Give bulk packaging as much attention as you do your primary packaging.
By Frank Bieganousky
Pharmaceutical companies carefully examine and follow FDA guidelines and CGMPs when choosing the container closure system for packaging drugs. For instance, considerable time and resources are spent to develop primary packaging to protect drug product quality. And secondary packaging is designed to enhance or protect the primary package and its precious contents.
Another form of packaging, however, may not always get the same scrutiny. Packaging for bulk drug substances and bulk drug products requires similar attention. Some firms, though, may not be in compliance with current expectations and regulations regarding the development, specification, and control of packaging systems used to contain bulk drug product and substances. The current guideline, Container Closure Systems for Packaging Human Drugs and Biologics (May 1999), has made it clear that requirements for bulk packaging have moved way beyond the “commodity poly bag” mentality. The following FDA guidances pertain to bulk packaging:
• Draft Guidance for Industry: Stability Testing of Drug Substances and Drug Products (June 1998).
• Guidance for Industry: Container Closure Systems for Packaging Human Drugs and Biologics, Chemistry, Manufacturing, and Controls Documentation (May 1999).
• Guidance for Industry: Container Closure Systems for Packaging Human Drugs and Biologics, Questions and Answers (May 2002).
Although FDA is generally more concerned about the primary market package, many requirements and information needed for a new drug application (NDA) regarding bulk packaging are the same. Specific references within each guidance concern bulk packaging for drug products and substances. (A drug product is the finished dosage form containing the active ingredient, while the drug substance is the active pharmaceutical ingredient prior to being formulated into a dosage form.)
Section VII.B. (Container/Closure) of the June 1998 Stability draft guidance clearly states that stability data are required for the container closure system for bulk drug product. “Stability data should be developed for the drug product in each type of immediate container and closure proposed for marketing, promotion, or bulk storage.” Bulk storage is defined as holding product longer than 30 days. Real-time stability data under the specified storage conditions are therefore needed.
The May 1999 Container Closure Systems guidance details what’s needed to show suitability of a bulk package for its intended purpose. Pertinent sections are Section III; Section VI.A. and Section VI.B.
According to Section III: Qualification and Quality Control of Packaging Components, every packaging system should adequately protect and be compatible with the product. It should be composed of materials considered safe for use with the dosage form and the route of administration. The applicant “should also describe the quality control measures that will be used to ensure consistency of the packaging component.”
Section VI.A. Containers for Bulk Drug Substances differentiates between solid and liquid drug substances. Qualification to establish packaging compatibility and safety is required for both solids and liquids and “may include characterization for solvent or gas transmission.” Other requirements spelled out for liquid products include “light transmittance, closure integrity, ruggedness in shipment, [and] protection against microbial contamination through the closure.” Regarding containers for bulk drug substances, the guidance states that “the application should include a detailed description of the complete container closure system,” including a description of all components, composition of each component, reference to the appropriate indirect food additive regulation, and “tests, methods, and criteria for acceptance and release of each packaging component.”
Section VI.B. Containers for Bulk Drug Products states that “the container closure system should adequately protect the dosage form and should be constructed of materials that are compatible and safe.” Container closure systems for on-site storage are generally considered a CGMP issue. “However, if a firm plans to hold bulk drug products in storage, then the container closure system and maximum storage time should be described and justified.” This means stability data should be generated, even when the storage time is short (see Section III.B.).
Recent FDA thinking regarding bulk packaging can be seen in the Guidance for Industry, Container Closure Systems for Packaging Human Drugs and Biologics, Questions and Answers (May 2002). FDA’s current position is that information need not be included in the NDA for container closure systems used for storage or shipping (between the applicant’s own facilities or to a contract packager) of bulk drug products, excluding biologics and protein drug products. For biologics and protein drugs, information requested in section VI.B. of the packaging guidance should be included in the application because of the greater potential for adverse effects during shipping and storage of these types of drugs. The guidance further states that the bulk drug product packaging should be shown to be suitable for use, supported by data retained by the applicant and/or manufacturer, and should be made available during FDA inspection upon demand. Basically, pharmaceutical companies still need to do the work to demonstrate suitability and must have the data available for inspection, but do not need to include these data in submissions.
Despite these guidances, many pharmaceutical companies still treat bulk packaging as a commodity. But a lack of attention to the technical and commercial considerations in bulk packaging development and specification and to the selection of a bulk packaging supplier is a recipe for trouble. A more-sophisticated approach to package development and control can ensure compliance to regulations and help avoid potential problems such as inconsistent quality, lack of control, poor traceability, poor communication, and insecurity of supply. For instance, bag/liner suppliers have been known to make resin changes without or with little notification. Distributors may source products opportunistically, and suppliers often exit the business.
Key considerations of bulk packaging design include raw material compatibility, performance characteristics such as puncture resistance, and seal integrity and strength. Specifications should describe the package in detail, including size, style, thickness, raw materials (e.g., specific resin grade), and any other critical characteristics such as seal strength. These requirements should be documented and communicated to the supplier, and the supplier should be held to them.
Wherever possible, eliminate the middleman. Look for suppliers that are vertically integrated or have good control over raw material sources. Audit the supplier prior to qualification and perform audits regularly thereafter. The supplier should follow CGMPs with the appropriate quality systems, traceability, change control, SOPs, process control, and housekeeping. Ideally, it should hold a current Drug Master File and use raw materials that are indirect-contact food grade and covered under their own Drug Master File. If you must use a distributor, work only with those that specialize in pharmaceutical industry supply.
Strategic considerations, such as choosing a readily available resin or one with FDA and EU regulatory status or standardizing on a rugged design, may also save considerable effort. For example, one pharmaceutical company has standardized the use of laminated foil bags as outer liners for bulk packaging. Instead of double-bagging with two polyethylene bags, which is standard in the industry, the firm chose to use an inner polyethylene bag with an outer foil bag. The advantages are twofold. First, the foil barrier provides significantly better protection against moisture ingress. Second, there is flexibility in choosing the outer container (fiber drum, plastic drum, corrugated shipper, etc.), as the foil barrier eliminates any concern with interaction between product and outer container. This company found that the incremental cost of a foil bag (negligible compared with the cost of the contents it’s protecting) was well worth the assurance of minimizing failures in the field and the flexibility to change the outer container as needed.
Taking the time and resources now to address bulk packaging comprehensively will help prevent crises such as loss of supply or a failure in the field. An approach that will ensure a robust system will serve firms well into the future.
Frank Bieganousky has more than 20 years of experience in the pharmaceutical packaging industry in both commercial and technical development. Prior to forming Montesino Associates LLC, he was most recently director of healthcare business development for Tekni-Films, a division of Tekni-Plex Inc. He has held business development and marketing positions at AlliedSignal (now Honeywell) and Rexam Medical Packaging as well as technical packaging development positions at Bristol-Myers Squibb and Becton Dickinson. Bieganousky has an MBA from Fairleigh Dickinson University and a B.S. in Packaging Engineering from Michigan State University.