In recent months, there has been an increase in product recalls because of particulate contamination. Throughout the production process, pharmaceutical manufacturers take various measures to keep foreign particles out of their drug products. In case any of these measures fails, drugmakers perform inspections intended to detect foreign particles and prevent contaminated products from being released. The recent recalls, including that of American Regent’s caffeine and sodium benzoate injection on May 5, 2011, highlight the importance of particulate inspection, and they might lead observers to ask whether current inspection methods are sufficiently effective.

“A firm should evaluate the effectiveness of its 100% final-inspection processes to identify any areas for improvement,” says a spokesperson for the Office of Compliance within FDA’s Center for Drug Evaluation and Research. “Improvement would seem to be indicated if quality-assurance samples of finished products showed an adverse pattern of visible-particulate detection even after 100% final inspection had been done.”

The reference inspection method described in all of the pharmacopeias is human visual inspection. These documents outline the recommended inspection conditions in various levels of detail. “In many respects, visual inspection is the very backbone of product release,” says Ronald Iacocca, senior research advisor for physical and structural characterization at Eli Lilly and Company. “Some individuals can see particles as small as 50 μm. The human eye is indeed the perfect camera,” he adds.

In addition, FDA permits drugmakers to use alternative methods, including automated inspection systems, as long as they are validated appropriately.

From companies’ perspective, “a large volume of a few product types is desirable to justify the significant capital investment and validation expense of an automated inspection system,” says John Shabushnig, senior manager at Pfizer and leader of the Parenteral Drug Association’s (PDA’s) Visual Inspection Interest Group and member of the US Pharmacopeia’s Visual Inspection Expert Panel. According to a 2008 PDA survey, 33% of firms used manual methods for particulate-matter inspection, 24% used semiautomated methods (e.g., a human inspector and a machine for container transport), and 43% used automated systems, says Shabushnig.

Human and machine inspection techniques are effective, but neither is perfect. Each method’s sensitivity depends on the size and location of the particle, and on the amount of contrast. Manufacturers must control variables such as lighting type, lighting intensity, and inspection time to achieve reliable and reproducible inspection results.

An analysis of several studies involving various groups of inspectors revealed that the probability that a human will detect a single 50-µm particle in clear solution in a 10-mL vial with diffuse illumination between 2000 and 3000 lux is slightly greater than 0%, says Shabushnig. The probability increases to approximately 40% for a 100-µm particle and becomes greater than 95% for particles equal to or greater than 200 µm. The results vary with the formulation and container type.

In general, the sensitivity of automated inspection systems is similar to that of human visual inspection, but automation can provide greater consistency than humans can. Both methods provide good sensitivity when they have been qualified or validated appropriately. “Current inspection methods are adequate when properly qualified and operated in a controlled manner, but there are still opportunities for improvement,” says Shabushnig.

Fortunately, equipment manufacturers are working to design better inspection devices. For example, companies are continuing to develop technologies that see inside powders and lyophilized cakes, as well as through opaque suspensions. “A practical, commercial system may be available in the near future to fill this gap in our current inspection capabilities,” says Shabushnig.

Improved inspection algorithms could reduce the time needed to train an inspection system to examine a new product or container. This training currently is time consuming and expensive. In addition, advances in the ability to inspect opaque or translucent containers and products would help drugmakers. “We would also benefit from advances in image processing to reduce the number of false rejects associated with automated inspection systems,” says Shabushnig.

But pharmaceutical professionals say that current techniques and methodologies for particulate inspection are generally effective, even if they have not achieved perfection. “Industry has demonstrated good performance with manual and automated inspection methods. The important point is that any inspection method, manual or automated, must be well characterized and controlled,” says Shabushnig.

Articles

Production Lines

Recent recalls, including that of American Regent?s caffeine and sodium benzoate injection on May 5, 2011, highlight the importance of particulate inspection, and they might lead observers to ask whether current inspection methods are sufficiently effective.

Do Particulate-Inspection Methods Need Scrutiny?

