Last issue's Advanced Degrees column emphasized the importance of accurately calling these drugs what they are (biosimilar), rather than what they are not (biogeneric), and explained the major differences between the two proposed bills currently before Congress, which would establish their licensure. I cautioned how the House and Senate, along with industry, need to resist the temptation of putting politics and profits ahead of patient safety. This is central to the debate of patent exclusivity terms, intellectual property rights and other ethical issues, and where the two bills radically differ.
This segment of the U.S. healthcare system overhaul has received little to no publicity, but it is critical for the future economic health of many biopharmaceutical and biosimilar manufacturers, in addition to the health of the public.
The money Americans spend on prescriptions represents only 8% of the overall U.S. healthcare spend1, yet lower prescription pricing continues to be beat into the American consciousness by special interests in Washington to help gain public support for both bills, with the misdirected blame that prescription pricing constitutes a substantial portion of America's skyrocketing healthcare costs. Along with this, there is a misguided hope and promise that biosimilars are going to contribute significantly to solving the problem.
For all the hype swirling around these issues, one thing is certain: biological drugs are the future the blockbusters of the new millennium. They will be the major force in the treatment and prevention of diseases. Half of the top 100, and seven of the top 10 leading drugs by sales will be biologics by 20142,overtaking traditional small molecule pharmaceuticals. This is good news for patients and for those in the business of supporting the packaging and delivery of these remedies.
Last issue's column concluded by stating that Congress must understand that there are no shortcuts in the manufacture of biological medicines. Likewise, there can be no shortcuts in the use of qualified packaging of these products either, and suitable qualified packaging, like the drugs they are intended to protect, can be costly, diverse and complex.
Consider the manufacturing processes for biologics. More often than not, they are created systematically in multiple stages at highly specialized (and highly regulated) locations that can be across town or across the globe. Developing a biological has gone from inter-plant to international and at each step in the process, proper handling and temperature must be maintained. Transporting them around the world is a tightly controlled cGMP process, as the product goes from its initial stages as a live culture to a finished product in a vial or syringe, with many intermediate processes in between. The packaging requirements necessary for transporting them at each stage can vary greatly. For example, there are different packaging requirements for transporting a portable bioreactor containing 100 liters of purified concentrated liquid protein than there is for a two liter bottle of frozen cell culture, or an aliquot of 20,000 glass-barrel syringes each containing 0.5 ml of finished product. Their temperature requirements may also vary. The point is that there are numerous opportunities necessitating the need for good, reliable packaging, but there is plenty that can go wrong. The further into the manufacturing process, the greater the risks become - expense is increased, the material becomes more valuable, and the margin for error becomes less and less.
Once the manufacturing process is complete and the finished product is sold, the downstream supply chain - arguably the weakest link in the entire process - must be vigilant in maintaining the quality of the drug until it is administered to the patient. Here, too, the packaging requirements are likely to be far different than that of the upstream supply chain process. Each step in this process has its own, unique design requirements.
In God We Trust, All Others - Show Me the Data
Those who have been in the business long enough have seen tremendous changes in the way regulators treat the manufacturing and transport of temperature-sensitive drugs. Distribution, a segment of the process once essentially ignored by regulators, has become an extension of the manufacturing process. In 2008, the FDA audited 40 wholesale distribution facilities and issued 13 483s for non-compliance; they intend to audit an additional 100 wholesaler warehouses in 20093. The FDA has never extended its authority that far downstream in the supply chain before. "Can they do that?" is the question I often hear. In a word, yes. The answer is yes, courtesy of the adulterated drug law.
The FDA so eloquently states in the Food Drug & Cosmetic Act Chapter V, Sect. 501 Sub-chapter A, (2)(B):
"A drug or device shall be deemed adulterated - if the methods used in, or the facilities or controls used for, its manufacture, processing, packing, or holding [holding means shipping and distribution in the eyes of the FDA] do not conform to or are not operated or administered in conformity with current good manufacturing practice to assure that such drug meets the requirements of this Act as to safety and has the identity and strength, and meets the quality and purity characteristics, which it purports or is represented to possess."
