bodies across the world are introducing new requirements to give patients more confidence in the authenticity of their medicines. The worldwide pharmaceutical industry has a complicated regulatory structure. With variations in the degrees of regulation, legislation and financial resources from country to country, the introduction of a standard approach is almost unique. Pack serialization is one of the first wholesale attempts to make the pharmaceutical industry universally responsible for its supply chain activities.
   
  

The European Union has approached the concept of serialization with the introduction of the Falsified Medicines Directive (FMD), and serialization requirements come into effect in most EU countries beginning in 2017 (2). The Directive will affect all branches of the pharmaceutical industry, from manufacturer and generics producer to wholesaler and distributor.

After years of debate, what once seemed a distant challenge is now a looming inevitability. The Directive stipulates the need for more rigorous inspections of the manufacturers of active pharmaceutical ingredients. It also places obligations on manufacturers and distributors to report any suspicion of falsified medicines. The implications of the Directive are widespread, ranging from the marketing office that will have to amend packaging designs, to the packing hall that will have to deal with implementing enhanced outer-pack features, all the way through the supply chain to the dispensary.

Although there is enough information available about the requirements of the Directive for preparations to begin before the delegated acts are announced, manufacturers in the relevant EU member states now realise that compliance by the deadline of Jan. 2, 2017 will not be as straightforward as hoped. Despite having three years to successfully implement serialization, the European Stakeholder Model (ESM) suggests that four to five years is actually more realistic. The repercussions of this discrepancy are therefore potentially huge: any company that doesn’t comply will no longer be able to sell its products within the European Union, and potentially worldwide. The race against time is on.

Although larger manufacturers have the resources to deal with the financial demands of serialization, smaller and mid-sized companies, including generic-drug producers who make a much smaller profit per pack, are faced with a greater challenge.  For them, as with any organisation undertaking serialization or aggregation projects, wholesale upgrade of their coding kit will need to be accompanied by a robust plan that touches on almost every department in the company and which has buy-in from senior management. The time is now to get that plan set in stone. 

With the focus at this stage on putting in place the hardware and software infrastructure for compliance, however, less attention is being paid to the anticipated impact of serialization on efficiency. Anecdotal evidence from early adopters of serialization schemes suggests that the reject or rework level in the early stages can be as much as 10%, far in excess of acceptable limits. Over time, the reject rate can fall to less than one percent, but it takes time, commitment and the engineering know-how to achieve preserialization reject levels. 

Addressing this challenge is an unenviable task for production teams and regulatory compliance teams alike and requires an examination of packaging line performance from every angle. At its heart is the choice of coding equipment. Beyond the obvious need for high-speed serialization capability, coders must also be able to produce clear, high-resolution codes with a good degree of contrast to facilitate reliable reading at the points of manufacture dispense and beyond. It is anticipated that the code carrier will be a 2D matrix code because this code format can hold a significant amount of data, is robust and legible for vision systems, and does not take up too much room on a pack.  

Beyond that, early serialization pilots have shown just how disruptive unplanned stoppages are, creating issues with both assigning physical and digital identities and handling and accounting for rejects. Addressing poor machine performance in advance is therefore highly recommended.

Making a plan now and considering the impact of serialization on operational efficiency is crucial for successfully meeting serialization requirements by the deadline.  


  1. World Health Organization, “Substandard and counterfeit medicines,” Fact Sheet 275 (Nov. 2003), 

http://www.who.int/mediacentre/factsheets/2003/fs275/en/

, accessed Feb. 14, 2014. 
2. EC Directive 2011/62/EU, 

Craig Stobie is Global Life Sciences sector manager at 

Packaging

Manufacturers should plan ahead when implementing a serialization project to comply with the Falsified Medicines Directive.

Equipment and Processing Report-02-19-2014

Complying with Revised USP Chapters on Weighing

Omega Design Corporation System Prints and Verifies Unit-Level Data on Cartons

Schreiner MediPharm Introduces SecuMed Labeling System

Developments in Producing Microspheres

Best Practices for Complying with European Union Serialization Requirements