Q: When a pharmaceutical quality-control or quality-assurance laboratory weighs a monogrammed substance for assay, the balance used to weigh the sample must conform to the requirements laid out in 

 <41>. How do you assign a minimum sample weight for a 

 <41> balance application when the tested repeatability gives a standard deviation (SD) of zero?

A: The idea that 0 SD for a repeatability test means an excellent result is a misconception. In fact, 0 SD indicates a problem with the choice of instrument or methodology used for the test.

If a measuring instrument indicates a 0 SD during testing, it does not have enough sensitivity to measure the tested mass accurately. Because most balances used for 

 <41> applications are analytical balances (i.e., those with 0.1 or 0.01mg readability), a result of 0 SD during a repeatability test should never be considered a pass criterion for minimum-weight verification. The same can be said for micro and ultramicro balances (i.e., those with 1 or 0.1µg readability). A 0 SD generally means that the balance does not have enough displayed digits (i.e., readability) for the tested minimum weight. 

 <41> recommends a limit of 0.1% error in the measurement. If the balance cannot display 0.1% of the desired minimum weight, then testing for suitability is pointless because you cannot meet the 

Course-reading top-loader balances sometimes give a 0 SD result during minimum-weight tests. The problem is that top-loader balances of low readability (e.g., 0.1 or 0.01 g) are inherently insensitive because of their course readability. The theoretical test mass needed to achieve suitable sensitivity levels with such an instrument may be way beyond the balance’s actual capacity. In compliance with current legislation, the correct solution is to employ a balance with the correct readability to display 0.1% of the net sample under investigation.

—Ian Ciesniewski, technical director at Mettler Toledo

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Troubleshooting

How do you assign a minimum sample weight for a US Pharmacopeia <41> balance application when the tested repeatability gives a standard deviation of zero?

Finding the Right Balance

David Round Company
 Lift tables incorporate protected hydraulic packages


 The David Round Company’s 304 stainless-steel lift tables are designed for bulk-material applications in controlled pharmaceutical manufacturing environments (e.g., cleanrooms). The machines’ hydraulic packages are laid out flat on the bottom of the tables, and the cylinders are in a horizontal position. This design enables the hydraulic components to be covered, thus protecting them and reducing opportunities for contamination.

Personnel can operate the tables’ hydraulic packages with pushbutton controls. The tables can be raised from 18 in. to as high as 42 in., which is within the appropriate ergonomic range. The tables’ reinforced scissors-type lift capacity is rated at 2000 lb.

The tables are mounted on wheels for portability, and personnel can collapse them to the floor. In addition, the tables’ highly polished finish, smooth welds, and few crevices enable easy wash down.

Globe Medical Tech
 Prefilled syringes enhance safety


Globe Medical Tech’s dual- and single-chamber prefilled syringes are designed to enhance safety. The syringes’ integrated needle-stick prevention feature and vacuum needle autoretraction technology provide full compliance with US and European safety regulations. After injection, the needle is retracted into the syringe body with a gentle push on the plunger. The syringe does not need any activation (e.g., twisting or capping) to engage the safety and contains no springs or metal components.

In combination with material and lubricant selections, the single- and dual-chamber syringes help maximize pharmaceutical compatibility. The dual-chamber syringe maintains the pharmaceutical components in separate chambers, thus extending the shelf life of some drugs. The syringes are made with medical-grade plastics that comply with FDA and international pharmacopoeial regulations. The plastics are compatible with a wide range of pharmaceutical drugs, and the components offer biocompatibility and low leachability. The syringes are designed to reduce dosing errors and contamination.

PharmTech's monthly newsletter, Equipment and Processing Report, reviews the Editor's Picks for the May 2011 edition from David Round Company and Globe Medical Tech.

May 2011 Editor's Picks: Products from David Round Company and Globe Medical Tech

The exploratory approach to developing formulations of oral solid dosage forms for first-in-human (FIH) studies is increasingly popular. This approach favors the simplest possible formulation, such as powder-in-capsule, sometimes without excipients. During the past several years, the emergence of systems that enable the automated and accurate filling of large quantities of active pharmaceutical ingredients (APIs) into capsules has expanded the popularity of the API-in-capsule dosage form. Filling APIs directly into capsules is probably the quickest option for entering clinical trials because it requires few or no excipients, thus saving three to four months that would have been spent on formulation development and stability testing.

