The United States Pharmacopeial Convention (USP) is a nonprofit scientific organization dedicated to improving the health of people around the world through standards that enhance the safety and quality of medicines. Those standards also include packaging and labeling requirements for primary pharmaceutical containment systems.

In a move intended to “reduce the likelihood of death and disability from misadministration . . . by standardizing the information that may appear on the top (circle) surface of the ferrule and/or cap overseal of a vial containing an injectable product,”¹ the USP has revised General Chapter Injections, Section on Labeling on Ferrules and Cap Overseals (USP 34-NF 29 November 1, 2010). Implementation of the revised standard limits what drugmakers can print or otherwise display on the top surface of cap overseals and ferrules (aluminum shells) used to secure injectable drug vials. The new standard will become effective on December 1, 2013, and affects all injectable drug products, human and veterinary, intended for sale in the U.S.

As the date for the revised standard moves closer, pharmac companies should assess their current portfolio of injectable products to determine first if there is a need for a change. Any printing on the cap or overseal needs be reviewed. Should it be determined that the statement meets the intent of the revised USP standard, then no change is necessary. For products that currently use non-cautionary printing, changes must be made in time to meet the December 1, 2013, effective date. Drugmakers need to initiate changes with their packaging suppliers now in order to ensure they maintain compliance with this revised standard for all injectable drug products sold in the U.S.

Many pharma companies currently print or display information on the surface of the plastic cap or aluminum shell. Printed information often includes the trademark of the drug product, company logos or the company name, dosage or storage directions. Such printing will no longer be allowed after the revision becomes effective. Instead, the revision will limit printing to cautionary statements, which are statements intended to prevent an imminent life-threatening situation, and may include instructional statements that provide potency or other safety-related instructions, if warranted. Examples of approved cautionary statements cited by the USP in the revision include “warning paralyzing agent” or “paralyzing agent” for neuromuscular blocking agents, or “must be diluted” for potassium chloride injections. Again, the cautionary statement indicated in the general chapter are examples only. Embossed information such as Flip-Off^®, Flip-Cap and other customizations are also considered prohibited.

Further information provided by the revision states the cautionary labeling statements must be simple, concise and devoid of non-essential information. Only cautionary statements may appear on the top surface of the ferrule and/or cap overseal of a vial containing an injectable product. The statement should be printed in a contrasting color and be clearly visible under ordinary conditions of use. Other statements or features, including but not limited to, identifying numbers or letters, such as code numbers, lot numbers, company names, logos or product names, may appear on the side (skirt) surface of the ferrule but not on the top (circle) surface of the ferrule or cap overseal.

According to USP’s Frequently Asked Questions for General Chapter Injections, Section on Labeling on Ferrules and Cap Overseals (August 4, 2010): “For those manufacturers who wish to maintain the information printed on the cap or ferrule, rationale must be provided to the FDA explaining why the instruction addressed in the statement in considered to be life threatening. In addition, the FDA will expect manufacturers to provide data to support that the statement is safe, unambiguous and offers the best message to minimize the life-threatening situation.”²

The revision also limits distinguishing marks, including logos and other markings intended to ensure that a drug is authentic and provided directly from the manufacturer. Many packaging suppliers offer covert solutions that pharma manufacturers may want to consider to ensure the safety of their drug product. Drug companies should discuss these options with their packaging suppliers to determine what will best suit the company and the drug product.

Pharma companies should be aware that no printing or information displayed on caps or ferrules is grandfathered by the revised standard. So although the printing or labeling may have been approved in the past, the company must make sure that it is in compliance with the revised standard or that any specific divergences are approved by FDA, moving forward.

What Changes Mean to Supply Chains
Many manufacturers have large amounts of unused seals in inventory and it takes time for those goods to be depleted. It is critical for pharma manufacturers to assess their demand needs and determine the appropriate inventory depletion plan to ensure that their supply chain is not interrupted.

Drugmakers should contact their component suppliers to request new seal items, determine specifications and acquire drawings. Packaging component manufacturers’ production lead times must also be considered in the transition process. It is our opinion that removing printing or embossing from the seal is cosmetic in nature; the raw materials, forming process, dimensions and functionality of the seals have not been changed, so performance and quality should not be affected. Pharma firms must assess for themselves how they interpret this change and if evaluation or testing is needed. Also, since the standard does not affect products for use outside of the U.S., or products that are not injectables, packagers will continue to produce seals currently in use that have labeling or anti-counterfeiting measures in place.

To prepare for the change, pharma companies should consider the following questions:

• What is the process and timing for specification and setup of new items within their own systems?
• How is the change (if any) being communicated to customers and patients?
• How much inventory is in place and what is the depletion plan?
• Do Instructions for Use need to be updated?
• Will there be a need for evaluation or testing of the new seal?
• Will the current seal still be used when exporting from U.S.?
• What other changes or enhancements might be incorporated into the seal during the change?
• What is the strategy (as applicable) for addressing counterfeit product in the market?

It may be helpful for companies to establish a transition team to work directly with the packaging manufacturer and within the company to ensure that all fill/finish processes, as well as any specification and validation issues, are handled before the implementation date.

While it is reasonable to expect that there will be product in the supply chain with printing for some time after the implementation date, production campaign schedules may dictate that new seals need to be in-house before the implementation date to meet manufacturing needs.

Talk to Your Supplier
Whether a pharma company works directly with a packager or with a contract manufacturing organization (CMO), it is important to discuss the revised standards now. Because secondary closures such as seals can be switched out without retesting or any compatibility issues with the drug product itself, CMOs may change seals unbeknownst to the pharma company in order to maintain compliance within its facility.

Also, because the revision is not a global change, packaging manufacturers will not force pharma companies to switch from their current closure. Tradenames currently printed on caps, such as Flip-Off® and Flip-Cap, will continue to be produced because they can be used in other markets and applications. Pharma manufacturers must contact their closure suppliers to initiate the change in order to meet the new standard.

Suppliers may also help with rationale, if needed, to maintain alignment with the standard for printing on the cap or overseal. A good supplier’s regulatory department may be able to provide a customized Regulatory Technical Package to help present additional information and rationale to assist in maintaining alignment of the ferrule and cap overseal printing with the USP standard. These customized packages should provide the rationale and data denoted in USP Frequently Asked Questions General Chapter Injections, Section on Labeling on Ferrules and Cap Overseals, dated August 4, 2010. USP recommended providing data and information to the FDA for support of their evaluation and determination for retention of the current printing consistent with the revised USP standard. 

References

1. USP, “Compendial Notice: General Chapter Injections, Labeling of Ferrules and Cap Overseals Section,” http://www.usp.org/usp-nf/notices/retired-compendial-notices/general-chapter-injections-labeling-ferrules-and-cap-overseals-section, Accessed on April 8, 2013.
2. Ibid.

Flip-Off^® is a registered trademark of West Pharmaceutical Services, Inc., in the U.S. and other jurisdictions.

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Carol Mooney is Global Market Segment director at West Pharmaceutical Services. For more information about this article, contact West.Pharmaceutical.Services@westpharma.com