Just in case there was any doubt or misunderstanding as to who is responsible to assure that a drug is not adulterated, the FDA also states in the FD&C Act Chapter III, Sect. 301.21:
"The following acts and the causing thereof are hereby prohibited: (a) The introduction or delivery for introduction into interstate commerce of any food, drug, device, or cosmetic that is adulterated or misbranded. (b) The adulteration or misbranding of any food, drug, device, or cosmetic in interstate commerce. (c) The receipt in interstate commerce of any food, drug, device, or cosmetic that is adulterated or misbranded, and the delivery or proffered delivery thereof for pay or otherwise."
And of course, there are penalties for knowingly violating this Act. Section 303:
"Penalties: (a)(1) Any person who violates a provision of section 301 [above] shall be imprisoned for not more than one year or fined not more than $1,000, or both. (2) Notwithstanding the provisions of paragraph (1) of this section, if any person commits such a violation after a conviction of him under this section has become final, or commits such a violation with the intent to defraud or mislead, such person shall be imprisoned for not more than three years or fined not more than $10,000 or both."
So everyone in the supply chain has a responsibility to the drug and can be held liable if that drug is found to be adulterated due to improper "manufacture, processing, packing, or holding." Temperature abuse, particularly when it comes to biological drugs, can be a leading contributor to adulteration.
With increased competition for biologic drugs on the horizon, and patent expirations, price pressures, and extended launch dates nibbling away at profits, it is tempting to skimp in areas such as packaging or distribution practices - where it may not seem critical - in order to expedite the process to boost profits. But increased regulatory scrutiny makes this a risky venture.
What Constitutes a Qualified Package?
A qualified package is one that can repeatedly demonstrate with a high degree of certainty that it will not cause or contribute to the adulteration of the product. It's all about due diligence, performance, and protecting the drug from physical or environmental threats within a specific supply chain not just within a laboratory. Too often, off-the-shelf packages offered by solution providers are marketed as "pre-qualified." However, there are no established standard criteria for such pre-qualification and without a level playing field, side-by-side comparisons cannot be made.
Products that are marketed as "design tested" generally indicate that limited test data is available under a pre-determined set of circumstances and are capable of meeting a minimum level of assurance.
Trying To Do More With Less
Determining the thermal performance of a passive packaging system is dependant on five main factors:
- The insulation capabilities and structure of the external package
- The amount and the temperature conditioning of the refrigerant
- The temperature maintenance requirements of the product
- The duration of the package in transport
- The temperature environment to which the package is exposed
There are lesser factors as well: thermal mass of the product, the phase temperature of the refrigerant and the configuration of the assembly, to name a few. Technical Report # 39, Guidance for Temperature-Controlled Medicinal Products: Maintaining the Quality of Temperature-Sensitive Medicinal Products through the Transportation Environment, published by the Parenteral Drug Association, is considered a best practices document for the qualifying of thermal packaging systems (both passive and active).
There is a disturbing trend in the industry to attempt to side-step the qualification process and commoditize these packaging systems and processes in an effort to save time and expense. You cannot change or fool the laws of physics. You can however, easily manipulate one key design factor in a laboratory the temperature environment to which the package is exposed, thus enabling less scrupulous companies to make fantastic claims of performance of their packaging systems unrealistic and unrelated to the actual distribution environment.
A principle factor in qualifying a thermal package is understanding what occurs in distribution. The key to a successful supply chain employs consistent practices, monitors performance, and documents what has been done. Properly designed packaging system meeting the specific requirements of a product and the expected hazards of a distribution environment requires a full and intimate knowledge of both the product and the distribution environment. There are no shortcuts. Proper packaging, handling and distribution of time and temperature-sensitive drugs, especially biologics and biosimilars, is critical and should not be overlooked or shortchanged. It should be treated as if your life depended on it. Chances are, someday it will.