A client asked Almac to provide supplies for an FIH study. The customer initially required fewer than 1000 capsules of two dosage strengths. To save time and API, the client decided not to conduct formulation studies. Almac manufactured these capsules manually using an analytical balance. The client subsequently asked Almac to resupply 25-mg and 100-mg capsules in quantities greater than 10,000 and 5500 units, respectively. Almac quickly decided that an automated process would be the best way to manufacture resupplies. 

Because of the lack of toxicological information about the API, Almac treated it as a potent compound and assigned an operator exposure limit of 0.1–10 µg/m

. The company decided that its Xcelodose dispensing system (Capsugel), in combination with the potent-handling capabilities of its Xcelohood containment system (Capsugel), would be the appropriate equipment to execute this resupply project. 

The solid-state characterization package provided the particle-size distribution of the batch of API to be used for the resupply (see Table I). This information, coupled with flowability data, suggested that the API possessed poor flow properties. Although poor flow does not affect hand filling, personnel thought that it might make filling with the Xcelodose difficult, particularly when using the high-throughput unit, in which the API must flow from the hopper into the dispense head. Fortunately, the API’s characteristics allowed operators to adjust the frequency of the equipment’s vibrations and the angle of the hopper to allow a reasonable flow of API into the dispense head.

Using a single-shift, 40-hour work week, Almac completed this project within three weeks. Less than one day was required to determine suitable processing parameters for the 25-mg and 100-mg strength capsules. The low-fill-weight capsules took approximately 76 h to complete, and the large-fill-weight capsules were completed in just over 36 h. 

When Almac manufactured the initial clinical supplies by hand filling with an analytical balance, the average rates of production of 25-mg and 100-mg capsules were 30 and 50 capsules/h, respectively. Therefore, if the Xcelodose had not been available for the resupply, manual capsule filling of the 25-mg capsules would have required approximately 400 h to complete, and the 100-mg capsules would have required 110 h. 

The lack of toxicology information about the client’s API is common in FIH studies. To ensure operator protection, the original clinical supplies were manufactured within a ventilated balance safety enclosure (VBSE). Because the analytical balance was in direct contact with the VBSE, however, any vibration from the latter unit made balance taring difficult. To manufacture the resupply, Almac used the Xcelodose within the specially designed Xcelohood. Because the Xcelodose was not directly in contact with the Xcelohood, the former’s microbalance was inherently more stable and resulted in much quicker taring than the hand-filling operation allowed.

Manufacturers can take various approaches to manufacture supplies for FIH studies. The increasingly popular exploratory-formulation approach allows firms to manufacture through hand-filling, capsule boards, and automated systems such as the Xcelodose. In this resupply project, the automated method resulted in direct cost savings by reducing labor expenses. The method enabled clinical supplies to be delivered approximately seven weeks earlier than a hand-filling operation would have done. 

In addition, timelines for this project were shortened further because no cleaning method was required. Operators were able to develop the Xcelodose process parameters immediately. Only 5 g of API was required for development activities, and processing resulted in minimal losses. As a consequence, the automated method used less API compared with the hand-filling technique. If an exploratory-formulation approach is suitable, and speed to clinic is imperative, an automated method, such as the Xcelodose system, is a viable option for the manufacture of supplies for FIH studies. 

Colin Lorimer is a senior formulation scientist at Almac Pharma Services, 22 Seagoe Industrial Estate, Craigavon, BT63 5QD, United Kingdom, tel. +44 0 28 3836 3363, fax +44 0 28 3836 3300, 

In the Mixer

Filling active ingredients directly into capsules is probably the quickest option for entering clinical trials. This case study compares manual and automated methods of capsule filling.

Equipment and Processing Report-05-18-2011

Do Particulate-Inspection Methods Need Scrutiny?

Finding the Right Balance

May 2011 Editor's Picks: Products from David Round Company and Globe Medical Tech

Manual and Automated Filling of Powder in Capsules for Clinical Trials